Elisabetta Farina

Thierry Pozzo

Embodied

Affordance:

 of the environment are what it offers the human or animal. Moreover, all transactions that are possible between an individual and their environment. Gibson's general ideas can be viewed as situated/embodied in the sense that he emphasized the importance of the interaction between the agent and the environment for intelligent behavior.

Enaction: In an enactive system, meaning is the result of the organization and history of the system itself. Hence, the organism and the environment have been developed and bound together, through the process of natural drift. In this view, the environment and the organism cannot be separated since they in fact are codetermined in evolution, which is dependent on the perceptually guided activity of the organism and the environmental regularities.

Mirror Neurons: A special kinds of visuo-motor neurons, which become activated both when performing specific goal-directed hand (and mouth) movements and when observing or hearing about the same actions. Since mirror neurons respond to both conditions, it has been argued that the mirror system functions as a kind of action representation, since it links action and perception of action.

Motor cognition: A biological phenomenon instead of a mental one; this notion proposed that it is the body which has the necessary 'knowledge' to perform the task at hand, since the body 'knows how to act' and 'how to perceive' through the history of its phylogenetic and ontogenetic interactions with the environment. For instance, the understanding of a sentence would be essentially achieved through a simulation of action using the same neural systems active in overt behavior.

Motor resonance:

The process that matches visual input directly onto observer's motor repertoire (e.g., it has been found that observers undertake motor facilitation in the same muscles as the one used by the observed individual). Considering the motor resonance as the neurobiological underpinning of 'intercorporeality' and simulation theories as the basis of social interaction and mindreading, motor resonance provides a significant example of more embodied views of social cognition. Compulsive imitation would be the pathological version of the motor resonance.

Theory of mind: Theory of Mind (ToM, or mind reading) can be broadly divided into 'theory theories' and 'simulation theories'. For the theory theorist, ToM is the ability to predict and interpret the behavior of others using folk psychological theory, based on the structure and function of the human mind. In contrast, in the simulation theory, the mind-reading ability is not any sort of theory. Instead, it is an ability to project oneself into another person's point of view; simulating what it is such as to be in the other person's situation. Simulation theory might be a part of, or a precursor to, a general mind-reading capability that allows one to adopt the sensorimotor point of view of other conspecifics in order to predict others' mental states and behavior.

Action Observation Training:

A rehabilitation approach, during which the patient is asked to wisely observe actions presented through a video-clip or performed by another person, in order to activate the motor system via the visual input and promote imitative behaviors.

FINANCEMENT

Cette thèse a été financée par le Ministère de l'Université et de la Recherche Italien (Ricerca Corrente 2015-2017)

DEDICACE

A ma famille entière sur terre et ailleurs A ceux qui m'ont appris les connaissances pour lesquelles je suis ce que je suis A mes amis de l'âme Aux personnes que j'ai soignées et à leurs familles, qui m'ont souvent donné des leçons de vie A mes collègues de FDG et du centre de jour « Grace » A Alex Carlini

REMERCIEMENTS

A mes enfants Angelo & Carmen, mon mari Igor et ma maman Bruna, qui m'ont supportée pendant les 5 années de thèse ; Au professeur Thierry Pozzo, qui a accepté une doctorante « hors tranche d'âge » et qui m'a guidée pendant mon parcours ; Aux membres de mon jury, qui se sont déplacés pour moi ; A Francesca Baglio, Alessandra D'Amico et leur équipe, qui ont permis la réalisation de la partie expérimentale (et essentielle) de ma thèse ;

A mes collègues Anna, Elena e Margherita, qui m'ont remplacée et supportée durant mes absences ;

A mon Chef de Service Raffaello Nemni pour avoir signé mes congés de travail et m'avoir épaulée avec l'administration ; A l'administration de l'IRRCS S. Maria Nascente Fondazione Don Carlo Gnocchi ONLUS pour la partie que je leur dois ; A Giulia Belloni, pour son aide précieuse ; Et « the last but not the least » un remerciement très spécial à Alex Carlini, sans lequel je n'aurais jamais eu la possibilité d'attendre le titre de doctorat.

PAS DE REMERCIEMENTS

A ceux qui m'ont refusée comme doctorante en Italie ;

A ceux qui ont décidé de ne pas me laisser du temps à consacrer à la recherche, mon grand amour ; Au système qui ne prend pas en compte le mérite personnel.

Résumé

Le concept de "cognition incarnée" considère que le schéma classique Perception-Cognition-Action proposant un flux séquentiel de traitement de l'information n'est pas approprié pour comprendre l'effet comportemental des troubles neurodégénératifs et trouver des solutions thérapeutiques innovantes. La découverte des neurones miroirs (NM) a donné un substrat biologique à cette théorie : on pense maintenant que les NM relient les connaissances sur les actions et les perceptions non seulement pour intégrer la perception dans la planification et l'exécution, mais aussi pour soutenir un large éventail de fonctions cognitives, par ex. empathie et langage. En même temps, il est maintenant clair que, dans chaque maladie neurodégénérative, les symptômes cognitifs et moteurs sont représentés le long d'un continuum. Les maladies neurodégénératives liées au vieillissement, comme la maladie d'Alzheimer (MA), la forme la plus courante de démence, sont devenues un enjeu social très important. Comme il n'y a pas de remède pour la MA, les études se concentrent sur la prévention. Une catégorie qui représente maintenant une cible privilégiée est le trouble cognitif léger (TCL), considéré comme une étape intermédiaire entre le vieillissement normal et la MA. Même si MA et TCL ont été caractérisés comme des maladies «cognitives» jusqu'à présent, un lien entre la fonction motrice et le risque de développer la MA a été reconnu.

Le but principal de cette recherche est d'étudier l'intégrité du réseau NM dans la MA, le TCL et le vieillissement normal. La caractérisation de son fonctionnement dans les maladies neurodégénératives serait utile pour une meilleure compréhension de leurs mécanismes fonctionnels et manifestations cliniques. Cela permettrait également d'exploiter le NM dans la réhabilitation des symptômes.

La thèse comprend deux parties : la première inclut une vaste recherche bibliographique destinée à décrire le cadre scientifique qui justifie une telle recherche.

Nous avons d'abord passé en revue les preuves sur l'existence d'un système NM chez les singes et les humains, et ses multiples rôles possibles et après brièvement décrit le tableau clinique des principaux troubles neurodégénératifs, en montrant comment les symptômes cognitifs et moteurs s'entrecroisent. Ensuite, nous avons détaillé les résultats de la recherche documentaire sur les maladies neurodégénératives, NM et cognition incarnée, en les commentant à la lumière de cette théorie.

La deuxième partie de la thèse décrit la procédure expérimentale qui a été réalisée dans le but de la recherche.

Trois groupes appariés de 16 sujets chacun (CA-sujets de contrôle âgées-, TCL amnésique avec atrophie hippocampique et MA) ont été évalués avec une batterie neuropsychologique centrée sur les fonctions liées au système NM, et une tâche IRMf spécifiquement créée pour tester les NM: celle-ci était constituée d'une tache d'observation, où ont été montrés des vidéos d'une main droite saisissant différents objets, et d'une tache motrice où les sujets ont observé des images d'objets orientés pour être saisis avec la main droite, et ont fait le geste correspondant.

Chez les CA, l'analyse de conjonction (comparant l'activation de l'IRMf pendant l'observation et l'exécution) a indiqué l'activation d'un réseau bilatéral fronto-pariétal dans les zones NM « classiques» et du gyrus temporal supérieur (STG), entrée visuelle corticale aux NM. Le groupe TCL a montré une activation similaire, cependant, les zones pariétales ont été moins activées et le STG n'a pas été activé, tandis que l'inverse était vrai pour la zone de Broca droite. Nous n'avons observé aucune activation du réseau fronto-pariétal chez le groupe MA. Dans tous les tests neuropsychologiques (y compris les tests de fonctions attribuées à NM), les sujets MA ont été plus mauvais que les CA, alors que les sujets TCL montraient seulement des troubles de mémoire épisodique et de fluidité sémantique.

Les résultats et leurs implications futures sont finalement discutés. Ils suggèrent que le réseau NM est préservé dans le vieillissement, alors qu'il est impliqué suivant un gradient antéro-postérieur dans le déclin neurodégénératif. Dans la MA, les performances aux épreuves cognitives diminuent et le réseau NM apparaît clairement déficient. La préservation de la partie antérieure du réseau NM dans le TCL pourrait éventuellement compenser la désintégration initiale de la partie postérieure, en préservant les performances cognitives. Encore plus de recherches sont nécessaires pour confirmer cette hypothèse, mais le concept de la cognition incarnée ouvre des voies encourageantes vers des solutions thérapeutiques non pharmacologiques.

ABSTRACT

The concept of "embodied cognition" considers that the classical Perception-Cognition-Action architecture proposing a sequential flow of processing with clean cuts between all modules is not appropriate to understand the behavioral effect of neurodegenerative disorders and to find innovative therapeutic solutions. In the last decades, the discovery of the mirror neurons (MN) has given a biological substrate to this theoretical perspective: the MN are now thought to link together knowledge about actions and perceptions not only to integrate perception in action planning and execution but also as a neural mechanism supporting a wide range of cognitive functions, e.g. empathy and language. At the same time, it is now clear that in each neurodegenerative disease both cognitive and motor symptoms are represented along a continuum. In the current demographic context, neurodegenerative diseases linked to aging have become a very important social issue. Alzheimer Disease (AD), the most common form of dementia, is a neurodegenerative disease strictly linked to aging. As actually there is no cure, several studies are focusing on prevention. A category which now represents a preferential target of intervention is Mild Cognitive Impairment (MCI), considered as an intermediate stage between normal aging and AD. Even if AD and MCI have been characterized as "cognitive" diseases until now, a link between motor function and the risk of developing AD has been recognized.

The main purpose of this research is to investigate the integrity of the MN network in AD, MCI and normal aging. Characterizing the functioning of the MN network in neurodegenerative diseases would be useful to better understand functional mechanisms and their clinical manifestations. It would also allow to capitalize on these kinds of neurons in the rehabilitation of motor and cognitive symptoms.

The thesis consists of two parts: the first part includes an extensive bibliographic research intended to describe the scientific frame which justifies such a research.

We first reviewed the evidence about the existence of a MN system in monkeys and humans, and its multiple possible roles in humans.

We then briefly reviewed the clinical picture of the main neurodegenerative disorders, showing how cognitive and motor symptoms intersect in all of them.

Next, we detailed the results of literature searching on neurodegenerative diseases, MN, and embodied cognition, commenting them at the light of this hypothesis.

The second part of the thesis describes the experimental procedure which has been performed to evaluate the integrity of the MN network in normal elderly and people with AD and MCI, and its results.

Three matched groups of 16 subjects each (normal elderly-NE, amnesic MCI with hippocampal atrophy and AD) were evaluated with a neuropsychological battery centered on functions thought to be linked to the MN system, and a fMRI task specifically created to test MN: that comprised of an observation run, where subjects were shown videos of a right hand grasping different objects, and of a motor run, where subjects observed visual pictures of objects oriented to be grasped with the right hand, and made the corresponding gesture.

In NE subjects, the conjunction analysis (comparing fMRI activation during observation and execution), indicated the activation of a bilateral fronto-parietal network in "classical" MN areas, and of the superior temporal gyrus (STG), an area thought to provide the cortical visual input to the MN. The MCI group showed the activation of areas belonging to the same network, however, parietal areas were activated to a lesser extent and the STG was not activated, while the opposite was true for the right Broca's area. We did not observe any activation of the fronto-parietal network in AD participants. They performed worse than NE subjects in all the neuropsychological tests (including tests of functions attributed to MN) whereas the MCI subjects were significantly different from the NE subjects only in episodic memory and semantic fluency.

Results and their future implications are finally discussed. They suggest that the MN network is largely preserved in aging, while it is involved following an anteriorposterior gradient in neurodegenerative decline. In AD, task performance decays and the MN network appears clearly deficient. The preservation of the anterior part of the MN network in MCI could possibly supplement the initial decay of the posterior part, preserving cognitive performance.

Even more researches are needed to confirm this hypothesis, the concept of embodied cognition opens encouraging ways to innovative non-pharmacological therapeutic solutions.

Key words

Mirror Neurons; Embodied Cognition; Alzheimer Disease; Mild Cognitive Impairment; neurodegenerative diseases; aging; fMRI; neuropsychological tests.

LIST OF ACRONYMS

References 6. Appendix

Frontotemporal Dementia: A heterogeneous group of neurodegenerative disorders characterized by frontal and temporal lobe atrophy associated with neuronal loss, gliosis, and dementia. Patients exhibit progressive changes in social, behavioral, and/or language function. In some cases, patients can also show motor signs such as motor neuron disease or parkinsonism.

Behavioral variant of Frontotemporal dementia:

The most common clinical form of frontotemporal dementia, this variant presents with personality and behavioral changes often associated with disinhibition or apathy, and lack of insight.

Primary Progressive Aphasia: A progressive form of dementia characterized by the global loss of language abilities and initial preservation of other cognitive functions. Fluent, nonfluent and logopenic subtypes have been described.

Semantic dementia: also known as semantic or fluent variant of primary progressive aphasia, is a progressive neurodegenerative disorder characterized by loss of semantic memory in both the verbal and non-verbal domains. Clinical signs include fluent aphasia with impaired comprehension of word meaning, anomia, and associative visual agnosia . As the disease progresses, behavioral and personality changes are often seen similar to those seen in the behavioral variant of frontotemporal dementia.

Lewy bodies: abnormal deposits of a protein called alpha-synuclein in the brain, contributing to Parkinson disease, Dementia with Lewy bodies (DLB), Parkinson disease dementia (PDD) and some other disorders.

Dementia with Lewy bodies:

A neurodegenerative disease characterized by dementia, mild parkinsonism, fluctuations in attention and alertness, REM behavior disorder and neuroleptic hypersensitivity.

Brain-Derived Neurotrophic Factor: A member of the nerve growth factor family of trophic factors. In the brain it has a trophic action on retinal, cholinergic, and dopaminergic neurons, and in the peripheral nervous system it acts on both motor and sensory neurons.

CHAPTER 1 -THEORETICAL FRAME

THE MIRROR NEURONS

The Mirror Neurons (MN) are one of the most important discoveries in the last decades of neuroscience. They represent a distinctive class of neurons that discharge both when an individual executes a motor act and when he observes another individual performing the same or a similar motor act (Figure 1). These neurons were first discovered in monkey's brain, in particular in the ventral premotor area F5 (and above all its F5c cytoarchitectural area) and in the inferior parietal lobule -IPL- (Rizzolatti et al., 2014). In humans, brain activity consistent with that of MN has been found in the premotor cortex (posterior regions of the inferior frontal gyrus -IFG-, considered the human homologue of the monkey F5; [START_REF] Kilner | Evidence of Mirror Neurons in Human Inferior Frontal Gyrus[END_REF][START_REF] Ferri | A human homologue of monkey F5c[END_REF], and in the IPL [START_REF] Rizzolatti | Neurophysiological mechanisms underlying the understanding and imitation of action[END_REF][START_REF] Rizzolatti | The mirror-neuron system[END_REF][START_REF] Rizzolatti | The mirror neuron system and its function in humans[END_REF][START_REF] Chong | fMRI Adaptation Reveals Mirror Neurons in Human Inferior Parietal Cortex[END_REF][START_REF] Arnstein | Suppression during Action Observation and Execution Correlates with BOLD in Dorsal Premotor, Inferior Parietal, and SI Cortices[END_REF][START_REF] Molenberghs | Brain regions with mirror properties: A meta-analysis of 125 human fMRI studies[END_REF][START_REF] Iacoboni | Reafferent copies of imitated actions in the right superior temporal cortex[END_REF][START_REF] Mukamel | Single-Neuron Responses in Humans during Execution and Observation of Actions[END_REF]Kilner e Lemon, 2013;[START_REF] Cook | Mirror Neurons: From Origin to Function[END_REF]. The presence of MN activity was additionally signaled in the primary motor cortex (M1; [START_REF] Fadiga | Human motor cortex excitability during the perception of others' action[END_REF] and even in the hippocampus [START_REF] Mukamel | Single-Neuron Responses in Humans during Execution and Observation of Actions[END_REF]. fMRI experiments showed that a parietofrontal network is activated during observation and execution of hand grasping acts [START_REF] Grèzes | Activations related to "mirror" and "canonical" neurons in the human brain: An fMRI study[END_REF], as well as during observation of grasping acts made with tools [START_REF] Peeters | The representation of tool use in humans and monkeys: Common and uniquely human features[END_REF]. This network is remarkably similar in monkeys and humans. MN discovery received a lot of attention from specialists (not only neuroscientists, but also psychologists and philosophers) and in the scientific and public media. Apart from action understanding [START_REF] Rizzolatti | Premotor cortex and the recognition of motor actions[END_REF][START_REF] Gallese | What is so special about embodied simulation[END_REF] and imitation [START_REF] Iacoboni | Cortical Mechanisms of Human Imitation[END_REF]Bonini e Ferrari, 2011), MN are now thought to be responsible for myriad of other sophisticated human behavior and thinking processes. For instance, the discovery of MN has given a biological complement to the simulation theory, that is the idea that actions involve both an overt and a covert stage [START_REF] Jeannerod | Mental imaging of motor activity in humans[END_REF][START_REF] Jeannerod | Neural Simulation of Action: A Unifying Mechanism for Motor Cognition[END_REF].

In humans, MN are now thought to have a part in understanding not only other people's actions but also their emotions [START_REF] Gallese | A unifying view of the basis of social cognition[END_REF][START_REF] Enticott | Mirror neuron activation is associated with facial emotion processing[END_REF][START_REF] Corradini | Mirror neurons and their function in cognitively understood empathy[END_REF], being therefore involved in empathy [START_REF] Avenanti | Transcranial magnetic stimulation highlights the sensorimotor side of empathy for pain[END_REF] and intention-reading [START_REF] Iacoboni | Grasping the intentions of others with one's own mirror neuron system[END_REF] and have been also proposed to have a main role in different aspects of language: acquisition [START_REF] Theoret | Language acquisition: Do as you hear[END_REF], speech perception [START_REF] Glenberg | Processing abstract language modulates motor system activity[END_REF], speech production [START_REF] Kuhn | Testing the connection of the mirror system and speech: How articulation affects imitation in a simple response task[END_REF], and evolutionary language development [START_REF] Arbib | From grasp to language: Embodied concepts and the challenge of abstraction[END_REF]. Even if there have been criticisms of this point of view [START_REF] Mahon | A critical look at the embodied cognition hypothesis and a new proposal for grounding conceptual content[END_REF], the supposed power of MN to explain a broad range of human phenomenon has been perceived as revolutionary [START_REF] Ramachandran | Mirror neurons and imitation learning as the driving force behind "the great leap forward[END_REF][START_REF] Iacoboni | Mesial frontal cortex and super mirror neurons[END_REF][START_REF] Oosterhof | Cross-modal and actionspecific: Neuroimaging the human mirror neuron system[END_REF] at the point that, in the last years, the exploitation of MN system for rehabilitation has been proposed [START_REF] Michielsen | Motor Recovery and Cortical Reorganization After Mirror Therapy in Chronic Stroke Patients[END_REF][START_REF] Michielsen | The neuronal correlates of mirror therapy: an fMRI study on mirror induced visual illusions in patients with stroke[END_REF][START_REF] Franceschini | Mirror neurons: action observation treatment as a tool in stroke rehabilitation[END_REF][START_REF] Sgandurra | Upper limb children action-observation training (UP-CAT): a randomised controlled trial in Hemiplegic Cerebral Palsy[END_REF][START_REF] Small | The mirror neuron system and treatment of stroke[END_REF][START_REF] Small | Brain repair after stroke -a novel neurological model[END_REF][START_REF] Chen | Mirror neuron system based therapy for aphasia rehabilitation[END_REF]. In addition, it has been suggested that MN dysfunction contributes to a number of disorders, above all autism [START_REF] Dapretto | Understanding emotions in others: mirror neuron dysfunction in children with autism spectrum disorders[END_REF][START_REF] Nishitani | Abnormal imitation-related cortical activation sequences in Asperger's syndrome[END_REF][START_REF] Williams | Imitation, mirror neurons and autism[END_REF] and schizophrenia [START_REF] Arbib | Schizophrenia and the mirror system: An essay[END_REF]. The MN were described for the first time 20 years ago in the monkey ventral premotor area F5 [START_REF] Di Pellegrino | Understanding motor events: A neurophysiological study[END_REF][START_REF] Rizzolatti | Premotor cortex and the recognition of motor actions[END_REF], Gallese et al., 1996), and subsequently in area PF/PFG of the monkey IPL [START_REF] Gallese | Action representation and the inferior parietal lobule[END_REF][START_REF] Fogassi | Parietal lobe: from action organization to intention understanding[END_REF][START_REF] Rozzi | Functional organization of inferior parietal lobule convexity in the macaque monkey: electrophysiological characterization of motor, sensory and mirror responses and their correlation with cytoarchitectonic areas[END_REF]; see Figure 2). Their discovery was preceded by a prolonged anatomical and functional investigation of the premotor areas that enabled Rizzolatti's group to highlight a series of unexpected functions of these areas [START_REF] Gentilucci | Functional organization of inferior area 6 in the macaque monkey: I. Somatotopy and the control of proximal movements[END_REF][START_REF] Rizzolatti | Functional organization of inferior area 6 in the macaque monkey: II. Area F5 and the control of distal movements[END_REF] Among these functions there were the coding of the goal of motor acts rather than movements that form them [START_REF] Rizzolatti | Functional organization of inferior area 6 in the macaque monkey: II. Area F5 and the control of distal movements[END_REF], the responsiveness to objects in area F5 [START_REF] Murata | Object representation in the ventral premotor cortex (area F5) of the monkey[END_REF]Jeannerod et al., 1995) and the coding of the peripersonal space in area F4 [START_REF] Gentilucci | Functional organization of inferior area 6 in the macaque monkey: I. Somatotopy and the control of proximal movements[END_REF][START_REF] Fogassi | Coding of peripersonal space in inferior premotor cortex (area F4)[END_REF]. F5 and PF and PFG areas (From Rizzolatti et al., 2014) At their first description in monkeys, the activity of these cells seemed to be strictly dependent upon the actions having a clear transitive goal (i.e., grasping a piece of food), although premotor MN coding communicative mouth gestures (e.g., lipsmaking), [START_REF] Ferrari | Mirror neurons responding to the observationof ingestive and communicative mouth actionsin the monkey ventral premotor cortex[END_REF] or intransitive hand movements [START_REF] Kraskov | Corticospinal neurons in macaque ventral premotor cortex with mirror properties: A potential mechanism for action suppression[END_REF] have been also described.

In area F5, besides purely motor neurons, two categories of visuomotor neurons were found. One, referred to as 'canonical neurons' (Rizzolatti & Fadiga, 1995), is responsive to the presentation of three-dimensional objects. The other, referred to as 'MN', is responsive to the observation of motor acts performed by others [START_REF] Rizzolatti | Premotor cortex and the recognition of motor actions[END_REF][START_REF] Gallese | Action recognition in the premotor cortex[END_REF]. The main property of canonical neurons is to match the shape and size of the observed object with a specific type of prehension, whereas the main property of MN is that of matching observation of hand and mouth motor acts with the execution of the same or similar motor acts. This matching mechanism enables the observing individual to achieve an automatic understanding-i.e. an understanding without inferential processing of others' goal-directed motor acts.

Early studies of the field properties of monkey MN-the sensory and motoric conditions in which they firerevealed three basic types: "Strictly congruent" MN discharge during observation and execution of the same action, for example, precision grip. "Broadly congruent" MN are typically active during the execution of one action (e.g., precision grip) and during the observation of one or more similar, but not identical, actions (e.g., power grip alone, or precision grip, power grip, and grasping with the mouth). "Logically related" MN respond to different actions in observe and execute conditions. For example, they fire during the observation of an experimenter placing food in front of the monkey, and when the monkey grasps the food to eat it. MN do not respond to the presentation of objects alone [START_REF] Di Pellegrino | Understanding motor events: A neurophysiological study[END_REF]. However, "canonical neurons," which are active during object observation and performance of an action that is commonly performed on that object, are co-located with MN both in area F5 [START_REF] Murata | Object representation in the ventral premotor cortex (area F5) of the monkey[END_REF]) and in the anterior intraparietal sulcus [START_REF] Murata | Selectivity for the shape, size, and orientation of objects for grasping in neurons of monkey parietal area AIP[END_REF].

A question posed by the discovery of F5 MN is why the observer does not move during action observation given the activation, in her/his premotor and parietal cortices, of the same neurons that are involved in action. A possible answer has been provided by a study by Kraskov and co-workers (2009). In this study, the authors first identified MN that project through the pyramidal tract, likely to the spinal cord, and then investigated their responses during action production and observation.

Half of these pyramidal tract MN (PTMNs) vigorously responded during action production but exhibited a complete suppression of discharge during action observation. Kraskov and coworkers speculated that the suppression of PTMNs' responses during action observation might serve the purpose of inhibiting, likely at the spinal cord level, self-movements during action observation [START_REF] Kraskov | Corticospinal neurons in macaque ventral premotor cortex with mirror properties: A potential mechanism for action suppression[END_REF].

To date, monkey MN have been found that are responsive to the observation and execution of hand and mouth actions. The hand actions include grasping, placing, manipulating with the fingers, and holding [START_REF] Di Pellegrino | Understanding motor events: A neurophysiological study[END_REF][START_REF] Gallese | Action recognition in the premotor cortex[END_REF]. The mouth actions include ingestive behaviors such as breaking food items, chewing and sucking, and communicative gestures such as lip-smacking, lip-protrusion, and tongue-protrusion [START_REF] Ferrari | Mirror neurons responding to the observationof ingestive and communicative mouth actionsin the monkey ventral premotor cortex[END_REF].

It was originally reported that F5 MN do not respond if the same action (e.g., grasping) is performed with a tool. However, more recent results showed that after extensive visual exposure of the monkey to actions executed with a tool, a subset of MN in the ventral part of area F5c started responding also to this type of visual stimuli [START_REF] Ferrari | Mirror neurons responding to observation of actions made with tools in monkey ventral premotor cortex[END_REF].

Further studies reported additional generalization properties of some F5 MN [START_REF] Casile | The mirror neuron system: A fresh view[END_REF] . For example, some of them responded in a similar manner to the same action executed with different effectors (e.g., grasping with the hand and grasping with the mouth) [START_REF] Ferrari | Mirror neurons responding to the observationof ingestive and communicative mouth actionsin the monkey ventral premotor cortex[END_REF][START_REF] Rizzolatti | Neurophysiological mechanisms underlying the understanding and imitation of action[END_REF], to the sound associated with familiar actions [START_REF] Kohler | Hearing sounds, understanding actions: Action representation in mirror neurons[END_REF], see also the paragraph "Enhancing the potential of mirror neurons stimulation in rehabilitation"), and even to partially sealed actions that can be inferred only from their initial motion path [START_REF] Umiltà | I know what you are doing: A neurophysiological study[END_REF].

Subsequently some Authors have shown that the response a subset of IPL MN (i.e., in the cytoarchitectonic area PF and PFG) [START_REF] Fogassi | Parietal lobe: from action organization to intention understanding[END_REF], during both the observation and execution of a complex grasping act (e.g., grasping to place or grasping to eat), are modulated by the final goal of the action (placing or eating) in which the grasping was embedded [START_REF] Bonini | Ventral premotor and inferior parietal cortices make distinct contribution to action organization and intention understanding[END_REF]Fogassi et al., 2005).

This kind of MN discharge when the monkey grasps a piece of food to eat it, but has a smaller response when the same piece of food is grasped to place it into a box. The same selectivity is present during action observation, that is, the neurons discharge while the monkey observes the experimenter grasping a piece of food to eat it, whereas it remains almost silent when the experimenter grasps the same piece of food to place it into a box. An important feature of these cells is that their activity seems not to be strictly linked to the precise time-deployment of the observed action; indeed, a certain proportion of parietal MN are activated in advance of achievement of the end-goal, e.g., during the initial grasping phase [START_REF] Fogassi | Parietal lobe: from action organization to intention understanding[END_REF]. This anticipatory feature was also shown in a single-cell study where monkey premotor MN fired both when directly seeing hand-food contact and when merely inferring that the observed hand was going to grasp a piece of food behind an occluder [START_REF] Umiltà | I know what you are doing: A neurophysiological study[END_REF]. Moreover, specific studies have excluded that the differential response of IPL MN according to the action goal could be due to different kinematic parameters [START_REF] Rizzolatti | The mirror mechanism: recent findings and perspectives[END_REF].

Fogassi and co-workers interpreted this pattern of response as an evidence about the possible specific cognitive role of IPL MN of encoding the intentions of others [START_REF] Fogassi | Parietal lobe: from action organization to intention understanding[END_REF], Figure 3). More recent investigations, however, have shown similar response properties also in F5 MN [START_REF] Bonini | Ventral premotor and inferior parietal cortices make distinct contribution to action organization and intention understanding[END_REF], even if less strong [START_REF] Rizzolatti | The mirror mechanism: recent findings and perspectives[END_REF]. Rizzolatti et al., 2014;Modified from Fogassi et al., 2005) Additional evidence in favor of goal coding was furnished by experiments in which the monkeys grasped the food with normal or inverted pliers (i.e. pliers which requested opening the hand to grasp the object). MN discharged according to the goal of the action and not to the hand movement [START_REF] Rizzolatti | Functional organization of inferior area 6 in the macaque monkey: II. Area F5 and the control of distal movements[END_REF][START_REF] Umiltà | How pliers become fingers in the monkey motor system[END_REF][START_REF] Cattaneo | The motor system resonates to the distal goal of observed actions: testing the inverse pliers paradigm in an ecological setting[END_REF]Figure 4). Other data in favor of this are already cited studies in which MN responded in a similar manner to the same action executed with different body parts (e.g., the hand and the mouth) [START_REF] Ferrari | Mirror neurons responding to the observationof ingestive and communicative mouth actionsin the monkey ventral premotor cortex[END_REF][START_REF] Rizzolatti | Neurophysiological mechanisms underlying the understanding and imitation of action[END_REF] and to the sound associated with familiar actions (Kohler et al., 2002, Figure 5). Rizzolatti et al., 2014, modified from Cattaneo et al,. 2013) Based on the existing studies in monkeys, we can therefore consider that MN modulate their responses according to characteristics of the observed actions that are directly related to motor goals, such as the type of grip or the intention of the actor.

However, other studies suggest that MN integrate in their responses additional pieces of information that are not directly related to the action itself. MN activity can be also modulated by the distance at which the observed motor acts were executed with respect to the monkey that is in the peri-personal space or on the contrary in the extra-personal space of the monkey of the monkey [START_REF] Caggiano | Mirror neurons differentially encode the peripersonal and extrapersonal space of monkeys[END_REF]. Half of these neurons code space in a metric (cartesian way), the other half from an operational point of view (i.e. the space is coded according to the possibility of the monkey to reach it; Rizzolatti & Fogassi, 2014: see Figure 6). From a functional perspective, the distance between observer and actor plays no role in understanding action goal. However, it can play a role in selecting possible subsequent behaviors, for example, interacting or approaching behaviors. Thus, the MN system could be part, together with other brain areas, of a system that contributes not only to understanding what others are doing but also in deciding the most appropriate behavioral response [START_REF] Caggiano | View-based encoding of actions in mirror neurons of area F5 in macaque premotor cortex[END_REF].

Figure 5: illustration of findings by [START_REF] Kohler | Hearing sounds, understanding actions: Action representation in mirror neurons[END_REF] Responses of the population of tested neurons selectively activated by the vision-and-sound, vision-only, soundonly, and In this latter condition, the object (and the act performed by the experimenter) is metrically in the monkey's peripersonal space, but operationally outside it. The lower panels show the visual responses of a mirror neuron in the three conditions. Before closure with the frontal panel, the neuron was activated only during observation of grasping in the monkey's extrapersonal space. However, after closure, the neuron also responded to observation of grasping performed close to the monkey's body.

According to another study, the majority of F5 MN seem to visually encode actions in a view dependent manner [START_REF] Caggiano | View-based encoding of actions in mirror neurons of area F5 in macaque premotor cortex[END_REF]. In this study, the responses of MN to action observation were studied by presenting the same actions as seen from different points of view, including also the actor's own point of view. The discharges of MN were modulated not only by the action being observed but also by the point of view under which it was observed (e.g., a frontal or a side view) [START_REF] Caggiano | View-based encoding of actions in mirror neurons of area F5 in macaque premotor cortex[END_REF]; see also Figure 7). Interestingly, a consistent percentage of MN visually responded not only during the observation of the actions of another individual but also during the observation of the visual representations of the actions seen in a first-person view. This characteristic suggests that MN could be visually activated not only by the actions of others but also by selfgenerated actions.

The modulations of mirror neuron discharges by the spatial position of the observed action or the point of view suggest an extension of their possible functional role. This finding is relevant for two important implications at phylogenetic and ontogenetic levels. Philogenetically, the mirror neuron system could have evolved to map monkeys' actions onto own motor representations possibly to provide feedback for visually directed graspings [START_REF] Bonaiuto | Extending the mirror neuron system model, II: What did I just do? A new role for mirror neurons[END_REF]Oztop & Arbib 2002; [START_REF] Rizzolatti | The mirror mechanism: recent findings and perspectives[END_REF]) [START_REF] Casile | The mirror neuron system: A fresh view[END_REF]. According to this proposal, the same system was, later in evolution, exploited to interpret the goal-directed behaviors of others for social interaction and communication purposes.

Ontogenetically, the development and refinement of a successful control strategy for visually guided reaching movements needs also execution of appropriate exploratory behaviors [START_REF] Von Hofsten | An action perspective on motor development[END_REF]. These self-generated exploratory behaviors serve likely both motor and cognitive purposes. The motor purpose likely consists of the integration of different functional motor circuits and their sensory consequences (e.g., gaze behavior with arm movements and proprioception). The possible cognitive purpose is the development of an internal representation of the space around the infant. The fact that this important cognitive development requires concurrent and coordinated visual and motor experience was demonstrated by [START_REF] Held | Visually guided reaching in infant monkeys after restricted reaching[END_REF]. In their experiments, they dissociated vision and proprioception by preventing newborn macaques from seeing their own arms at birth. When tested at 35 days of age, the subjects exhibited severe impairments in visually guided reaching and grasping despite their preserved capacity to grasp under tactile guidance [START_REF] Held | Visually guided reaching in infant monkeys after restricted reaching[END_REF]. This result strongly suggests that the correct development of spatial maps of the peri-personal space for goal-directed hand movements entails the observation of own movements [START_REF] Casile | The mirror neuron system: A fresh view[END_REF].

Another interesting property recently discovered about F5 MN is that they are influenced by the value attribution of the grasped object. The vast majority of monkey MN were stronger activated in response to observation of grasping food than of grasping objects without any value for the monkey [START_REF] Caggiano | Mirror neurons encode the subjective value of an observed action[END_REF]. It is remarkable that the value an observer attributes to an act is fundamental in choosing the appropriate behavioral response. According to [START_REF] Rizzolatti | The mirror mechanism: recent findings and perspectives[END_REF] this is possible due to the strong connections of the MN frontoparietal circuit with the superior temporal sulcus (STS; Figure 8) -which would provide the higher order visual input necessary to MN functioning-and with the inferotemporal lobe.

In the STS of the monkey, there are neurons exhibiting selective responses to human movements either performed by the experimenter in front of the monkey or presented on a computer screen [START_REF] Perrett | Visual analysis of body movements by neurones in the temporal cortex of the macaque monkey: a preliminary report[END_REF]. These neurons are sensitive to many characteristics of observed movements. For example, they encode the direction of motion of a walking person with respect to the observer [START_REF] Perrett | Visual analysis of body movements by neurones in the temporal cortex of the macaque monkey: a preliminary report[END_REF], and respond also to human figures presented as static snap-shots, both with arms and legs outstretched and close to the body [START_REF] Barraclough | The sensitivity of primate STS neurons to walking sequences and to the degree of articulation in static images[END_REF]. They also show a specificity for different body parts [START_REF] Wachsmuth | Recognition of objects and their component parts: responses of single units in the temporal cortex of the macaque[END_REF]. In addition to neurons responding to human movements, Perrett and co-workers described also a population of neurons in STS selectively responding during the observation of manipulative behaviors (i.e., hand-object interactions; [START_REF] Perrett | Frameworks of analysis for the neural representation of animate objects and actions[END_REF]. Interestingly, for their relationship with MN, STS neurons have a reduced discharge when the monkey observes hand movements alone miming the action, as well as objects alone with no hand movements elicited (Barraclough et al., 2008). It also deserves a mention the fact that a subset of the monkey STS units selective for human actions are significantly modulated by the sound associated with that action [START_REF] Barraclough | Integration of Visual and Auditory Information by Superior Temporal Sulcus Neurons Responsive to the Sight of Actions[END_REF]. This finding raises the possibility that STS would not only provide the higher order visual input necessary to MN functioning, but also the auditive one. The MN presence in humans have been studied through neuroimaging (fMRI) and neuropshysiological techniques (EEG, evoked potentials, transcranial magnetic stimulation-TMS), leading to discover neurons with mirror properties in the areas already described (particularly IFG and IPL, the "core MN system"- [START_REF] Pineda | Sensorimotor cortex as a critical component of an 'extended' mirror neuron system: Does it solve the development, correspondence, and control problems in mirroring?[END_REF], and to detect cerebral areas strictly connected to the MN system, i.e. STS, insula and the middle temporal gyrus ("extendend MN system"; see later in the chapter for relevant studies; see also Figure 9 and 10). and inferior frontal gyrus) and make up the 'core' system. The 'extended' mirror neuron system involves additional brain areas, e.g., insula, middle temporal gyrus, superior temporal sulcus and somatosensory cortex, which connect to the core system and perform transformations on the data critical for mirroring and simulation (from [START_REF] Pineda | Sensorimotor cortex as a critical component of an 'extended' mirror neuron system: Does it solve the development, correspondence, and control problems in mirroring?[END_REF]. [START_REF] Pineda | Sensorimotor cortex as a critical component of an 'extended' mirror neuron system: Does it solve the development, correspondence, and control problems in mirroring?[END_REF].

Neurophysiological techniques: EEG, TMS, evoked potentials, neuronal recordings

The reduction of magnitude of the μ rhythm during action observation, observed in several studies, has led to the conclusion that this rhythm indexes a brain system that is functionally comparable to the monkey mirror neuron system [START_REF] Muthukumaraswamy | Mu rhythm modulation during observation of an object-directed grasp[END_REF][START_REF] Pineda | EEG evidence for mirror neuron dysfunction in autism spectrum disorders[END_REF][START_REF] Lepage | EEG evidence for the presence of an action observation-execution matching system in children[END_REF].

The human μ rhythm was first described by Henri Gastaut [START_REF] Gastaut | Étude d'une activité électrocorticographique méconnue:'le rhythme rolandique en arceau[END_REF], and was termed the rolandic wicket rhythm, or the "rythme rolandique en arceau", due to the waves' arch-like or wicketlike shape. At the beginning, it was thought to be a rare rhythm and was associated to pathological significance [START_REF] Hobson | The interpretation of mu suppression as an index of mirror neuron activity: past, present and future[END_REF]. Later, when it became apparent that μ was not an unusual or particularly pathological phenomenon, new theories emerged about its origin.

Event-related desynchronization or synchronization (ERD/ERS) describes the reduction or increase of a given power band relative to a baseline. ERD and ERS are considered to reflect cortical activation and idling, respectively. [START_REF] Pfurtscheller | Event-related EEG/MEG synchronization and desynchronization: basic principles[END_REF]. Using ERD/S, researchers have demonstrated the reactivity of μ to people's own movements and suggested that there may be different types of μ rhythm, which could correspond to different areas of the motor cortex [START_REF] Pfurtscheller | Event-related synchronisation of mu rhythms in the EE over the cortical area in man[END_REF]. As well as reacting to participants' own movements, μ is suppressed by observing the movements of others and has been therefore used as an index of MN functioning in humans (Muthukumaraswamy & Johnson, 2004;[START_REF] Muthukumaraswamy | Mu rhythm modulation during observation of an object-directed grasp[END_REF]. Traditionally, the μ rhythm is considered an EEG oscillation occurring within the standard "alpha" band (i.e., ~8-13 Hz in adults; ~6-9 Hz in children) that is suppressed during the execution and perception of action and is speculated to reflect activity in the premotor and inferior parietal cortices as a result of MN system activation [START_REF] Fox | Assessing human mirror activity with EEG mu rhythm:a meta-analysis[END_REF]; see also Figure 11 and12). However, it is now considered that it has beta (14-25 Hz) components, too [START_REF] Pineda | Sensorimotor cortex as a critical component of an 'extended' mirror neuron system: Does it solve the development, correspondence, and control problems in mirroring?[END_REF]. (Rizzolatti et al., 2014, modified by Avanzini et al. 2012) μ suppression studies in humans found that stronger suppression occurred when viewing another's hand in a precision grip (i.e. a grip that could be used on an object) rather than in a neutral, non-grip position, and that object interaction produced greater μ suppression than conditions without object interaction (Muthukumaraswamy & Johnson, 2004;[START_REF] Muthukumaraswamy | Mu rhythm modulation during observation of an object-directed grasp[END_REF]. It has been proposed that this object effect supports the contention that μ suppression is related to MN activity in humans. As these pioneering studies suggested that μ suppression could be harnessed for research into the human MN system, many more action-observation experiments have been conducted. This line of inquiry was recently reviewed by [START_REF] Fox | Assessing human mirror activity with EEG mu rhythm:a meta-analysis[END_REF] in a meta-analysis: Authors concluded that their analysis did show that μ suppression can be used as a proxy for human MN activity. According to their review, results indicates that there is consistent EEG μ desynchronization during action execution and action observation and that these effects occur across diverse experimental conditions that vary in methodology (e.g., type of stimulus observed) and across a variety of actions (e.g., objectdirected and non-object-directed). Some authors have also speculated that MN responses to nonobject-directed actions are a distinctive property of human MN, and that this difference from other primates may represent a departure from our common ancestors which played an important role in the evolution of language [START_REF] Rizzolatti | The mirror-neuron system[END_REF] However, others have contested that μ suppression reflects mirror neuron activity, stating that μ suppression studies have failed to produce robust evidence of the role of MN system due to limitations in methodology: e.g. a few studies report changes in power at site other than the central electrodes, making it impossible to be sure that effects are not being due to changes in power in other areas [START_REF] Hobson | Mu suppression -a good measure of the human mirror neuron system?[END_REF][START_REF] Coll | Cross-modal repetition effects in the mu rhythm indicate tactile mirroring during action observation[END_REF], reported that μ suppression indexed sensory mirroring but not motor mirroring, a finding that undermines the important connection between action and perception that MN are thought to represent. The validity of μ suppression as a measure of the human MN system is therefore still a topic of debate.

Previous studies have demonstrated that perception of action presented audio-visually facilitates greater MN system activity in humans [START_REF] Kaplan | Multimodal action representation in human left ventral premotor cortex[END_REF] and non-human primates [START_REF] Keysers | Audiovisual mirror neurons and action recognition[END_REF] than perception of action presented unimodally. [START_REF] Mcgarry | Audio-visual facilitation of the mu rhythm[END_REF] examined whether audio-visual facilitation of the MN system can be indexed using electroencephalography (EEG) measurement of the μ rhythm. Participants observed experimental stimuli unimodally (visual-alone or audio-alone) or bimodally during randomized presentations of two hands ripping a sheet of paper, and a control video depicting a box moving up and down. Audio-visual perception of action stimuli led to greater event-related desynchrony (ERD) of the 8-13 Hz μ rhythm compared to unimodal perception of the same stimuli over the C3 electrode, as well as in a left central cluster when data were examined in source space.

The amplitude of the motor evoked potentials (MEPs) and in general evoked excitability induced by TMS is modulated by action observation training (AOT): this finding has been replicated by several studies [START_REF] Fadiga | Motor facilitation during action observation: a magnetic stimulation study[END_REF][START_REF] Gangitano | Phase-specific modulation of cortical motor output during movement observation[END_REF][START_REF] Gangitano | Modulation of premotor mirror neuron activity during observation of unpredictable grasping movements[END_REF][START_REF] Fadiga | Human motor cortex excitability during the perception of others' action[END_REF][START_REF] Avanzino | Motor cortical plasticity induced by motor learning through mental practice[END_REF][START_REF] Celnik | Encoding a motor memory in the older adult by action observation[END_REF][START_REF] Cohen | Formation of a motor memory by action observation[END_REF]. When TMS is applied to M1 during passive action observation, the amplitude of the MEPs recorded from the muscles required to execute that action is greater than the amplitude of the MEPs recorded when observing a different action. For example, observing index and little finger abduction movements selectively facilitates the amplitude of MEPs recorded from the first dorsal interosseus and abductor digiti minimi muscles, responsible for index and little finger movements, respectively [START_REF] Catmur | Making mirrors: Premotor cortex stimulation enhances mirror and counter-mirror motor facilitation[END_REF]. That action observation selectively increases corticospinal excitability to action relevant muscles is suggestive of "mirror" sensorimotor connectivity. Therefore, although the primary motor cortex (M1) is not classically considered an integral part of the core parietofrontal MN system, TMS studies support the role of M1 in observational learning.

Action observation can also modulate somatosensory evoked potentials (SEPs) in humans [START_REF] Rossi | Somatosensory processing during movement observation in humans[END_REF]. In a recent work [START_REF] Mcgregor | Functional Plasticity in Somatosensory Cortex Supports Motor Learning by Observing[END_REF] recorded SEPs associated with median nerve stimulation from primary somatosensory area (S1) before and after AOT (a tutorial video which taught how to reach a target in a force field): SEPs amplitude increased only for participants who observed the video and SEPs amplitude increase was proportional to the amount of learning exhibited by participants after watching at the tutorial video. According to the Authors, S1 plasticity would support motor learning by observing the actions of other people.

The late N30 component of SEPs is known to be modulated by sensory interference, motor action, movement ideation and observation. [START_REF] Cebolla | Modulation of the N30 generators of the somatosensory evoked potentials by the mirror neuron system[END_REF] have proposed a new paradigm in which the observation of another person's hand movement triggers the somatosensory stimulus, inducing the N30 response. Till now, there has been only one study in which MN have been studied with direct single neuron extracellular recording in humans: [START_REF] Mukamel | Single-Neuron Responses in Humans during Execution and Observation of Actions[END_REF] described neurons with mirror-like properties in motor supplementary area and in the hippocampus. [START_REF] Cerri | The mirror neuron system and the strange case of Broca's area: Broca is Not Part of Mirror Neuron System[END_REF] tested mirror properties of the human Broca's area (BA44). To this aim, they used an fMRI study to assess the activation of brain areas during a fluency task and during the execution and observation of hand and mouth grasping actions as well as nonverbal mouth communicative actions. Subsequently, an intraoperative neurophysiological study on 10 patients submitted to neurosurgery for glioma was designed to investigate whether the electrical stimulation of frontal premotor areas elicited a motor output in hand or mouth muscles. The results challenge the inclusion of Broca's area in the human MN system, because while ventral premotor/BA6 fully and consistently satisfied all the requirements to be considered a MN area, BA44/Broca did not (in particular, no motor response should be elicited by electrical stimulation of this area).

fMRI studies

Functional magnetic resonance imaging (fMRI) has caught on to study functional activity in the brain during a behavioral response. Most of these studies make use of blood oxygen level-dependent-(BOLD-) contrast imaging, which involves mapping particular areas of a functioning brain, from the changes in blood oxygen. fMRI recordings require the subject to perform a particular action in order to trigger a dynamic uptake of oxygen into the brain. This is because fMRI recordings are based on the subsequent increase in oxygen demand from the brain tissue upon the execution of a certain stimulus, whether it is motor, sensory or emotional. The images acquired are then superimposed on the neuroanatomical image of the corresponding slices, which facilitated the localization of the sites of recording [START_REF] Chow | Functional magnetic resonance imaging and the brain: A brief review[END_REF][START_REF] Gore | Principles and practice of functional MRI of the human brain[END_REF]. BOLD-contrast imaging fMRI has a good enough spatial resolution for the localization of activated brain areas and their delineation from neighboring regions to be visualized. The voxel representing the area of activation is usually defined as covering a few million neurons [START_REF] Huettel | Functional Magnetic resonance imaging[END_REF]. In addition, the BOLD response lags 1 to 2 s behind the stimulus in order for the vascular system to respond, and in general it peaks at 5 s after the stimulus. A continuation of the same stimulus would downregulate the BOLD response [START_REF] Huettel | Functional Magnetic resonance imaging[END_REF][START_REF] Dale | Selective averaging of rapidly presented individual trials using fMRI[END_REF][START_REF] Kahn | Characterization of the functional MRI response temporal linearity via optical control of neocortical pyramidal neurons[END_REF]. To eliminate noise in the recording, the stimulus must be repeated several times. This process often takes a few minutes to complete, and the results can then be compared across different individuals [START_REF] Huettel | Functional Magnetic resonance imaging[END_REF][START_REF] Rombouts | Clinical applications of functional brain MRI[END_REF]. fMRI experiments [START_REF] Peeters | The representation of tool use in humans and monkeys: Common and uniquely human features[END_REF][START_REF] Grèzes | Activations related to "mirror" and "canonical" neurons in the human brain: An fMRI study[END_REF] have shown that a parieto-frontal network, remarkably similar in monkeys and humans, is activated during observation and execution of hand grasping acts. Moreover, this network is also activated during observation of grasping acts made with tools, in line with previous single neurons studies in monkeys [START_REF] Ferrari | Mirror neurons responding to observation of actions made with tools in monkey ventral premotor cortex[END_REF]. fMRI has identified regions of premotor cortex (both classic BA6 and BA44) and inferior parietal areas that are active during both action observation and execution [START_REF] Aziz-Zadeh | Congruent embodied representations for visually presented actions and linguistic phrases describing actions[END_REF]Buccino et al. 2004;[START_REF] Carr | Neural mechanisms of empathy in humans: A relay from neural systems for imitation to limbic areas[END_REF][START_REF] Grèzes | Activations related to "mirror" and "canonical" neurons in the human brain: An fMRI study[END_REF][START_REF] Iacoboni | Cortical Mechanisms of Human Imitation[END_REF][START_REF] Leslie | Functional imaging of face and hand imitation: Towards a motor theory of empathy[END_REF][START_REF] Tanaka | Cortical involvement for action imitation of hand/arm postures versus finger configurations: An fMRI study[END_REF][START_REF] Vogt | Prefrontal involvement in imitation learning of hand actions: Effects of practice and expertise[END_REF], even if the more ancient studies have been criticized in term of methodology (e.g. some of them were lacking of a real execution part to compare with action observation [START_REF] Turella | Mirror neurons in humans: consisting or confounding evidence[END_REF]. Overlapping responses to action observation and execution have been found in single-subject analyses of unsmoothed data [START_REF] Gazzola | The observation and execution of actions share motor and somatosensory voxels in all tested subjects: Single-subject analyses of unsmoothed fMRI data[END_REF], confirming that the foregoing reports are not artifacts of group averaging [START_REF] Cook | Mirror Neurons: From Origin to Function[END_REF].

In humans, both goal-directed actions with the object present and goal-directed pantomimed actions [START_REF] Buccino | Action observation activates premotor and parietal areas in a somatotopic manner: an fMRI study[END_REF][START_REF] Montgomery | Communicative hand gestures and objectdirected hand movements activated the mirror neuron system[END_REF] appear to involve the MN system, as do communicative actions. [START_REF] Montgomery | Communicative hand gestures and objectdirected hand movements activated the mirror neuron system[END_REF] performed a fMRI experiment in which participants viewed, imitated and produced communicative hand gestures and object-directed hand movements. The observation and execution of both types of hand movements activated the MN system (IPL and frontal operculum) to a similar degree. [START_REF] Chong | fMRI Adaptation Reveals Mirror Neurons in Human Inferior Parietal Cortex[END_REF] identified movementselective MN during observation and execution of actions involving the pantomimed use of objects [START_REF] Chong | fMRI Adaptation Reveals Mirror Neurons in Human Inferior Parietal Cortex[END_REF].

A fMRI study in humans [START_REF] Buccino | Action observation activates premotor and parietal areas in a somatotopic manner: an fMRI study[END_REF] has shown that the observation of actions performed with the hand, the mouth and the foot leads to the activation of different sectors of Broca's area and premotor cortex. This activation is related to the effector involved in the observed action, following a somatotopic pattern which resembles the classical motor cortex homunculus. Therefore, some authors [START_REF] Rizzolatti | Language within our grasp[END_REF][START_REF] Buccino | Functions of the Mirror Neuron System: Implications for Neurorehabilitation[END_REF][START_REF] Tettamanti | Listening to action-related sentences activates fronto-parietal motor circuits[END_REF] have claimed that there is a homology between the motor related part of Broca's region, localized in the opercular portion of the inferior frontal premotor cortex (mainly in area 44 of Brodmann) and the monkey area F5 (see Figure 13). As already cited, however, a recent study have raised doubts about the presumed matching between the Broca's area and F5. [START_REF] Cerri | The mirror neuron system and the strange case of Broca's area: Broca is Not Part of Mirror Neuron System[END_REF].

Figure 13: Cytoarchitectonic map of the caudal part of the monkey frontal lobe and possible homologies with human frontal cortex

Similar colors in A and B indicate areas with anatomical and functional homologies. Brain regions colored yellow are areas with anatomical and functional homologies, mostly related to orienting behavior; areas colored red also share anatomical and functional homologies and are mostly related to interactions with the external world. The homology is based on cytoarchitectonics, electrical stimulation and sulci embryology (from [START_REF] Rizzolatti | Language within our grasp[END_REF] As far as more posterior areas of MN human system are concerned, a specific sector of human IPL (left anterior supramarginal gyrus -aSMG-) would be a region unique to hominid evolution as it is specifically activated in humans, but not monkeys, during observation of tool use (Peeters, et al., 2009, Figure 14). [START_REF] Molenberghs | The role of the superior temporal sulcus and the mirror neuron system in imitation[END_REF], to investigate the role of the MN system in imitation used fMRI to examine patterns of neural activity under four different conditions: passive observation of a pantomimed action, imitation of an observed action, execution of an action in response to a word cue and selfselected execution of an action. They employed pantomimed actions to avoid brain activity associated with object processing that has been found in studies of object directed actions [START_REF] Buccino | Action observation activates premotor and parietal areas in a somatotopic manner: an fMRI study[END_REF]. A network of cortical areas, including the left supramarginal gyrus, left superior parietal lobule, left dorsal premotor area and bilateral STS, was significantly active across all four conditions. The STS is strongly associated with activation of MN areas in humans [START_REF] Saxe | A region of right posterior superior temporal sulcus responds to observed intentional actions[END_REF], even if most Authors do not consider it a real MN area because it is not constantly activated for action execution [START_REF] Aziz-Zadeh | Congruent embodied representations for visually presented actions and linguistic phrases describing actions[END_REF]. As already noted in the description of studies in monkey, STS is considered by these Authors to provide a visual description of the action that is critical for the process of imitation [START_REF] Nishitani | Temporal dynamics of cortical representation for action[END_REF][START_REF] Carr | Neural mechanisms of empathy in humans: A relay from neural systems for imitation to limbic areas[END_REF][START_REF] Miall | Connecting mirror neurons and forward models[END_REF] According to another study [START_REF] Montgomery | Communicative hand gestures and objectdirected hand movements activated the mirror neuron system[END_REF], STS could be crucial in social communication [START_REF] Allison | Social perception from visual cues: role of the STS region[END_REF]. In fact, the Authors found significant activation in the STS and MN system for the observation, imitation and production of both object-directed hand movements and communicative hand gestures. They also demonstrated increased activation in the STS for the production of communicative hand gestures compared to object-directed hand movements.

An extensive quantitative metanalysis [START_REF] Molenberghs | Brain regions with mirror properties: A meta-analysis of 125 human fMRI studies[END_REF] has analyzed fMRI data from 125 studies. It appears from this review that human MN areas are localized in the inferior frontal gyrus, the ventral premotor cortex, the IPL (which are considered "classical" MN areas and are expected to be part of the MN system based on studies in monkeys) but also in the primary visual cortex, in the cerebellum and of the limbic system (Figure 15). The Authors underline that there are additional activation areas in different studies due to the sensorial modality of the stimulus presentation and that in only 30% of the studies there is an effective comparison between an observation and an execution condition.

Figure 15: [START_REF] Molenberghs | Brain regions with mirror properties: A meta-analysis of 125 human fMRI studies[END_REF] Overview of all significant clusters in the quantitative metaanalysis (activation likelihood estimation) analysis of the 125 human fMRI studies in which the authors attributed their findings to mirror system functioning.

Recently, repetition suppression protocols have been used to provide evidence of mirror populations encoding visual and motor representations of the same action [START_REF] Cook | Mirror Neurons: From Origin to Function[END_REF]. These paradigms exploit the logic that repeated stimulus presentation or action execution causes a decrease in neural responses [START_REF] Grill-Spector | Repetition and the brain: Neural models of stimulus-specific effects[END_REF]. Action observation followed by execution of the same action, or vice versa, elicits repetition suppression in inferior parietal regions [START_REF] Chong | fMRI Adaptation Reveals Mirror Neurons in Human Inferior Parietal Cortex[END_REF][START_REF] Lingnau | Asymmetric fMRI adaptation reveals no evidence for mirror neurons in humans[END_REF]) and in premotor areas [START_REF] Kilner | Evidence of Mirror Neurons in Human Inferior Frontal Gyrus[END_REF][START_REF] Lingnau | Asymmetric fMRI adaptation reveals no evidence for mirror neurons in humans[END_REF]. [START_REF] De La Rosa | fMRI Adaptation between Action Observation and Action Execution Reveals Cortical Areas with Mirror Neuron Properties in Human BA 44/45[END_REF] designed a fMRI study to provide evidence for the location of motor-visual units in humans by attempting to minimize methodological constraints. They wanted to reduce the effect of a priori assumptions about the location of MN by conducting a whole-brain analysis. Specifically, they combined across-modal adaptation paradigm using actions that differed mainly in their object-directedness with a whole-brain analysis for the identification of motor-visual areas. They further checked these voxels for their sensitivity to motor and visual stimulation. The specific location of MN voxels was associated with BA44 and BA45. Thus, this study would demonstrate that part of human IFG, specifically BA 44/45, has BOLD response characteristics very similar to monkey's area F5.

fMRI/neurophysiological techniques combined

Some groups have tried to correlate neurophysiological and fMRI data in the study of MN. Braadbaart et al., 2013 used a manual imitation paradigm to look at correlations between μ rhythm and BOLD response by recording sequential EEG and fMRI measures. They found that μ power modulation, defined as μ power changes between conditions, correlated negatively with BOLD response in putative MN areas: right inferior parietal lobe, premotor cortex and inferior frontal gyrus. Thanks to μ suppression they have also identified a range of structures that modulate motor preparation activities and are sensitive to visual input, including but not restricted to the human analogue of the MN system cluster (bilateral cerebellum, left medial frontal gyrus, right temporal lobe and thalamus [START_REF] Braadbaart | Do mirror neuron areas mediate mu rhythm suppression during imitation and action observation[END_REF].

Neuropsychological tests alone or combined with other techniques

Neuropsychological tests have been rarely included in studies on MN (with the exclusion of the aim to evaluate cognitive functions of participants).

A study on patients with stroke [START_REF] Fazio | Encoding of human action in Broca's area[END_REF]) selected a population with lesion of the Broca area who were aphasic but not apraxic and not demented. Patients were asked to reconstruct the correct sequence of human actions or physical events (control condition): they exhibited a clear difficulty in action sequencing in comparison with a good performance in sequencing physical events. As Broca area in human has been claimed to be part of the MN system (Buccino et al., 2004;[START_REF] Pobric | Action understanding requires the left inferior frontal cortex[END_REF], these results suggest an involvement of MN in understanding action meaning.

The same conclusion can be inferred by a fMRI experiment in which participants listened to sentences describing actions performed with the mouth, the hand or the leg. Abstract sentences were used as control condition. Listening to action-related sentences activated a fronto-parietal-temporal network including Broca's area, the premotor cortex, the inferior parietal lobule, the intraparietal sulcus and the posterior middle temporal gyrus [START_REF] Tettamanti | Listening to action-related sentences activates fronto-parietal motor circuits[END_REF]. In another work [START_REF] Hauk | Somatotopic Representation of Action Words in Human Motor and Premotor Cortex[END_REF] reading action words referring to face, arm or leg actions differentially activated areas adjacent to respectively motor areas.

Putative contributions of the human MN system to the perception of social information have been assessed by [START_REF] Perry | Feeling" the pain of those who are different from us: Modulation of EEG in the mu/alpha range[END_REF] measuring the suppression of EEG oscillations in the mu/alpha, beta and low-gamma ranges while participants processed social information revealed by point-light videoclips of human motion. Participants were instructed to distinguish the intention, the emotion, or the gender of a moving image of a person. Relative to a baseline presenting a nonbiological but meaningful motion display, all three biological motion conditions reduced the EEG amplitude in the mu/alpha and beta ranges, but not in the low-gamma range. Suppression was larger in the intention than in the emotion and gender conditions, with no difference between the latter two. The suppression in the intention condition was negatively correlated with a measure of empathy (EQ), revealing that participants high in empathy scores manifested less suppression. This result, which is opposite to what expected, has been tentatively explained by the Authors as due to the fact that people higher in empathy do not need to simulate the other's motor acts for such tasks (which may be trivial for them). [START_REF] Mehta | Mirror neuron dysfunction in schizophrenia and its functional implications: a systematic review[END_REF] used two questionnaires to evaluate social cognition in schizophrenia patients: the scores were positively correlated with mirror activity evaluated by TMS (they used TMS paradigms of eliciting MEP-in the right first dorsal interosseous -FDI-while the subjects observed a goal-directed action involving the FDI -actual action and its video-and a static image). The difference in the amplitude of the MEP while they observed the static image and the action provided a measure of MN activity. [START_REF] Alaerts | Functional Organization of the Action Observation Network in Autism: A Graph Theory Approach[END_REF], in a study on teenagers and young adults affected by autism, demonstrated a positive correlation between a cognitive task (recognizing movements and emotions of a computergenerated silhouette) and resting-state fMRI connectivity of the superior parietal lobule.

Finally, in a study on patients with amyotrophic lateral sclerosis (ALS) [START_REF] Jelsone-Swain | Action Processing and Mirror Neuron Function in Patients with Amyotrophic Lateral Sclerosis: An fMRI Study[END_REF] evaluated the integrity of MN system with a fMRI task of observation and execution of actions and a task of action understanding. Patients were also submitted to the Read the Mind in the Eyes (RME) test, which assesses a person's ability to infer the emotions of others by examining pictures of facial eye expressions. Performance in action understanding was positively correlated with a better RME test performance (see also the paragraph 2.2.2.2.1 for further details on this study).

Mirror Neurons functions in humans ▪ Recognizing actions of others

The first function attributed to MN in humans has been recognizing actions performed by other people. In a TMS study [START_REF] Fadiga | Motor facilitation during action observation: a magnetic stimulation study[END_REF] subjects were submitted to stimulation during observation of grasping acts, afinalistic movements and static objects observation. Evoked potentials of hand muscles were more marked during grasping observation, even if they were also present during observation of afinalistic movements. The most important point is the fact that evoked potentials were present in muscles exactly involved in the observed act: therefore observing a motor act had stimulated an efferent response conserving the aim of the act.

Another emblematic study has been conducted with fMRI on patients with upper limbs aplasia (Gazzola, et al., 2007;Figure 16): the observation of manual grasping by subjects that never used hands activated MN at the same extent than acts having the same aim and performed by the subjects with the mouth or the foot.

▪ Interpreting action intention

The next step in the study of MN function has been to verify whether they were also involved in interpreting the intention embedded in the action. [START_REF] Iacoboni | Grasping the intentions of others with one's own mirror neuron system[END_REF] performed a fMRI study where participants watched three kinds of stimuli: grasping hand actions without a context, context only (scenes containing objects), and grasping hand actions performed in two different contexts. In the latter condition the context suggested the intention associated with the grasping action (either drinking or cleaning: see Figure 17). Actions embedded in contexts, compared with the other two conditions, yielded a significant signal increase in the posterior part of the inferior frontal gyrus and the adjacent sector of the ventral premotor cortex where hand actions are represented. The Authors concluded that premotor MN areas are also involved in understanding the intentions of others. [START_REF] Iacoboni | Grasping the intentions of others with one's own mirror neuron system[END_REF]

Figure 17: Examples of stimuli used in the study of

. The ''before tea'' context suggested the intention of drinking (upper row), and the ''after tea'' context suggested the intention of cleaning (lower row). Whole-hand prehension (displayed in the upper row of the Intention column) and precision grip (displayed in the lower row of the Intention column) were presented an equal number of times in the ''drinking'' Intention clip and the ''cleaning'' Intention clip.

Other studies have confirmed this hypothesis. An American group (De C. Hamilton & Grafton, 2008) conducted a fMRI experiment to study actions with the same motor parameters but different physical outcomes, that is different intentions, e.g. the stimulus was represented by a video with a hand which opened or closed a box with different movements (a box with a sliding lid can be opened or closed by either pushing the lid with a finger or pulling with both finger and thumb). Videos were repeated to study adaptation of the activated areas. A stronger response to novel outcomes than to repeated outcomes was found in regions throughout the expected frontoparietal action circuits (particularly right IPL and the right IFG extending to the inferior frontal sulcus). In these regions, the robust response to novel outcomes was suppressed when the same outcome was repeated on a second trial, regardless of the hand action. This pattern of data suggests that outcomes rather than motor parameters are encoded in neuronal populations within these regions. Therefore, MN system would allow humans to understand the physical consequences of actions in the world and the intentions underlying those actions.

▪ Motor imitation and motor learning

The MN system has been shown to be involved in imitational learning of familiar elementary movements. [START_REF] Iacoboni | Cortical Mechanisms of Human Imitation[END_REF] demonstrated the activation of the inferior frontal cortex (pars opercularis) and of superior parietal lobule during the observation, spontaneous execution and imitation of a motor task in a fMRI study. The involvement of the pars opercularis of the frontal lobe in imitation has been also confirmed by a TMS study [START_REF] Heiser | The essential role of Broca's area in imitation[END_REF] Molenberghs et al. ( 2010) investigated the role of the MN system in imitation using fMRI to examine patterns of neural activity under four different conditions: passive observation of a pantomimed action (e.g., hammering a nail); (2) imitation of an observed action; (3) execution of an action in response to a word cue; and (4) self-selected execution of an action. A network of cortical areas, including the left supramarginal gyrus, left superior parietal lobule, left dorsal premotor area and bilateral STS, was significantly active across all four conditions. Buccino et al. (2004) have also proposed a role of the MN system in the acquisition of new motor skills. In a fMRI study, they recruited subjects which have never played a guitar. Subjects watched a video showing a music teacher which played some chords. After a pause, they had to reproduce chords. Control conditions were represented by: 1) observing the video without reproducing chords; 2) playing accords spontaneously 3) observing a video with a guitar alone, before to imitate; 4) executing movements not related to music, after chords observation. Watching to the video and then imitating was the condition which activated MN system the most, while observation not followed by imitation activated the MN circuit (IPL and the posterior part of the inferior frontal gyrus plus the adjacent motor cortex) at a lesser extent. During the pause, Buccino et al. observed the activation of BA46 in the frontal cortex and of regions of the anterior mesial cortex.

The Authors have advanced the view that in the acquisition of new motor abilities, the familiar elements of the observed novel complex movements would generate resonant activity within the MN system. By this mechanism, the selection of appropriate neuronal activation patterns underlying the intended movement would be greatly facilitated, and the recombination of elementary overlearned movements into movements of greater complexity could be more easily accomplished (Buccino et al., 2004). The activation of BA46 and mesial anterior cortex before MN system activation would suggest a possible control action of these areas on MN during motor learning. BA46 has been classically associated to working memory [START_REF] Levy | Segregation of working memory functions within the dorsolateral prefrontal cortex[END_REF], but according to other authors would be also responsible for selecting the target of the response [START_REF] Passingham | Specialisation within the prefrontal cortex: the ventral prefrontal cortex and associative learning[END_REF][START_REF] Rowe | The prefrontal cortex: Response selection or maintenance within working memory? 5th[END_REF].

In imitation-based motor learning, the formation of lasting motor memories was thought in the past to be provided through the physical practice of movements. According to this new view, in this kind of learning the MN system enables motor learning through facilitating the physical performance of the appropriate training movements. [START_REF] Mattar | Motor learning by observing[END_REF] used kinematic analyses to show that the acquisition of complex motor behaviors is facilitated by previous observation of subjects learning the novel task. Included subjects learned to manipulate a robotic arm through video observation.

Other subjects observed a video with a different movement or did not observe the action. Measuring kinematic parameters of the robotic arm and movement accuracy, the Authors demonstrated that it was possible to learn through action observation alone. The same group used a similar protocol with the association of a resting state fMRI study performed before and after motor learning [START_REF] Mcgregor | Changes in visual and sensory-motor resting-state functional connectivity support motor learning by observing[END_REF]. They observed a modification of the medio-temporal visual area (V5), cerebellum and the primary motor (M1) and sensory cortices (S1). According to the Authors, cerebral areas altered after motor learning belong to an action-observation network which also includes the MN system. They also underline that some studies suggest a role for cerebellum in action observation [START_REF] Calvo-Merino | Seeing or Doing? Influence of Visual and Motor Familiarity in Action Observation[END_REF][START_REF] Gazzola | The observation and execution of actions share motor and somatosensory voxels in all tested subjects: Single-subject analyses of unsmoothed fMRI data[END_REF]. According to Oh et al. (2013, see Figure 18), "imitation learning is accomplished through a two-phase process combining action observation and imitation, which is voluntarily triggered by the prefrontal cortex (specifically in the rostral part).

Figure 18: Model overview for the human MN system based on a model framework incorporating cerebellum, the intraparietal sulcus (IPS) and the superior parietal lobule (SPL), according to Oh et al., 2013. IPS/SPL play a critical role in the transformation between frames of reference, scales, or viewpoints. For the sake of clarity, the STS and its related connections are not shown. The imitator either observes or executes the action based on the current goal/intention. The yellow component (IPS/SPL) generates the neural signal required to process the frame of reference, scaling, and viewpoint transformation. The two gray components (IFG and IPL) indicate the core MN system.

During the observation phase, the kinematic (i.e., visual information) of the demonstrator is sent to the intraparietal sulcus and the superior parietal lobule, which transforms the visual information into the imitator's egocentric frame of reference, anthropometry, and viewpoint. The transformed observed action updates the IFG by means of mapping from visual to motor representations (i.e., inverse computation), which is then employed to imitate the observed action. Simultaneously, an efference copy of the motor plan is sent to the IPL that would predict the sensory consequences of the corresponding action (i.e., forward computation). Meanwhile, the cerebellum (CB) provides the prediction error for the IFG and the IPL to adjust their internal models". [START_REF] Cohen | Formation of a motor memory by action observation[END_REF] demonstrated that a specific motor memory is formed by observation in M1 (where MN has been also described), one that is like that induced by practicing movements, providing another evidence indicating that the MN system may be involved in generating lasting mnemonic representations of movements, a likely prerequisite of motor learning. After observation of thumb movements directed away from the baseline movement direction, the probability of TMS-evoked movements to fall into the training target zone increased, the acceleration of all TMS-evoked thumb movements was changed toward the direction of the observed movements, and the balance of corticomuscular excitability was altered in favor of the agonist of the observed movements.

▪ The simulation theory

The discovery of MN has given a biological complement to the simulation theory, that is the relatively recent idea that actions involve both an overt and a covert stage [START_REF] Jeannerod | Mental imaging of motor activity in humans[END_REF][START_REF] Jeannerod | Neural Simulation of Action: A Unifying Mechanism for Motor Cognition[END_REF]. The covert stage is a sort of cognitive representation of the future, and includes the goal of the action, the means to reach it, and its consequences on the organism and the external world. Covert and overt stages represent a continuum, such that every overtly executed action implies the existence of a covert stage, whereas the cognitive stage of action does not necessarily turn out into an overt action. The cognitive equivalent of action, in fact, includes a series of behaviorally defined states, which can be conscious or nonconscious: imagined action, prospective action judgments, perceptually based decisions, observation of graspable objects, observation of actions performed by others, and even action in dreams [START_REF] Jeannerod | Neural Simulation of Action: A Unifying Mechanism for Motor Cognition[END_REF]. These states can be studied through neuroimaging (fMRI) and neuropshysiological techniques [START_REF] Vogt | Multiple roles of motor imagery during action observation[END_REF].

EMBODIED COGNITION AS A LINK BETWEEN ACTING AND THINKING, MIRROR NEURONS AND COGNITIVE FUNCTIONS

"Embodied Cognition" is a new concept developed in the last two decades, which is strictly linked to the pathway of research previously leading to the simulation theory, and to the idea called "motor cognition": this last theory proposes that thinking is not only manipulating abstract symbol or logicodeductive reasoning, but also includes action simulation (see [START_REF] Jeannerod | Mental imaging of motor activity in humans[END_REF][START_REF] Jeannerod | Neural Simulation of Action: A Unifying Mechanism for Motor Cognition[END_REF][START_REF] Jeannerod | Motor cognition: What actions tell to the self[END_REF]. In the same vein, the action-perception coupling hypothesis postulates that a part of cognition results from the coupling between action and perception representations, and correspond to implicit action simulation (or "motor resonance") instead of explicit recall of abstract symbols [START_REF] Jeannerod | Motor cognition: What actions tell to the self[END_REF][START_REF] Boulenger | Subliminal display of action words interferes with motor planning: a combined EEG and kinematic study[END_REF][START_REF] Pulvermüller | Active perception: sensorimotor circuits as a cortical basis for language[END_REF][START_REF] Rizzolatti | The functional role of the parieto-frontal mirror circuit: interpretations and misinterpretations[END_REF][START_REF] Pulvermüller | Motor cognition-motor semantics: Action perception theory of cognition and communication[END_REF] see also Figure 19 from [START_REF] Uithol | Understanding motor resonance[END_REF] including the concepts of intrapersonal and interpersonal resonace).

Figure 19:

Intrapersonal and intrapersonal "motor resonance" according to [START_REF] Uithol | Understanding motor resonance[END_REF] In fact, in the past, psychology and neuropsychology have mainly conceived cognitive abilities as higher-level supervisor functions exploiting perception and action as two separated slave systems: according to this idea, specialized sensors provide sensory input to the cognitive computer for successive peripheral motor implementations [START_REF] Fodor | The psychological unreality of semantic representations[END_REF][START_REF] Hurley | Perception and action: alternative views[END_REF]. This view also specifies the subcomponents of cognition: language perception and production, attention, memory, emotion, and executive functions (decision, planning and conceptual thought). These high-level systems and the two low-level systems (modality-specific perception: visual, auditory, olfactory etc.; motor movement and action) are seen as functionally independent to a degree, although some interaction between them is generally acknowledged. Cognitive neuroscience relates these mental domains to brain structures and led to proposals to map each of the cognitive modules onto one or more brain regions (Pülvermuller, 2014, Figure 20).

This view has been characterized as "disembodied cognition" model [START_REF] Johnson | Embodied understanding[END_REF], where cognition is calibrated on the basis of a definition of intelligence not as a biological property, but as a computational mechanism. In such frame, cognition is made of explicit reasoning and it drives the body using meta-representations. However, it is not free of subjective judgment and is strongly culture-dependent. An instance of this is the notion of "executive function" used in psychology to describe motor planning: a central decision-making system supposed to be located in the frontal lobes and separated from sensorimotor areas [START_REF] Baddeley | Working memory and executive control[END_REF], elaborates and send abstract instructions to the body actuators located at the end of the process. Following this flow chart independent from any motor subjective constraints, an algorithm transposable on any kind of hardware would pilot the body whatever its individual biomechanical assets. On the other hand, neurophysiology has mainly focused on peripheral phenomena, e.g., muscle activities under reflex control [START_REF] Magnusson | Human tendon behaviour and adaptation, in vivo[END_REF] or more recently limbs' kinematic and kinetic of voluntary movement [START_REF] Goodman | Elucidating Sensorimotor Control Principles with Myoelectric Musculoskeletal Models[END_REF][START_REF] Nordin | Biomechanics and neural control of movement, 20 years later: what have we learned and what has changed[END_REF], with a limited interest for abstract and private mental representations. Several reasons may explain such divergence. Among them it can be briefly mentioned the over specialization of modern science (see [START_REF] Wehrwein | The Mind Matters: Psychology as an Overlooked Variable Within Physiology Studies[END_REF] and its academic apartheid: this is characterized by a strong disciplinary division of labor and consequently of methods and experimental models (animal vs human; child vs adult; microscopic vs macroscopic…) that produces very different and sometimes incompatible truths [START_REF] Kotchoubey | Methodological Problems on the Way to Integrative Human Neuroscience[END_REF].

Nevertheless, inside the multitude of ways to explain human and animal behaviors there is a growing body of experimental evidences suggesting that cognition and action production are strongly dependent and that motor representations are present at each level of cognitive (language, memory, spatial and temporal representations, social cognition) processes [START_REF] Barsalou | Perceptual symbol systems[END_REF][START_REF] Wilson | Six views of embodied cognition[END_REF][START_REF] Noe | Action in Perception[END_REF][START_REF] Gallagher | How the Body Shapes the Mind[END_REF][START_REF] Wheeler | Reconstructing the Cognitive World[END_REF][START_REF] Gavazzi | Time perception of visual motion is tuned by the motor representation of human actions[END_REF]. Otherwise, in contrast to the classical "five-sense theory", it is now accepted that perception is an active process: this process predicts sensory feedback instead of collecting independent input via isolated sensory organs passively waiting for external stimuli [START_REF] Hamilton | Kinematic cues in perceptual weight judgement and their origins in box lifting[END_REF][START_REF] Pezzulo | Navigating the Affordance Landscape: Feedback Control as a Process Model of Behavior and Cognition[END_REF].

A rapid inspection of the literature showing the presence of the motor system at all level of cognition confirms such paradigm shift, equally perceptible for numerous mental processes traditionally investigated as explicit logico-deductive reasoning. For instance, a specific activation of the motor system during learning improves the consolidation and/or the retrieval of memories [START_REF] Cherdieu | Make Gestures to Learn: Reproducing Gestures Improves the Learning of Anatomical Knowledge More than Just Seeing Gestures[END_REF][START_REF] Trevisan | A moving story: Whole-body motor training selectively improves the appraisal of action meanings in naturalistic narratives[END_REF], and motor affordances play a role during object retention [START_REF] Lagacé | When motor congruency modulates immediate memory for objects[END_REF]. Superimposition of cognitive onto motor processes is also supported by studies showing that social cognition ability is strongly embodied. Particularly, action understanding and mind reading processes ("Theory of Mind" -ToM) would not result exclusively from explicit mental inference but would be based on a mapping of visual input onto correspondent internal motor representations [START_REF] Rizzolatti | Neurophysiological mechanisms underlying the understanding and imitation of action[END_REF]; see also Ponari et al.2012[START_REF] Baumeister | When the mask falls: the role of facial motor resonance in memory for emotional language[END_REF], and Ferrari, 2014 for reviews onto the role of motor resonance during encoding and retrieval of emotional information). In this frame, the brain continuously anticipates what should be done next, all the way down to unfolding actions themselves, in contrast to the classical perception-cognition-action loop, a pure serial account of cognition that cannot work in real time. Embodied cognition stresses the coupled nature of thinking and acting: perception and action are directly relevant for our thinking, and it is a mistake to regard them as separate. [START_REF] O'regan | Solving the "real" mysteries of visual perception: the world as an outside memory[END_REF][START_REF] Van Gelder | The distinction between mind and cognition[END_REF][START_REF] Clark | Being There: Putting Brain, Body and World Together Again[END_REF][START_REF] Barsalou | Perceptual symbol systems[END_REF][START_REF] Wilson | Six views of embodied cognition[END_REF][START_REF] Noe | Action in Perception[END_REF][START_REF] Gallagher | How the Body Shapes the Mind[END_REF][START_REF] Wheeler | Reconstructing the Cognitive World[END_REF]. Il also considers cognition processes as resulting from brain and body co-evolution and from successive bodyenvironment interactions ("enactive perspective"; [START_REF] Ziemke | The body of knowledge: On the role of the living body in grounding embodied cognition[END_REF].

At last, recent investigations on supposed high-level cognitive processes (e.g., language) reveal the basic role of the motor system. In particular, according to the "embodied semantics", the meaning of a concept is represented in the brain by the same neuronal networks implicated in the motor and sensory experiences associated to it [START_REF] Perlovsky | Mirror neurons, language, and embodied cognition[END_REF]. According to this theory, for example, a prediction is that understanding sensori-motor concepts leads to activation of sensori-motor cortices. So, when people read about hand and foot actions, parts of the motor cortex involved in moving the hands and the feet are activated (e.g., [START_REF] Hauk | Somatotopic Representation of Action Words in Human Motor and Premotor Cortex[END_REF][START_REF] Tettamanti | Listening to action-related sentences activates fronto-parietal motor circuits[END_REF]; see Figure 21). In a most general way, Embodied Cognition views cortical neurons (and particularly the MN system) linking together knowledge about actions and perceptions not only to integrate perception in action planning and execution but, furthermore, as a brain basis for a wide range of higher cortical functions, including attention, meaning and concepts, goals and intentions, and even communicative social interaction [START_REF] Pulvermüller | Motor cognition-motor semantics: Action perception theory of cognition and communication[END_REF]. In fact, the evolution of the brain, and its volume increase, is associated to more complex behavior, which results in more sensorimotor sophisticated response to environmental constraints, an idea highly consensual in evolutionists [START_REF] Northcutt | Understanding Vertebrate Brain Evolution[END_REF]Krubitzer 2007).

Figure 21:

Activation peaks in left primary motor and premotor cortices reported by some of the fMRI studies that have probed the neural substrates of the motor features of verbs and sentences encoding leg/foot actions, arm/hand actions, and mouth actions (From Kemmerer et al., 2012; in the original article, the figure was created and kindly provided by Javier Gonzalez Castillo)

We will now briefly list the experimental evidences which link MN, considered as the neural substrates allowing action to perception coupling, to human cognitive functions, mainly intersubjectivity, language and memory in normal subject.

Inter-subjectivity and social cognition

A large body of experimental evidences suggest that the MN system contributes to understanding not only other people's actions but also their emotions (Gallese et al., 2003[START_REF] Gallese | A unifying view of the basis of social cognition[END_REF]Wicker, 2003;Agnew et al., 2007;Pineda and Hecht, 2009). In this sense, a crucial role of MN would be to foster empathy, which is defined as a sense of similarity between the feelings one experiences and those expressed by others. Empathy means not only to understand other people's emotional state, but to incorporate in his/her own body the experience of that state ("embodiement": [START_REF] Singer | Empathic neural responses are modulated by the perceived fairness of others[END_REF][START_REF] Singer | Empathic neural responses are modulated by the perceived fairness of others[END_REF]: it is thus considered as an affective resonance [START_REF] Decety | The functional architecture of human empathy[END_REF][START_REF] Lamm | What Are You Feeling? Using Functional Magnetic Resonance Imaging to Assess the Modulation of Sensory and Affective Responses during Empathy for Pain[END_REF] providing the way to shift from the third to the first-person perspective and consecutively to predict others' behavior. Studies on emotional states demonstrate that a large-scale neural network-including the ventral premotor cortex and the inferior frontal gyrus (two putative mirror neuron areas), in addition to classical cerebral regions involved in feeling emotions, such as the anterior insula and the amygdala-is active for instance during facial expression observation and imitation [START_REF] Carr | Neural mechanisms of empathy in humans: A relay from neural systems for imitation to limbic areas[END_REF]Rizzolatti & Craghiero, 2004;Iacoboni, 2009;Budell et al., 2010;[START_REF] Grosbras | Brain networks involved in viewing angry hands or faces[END_REF].

In children, activity in the frontal component of the MN system, elicited by observation and imitation of emotional expressions, correlates with measures of empathic behavior and interpersonal skills (Pfeifer et al., 2008). Likewise, it is now proposed that the core deficits of autism, which are motor, language and social impairments, are indicative of dysfunction of the MN system ( Williams et al., 2001;[START_REF] Nishitani | Abnormal imitation-related cortical activation sequences in Asperger's syndrome[END_REF]Iacoboni & Dapretto, 2006;[START_REF] Dapretto | Understanding emotions in others: mirror neuron dysfunction in children with autism spectrum disorders[END_REF][START_REF] Bernier | The Role of Mirror Neuron Dysfunction in Autism[END_REF]Fishman et al., 2014), and more and more works suggest a role of MN in schizophrenia (Kato et al., 2011;[START_REF] Schilbach | Differential patterns of dysconnectivity in mirror neuron and mentalizing networks in schizophrenia[END_REF][START_REF] Saito | Impaired white matter connectivity between regions containing mirror neurons, and relationship to negative symptoms and social cognition, in patients with first-episode schizophrenia[END_REF]. However, lack of empathy is a characteristic of other neurological diseases, such as in FTD (Laforce, 2013;[START_REF] Kargieman | Motor-language coupling in Huntington's disease families[END_REF] but also in AD [START_REF] Fernandez-Duque | Empathy in frontotemporal dementia and Alzheimer's disease[END_REF].

Language

According to Lieberman ( 2016), no brain mechanisms appear to be specific to speech or language. Rather, circuits linking the basal ganglia (a classical motor structure) with various areas of the prefrontal cortex, posterior cortical regions and other subcortical structures confer the ability to master and execute complex speech motor commands, and are active in linguistic tasks such as lexical retrieving and syntax comprehension. Moreover, a large body of data shows that the brain systems for language and action are heavily interwoven within each other. Hearing a word may automatically activate the motor system [START_REF] Gallese | Action representation and the inferior parietal lobule[END_REF], and performing actions may help us to understand words (Cartmill, et al.,2012). In the same vein, [START_REF] Tettamanti | Listening to action-related sentences activates fronto-parietal motor circuits[END_REF] demonstrated that listening to sentences describing actions performed with the mouth, the hand, or the leg activated a left frontoparieto-temporal network that included the pars opercularis of the inferior frontal gyrus (Broca's area), the intraparietal sulcus, and the posterior middle temporal gyrus, in a somatotopic manner. Based on these studies, as previously cited, it has been suggested that cerebral areas establishing a correspondence among performed and observed actions in monkeys (F5Area) match to those that are appointed to language production in humans (Broca's Area; [START_REF] Kohler | Hearing sounds, understanding actions: Action representation in mirror neurons[END_REF][START_REF] Iacoboni | Grasping the intentions of others with one's own mirror neuron system[END_REF][START_REF] Tettamanti | Listening to action-related sentences activates fronto-parietal motor circuits[END_REF][START_REF] Cooper | Broca's arrow: Evolution, prediction, and language in the brain[END_REF]), even if a recent study raised doubts about this presumed matching [START_REF] Cerri | The mirror neuron system and the strange case of Broca's area: Broca is Not Part of Mirror Neuron System[END_REF]. Other neuroimaging studies revealed areas in the human premotor cortex that activate both when participants observe actions being performed and when they read phrases relating to those actions [START_REF] Aziz-Zadeh | Congruent embodied representations for visually presented actions and linguistic phrases describing actions[END_REF]. Further, [START_REF] Hauk | Somatotopic Representation of Action Words in Human Motor and Premotor Cortex[END_REF] found a somatotopically-organized activation in the motor and premotor cortex when participants passively read action related words (i.e. leg-related action words lead to activations more medially than armor face-related action words, see Figure 22). Motor representations also play a role in language production: verb naming is facilitated by the degree of embodiment (characterized on the base of the bodily sense described by Borghi and Cimatti -2010-), but not by subjective imageability (Sidhu et al., 2014). All these studies have given support to the already cited theory of the "embodied semantics", according to which the meaning of a concept is represented in the brain by the same neuronal networks implicated in the motor and sensory experiences associated to it [START_REF] Perlovsky | Mirror neurons, language, and embodied cognition[END_REF]. Rizzolatti and others (2001) had already proposed a very tightly linked idea, the "direct matching hypothesis", according to which primates understand actions when they map their visual representations onto their correspondent internal motor representations. In other words, action, perception and understanding are not only the result of abstract processes relying only on visual representations. On the contrary, the observer's motor system is actively involved in this process, and the specific role of MN is to represent and possibly reenact actions in terms of their motor goal, in a bi-directional causal relationship allowing language comprehension [START_REF] Zarr | Language comprehension warps the mirror neuron system[END_REF].

If this theory is true, changing the motor system will causally affect language comprehension, and changing language comprehension will causally affect the motor system. [START_REF] Glenberg | Processing abstract language modulates motor system activity[END_REF] demonstrated half of the bi-directional link, namely that adapting the motor system through repeated literal action affects language comprehension. In their experiment, participants moved beans from a box to another for about 15min. For half of the participants, the direction of movement was from a location close to the participant to one further away, and for the other half the direction of movement was toward the body. This repeated action affected language comprehension: after repeated action in the Away direction, participants were slower to comprehend sentences describing action Away (e.g., "You give Alice the pizza"), and after repeated action Toward, participants were slower to comprehend sentences describing action Toward (e.g., "Alice gives you the pizza"). One possibility to explain this slowing is that the relevant action control system is fatigued. A second possibility is that the action control becomes specialized for the repeated movement. Then, when the action control system is asked to simulate a different movement, fewer neural resources are available. [START_REF] Zarr | Language comprehension warps the mirror neuron system[END_REF] demonstrated the other half of the bi-directional link: participants read blocks of multiple sentences where each sentence in the block described transfer of objects in a direction away or toward the reader. Following each block, adaptation was measured by having participants predict the endpoint of videotaped actions. The adapting sentences affected prediction of actions in the same direction, but only for videos of biological motion, and only when the effector implied by the language (e.g., the hand) matched the videos.

More generally, the role of MN system in evolutionary language development is recurrently proposed [START_REF] Rizzolatti | Language within our grasp[END_REF][START_REF] Fischer | Embodied language: a review of the role of the motor system in language comprehension[END_REF][START_REF] Meteyard | Visual motion interferes with lexical decision on motion words[END_REF]Chwilla et al., 2011, Fogassi and[START_REF] Fogassi | Cortical Motor Organization, Mirror Neurons, and Embodied Language: An Evolutionary Perspective[END_REF], see also Figure 23), even if it is still under discussion [START_REF] Caramazza | Embodied cognition and mirror neurons: a critical assessment[END_REF]. As an example, for [START_REF] Bonini | Evolution of Mirror Systems: A Simple Mechanism for Complex Cognitive Functions[END_REF] the MN system would be first exploited as a monitoring system for tracking one's own behavior, then by functioning as an extended recognition system matching one's own and other motor representations, and finally for contributing to speech perception and production in humans.

A critical review of the predictions of the action-perception circuits model and alternative theories in language, also providing discussion of some seemingly contradictory findings and of recent disputes about the role of MN and Embodied Cognition in language and communication can be found in [START_REF] Pulvermüller | Neural reuse of action perception circuits for language, concepts and communication[END_REF]; see also Figure 24)

Figure 23: Hand-arm gesture and vocalization, the language prototype (from [START_REF] Pollick | Ape gestures and language evolution[END_REF][START_REF] Pollick | Ape gestures and language evolution[END_REF][START_REF] Eisen | Tools and talk: An evolutionary perspective on the functional deficits associated with amyotrophic lateral sclerosis[END_REF]. A juvenile chimpanzee is reclaiming food taken away, by combining the reach out up begging gesture with a scream vocalization. [START_REF] Pulvermüller | Category-specific processing of color and form words in left fronto-temporal cortex[END_REF]) and e. by action words related to the face (green), hand (red) and leg (blue) as shown by a range of studies (Carota et al., 2012). f. Lesion in the white matter underlying the hand motor cortex in a patient with specific deficit in tool word recognition (from [START_REF] Dreyer | Is the motor system necessary for processing action and abstract emotion words? Evidence from focal brain lesions[END_REF] and g. in the motor and premotor cortex of a patient with specific action verb processing deficit (from [START_REF] Neininger | The right hemisphere's role in action word processing: a double case study[END_REF]. h. Semantic priming in the motor system, as revealed by EEG source localization. Face and leg motor regions, respectively, showed relatively reduced activity when action words were preceded by a body-part congruent action sound (from [START_REF] Grisoni | Somatotopic semantic priming and prediction in the motor system[END_REF]. i. Complex movements of the arms and feet impair the processing of arm-and leg-related words in healthy subjects (from Shebani and Pulvermüller, 2013). k-l. Semantic grounding of concrete and abstract symbols. Whereas a common set of sensorimotor features may be shared by the instantiations of concrete words such as "eye", and the corresponding neuronal elements may therefore strongly bind with the word form circuit (h), a pattern of family resemblance without feature overlap applies to the instantiations of an abstract term, thus leading to weaker correlation-based sensorimotor links but, interestingly, to a new combination of 'anchor' features, which may not be present in the environment [START_REF] Pulvermüller | Neural reuse of action perception circuits for language, concepts and communication[END_REF].

Memory

Several behavioral investigations support the idea of the embodied nature of memory processes. For instance, when normal subjects are asked to retain lists of objects in memory while performing a congruent or incongruent action with these objects, performing an incongruent action impaired memory performance, in comparison to congruent action. Interestingly, the manual experience with the object determines the amount of interference [START_REF] Yee | Manual experience shapes object representations[END_REF]. Further, accompanying words or phrases of a foreign language with gestures leads to better learning [START_REF] Macedonia | Bringing back the body into the mind: gestures enhance word learning in foreign language[END_REF]; retrieving autobiographical memories in body-congruent and body-incongruent positions relative to that of the original experience influences performance [START_REF] Dijkstra | Body posture facilitates retrieval of autobiographical memories[END_REF].

Neurophysiological approach similarly showed MN network involvement in imitational learning of familiar elementary movements [START_REF] Iacoboni | Cortical Mechanisms of Human Imitation[END_REF], and in the acquisition of new motor skills (Buccino et al., 2004;[START_REF] Mattar | Motor learning by observing[END_REF][START_REF] Gatti | Action observation versus motor imagery in learning a complex motor task: a short review of literature and a kinematics study[END_REF]. [START_REF] Cohen | Formation of a motor memory by action observation[END_REF] demonstrated that a specific motor memory similar to that induced by practicing movements is formed by observation. [START_REF] Gelbard-Sagiv | Internally Generated Reactivation of Single Neurons in Human Hippocampus During Free Recall[END_REF] showed, in patients with pharmacologically intractable epilepsy implanted with depth electrodes, that neurons in the medial temporal lobe are reactivated during spontaneous recall of previously seen audiovisual sequences (episodic memory). According to the Authors, these neurons could match the sight of actions of others with the memory of those same actions performed by the observer, in agreement with the idea that during action execution, a memory of the executed action is formed, and during action observation this memory trace is reactivated. The same group [START_REF] Mukamel | Single-Neuron Responses in Humans during Execution and Observation of Actions[END_REF], by recording extracellular activity, described neurons with mirror-like properties in the hippocampus, an important observation suggesting that in humans multiple neuronal systems might be endowed with mechanisms of mirroring: the functional significance of the mirror mechanism might vary according to the location of the MN, thus supporting different functions, memory included. Even if these data need to be confirmed by further studies, they open exciting perspectives for a novel interpretation of memory mechanisms.

AGING

In the current demographic context, aging and neurodegenerative diseases are well very known and discussed in the media as they become a very important societal issue. Interest has been rapidly growing in interventions which slow down the autonomy loss in elderly people. These interventions may also possibly prevent the onset of neurodegenerative diseases.

Aging is usually related to decline and losses of various kinds. Particularly, aging reduces the brain weight between 10 and 20%, and the cerebral blood flow between 30 and 40%. Shrinkage of prefrontal cortex, hippocampus, and basal ganglia [START_REF] Raz | Regional Brain Changes in Aging Healthy Adults: General Trends, Individual Differences and Modifiers[END_REF] is typically associated with a deterioration not only of cognitive functioning, which is seen in multiple domains, including memory, attention, decision-making, and cognitive control [START_REF] Brown | Aging and the neuroeconomics of decision making: A review[END_REF][START_REF] Fisk | Age-Related Impairment in Executive Functioning: Updating, Inhibition, Shifting, and Access[END_REF][START_REF] Luo | Aging and Memory: A Cognitive Approach[END_REF].

Decline is associated with a decrease in synthesis and binding of dopamine, serotonin and acetylcholine [START_REF] Wang | Comparison of two PET radioligands for imaging extrastriatal dopamine transporters in human brain[END_REF][START_REF] Volkow | Association between decline in brain dopamine activity with age and cognitive and motor impairment in healthy individuals[END_REF][START_REF] Schliebs | The cholinergic system in aging and neuronal degeneration[END_REF] and alterations in connectivity [START_REF] O'sullivan | Evidence for cortical "disconnection" as a mechanism of age-related cognitive decline[END_REF][START_REF] Madden | Cerebral white matter integrity mediates adult age differences in cognitive performance[END_REF]. Both functional (which reflects the organization of the brain in distinct performance-relevant networks) and structural (which represents the integrity of anatomical connections in white matter), connectivities have been demonstrated to change with aging. Structural degeneration has been found in the entire cerebral white matter with greatest deterioration in frontal areas, affecting whole brain structural network efficiency. With regard to functional connectivity, both higher and lower functional coupling has been observed in the aging compared to the young brain (Antonenko & Floel, 2013).

However, aging is not only related to some deterioration of cognitive functioning. Age-related motor decline is common and associated with a wide range of adverse health consequences. Motor impairment can include reduced gait speed, loss of muscle strength and bulk, and reduced balance, as well as dexterity. (Buchman & Bennett, 2011;[START_REF] Serbruyns | Bimanual motor deficits in older adults predicted by diffusion tensor imaging metrics of corpus callosum subregions[END_REF].

Several constructs based on assessments of different motor abilities have been used to document mild motor symptoms in old age, including sarcopenia, based on muscle bulk or mass and strength; physical frailty, based on grip strength, body composition, gait speed, fatigue and physical activity; parkinsonian signs, based on signs of bradykinesia, tremor, rigidity and parkinsonian gait; and various summary measures, based on testing for a wide range of common motor performances. [START_REF] Baumgartner | Epidemiology of Sarcopenia among the Elderly in New Mexico[END_REF][START_REF] Fried | Frailty in older adults: evidence for a phenotype. Cardiovascular Health Study Collaborative Research Group. The journals of gerontology[END_REF][START_REF] Stump | The metabolic syndrome: Role of skeletal muscle metabolism[END_REF]. Regardless of the motor measures that have been employed, most studies have demonstrated that mild motor symptoms are all associated with adverse health consequences, including all-cause mortality, as well as incident disability, and other outcomes, including the development of AD. Assessments that employ several motor measures may more accurately identify individuals at risk for adverse health consequences in old age (Buchman et al., 2011). These concepts will be further developed later in this chapter. In the early stages, the most common symptom is difficulty in remembering recent events. As the disease advances, symptoms include temporal and spatial disorientation, confusion, irritability, aggression, mood swings, trouble with language, visuospatial and executive functions. Gradually, motor and bodily functions are lost, ultimately leading to death [START_REF] Corey-Bloom | The ABC of Alzheimers Disease: Cognitive Changes and Their Management in Alzheimers Disease and Related Dementias[END_REF][START_REF] Grossberg | The ABC of Alzheimers Disease: Behavioral Symptoms and Their Treatment[END_REF].

Memory impairment is the most classic and pervasive feature of AD. Early in the disease course, recent episodic memories are most affected, while memories from the distant past are usually spared.

As the disease progresses, all aspects of episodic memory become affected. In contrast to episodic memory, working memory and semantic memory are compromised later in the disease course [START_REF] Apostolova | Alzheimer Disease[END_REF]. Implicit forms of memory, such as priming, conditioning and procedural memory are conserved until later stages (Thomas-Anterion and Laurent, 2006).

In everyday practice, AD diagnosis is still based in most cases on clinical criteria (National Institute on Aging and Alzheimer's Association-NIA-AA-criteria: [START_REF] Mckhann | The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease[END_REF]). However, biological markers of the disease are now available, and an influent scientific group has proposed to obligatory include these biomarkers in the diagnostic workup and definition (International Working Group-IWG criteria: [START_REF] Dubois | Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria[END_REF][START_REF] Dubois | Revising the definition of Alzheimer's disease: a new lexicon[END_REF][START_REF] Cummings | International Work Group Criteria for the Diagnosis of Alzheimer Disease[END_REF]: patients must show either pathophysiologic or topographic abnormalities characteristic of AD. Pathophysiologic markers include typical abnormalities in the cerebrospinal fluid (low amyloid ß peptide plus increased levels of tau or hyperphosphorylated tau) or abnormal amyloid imaging at positron emission tomography with one of the available ligands specific for fibrillar amyloid. Topographic markers include medial temporal/hippocampal atrophy at magnetic resonance imaging or bilateral parietal hypometabolism on positron emission tomography [START_REF] Cummings | International Work Group Criteria for the Diagnosis of Alzheimer Disease[END_REF].

When considering cognitive functions thought to be most tightly linked to mirror neurons -language and empathy-literature reports that worsening of language abilities, or aphasia, has been suggested to have more clinical relevance in AD than other domains, such as memory, orientation, and reasoning, in progression from the moderate to severe stages of AD: this given that decline in language has been shown to correlate with noncognitive items, such as personal care, hobbies, occupations, and behavior. Language impairment is a significant issue in most patients as they pass through moderate into severe disease stages. Yet even early in the disease state, aphasia is an important characteristic; recently published criteria for the clinical diagnosis of AD include language impairment at onset in one of the subtypes [START_REF] Mckhann | The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease[END_REF][START_REF] Ferris | Language impairment in Alzheimer's disease and benefits of acetylcholinesterase inhibitors[END_REF][START_REF] Hyman | National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease[END_REF].

Research about empathy in AD and other dementias has not been extensive till now. Lack of empathy is a well-recognized clinical characteristic of behavioral variant of Frontotemporal Degeneration (bvFTD-see after), but one study found impaired empathy also in AD patients [START_REF] Fernandez-Duque | Empathy in frontotemporal dementia and Alzheimer's disease[END_REF].

Mild Cognitive Impairment

As there is no cure for AD now, several studies are focusing on preventing or at least slowing its onset. A category which now represent a preferential target of intervention is represented by persons with Mild Cognitive Impairment (MCI).

MCI is characterized by cognitive decline that is greater than expected for an individual's age and education level, but it does not significantly interfere with everyday function (i.e., instrumental activities of daily living). As originally proposed, MCI was characterized primarily as an amnestic disorder that represented an intermediate stage between normal aging and Alzheimer's dementia (AD) [START_REF] Petersen | Mild cognitive impairment: clinical characterization and outcome[END_REF]. More recently, broader conceptualizations of MCI have emerged that too encompass cognitive domains other than memory. The term amnestic MCI (aMCI) was recommended for individuals in the predementia phase prior to AD as a separate group from those with MCI preceding other forms of dementia. Amnestic MCI can be single (only memory affected) or multi domains (other functions are affected along with memory; [START_REF] Petersen | Current concepts in mild cognitive impairment[END_REF][START_REF] Petersen | Mild cognitive impairment as a clinical entity and treatment target[END_REF].

In general, in the last years, MCI is considered as a "symptomatic pre-dementia stage" on the continuum of cognitive decline, characterized by objective impairment in cognition that is not severe enough to require help with usual activities of daily living [START_REF] Langa | The Diagnosis and Management of Mild Cognitive Impairment[END_REF]. In 2011, the diagnostic criteria for dementia due to AD were revised (NIA-AA guidelines, [START_REF] Mckhann | The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease[END_REF]. In this context, "MCI due to Alzheimer's disease," was also defined as "those symptomatic but nondemented individuals whose primary underlying pathophysiology is AD." These guidelines also proposed research criteria for the use of biomarkers-measures of amyloid-beta (Aβ) deposition and of neuronal injury-to increase the likelihood that a patient's MCI is due to AD, but these tests were not yet recommended for routine clinical use [START_REF] Mckhann | The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease[END_REF].

Even if MCI definition has been criticized (the degree of functional preservation is sometimes difficult to define), MCI is a clinical useful concept because it represents a well-recognized risk factor for dementia: longitudinal studies report that seniors with MCI develop Alzheimer's disease at a rate of 10-30% annually, compared to 1-2% of seniors without MCI [START_REF] Busse | Subclassifications for mild cognitive impairment: prevalence and predictive validity[END_REF][START_REF] Ward | Rate of Conversion from Prodromal Alzheimer's Disease to Alzheimer's Dementia: A Systematic Review of the Literature[END_REF] Variation was observed in conversion rates due to the population sampled, diagnostic criteria, and duration, and because many studies did not account for loss to follow-up. In any case, MCI represents a critical window of opportunity to intervene and alter the trajectory of both cognitive and functional decline in seniors.

Several reports indicate that MCI subjects can exhibit language impairment. In a recent study multidomain amnesic and not amnesic MCI people showed performance decrements in total words and switching production compared with healthy controls in fluency tasks, whereas the single-domain amnesic MCI group show unimpaired performance [START_REF] Weakley | Analysis of Verbal Fluency Ability in Amnestic and Non-Amnestic Mild Cognitive Impairment[END_REF]. Another study reported a significant impairment in word generation (semantic fluency) in the amnestic MCI group relative to normal elderly group [START_REF] Price | A review and synthesis of the first 20 years of PET and fMRI studies of heard speech, spoken language and reading[END_REF]. Furthermore, the amnesic MCI group produced significantly smaller cluster sizes and accessed fewer subcategories. MCI people also show difficulties in retrieving proper names in comparison with normal controls (Juncos-Rabadàn et al., 2012) and are consistently less accurate and slower than healthy comparison subjects in semantic decisions in which words are used as stimuli [START_REF] Kirchberg | Semantic Distance Abnormalities in Mild Cognitive Impairment: Their Nature and Relationship to Function[END_REF].

As far as empathy is concerned, a recent study found heightened emotional contagion in both MCI and AD, in association with temporal lobe degeneration [START_REF] Sturm | Heightened emotional contagion in mild cognitive impairment and Alzheimer's disease is associated with temporal lobe degeneration[END_REF].

2.2.2.1

The continuum AD-MCI and motor functions AD and MCI have always been viewed as "pure" cognitive disorders [START_REF] Rossor | Alzheimer's disease[END_REF]. However, over the last decade there has been increasing recognition of a link between deficiencies in motor function and these two clinical entities. Some studies have reported alterations of kinematic profile of simple arm movements in AD [START_REF] Ghilardi | Impaired movement control in Alzheimer's disease[END_REF][START_REF] Bisio | Motor resonance mechanisms are preserved in Alzheimer's disease patients[END_REF], see Figure 25) and even in MCI [START_REF] Yan | Alzheimer's disease and mild cognitive impairment deteriorate fine movement control[END_REF]. Movement inaccuracy increases without visual feedback, and correlates significantly with scores of disease severity [START_REF] Ghilardi | Impaired movement control in Alzheimer's disease[END_REF][START_REF] Ramachandran | Mirror neurons and imitation learning as the driving force behind "the great leap forward[END_REF]Tippet and Sergio, 2006;[START_REF] Bisio | Motor resonance mechanisms are preserved in Alzheimer's disease patients[END_REF]. Several community-based studies report that mild parkinsonian signs, including motor slowing, gait and posture disturbances, rigidity and resting tremor, may be present in up to 50% of communitydwelling older persons without clinical PD. They are associated with an increased risk of developing both MCI and AD [START_REF] Louis | Association between mild parkinsonian signs and mild cognitive impairment in a community[END_REF]. In general, motor performances, including gait and balance or finger tapping, are commonly impaired in older persons (Buchman and Bennet, 2011). Both a lower level and more rapid rate of motor decline in cognitively intact individuals predict the subsequent development of MCI and AD, and loss of motor function can precede cognitive impairment by several years [START_REF] Camicioli | Motor slowing precedes cognitive impairment in the oldest old[END_REF][START_REF] Aggarwal | Motor Dysfunction in Mild Cognitive Impairment and the Risk of Incident Alzheimer Disease[END_REF][START_REF] Wang | Performance-Based Physical Function and Future Dementia in Older People[END_REF].

Recent studies also suggest that changes in body mass index (BMI) may be an early noncognitive sign of AD. Several studies report that baseline lower BMI, as well as a more rapid rate of declining BMI, are associated with an increased risk of AD. Declining BMI may occur several years before the clinical diagnosis of dementia and raises the question of whether mild motor symptoms may represent an early sign of AD. BMI is also associated with incident MCI [START_REF] Buchman | Change in body mass index and risk of incident Alzheimer disease[END_REF](Buchman et al., , 2007(Buchman et al., , 2011)). Further, impaired motor function is a prominent characteristic of physical frailty: this is a heterogeneous syndrome which includes loss of muscle strength, reduced physiologic functions, impaired gait and fatigue [START_REF] Ringer | Relationship between family caregiver burden and physical frailty in older adults without dementia: a systematic review[END_REF]. Longitudinal studies suggest that a higher level of physical frailty is associated with the subsequent development of both MCI and AD (Buchman et al., 2007;[START_REF] Boyle | Physical Frailty Is Associated with Incident Mild Cognitive Impairment in Community-Based Older Persons[END_REF], and that low grip strength is associated with an increased risk of incident AD and MCI [START_REF] Boyle | Association of Muscle Strength With the Risk of Alzheimer Disease and the Rate of Cognitive Decline in Community-Dwelling Older Persons[END_REF].

On the other hand, physical activity (above all aerobic exercise) is recurrently associated to lower incidence of dementia and to better cognition in affected patients [START_REF] Groot | The effect of physical activity on cognitive function in patients with dementia: A meta-analysis of randomized control trials[END_REF][START_REF] Ginis | Formulation of evidence-based messages to promote the use of physical activity to prevent and manage Alzheimer's disease[END_REF]. The Brain Derived Neurotrophic Factor (BDNF), a member of the neurotrophin family [START_REF] Ponteri | RBANS. Repeatable Battery for the Assessment of Neuropsychological Status[END_REF], has been identified as a crucial mediator of the benefits of exercise for brain health [START_REF] Cotman | Exercise: a behavioral intervention to enhance brain health and plasticity[END_REF]. Voluntary exercise increases levels of BDNF mRNA and protein in the hippocampus and other brain regions [START_REF] Neeper | Exercise and brain neurotrophins[END_REF][START_REF] Cotman | Exercise: a behavioral intervention to enhance brain health and plasticity[END_REF], whereas the beneficial effect of exercise on cognitive function is inhibited when blocking BDNF action in the hippocampus [START_REF] Vaynman | Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition[END_REF]. Aerobic exercise training in adults increased the size of the anterior hippocampus and BDNF levels, leading to improvements in spatial memory and reversing age-related loss in volume by 1 to 2 years [START_REF] Erickson | Exercise training increases size of hippocampus and improves memory[END_REF]. A recent investigation has compared the effects of a dancing intervention and traditional health fitness training on hippocampal subfields volumes and balance abilities in seniors. Before and after intervention, both groups revealed hippocampal volume increases, mainly in the left hippocampus. The dancers showed additional increases in the left dentate gyrus and the right subiculum, and achieved a significant increase in the balance composite score [START_REF] Rehfeld | Dancing or Fitness Sport? The Effects of Two Training Programs on Hippocampal Plasticity and Balance Abilities in Healthy Seniors[END_REF] 1.

FRONTOTEMPORAL DEMENTIA AND AMYOTROPHIC LATERAL SCLEROSIS

Frontotemporal dementia (FTD) is a common cause of pre-senile dementia, accounting for 5-17% of autopsy-proven cases presenting under the age of 70 (even if it can be diagnosed at any age after twenties). It can manifest as a spectrum of clinical syndromes, ranging from behavioral impairment (behavioral variant of the frontotemporal dementia: bvFTD) to language (Primary progressive aphasia: PPA) or motor dysfunction. Recently published consensus criteria outline the diagnostic criteria for bvFTD and PPA [START_REF] Gorno-Tempini | Classification of primary progressive aphasia and its variants[END_REF][START_REF] Rascovsky | Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia[END_REF].

The bvFTD is a clinical syndrome characterized by progressive changes in personality, social attitude (either apathy or dis-inhibition), and mental functions. These symptoms are combined with a scarce awareness and, frequently, non-fluent language impairment. bvFTD is usually associated with frontal, insular and temporal atrophy [START_REF] Neary | Frontotemporal lobar degeneration: A consensus on clinical diagnostic criteria[END_REF][START_REF] Rascovsky | Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia[END_REF].

PPA is an aphasic dementia characterized by progressive decline in language function, but relative sparing of other cognitive domains associated with damage to the left hemisphere perisylvian language network [START_REF] Mesulam | Primary Progressive Aphasia -A Language-Based Dementia[END_REF]. Experts generally recognize three main variants of the syndrome: Three main variants of PPA are now recognized: non fluent or agrammatic, fluent (or semantic dementia) and logopenic [START_REF] Gorno-Tempini | Classification of primary progressive aphasia and its variants[END_REF][START_REF] Mesulam | Quantitative classification of primary progressive aphasia at early and mild impairment stages[END_REF][START_REF] Rascovsky | Clinical diagnostic criteria and classification controversies in frontotemporal lobar degeneration[END_REF][START_REF] Lashley | Review: an update on clinical, genetic and pathological aspects of frontotemporal lobar degenerations[END_REF].

Typical age of onset for bvFTD and PPA is under age 65 and collectively they are thought to represent the most common form of young-onset dementia [START_REF] Knopman | The incidence of frontotemporal lobar degeneration in Rochester[END_REF][START_REF] Ratnavalli | The prevalence of frontotemporal dementia[END_REF].

While true epidemiologic data are scarce, recent consensus estimates suggest prevalence rates of FTD range between 15 and 22 per 100,000 and incidence rates are between 2.7 and 4.0 per 100,000 personyears [START_REF] Knopman | Estimating the Number of Persons with Frontotemporal Lobar Degeneration in the US Population[END_REF].

The majority of FTD cases have no known cause ('sporadic' FTD), but approximately a third is due to autosomal dominant mutations in one of several FTD associated genes [START_REF] Onyike | The epidemiology of frontotemporal dementia[END_REF]. FTD is heterogeneous from a neuropathological and genetic point of view showing mostly tau or ubiquitin/TDP-43 positive inclusions at autopsy [START_REF] Mackenzie | Molecular neuropathology of frontotemporal dementia: insights into disease mechanisms from postmortem studies[END_REF], and mutations in MAPT, GRN and C9ORF72 genes as the most commonly identified causes of familial FTD [START_REF] Woollacott | The clinical spectrum of sporadic and familial forms of frontotemporal dementia[END_REF].

FTD is also the most striking example of cognitive and motor symptoms combination in a neurodegenerative disease In fact, FTD is strictly linked to motoneuron disease (MotND)/ALS (the form of MotND in which both central and spinal motor neurons degenerate). Around 10-15% of patients with FTD develop MotND [START_REF] Lomen-Hoerth | The overlap of amyotrophic lateral sclerosis and frontotemporal dementia[END_REF]Burrell et al. 2011), with an even higher prevalence of 'subclinical' evidence of motoneuron signs [START_REF] Lomen-Hoerth | The overlap of amyotrophic lateral sclerosis and frontotemporal dementia[END_REF]. Conversely, 10-20% of MotND patients meet diagnostic criteria for FTD, but at least 50% of patients presenting with MotND develop cognitive-behavioral impairment [START_REF] Strong | Consensus criteria for the diagnosis of frontotemporal cognitive and behavioural syndromes in amyotrophic lateral sclerosis[END_REF]. The hexanucleotide repeat expansion in the C9ORF72 gene is the most frequent genetic cause of both ALS and FTD (Cipolat [START_REF] Mis | Development of Therapeutics for C9ORF72 ALS/FTD-Related Disorders[END_REF] indicating that the same molecular mechanisms can be at the base of either a primarily motor or social-cognitive dysfunction, a biological finding which supports the idea of a strict relationship between motricity and social behavior.

There is also a strictly relationship between FTD and parkinsonism: along the course of the disease, extrapyramidal symptoms (mostly cogwheeling-rigidity, or bradykinesia or dystonia) can be present. It can even worsen till a frank atypical parkinsonian syndrome, with features of Corticobasal Degeneration (CBD; [START_REF] Graham | Language function and dysfunction in corticobasal degeneration[END_REF][START_REF] Josephs | Clinicopathological and imaging correlates of progressive aphasia and apraxia of speech[END_REF][START_REF] Josephs | Apraxia of speech and nonfluent aphasia: a new clinical marker for corticobasal degeneration and progressive supranuclear palsy[END_REF] or Progressive Supranuclear Palsy [START_REF] Josephs | Atypical progressive supranuclear palsy underlying progressive apraxia of speech and nonfluent aphasia[END_REF][START_REF] Josephs | Clinicopathological and imaging correlates of progressive aphasia and apraxia of speech[END_REF].

PARKINSON DISEASE AND DEMENTIA WITH LEWY BODIES

Parkinson Disease (PD), the most common extrapyramidal disorder, is characterized by three cardinals motor symptoms (bradykinesia, rigidity and resting tremor), then associated to postural instability. The diagnosis of PD in mainly a clinical one and based on the identification of characteristic signs and symptoms, along with exclusion with atypical symptoms (Linee Guida Italiane per la Diagnosi e la Terapia della Malattia di Parkinson, 2013). In the last years, however, the DAT scana nuclear medecine technique which demonstrate the loss of dopaminergic innervation in the striatum -has been more and more utilized as a support to the clinical diagnosis [START_REF] Tolosa | Accuracy of DaTSCAN (123I-ioflupane) SPECT in diagnosis of patients with clinically uncertain parkinsonism: 2-Year follow-up of an open-label study[END_REF][START_REF] Seifert | The impact of DaTscan on the diagnosis and management of movement disorders: A retrospective study[END_REF].

Due to the prevalent motor symptoms PD is usually classified in movement disorders. However, it is now recognized that non-motor symptoms, such as cognitive impairment, autonomic, affective (and behavioral) disturbances (e.g. depression, anxiety, anhedonia, psychotic symptoms, compulsive disorders) are of relevance in the disease course and change along the disease progression in each patient [START_REF] Moustafa | Neural and behavioral substrates of subtypes of Parkinson's disease[END_REF][START_REF] Rodríguez-Violant | Who Can Diagnose Parkinson's Disease First? Role of Pre-motor Symptoms[END_REF]. Cognitive symptoms in PD include first deficits in functions classically described as "executive" ones, such as working memory, explicit motor planning, and visuospatial attention. But they can also include an impairment of longterm memory, even if different from hyppocampal amnesia typical of AD [START_REF] Muslimovic | Cognitive profile of patients with newly diagnosed Parkinson disease[END_REF][START_REF] Pillon | Explicit memory in Alzheimer's, Huntington's, and Parkinson's diseases[END_REF]; at the end, they can turn out to a clear dementia picture (PD dementia -PDD; [START_REF] Emre | Clinical diagnostic criteria for dementia associated with Parkinson's disease[END_REF].

PD is mainly due to loss of dopaminergic projections in the striatum, due to the severe degeneration of neurons located in the substantia nigra (pars compacta). From the neuropathological point of view, PD is also characterized by the deposition of filamentous eosinophilic intracytoplasmatic inclusions, called "Lewy bodies", above all in the substantia nigra. These aggregates are present not only in the brainstem but also in the cortex and in the peripheral enteric nervous system [START_REF] Review Kövari | Neuropathology of Lewy body disorders[END_REF]. Lewy bodies link PD to the second most common cause of dementia, DLB. DLB is characterized by dementia, associated with visual hallucinations, prominent fluctuations and REM behavior disorder [START_REF] Mckeith | Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium[END_REF]. Extrapyramidal motor symptoms develop simultaneously or soon thereafter. The first affected cognitive domains are usually the same than in PDD, although anterograde memory can also be involved [START_REF] Salmon | Neuropsychological Deficits Associated with Diffuse Lewy Body Disease[END_REF][START_REF] Gomperts | Lewy Body Dementias: Dementia With Lewy Bodies and Parkinson Disease Dementia[END_REF]. Indeed, some Authors consider now that PD and DLB represent the extremes of a continuum, in which the presence of Lewy Body neurodegeneration can cause both motor and/or cognitive pictures in various combinations (see [START_REF] Goldman | The spectrum of cognitive impairment in Lewy body diseases[END_REF] for a discussion about this point).

MIRROR NEURONS AND NEUROREHABILITATION

In the last decade, AOT, which stimulates the MN network, was developed as a supplementary therapeutic tool for patients with stroke, in order to stimulate brain plasticity and obtain positive functional results [START_REF] Garrison | The Mirror Neuron System: A Neural Substrate for Methods in Stroke Rehabilitation[END_REF][START_REF] Small | The mirror neuron system and treatment of stroke[END_REF][START_REF] Sale | Action observation and mirror neuron network: a tool for motor stroke rehabilitation[END_REF]; see [START_REF] Carvalho | The mirror neuron system in post-stroke rehabilitation[END_REF] for a review on this topic). This has also been extended to motor deficits of children with Cerebral Palsy [START_REF] Sgandurra | Upper limb children action-observation training (UP-CAT): a randomised controlled trial in Hemiplegic Cerebral Palsy[END_REF][START_REF] Buccino | Improving upper limb motor functions through action observation treatment: a pilot study in children with cerebral palsy[END_REF]Masahup et al., 2012;[START_REF] Bassolino | Activating the motor system through action observation: is this an efficient approach in adults and children[END_REF] and, as we are seeing later, of patients with PD [START_REF] Buccino | Action observation treatment improves autonomy in daily activities in Parkinson's disease patients: results from a pilot study[END_REF][START_REF] Buccino | Action observation treatment: a novel tool in neurorehabilitation[END_REF]. Studies in monkeys and humans both suggest the possibility to activate the motor cortex not only by performing movements, but also by simply observing actions without any motor activity. The motor facilitation, revealed by the amplitude modulation of motor responses which are evoked by TMS applied to premotor cortex, maintains the temporal structure and the muscular organization of the observed actions [START_REF] Rizzolatti | The mirror-neuron system[END_REF][START_REF] Fadiga | Human motor cortex excitability during the perception of others' action[END_REF]. Importantly, the motor cortex atrophy due to normal subject arm immobilization can be totally prevented by AOT performed during the immobilization period (Bassolino et al., 2013, Figure 26).

PREVIOUS CLINICAL APPLICATIONS

The first proposal to use AOT in rehabilitation has been formulated for stroke patients. A significant functional limitation to the use of one superior arm due to a neurological lesion (e.g. a stroke) drives the person to perform most of the activities of daily living with the unaffected arm [START_REF] Gordon | Methods of constraint-induced movement therapy for children with hemiplegic cerebral palsy: Development of a child-friendly intervention for improving upper-extremity function[END_REF]. Moreover, in these patients, the regular participation to an intensive rehabilitation treatment can be associated to a great prevalence of pain [START_REF] Brattberg | Do pain problems in young school children persist into early adulthood? A 13year follow-up[END_REF]. In this context, the activation of the motor system in an alternative way could represent a further opportunity to improve classical rehabilitation programs.

Franceschini et al. ( 2010) evaluated the efficacy of the mirror therapy for chronic upper limb motor impairment in 28 post-stroke patients. They underwent a treatment consisting of watching videos of hand movements for 5 days a week for 4 weeks, and the subjects performed imitation of the movement. The Authors found improvement in all functional scales after treatment. This improvement was still present at the two-month follow-up. Due to the significant findings, they concluded that the observed action can be used as an effective strategy in post-stroke rehabilitations.

Other groups have proposed the use of virtual reality motor rehabilitation systems for stroke patients with upper limb paresis [START_REF] Eng | Interactive visuo-motor therapy system for stroke rehabilitation[END_REF]. [START_REF] Michielsen | Motor Recovery and Cortical Reorganization After Mirror Therapy in Chronic Stroke Patients[END_REF] divided 40 chronic post-stroke patients into two groups: control and mirror therapy groups. The control group had a direct view of both hands, whereas the mirror group practiced with the affected hand positioned behind a mirror while they looked at the reflection of the unaffected hand in the mirror. To ensure that patients focused at the mirror reflection of their unaffected hand instead of their moving unaffected hand itself, a cover was placed over their unaffected hand (see Figure 27). Both mirror and control groups performed bimanual exercises, with the difficulty of the exercises depending on the patients' individual levels of functioning. The Fugl-Meyer Scale (FMS, a scale which evaluates motor function) results showed that the group with mirror therapy significantly improved its scores, but these changes were not sustained in the follow-up trials. On the other hand, the Authors demonstrated that mirror therapy caused a shift in the activation balance of the primary motor cortex toward the lesioned hemisphere at fMRI. The same group used the mirror therapy in 22 post-stroke patients who performed unimanual and bimanual tasks under two conditions: hand observation (no mirror condition), and observation of the hand reflex in the mirror (mirror condition). They found a significant increase in precuneus and the posterior cingulate cortex, areas associated with awareness of the self and spatial attention, during the movement with the mirror in the bimanual task. However, the fact that the Authors did not observe mirror-related activity in areas of the motor or MN system questions the theory that attribute the clinical effects of mirror therapy to these systems [START_REF] Michielsen | The neuronal correlates of mirror therapy: an fMRI study on mirror induced visual illusions in patients with stroke[END_REF] Figure 27: The setup for mirror therapy [START_REF] Michielsen | Motor Recovery and Cortical Reorganization After Mirror Therapy in Chronic Stroke Patients[END_REF] Recently, a Korean group evaluated the effects of AOT to improve on balance and gait function of stroke patients, finding that the activation of MN through AOT, combined with a conventional stroke physiotherapy program, enhances lower-extremity motor recovery and motor functioning in stroke patients [START_REF] Lee | The effects of action observation training and mirror therapy on gait and balance in stroke patients[END_REF].

Even if most studies in stroke proposed MN stimulation as a method to improve arm recovery, this method has been also proposed to ameliorate aphasia. [START_REF] Lee | IMITATE: An intensive computer-based treatment for aphasia based on action observation and imitation[END_REF] have developed IMITATE, a computer-assisted system for aphasia therapy based on action observation and imitation. As we have already reported, it has also been demonstrated that changing the motor system affects language comprehension, and changing language comprehension affects the motor system, in a bi-directional causal relation. [START_REF] Glenberg | Processing abstract language modulates motor system activity[END_REF] demonstrated half of this bi-directional link, namely that adapting the motor system through repeated actions (moving beans from a box to another farther away or towards the body) affects language comprehension. [START_REF] Zarr | Language comprehension warps the mirror neuron system[END_REF] demonstrated the other half of the bi-directional link, that is adaptation due to repeated sentence reading affected prediction of actions in the same direction, but only for videos of biological motion. Altogether, these data clearly support promising clinical implications for aphasia rehabilitation.

In children affected by cerebral palsy, [START_REF] Buccino | Improving upper limb motor functions through action observation treatment: a pilot study in children with cerebral palsy[END_REF] showed functional gains after observation of video clips showing daily-appropriate actions, while Masahup et al. ( 2012) demonstrated that a MN stimulation program can improve motor function at least as much as the conventional physical therapy. Other trials on children with cerebral palsy with the use of AO as an innovative rehabilitation approach are in progress [START_REF] Sgandurra | Upper limb children action-observation training (UP-CAT): a randomised controlled trial in Hemiplegic Cerebral Palsy[END_REF].

ENHANCING THE POTENTIAL OF MIRROR NEURONS STIMULATION IN

REHABILITATION

The motor system activity can be also modulated as a response to an acoustic stimulus associated to action (e.g, breaking a peanut) [START_REF] Kohler | Hearing sounds, understanding actions: Action representation in mirror neurons[END_REF][START_REF] Aziz-Zadeh | Left hemisphere motor facilitation in response to manual action sounds[END_REF][START_REF] Fadiga | Motor facilitation during action observation: a magnetic stimulation study[END_REF][START_REF] Gazzola | Empathy and the Somatotopic Auditory Mirror System in Humans[END_REF]. Moreover, the cortical facilitation due to action observation is at its maximum when we furnish both acoustic and visual stimuli linked to the action [START_REF] Alaerts | Is the human primary motor cortex activated by muscular or direction-dependent features of observed movements[END_REF]. In fact, our experience with the world is typically mediated by multiple sensorial experiences and the sight of an action is usually influenced by the sound [START_REF] Alaerts | Is the human primary motor cortex activated by muscular or direction-dependent features of observed movements[END_REF]). The increase in MEPs recorded from the same muscles that would be active during actual execution of the same movement -Fadigaeffect, for short- [START_REF] Fadiga | Motor facilitation during action observation: a magnetic stimulation study[END_REF] is expanded by listening to action-related sounds [START_REF] Aziz-Zadeh | Left hemisphere motor facilitation in response to manual action sounds[END_REF]). Interestingly, this effect has been observed when stimulating the left, language-dominant hemisphere only: this finding supports the existence of a close link between action and language [START_REF] Aglioti | Representing actions through their sound[END_REF]. It seems that some MN are triple cells which can be activated not only by action observation and execution but also by the acoustic perception of action-related sounds [START_REF] Kohler | Hearing sounds, understanding actions: Action representation in mirror neurons[END_REF]. Others of these complex perceptuo-motor neurons respond strongly to action sounds but not to the observation of actions performed by another human or monkey agents thus indicating their audio-motor specificity [START_REF] Keysers | Audiovisual mirror neurons and action recognition[END_REF].

These data suggest the fascinating possibility to potentiate AOT. The success of a rehabilitation therapy based on a single sensory channel could improve if the related sound is furnished to recreate the action context. This method could influence the integration and coordination of different cerebral networks and functional strategies, which is considered one of the main limitations not only in patients with stroke but also in patients with neurodegenerative diseases. This kind of stimulation could push brain reorganization and functional results, in addition to cognitive development. That is, stimulation of MN through multimodal action observation could improve not only motor functions but also cognitive status, due the status of this neurons population which are involved in both motor learning and imitation, language functions ad empathy.

CHAPTER 2 -ISSUE OF THE THESIS: COGNITIVE DECLINE AT THE LIGHT OF THE EMBODIED COGNITION THEORY AND OF THE DISCOVERY OF THE MIRROR NEURONS SYSTEM

2.1 MIRROR NEURONS, EMBODIED COGNITION AND NEURODEGENERATIVE DISEASES When taking into consideration neurodegenerative diseases, it appears evident that in each of them both cognitive and motor symptoms are represented in a sort of continuum. We have also viewed that the theory of embodied cognition stresses the coupled nature of thinking and acting, reforming the traditional model of cognitive processing, with its strict perception-cognition-action scheme (e.g., [START_REF] Hurley | Perception and action: alternative views[END_REF]). The traditional model, according to which almost all studies on neurodegenerative diseases have been conducted, considers cognitive functions as higher-level supervisor functions which utilize perception and action as separated slave systems, providing input to cognitive processors (perception) and executing its commands (action). Instead, embodied cognition considers that it is a mistake regarding cognitive processors, perception and action as separate (e.g., [START_REF] O'regan | Solving the "real" mysteries of visual perception: the world as an outside memory[END_REF][START_REF] Van Gelder | The distinction between mind and cognition[END_REF][START_REF] Clark | Being There: Putting Brain, Body and World Together Again[END_REF][START_REF] Barsalou | Perceptual symbol systems[END_REF][START_REF] Wilson | Six views of embodied cognition[END_REF][START_REF] Noe | Action in Perception[END_REF][START_REF] Gallagher | How the Body Shapes the Mind[END_REF][START_REF] Wheeler | Reconstructing the Cognitive World[END_REF]. Reinterpreting neurodegenerative diseases, and particularly AD and MCI (thought as a pre-dementia phase of AD) at the light of this hypotheses could help a better comprehension of clinical manifestations and opening new pathways to rehabilitate patients affected by these diseases.

MN represent in fact the neuronal population which link perception and action, cognition and motility. Characterizing the functioning of MN system in neurodegenerative diseases could allow to better understand functional mechanisms underlining clinical manifestations. It would also allow to exploit this kind of neurons in rehabilitation of motor and cognitive symptoms. In this sense, there have been some theoretical proposals about interpreting some neurodegenerative diseases, in particular ALS and FTD, as linked to dysfunction of perception-motor circuits including MN. These proposals have been based on neuropsychological data which show preferential impairment of action verbs on tools and an impairment of ToM -strictly related to one of the putative MN functions, that is empathy-in these diseases [START_REF] Eisen | Tools and talk: An evolutionary perspective on the functional deficits associated with amyotrophic lateral sclerosis[END_REF][START_REF] Bak | The neuroscience of action semantics in neurodegenerative brain diseases[END_REF].

However, direct studies on MN functioning through neuroimaging or neurophysiological techniques in neurodegenerative diseases are scarce. Most data are available for PD, but they are controversial.

Even data about MN and aging are scarce, as most MN studies in normal humans were performed in young or adult subjects, with a few exceptions (see [START_REF] Vallet | The perceptual nature of audiovisual interactions for semantic knowledge in young and elderly adults[END_REF] for a discussion about embodied cognition and aging).

Given these premises we first performed a bibliographic research aimed to clarify the state of the Art on neurodegenerative disorders, embodied cognition and MN. Then, considering literature data, we conceived a study focused on MN in aging and cognitive impairment in neurodegeneration linked to aging.

2.2 STATE OF THE ART ON NEURODEGENERATIVE DISORDERS AND EMBODIED COGNITION

METHODS: LITERATURE SEARCHING OF STUDIES LINKING ACTION, COGNITION (MIRROR NEURONS) AND NEURODEGENERATIVE DISEASES

To understand the actual "state of the art" in this field I screened first all fields of the PubMed database at December, 31 2017 with the term "mirror neurons" and "embodied cognition" and any of the following terms: neurodegenerative diseases; Frontotemporal degeneration or dementia; Amyotrophic Lateral Sclerosis; Motoneuron Disease; Primary Progressive Aphasia; Alzheimer; Mild Cognitive Impairment; Parkinson. I also screened the Pubmed Database with the corresponding Mesh terms and with the Mesh term "cognitive dysfunction". That gave a result of 100 articles, but 78 articles were excluded after reading the title and the abstract because they did not fill with the scope of the review; 3 additional articles were excluded for the same reason after a full lecture. This procedure left 19 articles for the review. I then repeated a search with the same free terms in Web of Science, obtaining a list of 315 articles/proceedings. 265 articles were excluded after reading the title and the abstract because they did not fill with the scope of the review or because they doubled the findings of the previous search, and 11 articles after full lecture. This procedure left 39 additional articles for the present review. The reference list of the identified studies and reviews was then hand searched for additional articles, thus giving a total sum of (19+39+50=108) findings to report. Articles/proceedings were included if 1) they were published in a peer-review journal, 2) they investigated the MN or the embodied cognition theory and any of the neurodegenerative diseases, or 3) they proposed a theory/interpretation linking the MN or the embodied cognition theory and any of the neurodegenerative diseases, 4) previous reviews were included as a source of additional references or because they proposed theories linking embodied cognition and neurodegenerative diseases. Articles which not fitted in these criteria were excluded.

However, even I performed a systematic search of sources, the aim was appraising the existing studies considering the embodied cognition theory, MN system and neurodegenerative diseases (to stimulate research in this field) rather than to perform an exhaustive and comprehensive review. Few studies aimed to directly explore MN functioning through neurophysiological or neuroimaging techniques in neurodegenerative diseases were found, while more studies were available linking embodied cognition and any of the neurodegenerative diseases.

RESULTS

The Mirror Neurons network, embodied cognition and Parkinson Disease

Most available studies considering both cognition and action systems are focused on PD, and results are controversial. The functioning of the MN network in PD has been studied, as in normal subjects, through neurophysiological techniques (EEG, and TMS), neuroimaging (fMRI), and kinematic studies. Some neuropsychological and behavioral studies investigated task performance at the light of the embodied cognition theory. Several other studies suggested rehabilitative training based on stimulating the MN network and the embodied cognition framework in PD. We will also make a hint to studies on motor imagery (MI) in PD.

▪ Neurophysiological studies

Alegre et al. ( 2010) have proposed basal ganglia involvement in AOT, as the subthalamic nucleus shows changes in activity during movement observation like those observed during movement execution. The Authors recorded EEG and local field potentials in 18 parkinsonian patients through surgically implanted electrodes for deep brain stimulation (DBS). Oscillatory changes in electrical activities were recorded during movement execution, AOT and two control conditions. AOT (as movement execution) was associated to a bilateral reduction of subthalamic power in the beta range.

The effect was present in both on and off state, even if higher in the first one. This result suggests a substantial conservation of MN network in PD, with a possible influence of the medication state. Another recording study in DBS implanted patients again found a change in subthalamic nucleus oscillatory activity [START_REF] Marceglia | Modulation of beta oscillations in the subthalamic area during action observation in Parkinson's disease[END_REF] during action observation: this response could be driven by the modulation of cortical regions belonging to the MN system, thanks to connections between the basal ganglia and the frontal and prefrontal cortex.

Other groups however found different results: in a small study µ-rhythm desynchronization, classically recorded during movement observation, was impaired in patients with early PD [START_REF] Heida | Eventrelated mu-rhythm desynchronization during movement observation is impaired in Parkinson's disease[END_REF]; see Figure 28 a andb). [START_REF] Tremblay | Corticomotor facilitation associated with observation and imagery of hand actions is impaired in Parkinson's disease[END_REF] tested 11 PD patients in the on condition and the same number of healthy elderly controls, by recording MEPs amplitudes in four conditions: rest, AOT (a video depicting a hand cutting a piece of paper with scissors), MI and active action imitation (see Figure 29). The MEP amplitude (recorded at the first dorsal interosseous and abductor digiti minimi) increased in PD patients during active imitation (compared to resting state) but neither during AOT nor during action imagery. This indicated a failure to engage the motor system more at the covert than at the overt stage of action execution. According to the Authors, this failure is due to a deficit in motor activation affecting critical nodes in the motor cortical network normally involved in action preparation. [START_REF] Tremblay | Corticomotor facilitation associated with observation and imagery of hand actions is impaired in Parkinson's disease[END_REF] hypothesize that these nodes could be the supplementary motor area and the inferior parietal cortex. However, these observations may also be explained by the involvement of the frontal-subcortical circuits that connect the basal ganglia to the premotor cortex [START_REF] Alexander | Basal ganglia-thalamocortical circuits: parallel substrates for motor, oculomotor, "prefrontal" and "limbic" functions[END_REF]; see also Alegre et al., 2011 and Figure 30). A more recent study [START_REF] Gündüz | F-wave and motor-evoked potentials during motor imagery and observation in apraxia of Parkinson disease[END_REF] showed a normal facilitation of MEP amplitude by mental imagery and active movements in normal controls and non-apraxic PD patients. The same was true for F-wave amplitudes over the dominant upper extremity during mental imagery, AOT and active movements. This facilitation was lost in apraxic PD patients, raising the possibility that apraxia in these patients could be due to an impairment of MN network [START_REF] Mcgeoch | Apraxia, metaphor and mirror neurons[END_REF].

▪ fMRI studies

In an interesting neuroimaging study [START_REF] Anders | Compensatory premotor activity during affective face processing in subclinical carriers of a single mutant Parkin allele[END_REF] recruited 8 pre-symptomatic carriers of a single mutant Parkin gene, who presented a slight but significant reduction of dopamine metabolism in the basal ganglia. Indeed, it is well known that PD has a long pre-symptomatic stage, during which the brain compensates for dopaminergic nerve degeneration by increasing motor-related cortical activity thus preventing clinical manifestation of the disease [START_REF] Morrish | Regional changes in [18F]dopa metabolism in the striatum in Parkinson's disease[END_REF]. This work aimed to study whether similar compensatory mechanisms were effective in non-motor basal gangliacortical gating loops. Execution and perception of facial gestures are thought to be linked to MN in the ventrolateral premotor cortex [START_REF] Leslie | Functional imaging of face and hand imitation: Towards a motor theory of empathy[END_REF][START_REF] Hennenlotter | A common neural basis for receptive and expressive communication of pleasant facial affect[END_REF]. Parkin mutation carriers first performed fMRI while observing neutral and affective dynamic facial expressions and then performed a facial emotion recognition task. As expected, recruited participants showed significant stronger activity in the right ventrolateral premotor cortex during execution and perception of affective facial gestures than healthy controls. Furthermore, Parkin mutation carriers showed a slightly reduced ability to recognize facial emotions that was inversely proportional to the increase of ventrolateral premotor activity. According to the Authors, these findings are consistent with the hypothesis that compensatory activity in a MN area during processing of affective facial gestures can reduce impairment in facial emotion recognition in subclinical Parkin mutation carriers. A breakdown of this compensatory mechanism might lead to the impairment of facial expressivity and facial emotion recognition observed in clinically manifest PD. On the other hand, it is possible that the stimulation of MN could favor these compensation mechanisms at least in the first stages of the disease, thus allowing PD patients to have better social interaction.

An additional support to the putative link between MN area impairment and the well-known emotional deficit of PD patients [START_REF] Péron | Emotional processing in Parkinson's disease: a systematic review[END_REF] comes from a similar recent study by the same group [START_REF] Pohl | Impaired Emotional Mirroring in Parkinson's Disease-A Study on Brain Activation during Processing of Facial Expressions[END_REF]. In this investigation 13 PD patients and controls underwent an emotion recognition task: they observed video clips depicting emotional, non-emotional, and neutral facial expressions or were asked to produce these facial expressions, during fMRI measurement. Patients performed slightly worse in the emotion recognition task, but only for the most difficult expressions to be interpreted. Inferior frontal and anterior inferior parietal "mirror neuron" areas activated during observation and execution of the emotional expressions in both groups, but in PD patients they activated at a lesser extent; further, activation of the right anterior IPL positively correlated to patients' emotion recognition ability. [START_REF] Péran | Object naming and action-verb generation in Parkinson's disease: A fMRI study[END_REF] explored fMRI cortical activities during the generation of action-verbs, compared to object naming, in 14 non-demented PD patients. Data revealed the involvement of an extended cortical network during action-verb generation: differences in comparison with the object name generation were located above all in the premotor and prefrontal cortices (Figure 31). These results suggest an essential role of the frontal cortex in action verb generation, and that a motor striatalfrontal loops impairment leads to the recruitment of a cortical network aimed at compensating the deficits in these circuits. A following study demonstrated that the patient dopaminergic status conditions the cerebral activation [START_REF] Péran | Effect of levodopa on both verbal and motor representations of action in Parkinson's disease: A fMRI study[END_REF]. Abrevaya et al. (2016, Figure 32) found similar results when subjects listened action verbs and nouns, by considering cortical regions differentially engaged by action and non-action words. The verb lexical category elicited connectivity between primary motor areas and anterior areas (implied in action observation and imitation), in normal controls, while activated posterior areas in PD patients: this suggests that patients might afford alternative pathways to process words when motor substrates are altered. to classify visual stimuli (bar and door handles) according to shape and orientation. There was no difference in the overall reaction times for patients and controls but while the spatial compatibility effect (that is faster reaction times when the response hand and the stimulus direction were compatible) was larger in the handle than in the bar condition for controls, this was not true for PD patients. In a second experiment, the two groups observed video clips of finger or object movements and had to respond as quickly as possible if an X appeared at the end. Both patients and normal participants reduced significantly their reaction times after observing finger compared to objects movements, indicating a partial preservation of MN network in PD. However, parkinsonians showed a spatial compatibility effect only for non-living object movements: this result led the Authors to propose that in PD the MN system is not completely preserved, and that external cues would exert their influence through lower-level visual processes. [START_REF] Poliakoff | The effect of viewing graspable objects and actions in Parkinson's disease[END_REF] In contrast, the lack of any difference between healthy controls and PD patients, tested in off period, during an interference task, suggests a normal coupling between perception and action systems in PD. In this task subjects performed horizontal and vertical arm movements, while watching a person, or a moving dot, performing similar movements in the same-congruent-or orthogonal-incongruentplane [START_REF] Albert | Interference effects from observed movement in Parkinson's disease[END_REF], see also [START_REF] Alegre | The mirror system, theory of mind and Parkinson's disease[END_REF]. [START_REF] Castiello | Visuomotor priming effects in Parkinson's disease patients depend on the match between the observed and the executed action[END_REF] examining PD patients' imitation ability showed kinematic facilitation effects only when the model was a Parkinsonian patient (who performed slower and less fluid movements in contrast to a healthy model. Figure 34). Therefore, differently than normal controls, patients could reenact their motor representations only when the visual model belonged to patient's motor repertoire. In line with this, the authors proposed that basal ganglia play a role in setting frontal and parietal cortices not only for the execution of actions, but also for the internal simulation of observed behaviors, providing that the internal state of the simulated action is available.

Figure 33: Experimental set-up and study results from

Figure 34: From Castiello et al., 2009: Graphical representation of the experimental set-up. A schematic representation of the model reaching towards and grasping the object while being watched by the observer. The two call-outs represent the position of the markers on the participant's hand and the apparatus for the illumination of the stimulus (A). A schematic representation of the observer performing a reach-to-grasp movement after having observed the model acting upon the stimulus (B). Filled arrows indicate either the model or the observer reaching towards the stimulus (A and B, respectively).

Besides investigations testing the influence of action observation on movement production, ability of PD patients to perceive and recognize human action has been studied. Precisely, when displayed with limited visual attributes (a point-light walker) persons with PD showed a reduced visual sensitivity to biological motion [START_REF] Jaywant | Impaired perception of biological motion in Parkinson's disease[END_REF]. Likewise, when observing point-light human figures that conveyed communicative and PD non-communicative gestures, patients were impaired, relatively to normal controls, in describing the meaning of non-communicative gestures, while they normally perceived communicative gestures. However, men were more compromised than women and their ability to recognize both types of gestures was reduced. (Jaywant et al., 2016c).

▪ Neuropsychological studies

Action naming is an ability that depends on the inferior frontal gyrus, a "classical" MN area (see [START_REF] Kemmerer | Behavioral patterns and lesion sites associated with impaired processing of lexical and conceptual knowledge of actions[END_REF]. Action-verb deficits (with relative preservation of noun processing) have been repeatedly documented in PD. In the same vein, it has been reported that motor-language coupling (i.e., the influence between verbal processes and voluntary body movements, see García and Ibáñez, 2014, Figure 35) is altered in PD. For a detailed list of publications on these topics one can refer to the reviews by Cardona et. al. (2013), [START_REF] Silva | Action/Verb processing: Debates in neuroimaging and the contribution of studies in patients with Parkinson's disease[END_REF] and [START_REF] Birba | Losing ground: Frontostriatal atrophy disrupts language embodiment in Parkinson's and Huntington's disease[END_REF]. We report here some of the most significant results. [START_REF] Boulenger | Subliminal display of action words interferes with motor planning: a combined EEG and kinematic study[END_REF] investigated how non-demented PD patients performed on a lexical decision task in a masked repetition priming experiment, both in the on and off condition. Participants had to judge whether a letter string was either a real word or a non-word. The real words were either action verbs or object nouns and were preceded by masked stimuli that were either consonant strings or the same real words that were used for lexical decision. In the off condition, that is, when motor disability was strongest, masked priming effects for action words were nearly absent in PD patients, while robust priming effects were observed for concrete nouns. In the on condition, following Levodopa intake, priming effects for action verbs restored and appeared as strong as for concrete nouns, and comparable to those of healthy controls. According to the Authors their results support the motor theory of language, and provide "compelling evidence that processing lexico-semantic information about action words depends on the integrity of the motor system" (Boulenger et al., 2008, p. 743). Recently, [START_REF] Silva | Lexical-retrieval and semantic memory in Parkinson's disease: The question of noun and verb dissociation[END_REF] found PD patients' impairment not only in a lexical task (naming actions), but also in two semantic-association tasks (action/object), thus supporting a similar interpretation.

Figure 35: Neuroanatomical model of motor-language coupling according to García andIbàñez, 2014 and[START_REF] Cardona | Action-verb processing in Parkinson's disease: new pathways for motor-language coupling[END_REF] 2013) administered a semantic similarity judgment task about action (literal action, non-idiomatic metaphoric action, idiomatic action), and abstract verbs to non-demented PD patients and age-matched controls. Most PD patients were in the on phase at the time of testing. Compared to healthy controls, PD patients showed longer reaction times for literal and idiomatic action sentences. Parkinsonians also showed a tendency to be less accurate at judging metaphoric action verbs. At first glance, these findings appear to support the Embodied Cognition Framework. However, both studies have been highly criticized, in term either of interpretation [START_REF] Mahon | A critical look at the embodied cognition hypothesis and a new proposal for grounding conceptual content[END_REF] or of statistical method [START_REF] Kemmerer | An investigation of semantic similarity judgments about action and non-action verbs in Parkinson's disease: implications for the Embodied Cognition Framework[END_REF]. [START_REF] Kemmerer | An investigation of semantic similarity judgments about action and non-action verbs in Parkinson's disease: implications for the Embodied Cognition Framework[END_REF] attempted to clarify results from the previous studies by investigating the capacity of PD patients to make subtle semantic similarity judgments about action and non-action verbs. Such judgments were (except for "cutting" verbs), accurate but slow for both types of verbs, both in the on and off condition. According to the Authors, a definite conclusion is difficult to draw about two options, a strong one considering that motor simulations plays an essential role in action verb comprehension; and a weak one where the motor system would only play an augmentative role.

. Neuroanatomical model of motor-language coupling. Coronal and lateral view of the left hemisphere showing the proposed frontotemporal basal gangliathalamocortical network (light yellow, blue, and green regions of interest, respectively). The arrows indicate the suggested principal flow of information involved in action-verb processing through two main overlap subcircuits. The frontal lobe, the basal ganglia, and the thalamus (frontal-basal ganglia-thalamocortical component) comprise loops which integrate motor simulation and action programming. These cortical regions play a complementary role in action-verb processing. The temporal lobe, the basal ganglia, and the thalamus (temporal-basal ganglia-thalamocortical component) comprise loops that would play a central role in the grounding of abstract conceptual knowledge involved in words referring to motor concepts.

Fernandino et al. (

More recently, [START_REF] Silva | Deterioration of semantic memory in Parkinson's disease and the implication to embodied cognition[END_REF] again showed that semantic deficits in PD were more pronounced in verbs than nouns, using semantic memory tests that did not involve verbal response. Further, a deficit in the appraisal of action meanings evoked by naturalistic tests was able to distinguish between normal controls and PD patients with normal cognition from PD with initial cognitive decline [START_REF] García | Parkinson's disease compromises the appraisal of action meanings evoked by naturalistic texts[END_REF]). García at al. also found deficits in a syntactic test of actions involving the verb "to touch" even in presymptomatic genetic carriers of PD mutations (García et al., 2017). According to the Authors, "the crucial role of the basal ganglia for handling syntax (i.e., sequencing hierarchically organized patterns of linguistic information) stems from its more basic specialization for handling movement (i.e., sequencing hierarchically organized patterns of sensorimotor information, see García et al., 2017, p 155)". It has also been proposed that the impairment of motor to language coupling could be an early neurocognitive marker of PD [START_REF] García | Words in motion: Motor-language coupling in Parkinson's disease[END_REF]: this hypothesis is based on results showing an altered action-sentence compatibility (ACE) effect [START_REF] Ibáñez | Motor-language coupling: Direct evidence from early Parkinson's disease and intracranial cortical recordings[END_REF]Cardona et al., 2014). Of interest is the study by [START_REF] Kargieman | Motor-language coupling in Huntington's disease families[END_REF], reporting motor-language coupling deficits as earlier as 10 years before the appearance of clinical symptoms in Huntington disease carriers. Results pointing at action-language and syntactic deficits as a window into motor network integrity in PD have however been criticized because they mainly investigated Indo-European languages while data from other languages without a clear distinction between verbs and nouns [START_REF] Calvo | A core avenue for transcultural research on dementia: on the cross-linguistic generalization of language-related effects in Alzheimer's disease and Parkinson's disease[END_REF] are still lacking. [START_REF] Tomasino | To move or not to move: Subthalamic deep brain stimulation effects on implicit motor simulation[END_REF] studied the effect of DBS on lexical decisions of PD patients about hand action-related verbs, abstract verbs and pseudo-words presented either in a positive or negative sentence context. Presenting negative sentences is a way to explore implicit motor representations, as the negative context can suppress motor simulation processes: indeed, in normal subjects, reaction times to negative commands are slower than to positive ones [START_REF] Tomasino | To move or not to move: imperatives modulate action-related verb processing in the motor system[END_REF]. When the DBS was at 100% on, both normal controls and PD patients showed the normal pattern of reaction times; however, when the stimulation was reduced at 50%, PD patients exhibited identical reaction times to both positive and negative sentences. Here, DBS was able to improve the clinical signs and to restore the normal pattern shown by controls during an action lexical decision task.

An interesting finding to interpret deficits in PD at the light of the embodied cognition framework is the existence of a significant relationship between voluntary control of facial muscles and emotion recognition deficits in these patients [START_REF] Marneweck | Discrimination and recognition of facial expressions of emotion and their links with voluntary control of facial musculature in Parkinson's disease[END_REF][START_REF] Jacobs | Emotional facial imagery, perception, and expression in Parkinsons-disease[END_REF][START_REF] Ricciardi | Facial emotion recognition and expression in Parkinson ' s disease: an emotional mirror mechanism?[END_REF][START_REF] Livingstone | Deficits in the mimicry of facial expressions in Parkinson's disease[END_REF]. If the MN system is involved in both production and perception of facial emotional expression, one can expect an alteration of MN in PD. However, the MN network is not the only neuronal system involved in emotion perception (Wang et al., 2014). In any case, similar data to those ones reported in PD have been obtained in Huntington disease [START_REF] Trinkler | Embodied emotion impairment in Huntington's Disease[END_REF]. These data are important for caregivers of persons with PD and Huntington, who must take into account that this emotional impairment can affect both sides, that is the sender and the receiver of the emotional communication. Other studies reporting impaired emotion recognition in both PD and Huntington disease (e.g. [START_REF] Clark | Specific impairments in the recognition of emotional facial expressions in Parkinson's disease[END_REF]Sprengelmeyer et al., 1996), will not be detailed here. However, one must mention Nobis et al. study (2017) showing a relationship between the performance at the Reading the Mind in the Eyes test (RME) and the severity of motor symptoms, along with disease duration, in PD patients. In the RME (a test measuring empathic abilities) subjects must attribute mental states to persons (represented in pictures) by focusing on their eye-gaze (Baron- Cohen et al., 2001): a bad performance in this test correlates with autistic traits measured with a specific scale.

▪ Action Observation Training for PD Rehabilitation

Several works found that AOT has a positive effect in PD rehabilitation. Most studies focused on walking disturbances. One of first studies came from [START_REF] Buccino | Action observation treatment improves autonomy in daily activities in Parkinson's disease patients: results from a pilot study[END_REF], who, in a randomized controlled trial investigated the efficacy of AOT as a complementary therapy to standard pharmacological and rehabilitative treatment. After treatment, the experimental group reported better scores in the Unified Parkinson Disease Rating Scale and the Functional Independence Measure, while there was no objective difference in gait performance. Jaywant et al. (2016a) found similar results: no difference in gait performance was observed; however, the AOT group obtained a better score in a subscale of self-perceived mobility. [START_REF] Santamato | Postural and Balance Disorders in Patients with Parkinson's Disease: A Prospective Open-Label Feasibility Study with Two Months of Action Observation Treatment[END_REF] also performed a study on efficacy of AOT in balance and walking of parkinsonians. They obtained negative results, but there was no control group in the study.

An additional effect on recovery of walking ability in PD patients with freezing of gait was observed by [START_REF] Pelosin | Action Observation Improves Freezing of Gait in Patients With Parkinson's Disease[END_REF]. The patients were randomly attributed to an "action group", who watched video clips showing specific movements and strategies to circumvent freezing episodes, or to a "landscape group" who saw video clips of static landscape pictures. Both groups underwent identical physical therapy training. The same working group has subsequently shown that watching video clips showing repetitive finger movements paced at 3 Hz increased the spontaneous rate of finger movements. AOT significantly influenced movement rate in both the on and off conditions, but 45 minutes after training, the effect was still present only in the on condition. The Authors conclude that AOT could be a promising approach in the rehabilitation of bradykinesia, even if the dopaminergic state contributes to the effects of AOT [START_REF] Pelosin | Reduction of Bradykinesia of Finger Movements by a Single Session of Action Observation in Parkinson Disease[END_REF]. In another work focusing on arm bradikynesia, Bienkiewicz et al. (2013) demonstrated that it was possible to improve motor performances in PD patients, by using a LED display simulating biological motion.

Finally, the use a "mirror box", through which a motor training is performed with the non-affected limb, but the patient receives a visual feedback from the affected limb, has been proposed to reduce hand bradykinesia in PD [START_REF] Bonassi | Mirror Visual Feedback to Improve Bradykinesia in Parkinson's Disease[END_REF]. This procedure has been used above all for stroke patients [START_REF] Ramachandran | The use of visual feedback, in particular mirror visual feedback, in restoring brain function[END_REF] The involvement of the MN system or at least some areas strictly linked to the MN network (such as the superior temporal gyrus-STG) has been proposed among the possible neural substrates [START_REF] Deconinck | Reflections on Mirror Therapy[END_REF].

The mechanism through which AOT improves motor performances in PD needs however to be further elucidated. AOT does not directly stimulate basal ganglia, but might activate MN prefrontal areas that rely to the basal ganglia through frontal-subcortical circuits. Such a kind of connections has been proposed by several Authors [START_REF] Alegre | The mirror system, theory of mind and Parkinson's disease[END_REF][START_REF] Bonini | The Extended Mirror Neuron Network[END_REF]. Recent anatomical data [START_REF] Gerbella | Corticostriate Projections from Areas of the "Lateral Grasping Network": Evidence for Multiple Hand-Related Input Channels[END_REF] have in fact shown that most of the areas forming the cortical MN network for hand actions (inferior parietal areas, ventral premotor cortex, and the ventrolateral prefrontal cortex (which, according to some Authors - [START_REF] Borra | Anatomical Evidence for the Involvement of the Macaque Ventrolateral Prefrontal Area 12r in Controlling Goal-Directed Actions[END_REF][START_REF] Gerbella | Connectional Heterogeneity of the Ventral Part of the Macaque Area 46[END_REF][START_REF] Nelissen | Action Observation Circuits in the Macaque Monkey Cortex[END_REF]-could also have MN like properties), send convergent projections to specific sectors of the putamen. In birds, imitation learning would develop, assuming a Hebbian model, using pathways between basal ganglia and MN areas (Giret et al., 2013).

A recent study [START_REF] Agosta | Brain plasticity in Parkinson's disease with freezing of gait induced by action observation training[END_REF], showed a positive effect of AOT on gait freezing and associated brain functional changes. In a protocol like that one of [START_REF] Pelosin | Action Observation Improves Freezing of Gait in Patients With Parkinson's Disease[END_REF], PD patients with freezing of gait were randomized into two groups: AOT (action observation combined with practicing the observed actions) and ''Landscape'' (same physical training combined with landscape-videos observation). After 4 weeks, both groups showed reduced freezing of gait severity, improved walking speed and quality of life, but in the AOT group motor disability was additionally reduced and balance improved. After 8 weeks, only the AOT group showed a sustained positive effect on motor disability, walking speed, balance and quality of life. Patients were then scanned while executing foot movements, a MI task related to freezing of gait, and during AOT. The AOT group showed increased recruitment of fronto-parietal mirror areas during fMRI tasks, and in the same group, functional brain changes were associated with clinical improvements. It was concluded that AOT may enhance motor learning and facilitate the building of a motor memory in PD with gait freezing through MN network activation.

A recent review about the efficacy of AOT and MI in PD [START_REF] Caligiore | Action observation and motor imagery for rehabilitation in Parkinson's disease: A systematic review and an integrative hypothesis[END_REF] concluded that AOT facilitates motor behavior at least in the earlier stages while there is less agreement about MI efficiency. Another recent review [START_REF] Patel | Action observation in the modification of postural sway and gait: Theory and use in rehabilitation[END_REF] has taken into account studies on PD rehabilitation thought AOT as a mean to modify postural way and gait. As in the case of Caligiore et al., the general conclusion of the Author is that AOT could be an effective adjunctive therapy to conventional treatment in rehabilitation, by exploiting the MN network and its ability to understand the motor planning of other people, which could favor anticipatory postural responses and reactive reflexes.

However, we now know that the motor system activity can be also modulated not only by AOT but also by an acoustic stimulus associated to action (e.g, breaking a peanut) [START_REF] Kohler | Hearing sounds, understanding actions: Action representation in mirror neurons[END_REF][START_REF] Aziz-Zadeh | Left hemisphere motor facilitation in response to manual action sounds[END_REF][START_REF] Fadiga | Motor facilitation during action observation: a magnetic stimulation study[END_REF][START_REF] Gazzola | Empathy and the Somatotopic Auditory Mirror System in Humans[END_REF]. Moreover, the cortical facilitation due to action observation is at its maximum for both acoustic and visual stimuli linked to the action [START_REF] Alaerts | Is the human primary motor cortex activated by muscular or direction-dependent features of observed movements[END_REF]. This result agrees with the idea that daily life activities are typically mediated by multiple sensorial experiences and that action production is always multimodal. MN are multimodal cells, which can be activated not only by action observation and execution but also by the acoustic perception of action-related sounds [START_REF] Kohler | Hearing sounds, understanding actions: Action representation in mirror neurons[END_REF]. Others of these complex sensory-motor neurons respond strongly to action sounds but not to the observation of actions, thus indicating their audio-motor specificity [START_REF] Keysers | Audiovisual mirror neurons and action recognition[END_REF]. These data suggest the fascinating possibility to combine the visual information with the action sound to maximize the positive effect of AOT in subjects with PD. [START_REF] Schiavio | Exploring Music-Based Rehabilitation for Parkinsonism through Embodied Cognitive Science[END_REF] have proposed the use of music in the rehabilitation of PD. It is well known that periodicity, such as the fact to match their walking to the musical beat, or to a metronome, improve velocity, cadence, and stride length of parkinsonian gait (del Olmo and Cudeiro, 2005). Indeed, as Schiavio and Altenmüller underline, "timing and periodicity are fundamental aspects of human gait and because basal ganglia-cortical circuitry is typically involved in time-related processes", therefore musical stimulation could offer a way to for a better sensorimotor coupling [START_REF] Schiavio | Exploring Music-Based Rehabilitation for Parkinsonism through Embodied Cognitive Science[END_REF]. [START_REF] Bacigalupe | Movement from the social cognitive neuroscience: The case of Parkinson's disease[END_REF] propose that the external auditory and visual cues (often used in PD rehabilitation) represent the main stimulus for the paradoxical kinesia, the phenomenon according to which PD patients improve their motor performance thanks to external stimuli relevant for movement (e.g. bradykinetic PD patients begin, suddenly and for a while, to run). Provoking this phenomenon would be possible by exploiting the two main streams of the perceptual-action coupling (but above all the dorsal stream, more linked to action) and the MN system. Exploiting paradoxical kinesia could be useful in rehabilitation, and it could be done by using motor affordances in recreational and artistic activities.

Therefore, multimodal stimulation could boost AOT effect and it could also be used in the frame of art therapy [START_REF] Mirabella | Is Art Therapy a Reliable Tool for Rehabilitating People Suffering from Brain/Mental Diseases[END_REF], by promoting creativity with artistic activities [START_REF] Miller | Creativity in the Context of Neurologic Illness[END_REF].

For a summary of the literature searching about Action, Cognition (Mirror Neurons) and PD, see Appendix, Table 1a-e.

▪ Explicit Motor Imagery

Motor Imagery (MI) is a cognitive process in which subjects imagine performing a movement without actually doing it. According the simulation theory, actions involve both an overt and a covert stage [START_REF] Jeannerod | Mental imaging of motor activity in humans[END_REF][START_REF] Jeannerod | Neural Simulation of Action: A Unifying Mechanism for Motor Cognition[END_REF]. MI would represent the result of conscious access to the intention to move [START_REF] Jeannerod | Mental motor imagery: a window into the representational stages of action[END_REF]. Many studies, since the last decade of the twentieth century (e.g. [START_REF] Abbruzzese | The excitability of the human motor cortex increases during execution and mental imagination of sequential but not repetitive finger movements[END_REF][START_REF] Decety | Do imagined and executed actions share the same neural substrate?[END_REF] have shown that this process involve many areas also recruited during action execution. Among these areas, there are regions thought to be part of MN network in humans, such as the premotor cortex and the inferior parietal lobule. Differently than AOT, which is an implicit on-line process, MI can only be performed off-line that is when one is disconnected from other potential interactions with other subjects or objects. Moreover, while AOT is automatic, MI in rehabilitation requires attention sometimes difficult to obtain. Several studies investigated MI in PD with different approaches (electrophysiological, neuroimaging and neuropsychological ones): results are once again controversial. Studies performed in patients implanted with DBS suggest an engagement of basal ganglia during MI [START_REF] Leiguarda | Globus pallidus internus firing rate modification after motor-imagination in three Parkinson's disease patients[END_REF][START_REF] Kühn | Modulation of beta oscillations in the subthalamic area during motor imagery in Parkinson's disease[END_REF][START_REF] Thobois | Effects of subthalamic nucleus stimulation on actual and imagined movement in Parkinson's disease : a PET study[END_REF]. A TMS research [START_REF] Tremblay | Corticomotor facilitation associated with observation and imagery of hand actions is impaired in Parkinson's disease[END_REF] and a neurophysiological study (Cunnington et al., 1997) recording movement-related potentials (usually associated with voluntary movements preparation and execution) reported an impaired facilitation by MI in PD. [START_REF] Conson | The role of embodied simulation in mental transformation of whole-body images: evidence from Parkinson's disease[END_REF] tested whether the most affected side by PD influenced patients' ability to mentally manipulate whole-body images (Figure 36). PD patients were specifically impaired in judging laterality of the hand corresponding to their own affected side when presented with backfacing human figures, in comparison with normal subjects. However, no difference was found for front-facing figures. Authors hypothesized that two kinds of whole-body transformation could exist: an "embodied" one, for back-facing figures, and a "perspective one", activated for front-facing bodies. However, their interpretation is questionable, and their results could be also interpreted in another way: a defective "embodied" mechanism could succeed in judging front-facing figures, but not back-facing ones, because this kind of judgment is less frequently requested (and therefore exerted) in everyday life. It must be also kept in mind that aging affects MI abilities, particularly for the non-dominant side of the body [START_REF] Saimpont | Aging Affects the Mental Rotation of Left and Right Hands[END_REF][START_REF] Saimpont | Aging affects the mental simulation/planning of the "rising from the floor" sequence[END_REF]: this could exert a confounding effect in studies focusing on MI, PD and laterality.

Figure 36: Instances of stimuli used in the three mental transformation tasks used by Conson et al., 2014: front-facing figures (first row), back-facing-figures (second row), and letter rotation task (third row), in the four spatial orientations: 0°, 90° clockwise, 90° counterclockwise and 180° (schematic human figures with their left hand marked in black.

Recent investigations testing MI through ad hoc assessment batteries did not find differences between parkinsonians and normal controls [START_REF] Heremans | Motor Imagery Ability in Patients With Early-and Mid-Stage Parkinson Disease[END_REF][START_REF] Maillet | Neural substrates of levodopa responsive gait disorders and freezing in advanced Parkinson's disease: A kinesthetic imagery approach[END_REF] both during the on and off phases [START_REF] Peterson | Effects of levodopa on vividness of motor imagery in Parkinson disease[END_REF], see Abbruzzese et al.-2015-for a complete review). A position emission tomography (PET) investigation showed that MI in PD was associated with a normal activation when imagining movements in the supplementary motor area, and a significant activation of the ipsilateral inferior parietal cortex (both in the "off" and the "on" state) and the ipsilateral premotor cortex (when "off" only). Inferior parietal cortex hyperactivation could compensate the reduced activation of other areas in comparison with controls, including the right dorsolateral prefrontal area, which deals with the working memory component of the imagery task [START_REF] Cunnington | Motor imagery in Parkinson's disease: a PET study[END_REF]. Another PET study found hypoactivation of motor regions, basal ganglia and cerebellum along with the dorsolateral prefrontal areas, with a compensatory hyperactivation of the left lateral premotor-parietal cortices and of ponto-mesencephalic areas in off, while in on the activation was similar to that one of normal controls [START_REF] Maillet | Neural substrates of levodopa responsive gait disorders and freezing in advanced Parkinson's disease: A kinesthetic imagery approach[END_REF]. A possible cortical (and subcortical) compensation was also shown in a paper reporting fMRI results [START_REF] Helmich | Cerebral compensation during motor imagery in Parkinson's disease[END_REF]. Therefore, a possible hypothesis is that neural compensation mechanisms can maintain a good performance in MI tasks.

The Mirror Neurons network, embodied cognition and the Amyotrophic Lateral

Sclerosis/Frontotemporal Dementia continuum

▪ MRI studies

In the study of [START_REF] Li | Altered cortical activation during action observation in amyotrophic lateral sclerosis patients: a parametric functional MRI study[END_REF] 30 patients with ALS and 30 matched healthy controls underwent fMRI while observing a video of repetitive flexion-extension of the fingers at three frequency or complexity levels, alternated with periods of a static hand. AOT activated brain regions related to the MN system in both ALS and healthy subjects. In ALS patients, however, the dorsal lateral premotor cortex, inferior parietal gyrus, and supplementary motor area, were more activated compared with the activation in the controls. Increased activation within the primary motor cortex, the dorsal lateral premotor cortex, the inferior frontal gyrus, and superior parietal gyrus correlated with hand movement frequency/complexity in patients. This finding indicates an ongoing compensatory process occurring within the motor-processing system of ALS patients that would overcome the loss of function.

However, this study was restricted to action observation.

Using fMRI, while subjects observed an actor's hand rhythmically squeezing a ball or squeezed themselves a ball, [START_REF] Jelsone-Swain | Action Processing and Mirror Neuron Function in Patients with Amyotrophic Lateral Sclerosis: An fMRI Study[END_REF] showed greater activity in ALS patients than in controls in MN regions within the right frontal inferior operculum, and the right frontal and the left parietal lobes. These results suggest a compensatory response of the MN system during action observation processing in ALS. The second experiment aimed to test ability in understanding actions. Participants watched a short video of an actor pantomiming an action with his hands; they had either to passively observe it or to "actively recognize" the action by choosing the correct action from two phrases displayed on the screen. The contrast analysis of the cerebral activity during active recognition versus passive observation displayed greater activity in various anterior and posterior regions in the normal group; on the contrary, in the ALS group only the right occipital activity increased. Patients were then divided into two groups according to their performance at the recognition task: only the best performers showed activation in bilateral frontal superior gyri. Their performance was also proportional to that one at the RME test. Thus, social cognition would be affected in some ALS patients, an impairment which may be related to a MN system dysfunction [START_REF] Jelsone-Swain | Action Processing and Mirror Neuron Function in Patients with Amyotrophic Lateral Sclerosis: An fMRI Study[END_REF].

Emotions are physiologic responses embodied by nature. Emotional response and feelings represent the engagement of individuals with their surroundings [START_REF] Johnson | Embodied understanding[END_REF]. [START_REF] Jastorff | Functional dissociation between anterior temporal lobe and inferior frontal gyrus in the processing of dynamic body expressions: Insights from behavioral variant frontotemporal dementia[END_REF] investigated brain regions involved in the processing of emotional stimuli in patients diagnosed with bvFTD. They combined behavioral testing with structural and resting state imaging. bvFTD patients were impaired in emotion detection as well as emotion categorization tasks in comparison with controls. Their performance in emotion categorization inversely correlated with atrophy of the left IFG, a region belonging to the MN network. Functional connectivity analysis also showed a reduced connectivity of this area. An explanatory hypothesis is the fact that, due to the IFG atrophy, an absence of motor mirroring could prevent emotion recognition. Similarly, [START_REF] Brioschi Guevara | Theory of mind impairment in patients with behavioural variant fronto-temporal dementia (bv-FTD) increases caregiver burden[END_REF], found that the atrophy of prefrontal and premotor regions at structural MRI inversely correlated with the ability of bvFTD patients to infer intention and emotional beliefs of others. Data from bvFTD patients support the role of the MN system in emotion recognition, as summarized in a previous section. [START_REF] Marshall | Embodied cognition of dynamic emotion in frontotemporal lobar degeneration[END_REF] found different grey matter correlates between impaired emotion recognition and automatic imitation according to the different clinical forms of FTD. The brain regions involved delineated a distributed neural network previously linked to embodied cognition.

Finally, another study in ALS deserves to be reported. [START_REF] Verstraete | Structural brain network imaging shows expanding disconnection of the motor system in amyotrophic lateral sclerosis[END_REF] investigated the longitudinal effects of the disease on brain networks using diffusion tensor imaging. Their analyses revealed an expanding sub-network of affected brain connections over time, with a central role for the primary motor cortex and loss of structural connectivity mainly propagating to frontal and parietal brain areas (regions also belonging to the MN network).

Some papers suggested a possible role of the MN network alteration in the pathogenesis of ALS and FTD. According to [START_REF] Eisen | Tools and talk: An evolutionary perspective on the functional deficits associated with amyotrophic lateral sclerosis[END_REF], in the ALS/FTD complex the disruption of MN network might be associated to an impairment of different evolutionarily-interlinked functions, leading to the different clinical forms of the disease, and in particular: 1) hand function specialization, and the associated development of bipedalism (associated to the "classical" form beginning from the upper limbs or to the pseudo-polyneuritic form, beginning from the lower limbs); 2) sound production, swallowing, and breathing (which the Authors designate as "the brainstem functional complex"; this impairment would be associated to the "bulbar" ALS variant); 3) cognitive functions linked to social behavior and communication ability, through gestures and language (associated to FTD).

Previously, [START_REF] Bak | What wires together dies together: Verbs, actions and neurodegeneration in motor neuron disease[END_REF] had already proposed that dementia associated with MotND could be interpreted as the fifth major clinical presentation of the disease, alongside with bulbar thoracic, upper and lower limb presentation. Accordingly, in ALS the most impaired aspects of cognitive functions are those with the tightest functional links to the motor system, such as verb and action processing (see the following paragraph).

▪ Neuropsychological and behavioral studies

A series of neuropsychological researches showed an impairment of action rather than object naming in ALS [START_REF] Bak | Noun-verb dissociation in three patients with motor neuron disease and aphasia[END_REF][START_REF] Bak | Selective impairment of verb processing associated with pathological changes in Brodmann areas 44 and 45 in the motor neuron disease-dementia-aphasia syndrome[END_REF][START_REF] Grossman | Impaired action knowledge in amyotrophic lateral sclerosis[END_REF][START_REF] York | Action verb comprehension in amyotrophic lateral sclerosis and Parkinson's disease[END_REF], and FTD [START_REF] Cappa | Object and action naming in Alzheimer's disease and frontotemporal dementia[END_REF][START_REF] Hillis | Deterioration of naming nouns versus verbs in primary progressive aphasia[END_REF]. When combining neuropsychological assessment and morphological MRI, [START_REF] York | Action verb comprehension in amyotrophic lateral sclerosis and Parkinson's disease[END_REF] showed that performance in action verb judgment was related to gray matter atrophy in bilateral frontal regions, including motor association cortex and pre-frontal regions. Similarly, [START_REF] Grossman | Impaired action knowledge in amyotrophic lateral sclerosis[END_REF]; had shown that cortical atrophy in premotor areas associated with the representation of the face, arm, and leg correlated with performance on measures requiring action knowledge. This supports the hypothesis that the difficulty shown by ALS patients in naming actions is partly related to the degradation of action-related conceptual knowledge represented in motor-associated cortex. [START_REF] Bak | What wires together dies together: Verbs, actions and neurodegeneration in motor neuron disease[END_REF], focusing on cognitive impairment in some ALS patients, underlined that the most impaired aspects of cognitive function are those with the closest functional links to the motor system, a pattern explaining the disproportionate impairment of verb and action processing in this disease (see also [START_REF] Bak | The neuroscience of action semantics in neurodegenerative brain diseases[END_REF]. It would be of interest testing whether AOT is able to improve this kind of cognitive impairment. Otherwise, it must be cited a well-conducted case study by Vannuscorps et al. (2016, Figure 38), who longitudinally examined a patient with CBD, a clinical picture related to FTD, for 4 years. During the period of investigation, the patient presented with increasing action production disorders with associated increasing bilateral atrophy in cortical and subcortical regions involved in sensorimotor control (the superior parietal cortex, mostly on the right side, the primary motor and premotor cortex, the inferior frontal gyrus, and the basal ganglia). In contrast, the patient's performance in processing action-related concepts (e.g action naming and action comprehension) was spared during the same period. These data, suggesting that action concept processing is based on distinct cognitive and neural resources from those underlying the sensorimotor control of actions, defies the "strong" embodied view, while being compatible with a "weak embodiment" view [START_REF] Meteyard | Coming of age: A review of embodiment and the neuroscience of semantics[END_REF]). In the "weak option" of the embodied theory, sensorimotor information (activated within the action production system while conceptual processing takes place) is constitutive, but not central, of actions meaning. However, in our opinion, it cannot be excluded that the relative sparing of some brain areas (both the inferior parietal lobes, the right superior parietal lobe, the right precentral gyrus and both the caudal middle frontal gyri) could have support the preservation of action naming of Vannuscorps' patient.

Figure 38: results from the study of [START_REF] Vannuscorps | Persistent sparing of action conceptual processing in spite of increasing disorders of action production: A case against motor embodiment of action concepts[END_REF] For a summary of the literature searching about Action, Cognition (Mirror Neurons) and FTD/ALS, see Appendix, Table 2a-b.

The Mirror Neurons network, embodied cognition and the Mild Cognitive

Impairment/Alzheimer disease continuum

▪ Correlation between morphological MRI data and EEG spectral analysis

Recently, 74 adult subjects with MCI have undergone EEG recording and high resolution MRI by [START_REF] Moretti | Involvement of mirror neuron system in prodromal Alzheimer's disease[END_REF]. Alpha3/alpha2 frequency power ratio -whose increase has been detected in MCI subjects who will convert in AD [START_REF] Moretti | Volumetric Differences in Mapped Hippocampal Regions Correlate with Increase of High Alpha Rhythm in Alzheimer's Disease[END_REF] -as well as cortical thickness were computed for each subject. High EEG alpha3/alpha2 frequency power ratio was correlated with atrophy of cortical regions belonging to the posterior MN network (IPL) areas in MCI subjects. Thus, a possible pathological uncoupling of the MN system would explain the cognitive deficits in prodromal AD.

The location of the IPL at the junction of the parietal, temporal and occipital lobes makes it ideally situated to perform cross-modal integration (hearing/vision/proprioceptive): its impairment would induce both praxis, language, calculation and topographical deficits characterizing AD, a hypothesis agreeing with traditional neurological views [START_REF] Greene | Subregions of the inferior parietal lobule are affected in the progression to AD[END_REF].

▪ fMRI studies

A fMRI study by [START_REF] Lee | Neural activities during affective processing in people with Alzheimer's disease[END_REF] aimed at evaluating neural activities during processing of facial expressions of others in AD patients. The patients showed weaker activations in left cerebral regions associated with MN or empathic simulation (ventral premotor cortex and the anterior insula and adjacent frontal operculum, respectively) compared to matched controls. Importantly, levels of brain activation in those regions also predicted the level of affect in the AD group. Thus, neural changes in regions associated with motor and emotional simulation (comprised MN regions) could play a role in the development of AD symptoms, and explain affective impairment associated with this disease. [START_REF] Peelle | Frontotemporal neural systems supporting semantic processing in Alzheimer's disease[END_REF] tested a semantic judgment task, involving shape and color of natural kinds or manufactured items. AD patients were impaired in this task, and exhibited significantly less activation the in left temporal-occipital cortex than did healthy seniors, and a reduced activity in the left inferior frontal cortex. According to the Authors, these results are consistent with a sensory-motor approach of semantic memory: knowledge associated with object concepts would be stored in brain regions that are responsible for perceptual and motor functions of a certain material (Barsalou et al. 2003).

▪ Behavioral studies

In a first study [START_REF] Bisio | Motor resonance mechanisms are preserved in Alzheimer's disease patients[END_REF] tested AD patients in mild and moderate stages of the pathology, if the implicit imitation is preserved. AD patients and healthy elderly participants were required to observe a dot moving on a screen and to point to its final position when it stopped. The dot speed similarly influenced AD patients' and healthy elderly participants' actions, suggesting that perception-action matching is not prevented by pathology. In contrast, only patients had anticipatory motor response: i.e. they started moving before the end of the stimulus motion, unlike what was requested by the experimenter. While the imitation of the stimulus velocity suggests an intact ability to match the internal motor representations with that of the visual model, the uncontrolled motion initiation would indicate AD patients' deficiency to voluntarily inhibit response production. The Authors hypothesize that the first part to their results would point to a relative preservation of the MN network (responsible of perception-action matching). However, MN parietal areas would be less spared than frontal ones, leading to the impaired movement inhibition.

In a second experiment [START_REF] Bisio | Voluntary Imitation in Alzheimer's Disease Patients[END_REF] the authors tested voluntary imitation in AD and how this ability was modulated by the nature of the observed stimulus by comparing the ability to reproduce the kinematic features of a human demonstrator with that of a dot moving on a screen (Figure 39). Results showed that when asked to imitate the velocity of the stimulus AD patients showed an intact ability to reproduce it. This ability improved when the stimulus was a human agent. This result suggests that high-level cognitive processes involved in voluntary imitation might be preserved in mild and moderate stages of AD and that voluntary imitation abilities might benefit from the implicit interpersonal communication established between the patient and the human demonstrator. These findings open new clinical perspectives and innovative techniques in training programs for people with dementia. In particular, the preservation of the motor resonance mechanisms, not dependent on conscious awareness, constitutes an intact basis upon which clinicians could model both physical and cognitive interventions for healthy elderly and AD patients. Furthermore, by stimulating the voluntary imitation of everyday activities the caregivers might help the patients to maintain intact, as long as possible, the ability to easily move in their familiar environment and to feel they are still part of their family community. The upper part of the figure represents the set-up when the participants observed the Dot stimulus. They were seated in front of a large screen and they observed the upward displacement of the Dot at three different speeds and durations. The bottom part of the figure shows the experimental set-up for the human observation condition, with the participants and human demonstrator seated face to face. In both conditions participants were requested to observe the stimulus movements and when the stimulus stopped to reach its/his final position, imitating its/his velocity.

▪ Neuropsychological studies

Some studies pointed out a more severe impairment in action than in object naming in AD patients (Robinson et al., 1996, Kim and[START_REF] Kim | Verb deficits in Alzheimer's disease and agrammatism: Implications for lexical organization[END_REF][START_REF] Druks | Is action naming better preserved (than object naming) in Alzheimer's disease and why should we ask?[END_REF], even if at a lesser extent than in FTD [START_REF] Cappa | Object and action naming in Alzheimer's disease and frontotemporal dementia[END_REF]. [START_REF] Cotelli | Limb apraxia and verb processing in Alzheimer's disease[END_REF] found a correlation between action comprehension, action naming abilities, language impairment and apraxia. These studies not only suggest a tight link between language and execution of complex motor movements, but also support the idea that a stimulation of the motor system could improve language performance, and in general cognitive abilities in people with AD. In contrast, other researchers reported that nouns were more impaired than verbs in AD patients [START_REF] Williamson | Object and action naming in Alzheimer's disease[END_REF] or did not report any difference between nouns and verbs [START_REF] Masterson | Selective naming (and comprehension) deficits in Alzheimer's disease?[END_REF][START_REF] Rodríguez-Ferreiro | Name agreement, frequency and age of acquisition, but not grammatical class, affect object and action naming in Spanish speaking participants with Alzheimer's disease[END_REF]. According to [START_REF] Vonk | Object and action processing in Alzheimer Disease: the embodied view of cognition[END_REF][START_REF] Vonk | Semantic subcategories of nouns and verbs A neurolinguistic review on healthy adults and patients with Alzheimer's disease Edited by: Astesano, C; Jucla, M. Neuropsycholinguistic Perspectives On Language Cognition: Essays In Honour Of Jean-Luc Nespoulous[END_REF], these contrasting results remain consistent with an embodied cognition framework. In fact, both verb and nouns subcategories with semantic features (e.g. words indicating a "change or state") linked to brain areas particularly altered by AD (temporoparietal areas) seem to be more affected in this disease than other subcategories.

Behavioral studies have also shown deficits among individuals with AD in recognizing facial emotions [START_REF] Guaita | Impaired Facial Emotion Recognition And Preserved Reactivity To Facial Expressions In People With Severe Dementia[END_REF][START_REF] Bediou | Impaired Social Cognition in Mild Alzheimer Disease[END_REF]; see also [START_REF] Mclellan | The recognition of facial expressions of emotion in Alzheimer's disease: a review of findings[END_REF] for a review), mainly in the recognition of happy, sad, and fearful expressions [START_REF] Kohler | Emotion-Discrimination Deficits in Mild Alzheimer Disease[END_REF]. These data appear coherent with a putative impairment of the MN network in AD, since this network is involved in recognizing other people emotions.

On the contrary, [START_REF] Scalzi | Embodiment effects and language comprehension in Alzheimer's disease[END_REF] found a conservation of the action compatibility effect in people with AD: when patients are asked to make judgments on sentences that describe a transfer of an object toward or away from their body, they are faster to respond when the response requires a movement in the same direction as the transfer described in the sentence. This raises the possibility to exploit the motor systems to improve language comprehension of AD (e.g., by requiring performing the action while listening to a sentence).

Recently, [START_REF] Vallet | A SEMantic and EPisodic Memory Test (SEMEP) Developed within the Embodied Cognition Framework: Application to Normal Aging, Alzheimer's Disease and Semantic Dementia[END_REF] tested young and elderly people, and persons with AD or semantic dementia (the fluent form of PPA) with the SEMEP: SEMantic-Episodic memory test: see Figure 40). This test allows to test both episodic and semantic memory at the same time. In the free recall and recognition tasks of the SEMEP, a confusion error is defined as the recall or recognition of an item presented in the encoding phase that was not to be learned, while an intrusion error consists in the recall or recognition of an item never presented to the participant in the encoding phase. According to "embodied cognition" theory, memory and perception are very tightly bound, and multimodal integration occurs during the retrieval of a memory trace (e.g., [START_REF] Zimmer | Handbook of Binding and Memory: Perspectives from Cognitive Neuroscience[END_REF],. The different groups showed specific patterns of performance: normal elderly committed confusion errors for presented items, but not intrusions (recall or recognition of items never presented). AD patients presented the worst episodic memory performance associated with intrusion errors and did not benefit from a visual isolation (addition of a yellow background), a method known to increase the distinctiveness of the memory traces. The sematic dementia group evidently suffered from the most severe semantic impairment. The increase of memory errors in normal elderly is supposed to reflect the sensory/perceptual decline in healthy aging (see Roberts and Allen, 2016 for a review). On the contrary, the lack of efficacy of visual isolation in AD would be linked to the impaired multisensory integration [START_REF] Vallet | The perceptual nature of audiovisual interactions for semantic knowledge in young and elderly adults[END_REF] due to the AD related disconnection syndrome [START_REF] Delbeuck | Is Alzheimer's disease a disconnection syndrome? Evidence from a crossmodal audio-visual illusory experiment[END_REF]. If confirmed, these results would prompt for a training based on motor cognition framework in normal elderly or at least in a very early phase of memory impairment, when methods such as visual isolation still work.

Figure 40:

The SEMEP: SEMantic-Episodic memory test [START_REF] Vallet | A SEMantic and EPisodic Memory Test (SEMEP) Developed within the Embodied Cognition Framework: Application to Normal Aging, Alzheimer's Disease and Semantic Dementia[END_REF]. During the encoding phase, the instructions insist on the fact that two tasks had to be done at the same time: a matching task (judging which one of the two pictures, presented at the bottom, best matches the model) and a learning task (learning the corresponding name of the correct answer of the matching task).

▪ TMS studies

In a study from [START_REF] Cotelli | Effect of Transcranial Magnetic Stimulation on Action Naming in Patients With Alzheimer Disease[END_REF], TMS of both the left and right dorsolateral prefrontal areas (a region) improved action naming but not object naming in 15 AD patients. Similar results were obtained for a mild AD group [START_REF] Cotelli | Transcranial magnetic stimulation improves naming in Alzheimer disease patients at different stages of cognitive decline[END_REF], while an improved naming accuracy for both action and objects was found in the moderate to severe group. These results are difficult to interpret. The role of the dorsolateral prefrontal cortex in action naming must be further elucidated. A possibility might be the fact that this cerebral area can intervene by selecting and combining motor representations in the MN system [START_REF] Vogt | Prefrontal involvement in imitation learning of hand actions: Effects of practice and expertise[END_REF] It must be also mentioned a recent study finding neurons with mirror-like properties in the dorsolateral prefrontal cortex, linked to self and other people head rotation [START_REF] Lanzilotto | Neuronal Encoding of Self and Others' Head Rotation in the Macaque Dorsal Prefrontal Cortex[END_REF]. In any case, TMS studies raise the interesting possibility to improve language performance in AD via magnetic stimulations of the motor system.

▪ Rehabilitative studies

So far, the only published research about AOT with AD is from [START_REF] Eggermont | Observation of Hand Movements by Older Persons with Dementia: Effects on Cognition[END_REF]. Nursing home residents with dementia watched either videos showing hand movements (19 subjects, AOT group) or a documentary (25 subjects) for 30 min, 5 days a week, for 6 weeks. At the end of treatment, patients treated with AOT showed improvements in attention and facial recognition (which depends on the STS, a region tightly linked to the MN system). A preliminary research in progress, performed on small groups (9 each) of patients diagnosed with mild to moderate AD, compared AOT with multidimensional stimulation [START_REF] Spada | Neural structures associated with recognition of facial expressions of basic emotions[END_REF]. The data analysis showed a significant improvement between test and retest in a naming action task. However, recently an intervention focused on MN in AD patients showed negative results (Caffarra P, 2016, oral communication at XI Sindem National Congress, Florence, Italy).

For a summary of the literature searching about Action, Cognition (Mirror Neurons) and AD/MCI, see Appendix, Table 3a-f.

CONCLUSIONS OF THE REVIEW ON STUDIES LINKING ACTION, COGNITION (MIRROR NEURONS) AND NEURODEGENERATIVE DISEASES

Data about the status and role of MN network, and in general studies based on embodied cognition concepts, in neurodegenerative diseases are poor with the partial exception of PD. A hypothetic conclusion of existing studies in PD could be that the MN network is in some way altered in this disease (the rationale in this case could be the degeneration of cortical-subcortical loops linking the basal ganglia to the frontal cortex): an hyperactivation of this system might support motor and cognitive performances, at least in early stages, while in later stages the more severe impairment of the MN network could prevent compensation at least in a part of patients. The dopaminergic state, and DBS, could have a role in compensating the functional deficits of circuits linked to motor cognition, too. The compensation mechanism could explain why studies on AOT as a rehabilitative method for people with PD report positive results. Interestingly, a very recent study on mild to moderate PD patients showed that they can be highly influenced by motor contagion induced by AOT also in a negative sense [START_REF] Pelosin | Postural Stabilization Strategies to Motor Contagion Induced by Action Observation Are Impaired in Parkinson's Disease[END_REF]. Most studies in the field of PD rehabilitation have recruited very small samples. On the other hand, it must not be forgotten that, in rehabilitative studies, studying large samples of people does not allow to individualize the treatment according to the clinical picture that, as we have seen, can be very various along the course of the disease in each patient. Therefore, in the field of rehabilitation, the ideal situation would be often to characterize each patient to follow him/her as a single case experiment.

In the ALS/FTD continuum, preliminary evidences point out to an involvement of the MN network, a possibility, which is not unexpected, as MN are primarily motor neurons. The MN system decay could explain language and inter-subjectivity deficits shown in these patients. In the MCI/AD spectrum, data are very scarce. Recent studies suggest a possible involvement of the MN network. However, more researches are needed to confirm this hypothesis, also because previous behavioral researches pointed in the opposite direction.

REASONS AND AIM OF THE EXPERIMENTAL STUDY

As already stated, almost all studies on neurodegenerative diseases have been conducted according to the traditional model, which considers cognitive abilities as higher-level supervisor functions, and perception and action as separated lower-level systems. Reinterpreting neurodegenerative diseases at the light of the embodied cognition hypothesis could help a better comprehension of clinical manifestations and open new pathways to rehabilitation.

According to [START_REF] Vallet | Embodied cognition of aging[END_REF], exploring embodiment in normal and abnormal aging would be of interest both from a theoretical point of view, as becoming older is associated with changes in all brain, sensory and bodily functions, and from a practical point of view, because it would possibly allow to develop interventions to help patients. Vallet briefly reviews the few studies that explored cognition in elderly people according to the embodied cognition theory and concludes that it would be possible to influence their memory performance by focusing on multisensory features of the stimulus and/or the motor context of learning. At the same time, it would be possible to improve cognition in aging by focusing on the whole-body functioning of the individual. Interestingly, [START_REF] Tia | Improvement of motor performance by observational training in elderly people[END_REF] demonstrated that training elderly people through AOT could induce a reactivation in mental representation of action, leading to an increase of their walking speed and a decrease of the duration of back-to-sit movements. It is obvious that these data open exciting possibilities to improve motor performance in elderly population after an inactivity period.

On the other hand, several studies have shown positive effects of cognitive (e.g., [START_REF] Davis | Cognitive Intervention in Alzheimer Disease: A Randomized Placebo-Controlled Study[END_REF][START_REF] Rebok | Ten-Year Effects of the Advanced Cognitive Training for Independent and Vital Elderly Cognitive Training Trial on Cognition and Everyday Functioning in Older Adults[END_REF] or physical training [START_REF] Colcombe | Cardiovascular fitness, cortical plasticity, and aging[END_REF][START_REF] Miller | The Memory Fitness Program: Cognitive Effects of a Healthy Aging Intervention[END_REF]; see also Kramer et al., 2007) on elderly people's cognition and quality of life. Some studies included both physical and cognitive aspects in the training (e.g. Cesari et al., 2014;[START_REF] Gajewski | Training-Induced Improvement of Response Selection and Error Detection in Aging Assessed by Task Switching: Effects of Cognitive, Physical, and Relaxation Training[END_REF]. Some Authors showed more benefits from combined training [START_REF] Oswald | Differential effects of single versus combined cognitive and physical training with older adults: the SimA study in a 5-year perspective[END_REF]; see also the review of [START_REF] Bamidis | A review of physical and cognitive interventions in aging[END_REF] while other ones [START_REF] Theill | Effects of simultaneously performed cognitive and physical training in older adults[END_REF] did not. Therefore, further systematic investigations are necessary to determine the respective role of these two types of training in cognitive improvement in older people, even if more and more scientists claim for a multimodal stimulation [START_REF] Bamidis | A review of physical and cognitive interventions in aging[END_REF]). In the last years, studies combining cognitive and physical training have been also performed with people suffering from MCI or AD [START_REF] Suzuki | Effects of multicomponent exercise on cognitive function in older adults with amnestic mild cognitive impairment: a randomized controlled trial[END_REF][START_REF] Singh | The Study of Mental and Resistance Training (SMART) Study-Resistance Training and/or Cognitive Training in Mild Cognitive Impairment: A Randomized, Double-Blind, Double-Sham Controlled Trial[END_REF][START_REF] Baglio | Multistimulation Group Therapy in Alzheimer's Disease Promotes Changes in Brain Functioning[END_REF][START_REF] Kim | Physical Exercise with Multicomponent Cognitive Intervention for Older Adults with Alzheimer's Disease: A 6-Month Randomized Controlled Trial[END_REF]. The results of a recent metanalysis emphasize the clinical relevance of combined cognitive and physical training strategies, on global cognitive function, activities of daily living and mood [START_REF] Karssemeijer | Positive effects of combined cognitive and physical exercise training on cognitive function in older adults with mild cognitive impairment or dementia: A meta-analysis[END_REF]. The positive impact of such combination would reflect the strong link between the two components arbitrarily dissociated and gives support to the idea that that cognition is embodied. Action could also represent a way to support memory performance in AD. It has been assumed that the superiority of action to support retrieval is explained by the non-explicit nature of encoding during action (as opposed to a verbal encoding) and by richer set of cortical area involvement including visual, spatial, and motor input [START_REF] Zimmer | Memory for Action: A Distinct Form of Episodic Memory?[END_REF]. Indeed, AD patients improve their memory performance when memory is feed-back by voluntary movement and associated sensory modalities, such as vision, proprioception, tactile and auditory cues (which could involve different preserved brain areas such as cerebellum, and premotor cortex; [START_REF] Ghio | Cognitive training with action-related verbs induces neural plasticity in the action representation system as assessed by gray matter brain morphometry[END_REF]: better memory resulting from action production has been observed at the early, moderate and severe stages of AD [START_REF] Lekeu | Exploring the Effect of Action Familiarity on SPTs Recall Performance in Alzheimer?s Disease[END_REF], after a delay [START_REF] Masumoto | Influence of motoric encoding on forgetting function of memory for action sentences in patients with Alzheimer's disease[END_REF], and in working memory [START_REF] Charlesworth | Working Memory and the Enactment Effect in Early Alzheimer's Disease[END_REF]. Other studies demonstrated that recall of different aspects of episodic memory (recall of what, where, when and binding) has been enhanced after an active exploration in MCI or AD patients [START_REF] Plancher | Using virtual reality to characterize episodic memory profiles in amnestic mild cognitive impairment and Alzheimer's disease: influence of active and passive encoding[END_REF]2013). Indeed, in an active exploration strategy, the brain closes the loop by linking intentionality and predictions to sensory feedbacks. In contrast, passive movements (i.e., guided by a robot arm or a physiotherapist) provide feedback unrelated to a specific goal and unverifiable. These results promote the idea that memory can be treated as embodied in nature by proposing that the past is 'situated' in the body of the individual. In consequence, all episodic memories would contain links with actions and could efficiently subserve the need of perception and action coupling [START_REF] Wilson | Six views of embodied cognition[END_REF] for a review).

As explained in a previous paragraph, AOT, which is a mean to stimulate the MN network, has been proposed as a rehabilitative motor tool (see [START_REF] Bassolino | Activating the motor system through action observation: is this an efficient approach in adults and children[END_REF] for a review). However, AOT could also play a role in maintaining cognitive functions, if one accepts the indissociable nature of cognition from the motor system. Based on the supposed role of the motor system in memory building-up, it is hypothesized that MN stimulation through AOT maintain and speed the execution of complex motor sequences needed to perform activities of daily living and facilitate the formation of memory traces of actions executed during a normal day in people with AD or at least with MCI. It might be a powerful tool to improve motor, language and/or social cognition deficits in people with PD or FTD, too.

However, studies evaluating the integrity of motor resonance in neurodegenerative diseases would be a prerequisite for rehabilitation. Of interest, too, is to study MN with fMRI or neurophysiological techniques and correlating data with neuropsychological tests exploring functions traditionally linked to MN. As it has emerged from the literature review, data in this domain are still scarce.

The aim of the current study was to investigate integrity of MN network in normal aging, MCI and AD. For this purpose, three matched groups of subjects (normal elderly people, people affected by MCI and AD patients) were evaluated with a fMRI task specifically constructed to test functioning of MN [START_REF] Cabinio | The shape of motor resonance: Right-or left-handed?[END_REF]. According to this previous fMRI study in normal subjects and to fMRI MN literature, we expected activation of the frontal cortex (Brodmann area BA6 and precentral gyrus,) the parietal cortex (rostral part of the inferior parietal lobule, BA40) and the temporal cortex (STG, BA22 and BA42) in the case of preservation of MN system functioning.

CHAPTER 3 -EXPERIMENTAL CONTRIBUTION

MATERIALS AND METHODS

SUBJECTS

Sixteen AD patients and an equal number of aMCI subjects and aged healthy subjects (NE) were enrolled and performed a fMRI study and a neuropsychological assessment.

Table 1 summarizes the demographic data of the three groups. Age, education level and gender was not significantly different (ANOVA). Probable AD was diagnosed according to NIA-AA criteria [START_REF] Mckhann | The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease[END_REF]. aMCI subjects were diagnosed according to Petersen's criteria [START_REF] Petersen | Mild cognitive impairment: clinical characterization and outcome[END_REF][START_REF] Petersen | Current concepts in mild cognitive impairment[END_REF]. Only MCI subjects with significant atrophy of at least one hippocampus were included in the study (see later). The following is the exclusion criteria: patients unable to understand and/or follow instructions; severe attentional deficits, untreated psychiatric disorders, joint deformity of arthritic origin, visual or hearing deficits, previous stroke or other neurological disorders, contraindications to MRI. Persons with MCI or dementia were consecutively recruited from the Don Carlo Gnocchi Foundation Service for Cognitive Disorders and Dementia. Patients were diagnosed after taking their clinical history and carrying out medical and neurological examinations, routine blood tests and neuropsychological assessment. All patients also underwent either brain CTs or MRIs to evaluate the vascular lesion load and to exclude rarer causes of dementia (e.g. tumors, hematomas, etc.). The control group consisted of spouses or hospital volunteers. This study was carried out in accordance with the recommendations of the Don Gnocchi Foundation ethical hospital committee, with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the Don Gnocchi Foundation ethical hospital committee.

fMRI EXPERIMENTAL PARADIGM

During the fMRI scanning, participants were asked to perform 2 block-designed runs (A-B structure): in one run, they were instructed to observe (observational runs) and in the remaining run to execute hand grasping movements (motor run), according to a paradigm described in [START_REF] Cabinio | The shape of motor resonance: Right-or left-handed?[END_REF] Briefly, in the observation run, all subjects viewed movies of hand grasping different objects (see fig 1-A). In the motor run, subjects observed visual stimuli consisting of objects oriented in order to be grasped with the right hand; and they were asked to perform a grasping movement appropriate to the shape of the object (see fig 1 -B; subjects were asked to perform movements as if they had the observed object actually in their hand, therefore the execution condition was a mime of the action).

The motor act was performed continuously during the observation of the image of each object, with a frequency of about 0,5 Hz and a total number of 27 objects (brush, manual perforator, coffee cup, eraser, box, torch, knife, screwdriver, sun glasses, pen, lighter, bottle, glass, pot, fork, lego brick, keys, meterstick, stapler, phone, scissors, padlock, nail polish, wrench, ball, sponge, cup). The decision to use different types of grasp (both observed and executed) was driven by the need to recruit the highest percentage of MN and thus increment the BOLD signal [START_REF] Iacoboni | Grasping the intentions of others with one's own mirror neuron system[END_REF][START_REF] Cabinio | The shape of motor resonance: Right-or left-handed?[END_REF][START_REF] Marino | The modulation of the motor resonance triggered by reachto-grasp movements: No role of human physical similarity as conveyed by age[END_REF][START_REF] Ehrsson | Cortical activity in precision-versus power-grip tasks: an fMRI study[END_REF]. Figure 41 shows some visual stimuli presented to the subjects in each experimental condition. Before the fMRI experiment, the participants were verbally instructed to execute the movements as if the object was close to their hand, and to carry out the task only with the hand and the wrist: repeating this action, until the appearance of the next picture. Participants were trained outside the scanner for 15 min before data acquisition. During the training session, subjects were instructed to keep their gaze on the fixation point for the entire duration of the experiment, and to execute grasping movements about once every 2 seconds. If the training task (that was conducted with different parallel versions), was not properly executed by the subjects, they were not included in the study.

We used an MR-compatible visual system to present the stimuli (VisuaStim Digital system, Resonance Technology Inc.). The use of E-Prime software (E-Prime 2.0 Psychology Software tool, http://www.pstnet.com) ensured exact timing of prompts during MR acquisition. The performance was visually checked by the examiner during the execution of the task. The examiner maintained accuracy by reporting all the tasks correctly performed. The design was fully randomized (both blocks and runs).

MRI acquisition

Functional images were collected by a gradient echo-planar (EPI) T2* sequence (TR = 3000 ms; TE = 50 ms; flip angle = 90°; voxel size = 2,8125 × 2,8125 × 4 mm; matrix size = 448 × 448; number of slices = 38; thickness = 4 mm) using BOLD (blood oxygenation level dependent) contrast. Each fMRI session included two runs of 122 dynamics.

MRI data was acquired on a 1.5 Tesla Siemens Magnetom Avanto at Santa Maria Nascente Institute IRCCS, Don Carlo Gnocchi Foundation.

A conventional T2-weighted scan (TR = 2920 ms; TE = 108 ms; voxel size = 0,75 × 0,75 × 5,2 mm; matrix size = 320 × 320; slice thickness = 4 mm; number of slices = 25) was performed in every subject in order to exclude brain abnormalities. A 3D T1-weighted FFE scan (TR = 1900 ms; TE = 3.37 ms; voxel size = 1 × 1 × 1 mm; matrix size = 192 × 256; slice thickness = 1 mm; number of slices = 176) was acquired to be used as an anatomical reference for fMRI analysis and to compute hippocampal volumes on every subject.

Hippocampal segmentation

Bilateral hippocampi were segmented using a dedicated software (FSL- FIRST Patenaude et al, 2011). Brain tissue volume, normalized for subject head size, was estimated with SIENAX [START_REF] Smith | Accurate, Robust, and Automated Longitudinal and Cross-Sectional Brain Change Analysis[END_REF], part of FSL [START_REF] Smith | Advances in functional and structural MR image analysis and implementation as FSL[END_REF]). An ANCOVA analysis was performed to compare hippocampal volumes between groups. The Scaling Factor, obtained using SIENAX, was included as a covariate in the analysis. Results were considered as statistically significant if surviving p<.05 with Bonferroni correction for multiple comparisons.

fMRI analysis

fMRI data was analyzed in agreement with the General Linear Model running on MATLAB 7.6 (MathWork, Natick, MA) and SPM12 (Wellcome Dept. Cogn. Neurol., London; http://www.fil.ion.ucl.ac. uk/spm). Images were first corrected for motion, then they were realigned and movement parameters were estimated. Anatomical and functional images were then spatially normalized to the MNI template using a 2 × 2 × 2 voxel size with a trilinear algorithm. The normalized functional images were spatially smoothed using a 8-mm full-width at half-maximum isotropic Gaussian kernel.

At the first-level, we modeled the expected hemodynamic response function of the software package with a block design. Six parameters related to head movement during scanning, were included as regressors of no interest. For each subject, we estimated two t-contrasts: observation of a hand grasping (O) and execution of grasping movements (M).

All contrasts defined in the First Level were included in the Second Level analysis of the three groups: NE, MCI and AD.

In order to identify MN areas active during both movement, observation and execution, we performed on each group a conjunction analysis, between O and M contrasts. We exclude from the analysis, voxels not active in both contrasts at a certain threshold. To this aim, we masked the conjunction analysis with voxels active in both contrasts used to perform the conjunction at a threshold of p<.05, as done elsewhere [START_REF] Cabinio | The shape of motor resonance: Right-or left-handed?[END_REF][START_REF] Cerri | The mirror neuron system and the strange case of Broca's area: Broca is Not Part of Mirror Neuron System[END_REF]. We also included in the model, age and MMSE value as nuisance covariates. With this analysis, we determined voxels active during both observation and execution of hand movements. The assumption is that neurons involved in the MN system are among those activated during both conditions. Thus, the conjunction analysis can be considered as a mask through which only those voxels that are significantly active in the two conditions are selected (O, M), even if they have different p values (provided that the p values are above the selected threshold). Moreover, one-way analysis of variance (ANOVA) was used to determine whether there were any significant differences between the three groups (NE, MCI, AD) in the single experimental conditions (O, M) including age and MMSE value as nuisance covariates in the GLM. F-Contrasts tested for the difference between the three groups and for mean activations in the entire sample. All these second-level results have been considered as statistically significant if surviving a threshold of p<.05 FWE-corrected with a k=50 contiguous voxels.

NEUROPSYCHOLOGICAL ASSESSMENT

The neuropsychological assessment was centered on functions considered to be linked to the MN system, such as language (particularly action naming; [START_REF] Kemmerer | Behavioral patterns and lesion sites associated with impaired processing of lexical and conceptual knowledge of actions[END_REF] and empathy; we also tested memory (as memory deficits characterize AD and aMCI) and attention/executive functions (abilities which are associated to frontal lobe functioning) (see Table 2 for test list). Subjects were all right-handed in according to the Edinburgh Handedness Inventory [START_REF] Oldfield | The assessment and analysis of handedness: The Edinburgh inventory[END_REF]. 3.2 RESULTS

HIPPOCAMPAL VOLUME MEASUREMENTS

The ANCOVA analysis showed statistically significant differences in bilateral hippocampal volume between the NE and the MCI groups, as well as between the Control and the AD groups. No volumetric differences were observed between the MCI and the AD groups. Differences were found in both Left and Right Hippocampi (see Tab. 3).

fMRI CONJUNCTION ANALYSIS

All subjects correctly performed the fMRI runs. Given the premise that regions included in the MN network must be activated both in movement execution and in movement observation, to identify cortical areas involved in this network we performed conjunction analysis between activation of the two conditions M and O. This analysis was carried out separately for the three groups of NE, MCI and AD subjects. All regions of significantly increased activation (pFWE<.05 at cluster level with K=50 contiguous voxels) are summarized in Table 4 and illustrated in Figure 42, each group separately. In NE subjects the conjunction analysis showed a statistical significant [t contrast 3.41; k=50; pcluster (FWE-corr)<.05] activation of the bilateral fronto-parietal network (left>righ side) formed by the frontal cortex (Precentral Gyrus, PrCG, BA6) and the parietal cortex (Inferior Parietal Lobule, IPL, BA40) along with activation of the right STG (BA22/42) and the right Fusiform Gyrus (FuG),

In MCI subjects the same conjunction analysis [t contrast 3.41; k=50; pcluster(FWE-corr)<.05] revealed the activation of the frontal-parietal network (right<left side) including also the left Inferior Frontal Gyrus (IFG, BA44), but activation of BA40 was not as strong as in NE participants. A bilateral cerebellar activation was also detected. See Table 4.

Finally, in AD patients the conjunction analysis [t contrast 3.41; k=50; pcluster (FWE-corr)<.05] showed a statistical significance recruitment in the bilateral FuG and in the left cerebellum. It found no activations in the fronto-parietal network.

An additional analysis to investigate potential differences in brain activation between the three groups for the M or O condition was carried out separately, and did not reveal any significant group differences. The Figure 43 [ANOVA,F contrast 14.74;k=50] and Movement condition [ANOVA,F contrast 13.48;k=50], at statistical threshold voxel-wise pFWE-corrected<.05.

NEUROPSYCHOLOGICAL TESTS

The results of AD patients were worse than NE subjects in all neuropsychological tests. These tests comprised tests of action naming and empathy, functions attributed to MN network. The only exception was the object naming test (probably due to a ceiling effect). aMCI subjects were significantly different from NE participants only in the episodic memory test, the FCRST, and in semantic fluency (see Table 6 for results) .

CHAPTER 4 -GENERAL DISCUSSION

We investigated the integrity of MN areas through fMRI in three groups: NE subjects, people with aMCI and AD patients. We detected differences among the 3 groups, suggesting a progressive weakening of the MN network with respect to neurodegenerative process. These differences are discussed in the following sections.

MIRROR NEURONS NETWORK ALTERATION

In the NE group, the conjunction analysis (fMRI activation recorded during observation of hand grasping compared to overt execution of grasping movements) showed the activation of a bilateral, though strongly left-lateralized, fronto-parietal network (PrCG, BA6; IPL, BA40). The fronto-parietal network activated in our study is considered part of the human MN network [START_REF] Rizzolatti | The mirror-neuron system[END_REF], given the established homology between the BA6 (human) and the ventral premotor cortex (monkey), the BA40 (human) and PF-PFG (monkey) parietal cortex [START_REF] Cook | Mirror Neurons: From Origin to Function[END_REF]. We also found activation of the STG (BA22/42) considered an area which is strongly associated with activation of MN in humans [START_REF] Aziz-Zadeh | Congruent embodied representations for visually presented actions and linguistic phrases describing actions[END_REF]. fMRI and neurophysiological investigations aimed to study the MN network in human were mostly performed on young or adult subjects. We found that the MN network is largely preserved in aging. Our results are in accordance with those of [START_REF] Tremblay | Corticomotor facilitation associated with observation and imagery of hand actions is impaired in Parkinson's disease[END_REF], who analyzed corticomotor facilitation associated with observation, imagery and imitation of hand actions in younger and older adults by monitoring changes of MEPs elicited in hand muscles by TMS. They found that corticomotor facilitation in association with covert action execution was largely preserved with aging, although with a loss in selectivity for activated muscles. Unlike the original study of [START_REF] Cabinio | The shape of motor resonance: Right-or left-handed?[END_REF], in this study (where we exactly replicated their procedure), we noted a loss of selectivity, as the activation of mirror areas was more bi-lateralized than in the younger subjects. This could be explained by a specific mode of brain activation in aging. In fact, fMRI recording in younger, middleaged and older participants performing the same unilateral hand movements [START_REF] Fang | A fMRI Study of Age-Related Differential Cortical Patterns During Cued Motor Movement[END_REF] showed stronger premotor/motor cortex activity in the contralateral hemisphere in the "older" group when compared to the younger and middle-aged groups. Therefore, together with other authors, we concluded that the older brain requires larger areas to achieve the same task [START_REF] Fang | A fMRI Study of Age-Related Differential Cortical Patterns During Cued Motor Movement[END_REF][START_REF] Chow | Functional magnetic resonance imaging and the brain: A brief review[END_REF], a hypothesis that could also explain the results obtained during a task inducing a motor resonance mechanism [START_REF] Rizzolatti | The mirror neuron system and its function in humans[END_REF]. In order to exclude any bias, due to differences in the scanners, it would be worthwhile recruiting a subject pool from our center to definitively confirm the data.

Concerning the MCI subjects, we found a different pattern at the conjunction analysis in comparison with the NE subjects. The MCI and the NE groups showed similar activation of frontal and parietal areas. However, in the MCI group the left IPL (parietal BA40) was activated at a lesser extent than in the NE group and neither the right IPL nor the STG (BA22/42) were activated. Moreover, only the MCI participants exhibited activation of the left frontal area IFG-BA44. Therefore, even if the MN network is preserved in MCI, it is mainly recorded towards frontal areas. This suggests a greater resilience to the aging process of the MN areas located in the anterior part of the brain versus posterior areas, and maybe consecutively the capacity of these areas to take on a part of the "work" done by the posterior MN regions. Interestingly, we did not observe any activation of the fronto-parietal network in AD participants. Altogether, our results suggest that the MN network is progressively affected in neurodegenerative cognitive decline following a posterior-anterior gradient. The hypothesis of a posterior-anterior decay in Alzheimer-type degeneration agrees with recent data obtained in MCI using EEG and MRI recording [START_REF] Moretti | Involvement of mirror neuron system in prodromal Alzheimer's disease[END_REF]. In this investigation, alpha3/alpha2 frequency power ratio, considered as a predictor of conversion into AD [START_REF] Moretti | Volumetric Differences in Mapped Hippocampal Regions Correlate with Increase of High Alpha Rhythm in Alzheimer's Disease[END_REF] as well as cortical thickness at MRI were computed. Three MCI groups were obtained considering increasing tertile values of alpha3/alpha2 ratio. From this morphological MRI and EEG parameter data the author inferred that MN are impaired in prodromal AD. Conversely, we directly measured the activation of human MN with a specific fMRI task, thus giving a functional support to the hypothesis for the MCI and the AD group.

COGNITIVE IMPAIRMENT, MIRROR NEURONS AND NEURODEGENERATIVE PROCESSES

The lack of any activation in "classical" mirror areas in AD is a new result. If other studies confirmed these results, it might be speculated that the degeneration of the MN network is somehow involved in the typical language, praxis and visuospatial dysfunction recorded in AD. This possibility is supported by the damage of hand and eye-derived treatment of information (e.g. ideomotor apraxia, visuospatial deficit and agnosia) associated to frontal degeneration [START_REF] Futamura | Functional coupling of the frontal and parietal lobes in action[END_REF][START_REF] Pisella | No double-dissociation between optic ataxia and visual agnosia: Multiple sub-streams for multiple visuo-manual integrations[END_REF] and the related "embodied semantics" theory stating that propose that humans use sensorimotor systems in processing language [START_REF] Pulvermüller | Semantic embodiment, disembodiment or misembodiment? In search of meaning in modules and neuron circuits[END_REF]. Otherwise, frontal and parietal regions are also recurrently associated to memory. Maturation of prefrontal cortex would determine the development of episodic memory during middle childhood and beyond, in addition to the ability to monitor and manipulate information [START_REF] Ghetti | Neural changes underlying the development of episodic memory during middle childhood[END_REF]. It is also known that prefrontal cortex is tightly linked to hyppocampal formation where novel associations are formed [START_REF] Ghetti | Neural changes underlying the development of episodic memory during middle childhood[END_REF]. Further, parietal areas belonging to human MN network (particularly BA40) have a role in memory retrieval [START_REF] Shannon | Functional-anatomic correlates of memory retrieval that suggest nontraditional processing roles for multiple distinct regions within posterior parietal cortex[END_REF]. Remarkably, [START_REF] Nelson | A Parcellation Scheme for Human Left Lateral Parietal Cortex[END_REF] have divided the left lateral posterior parietal cortex into 6 subregions as a function of resting-state functional connectivity profiles, as well as their episodic memory activation profiles. Among these regions, the left intraparietal sulcus area and the left anterior IPL (MN areas) exhibited retrieval success effects. In the same vein, these areas are functionally connected with portions of the lateral prefrontal cortex that are implicated in episodic memory [START_REF] Nelson | A Parcellation Scheme for Human Left Lateral Parietal Cortex[END_REF][START_REF] Seghier | The Angular Gyrus[END_REF]. All these experimental evidences agree with the idea that an alteration of MN network can affect memory performance in AD. A possible explanation of this alteration is the 'last-developed-first-atrophied' principle [START_REF] Di Patre | Cytoskeletal alterations might account for the phylogenetic vulnerability of the human brain to Alzheimer's disease[END_REF][START_REF] Jacobs | Increasing the diagnostic accuracy of medial temporal lobe atrophy in Alzheimer's disease[END_REF], since prefrontal and inferior parietal areas are phylogenetically and ontogenetically the last to develop. The "retrogenesis hypothesis" [START_REF] Reisberg | Retrogenesis: clinical, physiologic, and pathologic mechanisms in brain aging, Alzheimer's and other dementing processes[END_REF]) also postulate that late-myelinated white matter fibers are most vulnerable to age and disease-related degeneration, which in turn mediate cognitive decline [START_REF] Brickman | Testing the white matter retrogenesis hypothesis of cognitive aging[END_REF][START_REF] Braak | Reply: the early pathological process in sporadic Alzheimer's disease[END_REF][START_REF] Alves | Integrating Retrogenesis Theory to Alzheimer's Disease Pathology: Insight from DTI-TBSS Investigation of the White Matter Microstructural Integrity[END_REF].

Neuropsychological tests exploring cognitive functions considered to be tightly linked to MN system (language and empathy) were normal in aMCI subjects. The preservation and may be hyperactivation of the anterior MN network seen in aMCI might supplement the initial decay of the posterior part of the neural circuit thus preserving their cognitive performance. The only "language" test impaired in aMCI was semantic fluency, but this impairment could be due to a semantic memory damage rather than a true language impairment. As an alternative explanation, the preservation/hyperactivation of the anterior MN network could not be sufficient to support performance in this kind of task because it is highly dependent from parietal areas [START_REF] Seghier | The Angular Gyrus[END_REF]. In contrast, in AD group MN network appears to be deficient and task performance in both language and empathy tests decays.

While unexpected, the present results also raise other questions. How to explain the cerebellar activation recorded in AD patients and to a lesser extent in MCI subjects? Based on models incorporating the MN system in social learning, the STG-IPL-IFG circuit would create the motor representation available for imitation, starting with the visual input [START_REF] Iacoboni | Cortical Mechanisms of Human Imitation[END_REF][START_REF] Oh | Modeling of visuospatial perspectives processing and modulation of the fronto-parietal network activity during action imitation[END_REF]. During the imitation phase, the overall processes are equivalent to those of the observation phase, the only difference is that, in parallel with the IFG to the IPL pathway, neural drive is sent to the musculoskeletal system through M1 to perform the action [START_REF] Oh | Modeling of visuospatial perspectives processing and modulation of the fronto-parietal network activity during action imitation[END_REF][START_REF] Bassolino | Training the Motor Cortex by Observing the Actions of Others During Immobilization[END_REF]. It has been suggested that the cerebellum provides the prediction error for the IFG and the IPL to adjust internal models [START_REF] Miall | Connecting mirror neurons and forward models[END_REF][START_REF] Oh | Modeling of visuospatial perspectives processing and modulation of the fronto-parietal network activity during action imitation[END_REF]. In this context, the AD patient activation of cerebellar neurons involved in the MN network would correspond to an attempt to compensate for damage of prefrontal and parietal areas. This mechanism would already be present in aMCI. The activation of the cerebellum as a substitute of cerebral cortex alteration has also been suggested to enhance motor control and motor learning in functional recovery from a stroke following mirror therapy [START_REF] Arya | Underlying neural mechanisms of mirror therapy: Implications for motor rehabilitation in stroke[END_REF]. In conclusion, cerebellar activation in AD might simply reflect the response of this neural structure to visual inputs during guided limb movements (Liu et al., 2003)

CLINICAL IMPLICATIONS AND LIMITATIONS

The alteration of the MN motor circuitry in AD patients raises an interesting question related to the link between action and cognition and supports an interesting direction of research. Precisely, it allows the interpretation of AD -as other neurodegenerative diseases [START_REF] Bak | The neuroscience of action semantics in neurodegenerative brain diseases[END_REF][START_REF] Eisen | Tools and talk: An evolutionary perspective on the functional deficits associated with amyotrophic lateral sclerosis[END_REF] in the light of the action-perception coupling hypothesis, which postulates that a part of cognition results from the coupling between action and perception representations, and corresponds to implicit action simulation (or "motor resonance") instead of explicit recall of abstract symbols (Jeannerod, 1994[START_REF] Jeannerod | Neural Simulation of Action: A Unifying Mechanism for Motor Cognition[END_REF][START_REF] Jeannerod | Motor cognition: What actions tell to the self[END_REF]Jeannerod et al., 1995;[START_REF] Braitenberg | Introduction. Cortex: Statistics and Geometry of Neuronal Connectivity[END_REF][START_REF] Boulenger | Subliminal display of action words interferes with motor planning: a combined EEG and kinematic study[END_REF][START_REF] Pulvermüller | Active perception: sensorimotor circuits as a cortical basis for language[END_REF]). As we have already noted, the preservation and maybe hyperactivation of the anterior MN network in aMCI might supplement the initial decay of the posterior part of the neural circuit, thus preserving cognitive performance. In contrast, in the AD group the MN network appears to be deficient and cognitive performance deteriorates.

The present study is limited by several factors: the number of subjects tested and the spatial and temporal resolution of our measurements (see [START_REF] Oosterhof | A comparison of volumebased and surface-based multi-voxel pattern analysis[END_REF]2013;[START_REF] Möhring | ERP adaptation provides direct evidence for early mirror neuron activation in the inferior parietal lobule[END_REF][START_REF] Thibault | Imaging Posture Veils Neural Signals[END_REF]; the fact that in the execution condition the hand movements were only visually controlled by the examiner. In particular, our results should now be replicated in AD/MCI population on the basis of data collected with different methods dedicated to record MN activity, as MEPs induced by TMS [START_REF] Gangitano | Modulation of premotor mirror neuron activity during observation of unpredictable grasping movements[END_REF][START_REF] Fadiga | Human motor cortex excitability during the perception of others' action[END_REF], or the reduction of magnitude (desynchronization) of the μ rhythm at EEG [START_REF] Fox | Assessing human mirror activity with EEG mu rhythm:a meta-analysis[END_REF] for a review). Neurophysiological techniques are easier to perform in people affected by neurodegenerative diseases and allow a better time resolution. Researches studying the MN network in PD and FTD/ALS would be also of interest. Furthermore, we have studied task-evoked neural activity during action observation and execution. [START_REF] Schilbach | Differential patterns of dysconnectivity in mirror neuron and mentalizing networks in schizophrenia[END_REF], in a recent study, demonstrated differential patterns of dysconnectivity in MN and mentalizing networks in schizophrenia. Further research, therefore, needs to investigate functional organization of self-related brain networks during a "resting state". This clinically available measure of functional connectivity could provide further knowledge of alterations of neurofunctional systems in AD and support our findings of MN network dysfunction.

The results of our study have possible implications in rehabilitation. As we have seen in a previous paragraph, the use of AOT as a supplementary for patients who have had strokes, to stimulate brain plasticity and obtain positive functional results, was reported [START_REF] Carvalho | The mirror neuron system in post-stroke rehabilitation[END_REF]. This has been extended to motor deficits in children with Cerebral Palsy [START_REF] Sgandurra | Upper limb children action-observation training (UP-CAT): a randomised controlled trial in Hemiplegic Cerebral Palsy[END_REF][START_REF] Buccino | Improving upper limb motor functions through action observation treatment: a pilot study in children with cerebral palsy[END_REF][START_REF] Bassolino | Activating the motor system through action observation: is this an efficient approach in adults and children[END_REF] and patients with PD [START_REF] Buccino | Action observation treatment improves autonomy in daily activities in Parkinson's disease patients: results from a pilot study[END_REF]. The concept of motor cognition, if verified, would provide a clinical support to cognitive stimulation based on the motor resonance mechanism. However, the efficiency of such training is only conceivable if the MN system remains partly achievable. So far, the only published research of this kind of cognitive training via the stimulation of the MN in people with AD, showed improvements in attention and facial recognition [START_REF] Eggermont | Observation of Hand Movements by Older Persons with Dementia: Effects on Cognition[END_REF] whereas another research showed negative results (Caffarra P, 2016, oral communication at XI Sindem National Congress, Florence, Italy). However, this last study did not test MN system integrity that is supposed to be stimulated in the training program. As our data showed a malfunction in the MN network in the case of AD, our study explains why that intervention obtained negative results. A rehabilitative intervention based on the MN system would be better implemented at the predementia phase.

In general, AOT might be a powerful tool to improve motor, language and/or social cognition deficits in people with neurodegenerative diseases. The possibility to exploit the motor resonance to stimulate cognitive function in this frame appears fascinating because it represents a potential therapeutic solution that does not exist yet: specific drugs have not still been approved for the MCI phase and pharmacotherapy effects are extremely limited in AD [START_REF] Raina | Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline[END_REF][START_REF] Petersen | Practice guideline update summary: Mild cognitive impairment[END_REF]; cognitive stimulation and serious game trainings have positive but limited effects [START_REF] Woods | Cognitive stimulation to improve cognitive functioning in people with dementia[END_REF][START_REF] Hill | Computerized Cognitive Training in Older Adults With Mild Cognitive Impairment or Dementia: A Systematic Review and Meta-Analysis[END_REF][START_REF] Manera | Recommendations for the Use of Serious Games in Neurodegenerative Disorders: 2016 Delphi Panel[END_REF] probably because of training performed in artificial environment developing specific skills not transferable to daily normal life activities. No substantial pharmacological therapy is available for ALS/FTD. Even in PD, where various drugs are available, they have only symptomatic effects and do not avoid progression of the motor and cognitive impairment. Other advantages of a rehabilitative treatment based on motor cognition are the fact that it promotes an active involvement of the patient in her/his recovery process instead of rendering him/her a passive medicine consumer and the large possibility to easily personalize the training.

Finally, protocols based on motor cognition, easy and cheap to implement, and less risky than pharmacotherapy, might have a strong impact on prevention of neurodegenerative diseases in the growing elderly population, a very interesting perspective from the public health point of view. As usual in neurodegeneration, a preventive intervention could in fact be far more effective than an intervention applied in the overt phase of the disease. This view is supported both from data coming from PD studies [START_REF] Anders | Compensatory premotor activity during affective face processing in subclinical carriers of a single mutant Parkin allele[END_REF], recent data on the MCI/AD spectrum [START_REF] Moretti | Involvement of mirror neuron system in prodromal Alzheimer's disease[END_REF][START_REF] Vallet | A SEMantic and EPisodic Memory Test (SEMEP) Developed within the Embodied Cognition Framework: Application to Normal Aging, Alzheimer's Disease and Semantic Dementia[END_REF] and our own study.

See [START_REF] Anders | Compensatory premotor activity during affective face processing in subclinical carriers of a single mutant Parkin allele[END_REF] Patients performed slightly worse in the emotion recognition task, but only for the most difficult expressions to be interpreted. Inferior frontal and anterior inferior parietal "mirror neuron" areas activated during observation and execution of the emotional expressions in both groups, but at a lesser extent in PD patients. Activation of the right anterior inferior parietal lobule positively correlated to patients' emotion recognition ability. The fMRI experiment consisted of two tasks in which the same set of object drawings was used: in the first task subjects were asked to name aloud objects drawings; in the second task subjects had to orally produce a verb denoting an action that could be performed with the object depicted. Manipulable objects were selected from Snodgrass and Vaderwart normalized data set.

Data showed the involvement of an extended cortical network during action-verb generation, with differences from the object name generation located above all in the premotor and prefrontal cortices. The fMRI experiment consisted of 3 tasks: subjects were asked 1) to name aloud objects drawings, 2) to orally produce a verb denoting an action that could be performed with the object depicted, and 3) to mentally simulated the action related to the object. The Snodgrass and Vaderwart normalized data set was again used.

Compared to object naming, action naming generated greater activation of the left prefrontal cortex and the left medial precuneus. Mental simulation of actions generated greater activation of prefrontal cortex and occipito-parietal junction bilaterally. Motor, premotor and prefrontal regions were more activated in the ON than in the OFF state.

Patients on their usual medication

Measuring the effect of movementrelevant visual stimuli (graspable door handles and finger movements) on reaction times. Evaluation of the SCE, that is faster reaction times when the response hand and the stimulus direction are compatible. Bars and object movements represented the control condition.

In a first experiment, participants had to classify visual stimuli (bar and door handles) according to shape and orientation. In a second experiment, the two groups observed video clips of finger or object movements and had to respond as quickly as possible if an X appeared at the end.

First experiment: no difference in the overall reaction times for patients and controls: however, while the SCE was larger in the handle than in the bar condition for controls, this was not true for PD patients. Second experiment: Both patients and normal participants reduced significantly their reaction times after observing finger compared to objects movements. However, parkinsonians showed a SCE only for non living object movements. Participants had to judge whether a letter string was either a real word or a non-word. The real words were either action verbs or object nouns, and were preceded by masked stimuli that were either consonant strings or the same real words that were used for lexical decision

In the off condition masked priming effects for action words were nearly absent in PD patients, while robust priming effects were observed for concrete nouns. In the on condition, priming effects for action verbs restored and appeared as strong as for concrete nouns, and comparable to those of healthy controls The four classes of action verbs were running, hitting, cutting and speaking; the two classes of non action verbs were change of state and emotional states. Verbs were similar in frequency and letter lenght (with the exception of verbs of emotional states which had more letters than others)

In PD patients judgments were (except for "cutting" verbs) as accurate as controls for both types of verbs. However, they were slower, both in the on and off condition Appendix: Comparing PD patients and control subjects on perceptual and imagery emotional tasks and evaluating their ability to make emotional faces

To test the ability to perceive emotional faces, subjects were given subtests 1, 2, and 5 from the Florida Affect Batteryrevised. Subjects also performed a test of facial imagery, and two control tasks: the emotion facial characteristics task and an object imagery test. 11 PD subjects and 17 controls were asked to make emotional faces for a video camera Patients were significantly impaired on a task of emotional facial imagery and in perceiving emotional faces but not on a control task of object imagery. PD patients were impaired on making emotional faces. Performance on both the perceptual and motor tasks of facial expression significantly correlated with performance on the emotional facial imagery task [START_REF] Ricciardi | Facial emotion recognition and expression in Parkinson ' s disease: an emotional mirror mechanism?[END_REF] 20 PD patients and twenty healthy matched controls

Patients on their usual medication

Assessing emotion recognition and performing a facial emotion expressivity task

The ability of recognizing emotional facial expressions was assessed with the Ekman 60-faces test.

Participants were also video-recorded while posing facial expressions of 6 primary emotions. The most expressive pictures for each emotion were derived from the videos. Ten healthy raters were asked to look at the pictures to identify the emotional label (Emotion expressivity task). Reaction time and accuracy of responses were recorded PD patients showed difficulties in recognizing emotional facial expressions produced by others and in posing facial emotional expressions compared to healthy subjects. There was a significant positive correlation between the emotion facial recognitionand expressivity in both groups [START_REF] Buccino | Action observation treatment improves autonomy in daily activities in Parkinson's disease patients: results from a pilot study[END_REF] 15 PD patients Not specified Randomized controlled trial investigating the efficacy of AOT as a complementary therapy to standard pharmacological and rehabilitative treatment Patients in the case group ( 7) were asked to observe, and subsequently execute, different daily actions presented through video clips (AOT). Controls (8) observed video clips with no motor content and subsequently performed the same actions.

After treatment, the experimental group reported better scores in the UPDRS, and the Functional Independence Measure, while there was no objective difference in gait performance. The patients were randomly attributed to an "action group", who watched video clips showing specific movements and strategies to circumvent freezing episodes, or to a "landscape group" who saw video clips of static landscape pictures. Both groups underwent identical physical therapy training

The freezing of gait was significantly reduced in both groups after training. Motor performance and quality-oflife assessments were also significantly improved in both groups. However, at 4 weeks follow-up examination, a significant reduction in the number of freezing episodes was observed only in the AOT group Pelosin et al., 2013 38 The dynamic information presented in the visual point light LED display depicted three different movement speeds of the same amplitude. The displays were formerly tested and validated on healthy participants. In the validation stage it was found that young healthy adults were able to use the temporal information conveyed by the LED display to prospectively guide their movements.

Patients demonstrated a significant improvement in terms of movement time and peak velocity when executing movement in accordance with the information afforded by the point light display, compared to when the movement was performed without the display. The brain network was reconstructed based on "whole brain" diffusion tensor imaging data. The network integrity was examined in ALS patients at baseline and at a more advanced stage of the disease (interval 5.5 months) in comparison with controls; progressive brain network impairment was also examined by comparing patients at two time-points in a paired-analysis

Analyses revealed an expanding sub-network of affected brain connections over time, with a central role for the primary motor cortex and loss of structural connectivity mainly propagating to frontal and parietal brain areas (regions belonging to the MN network)

Appendix: Associativity judgments: patients were given a target verb for an action, or a noun for an object, and were asked to select the one of two choices that goes best with the target. Worddescription matching : Patients were given a phrase describing an action or object, and then were asked to select the best matching among 4 stimuli.

Patients with ALS were significantly more impaired on measures requiring knowledge of actions than measures requiring knowledge of objects.

Difficulty on measures requiring action knowledge correlated with cortical atrophy in motor cortex [START_REF] York | Action verb comprehension in amyotrophic lateral sclerosis and Parkinson's disease[END_REF] 36 patients with ALS (5 with MCI and 4 with FTD); 22 patients with PD spectrum disorders (clinically definite PD, n = 8, PD-MCI, n = 3) PD-DLB, n = 3, PDD, n = 8) Two-alternative forcedchoice associativity judgment task plus T1 MRI imaging of gray matter atrophy 120 frequency-matched action verbs, cognition verbs, concrete nouns and abstract nouns were probed. Performance was related to T1 MRI imaging of gray matter atrophy Patients with ALS were significantly impaired relative to control participants for action verbs. Patients with PD did not differ from controls Regression analyses related action verb performance to motor-associated cortices in ALS, but not in PD. Patients were administered tasks of oral and written naming of 30 "pure" nouns and 30 "pure" verbs, matched for word frequency, pictured as black and white line drawings elicited a high degree of name agreement in pilot testing.

Patients with nonfluent PPA and ALS-FTD were more impaired on verb than on noun naming and significantly more impaired on oral naming than written naming. Patients with fluent PPA showed the opposite pattern for both word class and modality. For simplex movement production: the Jamar Hydraulic Hand Dynamometer test, which evaluates hand grip strength; the Box and Block Test, which tests gross hand dexterity, and the Purdue Pegboard Test. For complex movements: gesture imitation and interpretation tasks. For conceptual processing of actions and of manipulable objects: two picture naming tasks. For tasks of gesture and conceptual processing: an object/gesture matching task; a task eliciting gesture production from the name of the object; a picture naming task; a picture association task

The patient presented with increasing action production disorders associated with increasing bilateral atrophy in cortical and subcortical regions involved in the sensorimotor control of actions (i.e., the superior parietal cortex, the primary motor and premotor cortex, the inferior frontal gyrus, and the basal ganglia). In contrast, the patient's performance in processing action-related concepts remained intact during the same period.

Appendix:

  Mot clés : Neurones miroirs ; Maladie d'Alzheimer ; Trouble Cognitif Léger ; maladies neurodégénératives ; vieillissement ; Résonance Magnétique fonctionnelle ; Tests neuropsychologiques.

FMS

  -Related Synchronization FCSRT: Free and Cued Selective Reminding Test FDI: First Dorsal Interosseous FIRST : FMRIB's Integrated Registration and Segmentation Tool fMRI: functional Magnetic Resonance Imaging Tract Mirror Neurons REM: Rapid Eye Movements: RME: Reading the Mind in the Eyes Test S1

Figure 1 :

 1 Figure 1: Response properties of a mirror neuron. Each row in the left column schematically represents the experimental condition. The panels in the right column show the corresponding responses of the same neuron in the form of a raster plot (upper part) and peri-stimulus spike density (bottom part). (top row, right panel) Response of a neuron during active goal-directed motor acts of the monkey (e.g., grasping small objects of different shapes). (bottom row, right panel) Response of the same neuron during the observation of the same goal-directed motor acts performed by the experimenter. In the two raster plots, each vertical bar signifies the occurrence of an action potential, and different lines refer to different trials. In both figures, time t = 0 represents the moment of contact between the monkey's (top panel) or experimenter's (bottom panel) hand with the goal object. (From[START_REF] Casile | The mirror neuron system: A fresh view[END_REF]

Figure 2 :

 2 Figure 2: Lateral and mesial view of the monkey brain showing a modern anatomical and functional parcellation of the agranular frontal cortex and the posterior parietal cortex along with the localization ofF5 and PF and PFG areas (From Rizzolatti et al., 2014)

Figure 3 :

 3 Figure 3: Example of motor neuron in PFG modulated by action intention. Top left: lateral view of the monkey brain showing area PFG. Top right: paradigm used for the motor task. The monkey, starting from a fixed position, reaches and grasps a piece of food or an object, then it brings the food to the mouth and eats it (I, grasp-to-eat), or places it into a container (II/III, grasp-to-place). Bottom left: activity of three IPL neurons during grasping in the two actions. Rasters and histograms are aligned with the moment when the monkey touched the object to be grasped. Bottom right: responses of the population of neurons selective for grasping to eat and grasping to place. The vertical lines in the two panels indicate the moment when the monkey touched the object and the moment in which the grasping was completed, respectively. (fromRizzolatti et al., 2014; Modified from Fogassi et al., 2005)

Figure 4 :

 4 Figure 4: Evidence for action goal coding by the mirror mechanism. Participants watched the experimenter grasping objects with two types of pliers: direct pliers and reverse pliers (left panel). Finger flexion produced closure of the direct pliers, but opening of the reverse ones (right part of the left panel). Finger extension produced opening of the direct pliers, but closing of the reverse ones (left part of the left panel). The right panel shows MEP amplitudes obtained from the opponens pollicis muscle during the observation of different movement phases. Right panel, top: MEPs during the observation of grasping with direct pliers. Right panel, bottom: MEPs during the observation ofgrasping with reverse pliers. The observers' motor systems encode the goal of the action, regardless of whether it is achieved by closing or opening the hand.Rizzolatti et al., 2014, modified from Cattaneo et al,. 2013)

Figure 6 :

 6 Figure 6: Space-selective mirror neurons (from Rizzolatti and Fogassi, 2014). (a) Schematic view of the visual conditions of the experimental paradigm: the monkey observes an experimenter executing a grasping act in the peripersonal (left) and extrapersonal (right) space of the monkey. (b) Examples of the responses of three mirror neurons during observation of grasping acts executed in the monkey's periand extrapersonal space and during monkey execution. Each panel shows the raster plot (top) and the cumulative histogram (bottom) of the neuron responses. Neuron 1 responds more strongly when the observed grasping is performed in the extrapersonal space, while neuron 2 presents a stronger discharge during observation of grasping performed in the peripersonal space. Neuron 3 does not show any space-selective visual response. (c) Operational encoding of the monkey peri-and extrapersonal space. The top part shows the experimental conditions: the experimenter grasps an object in the extrapersonal(left) or in the peripersonal space without (centre) or with (right) a frontal panel impairing the monkey's reach into its peripersonal space. In this latter condition, the object (and the act performed by the experimenter) is metrically in the monkey's peripersonal space, but operationally outside it. The lower panels show the visual responses of a mirror neuron in the three conditions. Before closure with the frontal panel, the neuron was activated only during observation of grasping in the monkey's extrapersonal space. However, after closure, the neuron also responded to observation of grasping performed close to the monkey's body.

Figure 7 :

 7 Figure 7: Responses of mirror neurons to grasping observed from three visual perspectives. (a) Experimental conditions (subjective view: 0°; side view: 90°; frontal view: 180°). (b) Examples of the responses of four mirror neurons during observation of grasping from the three perspectives. Rasters and histograms are temporally aligned (vertical grey line) with the moment at which the observed hand touches the object. Neuron 1 is selective for the subjective view, neuron 2 for the frontal view, neuron 3 for the side view. The activity of neuron 4 discharged equally well for all points of view (from[START_REF] Rizzolatti | The mirror mechanism: recent findings and perspectives[END_REF]

Figure 9 :

 9 Figure 9: Schematic of areas in the human brain that contain mirror neurons (inferior parietal lobule

Figure 10 :

 10 Figure 10: Mirror neurons areas in humans[START_REF] Pineda | Sensorimotor cortex as a critical component of an 'extended' mirror neuron system: Does it solve the development, correspondence, and control problems in mirroring?[END_REF].

Figure 11 (

 11 Figure 11 (from Fox et al., 2016): Simulation of mu rhythm desynchronization in the 8-to 13-Hz frequency band. There is a decrease in amplitude in the electroencephalogram from baseline during action observation or execution (action event; highlighted).

Figure 12 :

 12 Figure 12: EEG rhythms during action observation. The graph shows the EEG power time course for each frequency band: alpha band (8-13 Hz) in green, lower beta (13-18 Hz) in red, and upper beta (18-25 Hz) in cyan. Each epoch (fix, still, movement, and post movement) is labeled by a different color. At the top of the figure, a film strip shows an example illustrating the different epochs of the observed video clips.(Rizzolatti et al., 2014, modified by Avanzini et al. 2012)

Figure 14 :

 14 Figure 14: Results from the work of Peeters et al., 2009 A, Cortical regions activated (colored red to yellow) by the observation of hand grasping actions relative to their static controls, rendered on lateral views of the standard (MNI) human brain.

Figure 16 :

 16 Figure 16: from Gazzola et al., 2007: The left two columns show putative hand MN System for aplasic subjects (APL1 and APL2) and typically developed individuals (TD), defined by inclusively masking the visual contrast Hand Action-Hand Static with their Feet Execution or Mouth Execution. The right two columns show the same but defined by masking with TD's Hand Execution.

Figure 20

 20 Figure 20 Brain organization according the « traditional" neuropsychological view (Modified by Pülvermuller et al., 2014):

Figure 22 :

 22 Figure 22: (From Hauk et al., 2004) Brain areas activated by subcategories of action words are adjacent to and partly overlap with activations produced by the corresponding movement types (A) Hemodynamic activation during tongue, finger, and foot movements (B) Hemodynamic activation during reading action words related to face (green), arm (red), and leg (blue) movements Results are rendered on a standard brain surface

Figure 25 :

 25 Figure 25: Alzheimer's patient (AD, red lines) and healthy ageing participant' (CG, blue lines) velocity profiles in the work ofBisio et al., 2012. The velocity values (y-axis) are represented as function of time (x-axis).

Figure 26 :

 26 Figure 26: Mean first dorsal interosseous corticomotor maps recorded before (Pre) and after (Post) immobilization in the 3 groups. (a) In control (on the left), AOT (in the middle), and MI (on the right) groups, participants performed the requested task for 10 hourly sessions during the immobilization period. (b) Each map was centered on the maximal response obtained for each participant in every condition. Colors indicate the amplitude of MEP, normalized with respect to the maximal response obtained in the Pre-condition in every subject, from "blue" (the lowest values) to "red" (the highest responses; modified byBassolino et al., 2014).

Figure 28a :

 28a Figure 28a: Grand average Event-Related-Desynchronization maps of the control group resulting from the observation of the ball grasping movement performed by the right hand. Bilateral alpha and beta band desynchronization (around C3 and C4) indicate mu-rhythm desynchronization[START_REF] Heida | Eventrelated mu-rhythm desynchronization during movement observation is impaired in Parkinson's disease[END_REF].

Figure 28b :

 28b Figure 28b: Grand average Event-Related-Desynchronization maps of the Parkinson group. The alpha and beta band ERD levels around C3/C4 are much lower compared to the control group[START_REF] Heida | Eventrelated mu-rhythm desynchronization during movement observation is impaired in Parkinson's disease[END_REF].

Figure 29 :

 29 Figure 29: paradigm used to assess corticomotor facilitation associated with observation, imagery and imitation of actions in the study of[START_REF] Tremblay | Corticomotor facilitation associated with observation and imagery of hand actions is impaired in Parkinson's disease[END_REF]

Figure 30 :

 30 Figure 30: Schematic representation of frontostriatal circuits according toBirba et al., 2017. The striatum (caudate nucleus, putamen, and nucleus accumbens) receives inputs from a range of cortical areas, including various motor and frontal regions. Connections between such regions and striatal structures comprise three distinct circuits: motor, associative and limbic, which overlaps each other. SMA: supplementary motor area; pMA: premotor area; PMC: primary motor cortex; CN: caudate nucleus; NAc: nucleus accumbens; SN: substantia nigra; Thal: thalamus; Put: putamen; GP: globus pallidus; DLPFC: dorsolateral prefrontal cortex; LOFC: lateral orbitofrontal cortex; PFC: prefrontal cortex.

Figure 32 :Figure 31

 3231 Figure32: results from the study of[START_REF] Abrevaya | The Road Less Traveled: Alternative Pathways for Action-Verb Processing in Parkinson's Disease[END_REF]

Fiori

  et al. (2013) investigated controls and ALS patients' responses during a task testing the effects of biomechanical constraints on MI. Effects present in normal subjects were compromised in ALS, at least for the proximal muscles (comfortable/awkward postures: see Figure37).

Figure 37 :

 37 Figure 37: stimuli used in the work ofFiori et al., 2013. For the letter task, canonical (c) and mirror form (d) letters were shown at each orientation (0°, 90°, 180°, 270°). For the hand laterality task stimuli, left hands (a) and right hands (b) were shown to highlight that left hand images are considered mirror-images of right hands. Fiori et al. labeled the right hand stimuli from 0°, +90°, 180° and +270° in clockwise direction, whereas the left hand stimuli were labeled from 0°, -90°, 180° and -270° in counter clockwise direction. Adopting this data set allowed to distinguish between stimuli across and away from the body's midsaggital plane: the +270° right hand and -270° left hand were considered across body plane stimuli, whereas the +90° right hand and -90° left hand were considered away body's plane stimuli. Furthermore, this methodology allowed also to distinguish easily between comfortable postures (-270° left hand and 270° right hands) and awkward postures (-90° left hand and 90° right hands). a Left hand; b right hand; c F in the canonical form; d F in the mirror form.

Figure 39 :

 39 Figure 39: Experimental set-up in[START_REF] Bisio | Voluntary Imitation in Alzheimer's Disease Patients[END_REF]

Figure 41 :

 41 Figure 41: Visual stimuli presented to the subjects in each experimental condition. (A) Picture used during rest conditions and samples of frames from one of the videos presented to the subjects during the observation condition. (B) Pictures shown to the subjects during the rest and execution condition.

Figure 42 :

 42 Figure 42: Conjunction analysis (comparing fMRI activation during observation of transitive hand grasping and execution of grasping movements) results respectively, in NE, MCI and AD. [A] Normal elderly (NE) group; [B] Mild Cognitive Impairment (MCI) group [C] Alzheimer's Disease (AD) group [t contrast 3.41; k=50; pcluster(FWE-corr)<.05 only].

  and Table 5 report the statistical results of the main effect in the O condition [ANOVA, F contrast 14.74; K=50; p(FWE-corr)<.05] and in the M condition [ANOVA, F contrast 13.48; k=50; p(FWE-corr)<.05].

Figure 43 :

 43 Figure 43: At the left: Representation of the cerebral areas involved in the Observed condition versus the Rest condition in the three groups (NE, MCI and AD). At the right: Representation of the cerebral areas activated in the Movement condition versus the Rest condition in the three groups (NE, MCI and AD). In the Observed condition, visual areas are also highly activated. [Main effect of fMRI task: [left] Observed condition (F contrast 14.74; k=50; p(FWE-corr)<.05); [right] Movement condition (F contrast 13.48; k=50;p(FWE-corr)<.05)].

  Jaywant et al., 2016a 23 individuals with PD Not specified Randomized controlled home-based AOT intervention (gait observation) for walking in PD In the Gait Observation (intervention) condition, participants viewed videos of healthy and parkinsonian gait. In the Landscape Observation (control) condition, participants viewed videos of moving water No difference in gait performance was observed; however, the AOT group obtained a better score in a subscale of self-perceived mobility Santamato et al., 2015 15 PD patients with age of < 80 years, time from PD diagnosis of ≤ 10 years Not specified AOT (video-therapy) for the treatment of postural instability and balance impairmentParticipants underwent an 8-week rehabilitation programme for 3 times a week, under the supervision of a physiotherapist. Patients were sitting and a monitor screen was placed in front of them. They were instructed to carefully watch the videos projected concerning motor tasks and motor sequences linked to balance. At the end of each video, patients were requested to perform the observed action for other 5 minutesNo positive effect of AOT on balance Pelosin et al.

TABLE OF CONTENTS 1. Theoretical frame

 OF

	▪	Neurophysiological studies
	▪	fMRI studies
	▪	Behavioral studies
	▪	Neuropsychological studies
	1.1. The Mirror Neurons ▪ Action Observation Training for PD rehabilitation
	1.2. The Mirror Neurons system in monkeys and humans ▪ Explicit Motor Imagery
	1.2.1. Mirror Neurons in monkeys 2.2.2.2. The Mirror Neurons network, embodied cognition and the Amyotrophic
	1.2.2. Methods, results and implications of Mirror Neurons studies in humans Lateral Sclerosis/Frontotemporal Dementia continuum
	1.2.2.1. Neurophysiological techniques: EEG, TMS, evoked potentials, neuronal ▪ MRI studies
	▪	recordings Neuropsychological and behavioral studies
	1.2.2.2. fMRI studies 2.2.2.3. The Mirror Neurons network, embodied cognition and the Mild Cognitive
	1.2.2.3. fMRI/neurophysiological techniques combined Impairment/Alzheimer disease continuum
	1.2.2.4. Neuropsychological tests ▪ Correlation between morphological MRI data and EEG spectral analysis
	1.2.2.5. Mirror Neurons functions in humans ▪ fMRI studies
	▪ ▪	Recognizing actions of others Behavioral studies
	▪ ▪	Interpreting action intention Neuropsychological studies
	▪ ▪	Motor imitation and motor learning TMS studies
	▪ ▪	The simulation theory Rehabilitative studies
	1.2.3. Embodied cognition as a link between acting and thinking, Mirror Neurons and 2.2.3. Conclusions of the review on studies linking Action, Cognition (Mirror Neurons) and
	cognitive functions neurodegenerative diseases
	1.2.3.1. Intersubjectivity and social cognition 2.3. Reasons and aim of the experimental study
	1.2.3.2. Language 1.2.3.3. Memory 3. Experimental contribution
	1.3. Aging and Neurodegenerative diseases 3.1. Materials and methods
	1.3.1. Aging 3.1.1. Subjects
	1.3.2. Alzheimer Disease and Mild Cognitive Impairment 3.1.2. fMRI Experimental paradigm
	1.3.2.1. Alzheimer Disease 3.1.2.1. MRI acquisition
	1.3.2.2. Mild Cognitive Impairment 3.1.2.2. Hippocampal segmentation
	1.3.2.3. The continuum AD-MCI and motor functions 3.1.2.3. fMRI analysis
	1.3.3. Frontotemporal Dementia and Amyotrophic Lateral Sclerosis 3.1.3. Neuropsychological assessment
	1.3.4. Parkinson Disease and Dementia with Lewy Bodies 3.2. Results
	1.4. Mirror Neurons and neurorehabilitation 3.2.1. Hippocampal volume measurements
	1.4.1. Previous clinical applications 3.2.2. fMRI Conjunction analysis
	1.4.2. Enhancing the potential of Mirror Neurons stimulation in rehabilitation 3.2.3. Neuropsychological tests
	2. Issue of the thesis 4. General Discussion
	2.1. Mirror Neurons, embodied cognition and neurodegenerative diseases 4.1. Mirror Neurons network alteration
	2.2. State of the Art on neurodegenerative disorders and embodied cognition 4.2. Cognitive impairment, Mirror Neurons and neurodegenerative processes
	2.2.1. Methods: Literature searching of studies linking Action, Cognition (Mirror Neurons) 4.3. Clinical implications and limitations
	and neurodegenerative diseases
	2.2.2. Results
	2.2.2.1. The Mirror Neurons network, embodied cognition and Parkinson Disease

  Areas proposed in the literature to process semantic meaning across categories. b. Cluster analysis reveals left-perisylvian activation for all word types (in brown and orange) and, in addition, widespread topographically specific brain activation for different semantic word types (face related action words in light blue, arm word in purple, leg words in yellow, abstract shape words in dark blue). c. Cell assembly model of cortical circuits for different semantic word types. d. Foci of significantly different brain activity elicited by color (in red) and shape words (in blue,

Figure 24: From Pulvermüller, 2018: Semantic grounding in action and perception systems: a.

  Aging is strictly linked to neurodegeneration. Alzheimer Disease (AD), the most common form of dementia, is a neurodegenerative disease whose incidence grows exponentially in aging. Worldwide, it is currently estimated that 35 million people have AD or a related dementia, and with increasing life expectancy, global prevalence is projected to increase to around 66 million by 2030 and to more than 115 million by 2050 (Alzheimer's Disease International [ADI], 2012).

	1.3 AGING AND NEURODEGENERATIVE DISEASES
	1.3.2 ALZHEIMER DISEASE AND MILD COGNITIVE IMPAIRMENT
	2.2.2.1	Alzheimer Disease

Table 1 :

 1 Demographic data of the 3 groups (ANOVA)*

		NE	MCI	AD	p
	#	16	16	16
	Age	73.8 ± 6.8	77.0 ± 4.8	77.8 ± 5.4	NS
	Level of education	0\3\8\5	2\3\9\2	5\5\4\1	NS
	(Primary, Secondary,
	High Scool, University
	Gender: F\M (F%)	9\7 (56.3)	6\10 (37.5)	9\6 (60)	NS
	* non parametric tests (Kruskal -Wallis) give the same results.
	NE= Normal Elderly people; MCI: Mild Cognitive Impairment; AD: Alzheimer Disease.

Table 2 :

 2 List of Neuropsychological tests

	Test	Acronym		Description	References
	Mini Mental State	MMSE	The most popular instrument to	Folstein et al., 1975
	Examination		screen dementia and to quantify	Measso et al., 1993
			global cognitive level
	Free and Cued Selective	FCSRT	A test of verbal memory which	Grober and Buschke,
	Reminding Test		controls for individual differences	1987
	Immediate Free Recall FCRST-IFR	in attention and cognitive	Frassoni et al., 2011
	Immediate Total Recall FCRST-ITR	processing through a "controlled learning" study procedure in which
	Delayed Free Recall FCRST-DFR	the examinee searches for study items in response to a category
	Delayed Total Recall FCRST-DTR	cue. The category cues are then used to facilitate the recall of items
	Cueing Sensitivity Index FCRST-CSI	not retrieved during a free recall test phase of the task. The FCSRT
			has been used to identify MCI, and
			distinguish AD from other types of
			dementia
	Phonemic Fluency	PF	Assessing the timed production of	Novelli et al., 1996
			words after phonemic cues.
	Semantic Fluency	SF	Assessing the timed production of	Novelli et al., 1996
			words after semantic cues.
	Trail Making Test	TMT	Assessing cognitive abilities such	Giovagnoli et al., 1996
	Part A	TMT-A	as visual scanning and visual-motor tracking (Part A), executive
	Part B	TMT-B	function,	visuo-conceptual
			function, visuo-motor tracking and
			sustained attention (Part B)
	Repeatable Battery for	RBANS-N	The naming test taken from the	Randolph et al., 1998
	Assessment of		Repeatable Battery for Assessment	Ponteri et al., 2007
	Neuropsychological		of Neuropsychological Status, a
	Status naming test		brief battery which measures
			immediate and delayed memory,
			attention,	language,	and
			visuospatial skills
	Revised Reading the	RRME	Testing the ability of inferring	Baron-Cohen et al.,
	Mind in the Eyes		others' mental states. Performance	2001
			on this test correlates with an	Vellante et al., 2013
			empathic personality
	Action naming	AN	An ad-hoc task to test of action	Spada, 2012
			naming, a function considered to
			be linked to MN

Table 3 :

 3 Hippocampal (HP) volumetric comparison between the three groups

		2	3	1
	HP Volume	CTR	MCI	AD		Post HOC
				[MM+SdE		(Bonferroni)
	Left HP	3521.6542	2872.3732	2791.97	*p<001	1vs2
	[MM, SdE]	[123,1601]	[126,4296]	[125.35]		2vs3
	Right HP	3718.7444	3086.8005	2763.1426	*p<001	1vs2
		[111,7622]	[108,872]	[110,804]		2vs 3
	MM= marginal mean
	SdE= standard Error
	NE= Normal Elderly people; MCI: Mild Cognitive Impairment; AD: Alzheimer Disease.

Table 4 :

 4 Conjunction analysis results respectively, in NE, MCI and AD

	cluster	cluster level	Z_score	coordinates	Brain Region [BA]
	[k]	p FWE-corr p uncorr		x,y,z [mm]
	[A] NE
	1719	0.000	0.000	5.48	-42 -36 42	L Inferior Parietal Lobule [40]
				5.14	-36 -38 48
				4.75	-50 -30 42
	591	0.002	0.000	4.79	40 4 28	R Precentral Gy [9 /6]
				4.37	46 12 30
				4.11	46 4 40
	383	0.013	0.002	4.73	50 -34 54	L Inferior Parietal Lobule [40]
				4.14	58 -28 48
				3.81	40 -46 58
	361	0.017	0.002	4.54	-42 -6 50	L Precentral Gy [6]
				3.75	-32 -6 64
				3.60	-32 2 62
	292	0.038	0.005	4.14	62 -40 22	R Inferior Parietal Lobule [40]
				4.06	68 -24 22
				3.57	60 -32 20
	351	0.019	0.003	4.05	32 -54 -22	R Fusiform Gy
				4.04	60 -60 -14
				4.03	38 -72 -20
	[B] MCI
	506	0.004	0.001	5.49	38 2 58	R Precentral Gy [6 / 9]
				5.08	46 4 36
				4.06	44 2 46
	1060	0.000	0.000	5.03	-36 0 58	L Precentral Gy [6]
				4.47	-50 4 14	L Inferior Frontal Gy [44]
				4.41	-36 6 20
	271	0.047	0.007	4.50	30 -60 -18	R Cerebellum / Fusiform Gy
				4.19	28 -44 -24
	326	0.025	0.004	4.04	-52 -66 -14	L Middle Occipital Gyrus / Fusiform Gy
				4.02	-42 -70 -22	L Cerebellum
				3.99	-34 -52 -26
	332	0.023	0.003	4.00	-62 -28 26	L Inferior Parietal Lobule [40]
				3.78	-56 -24 22
				3.53	-52 -34 48
	[C] AD
	831	0.000	0.000	5.16	36 -62 -18	R Fusiform Gyrus [37]
				4.45	44 -46 -20
				4.34	44 -54 -24
	1222	0.000	0.000	4.91	-40 -72 -22	L Cerebellum
				4.75	-34 -48 -24
				4.58	-30 -72 -20	L Fusiform Gyrus [37]

Table 5 :

 5 Main effect of fMRI task in the Observe run and Movement run

	cluster	Z_score	coordinates	Brain Region [BA]
	[k]		x,y,z [mm]
	OBSERVE vs REST
	7451	7.68	-42 -70 -12	L MTG / MOG
		7.58	-34 -44 46	L IPL [40]
		7.49	-46 -72 10
	3617	7.34	50 -68 -8	R MTG /MOG
		6.97	44 -64 2
		6.96	58 -60 6
	549	6.83	38 2 58	R PrCG [9 / 6]
		6.13	40 6 48
		5.86	46 4 40
	935	6.79	-44 0 50	L PrCG [9 / 6]
		6.33	-34 -2 60
		5.80	-48 4 34
	736	6.20	44 -38 58	R IPL [40]
		5.96	28 -54 44
		5.42	38 -50 56
	369	6.11	-4 -78 -34	L cbl
		5.61	8 -80 -36	R cbl
		5.43	-12 -76 -46
	MOVEMENT vs REST
	1670	7.11	-40 -20 54	L PrCG / PoCG [6 / 4]
		6.69	-32 -18 66
		5.29	-56 -30 50
	350	6.64	54 14 -8	R IFG
	600	6.52	18 -52 -22	R cbl
		5.24	38 -72 -22
	151	6.36	-50 16 -8	L IFG
	1081	6.33	-2 -6 52	L SMA [6]
		6.12	2 6 58
		5.75	-4 -6 66
	209	6.10	36 -6 60	R MFG [6]
		5.51	24 -2 64
		5.03	28 -4 48
	65	5.86	-42 -72 -22	L cbl
	396	5.66	4 -58 20	R PC [23]
		4.70	2 -44 30
	207	5.33	48 4 46	R PrCG [9 / 6]
		5.25	54 4 38
		5.06	46 8 30
	52	5.28	-64 -26 24	L IPL [40]
		4.85	-62 -26 36

Table 6 :

 6 Neuropsychological tests -Group comparison (ANOVA)

		NE	MCI	AD	P §	Post hoc (Bonferroni)	NE vs. MCI *	NE vs. AD *	MCI vs. AD *
	#	16	16	16
	Age	73.8 ± 6.8	77.0 ± 4.8	77.2 ± 5.7	NS -	.544 (-.454 : 1.542)	.542 (-.456 : 1.54)	.038 (-.942 : -1.018)
	Education	12.5 ± 3.3	11.1 ± 3.8	8.9 ± 4.5	.041 NE < AD	-.393 (-1.383 : . 596)	-.912 (-1.942 : .117)	-.528 (-1.525 : .469)
	MMSE	28.8 ± 0.9	27.0 ± 2.0	22.4 ± 3.5	< .001 NE>MCI>AD	-1.161 (-2.22 : -.101)	-2.505 (-3.813 : -1.196)	-1.614 (-2.742 : -.485)
	FCSRT -IFR	29.0 ± 3.5	19.2 ± 6.0	10.3 ± 7.3	< .001 NE>MCI>AD	-1.195 (-3.195 : -.796)	-3.267 (-4.764: -1.77)	-1.332 (-2.415 : -.249)
	FCSRT -ITR	36.0 ± .0	34.9 ± 2.0	27.2 ± 7.5	< .001	NE>AD, MCI>AD	-.778 (-1.794 : .239)	-1.659 (-2.796 : -.523)	-1.403 (-2.497 : -.309)
	FCSRT -DFR	9.8 ± 1.7	5.9 ± 3.3	2.9 ± 3.2	< .001 NE>MCI>AD	-1.486 (-2.593 : -.379)	-2.693 (-4.046 : -1.34)	-.923 (-1.954 : .108)
	FCSRT -DTR	11.9 ± .5	10.7 ± 2.4	7.3 ± 3.6	< .001	NE>AD, MCI>AD	-.692 (-1.701 : .317)	-1.79 (-2.95 : -0.63)	-1.111 (-2.164 : -.058)
	FCSRT -CSI	1.0 ± .0	.94 ± .09	.68 ± .25	< .001	NE>AD, MCI>AD	-.943 (-1.976 : .09)	-1.81 (-2.974 : -.647)	-1.384 (-2.475 : -.293)
	PF	37.9 ± 9.6	31.8 ± 9.6	20.4 ± 7.0	< .001	NE>AD, MCI>AD	-.635 ( -1.64 : .369)	-2.131 (-3.358 : -.904)	-1.405 (-2.499 : -.31)
	SF	39.6 ± 10.4	31.7 ± 9.2	17.6 ± 5.7	< .001 NE>MCI>AD	-.805 (-1.823 : .214)	-2.623 (-3.96 : -1.287)	-1.842 (-3.012 : -.673)
	TMT-A	45.2 ± 19.3	53.0 ± 14.6 88.4 ± 43.0	< .001	NE<AD, MCI<AD	.456 (-.537 : 1.448)	1

.296 (.218 : 2.374) 1.102 (.051 : 2.154)

	TMT-B	95.6 ± 48.3	175.9 ± 106.6	391.1 ± 148.1	< .001	NE<AD, MCI<AD	.97 (-.066 : 2.006)	2.

683 (1.332 : 4.033) 1.668 (.53 : 2.806)

	RBANS-N	10.0 ± .0	9.7 ± .9	8.8 ± 1.8	.019 NE>AD	-.471 ( -1.465 : .522)	-.943 (-1.976 : .09)	-.632 (-1.637 : .372)
	RRME	21.3 ± 4.0	18.4 ± 4.9	12.2 ± 4.7	< .001	NE>AD, MCI>AD	-.648 (-1.654 : .357)	-2.085 (-3.303 : -.868)	-1.291 ( -2.369 : -.214)
	AN	35.3 ± 3.6	31.6 ± 4.7	22.8 ± 6.4	< .001	NE>AD, MCI>AD	-.884 (-1.911 : .143)	-2.407 (-3.694 : -1.12)	-1.567 (-2.688 : -.447)
	§ ANOVA (non parametric tests -Kruskal -Wallis-give the same results.)
	* Effect size (Cohen's d -95% CI): < .2: no effect; .2 to .5: small effect; .5 to .8: intermediate effect; .8 and higher: strong effect
	For test acronyms, see Table 2.

Table 1b: Summary of experimental studies investigating embodied cognition and/or mirror neurons in Parkinson Disease -fMRI studies

  (PD: Parkinson Disease; AOT: Action Observation Training)

	Authors	Participants	Medication	Methods	Experimental details	Principal findings
	Poliakoff et al., 2006	24 mild to moderate PD
		patients (21 right handed) and
		21 age-matched healthy
		controls (20 right handed) .
	Abrevaya et al., 2017	17 PD patients and 15 healthy	ON State	Exploring fMRI cortical activities	Participants carried out two fMRI single-word processing	The verb lexical category elicited connectivity between
		controls		during listening of action verbs and	studies. In the Noun Study, participants listened to concrete,	primary motor areas and anterior areas (implied in action
				nouns	non-graspable entities (n = 147). In the Action verb Study,	observation and imitation), in normal controls, while
					stimuli consisted of infinitive verbs(n = 150) denoting bodily	activated posterior areas in PD patients.
					movements

Appendix:

Table 1c: Summary of studies investigating embodied cognition and /or mirror neurons in Parkinson Disease -Behavioral studies

  (PD= Parkinson Disease; SCE: Spatial Compatibility Effect)

	Authors	Participants	Medication	Methods	Experimental details	Principal findings
	Boulenger et al., 2008	10 PD patients and 10 normal	ON and OFF	A masked repetition priming
		controls matched for age,	states	experiment with a lexical decision
		gender, education and socio-		task
		economic
		status
	Albert et al., 2010	Ten patients with PD and ten	OFF state	Studying the effect of an interference	Subjects performed horizontal and vertical right arm	No difference between healthy controls and PD patients
		neurologically age-matched		task on movement accuracy	movements, in phase with a stimulus displayed on a video
		unimpaired control participants			screen. The stimulus was represented by a person, or by a
					moving dot performing similar movements in the same-
					congruent-or orthogonal-incongruent-plane
	Castiello et al., 2009	16 patients with PD and 16	Patients were at	Kinematic study to test whether PD	Participants observed either a PD or a neurologically healthy	Differently than normal controls, PD patients' showed
		neurologically age-matched	their optimal	patients' imitation ability showed	model grasping an object. Subsequently, they were requested to	kinematic facilitation effects in their imitation ability
		normal control participants	dopaminergic	kinematic facilitation effects (shorter	perform a grasping action towards the same object. Two control	only when the model was a Parkinsonian patient in
			response. No	movement duration and anticipation	conditions. In the first, the model performed a kicking rather	contrast to a healthy model
			significant	of the time at which peak velocity	than a grasping action with the right foot. For the second, the
			motor	occurred) by observing either a PD or	model was standing behind the object without performing a
			complications	a neurologically healthy model	grasping action
				grasping an object
	Jaywant et al., 2006b	26 non-demented individuals	ON state	Testing the ability of PD patients to	Participants viewed videos of point-light walkers and scrambled	Persons with PD showed a reduced visual sensitivity to
		with PD and 24 normal control		perceive and recognize human motion	versions that served as foils, and indicated whether each video	biological motion, regardless of stimulus gait type or
		participants matched for age,		with limited visual attributes (a point-	depicted a human walking. Point-light walkers varied by gait	speed, with a less substantial deficit in object motion
		education, and male:female		light walker)	type (natural, parkinsonian) and speed. Participants also	perception.
		ratio			completed control tasks (object motion, coherent motion
					perception), a contrast sensitivity assessment, and a walking
					assessment
	Jaywant et al., 2006c 23 individuals with PD and 24	ON state	Testing the ability of PD patients to	Participants viewed point-light human figures that conveyed	Patients were impaired, relatively to normal controls, in
		normal controls matched for		discriminating between	gestures made with the arms, hands, and fingers. The stimuli	describing the meaning of non-communicative gestures,
		age and education level.		communicative and non-	were composed of 23 white point-lights on a black background.	while they normally perceived communicative gestures
				communicative gestures, and in	The point-lights depicted gestures that were either	as a group. Men were compromised in describing both
				describing communicative gestures	communicative ones with commonly accepted meanings, or non-	types of gestures.
				with limited visual attributes (point-	communicative -instrumental pantomimes.
				light figures)

Appendix:

Table 1d : Summary of experimental studies investigating embodied cognition and /or mirror neurons in Parkinson Disease -Neuropsychological studies (

 1d PD:Parkinson Disease; MMSE: Mini Mental State Examination; MCI: Mild Cognitive Impairment; BDAE: Boston Diagnostic Aphasia Examination; RME: Reading the Mind in the Eyes test; ToM: Theory of Mind; DBS: Deep Brain Stimulation: ACE: Action-sentence Compatibility Effect).For a detailed list of publications on this topic refer to the reviews byCardona et. al. (2013),[START_REF] Silva | Action/Verb processing: Debates in neuroimaging and the contribution of studies in patients with Parkinson's disease[END_REF] and[START_REF] Birba | Losing ground: Frontostriatal atrophy disrupts language embodiment in Parkinson's and Huntington's disease[END_REF]. Participants listened to sentences that implied an action with the hand in a particular shape (open, or closed) as well as neutral sentences that did not imply an action with the hand. Participants indicated as quickly as possible when they understood each sentence by pressing a button using a preassigned hand-shape (open or closed). They also completed the Kissing and Dancing Test The subjects were seated facing a computer screen. They listened to 52 sentences conveying open-hand actions, 52 sentences conveying closed-hand actions, and 52 neutral sentences that did not convey manual actions. Participants indicated as quickly as possible when they understood each sentence by pressing a button using a pre-assigned hand-shape (open or closed). All responses were performed with the dominant hand Early PD patients exhibited impaired ACE and verbal processing relative to healthy participants, and neuromyelitis optica and acute transverse myelitis patients.

		Appendix:
			Not specified	Semantic memory tests that do not	The Kissing and Dancing Test for actions and the Camels and	Patients performed worse compared to
		dementia and 64		involve verbal response and assess the	Cactus Test	controls in both the semantic association tasks, but
		matched controls with (similar		understanding of actions and nouns	for nouns were used	semantic deficits were more pronounced in verbs than
		age, education level, economic				nouns.
		status and performance at
		MMSE)
	García et al., 2018	40 PD patients with and	ON state	Evaluating difficulties in	Participants read two naturalistic stories (an action text and a	In PD-MCI, impairments in the appraisal of action
		without mild cognitive		processing units which denote bodily	neutral text) and responded to questions tapping the appraisal of	meanings were independent from general cognitive
		impairment (PD-MCI: 16 and		movements, for meanings evoked by	verb-related and circumstantial information	dysfunction. In PD-non MCI, deficits were observed
		PD-nMCI: 24, respectively)		context-rich narratives		only for action meanings. A deficit in the appraisal of
		and matched controls for each				action meanings evoked by naturalistic tests was able to
		group.				distinguish between normal controls and non -MCI PD
						patients from PD-MCI
	García et al., 2017	33 sporadic PD patients, 8	ON state	Evaluating semantic representation of	Semantic representation of objects and actions was assessed	The two clinical groups showed impairments in all
		genetic PD patients with		objects and actions plus general	through the Pyramids and Palm Trees test and the Kissing and	measures. Asymptomatic mutation carriers showed
		PARK2 (parkin) or LRRK2		assessment of cognitive functions	Dancing Test, respectively; action-verb processing was also	deficits in a syntactic test of actions involving the verb
		(dardarin) mutation, 9			assessed through the Action Naming subtest of the BDAE.	"to touch"
		asymptomatic first-degree			Syntactic comprehension was assessed with two BDAE
		relatives of the latter, socio-			subtests: Embedded Sentences and Touching A with B
		demographically matched
		controls
	Ibañez et al., 2013	17 early Parkinson's disease	ON state	Investiganting the ACE		PD participants showed a much diminished ACE
		patients and 15 normal matched				relative to normal volunteers. Moreover, a correlation
		volunteers. Epileptic patients				between ACE performance and action-verb processing
		with direct electrocorticography				was observed
		recordings
	Cardona et al., 2014	3 patient groups: early	ON state	Investiganting the ACE
		Parkinson's disease (15
		patients), neuromyelitis optica
		(10) and acute transverse
		myelitis patients (10), healthy
		controls

Table 1d: Summary of experimental studies investigating embodied cognition and /or mirror neurons in Parkinson Disease -Neuropsychological studies Following

  Studying the effect of DBS on lexical decisions of PD patients about hand action-related verbs, abstract verbs and pseudo-wordsThe 3 classes of stimuli was presented either in a positive or negative sentence context. Patients performed the experiment twice in the same day in two stimulation conditions: once on stimulation, and the second time, with a 50% reduction in intensity stimulationIn normal subjects, reaction times to negative commands are slower than to positive ones. When the DBS was at 100% on, both normal controls and PD patients showed the normal pattern of reaction times; however, when the stimulation was reduced at 50%, PD patients exhibited identical reaction times to both positive and negative sentences Authors investigated the perceptual ability to discriminate (a) graded intensities of emotional from neutral expressions, (b) graded intensities of the same emotional expressions, (c) full-blown discrepant emotional expressions from 2 similar expressions and the more complex recognition ability to label full-blown emotional expressions. A modification of the Upper and Lower Face Apraxia Test was used to test voluntary facial musculature control PD patients were, as a group, impaired in all measures of discrimination and recognition of emotional expressions. Discrimination and recognition of emotional expressions correlated positively with voluntary control of facial musculature (after partialing out disease severity and age)

	Tomasino et al., 2014	10 right handed PD patients	Patients on
		with DBS electrodes bilaterally	their usual
		implanted into the subthalamic	medication
		nucleus
	Marneweck et al., 2014 32 PD patients and 34 normal controls in Experiment 1 and 25 patient and 25 controls in Experiment 2, approximately one year after Experiment 1. 40 subjects participated in both experiments. In two experiments, Jacobs et al., 1995 Patients were tested 1,5 hours before taking anti-Parkinson medication Exploring perception of facial expressions of emotion and its link with voluntary facial musculature control 12 PD patients and 30 control Not specified
		subjects

Appendix: Table 1d: Summary of experimental studies investigating embodied cognition and /or mirror neurons in Parkinson Disease -Neuropsychological studies Following

  Stimuli from the Ryerson Audio-Visual Database of Emotional Speech and Song were used. Participants had to identify emotion of people speaking or singing with different emotions and to rate the intensity of the expressed emotion PD patients exhibited a deficit in their facial mimicry responses to emotional displays, showing a particular deficit in mimicking response to happy faces Nobis et al., 2017 44 PD patients Not specified Assessing mind-reading abilities Patients performed RME, which measures empathic abilities, and The Faux Pas detection test, a measure of "cognitive" ToM Affective ToM was found associated with motor symptom severity and cognitive ToM predominantly with executive function, but no effect of PD lateralization on this was identified

	Authors	Participants	Medication	Methods	Experimental details	Principal findings
	Livingstone et al., 2016	27 PD patients and 28 age	Not specified	EMG of facial muscles recording
		matched controls		while subjects observed presentations
				of calm, happy, sad, angry, and fearful
				emotions

Appendix: Table 1e: Summary of experimental studies investigating embodied cognition and /or mirror neurons in Parkinson Disease -Rehabilitative studies

  Participants were randomly divided into 2 groups: the VIDEO group watched video clips showing repetitive finger movements paced at 3 Hz; the ACOUSTIC group listened to an acoustic cue paced at 3 Hz. All participants performed a spontaneous finger sequence at different intervals before and after the intervention. 8 PD patients watched a video representing a static hand (sham intervention). Ten patients participated in the same protocol of the VIDEO group but were tested in the ON and OFF medication states. Both VIDEO and ACOUSTIC training increased the spontaneous rate in all participants. VIDEO intervention showed a greater effect over time. AOT significantly influenced movement rate in ON and OFF conditions, but 45 minutes after training, the effect was still present only in the ON condition. No effect after sham intervention. (PD: Parkinson Disease; AOT: action observation training; UPDRS: Unified Parkinson Disease Rating Scale; MVF: Mirror Visual Feedback therapy )

	Bienkiewicz et al., 2013	7 PD patients		Testing patients in an upper limb
				mediolateral movement task, with and
				without a visual point light display,
				travelling at 3 different speeds.
		subjects with PD and 14	ON state; ON	Randomized controlled trial of AOT
		healthy controls; 8 participants	and OFF states	(10 PD, 7 controls) versus acoustic
		with PD were recruited for a	for a subgroup	cues (10 PD, 7 controls); a subgroup
		control intervention		of 10 patients was tested in both ON
				and OFF states. Another group (10
				PD) underwent sham intervention.

Table 1e: Summary of experimental studies investigating embodied cognition and /or mirror neurons in Parkinson Disease -Rehabilitative studies Following

  12 control subjects were involved in the MVF while 9 additional patients with PD performed a control experiment (training without MVF). Before and after MVF training, participants performed a finger sequence at their spontaneous pace with both hands. M1 excitability was assessed in the trained and untrained hemispheres by means of transcranial magnetic stimulation.Movement speed increased after MVF training in either hand of both groups. MVF therapy enhanced cortical excitability of M1s in both groups. AOT (combined with practicing the observed actions) and ''Landscape'' (same physical training combined with landscape-videos observation). At baseline and 4-week, patients underwent clinical evaluation and fMRI. Clinical assessment was repeated at 8-week.After 4 weeks, both groups showed reduced freezing of gait severity, improved walking speed and quality of life, but in the AOT group motor disability was additionally reduced and balance improved. After 8 weeks, only the AOT group showed a sustained positive effect. Patients were then scanned while executing foot movements, and during AOT. The AOT group showed increased recruitment of fronto-parietal mirror areas during fMRI tasks. Functional brain changes were associated with clinical improvements. AOT Participants observed a video of repetitive flexionextension of the fingers at three frequency or complexity levels, alternated with periods of a static hand AOT activated brain regions related to the MN system in both ALS and healthy subjects. In patients some areas (dorsal lateral premotor cortex, inferior parietal gyrus, and supplementary motor area) were more activated. Increased activation within the primary motor cortex, the dorsal lateral premotor cortex, the inferior frontal gyrus, and superior parietal gyrus correlated with hand movement frequency/complexity in patients.Behavioral testing consisted of the presentation of a motion morph on a screen for 10 s. The subject had to first answer whether the stimulus was emotional or neutral, and, dependent on this answer, categorize the emotion as happy, angry, fearful, or sad. For the MRI study: 1) Voxel-based morphometry analysis based on a structural, high resolution, T1-weighted image. 2) Resting state study. A fMRI study during behavioral testing was also performed in young controls.bvFTD patients were impaired in emotion detection as well as emotion categorization tasks. Their performance in emotion categorization inversely correlated with atrophy of the left IFG, a region belonging to the MN network. Functional connectivity analysis also showed a reduced connectivity of this area.

	Bonassi et al, 2016 12 PD and Agosta et al., 2016 21 patients with mild to moderate PD and 12 healthy subjects Stable medication regimen Controlled trial with MVF performed with the use of a mirror box to reduce bradikinesia 25 PD patients with freezing of gait stable dopaminergic medication regimen Sigle randomized controlled trial of AOT plus physical therapy versus Participants Methods Experimental details PD patients were randomized into two groups: Appendix: Authors Li et al., 2015 30 patients with ALS and 30 matched healthy controls fMRI study during Jelsone-Swain et al., 19 patients with ALS and 20 fMRI study during AOT Subjects observed an actor's hand rhythmically sham intervention plus physical therapy 2015 helathy controls squeezing a ball or squeezed themselves a ball	Principal findings Authors observed greater activity in ALS patients than in controls in MN regions (right frontal inferior operculum,
		for at least 4	right frontal and left parietal lobes)
	Jastorff et al., 2016	weeks 14 patients with bvFTD and 19	Behavioral testing plus
		age-matched controls	structural and resting
			state MRI
	Verstraete et al., 2013	24 patients with ALS and a	Diffusion tensor
		group of healthy controls	imaging study

Table 2a : Summary of experimental studies investigating embodied cognition and /or mirror neurons in Frontotemporal Dementia or Amyotrophic Lateral Sclerosis -MRI studies (

 2a bvFTD: behavioral variant of Frontotemporal Dementia; ALS: Amyotrophic Lateral Sclerosis; AOT: Action Observation Training: Impairment; MRI: Magnetic Resonance Imaging; fMRI: functional MRI; IFG: Inferior Frontal Gyrus; MN: Mirror Neurons) Sentence comprehension was assessed with the test of the reception of grammar (TROG); verb and noun processing was evaluated with Berndt's test Comprehension and production of verbs were consistently more affected those that of nouns and this effect remained stable upon subsequent testing, despite overall deterioration

	Authors	Participants	Methods	Experimental details	Principal findings
	Bak and Hodges, 1997	three ALS patients with	word-picture matching		Performance was poorer with verbs than nouns, in a word-
		aphasia and FTD	task and naming		picture matching task. Moreover, the only patient who
					could complete the task exhibited significantly poorer
					performance in action naming than object
	Bak et al., 2001	6 patients with MotND, in	Tests of comprehension,
		whom communication	verb and noun
		problems were an early and	processing, visuospatial
		dominant feature	functions
	Grossman et al., 2008	34 patients with ALS (26 for	Word-description
		the MRI study)	matching
			and associativity
			judgments with actions
			and objects. Voxel-
			based MRI

Table 2b: Summary of experimental studies investigating embodied cognition and /or mirror neurons in Frontotemporal Dementia or Amyotrophic Lateral Sclerosis - Neuropsychological or Behavioral studies (

  bvFTD= behavioral variant of Frontotemporal Dementia; ALS: Amyotrophic Lateral Sclerosis; AD: Alzheimer Disease; PD: Parkinson Disease: PDD: Parkinson Disease Dementia; MRI: Magnetic Resonance Imaging; BORB: Birmingham Object Recognition Battery)

	Hillis et al., 2004	15 patients with nonfluent	Oral and written naming
		nonfluent PPA, 7 patients with	of nouns and verbs,
		fluent PPA and 6 patients with	matched in difficulty
		ALS-FTD
	Cappa et al., 1998	19 mild to moderate AD	Action and object	Confrontation naming was assessed with realistic	AD and FTD patients were impaired in naming compared
		patients, 10 FTD patients and	naming	pictures of 40 objects and 40 actions. The objects	with control subjects; action naming was more severely
		15 age-and education-matched		belonged to different semantic categories (both	impaired. The discrepancy between object and action
		normal controls		natural and artefactual); the actions involved largely,	naming was significantly greater in FTD than in AD.
				but not exclusively, tool utilization

Appendix:

  The hand laterality task requires participants to decide whether a picture represents a right or a left hand. In this modified version, participants respond by means of eye-gazes. In the mirror letter discrimination task, participants are requested to indicate whether the displayed alphanumeric characters are in their normal or mirrorreversed orientationThe effects of biomechanical constraints on MI (comfortable/awkward posture) were compromised in ALS at the hand laterality task. No difference was present at the mirror letter discrimination task between patients and controls.

	Fiori et al., 2013	34 ALS patients and 23	A hand laterality and a
		normal controls	mirror letter
			discrimination task
	Vannuscorps et al., 2016	A patient diagnosed with	Longitudinal study.
		corticobasal degeneration	Voxel-based
			morphometric
			MRI, testing of
			movement production,
			tasks of conceptual
			processing of actions
			and manipulable
			objects, tasks of gesture
			and conceptual
			processing,
			neuropsychological
			assessment

Table 2b : Summary of experimental studies investigating embodied cognition and /or mirror neurons in Frontotemporal Dementia or Amyotrophic Lateral Sclerosis - Neuropsychological or Behavioral studies Following

 2b

Authors

Participants

Medication Methods Experimental details Principal findings [START_REF] Alegre | Changes in subthalamic activity during movement observation in Parkinson's disease: Is the mirror system mirrored in the basal ganglia[END_REF] 18 PD patients, with surgically implanted electrodes for DBS ON and OFF states EEG and local field potentials recording through surgically implanted electrodes for DBS Oscillatory changes in electrical activities were recorded during movement execution (right wrist extensions), AOT (left wrist extension movements by an investigator seated in front of the patient) and two control conditions (simple stimulus-yellow squares-and rotating stimulus observation on a screen) AOT (as movement execution) was associated to a bilateral reduction of subthalamic power in the beta range. The effect was present in both on and off state, even if higher in the first one. In the EEG channels, the pattern observed in the beta band was parallel to that observed in the subthalamic nucleus

ON state

Recording MEP amplitudes at the first dorsal interosseous and abductor digiti minimi of the right hand MEP amplitudes were recorded in four conditions: rest, AOT (a video depicting a hand cutting a piece of paper with scissors), motor imagery and active action imitation. In each presentation,MEPs were recorded by delivering TMS at a predetermined delay (7 s) in the video sequence.

The MEP amplitude increased in PD patients during active imitation (compared to resting state) but neither during AOT nor during action imagery.

Gündüz et al., 2015

Eight idiopathic PD patients with apraxia, 11 idiopathic PD patients without apraxia, and 8 healthy subjects (control group) Patients were at their optimal dopaminergic response Recording F-waves and MEPs bilaterally at abductor policis brevis F-waves and MEPs were recorded during 4 states (resting, imagination, observation, and active movement: abduction with the abductor policis brevis). For F-waves, the median nerve was stimulated at the wrist. The MEP recordings were performed using the minimum TMS intensity required to evoke a 1 mV amplitude response.

Normal facilitation of MEP amplitudes by mental imagery and active movements in normal controls and non-apraxic PD patients. The same was true for F-wave amplitudes over the dominant upper extremity during mental imagery, observation and active movements.This facilitation was lost in apraxic PD patients. Three types of gestures were selected: 'smile','kiss', and 'neutral' for a total of 72 video clips. In addition, a scrambled version was produced of each clip. Participants were instructed to execute a facial gesture ('do') whenever they saw a scrambled video and to attentively watch the actor('view') whenever they saw an unscrambled video .To measure the participants' ability to decode emotions from facial expressions, a set of facial stimuli taken from the Facial Expression of Emotions: Stimuli and Test was used.

APPENDIX

Participants showed significant stronger activity in the right ventrolateral premotor cortex during execution and perception of affective facial gestures than healthy controls. They also showed a slightly reduced ability to recognize facial emotions that was inversely proportional to the increase of ventrolateral premotor activity. The ability to reproduce the kinematic features of a human demonstrator and those of a dot moving on a screen was tested.

Participants were asked to imitate the velocity of the stimulus When asked to imitate the velocity of the stimulus AD patients showed an intact ability to reproduce it. This ability improved when the stimulus was a human agent Appendix: A correlation between action comprehension, action naming abilities, language impairment and apraxia was found in AD patients [START_REF] Williamson | Object and action naming in Alzheimer's disease[END_REF] 10 patients with AD and 10 normal control subjects

Picture-naming tasks

The Boston Naming Test and the Action Naming Test were used

Object naming was impaired to a significantly greater extent than action naming in AD. This difference remained after controlling for the effects of word frequency [START_REF] Masterson | Selective naming (and comprehension) deficits in Alzheimer's disease?[END_REF] 23 AD patients and agematched controls Picture-naming tasks and a word-picture verification task

The word-picture verification task consisted of 62 verb and 62 noun items, a subset of the stimuli in the Object and Action Naming Battery. Each item in the task consisted of a single picture presented three times with different printed words: once with the target picture name, once with a semantically related distractor, and once with an unrelated distractor

In the picture naming tasks both patients and controls were faster and produced more target responses for objects than actions. In the comprehension task, accuracy levels were comparable for nouns and verbs, but response times were longer for verbs [START_REF] Guaita | Impaired Facial Emotion Recognition And Preserved Reactivity To Facial Expressions In People With Severe Dementia[END_REF] 79 patients with dementia and 64 healthy elderly subjects

Assessing the capability of understanding facial emotions

The test consisted in showing 14 photographic representations of 7 emotions both from male and from female faces, representing happiness, sadness, fear, disgust, boredom, anger and surprise. Patients were asked to observe the face and to recognize the emotion either with a denomination or a description. The spontaneous reactivity to the face expressions was videotaped and classified as a congruous or incongruous reaction AD patients were impaired in recognizing emotions but did not differ from controls in the spontaneous reaction to facial expressions Appendix: Subjects were asked to make judgments on sentences that describe a transfer of an object toward or away from their body Patients were faster to respond when the response required a movement in the same direction as the transfer described in the sentence