Neurosciences Cognitive

D Vi

G R Poeppel

M S Mangun

Eds Gazzaniga

Ghislaine Dehaene-Lambertz

Claire Kabdebon

The brain bases of language development in The

The development of noninvasive brain-imaging techniques has opened the black box of the infant brain. Instead of postulating theories based on the delayed consequences of, fortunately rare, early lesions, we can now study healthy infant responses to speech. Rather than a brain limited to primary areas or, on the contrary, a poorly specialized brain, brain-imaging studies have revealed a functional architecture in infants that is close to what is described in adults. In particular, a hierarchy of increasingly integrated computations is observed along the superior temporal regions, and the processing of different speech features is already segregated along parallel neural pathways with different hemispheric biases. Yet, although highly structured, the infant brain still differs from the adult brain, with particularly delayed brain responses arising from frontal regions. We can expect that a better understanding of the computational abilities of this early network may provide insight into the mechanisms underlying language acquisition.

Speech is a remarkable communication device whose efficiency to convey information is based on the combination of units (phonemes in words, words in sentences) according to rules. Before the end of the first year of life, human infants display amazing capacities in processing speech. First, they show an extraordinary ability to analyze the auditory content of the speech stream. They learn the repertoire of sounds (or phonemes) used by their native language [START_REF] Kuhl | Linguistic experience alters phonetic perception in infants by 6 months of age[END_REF][START_REF] Werker | Phonemic and phonetic factors in adult cross-language speech perception[END_REF] and the rules (phonotactics) for combining these sounds within words [START_REF] Jusczyk | Infants' sensitivity to phonotactic patterns in the native language[END_REF]. They notice the frequent words of stories they have heard a few times [START_REF] Jusczyk | Infants' memory for spoken words[END_REF] and that content words are surrounded by recurrent syllables (e.g., ing, the, a) that have a different function in the sentence [START_REF] Shi | Functional morphemes and early language acquisition[END_REF], as they start to figure out sentence organization. This early learning is based on distributional analyses at different levels of the linguistic structure, from the syllabic level [START_REF] Saffran | Statistical learning by 8-month-old infants[END_REF] to a more abstract level, such as word category [START_REF] Gervain | Bootstrapping word order in prelexical infants: A Japanese-Italian cross-linguistic study[END_REF]. Second, they rapidly discover the referential aspect of speech: they know that speech conveys information from at least 4 months of age [START_REF] Marno | Can you see what I am talking about? Human speech triggers referential expectation in four-month-old infants[END_REF], and at 6-9 months of age, they already know the meaning of a few words, such as mommy, hug, some body parts, and more [START_REF] Bergelson | At 6-9 months, human infants know the meanings of many common nouns[END_REF][START_REF] Tincoff | Some beginnings of word comprehension in 6-month-olds[END_REF]. Third, infants might also rapidly understand that speech is a symbolic system. They can create equivalence between a label and a category [START_REF] Kabdebon | Symbolic labelling in 5-month-old human infants[END_REF], which helps them to sort items into named categories (e.g., dinosaur vs. fish pictures; [START_REF] Ferry | Nonhuman primate vocalizations support categorization in very young human infants[END_REF].

What are the cerebral bases of these impressive competences? Is language acquisition based on a functional organization similar to the adult linguistic network? This question is not trivial, as the development of the human brain is complex and extends over two decades. Its weight increases from 400 g at birth to 1400 g in adults. The organization of cortical layers and large fiber networks is well established at term birth (Dubois & Dehaene-Lambertz, 2015), although neuronal migration is still ongoing in the frontal areas during the first months of life [START_REF] Paredes | Extensive migration of young neurons into the infant human frontal lobe[END_REF]. Maturation consists of waves of synaptogenesis followed by pruning with an acceleration of signal transmission speed due to myelination of the tracts. These phenomena are relatively well described, but brain maturation covers many other aspects essential to the effectiveness of neural networks, such as the maturation of glia and various types of neurons, the production of neurotransmitters, changes in receptors, the accumulation of proteoglycan chains, and more, whose maturational sequences are unknown in the human brain. Additionally,

The Organization of Perisylvian Regions

In human adults, linguistic and nonlinguistic representations of speech are computed in parallel along distinct hierarchical pathways in the superior temporal lobe, reaching the inferior frontal regions. This hierarchical and parallel functional organization is already observed in infants' perisylvian regions.

A hierarchy of linguistic processes When infants-even neonates-listen to speech, activation occurs along the superior temporal region bilaterally and extends to distant left inferior parietal and frontal regions (Dehaene-Lambertz, [START_REF] Dehaene-Lambertz | Functional organization of perisylvian activation during presentation of sentences in preverbal infants[END_REF][START_REF] Pena | Sounds and silence: An optical topography study of language recognition at birth[END_REF][START_REF] Shultz | Neural specialization for speech in the first months of life[END_REF][START_REF] Sato | Cerebral hemodynamics in newborn infants exposed to speech sounds: A whole-head optical topography study[END_REF]. Interestingly, the phase of the BOLD response progressively slows down as we move away from the primary auditory cortex (Heschl's gyrus) toward the temporal pole and toward the temporoparietal junction (Dehaene-Lambertz, [START_REF] Dehaene-Lambertz | Functional organization of perisylvian activation during presentation of sentences in preverbal infants[END_REF]. Whereas the Blood Oxygen Level Dependent (BOLD) response rapidly peaks and decreases in Heschl's gyrus, it becomes more and more delayed and sustained anteriorly in the superior temporal sulcus and even starts at the end of a sentence in the most anterior regions (figure 78.1). This temporal gradient is not related to an immature neurovascular coupling since a similar, although faster, gradient is visible in adults (Dehaene-Lambertz, Dehaene, et al., 2006). Because in infants, as in adults, the superior region of the temporal areas is more sensitive to acoustic features than the more ventral regions involved in the computation of abstract and integrated representations [START_REF] Bristow | Hearing faces: How the infant brain matches the face it sees with the speech it hears[END_REF][START_REF] Dewitt | Phoneme and word recognition in the auditory ventral stream[END_REF], we proposed that this gradient might be the consequence of the hierarchical organization of the perisylvian networks: the increasingly delayed and sustained responses would correspond to larger and larger windows for integrating speech chunks, as described in adults [START_REF] Ding | Cortical tracking of hierarchical linguistic structures in connected speech[END_REF].

Dehaene-Lambertz & Kabdebon -The cerebral bases of language development-2020 4 Such hierarchical organization might explain infants' early sensitivity to sentence organization and why they prefer listening to sentences with pauses located at prosodic boundaries rather than within prosodic units [START_REF] Hirsh-Pasek | Clauses are perceptual units for young infants[END_REF]. With its embedded units, the prosodic hierarchy is a natural input for these regions, helping infants segment the speech stream into coherent chunks. Analyses can then be restricted to each prosodic unit, explaining why the computations of transitional probabilities between syllables-which is the main proposed mechanism in infants for extracting words from a stream of speech [START_REF] Saffran | Statistical learning by 8-month-old infants[END_REF]-cannot occur across a prosodic boundary [START_REF] Shukla | Prosody guides the rapid mapping of auditory word forms onto visual objects in 6-mo-old infants[END_REF]. Finally, as prosody and syntax are tightly related, this hierarchical organization might also secondarily facilitate the learning of native syntax [START_REF] Christophe | Bootstrapping lexical and syntactic acquisition[END_REF]. , et al., 2006;Dehaene-Lambertz, Dehaene, et al., 2006).

Parallel pathways for voice and phoneme processing Speech conveys information not only about the language but also about the speaker. Both elements are crucial for infants to understand what is said and to identify who is speaking. Thus, they should simultaneously neglect local variations in timbre, pitch, speech rate, and so on to extract the linguistic information and use them to be able to keep track of the speaker's identity, actual emotion, and location in space. Using event-related potentials (ERPs), we showed that these computations are done in parallel: After a series of repeated auditory-visual vowels, a change in vowel identity or the speaker's gender evokes two different mismatch responses, characterized by a different voltage topography on the scalp but within the same time window, in 3-month-olds [START_REF] Bristow | Hearing faces: How the infant brain matches the face it sees with the speech it hears[END_REF]. Although spatial information is coarse with electroencephalography (EEG), a model of brain sources suggests a right-lateralized response for the change of voice, contrasting with a left-lateralized response for a change of vowel.

These hemispheric biases are confirmed with functional magnetic resonance imaging (fMRI) in 2-month-old infants who listened to their mother's voice or to the voice of an unknown mother. In the left posterior temporal region, activations are enhanced in response to the voice of one's own mother, probably because familiarity with the voice allows for better phonetic access. Right-hemisphere differences are also observed in a more anterior temporal region, described as the voice region in adults. This region is also found when nonlinguistic vocal sounds are contrasted with environmental sounds in 3-to 7-month-olds [START_REF] Blasi | Early specialization for voice and emotion processing in the infant brain[END_REF]. All of these experiments underline a parallel organization from the first months of life channeling voice and phoneme processing along different pathways.

Early lateralization of speech processing The previous studies suggest that adults' left-right functional differences have their roots in early development. Indeed, a larger lefthemispheric response is reported in most studies using speech during the first trimester of life: and less precisely over the superior temporal region in near-infrared spectroscopy (NIRS) studies [START_REF] Pena | Sounds and silence: An optical topography study of language recognition at birth[END_REF][START_REF] Sato | Cerebral hemodynamics in newborn infants exposed to speech sounds: A whole-head optical topography study[END_REF][START_REF] Vannasing | Distinct hemispheric specializations for native and non-native languages in one-day-old newborns identified by fNIRS[END_REF]. Activations in response to one's native language are also more left-lateralized than to music [START_REF] Dehaene-Lambertz | Language or music, mother or Mozart? Structural and environmental influences on infants' language networks[END_REF] and to other biological sounds, such as nonspeech vocalization, footsteps, and monkey calls [START_REF] Shultz | Neural specialization for speech in the first months of life[END_REF], but not compared to a foreign language and backward speech (Dehaene-Lambertz, Dehaene, & Hertz-Pannier, 2002), at least initially. After a few months,

Dehaene-Lambertz & Kabdebon
-The cerebral bases of language development-2020 6 however, the difference between native and nonnative speech becomes larger. Five-month-olds, but not 3-month-olds, show larger NIRS activation for their own dialect than for a foreign dialect (Quebecois vs. Parisian French) over only the left, but not the right, temporal region [START_REF] Cristia | Neural correlates of infant accent discrimination: An fNIRS study[END_REF]. A left-hemispheric advantage to process fast temporal transitions [START_REF] Zatorre | Structure and function of auditory cortex: Music and speech[END_REF] might explain an early left bias for speech-like stimuli that is further reinforced through linguistic experience. However, the fact that sign language is also left lateralized in adults argues for a multifactorial contribution to the robust left lateralization of language in humans (see chapter 73).

A Precise Temporal Encoding since the Fetal Life

This functional organization finds its roots during fetal life. At 6 months gestation, 3 months before term, the subcortical sensory system begins to react to external sounds, and the thalamocortical connections reach the cortical plate, feeding the first cortical circuits with external information [START_REF] Kostovic | The development of the subplate and thalamocortical connections in the human foetal brain[END_REF]. Although the local microcircuitry is very different from later ages since most of the neurons are still migrating to reach their final location and dendritic trees are sparse, the brain's general connectivity is already visible at the structural [START_REF] Takahashi | Emerging cerebral connectivity in the human fetal brain: An MR tractography study[END_REF] and functional level [START_REF] Fransson | Resting-state networks in the infant brain[END_REF][START_REF] Smyser | Functional connectivity MRI in infants: Exploration of the functional organization of the developing brain[END_REF] Several experiments have illustrated the relation between the precision of temporal encoding and better performance in tasks using speech stimuli in normal subjects. For example, [START_REF] Kabdebon | Electrophysiological evidence of statistical learning of long-distance dependencies in 8-month-old preterm and full-term infants[END_REF] recorded high-density EEG in 8-month-old infants while they were listening to a stream of syllables concatenated according to an AxC structure (i.e., the first syllable (A) predicted the third syllable (C) of successive triplets whereas the middle syllable (x) is variable). The infants were then tested with isolated trisyllabic words that either respected or did not respect the hidden structure of the training stream. The difference between these two conditions at test was significantly correlated with the temporal locking to the syllable frequency during the training stream, as observed with EEG. Similarly in adults, the temporal similarity between auditory cortical activity and speech envelopes predicted speech comprehension [START_REF] Ahissar | Speech comprehension is correlated with temporal response patterns recorded from auditory cortex[END_REF]. A deficit in temporal encoding has been proposed as one of the mechanisms underlying some oral and written language impairments (Abrams, Nicol, Zecker [START_REF] Abrams | Abnormal cortical processing of the syllable rate of speech in poor readers[END_REF][START_REF] Lehongre | Altered low-gamma sampling in auditory cortex accounts for the three main facets of dyslexia[END_REF], and the size of the production lexicon can be predicted from the performance of a phonetic discrimination task at 6 months (Tsao, Liu, & Kuhl, 2004). Lexicon size is also correlated with the speed of recognition of auditorily presented words at 18 months [START_REF] Fernald | Picking up speed in understanding: Speech processing efficiency and vocabulary growth across the 2nd year[END_REF], demonstrating the interplay between early refined phonetic encoding abilities and later higherlevel linguistic abilities.

Immature but Nonetheless Functional Frontal Areas

Activation to speech does not remain limited to auditory areas but extends to higher levels in the parietal and frontal lobes (figures 78.1 and 78.2). Because of their protracted development, frontal areas were classically assumed to function poorly in infants. Many brainimaging studies have now revealed their involvement in infant cognition: the inferior frontal region reacts to a change in auditory sequences as early as 6 months gestation, on the left for a change of phoneme and on the right for both a change of voice and a change of phoneme [START_REF] Mahmoudzadeh | Syllabic discrimination in premature human infants prior to complete formation of cortical layers[END_REF]. At 3 months post-term, an increase in activation in the frontal areas is observed in response to the repetition of a short sentence (Dehaene-Lambertz, [START_REF] Dehaene-Lambertz | Functional organization of perisylvian activation during presentation of sentences in preverbal infants[END_REF] or in response to repetition of the same vowel across modalities [START_REF] Bristow | Hearing faces: How the infant brain matches the face it sees with the speech it hears[END_REF]. Enhanced frontal activations are also recorded when a complex auditory pattern is violated [START_REF] Basirat | A hierarchy of cortical responses to sequence violations in three-month-old infants[END_REF]. These results reveal the frontal regions' involvement in short-term memory. At the same age, recognition of the prosodic contours of one's native language activates the right dorsolateral prefrontal region in attentive infants (Dehaene-Lambertz, Dehaene, & Hertz-Pannier, 2002), whereas voice familiarity modulates the balance between the median prefrontal regions, sensitive to stimulus familiarity, and the orbitofrontal limbic circuit, involved in stimulus emotional valence [START_REF] Dehaene-Lambertz | Language or music, mother or Mozart? Structural and environmental influences on infants' language networks[END_REF]. Thus, the frontal lobes in infants are not only activated but are also parceled into different regions distinctively engaged depending on the task, exactly as in older participants.

However, frontal regions react at a slower pace in infancy than later in life. ERP studies have shown that late responses, which depend on higher levels of processing, are disproportionally slower in infants, relative to adults, compared to the infant-adult differences in early sensory regions. Electrical components proposed to be the equivalent of the adult P300 have been recorded after 700 ms, and even around 1 s, until at least the end of the first year [START_REF] Kouider | A neural marker of perceptual consciousness in infants[END_REF]. By contrast, the latency of the visual P1 reaches adult values around 3

Dehaene-Lambertz & Kabdebon -The cerebral bases of language development-2020 9 months of age [START_REF] Mcculloch | Maturation of the pattern-reversal VEP in human infants: A theoretical framework[END_REF]. These time delays should be further studied to analyze whether, and how, they might confer an advantage in learning.

Because maturation improves both local computations and the speed in the connections between regions, the balance between networks may change with development, and patterns of maturation may thus reveal the crucial role of certain circuits at a given moment in acquiring new skills. Adjusting the weights of the different pathways-and thus how they learn-through maturational lags at precise nodes of the perisylvian cortex might be a way to genetically control language development. Combining different techniques makes it possible to study this question-for example, the efficiency of the dorsal and ventral pathway connecting inferior frontal areas and superior temporal areas. A longitudinal study of the functional connectivity over the first 2 years of life reports a rapid increase of connectivity within the left linguistic network between the frontal and posterior temporal areas within the first year of life [START_REF] Emerson | Longitudinal study of the emerging functional connectivity asymmetry of primary language regions during infancy[END_REF]. At the structural level, the T2 MRI signal component, which is sensitive to free water in the tissues, and diffusion tensor imaging (DTI), which provides measures of the movement of water molecules (measures of diffusivity) and their direction (measure of fractional anisotropy), can be used to study gray and white matter maturation. These markers show that structures belonging to the dorsal pathway (frontal area 44, the posterior superior temporal sulcus, and the arcuate fasciculus) mature in synchrony. While the dorsal pathway displays a delayed maturation relative to the ventral pathway, it starts to catch up after 3 months of age (Dubois et al., 2015;[START_REF] Leroy | Early maturation of the linguistic dorsal pathway in human infants[END_REF]. This adjustment might be related to the increase in vocalization and progression in the analysis of the segmental part of speech observed at the same age.

The involvement of the inferior frontal regions and the dorsal pathway provides infants with a short-term auditory memory, which seems to be lacking in macaques [START_REF] Fritz | In search of an auditory engram[END_REF]. A long buffer may favor the discovery of second-order rules by keeping track of segmental elements [START_REF] Basirat | A hierarchy of cortical responses to sequence violations in three-month-old infants[END_REF][START_REF] Kovacs | Hierarchical processing in seven-month-old infants[END_REF]. Coupled with hierarchical coding along the superior temporal regions, this may favor computations on chunks of chunks and increase sensitivity to deeper hierarchical structures, as well as algebraic rules, as demonstrated in 8-month-olds [START_REF] Marcus | Rule learning by seven-month-old infants[END_REF]. The early role of the dorsal pathway is confirmed by the observation that fractional anisotropy values measured at term birth in the arcuate fasciculi are correlated with linguistic scores at 2 years of age [START_REF] Salvan | Language ability in preterm children is associated with arcuate fasciculi microstructure at term[END_REF].

Dehaene-Lambertz & Kabdebon

-The cerebral bases of language development-2020 10 When infants listen to speech, activations are not limited to the classical linguistic areas, and the involvement of frontal areas outside the linguistic system may improve infants' focus on speech as a relevant stimulus. Motivation and pleasure, as well as understanding the referential aspect of speech through social cues, have been shown to be important for speech learning (Kuhl, Tsao, & Liu, 2003). The activation in dorsolateral prefrontal regions shown in awake infants recognizing their native language, as well as activation in prefrontal median regions when the voice is familiar, may very well explain these behavioral observations.

Nature versus Nurture

During the first year of life, infants become attuned to the prosody and phonetic repertoire of their native language [START_REF] Kuhl | Linguistic experience alters phonetic perception in infants by 6 months of age[END_REF][START_REF] Werker | Phonemic and phonetic factors in adult cross-language speech perception[END_REF], which can have long-term effects. Chinese adoptees in Quebec, no longer exposed to Chinese after the first year of life, on average, still perceive a tonal contrast and activate the left planum temporale similarly to native Chinese speakers. This contrasts with

French-speaking controls never exposed to Chinese, who activate only the right hemisphere (Pierce, Klein, Chen, Delcenserie, & Genesee, 2014). Because preterm infants are exposed earlier than full-term neonates to aerial speech, they can be compared to full-term neonates to study the effects of ex-utero exposure versus the brain's developmental age on the sensitivity to foreign speech. In two different studies in preterm infants, Pena and colleagues reported that the decrease in the sensitivity to foreign-language prosody [START_REF] Pena | Language acquisition in premature and full-term infants[END_REF] and foreign phonetic contrasts [START_REF] Pena | Earlier speech exposure does not accelerate speech acquisition[END_REF]) is related to the brain's developmental age rather than the duration of ex-utero life. By contrast, learning the phonotactic rules of one's native language is dependent on the duration of exposure to aerial speech [START_REF] Gonzalez-Gomez | Phonotactic acquisition in healthy preterm infants[END_REF]. This discrepancy may point to a critical distinction between a learning mechanism (here, statistical learning allowing for the accumulation of positive evidence on the frequency of phonetic categories and combinations of phonemes) and the critical period during which this learning mechanism is workable. In the mouse visual cortex, it has been proposed that the opening and closing of "critical" windows relies on two thresholds in the accumulation of a homeoprotein, Otx2, in GABAergic parvalbumin interneurons [START_REF] Hensch | Critical period regulation[END_REF]. When the Otx2 level reaches one threshold, learning starts; when it reaches the other, learning then stops or at least becomes more difficult. A similar mechanism might explain how computation of the statistics of the native phonetic environment can only begin after a certain maturational age (probably after 35 weeks gestational age, when the

Conclusion

We have emphasized here the early brain organization and its similarities with adult networks and have sought to relate brain-imaging results to behavioral performance. This architecture and its complex maturational calendar have been selected through human evolution as the most efficient in helping infants detect correct cues in the environment in order to learn their native language. A better understanding of brain plasticity and, notably, its changes with age and learning at the microstructural and network levels is a necessary step to refine models of language acquisition.

  region, maturational spurts occur at different moments and at different rates, generating dynamic shifts within and between regions and adding a dimension of complexity to how networks interact. Although the description of the immature human brain becomes more refined thanks to the development of noninvasive brain-imaging techniques, we are still far from understanding what crucial features of the infant brain allow for this rapid linguistic development. Nevertheless, based on the brain-imaging data acquired from the last trimester of gestation onward, we can start to propose hypotheses on how the functional architecture of the infant brain may explain some of the early linguistic competencies.

Figure 78 . 1

 781 Figure78.1 Hierarchical organization of the perisylvian regions in 3-month-old infants and adults, illustrated by the phase gradient of the BOLD response to a single sentence. The mean phase is presented on axial slices placed at similar locations in the adult (top row) and infant (bottom row) standard brains and on a sagittal slice in the infant's right hemisphere. Colors encode the circular mean of the phase of the BOLD response, expressed in seconds relative to sentence onset. The same gradient is observed in both groups along the superior temporal region, extending until Broca's area (arrow). Blue regions are out of phase with stimulation (Dehaene-Lambertz,[START_REF] Dehaene-Lambertz | Functional organization of perisylvian activation during presentation of sentences in preverbal infants[END_REF] Dehaene-Lambertz, Dehaene, et al., 2006).

  at the level of the planum temporale in fMRI studies (Dehaene-Lambertz, Dehaene, & Hertz-Pannier, 2002; Dehaene-Lambertz,[START_REF] Dehaene-Lambertz | Functional organization of perisylvian activation during presentation of sentences in preverbal infants[END_REF][START_REF] Dehaene-Lambertz | Language or music, mother or Mozart? Structural and environmental influences on infants' language networks[END_REF]

  . Already at this age, preterm neonates react to a change of consonant (/ba/ vs. /ga/) and to a change of voice (male vs. female) randomly occurring in a series of repeated syllables (figure 78.2). Furthermore, as in older infants, the temporal and spatial responses generated by both types of changes measured with EEG and NIRS are different, with larger and more mature responses for the change of phoneme than for the change of voice, revealing not only that these two features are processed differently but that the human brain is very sensitive to the temporal dimension of speech from the onset of the thalamocortical circuitry[START_REF] Mahmoudzadeh | Syllabic discrimination in premature human infants prior to complete formation of cortical layers[END_REF][START_REF] Mahmoudzadeh | Functional maps at the onset of auditory inputs in very early preterm human neonates[END_REF]. These results are not trivial since anesthetized rats tested in the same paradigm reacted more strongly to a change in voice than consonant, with a right-lateralized response for both changes(Mahmoudzadeh, Dehaene-Lambertz, & Wallois, 2017). Rats also display a strong reaction to differences in voice, obscuring language discrimination[START_REF] Toro | Effects of backward speech and speaker variability in language discrimination by rats[END_REF]. By contrast, human adults and infants are commonly better at recovering linguistic content, even for different voices, than at recognizing the same voice for different linguistic content(Dehaene-Lambertz, Dehaene, et al., 2006;[START_REF] Johnson | Infant ability to tell voices apart rests on language experience[END_REF] Dehaene-Lambertz & Kabdebon -The cerebral bases of language development-2020 7 Nazzi, & Cutler, 2011), suggesting a particular human sensitivity to linguistic features beyond general mammal auditory responses. A fine temporal encoding of the auditory world, observed from 30 weeks of gestational age onward, might be one of the important human auditory features.

Figure 78 . 2

 782 Figure 78.2 Parallel pathways in preterms. Oxyhemoglobin responses to a change of phoneme (/ba/ vs. /ga/) and a change of voice (male vs. female) measured with NIRS in 30 weeks gestational age-old preterm neonates. A significant increase in the response to a change of phoneme (DP, deviant phoneme) relative to the standard condition (ST) was observed in both temporal and frontal regions, whereas the response to a change of voice (DV, deviant voice) was limited to the right inferior frontal region. The left inferior frontal region responded only to a change of phoneme, whereas the right responded to both changes. The colored rectangles represent the periods of significant differences between the deviant and the standard conditions in the left and right inferior region (black arrows; Mahmouzadeh et al., 2013).

  of interneurons is sufficiently advanced, but no study has yet examined this point) and stops around the end of the first year, when the second threshold is reached.

Dehaene-Lambertz & Kabdebon-The cerebral bases of language development-2020

Acknowledgments

This research was supported by grants from Sodiaal-Fondation Motrice, the Fondation de France, the Fondation NRJ-Institut de France, and the European Research Council (Babylearn project).


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REMERCIEMENTS

En premier lieu, je tiens à remercier Professeur Guérin, le président de jury, pour avoir accepté de présider ce jury.

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J'adresse tous mes remerciements à Docteur Raffaelli pour m'avoir permis d'approfondir mes connaissances en échographie au sein du Département d'Ultrasons. C'est grâce à lui, ses connaissances et soutien que j'ai développé une passion pour l'imagerie.

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À mes cointernes : Damien, Serena, Akshay, Lydie, Axelle, Pauline, Wiktoria, Camille, Julien, Dimithri et Luca merci pour les moments passés ensemble, soit pendant le stage, soit pendant les pauses sur l'herbe soit lors des séances de fitness improvisés.

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À Wiktoria, pour les journées passées dans les mauvaises conditions météorologiques et en

Sonoelastography to assess muscular stiffness among older adults and its

use for the diagnosis of sarcopenia: a systematic review.

Ewa JANCZYK 1 Noémie CHAMPIGNY 1

Emeline MICHEL 1,2 Charles RAFFAELLI 3 Cédric ANNWEILER 4,5,6 Raphael ZORY 2 Olivier GUERIN 1,7 Guillaume SACCO

INTRODUCTION

The European Working Group On Sarcopenia in Older People (EWGSOP) [START_REF] Alfonso | Sarcopenia: Revised European Consensus on Definition and Diagnosis[END_REF] recently updated recommendations on definition and diagnosis of sarcopenia, a progressive and generalized alteration of skeletal muscle structure and function exerting a negative impact on one's health, quality of life and entailing increased costs on the public health system [START_REF] Sousa | Financial Impact of Sarcopenia on Hospitalization Costs[END_REF]. Indeed, there is a proven correlation of sarcopenia with an increased risk of adverse outcomes such as falls [START_REF] Francesco | Sarcopenia as a Risk Factor for Falls in Elderly Individuals: Results from the IlSIRENTE Study[END_REF],

fractures [START_REF] Monaco | Prevalence of Sarcopenia and Its Association with Osteoporosis in 313 Older Women Following a Hip Fracture[END_REF], dependence [START_REF] Guralnik | Lower-Extremity Function in Persons over the Age of 70 Years as a Predictor of Subsequent Disability[END_REF], neurocognitive impairment [START_REF] Ke-Vin | Association Between Sarcopenia and Cognitive Impairment: A Systematic Review and Meta-Analysis[END_REF] and death [START_REF] Brown Justin | Sarcopenia and mortality among a population-based sample of community-dwelling older adults[END_REF]. Sarcopenia is mainly caused by structural changes such as loss of muscle fibers, reduction in their size, the lower ratio of fast (type II) to slow (type I) muscle fibers, adipose and fibrotic tissue infiltrations [START_REF] Yosuke | Muscle Mass, Quality, and Composition Changes During Atrophy and Sarcopenia[END_REF][START_REF] Goodpaster | The loss of skeletal muscle strength, mass, and quality in older adults: the health, aging and body composition study[END_REF][START_REF] Lars | Sarcopenia: Aging-Related Loss of Muscle Mass and Function[END_REF] and muscular mass loss that occur with aging. The process may be accelerated and worsened by sedentary lifestyle, poor nutritional status [START_REF] Satsuki | Association between the nutritional status and the severity of sarcopenia among communitydwelling elderly Japanese people[END_REF] and chronic diseases, that cause inflammation [START_REF] Sebastiaan | The Role of Inflammation in Age-Related Sarcopenia[END_REF] along with hormonal and metabolic dysregulations [START_REF] Ng Tze Pin | Dysregulated homeostatic pathways in sarcopenia among frail older adults[END_REF].

Currently the diagnosis of sarcopenia may be confirmed by one of the 4 imaging technics: computed tomography (CT), magnetic resonance (MR), dual-energy X-ray absorptiometry (DXA) or bioelectrical impedance analysis (BIA). In clinical practice all the above-mentioned methods have their limitations. CT and MR are both too expensive to be used for screening. It is particularly difficult for geriatric patients to hold a steady position, due to cognitive impairment and frequent arthropathic pains. Thus, they are currently only used in research protocols. Bioelectrical impedance analysis (BIA) is susceptible to underestimate lean muscle mass in case of fluid overload, often present in hospitalized, elderly patients. Moreover, its degree of concordance varies, depending on the type of equation used. They require validation for use in elderly population [START_REF] Bussolotto | Assessment of Body Composition in Elderly: Accuracy of Bioelectrical Impedance Analysis[END_REF]. DXA seems to be the most appropriate option is terms of cost-accuracy balance, but lean body mass estimation may vary depending on the device manufacturer [START_REF] Kistorp | Body Composition Analysis by Dual Energy X-Ray Absorptiometry in Female Diabetics Differ between Manufacturers[END_REF] and its availability in clinical practice remains heterogenous.

Sonoelastography could be an interesting alternative to these imaging techniques. To simplify, we can refer to sonoelastography as an ultrasonographic palpation of an organ or lesion of interest. We can distinguish acoustic radiation force (ARFI) imaging, strain elastography (SE), transient elastography (TE), pSWE (point shear wave elastography) and shear wave elastography (SWE). The difference between them is the type of force applied and the way of displaying the tissue's response.

Thus, we performed a systematic review of the literature aiming to investigate the use of sonoelastography in the assessment of muscular stiffness in elderly and its potential use in a diagnosis of sarcopenia. We intended to learn which types of elastography have been tested, whether the reproducibility and repeatability of such measures have been evaluated and if they have been compared to the currently accepted diagnostic methods (CT, MRI, DXA, BIA).

METHODS

Protocol and registration

The study protocol has been admitted to PROSPERO and is currently awaiting registration.

The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA).

Eligibility criteria

The aim of this review was to identify studies that aim to evaluate structural changes in aging muscles and that include different kinds of sonoelastography, such as ARFI imaging, strain elastography, transient elastography and shear wave elastography. The conditions of eligibility were specified before the onset of screening. We took under consideration only human studies, in which patients over 70 years old were a part of a study sample. For our purpose, no comparators and/or controls were required. However, if the studies included other validated imagery techniques, they were included and used to answer the sub-question of this review (whether sonoelastography was compared with other validated diagnostic methods).

The following study designs were accepted: randomized trials, diagnostic case-controlled studies, diagnostic cohort studies, prospective, retrospective, or non-reported cohort studies, cross-sectional studies, observational studies, and case series. Data could be collected from the diagnostic settings across all stages of the continuum of care including inpatient, outpatient or other. The studies had to be published since 1990 up to 01/04/2020. This year has been chosen due to the history of elastography, which started in the early 80s, by data used from the M-mode to track movement, then in the late 80s by modified color Doppler and finally led to the invention of strain elastography in 1991 by Cespedes and Ophir [START_REF] Brian | Elastography: History, Principles, and Technique Comparison[END_REF]. Only studies written in English, French, Italian, Spanish, Russian, Polish, or German were accepted, because of the author's limited linguistic skills. All the studies not available in full-text version were excluded.

The inclusion criteria were as follows: i) the ultrasound equipment operator or technician is definable (physician, radiologist, clinician, researcher, etc.), ii) the evaluation of muscle stiffness using ultrasound elastography is either the primary or secondary diagnostic objective or intervention.

Information sources and search

We performed the screening of 5 medical databases: MEDLINE (Pubmed), Google Scholar

Study selection

All abstracts retrieved during the search were uploaded to Rayyan [START_REF] Ouzzani | Rayyana web and mobile app for systematic reviews[END_REF], a web-based abstract selection program. The duplicates were eliminated from search results. EJ searched through all the abstracts, and two other members (EM and GS) divided the same abstracts in two parts, so that each abstract was judged for eligibility by two team members independently. The abstracts were divided into one of 3 groups "excluded", "included" and "maybe". When the screening was finished, during a meeting of all researchers the inclusion/exclusion of the contentious abstracts were discussed, and the discrepancies resolved. The reference lists of the original research articles were then screened for any further relevant materials. The full texts of chosen abstracts were obtained, and the suitability of each study judged considering the PICO characteristics, as well as inclusion and exclusion criteria. Reasons for exclusion were documented at each stage.

Data collection process and items

Extracted data was documented on pre-defined form and comprised of the title, author's information, year of publication, study design, subjects demographics and baseline characteristics, equipment used (type of transducer and ultrasound machine), details about the taken measures (type of muscle, number of repetition, axis), repeatability, type of elastography, results, comparison (if present) and missing data.

Risk of bias

The assessment of bias was conducted separately for each study included. EJ and NC evaluated independently all the articles using the QUADAS-2 checklist for the diagnostic test accuracy studies [START_REF] Penny | et QUADAS-2 Group. « QUADAS-2: A Revised Tool for the Quality Assessment of Diagnostic Accuracy Studies[END_REF]. All the discrepancies including the risk of bias level were resolved by a consensus between the two researchers and if necessary, the opinion of the third member of the review team (GS) was taken.

RESULTS

From the initial 8477 abstracts screened, 463 were identified as duplicates and 7926 were excluded. The reasons were: not matching the inclusion criteria or PICO characteristics, full text unavailable, foreign language. The remaining 88 articles were then accepted for the fulltext assessment and 78 of them revealed discrepancies with the review criteria. Ten articles were included in the systemic review (Fig1).

As the presence of reference standard was not obligatory for this systemic review, nine out of ten articles did not include any of the four imaging technics (BIA, DXA, CT, MRI) as comparison. In Sun et al., 2020 [START_REF] Yang | Diagnosing Muscle Atrophy by Use of a Comprehensive Method of Assessing the Elastic Properties of Muscle During Passive Stretching[END_REF] BIA of the lower right limb was performed at the inclusion stage among the patients of rehabilitation ward to confirm sarcopenia (using the criteria of Asian Working Group for Sarcopenia [START_REF] Liang-Kung | Sarcopenia in Asia: Consensus Report of the Asian Working Group for Sarcopenia[END_REF]). The elastic parameters tested in this study: "E °" (slack elastic modulus) and "k" (passive elastic constant) had shown moderate to high sensitivity and specificity in sarcopenia diagnosis when compared with BIA. Respectively for E °: sensitivity in women (83.3%), in men (50%); specificity in women (75%), in men (87.5%) and for k: sensitivity in women (83.3%), in men (66.7%); specificity in women (87.5%), in men (93.8%).

In Alfuraih et al., 2019 [START_REF] Abdulrahman | The Effect of Ageing on Shear Wave Elastography Muscle Stiffness in Adults[END_REF] participants underwent a bioelectrical impedance analysis by Tanita DC-430 MA system. However, the measurements were performed at the stage of inclusion, to ensure that none of the participants were sarcopenic. patients with lower leg weakness treated in a rehabilitation ward.

Elastography was performed on different striated muscles (Fig2.), both in the upper and lower limb, such as vastus lateralis [START_REF] Abdulrahman | The Effect of Ageing on Shear Wave Elastography Muscle Stiffness in Adults[END_REF], vastus intermedius [START_REF] Abdulrahman | The Effect of Ageing on Shear Wave Elastography Muscle Stiffness in Adults[END_REF][START_REF] Cong-Zhi | Age and Sex Effects on the Active Stiffness of Vastus Intermedius under Isometric Contraction[END_REF][START_REF] Cong-Zhi | Shear Modulus Estimation on Vastus Intermedius of Elderly and Young Females over the Entire Range of Isometric Contraction[END_REF], vastus medialis [START_REF] Abdulrahman | The Effect of Ageing on Shear Wave Elastography Muscle Stiffness in Adults[END_REF], rectus femoris [START_REF] Abdulrahman | The Effect of Ageing on Shear Wave Elastography Muscle Stiffness in Adults[END_REF][START_REF] Saito Akira | Age-Related Changes in Muscle Elasticity and Thickness of the Lower Extremities Are Associated with Physical Functions among Community-Dwelling Older Women[END_REF][START_REF] Ryota | Age-Related Differences in Muscle Shear Moduli in the Lower Extremity[END_REF] medial [START_REF] Saito Akira | Age-Related Changes in Muscle Elasticity and Thickness of the Lower Extremities Are Associated with Physical Functions among Community-Dwelling Older Women[END_REF][START_REF] Yang | Diagnosing Muscle Atrophy by Use of a Comprehensive Method of Assessing the Elastic Properties of Muscle During Passive Stretching[END_REF][START_REF] Masatoshi | Acute Effects of Static Stretching on the Shear Elastic Moduli of the Medial and Lateral Gastrocnemius Muscles in Young and Elderly Women[END_REF] and lateral gastrocnemius [START_REF] Ryota | Age-Related Differences in Muscle Shear Moduli in the Lower Extremity[END_REF][START_REF] Yang | Diagnosing Muscle Atrophy by Use of a Comprehensive Method of Assessing the Elastic Properties of Muscle During Passive Stretching[END_REF][START_REF] Masatoshi | Acute Effects of Static Stretching on the Shear Elastic Moduli of the Medial and Lateral Gastrocnemius Muscles in Young and Elderly Women[END_REF], soleus [START_REF] Ryota | Age-Related Differences in Muscle Shear Moduli in the Lower Extremity[END_REF], the hamstrings [START_REF] Abdulrahman | The Effect of Ageing on Shear Wave Elastography Muscle Stiffness in Adults[END_REF], biceps brachii [START_REF] Sarah | Shear Wave Elastography of Passive Skeletal Muscle Stiffness: Influences of Sex and Age throughout Adulthood[END_REF] and supraspinatus [START_REF] Timothy | Effects of Age and Pathology on Shear Wave Speed of the Human Rotator Cuff[END_REF]. One study evaluated postural muscles: trapezius and erector spinae [START_REF] Anne | Measurements of the Trapezius and Erector Spinae Muscles Using Virtual Touch Imaging Quantification Ultrasound-Elastography: A Cross Section Study[END_REF]. Most frequently appearing were lateral and medial gastrocnemius (four studies) and the quadriceps muscles: vastus intermedius and rectus femoris (both evaluated in three studies).

Most muscle measurements were taken in the longitudinal axis, except from two studies. The first one used transversal axis for the evaluation of rectus femoris and the medial head of the gastrocnemius (Saito et al., 2018 [25]) and the second one used transversal axis for erector spinae and transversal, but longitudinal to the fascicles, placement for trapezius muscle (Heizelmann et al., 2017 [29]).

In all studies a linear probe was used. The complete list of the commercial ultrasound machines and transducers is listed in the Table 1.

Wang et al. constructed and used in their studies from 2014 and 2017 [START_REF] Cong-Zhi | Shear Modulus Estimation on Vastus Intermedius of Elderly and Young Females over the Entire Range of Isometric Contraction[END_REF][START_REF] Cong-Zhi | Age and Sex Effects on the Active Stiffness of Vastus Intermedius under Isometric Contraction[END_REF] a vibro-ultrasound system consisted of a mechanical vibrator, a programmable ultrasound scanner and a custom-made program for radio-frequency data acquisition, based on a commercial ultrasound scanner SonixRP. Its measurement accuracy has been tested in the first study on a set of silicon phantoms of known shear moduli.

All studies used shear wave elastography to evaluate muscle stiffness, except from Saito et al.,

2018 [START_REF] Saito Akira | Age-Related Changes in Muscle Elasticity and Thickness of the Lower Extremities Are Associated with Physical Functions among Community-Dwelling Older Women[END_REF] which used strain elastography performed with an acoustic coupler. Strain ratio (strain of the muscle to that of the acoustic coupler) was significantly higher in the older adults than in the young (RF in young: 0.31± 0.08 vs. older adults: 0.53 ± 0.17, p˂ 0.001; MG in young: 0.28 ± 0.07 vs. older adults: 0.45 ± 0.14, p˂ 0.001), signifying harder tissue.

Similar results can be seen in Eby et al., 2014 [28]: the biceps brachii muscle showed increased stiffness with advanced age in full elbow extension (p=0.03). In Heizelmann et al., 2017 [START_REF] Anne | Measurements of the Trapezius and Erector Spinae Muscles Using Virtual Touch Imaging Quantification Ultrasound-Elastography: A Cross Section Study[END_REF] the shear wave velocity (m/s) was significantly higher in the older adults (˃ 60 years old) versus young group (˂ 60 years old) in right erector spinae (2.84 ± 0.58 vs. [START_REF] Timothy | Effects of Age and Pathology on Shear Wave Speed of the Human Rotator Cuff[END_REF] for the control group mean SWV was significantly associated with age both in active muscle (p=0.049, R 2 = 0.24) and passive muscle (p=0.039, R 2 =0.23).

On the other hand, in Alfuraih et al., 2019 [START_REF] Abdulrahman | The Effect of Ageing on Shear Wave Elastography Muscle Stiffness in Adults[END_REF] the SWV were significantly lower between the young and middle-aged adults, and the older adults in all the tested muscles (quadriceps, the hamstrings and biceps brachii). The mean difference between older adults and middle-aged group was -12.9% (ranging from -6.5% to -18.8%) and the difference between the young and the older adults was the highest -16.5% (ranging from -11% to -23.3%). It is important to note that older participants in this study were non-sarcopenic, which may explain the discordance with the results of previously described studies.

In three of included articles repeatability was tested [START_REF] Cong-Zhi | Shear Modulus Estimation on Vastus Intermedius of Elderly and Young Females over the Entire Range of Isometric Contraction[END_REF][START_REF] Saito Akira | Age-Related Changes in Muscle Elasticity and Thickness of the Lower Extremities Are Associated with Physical Functions among Community-Dwelling Older Women[END_REF][START_REF] Ryota | Age-Related Differences in Muscle Shear Moduli in the Lower Extremity[END_REF] and one reported result from their previous work [START_REF] Timothy | Effects of Age and Pathology on Shear Wave Speed of the Human Rotator Cuff[END_REF]. The intraclass correlation coefficients were high ranging from 0.87 to 0.978 when performed by the same operator. Day-to-day repeatability was measured in Regarding bias, the quality of included studies evaluated by QUADAS-2 checklist was moderate. Detailed results of bias evaluation are presented in Fig3. Concerns were mainly raised about the patient selection, either because the included sample was not random or because the case-control design was adopted. The applicability of certain studies was also put into question, because of the mean age of participants. Even though all studies included patients over 70 years old, the mean age of elderly subgroup in some of them was too low.

DISCUSSION

Our systemic review revealed that currently there is a lack of consensus in the literature on whether muscle stiffness increases, decreases or remains constant with age. Amongst ten included articles, four reported higher stiffness in elderly muscles, two in contrary-lower and four found that there is no significant difference.

There may be many reasons for these discrepancies. First, muscles are anisotropic tissues and the propagation of shear waves may differ depending on direction. Therefore, taken measures may by highly influenced by position of the probe (longitudinal or transversal axis) [START_REF] Green | Measuring Anisotropic Muscle Stiffness Properties Using Elastography[END_REF] and muscle architecture (parallel, unipennate, bipennate).

Secondly, muscles are viscoelastic and dynamic tissues. Their stiffness may depend on their recent history of movement or on their current state: relaxed, passively stretched or actively contracted. Different flexion angle of adjacent joints may be responsible for fascicule extension and altered results. For example, elastic measures of biceps brachii taken on patients with flexed elbow should not be compared with those obtained in full extension. Furthermore, SWV may also differ depending on the external source of pressure, for example the compression applied by a transducer. Certain studies reported that the operator paid attention to put a minimal pressure while performing an examination [START_REF] Anne | Measurements of the Trapezius and Erector Spinae Muscles Using Virtual Touch Imaging Quantification Ultrasound-Elastography: A Cross Section Study[END_REF] and others used rigid holders to eliminate the involuntary compression [START_REF] Yang | Diagnosing Muscle Atrophy by Use of a Comprehensive Method of Assessing the Elastic Properties of Muscle During Passive Stretching[END_REF].

Moreover, the results may be affected by ultrasound parameters such as depth and size of the region of interest [START_REF] Marga | Influencing Factors of 2D Shear Wave Elastography of the Muscle -An Ex Vivo Animal Study[END_REF][START_REF] Xiuming | Effect of Acquisition Depth and Precompression from Probe and Couplant on Shear Wave Elastography in Soft Tissue: An in Vitro and in Vivo Study[END_REF]. Lower SWV have been reported with increasing depth, so the position of muscle must be considered a variable. For example, SWV of vastus intermedius, which is located underneath rectus femoris or soleus lying underneath gastrocnemius muscle may be difficult to compare with more superficially placed muscles, such as trapezius. The included studies had shown substantial differences on the data acquisition. The ROI size differed from one to another, SWV were either measured as the mean from the whole ROI or by circles drawn in the ROI box (one or many). Young modulus was calculated using different values of muscle density (either 1000 kg/m3 [START_REF] Cong-Zhi | Shear Modulus Estimation on Vastus Intermedius of Elderly and Young Females over the Entire Range of Isometric Contraction[END_REF] as it is a presumed density of soft tissues or 1084 kg/m3 [START_REF] Ryota | Age-Related Differences in Muscle Shear Moduli in the Lower Extremity[END_REF],

which was the value chosen by the authors, based on previous studies).

The above-mentioned dissimilarities did not allow us to complete the review with a metanalysis.

Ultrasonographic settings and measurements may not be the only ones to be held responsible for the differences. It was reported that the muscle mass loss in sarcopenia is not progressing at the same pace, with lower limb exceeding upper limb. The later may explain the discrepancies between the shear modulus of shoulder rim muscles (biceps brachii, supraspinatus), the back muscles (trapezius, erector spinae) [START_REF] Carl | Age-Related Muscle Atrophy Does Not Affect All Muscles and Can Partly Be Compensated by Physical Activity: An Ultrasound Study1[END_REF]and the lower limb muscles, such as quadriceps or the hamstrings.

Amongst four studies that had shown increased stiffness with age, three were performed on the upper limb or dorsal muscles: [START_REF] Abdulrahman | The Effect of Ageing on Shear Wave Elastography Muscle Stiffness in Adults[END_REF]. In this study the elderly non-sarcopenic participants (confirmed by BIA) were compared with young participants and it has been shown that age was responsible for 45.5% of the variance in SWV. If the impact is this important even in absence of sarcopenia, it is possible that the differences in SWV may be too small to differ significantly between a healthy elderly subject and an elderly with sarcopenia.

We pondered which types of elastography and what kind of measurements were used to assess muscle changes in sarcopenia. As we already mentioned in nine out of ten articles shear wave elastography has been used. This method seems to be more suitable for becoming a screening test, as it is less operator dependent and provides quantitative results. In Saito et al. 2018 [START_REF] Saito Akira | Age-Related Changes in Muscle Elasticity and Thickness of the Lower Extremities Are Associated with Physical Functions among Community-Dwelling Older Women[END_REF] strain elastography was used. It is a valuable imagery technique, but in the hands of experienced ultrasonographer, as many artefacts produced by this method may either provide guidance or constitute an obstacle. The out-of-plane structures may exercise strain influencing in-plain measures, fluid displacement may entrain time-dependent reduction in strain (which is important in case of fluid overload), soft tissue in the close proximity of hard tissue strains more, the boundaries are enhanced by slippery borders and many more [START_REF] Bamber | EFSUMB Guidelines and Recommendations on the Clinical Use of Ultrasound Elastography. Part 1: Basic Principles and Technology[END_REF].

To become a reliable diagnostic method, a test needs to show high intra-and interobserver correlation. The intraclass correlation coefficients were high when performed by the same operator, both on young and elderly participants. The evaluation of interobserver variability is however lacking and should be explored in further studies.

CONCLUSION

Due to the substantial heterogenicity of actual data, we could not conclude on the potential usefulness of elastography to assess sarcopenia. Further studies are needed, including larger sample of older patients, and using standardized and reproducible protocol.

TABLES

Figure 3 .

 3 Figure 3. 'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item

Figure 4 .

 4 Figure 4. 'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item

(

  Google), Scopus, SpringerLink and ScienceDirect. The search strategy used for MEDLINE database was as follows: (((((((((sarcopenia[MeSH Terms]) OR muscle atrophy[MeSH Terms]) AND elastography[MeSH Terms]) OR elasticity imaging techniques[MeSH Terms]) OR Vibro-Acoustography[MeSH Terms]) OR sonoelastography[MeSH Terms]) OR acoustic radiation force impulse imaging[MeSH Terms]) OR arfi imaging[MeSH Terms]) OR elastogram*[MeSH Terms])

FIGURESFigure 1 .Figure 2 . Muscles assessed in included studies 1 :

 121 FIGURES

Figure 3 .

 3 Figure 3. 'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item

Figure 4 .

 4 Figure 4. 'Risk of bias' summary: review authors' judgements about each 'Risk of bias'

des enseignants au 1er septembre 2019 à la Faculté de Médecine de Nice MAITRE DE CONFÉRENCES DES UNIVERSITÉS

	UNIVERSITE NICE SOPHIA ANTIPOLIS
	UFR MEDECINE
	Liste M. DARMON David	Médecine Générale (53.03)
	Mm e	GROS Auriane	Orthophonie (69)
	PROFESSEURS AGRÉGÉS
	Mme	LANDI Rebecca	Anglais
	PRATICIEN HOSPITALIER UNIVERSITAIRE
	M.	DURAND Matthieu	Urologie (52.04)
	M.	SICARD Antoine	Néphrologie (52-03)
	PROFESSEURS ASSOCIÉS
	M.	GARDON Gilles	Médecine Générale (53.03)
	Mm e	MONNIER Brigitte	Médecine Générale (53.03)
	MAITRES DE CONFÉRENCES ASSOCIÉS
	Mm e	CASTA Céline	Médecine Générale (53.03)
	M. M. M.	TOULON Pierre GASPERINI Fabrice HOGU Nicolas	Médecine Générale (53.03) Hématologie et Transfusion (47.01) Médecine Générale (53.03)
	màj27/09/19

ACKNOWLEDGMENTS .................................................................................................. Funding sources

  sueur, mais toujours au sein des paysages magnifiques et bouquetins. C'est la vraie amitié basée sur des kilomètres traversés ensembles. C'est toi le renard le plus occupé. Liste des enseignants au 1er septembre 2019 à la Faculté de Médecine de Nice .................2 INTRODUCTION ................................................................................................................ METHODS .......................................................................................................................... Protocol and registration ................................................................................................... Eligibility criteria .............................................................................................................. Information sources and search ......................................................................................... Study selection ................................................................................................................. Data collection process and items ..................................................................................... Risk of bias ....................................................................................................................... RESULTS ............................................................................................................................ ................................................................................................................ Ethics approval ................................................................................................................. Contributions of Authors .................................................................................................. .............................................................................................................................. FIGURES .............................................................................................................................Figure 1. Prisma flow diagram ..........................................................................................Figure 2. Muscles assessed in included studies ..................................................................

	Tableau des matières
	Mots clés : sarcopénie, personnes âgées, élastographie, atrophie musculaire, technique
	d'imagerie
	DISCUSSION ......................................................................................................................
	CONCLUSION ....................................................................................................................
	Declaration of interests .....................................................................................................
	Availability of data and materials .....................................................................................
	REFERENCES .....................................................................................................................

À Pauline pour son amitié, son humeur et tous les moments passés ensembles. Comme tu es déjà bilingue, je tiens à t'informer que j'ai commencé les démarches pour t'accorder la citoyenneté franco-polonaise.

A mes parents et mes amis en Pologne, je me permets d'exprimer ma gratitude en polonais, afin qu'ils comprennent : Kocham was mamuṥ i tatuṥ, wiem że jestem nieznośna i trudno ze mną wytrzymać, ale tak mnie wychowaliście. Dzejowi, Sykale, Schodkowi, Kunderze i Pysiowi dziękuję za to, że zawsze mogę na was liczyć, nawet jeżeli jesteście daleko. Przed spinami nie ucieknę nawet zagranicę. À la fin, je tiens à remercier toutes les personnes qui j'ai croisé sur mon chemin, avec qui j'ai partagé les moments agréables ou désagréables et qui m'ont permises d'apprendre quelque chose de nouveau.

RÉSUMÉ

Les modifications structurelles apparaissant avec la sarcopénie sont susceptibles de modifier la qualité contractile du muscle. La sonoélastographie est une méthode accessible et non-irradiante permettant de quantifier les propriétés élastiques du tissu musculaire. Nous avons réalisé une revue systématique de la littérature afin de déterminer si la sonoélastographie peut être une méthode fiable pour évaluer l'importance de la sarcopénie chez les sujets âgés. Nous avons cherché les articles publiés sur 5 bases des donnés : Medline, Google Scholar, Scopus, SpringerLink and Science direct du 1 er Janvier au 1 er Avril 2020. Trois investigateurs indépendants ont évalué l'éligibilité des études, réalisé l'extraction des données et l'évaluation du risque de biais. Nous voulions connaître quels types d'élastographie ont été réalisé, si la répétabilité des mesures a été vérifié et si la sonoélastographie a été comparé avec les autres méthodes diagnostiques. Dix études remplissaient les critères d'inclusion. La majorité des études étaient des études transversales avec des sous-groupes de personnes jeunes et âgées. Le muscle gastrocnémien, le muscle quadriceps fémoral et le muscle vaste intermédiaire étaient les muscles les plus évalués. Neuf études utilisaient l'élastographie par ondes de cisaillement et une étude utilisait l'étude du strain (déformation du tissu sous une contrainte). La constante élastique passive « k » été plus élevée chez les patients atteints de sarcopénie (124.98 ± 60.82 vs. 46.35 ± 15.85, p = 0.004).

Cependant, même chez les sujets âges non-sarcopéniques l'âge était responsable de 45.5% de la variance de la vitesse des ondes de cisaillement. Parmi les dix articles inclus, quatre ont démontré l'augmentation de la rigidité musculaire avec l'âge, deux, au contraire, la diminution et quatre n'ont pas retrouvé de différence significative.

En définitive, au vu de l'importante hétérogénéité des données actuelles, nous n'avons pas pu conclure sur l'utilisation de l'élastographie dans l'évaluation de la sarcopénie. D'autres études sont nécessaires, avec un protocole standardisé et reproductible sur un échantillon plus important de personnes âgées. TABLES

  Nine out of ten articles were prospective, except forBaumer et al., 2017 [22], which was a retrospective study. The most repetitive scheme was a cross sectional study design with participants divided into young and older adults' groups or eventually young, middle-aged, and older adults' groups (eight out of 11 articles). Two studies were an exception. Baumer et al., 2017[START_REF] Timothy | Effects of Age and Pathology on Shear Wave Speed of the Human Rotator Cuff[END_REF] was a case-control study with 30 participants, amongst which 19 were asymptomatic control subjects and 11 were patients, diagnosed with a full-thickness rotator cuff tear of the supraspinatus tendon. InSun et al., 2019 [19], 16 healthy volunteers were compared with 12

	Nevertheless, age was a significant
	predictor of shear wave velocity (SWV) in the regression model [R 2 VL=0.455, RF=0.314,

VM=0.587, VI=0.205, BB=0.191, BF=0.547, ST= 0.600, SM=0.671] showing that even in nonsarcopenic patients age is responsible for about 45.5% of variance in SWV.

  Eby et al., 2015 on biceps brachii; Baumer et al.,2017 on supraspinatus and Sun at el.,2020 on trapezius and erector spinae. It may constitute a pattern with stiffness increasing with age in the muscles of the upper parts of the body and decreasing in limb muscles, but further studies are needed to confirm or disprove this hypothesis.A weakness of this systematic review was that a majority of included articles was based on a cross-sectional design, comparing young to elderly subjects. Only in the study ofSun et al., 2020 the sample of elderly patients had sarcopenia, confirmed following the recommendations on Asian Group for Sarcopenia[START_REF] Liang-Kung | Sarcopenia in Asia: Consensus Report of the Asian Working Group for Sarcopenia[END_REF]. Thus, their results do not allow us to draw a conclusion whether sonoelastography can differentiate a healthy muscle from sarcopenic one. Interesting inside was brought by[START_REF] Abdulrahman | The Effect of Ageing on Shear Wave Elastography Muscle Stiffness in Adults[END_REF]

Table 1 . Characteristics of studies included in qualitative synthesis.

 1

	Study	Type	Inclusion / exclusion criteria	n/N	Women (n, %)	Age* (mean±sd, range)

Table 2 . Technical characteristics of included studies.

 2

		Operators (n,	Measurements per
	Study	experience in years)	muscle	Ultrasound machine	Probe	Muscle	Axis
				Aixplorer (Supersonic	SuperLinear™
	Alfuraih et
		NA, NA	3	Imagine, Aix-en-	SL10-2 MHz
	al., 2019
				Provence, France)

ACKNOWLEDGMENTS

The authors have listed everyone who contributed significantly to the work in the Acknowledgments section. Permission has been obtained from all persons named in the Acknowledgments section.

All authors of this manuscript comply with the guidelines of ethical authorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle [35]

Funding sources

GS is supported by a postdoctoral grant from the Research Center on Autonomy and Longevity, University Hospital of Angers, France (2019-2020).

The sponsors had no role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript.

Availability of data and materials

There are no linked research data sets for this paper

ABSTRACT

Background. Structural changes susceptible to modify its stiffness have been reported in sarcopenic muscle. Sonoelastography is an accessible and non-radiating imaging technic allowing quantification of elastic properties of the tissue. We performed a systematic review of the literature to investigate whether sonoelastography can be a reliable method to assess sarcopenia in older patients.

Methods. We search Medline, Google Scholar, Scopus, SpringerLink and Science direct from January 1 st , 1990 up to April 1 st , 2020. Three independent review authors assessed trial eligibility, extracted the data and assessed risk of bias. We intended to learn which types of elastography have been tested, the repeatability of such measures and if they have been compared to the currently accepted diagnostic method Results. Ten studies met the inclusion criteria. Most followed a cross-sectional design with young and older adults' subgroups. Gastrocnemius, rectus femoris and vastus intermedius appeared the most. Nine of included studies used shear wave elastography and one-strain elastography. Passive elastic constant(k) was significantly greater in sarcopenic versus healthy subjects after passive stretching (124.98 ± 60.82 vs. 46.35 ± 15.85, p=0.004), but even in nonsarcopenic patients age was responsible for about 45.5% of variance in SWV. Amongst ten included articles, four reported higher stiffness in older adults' muscles, two in contrary-lower, and four found no significant difference.

Conclusions. Due to the substantial heterogenicity of actual data, we could not conclude on the potential usefulness of elastography to assess sarcopenia. Further studies are needed, including larger sample of older patients, and using standardized and reproducible protocol.

Nevertheless, similar outcomes were reported by Akagi et al., 2015 [26] which revealed that RF and LG shear moduli are significantly higher in young vs. older adults group (RF η 2 =0.201, p ˂ 0.001, LG η 2 =0.055, p=0.039) except for soleus muscle, which did not show significant difference.

Four out of ten articles reported no significant difference between young and older participants.

Wang et al. 2017 [START_REF] Cong-Zhi | Age and Sex Effects on the Active Stiffness of Vastus Intermedius under Isometric Contraction[END_REF] presented results that were already partially released in their 2014 study [START_REF] Cong-Zhi | Shear Modulus Estimation on Vastus Intermedius of Elderly and Young Females over the Entire Range of Isometric Contraction[END_REF]. They tested shear moduli of vastus intermedius in all levels of mean voluntary contraction (MVC), starting with a relax state and ranging from 0° to 100°, increasing by 10° at each step and at two different knee joint angles (60° and 90°). There was no significant difference in VI shear modulus in a relaxed state (p=0.221), but the shear moduli increased faster in young subjects with the degree of MVC, especially for the higher isometric contraction levels.

In Nakamura et al. 2017 [START_REF] Masatoshi | Acute Effects of Static Stretching on the Shear Elastic Moduli of the Medial and Lateral Gastrocnemius Muscles in Young and Elderly Women[END_REF] the shear moduli of lateral and medial heads of the gastrocnemius muscle were tested at 3 ankle joint positions before and after 5 minutes of static stretching.

There were no significant differences in shear moduli between young and older adults before the stretching (p=0.92 for LG at 30° plantar flexion, p=0.14 for MG at 30° PF, p=0.62 for LG at 0° PF, p=0.24 for MG at 0° PF, p=0.21 for LG at 20° PF, p=0.72 for MG at 20° PF). Sun et al. 2019 [START_REF] Yang | Diagnosing Muscle Atrophy by Use of a Comprehensive Method of Assessing the Elastic Properties of Muscle During Passive Stretching[END_REF] performed experimental measures of elastic modulus as a function of length (displacement of distal muscle-tendon junction of gastrocnemius muscle during passive stretching). The use of both, elastography and B mode evaluation, enabled them to define E ° (slack elastic modulus), l ° (slack length) and k (passive elastic constant). There was no significant difference between sarcopenic patients and healthy controls in E ° and l °, but k was significantly greater in sarcopenic versus healthy subjects after passive stretching (46.35 ± 15.85 vs. 124.98 ± 60.82, p=0.004).

Ethics approval

Ethical approval was not required for this research.

Contributions of Authors

GS has full access to all of the data in the study, takes responsibility for the data, the analyses and interpretation and has the right to publish any and all data, separate and apart from the attitudes of the sponsors. All authors have read and approved the manuscript.

Declaration of interests

All authors state that they have no conflicts of interest with this paper. The authors have no relevant personal financial interest in this manuscript.