Rochelle Ackerley
email: rochelle.ackerley@univ-amu.fr

Somatosensation and body perception: the integration of afferent signals in multisensory cognitive processes

Keywords: Touch, tactile, body, human, perception, temperature, nociception, mechanoreception, afferent

Humans have evolved to interact smoothly with their environment and with others. There are highly complex processes that enable these interactions and many systems are engaged, from the peripheral somatosensory system to a distributed network of cortical regions. This chapter will address the pathway from the peripheral receptors to the brain, including steps where there is the potential for the processing and integration of information, as well as why these have occurred in our evolution. We have a vast system of somatosensory afferents that are distributed over our skin and in our bodies to capture precise signals about our interactions with the world. Somatosensory afference comes from mechanical, thermal, and chemical stimuli, where numerous different types of somatosensory afferent, namely those that respond to mechanoreceptive, thermoreceptive, and/or nociceptive signals respectively, register specific contact and behavior. These signals are persistent and there is considerable integration of this information even before it reaches the brain. Once the input reaches sub-cortical structures and is passed on to the cerebral cortex, there is again a wealth of processes that interact smoothly, to produce the awareness of our body in space and its interactions. These include principal somatosensory targets, such as the primary (S1) and secondary (S2) somatosensory cortices, and the insula. In the integration of information, many other regions are involved, including the activation of a range of cognitive (e.g. attention, memory, learning) and emotional/affective mechanisms, as well as multisensory processing. This chapter will consider the intricacies of these processes, by exploring the sensory origin of body perception.

The sensory origin of body perception

The sensory input from our body comes in the form of many different channels, which are integrated centrally to give our sense of self and bodily perception. The source of these signals is primarily from the skin, but internal sensors in tissue such as muscles, joints, and receptors inside the core of the body, also contribute. Further, our other senses can influence body perception, for example, seeing our body (e.g. looking at our feet to help us walk over rough terrain), hearing our body (e.g. when something touching our skin makes a noise), and even how our body normally smells and tastes, where we may feel different if these inputs change. Although the direct measurement of these processes can be challenging, often due to the complicated nature of our body and environment, there are a number of useful methods to approach these questions. For example, microneurography can be used to measure the activity in peripheral nerves (for a review, see [START_REF] Ackerley | Microneurography: Recordings from single neurons in human peripheral nerves[END_REF], electrodermal analysis can tell us about emotional responses to touch [START_REF] Ree | Touch targeting C-tactile afferent fibers has a unique physiological pattern: A combined electrodermal and facial electromyography study[END_REF][START_REF] Fedato | Hand morphometrics, electrodermal activity, and stone tools haptic perception[END_REF]; see also Chapter 12), electromyography can be used to quantify the use of muscles [START_REF] Mayo | Putting a good face on touch: Facial expression reflects the affective valence of caress-like touch across modalities[END_REF][START_REF] Ree | Touch targeting C-tactile afferent fibers has a unique physiological pattern: A combined electrodermal and facial electromyography study[END_REF], and perceptual ratings help us to understand the feelings generated [START_REF] Ackerley | Quantifying the sensory and emotional perception of touch: differences between glabrous and hairy skin[END_REF][START_REF] Sailer | Pleasantness Only?: How Sensory and Affective Attributes Describe Touch Targeting C-Tactile Fibers[END_REF]. Below, information from the skin will be first covered in detail, then with consideration of the impact of other sensory inputs.

Somatosensation from the skin

The skin contains numerous specialized receptors to sense mechanical, thermal, and chemical stimuli applied to the body (Figure 1). A recent comprehensive review and analysis of body innervation density stated that there are >1 million fibers in the dorsal roots of the spinal cord in total, which include large-, medium-, and thinly-myelinated fibers to unmyelinated fibers, and it was estimated that a young human adult body has ~230,000 myelinated Aβ mechanoreceptive afferents, although we lose about 5% of our afferents every decade of adulthood [START_REF] Corniani | Tactile innervation densities across the whole body[END_REF]. The capacity of the sensory afferent system is therefore vast; however, the brain processes this input efficiently and effortlessly. The skin itself is highly heterogenous, where different skin regions have different sensitivities to stimuli, containing several afferent classes, in varying densities. Skin can be generally divided into glabrous skin of the ventral hands and feet, hairy skin, and mucocutaneous skin (e.g., mouth, nose, eyes, genitals). Three main types of stimuli can impact the body, namely of mechanical, thermal, and/or chemical sources, where these are encoded by different types of receptors.

Overall, the skin can be divided into glabrous (non-hairy), hairy, and mucocutaneous skin (Figure 1). The vast majority of the skin (90%) can be classed as hairy skin, as it contains hair follicles. The hairs can be very small and thin (e.g., vellus hairs), or thick and long (e.g., scalp terminal hairs), but this is all defined as hairy skin. Thus, the length and diameter of hairs can differ greatly, as well as hair follicle density, which can vary by more than an order of magnitude across the skin [START_REF] Szabo | The regional anatomy of the human integument with special reference to the distribution of hair follicles, sweat glands and melanocytes[END_REF], and vellus hairs account for 80-90% of all hairs [START_REF] Halata | Sensory innervation of the hairy skin (light-and electronmicroscopic study)[END_REF]. It is clear that some skin regions contain many thick, terminal hairs (e.g., scalp, dorsal arms), but there is no significant difference between males and females in hair density itself [START_REF] Szabo | The regional anatomy of the human integument with special reference to the distribution of hair follicles, sweat glands and melanocytes[END_REF], only the type of hair differs (i.e., whether it is thick terminal hair or thin vellus hair). It is also noteworthy that the density of hair follicles in human skin is equivalent to that of an similar-sized animal [START_REF] Schwartz | Allometry of primate hair density and the evolution of human hairlessness[END_REF]. Glabrous skin is defined as the non-hairy skin of the ventral hands and feet, which also has ridges (e.g., fingerprints) that are most obvious on the finger and toe pads. Mucocutaneous skin can almost be classed as a type of border skin, which is the surface between the outer skin and inner bodily tissue. Mucocutaneous skin is often wet (e.g., eyes, mouth, genitals) and needs to be maintained in this state of higher water content. The borders between all skin types are not welldefined, where there is often a smooth transition between skin types, for example, the dorsal sides of the finger tips are classed as hairy skin, but there are virtually no hairs present.

The skin can be divided into at least two layers that are somewhat different in thickness over the skin and estimates of thickness can vary. The epidermis is the top, outer layer of the skin, which also includes the very most outer surface: the stratum corneum. Underneath is the thicker dermis, which is a supporting layer that contains connective tissue. Although the glabrous skin appears to be thicker, the general thickness of the skin is similar across the body, at around 2 mm thick; however, there is regional variation (Figure 2). The hairy skin in general has an epidermis of ~80 µm thickness [START_REF] Robert | The skin[END_REF][START_REF] Mogensen | Morphology and epidermal thickness of normal skin imaged by optical coherence tomography[END_REF], whereas the glabrous skin has a thicker epidermis, where the stratum corneum alone is ~500 µm, and a relatively reduced dermal layer. The overall thickness of the scalp skin is also reduced at ~1.3 mm and the eyelid is very thin at around 0.5 µm [START_REF] Hwang | Surgical anatomy of the upper eyelid relating to upper blepharoplasty or blepharoptosis surgery[END_REF], whereas the back has an extremely thick dermis of ~4 mm [START_REF] Robert | The skin[END_REF] (Figure 2). Depending on the individual, some of the skin on the foot sole can be around ~5 mm thick also, for obvious reasons due to the impact of weight enforced on this skin. These characteristics of the skin show its high heterogeneity and complexity. This is mirrored in the receptors that are present, which can be generally classified as mechanoreceptive, thermoreceptive, or nociceptive. Although numerous receptors can respond to more than one stimulus type (mechanical/thermal/chemical), they typically show a preference (e.g., peak response) for one type of stimulus. Concerning mechanoreceptors, humans have many different types that are present at different densities across the skin. Low-threshold mechanoreceptive afferents can be generally classed as fast-conducting Aβ and slowly-conducting C-fiber. Vellus hairs may be innervated by more thinly-myelinated (or unmyelinated) fibers, although this classification cannot be verified, as virtually no recordings from vellus hair afferents [START_REF] Adriaensen | Response properties of thin myelinated (A-delta) fibers in human skin nerves[END_REF] have been found in microneurography (i.e., peripheral axonal nerve recordings in humans; for an overview of the technique, see [START_REF] Ackerley | Microneurography: Recordings from single neurons in human peripheral nerves[END_REF]. There are a number of different types of Aβ mechanoreceptive afferent, which can be classed as fast-adapting (i.e., when a mechanical stimulus is applied to the skin, held stationary, then lifted off, there are only responses to the onset and/or offset of touch) or slowly-adapting (i.e., when the same stimulus is applied, there will be clear onset and/or offset responses, as well as firing during the sustained indentation). Four types of Aβ mechanoreceptive afferent exist in the glabrous skin (Table 1), namely: fast-adapting type I (FA-I, putatively connected to Meissner corpuscles), fast-adapting type II (FA-II, putatively connected to Pacinian corpuscles), slowly-adapting type I (SA-I, putatively connected to Merkel disks), and slowly-adapting type II (SA-II, putatively connected to Ruffini endings) afferents [START_REF] Vallbo | Properties of cutaneous mechanoreceptors in the human hand related to touch sensation[END_REF]. It is postulated that there are around 17,000 mechanoreceptive afferents in each human hand [START_REF] Johansson | Tactile sensibility in the human hand: relative and absolute densities of four types of mechanoreceptive units in glabrous skin[END_REF], which along with the face, is one of the most densely-packed areas of mechanoreceptors. This is why the hands are essential in exploring the world, where we use them for the dexterous manipulation of objects [START_REF] Johansson | First spikes in ensembles of human tactile afferents code complex spatial fingertip events[END_REF] and to sense a multitude of different textures [START_REF] Weber | Spatial and temporal codes mediate the tactile perception of natural textures[END_REF], which is encoded precisely with millisecond timing [START_REF] Johansson | First spikes in ensembles of human tactile afferents code complex spatial fingertip events[END_REF][START_REF] Mackevicius | Millisecond precision spike timing shapes tactile perception[END_REF][START_REF] Saal | Simulating tactile signals from the whole hand with millisecond precision[END_REF] and is essential in our modern-day lives. Further, in line with the development of skillful tool manipulation in humans, studies have shown that the biomechanical context of tool use and tool making has itself influenced the evolution of the human hand [START_REF] Williams-Hatala | The manual pressures of stone tool behaviors and their implications for the evolution of the human hand[END_REF]. This is important to consider, as the way our body encodes interactions with our world have been highly shaped by our environment and the objects we interact with, whether these be things like tools or other humans.

In hairy skin, the FA-I Meissner afferents are not present, but instead, fastadapting hair follicle afferents (HFA) and field afferents are present [START_REF] Vallbo | Receptive field characteristics of tactile units with myelinated afferents in hairy skin of human subjects[END_REF], which are highly sensitive mechanoreceptors (Table 1). Lowthreshold mechanoreceptive C-fibers are called C-tactile (CT) afferents (for a review, see [START_REF] Ackerley | C-tactile (CT) afferents: evidence of their function from microneurography studies in humans[END_REF] that are intermediate-adapting and are abundant over the arm [START_REF] Vallbo | Unmyelinated afferents constitute a second system coding tactile stimuli of the human hairy skin[END_REF][START_REF] Löken | Coding of pleasant touch by unmyelinated afferents in humans[END_REF][START_REF] Ackerley | Human C-tactile afferents are tuned to the temperature of a skin-stroking caress[END_REF] and face [START_REF] Nordin | Low-threshold mechanoreceptive and nociceptive units with unmyelinated (C) fibres in the human supraorbital nerve[END_REF], but are much more sparse on the leg [START_REF] Edin | Quantitative analysis of static strain sensitivity in human mechanoreceptors from hairy skin[END_REF][START_REF] Löken | A topographical and physiological exploration of C-tactile afferents and their response to menthol and histamine[END_REF]. It is postulated that CTs are also abundant on the torso, but this has never been shown directly. In addition, CTs have occasionally been found on the glabrous skin of the hand [START_REF] Watkins | Evidence for sparse C-tactile afferent innervation of glabrous human hand skin[END_REF]. Where Aβ mechanoreceptive afferents have been implicated in the signaling of discriminative touch process, due to their fast conduction velocity, the CT information arrives after a delay, thus they are believed to reinforce gentle contact, such as in pleasant, positive affective touch [START_REF] Mcglone | Discriminative and affective touch: sensing and feeling[END_REF]. Interestingly, it is accepted that there is a general decline in the acuity of the mechanosensory system with age [START_REF] Stevens | Spatial Acuity of the Body Surface over the Life Span[END_REF]however, see Skedung et al., 2018 who show that some participants do not decrease much in tactile capacity), although work has shown that touch actually becomes more pleasant with age [START_REF] Sehlstedt | Gentle touch perception across the lifespan[END_REF]; however, the reason for this is unknown.

Mechanoreceptors primarily encode different types of mechanical event that are applied to the skin (e.g., FA-II afferents encode vibration well, slowlyadapting mechanoreceptors encode pressure well); however, mechanoreceptors can show some sensitivity to thermal and chemical stimuli. Although these have been little-explored, work has shown that SA-IIs may increase their response to cool touch [START_REF] Konietzny | Peripheral neural correlates of temperature sensations in man[END_REF]; also unpublished observations from [START_REF] Ackerley | Human C-tactile afferents are tuned to the temperature of a skin-stroking caress[END_REF]. Further, SA-Is may have decreased responses to cool touch [START_REF] Bouvier | Merkel Cells Sense Cooling with TRPM8 Channels[END_REF], but animal work has also shown dynamic SA-I firing increases to cooling [START_REF] Iggo | The structure and function of a slowly adapting touch corpuscle in hairy skin[END_REF][START_REF] Duclaux | The temperature sensitivity of the type I slowly adapting mechanoreceptors in cats and monkeys[END_REF]. CT afferents have been shown to have decreased firing to mechanical stimulation that is warmer or colder than skin temperature [START_REF] Ackerley | Human C-tactile afferents are tuned to the temperature of a skin-stroking caress[END_REF], although mechanical skin cooling appears to be more complex, where sustained, additional lower-frequency firing can be found [START_REF] Ackerley | Microneurography as a tool to study the function of individual C-fiber afferents in humans: responses from nociceptors, thermoreceptors, and mechanoreceptors[END_REF]. It is also likely that hair follicle afferents show no sensitivity to thermal stimulation of the skin [START_REF] Ackerley | Human C-tactile afferents are tuned to the temperature of a skin-stroking caress[END_REF], but it is clear that when the body is cold, the autonomic nervous system can induce piloerection of hairs, which would lead to afferent activation. Therefore, although mechanoreceptors always encode mechanical events, their responses can be modified by temperature and firing can even be induced with chemicals, such as the sensation of tingling/buzzing induced by sanshool (which also activates thermoreceptors and nociceptors) [START_REF] Bautista | Pungent agents from Szechuan peppers excite sensory neurons by inhibiting two-pore potassium channels[END_REF][START_REF] Lennertz | Physiological basis of tingling paresthesia evoked by hydroxyalpha-sanshool[END_REF][START_REF] Cataldo | Touch inhibits touch: sanshool-induced paradoxical tingling reveals perceptual interaction between somatosensory submodalities[END_REF]. The complexity of receptor encoding of mixed-modality stimuli again points to the specific adaptation of biological organisms to their environment and the interactions they have. Adapted from [START_REF] Robert | The skin[END_REF].

The skin contains many receptors that primarily encode thermal and noxious stimuli. The thermoreceptive system has received less attention, although it is central in somatosensation: imagine touch without temperature? This is like vision without color. When something touches us, it is always accompanied by the encoding of its temperature. Only a handful studies have looked at pure thermoreceptors, which can be putatively classed into cool Aδ fibers, cold C-fibers, and warm C-fibers, although these classes are debatable, due to a lack of evidence of existence [START_REF] Konietzny | Peripheral neural correlates of temperature sensations in man[END_REF][START_REF] Campero | Slowly conducting afferents activated by innocuous low temperature in human skin[END_REF][START_REF] Paricio-Montesinos | The Sensory Coding of Warm Perception[END_REF]. It is agreed that C-cold fibers exist and respond to cooling [START_REF] Konietzny | Peripheral neural correlates of temperature sensations in man[END_REF][START_REF] Campero | Slowly conducting afferents activated by innocuous low temperature in human skin[END_REF][START_REF] Campero | Human cutaneous C fibres activated by cooling, heating and menthol[END_REF] and the application of menthol [START_REF] Campero | Human cutaneous C fibres activated by cooling, heating and menthol[END_REF], but are generally not sensitive to touch. However, it could be that they are related to C-mechano-heat-cold (CMHC) nociceptors (Table 1), as C-cold fibers can also paradoxically respond to heating [START_REF] Campero | Human cutaneous C fibres activated by cooling, heating and menthol[END_REF]. It is also noteworthy that the bodily thermal representation is likely very different to the tactile representation. Contrary to the acuity of the hands and face in tactile discrimination, there is a general trend that we sense temperature changes more readily on the upper half of our body. Our face is the most sensitive, especially the lips, where throughout our whole life, we can sense ~0.05 o C change in lip temperature [START_REF] Stevens | Temperature sensitivity of the body surface over the life span[END_REF]. Temperature sensing on the lower leg is rather poor, especially the toe, which for young adults (<30 years) requires ~2.5 o C increase or ~0.5 o C decrease in temperature; however, for older adults (>65 years), this rises greatly to ~10 o C increase or 3 o C decrease in temperature [START_REF] Stevens | Temperature sensitivity of the body surface over the life span[END_REF]. Therefore, as well as the general decrease in touch capacity with age, the thermosensory system also has some degradation.

Potentially noxious stimuli, as encoded by nociceptors, has been much more researched, with many publications demonstrating the diversity of C-fiber nociceptors (for overviews, see [START_REF] Bostock | Velocity recovery cycles of C fibres innervating human skin[END_REF][START_REF] Ackerley | Microneurography as a tool to study the function of individual C-fiber afferents in humans: responses from nociceptors, thermoreceptors, and mechanoreceptors[END_REF]. Although humans usually aim to decrease nociceptive input, it is essential, as it provides a warning that the skin could be damaged. This important source of afference can greatly shape our body perception, as a strong nociceptive input is difficult to ignore and causes negative affect, driving us to do something to alleviate it. There exist many different types of nociceptor, from ultrafast conducting nociceptors [START_REF] Nagi | An ultrafast system for signaling mechanical pain in human skin[END_REF] through to very slow C-fibers (for a review, see [START_REF] Ackerley | Microneurography as a tool to study the function of individual C-fiber afferents in humans: responses from nociceptors, thermoreceptors, and mechanoreceptors[END_REF] (Table 1). Nociceptors respond to all different types of stimuli, even those that are not particularly noxious, for example, C-mechanosensitive (CM) nociceptors can have low force activation thresholds, similar to low threshold mechanoreceptors, but only respond weakly to gentle touch [START_REF] Nordin | Low-threshold mechanoreceptive and nociceptive units with unmyelinated (C) fibres in the human supraorbital nerve[END_REF][START_REF] Watkins | Optimal delineation of single C-tactile and C-nociceptive afferents in humans using latency slowing[END_REF]. However, the optimal responses from nociceptors are normally into the painful range (e.g., heating over 42 o C, cooling less than 20 o C, strong mechanical force).

Overall, it is evident that the skin somatosensory system is highly complex, where many different types of receptors encode bodily interactions, as well as there being large variability at all levels. Even giving someone a hug will activate numerous receptors from all classes, such as all types of low threshold mechanoreceptor, thermoreceptors, nociceptors (mechanoreceptive nociceptors that have lower force activation thresholds), and even muscle proprioceptors (these may fire due to pressure on muscles, as covered below). It is therefore the balance and synergy between the activation of all these different types of somatosensory receptors that shape our bodily perception. For example, lots of input from low threshold mechanoreceptors, with little input from other types, would likely signal a pleasant contact; however, high activation in all classes of receptor would likely be unpleasant (e.g. intense firing, addition of nociception). Further, the balance between the activation of fast-conducting afferents, which give temporally-precise information about actual tactile events, is complemented by the activation of slower afferents (e.g. some thermoreceptors, nociceptors, and CT afferents) that provide 'color' There is considerable variability within each type, where some types have subclasses. *C-tactile afferents were believed to only be present in hairy skin, but a recent study has shown a sparse projection in glabrous hand skin [START_REF] Watkins | Evidence for sparse C-tactile afferent innervation of glabrous human hand skin[END_REF]. **The innervation of these afferents in human glabrous skin is unknown from microneurography, but can be inferred from psychophysical tests and animal work. For further reading: mechanoreceptors [START_REF] Vallbo | Properties of cutaneous mechanoreceptors in the human hand related to touch sensation[END_REF][START_REF] Vallbo | Receptive field characteristics of tactile units with myelinated afferents in hairy skin of human subjects[END_REF][START_REF] Corniani | Tactile innervation densities across the whole body[END_REF][START_REF] Ackerley | C-tactile (CT) afferents: evidence of their function from microneurography studies in humans[END_REF], thermoreceptors [START_REF] Konietzny | Peripheral neural correlates of temperature sensations in man[END_REF][START_REF] Campero | Slowly conducting afferents activated by innocuous low temperature in human skin[END_REF][START_REF] Green | Temperature perception and nociception[END_REF][START_REF] Schepers | Thermoreceptors and thermosensitive afferents[END_REF][START_REF] Ackerley | Microneurography as a tool to study the function of individual C-fiber afferents in humans: responses from nociceptors, thermoreceptors, and mechanoreceptors[END_REF], nociceptors [START_REF] Campero | C-polymodal nociceptors activated by noxious low temperature in human skin[END_REF][START_REF] Serra | Activity-dependent slowing of conduction differentiates functional subtypes of C fibres innervating human skin[END_REF][START_REF] Bostock | Velocity recovery cycles of C fibres innervating human skin[END_REF][START_REF] Green | Temperature perception and nociception[END_REF][START_REF] Ackerley | Microneurography as a tool to study the function of individual C-fiber afferents in humans: responses from nociceptors, thermoreceptors, and mechanoreceptors[END_REF][START_REF] Nagi | An ultrafast system for signaling mechanical pain in human skin[END_REF], and proprioceptors [START_REF] Matthews | Mammalian Muscle Receptors and Their Central Actions[END_REF][START_REF] Hulliger | The mammalian muscle spindle and its central control[END_REF][START_REF] Burke | Responses to passive movement of receptors in joint, skin and muscle of the human hand[END_REF][START_REF] Macefield | Physiological characteristics of low-threshold mechanoreceptors in joints, muscle and skin in human subjects[END_REF].

to sensations, such as by reinforcing specific aspects of contact (e.g. CTs may reinforce gentle interpersonal interactions).

Internal somatosensory sensing: muscles, joints, and viscera

The division between the outside and inside of the body is rather vague, where there is not a sharp border between external skin and internal tissue. Rather, just like the borders between hairy and glabrous skin, the boundary between external hairy skin and mucocutaneous skin is imprecise. This can be readily seen in the change in skin near mucocutaneous regions (e.g. although our lips seem rather defined, on inspection, there is no sharp border) and felt in that it is difficult to sense exactly where our internal sensation of touch ends (e.g. for rectal sensations, [START_REF] Rogers | Testing for and the role of anal and rectal sensation[END_REF]. If you concentrate on the border between sensing internal 'touch', such as when food goes down our esophagus, it not easy to sense the point at which the sensation ends. However, it is clear that we can feel sensations such as pressure and vibration internally, but it is not like feeling external touch; we are aware that it comes from inside the body. Therefore, it is apparent that we can define external contact as touch, but internal sensations are more related to interoception, body schema, and body wellness.

We have numerous receptors encapsulated in our deeper tissue, including in skeletal muscle, joints, and viscera. We gain our sense of self-in-space, proprioception, though four types of sensitive mechanoreceptive afferent: primary muscle spindles (group Ia, situated in the muscle), secondary muscle spindles (group II, situated in the muscle), Golgi tendon organs (group Ib, situated in tendons), and joint receptors (situated in joints) (see Table 1; and for a review, see [START_REF] Macefield | Physiological characteristics of low-threshold mechanoreceptors in joints, muscle and skin in human subjects[END_REF]. These proprioceptive afferents have thickly myelinated axons and send information very quickly to the brain. Muscle spindles have the peculiarity of being innervated by a sophisticated, descending, efferent system: the (gamma) γ-fusimotor system. This efferent drive can change muscle spindles sensitivity, meaning that the encoding of muscle activity may be influenced by descending factors such as vision, attention, learning, and emotions (for a review on the effects of the γ-drive on muscle afferent firing, see Ribot-Ciscar & Ackerley, 2021). Proprioceptors are important in encoding the position of the body in space, as well as its movement, but they are also activated simply by pressing on muscle. Although tendon and joint receptors are quite insensitive to pressure, muscle spindle afferents will readily respond to pressure applied to the muscle belly. The exquisite sensitivity of muscle afferents is intriguing; they respond to rather gentle touch, including light tapping, pressure, and a range of vibration applied to the skin over muscle receptive field, and will even respond to more remote stimuli, such as via tendon manipulation or more remote vibration [START_REF] Macefield | Physiological characteristics of low-threshold mechanoreceptors in joints, muscle and skin in human subjects[END_REF]. This implies that the input from muscle afferents during tactile interactions, even passive ones, can provide information about bodily contact. In a similar way, cutaneous afferents have also been shown to respond well to body movements, where it has been demonstrated that mechanoreceptive afferents, particularly type IIs, are tuned to joint orientation [START_REF] Aimonetti | Cutaneous afferents provide a neuronal population vector that encodes the orientation of human ankle movements[END_REF].

We also have receptors that have thinly-myelinated axons (group III, Aδ fibers, mainly mechanosensitive) and are unmyelinated (group IV, C-fibers, mainly metabosensitive) in our skeletal muscle, which send information more slowly to the brain and can signal mechanical, thermal, and chemical changes in our muscles. Where muscle and joint proprioceptive afferents likely contribute at least to some direct awareness of the body in space [START_REF] Macefield | Perceptual responses to microstimulation of single afferents innervating joints, muscles and skin of the human hand[END_REF][START_REF] Macefield | Physiological characteristics of low-threshold mechanoreceptors in joints, muscle and skin in human subjects[END_REF], the group III and IV fibers are tentatively classed as nociceptors. They can signal neuromuscular fatigue and pain, as they are optimally activated through exercise contraction-induced mechanical, thermal, and metabolic stimuli [START_REF] Mccord | Reflex autonomic responses evoked by group III and IV muscle afferents[END_REF][START_REF] Amann | On the influence of group III/IV muscle afferent feedback on endurance exercise performance[END_REF]. Thus, where proprioceptors can be classed as more exteroceptive, group III and IV muscle afferents are more interoceptive, as their direct stimulation can cause cardiovascular reflex adjustments. The majority of group III and IV muscle afferents are chemosensitive (around half), while around a third respond to mechanical stimulation, and a third to thermal stimuli [START_REF] Jankowski | Comprehensive phenotyping of group III and IV muscle afferents in mouse[END_REF].

There are receptors deep in our bodies that contribute to our visceral sense of interception and internal sensing. Much less is known about these, as it extremely challenging to conduct microneurography recordings from internal sources (cf. [START_REF] Dunham | Ultrasound-guided, open-source microneurography: Approaches to improve recordings from peripheral nerves in man[END_REF][START_REF] Ottaviani | In vivo recordings from the human vagus nerve using ultrasound-guided microneurography[END_REF]. However, it is clear that we can receive mechanical, thermal, and nociceptive afferent information from our internal bodies. One type of mechanoreceptor, the Pacinian corpuscle (FA-II afferent in the skin) is found throughout the entire body, from the internal organs and nerves of the torso and pelvis, to within the connective tissue of joints, and in blood vessels [START_REF] Roberts | Lamellated corpuscles (pacinian) in relation to the larger human limb vessels and a comparative study of their distribution in the mesentery[END_REF], although these Pacini end-organs can be of considerably different size and shape [START_REF] Sheehan | The Afferent Nerve Supply of the Mesentery and its Significance in the Causation of Abdominal Pain[END_REF]. Mechanosensing is important in our body, but especially in the gut, where we have other myelinated afferents (unencapsulated fibers, Merkel-like enterochromaffin cells) and unmyelinated afferents that capture specialized and non-specialized sensory signals in the gut [START_REF] Sheehan | The Afferent Nerve Supply of the Mesentery and its Significance in the Causation of Abdominal Pain[END_REF][START_REF] Mercado-Perez | Gut feelings: mechanosensing in the gastrointestinal tract[END_REF], which often can be linked to visceral affective sensations, such as fullness after a meal and in painful pathologies. Although there is a lot to learn about human internal sensing and what it contributes to body representations, it cannot be overlooked, as it has evolved to give us an integrated sense of self and is essential in our well-being.

Central processing and integration of somatosensory signals

Once a peripheral receptor has been activated, the signal is transmitted towards the central nervous system, where somatosensory signals are forwarded mainly to the parietal lobe. Although this pathway is simplified in textbooks, there is incredible complexity at all levels, with divergence and convergence of afference well before the information enters the brain. Below is an overview of this complex system and the potential points at which information changes along the afferent pathway.

Classic central pathways activated by somatosensory afference

Our sense of tactile awareness is mainly subserved by myelinated Aβ mechanoreceptive afferents, which is part of the so-called, 'discriminative touch pathway' [START_REF] Mcglone | Discriminative and affective touch: sensing and feeling[END_REF]. The canonical view is that these afferents constitute a direct route or 'labelled-line' for touch information to be transmitted very quickly to the brain. Typically, the afference enters the spinal cord via the dorsal root, then ascends ipsilaterally up the dorsal columns in a topographically-organized fashion. The input from the main body is relayed by the cuneate (input from the upper body) or gracile (input from the lower body) parts of the dorsal column nuclei (DCN), then the signals cross the midline (decussation) to synapse in the thalamus, and then on to primary (S1) and secondary (S2) somatosensory cortical areas. These responses shape our reactions about touch and how we explore our world with millisecond precision. On the other hand, more slowly-conducting information in the anterolateral system takes a different route. C-fiber input is typically seen as entering the spinal cord, then ascending 1-2 vertebral levels to make ipsilateral synapses in the dorsal horn. Secondary neurons at this site project over the midline (decussation) and the information ascends via lamina I of the dorsal horn, through the spinothalamic tract, to synapse in the ventral posterior thalamus, and then on to cortical areas such as the insular cortex, S1, and cingulate cortex. However, this canonical textbook view is far from the actual complexity of this pathway: the ascending information is not simply relayed, rather, there is the potential for processing and interaction at each step.

There are multiple points where ascending information transmission becomes more complex. Even the peripheral nerve afferent is highly complex. The receptor end is very sensitive to stimulation, but the axon and dorsal root ganglion (DRG) cell body are also electrically excitable [START_REF] Devor | Unexplained peculiarities of the dorsal root ganglion[END_REF][START_REF] Ackerley | Microneurography as a tool to study the function of individual C-fiber afferents in humans: responses from nociceptors, thermoreceptors, and mechanoreceptors[END_REF]. It has even been postulated that the DRG neuron serves as a source of afferent input, as some DRG cells are able to fire repetitively [START_REF] Devor | Unexplained peculiarities of the dorsal root ganglion[END_REF]. For afferent fibers that ascend directly up the spinal cord (e.g. Aβ mechanoreceptive afferents), the principle branch of the axon ascends in the dorsal column; however, collateral branches of the entering axon also terminate in the spinal cord locally, or within a few segments, adding to the potential for interactions (for an in-depth overview, see [START_REF] Abraira | The sensory neurons of touch[END_REF]. Small-diameter afferents have an even more complex termination pattern, with a high degree of interaction, where different dorsal horn interneurons play a key role in integrating information and there are neurons that projection these signals from the vast majority of the whole dorsal horn (layers I-V). The information, which can come from a number of afferent types, is then sent via the dorsal columns, the spinothalamic tract, or the spinocervical tract [START_REF] Abraira | The sensory neurons of touch[END_REF].

For signals that reach the DCN, each ascending main afferent contacts ~1700 DCN neurons and each one receives input from ~300 afferents [START_REF] Johansson | Coding and use of tactile signals from the fingertips in object manipulation tasks[END_REF]. The synaptic interruption in the DCN provides a processing step for ascending information. A single DCN neuron can have a similar receptive field and response properties to other DCN neurons, yet each individual neuron responds to a unique combination of convergent input, where it has been demonstrated that tactile and object features have already been computed, making their activity more similar to cortical responses than peripheral nerve input [START_REF] Jörntell | Segregation of tactile input features in neurons of the cuneate nucleus[END_REF][START_REF] Suresh | Sensory computations in the cuneate nucleus of macaques[END_REF].

The vast majority of all sensory afference is relayed to the cortex via the thalamus, notably apart from olfactory signals. Some postural information is sent to the cerebellum, via the spinocerebellar tracts, and sympathetic afferents terminate in medullary nuclei and the hypothalamus, before entering cortical areas. The thalamic nuclei are thought to be the gateway to the brain, where incoming signals are relayed to cortical areas; however, the thalamus is a potential source of large integration of both incoming afference and for reciprocal exchange between cortical areas via cortico-thalamo-cortical connections [START_REF] Cappe | The thalamocortical projection systems in primate: an anatomical support for multisensory and sensorimotor interplay[END_REF]. The circuitry of the thalamic nuclei will not be covered presently, but, in brief, specific areas have been identified that are associated with somatosensory input, such as the ventral posterolateral (VPL) nucleus of the thalamus for tactile bodily inputs, the ventral posteromedial nucleus for facial input, and the posterior part of the ventromedial nucleus (VMpo) and the basal part of the ventromedial nucleus (VMb) that are involved in affective and visceral sensing (for a review on interoceptive pathways, see [START_REF] Craig | How do you feel? Interoception: the sense of the physiological condition of the body[END_REF]. Studies have demonstrated that thalamic responses, like in the DCN, resemble more the firing patterns of somatosensory cortical neurons than the peripheral code, where tactile feature extraction has been demonstrated in VPL [START_REF] Vazquez | Transformation of the neural code for tactile detection from thalamus to cortex[END_REF]. Thus, the responses of neurons, both in the DCN and thalamus, are similar to somatosensory cortical activity, but they are not identical: there is processing and extraction of pertinent information in these sub-cortical structures.

After passing through the sub-cortical nuclei, somatosensory afference is mainly sent to the parietal lobe, where Brodmann area (BA) 3 of the S1 receives a vast input from the thalamus [START_REF] Kaas | The somatotopic organization of the ventroposterior thalamus of the squirrel monkey, Saimiri sciureus[END_REF]; however, mechanoreceptive, thermoreceptive, and nociceptive information are all represented in the S1, S2, and insula [START_REF] Davis | Functional MRI study of thalamic and cortical activations evoked by cutaneous heat, cold, and tactile stimuli[END_REF][START_REF] Stancák | Source imaging of the cortical 10 Hz oscillations during cooling and warming in humans[END_REF][START_REF] Rolls | Warm pleasant feelings in the brain[END_REF][START_REF] Peltz | Functional connectivity of the human insular cortex during noxious and innocuous thermal stimulation[END_REF][START_REF] Mancini | Fine-grained nociceptive maps in primary somatosensory cortex[END_REF][START_REF] Panchuelo | A nociresponsive specific area of human somatosensory cortex within BA3a: BA3c?[END_REF]. There are multiple, precise body representations in S1 [START_REF] Kaas | Multiple representations of the body within the primary somatosensory cortex of primates[END_REF][START_REF] Sánchez-Panchuelo | Regional structural differences across functionally parcellated Brodmann areas of human primary somatosensory cortex[END_REF], but somatotopical relations are less evident in the S2 and insula. There is a wealth of research on tactile responses in S1, which will not be covered in-depth here, but it is clear that the human S1 responds to a broad spectrum of mechanosensory input, from vibration to pressure, and all types of tactile discrimination, yet it is also evident that activity in both the S1 and thalamus is highly related to the period of sensory activation, thus the processing of the direct somatosensory signal [START_REF] Romo | Turning Touch into Perception[END_REF]. Therefore, it is believed that the S1 is the main tactile awareness detection center that then drives other areas in the parietal and frontal lobes to act and make decisions [START_REF] Romo | Somatosensory discrimination based on cortical microstimulation[END_REF]. However, S1 does not function alone and has, amongst others, dense connections with the primary motor cortex (M1), S2, and insula.

The wide activation of cortical areas in 'quantal touch' (the basic, elementary sensation provoked from stimulating a single afferent) been demonstrated using a unique approach to stimulate a single mechanoreceptive afferent and measure the resulting the cortical activity, i.e. using single unit intraneural microstimulation with brain imaging [START_REF] Trulsson | Cortical responses to single mechanoreceptive afferent microstimulation revealed with fMRI[END_REF][START_REF] Sanchez Panchuelo | Mapping quantal touch using 7 Tesla functional magnetic resonance imaging and single-unit intraneural microstimulation[END_REF][START_REF] O'neill | Imaging human cortical responses to intraneural microstimulation using magnetoencephalography[END_REF]. This approach uses microneurography to identify and record from single Aβ mechanoreceptive afferents, then the same peripheral neuronal axon is electrically stimulated using very low current pulses. It is possible to gain a 'quantal' percept of a tactile sensation, where it is believed that the activity in one mechanoreceptor can be felt as a specific point on the skin, for example, an FA-I afferent feel like a small point of vibration, whereas an SA-I feels like a small point of pressure [START_REF] Vallbo | Microstimulation of single tactile afferents from the human hand[END_REF][START_REF] Torebjörk | Intraneural Microstimulation in Man[END_REF][START_REF] Watkins | Slowly-adapting type II afferents contribute to conscious touch sensation in humans: Evidence from single unit intraneural microstimulation[END_REF]. Although it is clear that this percept is likely evoked by the activity of many thousands of neurons, there is conservation along the somatosensory path and the selective artificial stimulation of one mechanoreceptive afferent activates a network of cortical areas. This was demonstrated to a high degree at 7 Tesla (T) functional magnetic resonance imaging (fMRI), where single unit intraneural microstimulation gave rise to a small area of contralateral S1 being activated, which was in correspondence with a larger area activated at the same cortical region by point-vibration at the skin receptive field site of the afferent. Further, activity to single unit intraneural microstimulation was also found bilaterally in the S2, M1, premotor cortex, insula, and posterior parietal cortex, as well as in contralateral prefrontal cortex and in the ipsilateral S1 (Sanchez [START_REF] Sanchez Panchuelo | Mapping quantal touch using 7 Tesla functional magnetic resonance imaging and single-unit intraneural microstimulation[END_REF]. It is noteworthy that the M1 was co-activated during this pure tactile input, demonstrating the common, yet lesser-reported finding of S1/M1 synchrony, whether the source is motor or somatosensory. However, due to the close anatomical proximity of S1 and M1, as well as the strong links between somatosensation and movement, this co-dependence is to be expected. Further, many of the activations from intraneural microstimulation were bilateral, even S1, showing the integrated nature of bodily touch processing. These findings show the need for constant interplay between movement and its feedback, which is especially important in complex manipulations, such as in tool use, and points to why these functions are difficult to separate.

The S2 is very much implicated in the processing of more complicated aspects of touch, such as form, orientation, and pattern. Where S1 is closely related to somatosensory discrimination, S2 encodes task performance and influences decision making, which is associated with knowledge of both present and past tactile events [START_REF] Romo | Neuronal correlates of decision-making in secondary somatosensory cortex[END_REF]. There is often a contralateral predominance in S1 activity to touch, but both S2 cortices often respond, which is similarly seen with the insula [START_REF] Olausson | Unmyelinated tactile afferents signal touch and project to insular cortex[END_REF]. Concerning the insula, this structure has been more implicated in the processing of homeostatic and affective stimuli, such as the perception of gentle touch, temperature, and pain in the posterior insula [START_REF] Craig | Thermosensory activation of insular cortex[END_REF][START_REF] Craig | How do you feel? Interoception: the sense of the physiological condition of the body[END_REF][START_REF] Olausson | Unmyelinated tactile afferents signal touch and project to insular cortex[END_REF]. However, the insula is activated during all tactile interactions [START_REF] Morrison | ALE meta-analysis reveals dissociable networks for affective and discriminative aspects of touch[END_REF]. Other somatosensory association areas over parietal regions, such as Brodmann area (BA) 5 and 7, are typically also activated during somatosensory interactions [START_REF] Ackerley | An fMRI study on cortical responses during active self-touch and passive touch from others[END_REF], but these have been less-studied as compared to the main areas and respond in the integration of somatosensory signals with other processes. Somatosensory association cortex is involved in multisensory, motor, and vestibular processing, where the more caudal areas, going towards visual cortex, have more been implicated in the integration of somatosensory and visual signals [START_REF] Iwamura | Somatosensory association cortices[END_REF].

Overall, it is evident that for each step of information being encoded peripherally and sent to be integrated centrally, there is the potential for complexity, where signals are filtered, processed, and integrated to better adapt the information and extract relevant features. This is highlighted in a rare group of people who have sensory neuronopathy, losing large myelinated somatosensory fiber function below the level around their head. They have no fast-feedback from touch or movements, although they can complete some sensorimotor tasks, with the aid of slowly-conducting fiber input, vision, and their residual motor memory [START_REF] Cole | The perceptions of force and of movement in a man without large myelinated sensory afferents below the neck[END_REF]. This shows that damage to the afferent pathway can be compensated by other mechanisms. This complexity continues well into the cortex, where primary targets for somatosensory information represent stimulus characteristics well, but other activated areas, as covered below, are more implicated in the integration and understanding of what the input means to us.

Integration of somatosensory signals with other senses and with internal mechanisms

As mentioned above, somatosensory stimuli can activate a widespread network of brain areas, including areas in all lobes, sub-cortical structures, and the cerebellum. However, these additional regions often involve more specific tasks, such as the engagement of cognitive and emotional mechanisms, which are well-ingrained into everyday life and have thus evolved in complex ways to be co-activated at different levels. Concerning multisensory integration, there are senses that are heavily interlinked, such as taste and smell, yet touch is impacted by all our senses. Vision, audition, and proprioception are inherently highly associated with touch, and how we explore something tactually can be influenced by smell and even taste, such as when we eat something, the food has specific gustatory and olfactory qualities, but you also feel its texture. Touch is also very important in vestibular mechanisms, such as when you reach out to help balance, which becomes particularly evident with aging.

Internal central mechanisms may engage the more typically-activated somatosensory areas, for example, S1 that can respond to visual input, which includes seeing touch of objects and between humans. The discovery of mirror neurons in the motor system, which respond during a self-action and on the observations of another's action (for a review, see [START_REF] Rizzolatti | The mirror-neuron system[END_REF], has opened up many lines of research concerning the internal representations of others. The mere exposure of watching touch interactions between humans (i.e. vicarious touch) readily activates the S1, S2, and insula, as well as other parietal-opercular areas [START_REF] Blakemore | Somatosensory activations during the observation of touch and a case of vision-touch synaesthesia[END_REF][START_REF] Mccabe | Cognitive influences on the affective representation of touch and the sight of touch in the human brain[END_REF][START_REF] Keysers | Somatosensation in social perception[END_REF][START_REF] Ebisch | Differential involvement of somatosensory and interoceptive cortices during the observation of affective touch[END_REF][START_REF] Morrison | Vicarious responses to social touch in posterior insular cortex are tuned to pleasant caressing speeds[END_REF][START_REF] Bolognini | Sharing social touch in the primary somatosensory cortex[END_REF], although the specific network may depend on the exact situation. For example, there are differences in the somatosensory brain activity found during active self-touch and passive touch delivered at the same skin, where strong activity is provoked in self-touch in S1, but also that self-touch activates somatosensory association areas, including the precuneus [START_REF] Ackerley | An fMRI study on cortical responses during active self-touch and passive touch from others[END_REF]. These findings demonstrate that networks exist to distinguish between self-touch and interpersonal-or objecttouch, which include how we can cancel feedback from our own movements in a context-dependent manner [START_REF] Blakemore | Central cancellation of selfproduced tickle sensation[END_REF][START_REF] Ackerley | An fMRI study on cortical responses during active self-touch and passive touch from others[END_REF]. Further, it highlights the importance of our ability to actively manipulate tools and their incorporation into our body schema [START_REF] Miller | Sensing with tools extends somatosensory processing beyond the body[END_REF][START_REF] Miller | Somatosensory Cortex Efficiently Processes Touch Located Beyond the Body[END_REF], which has also been implicated in the expansion of the precuneus in our evolutionary development [START_REF] Bruner | Evidence for expansion of the precuneus in human evolution[END_REF].

In evolutionary terms, our social interactions have heavily shaped our development [START_REF] Dunbar | The social role of touch in humans and primates: behavioural function and neurobiological mechanisms[END_REF]. This includes the propensity for touch, such as in grooming, to strengthen social bonds and conspecific relationships. Direct interactions with others and the development of our complex social network is underpinned by verbal and non-verbal communication, but in the case of touch, it is hypothesized that CT afferents form a basis to help reinforce and rewards gentle interpersonal contact [START_REF] Löken | Coding of pleasant touch by unmyelinated afferents in humans[END_REF][START_REF] Vallbo | Pleasant Touch[END_REF][START_REF] Olausson | The neurophysiology of unmyelinated tactile afferents[END_REF][START_REF] Ackerley | Human C-tactile afferents are tuned to the temperature of a skin-stroking caress[END_REF]. CT-optimal touch has been shown to activate the insula well [START_REF] Olausson | Unmyelinated tactile afferents signal touch and project to insular cortex[END_REF][START_REF] Morrison | ALE meta-analysis reveals dissociable networks for affective and discriminative aspects of touch[END_REF]. Some studies have found activity in the superior temporal sulcus (STS) during affective touch stimulation, although it is likely that this area is more involved in the integration of touch with information from the other senses and ongoing integrative processes [START_REF] Morrison | ALE meta-analysis reveals dissociable networks for affective and discriminative aspects of touch[END_REF]. However, the premotor cortex and STS are often recruited during the observation of social touch, often more than when the person views an object being touched. The STS and surrounding cortical regions have been implicated in processing biological motion and the movements involved in social situations [START_REF] Deen | Functional Organization of Social Perception and Cognition in the Superior Temporal Sulcus[END_REF], as well as being activated in multisensory motion processing [START_REF] Beauchamp | Touch, sound and vision in human superior temporal sulcus[END_REF], thus encode higher level aspects about our everyday and inter-personal interactions. There is a clear importance of social context in our lives, which is heavily engrained in our contact with others. This is also reflected in processing the meaning of touch, where social significance can also impact on central processing [START_REF] Gazzola | Primary somatosensory cortex discriminates affective significance in social touch[END_REF].

The prefrontal cortex is often activated during situations of somatosensory comparison, where working memory is engaged, such as in the discrimination between two tactile tasks [START_REF] Romo | Neuronal correlates of parametric working memory in the prefrontal cortex[END_REF]. There are clear attentional and context-dependent mechanisms that modulate activity in primary somatosensory areas, where information from various brain structures concerning memory, attention, motivation, and emotion, will shape responses [START_REF] Romo | Touch and go: decision-making mechanisms in somatosensation[END_REF]. For example, task-dependent activity during a vibrotactile attention paradigm has shown many different cortical areas that can respond to help the task at hand, including regions in the frontal eye fields, premotor cortex, superior temporal sulcus, and supplementary motor area [START_REF] Burton | Cortical network for vibrotactile attention: a fMRI study[END_REF]. Another study found that sensory stimuli that change and capture our attention and awareness recruit multimodal mechanisms, such as the additional activation of the temporoparietal junction, inferior frontal gyrus, cingulate, and supplementary motor areas [START_REF] Downar | A multimodal cortical network for the detection of changes in the sensory environment[END_REF]. The recruitment of such diverse and distributed networks demonstrates the complex involvement of numerous cortical areas in the full processing of somatosensory stimuli, in line with the needs for the current situation, enabling us to act in appropriate ways.

Frontal areas, including the orbitofrontal cortex, are recruited in the affective evaluation of touch, as in pleasantness processing [START_REF] Rolls | Warm pleasant feelings in the brain[END_REF][START_REF] Rolls | Representations of pleasant and painful touch in the human orbitofrontal and cingulate cortices[END_REF]. The OFC is also known to be activated by other senses in a similar fashion, for example, in the processing of gustatory pleasantness and even in bodily pain [START_REF] Francis | The representation of pleasant touch in the brain and its relationship with taste and olfactory areas[END_REF][START_REF] Rolls | Representations of pleasant and painful touch in the human orbitofrontal and cingulate cortices[END_REF][START_REF] Rolls | Warm pleasant feelings in the brain[END_REF], thus represents a multisensory area for the evaluation of reward, be it for positive or negative reinforcement. The cingulate cortex has also been implicated in similar affective processing of stimuli from different senses and is subject to cognitive modulation [START_REF] Francis | The representation of pleasant touch in the brain and its relationship with taste and olfactory areas[END_REF][START_REF] Rolls | Representations of pleasant and painful touch in the human orbitofrontal and cingulate cortices[END_REF][START_REF] Mccabe | Cognitive influences on the affective representation of touch and the sight of touch in the human brain[END_REF]. Overall, these higher-order brain areas are clearly modulated in different ways, depending on the task at hand and the behavioral situation, where decision-making and orientation towards goals play a large role in determining the processing.

One further central area that makes a major contribution to somatosensory integration is the cerebellum and the pre-cerebellar nuclei (e.g., pons, inferior olive). The cerebro-cerebellar projection is one of the major pathways of the brain, linking many cerebral cortical regions, especially somatosensory, motor, and visual areas, with the cerebellar cortex. There is considerable integration in the cerebellum, where the afferent input greatly outnumbers the efferent output (ratio 40:1, [START_REF] Brodal | The Cerebellum[END_REF]. The cerebellum is highly involved in the modulation and regulation of behavior, and in the acquisition of new skills, where timing and learning are important. Concerning touch and interactions with the environment, the cerebellum is believed to be important in generating feed-forward sensory prediction for the consequences of behavior. Thus, there is the ongoing comparison of motor output with sensory input and whether this matches or there is any error, where tactile pathways play a central role in shaping this [START_REF] Blakemore | Why can't you tickle yourself?[END_REF][START_REF] Bower | Functional implications of tactile projection patterns to the lateral hemispheres of the cerebellum of the albino rat: the legacy of Wally Welker[END_REF][START_REF] Schäfer | Convergence of primary sensory cortex and cerebellar nuclei pathways in the whisker system[END_REF].

The point at which information becomes truly 'multisensory' is difficult to identify, as the brain is heavily interconnected, thus is it likely that somatosensory signals are influenced very early by the other senses, as well as by ongoing cognitive and emotional mechanisms, as outlined above. However, there are specific situations where somatosensory information is highly coprocessed with other sensory information. For example, in the case of tactile motion, as well as the STS that is involved in biological motion perception, area V5/MT, which plays a key role in visual motion perception, is activated when the skin is stroked [START_REF] Hagen | Tactile motion activates the human middle temporal/V5 (MT/V5) complex[END_REF]. However, a further study using vibrotactile stimulation of the skin found responses only in MST, where these were as strong as in S1 [START_REF] Beauchamp | Human MST but not MT responds to tactile stimulation[END_REF]. Further, in touch-audition interactions, sounds can modulate how touch is perceived, as clearly found in the classic parchment illusion and roughness perception [START_REF] Jousmäki | Parchment-skin illusion: sound-biased touch[END_REF][START_REF] Guest | Audiotactile interactions in roughness perception[END_REF].

In addition to any processing of incoming somatosensory information, the brain needs to act on that information. The mechanisms of this will not be covered presently, although it is noteworthy that the brain can directly adapt its own input, depending on the circumstances. As mentioned above, proprioceptive muscle afferents are innervated by the descending γ-fusimotor efferent system, which can directly modify muscle spindle sensitivity to better adapt actions to the behavioral situation. This has been shown for cognitive mechanisms, such as attention and learning, as well as the impact of emotion (for a review see Ribot-Ciscar & Ackerley, 2021). There has even been shown to be a direct influence of vision on muscle afferent firing. A recent study has shown that when participants did not see their foot move, muscle spindle firing was slightly increased, as compared to when participants had congruent proprioceptive and visual information [START_REF] Ackerley | Seeing your foot move changes muscle proprioceptive feedback[END_REF]. This demonstrates a weighting of information, where proprioceptive signals may be augmented from a central command when visual feedback is not available. In another study, it was shown that when muscle afference feedback from a moving hand was coupled with incongruent visual information, proprioceptive sensitivity was reduced to resolve such bisensory discrepancy [START_REF] Jones | Proprioceptive feedback is reduced during adaptation to a visuomotor transformation: preliminary findings[END_REF]. In all, the descending γ-fusimotor drive shows the influence of the brain on our own sensory feedback, where there are feed-forward processes that enable the rapid and efficient adaptation to an external situation, which helps us prepare responsive and appropriate action. This process is ongoing and is updated continually, showing the complex, intricate nature of our interactions with our environment.

Conclusion and future perspectives

In all, this chapter has examined the sensory origin of bodily perception, in looking at the different types of somatosensory afference that is received and processed by the brain, and why these have been selected in evolutionary terms to help us encode interactions with our environment. It highlights the complexity throughout this process, where even at the receptor level, there can be an integration of signals (e.g., the encoding of mechanical and thermal signals by mechanoreceptors). Somatosensory processes clearly involve multisensory integration, as well as being influenced by ongoing cognitive and emotional/affective mechanisms. In the case of touch especially, vision is a key component in humans, where we are driven by the dominance of visual inputs, and it is evident that these interact with somatosensory areas to understand our contact with the environment (e.g., texture perception) and with others (e.g., social significance). However, our tactile sense provides us with the means to do many complex tasks, such as object manipulation, which has greatly shaped who we are. The progression from early occasional tool use, many millions of years ago, to the habitual incorporation of tools in our lives, through to these tools now being obligatory, highlights how touch and our need to manipulate and explore things in our world has modified our own bodies over time [START_REF] Shea | Occasional, obligatory, and habitual stone tool use in hominin evolution[END_REF]. Rather, we now possess 'prosthetic capacities' that allow us to treat tools as an extension of our own bodies [START_REF] Miller | Sensing with tools extends somatosensory processing beyond the body[END_REF], see also Chapter 3), which have been shaped by biological and environmental influences [START_REF] Bruner | Evolving Human Brains: Paleoneurology and the Fate of Middle Pleistocene[END_REF]. It seems that humans can integrate external objects, likely even other people, into body schema, meaning that these external entities can become temporarily integrated into our self.

There are many avenues yet to explore in bodily perception and it is of interest to use increasingly sophisticated techniques, such as high-field fMRI, to probe mechanisms in humans precisely, especially sub-cortical structures. It is also of interest to investigate the relevance of the expansion of the human parietal cortex [START_REF] Bruner | The parietal lobe evolution and the emergence of material culture in the human genus[END_REF], especially in comparison with other animals and their differences in object manipulation capacities and social structures. Further, it is of importance to define tasks and protocols to unravel the exact processes underlying cognitive influences on somatosensation, where open science and the availability of data will mean access to a vast amount of information that can be used to gain further, meaningful insights into somatosensory processes, with increased power to enable the reliable generalization of findings. This would advance our understanding of bodily perception, both on a fundamental level, but also in combating somatosensory diseases.

Figure 1 :

 1 Figure 1: Overview of different skin types, stimuli that impact on the body, and the classes of receptors that can encode this.

Figure 2 :

 2 Figure 2: Different thicknesses of skin across the body.

  Funding: R. Ackerley is funded by a European Research Council (ERC) Consolidator grant under the European Union's Horizon 2020 research and innovation programme [grant agreement No. 772242]. Conflict of interest statement: None.

Table 1 . Proposed division of types of cutaneous mechanoreceptor, thermoreceptor, nociceptor, and muscle proprioceptor.

 1 Very sensitive touch afferents that likely signal minimal-force wetness interactions in hairy skin.

	Main class	Afferent type	Putative receptor	Axon type	Body region	Further information
	Low threshold mechano-	Fast-adapting type 1 (FA-I)	Meissner corpuscles	Myelinated Aβ	Glabrous skin	Signal discriminative aspects of tactile interactions, including form.
	receptor	Fast-adapting type 2 (FA-II)	Pacinian corpuscles	Myelinated Aβ	All skin	Highly sensitive to all touch (including remote touch) and signals vibrations well.
		Slowly-adapting type 1 (SA-I)	Merkel disks	Myelinated Aβ	All skin	Signals discriminative aspects of tactile interactions, including pressure.
		Slowly-adapting type 2 (SA-II)	Ruffini endings	Myelinated Aβ	All skin	Usually considered to signal deeper pressure and skin stretch.
		Field afferent	Unknown	Myelinated Aβ	Hairy skin
		Hair follicle afferent	Hairs	Myelinated Aβ, thinly myelinated Aδ	Hairy skin	Signals hair movements, from both terminal (thick hairs, myelinated axon) and vellus (fine hairs, thinly-myelinated axon) hairs.
		C-tactile (CT), C-low threshold mechanoreceptor, CLTM), type 3	Free nerve ending	Unmyelinated C	All skin*	May signal more sub-conscious and affective aspects of touch. Responds preferentially to slow, gentle, stroking touch delivered at skin temperature.
	Thermo-receptor	Aδ cool	Free nerve ending	Thinly myelinated Aδ	All skin**	Cool-sensitive with a maximum discharge at temperatures around 27°C, believed to be the main neuronal population subserving innocuous cold sensations.
		C-cold, type 2 (C2)	Free nerve ending	Unmyelinated C	All skin**	Cooling, with no sensitivity to touch; can show activity at typical skin temperature and fire down to 0 o C. May show paradoxical responses to heating.
		C-warm	Free nerve ending	Unmyelinated C	All skin**	Sensitive to warming, no sensitivity to touch. Subclasses: low threshold warm receptors (LTWR), high threshold warm receptors (HTWR)
	Nociceptor	High threshold mechanoreceptor	Free nerve ending?	Myelinated Aβ	All skin**	These have been recently demonstrated in hairy skin (Nagi et al., 2019). High speed sensing of sharp mechanical pain.
		Aδ nociceptor	Free nerve ending?	Thinly myelinated Aδ	All skin**	Very little evidence of their existence (see Adriaensen et al., 1983), signals pain.
		C-mechanosensitive (CM), type 1A, polymodal	Free nerve ending	Unmyelinated C	All skin**	Signals noxious touch (CM) and some chemical sensitivity. Subclasses also respond to noxious temperature, namely C-mechano-heat (CMH) and C-mechano-heat-cold (CMHC) nociceptors.
						Noxious heat, little mechanical sensitivity within measurable limits. Some chemical sensitivity.
		C-mechanoinsensitive (CMi or C-MIA), type 1B	Free nerve ending	Unmyelinated C	All skin**	Subclasses: C-mechanoinsensitive-heat-insensitive (CMiHi) nociceptors have little thermal sensitivity either, while C-mechanoinsensitive histamine-positive (CMi(His+), also known as C-
						pruritic, C-itch) are pruriceptors and sensitive to histamine.
	Proprioceptor	Primary muscle spindle, type Ia	Annulospiral endings	Myelinated Aα	Muscle	Slowly-adapting response to muscle stretch, with higher dynamic sensitivity, signaling the degree of change in muscle movement.
		Secondary muscle spindle, type II	Flower spray endings	Myelinated Aα	Muscle	Slowly-adapting response to muscle stretch, with lower dynamic sensitivity, signaling the length of the muscle.
		Golgi tendon organ, type Ib	Golgi organ	Myelinated Aα	Tendon	Directly encodes the contraction of the muscle, i.e. muscle tension. Little response to muscle length changes.
		Joint receptors	Ruffini, Golgi, Pacini, ?	Myelinated Aα

Joint

Responds well to joint movement, especially at the extremity. Some responses to joint rotation.

Little response to mechanical joint pressure.


Rochelle Ackerley

Roger Watkins

Mariama Dione

Ressentir le toucher sans être touché

La microstimulation électrique de nerfs périphériques va nous permettre de ressentir le toucher sans être touché directement sur la peau. Le système tactile est donc activé de manière artificielle, rendant possible son étude fondamentale, et ouvrant ainsi la voie de la réhabilitation clinique.

La peau est l'organe le plus étendu de notre corps. Elle recouvre le corps entier tout d'abord pour le protéger. Elle permet également d'interagir avec notre environnement, et cela via les centaines de milliers de récepteurs neuronaux qui viennent s'y loger. Ces récepteurs, une fois stimulés, vont traduire une information physique (ex. un contact, une pression, une température) en un message nerveux électrique, qui, traversant le corps via un réseau câblé complexe, va atteindre le cerveau pour donner lieu à une perception. L'importance du codage neuronal du toucher et de la température a été mise en avant récemment grâce à l'attribution du prix Nobel de physiologie ou médecine 2021 aux chercheurs Ardem Patapoutian et David Julius, pour avoir contribué à élucider les mécanismes initiant la cascade d'événements neuronaux amenant à percevoir ce que l'on touche. Ou autrement dit, pour avoir identifié et décrit les structures membranaires, les canaux ioniques, du récepteur permettant de traduire une information mécanique ou thermique, en un signal nerveux électrique.

-Prothèse de bras ostéo-intégrée utilisée par le participant testé dans les articles (10) et (11) (figure publiée dans l'article de revue de Ackerley et Kavounoudias (2015) (14)). (a) Diagramme du processus d'ostéo-intégration, où la fixation servant à attacher la prothèse (clipsable) est implantée directement dans l'os avec une extension sortant du moignon. (b) Un individu amputé portant la prothèse ostéo-intégrée, donc fixée directement au squelette et au système neuromusculaire. (c) Le patient dispose d'une amplitude de mouvement maximale et d'un contrôle prothétique robuste.

(nommées FA-I, corpuscules de Meissner) ou 2 (FA-II, corpuscules de Pacini) répondent davantage aux aspects dynamiques du toucher, telles que les vibrations générées par le glissement d'un objet entre les doigts, tandis que les afférences à adaptation lente de type 1 (SA-I, disques de Merkel) ou 2 (SA-II, terminaisons de Ruffini) répondent plutôt à la pression sur la peau. La stimulation électrique unitaire de ces afférences produit des perceptions claires et spécifiques : une stimulation FA-I ou FA-II produit une zone de vibration plus ou moins large, tandis qu'une stimulation SA-I génère un point de pression (2). En revanche, le fait que la stimulation des SA-II puisse évoquer des sensations est sujet à débat.

Nos avancées techniques les plus récentes, nous ont permis d'observer que les fibres de type SA-II évoquent bien un percept tactile spécifique de manière systématique : une sensation de pression naturelle et diffuse dans la peau (6) (Figure 1). Ces travaux précisent donc le rôle de ces afférents, qui n'existent pas dans la peau glabre chez le singe et ne sont donc pas toujours considérés dans les modèles computationnels qui simulent le toucher en se basant sur les données de la neurophysiologie animale. Dans nos études récentes (7,8,9), nous avons voulu explorer si la stimulation unitaire pouvait générer une activité cérébrale mesurable. La mise en place de ce genre d'études représente un véritable défi car l'électrode placée dans le nerf ne doit pas bouger, auquel cas le signal est perdu. En combinaison avec l'imagerie cérébrale, le risque de perdre le signal est augmenté. De plus, étant donné qu'une seule fibre périphérique est activée, on peut s'attendre à ce que l'activité cérébrale générée soit restreinte. Ceci rend l'utilisation de techniques d'imagerie à haute résolution nécessaire. Nous avons donc utilisé, en collaboration avec des physiciens de l'université de Nottingham (Royaume-Uni), l'imagerie par résonnance magnétique fonctionnelle 7T (7, 9) et la magnétoencéphalographie (8, 9). Nos résultats montrent, que la stimulation d'une seule fibre en périphérie, qui évoque donc une perception spécifique et focale, permet bien d'activer des zones cérébrales restreintes et focales dans le cortex somatosensoriel primaire (S1). Comparativement à une stimulation de la peau par un vibrateur à une intensité jugée comme équivalente, mais qui active sans doute plus de neurones à la fois, la zone cérébrale activée par la microstimulation était de taille bien inférieure (7). Cependant, les activités générées électriquement ou par vibration arrivent bien au même endroit dans S1, permettant de confirmer la justesse des cartes corticales, et également d'en apprendre davantage sur la relation entre les sensations générées par ces deux types de stimulation. D'autres travaux du groupe sur cette même thématique sont à venir.

L'avenir : vers la génération de sensations tactiles pour l'innovation prothétique

Des avancées technologiques majeures ont été réalisées ces dernières années concernant l'innovation prothétique, c'est-à-dire la création de prothèses de bras ou de jambes pour remplacer les membres chez les personnes ayant subi une amputation. Les prothèses deviennent des robots intelligents connectés à la musculature restante voire aux nerfs par chirurgie (10, 11) (Figure 2). Les électrodes connectées aux muscles permettent de lire les intentions motrices des utilisateurs et d'exécuter des gestes intuitifs avec leur prothèse, par exemple d'ouvrir la pince de la main robotique pour saisir des objets. Le retour sensoriel, qui se base donc sur une stimulation électrique des nerfs restants, va permettre de ressentir les qualités des surfaces touchées (12) ou encore d'ajuster la force de saisie des objets pour une meilleure manipulation (13). Plusieurs membres de notre équipe ont eu l'opportunité de collaborer à des études ayant pour but de définir les paramètres de ces retours sensoriels afin de créer des sensations utiles pour l'utilisateur (11, 13) (Figure 2). Le champ est émergent et la microstimulation électrique a sa place pour contribuer à développer les connaissances qui concernent la création de nouvelles sensations via la stimulation électrique de nerfs périphériques. Dans une étude en cours, nous avons utilisé la microstimulation pour stimuler le nerf entier plutôt que les fibres individuelles chez des participants non amputés afin de mimer ce que font les électrodes implantées chez les amputés. Le but de l'étude était de produire des sensations tactiles en manipulant les paramètres de la stimulation électrique (amplitude, fréquence, etc.) dans un groupe d'individus, là où les études actuelles se basent sur les résultats obtenus chez un nombre restreint d'individus amputés. En effet, seule une poignée d'amputés bénéficient aujourd'hui de ce genre de prothèse. Cela nous permettra d'obtenir une vision plus globale et statistiquement robuste de la nature des perceptions générées par la stimulation électrique en périphérie.

Pour le futur, nous souhaitons continuer à faire évoluer les techniques de microneurographie et de microstimulation. Par exemple, nous souhaitons développer nos électrodes pour pouvoir enregistrer ou stimuler plusieurs fibres à la fois. Stimuler plusieurs fibres simultanément et de manière structurée devrait nous permettre à terme de créer de nouveaux percepts tactiles plus intégrés. En parallèle de nos études utilisant la microstimulation, nous poursuivons nos travaux fondamentaux sur le codage du toucher en utilisant la microneurographie, afin de comprendre comment les afférences tactiles répondent à des stimulations naturelles chez l'humain (textures, liquides, etc.). Mieux comprendre le message nerveux tel qu'il est généré dans des situations écologiques nous servira également de base et de guide pour la création de stimulations innovantes pour l'innovation prothétique. rochelle.ackerley@univ-amu.fr roger.watkins@univ-amu.fr mariama.dione@univ-amu.fr

Figure

  Figure 2 -Prothèse de bras ostéo-intégrée utilisée par le participant testé dans les articles (10) et (11) (figure publiée dans l'article de revue de Ackerley et Kavounoudias (2015) (14)). (a) Diagramme du processus d'ostéo-intégration, où la fixation servant à attacher la prothèse (clipsable) est implantée directement dans l'os avec une extension sortant du moignon. (b) Un individu amputé portant la prothèse ostéo-intégrée, donc fixée directement au squelette et au système neuromusculaire. (c) Le patient dispose d'une amplitude de mouvement maximale et d'un contrôle prothétique robuste.

  Actuellement, en collaboration avec le groupe de Göteborg, nous rassemblons plusieurs études en une pour analyser les réponses perçues pour plus de 250 stimulations unitaires. Dans cette étude, nous rapportons également les résultats d'évaluations psychophysiques des sensations évoquées par la microstimulation. Pour ce faire, nous avons comparé les sensations produites par des stimulations courtes (1.5 s) d'afférences mécanoréceptives individuelles à des fréquences variables (15-600 Hz). Le même protocole a aussi été testé en stimulant la peau à l'aide d'un vibrateur. Les résultats encore en cours d'analyse et d'interprétation seront publiés prochainement. Dans une autre série d'expériences, nous avons modifié la durée du stimulus et identifié une interdépendance entre la durée et la fréquence dans la perception de l'intensité. Nous allons également poursuivre ces travaux afin d'étudier des stimulations électriques plus variables (ex. avec variations de fréquence au sein même d'une stimulation). L'ensemble de ces travaux parviendra, nous l'espérons, à renforcer les connaissances sur les mécanismes fondamentaux du traitement central du toucher.


Élise Maigné

Céline Noirot

Jérôme J Mariette

Yaa Adu Kesewaah

Sébastien Dejean
email: sebastien.dejean@math.univ-toulouse.fr

Camille Guilmineau

Julien Henry

Arielle Krebs

Laurence Liaubet
email: laurence.liaubet@inrae.fr

Fanny Mathevet

Élise Maign É1

Sébastien D Éjean

Christine Gaspin

Nathalie Vialaneix

ASTERICS: A Tool for the ExploRation and Integration of omiCS data

niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

The rapid development of omics acquisition techniques has induced the production of a large volume of heterogeneous and multi-level omics datasets measured on the same individuals. Complex information of biological interest is obtained from so-called integration methods, which have been increasingly developed in the past few years. Some of these methods are already available in R packages (like mixOmics [START_REF] Rohart | mixomics: an R package for 'omics feature selection and multiple data integration[END_REF] or mixKernel [START_REF] Mariette | Unsupervised multiple kernel learning for heterogeneous data integration[END_REF] to which our team has contributed). However, the use of these packages still requires to learn a programming language and to have access to sufficient statistical knowledge to choose method parameters and interpret outputs.

ASTERICS

Features

ASTERICS is a web application that aims at making complex exploratory and integration analysis workflows easily available to biologists. Data edition, exploration and integration menus organize the interface to perform 1. data edition, missing value imputation, and normalization, 2. data exploration with interactive plots, numerical summaries, PCA, tests, clustering, and self-organizing maps, 3. data integration with differential analysis, MFA, or PLS-based methods.

Analyses are adapted to the most standard omics datasets (RNA-seq or count data from sequencing technologies, microarray, metabolomics, metagenomics or other compositional data). ASTERICS is also designed to make the analysis flow understandable with a navigable workspace that displays uploaded or obtained datasets and performed analyses in a graph (see Figure 1). Finally, it also comes with a documentation for beginners that helps interpret the results, choose proper options or the next analysis to perform.

Technical information

ASTERICS is based on Rserve, pyRserve, and flask. R package versions are controlled using renv. Frontend is developed in Vue.js and uses the CSS framework Bulma. ASTERICS is available online at https://asterics.miat.inrae.fr/ and will also be released as a docker image for local usage.

Figure 1 .

 1 Figure 1. Example of a workspace as displayed in ASTERICS.

Acknowledgements

This work is funded by Région Occitanie (Grant 20008788 -ASTERICS).


Marcellin Nouaman

Patrick Coffie

Mélanie Plazy

Valentine Becquet

Aline Agoua

Clémence Zébago

Hervé Dao

Joseph Zonhoulou

Serge Larmarange

Eholié

Prevalence and incidence of sexually transmitted infections in a cohort of female sex workers in San Pedro, Côte d'Ivoire (ANRS 12381 PRINCESSE)

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Presented at AIDS 2022 -The 24th International AIDS Conference At inclusion, 6.8% [95% confidence interval: 4.4-10.5] had cervical lesions with 3.5% leukoplakia and 2.1% haemorrhagic cervical junction zone. The prevalence of syndromic STIs was 24. 6% [20.7-29.1]; associated clinical signs were vaginal discharge (17.8%), vaginal ulceration (2.6%), lower abdominal pain (4.7%) and cervical inflammation (3.5%).

The prevalence of anovaginal ] and 3.2% [1.6-6.2], respectively; clinical signs were found in 2.6% of CT-positive and 12.2% of NG-positive FSWs. Most FSWs with syndromic STIs did not have CT or NG infection.

At the end of June 2022, 431 FSWs were included in the cohort. The median age was 29 years, 34% had never been to school, 56% were Ivorian, and the median duration of sex work was 2 years. The median usual price with clients was 2000 CFA (≈2.3 USD).

The vulnerability of female sex workers (FSWs) and their working conditions put them at high risk of HIV infection and other sexually transmitted infections (STIs). This exposure to HIV/STIs and their sexual and reproductive health needs led us to set up a community-based sexual health cohort for FSWs in Côte d'Ivoire (ANRS 12381 PRINCESSE study).

To assess the prevalence (at inclusion) and incidence (during follow-up) of STIs in the PRINCESSE cohort.

The ANRS 12381 PRINCESSE study is an interventional single-arm cohort which started in November 2019 among FSWs aged ≥ 18 years in the San Pedro area.

Care services included quarterly syndromic screening for STIs, as well as vaginal and anal swabs for the screening of chlamydia trachomatis (CT) and neisseria gonorrhoea (NG) by polymerase chain reaction (PCR) at M0, M12 and M24. At the same visits, identification of dysplasias and precancerous lesions of the cervix was performed by visual inspection after applying acetic acid and Lugol's iodine. STIs were managed according to the national algorithm, or referred to specialised facilities in case of complications.

Our analyses, performed with Stata 14.0, covered all participants included until 30 June 2022.

We described: › the prevalence, at inclusion (M0) of HIV, STIs (syndromic and PCR), cervical lesions and condylomas; › the incidence (during follow-up) of STIs (syndromic and PCR).

Poster #EPC055

This study shows a high prevalence and incidence of syndromic STIs among the FSWs in the PRINCESSE cohort, highlighting the importance and interest of regular follow-up. However, a relatively low prevalence of NG and CT was noted, which could be linked to self-medication or the high condom use during sex with clients, as previously shown in this same population (Becquet et al. BMJ Open 2020). There is therefore an interest in insisting on the offer of condoms and lubricant in the sexual health offer, as we are doing in the PRINCESSE cohort. Our results also showed the predominantly asymptomatic nature of STIs discovered by PCR in this at-risk population and, therefore, the importance of coupling syndromic screening and PCR analysis.

Background

Objective

Methods

Study area

Sex work site

Discussion • Conclusion

Results

Mobile clinic Clinic staff Using PCR data at M12 and M24, the incidence of CT and NG was estimated to be respectively 6.3% [2.1-14.8] and 2.5 [0.3-8.9].

Precancerous cervical lesion Condylomas

  Prevalence and incidence of sexually transmitted infections in a cohort of female sex workers in San Pedro, Côte d'Ivoire (ANRS 12381 PRINCESSE project) NM Nouaman 1,2 , PA Coffie 1,3 , M Plazy 4 , V Becquet 5,6 , A Agoua 7 , C Zébago 7 , H Dao 7 , J Larmarange 6 , S Eholie 8 1. Programme PAC-CI, site ANRS Côte d'Ivoire, Abidjan, Cote d'Ivoire. 2. Université Félix Houphouët-Boigny, Département de Santé Publique et d'Odontologie légale, UFR d'Odonto-Stomatologie, Abidjan, Cote d'Ivoire. 3. Université Félix Houphouët Boigny, Département de Dermatologie et Infectiologie, UFR des Sciences Médicales, Abidjan, Cote d'Ivoire, 4. Bordeaux Population Health Research Center, Université de Bordeaux, Inserm, IRD, France. 5. Ined, Aubervilliers, Paris, France. 6. Ceped, Université Paris Cité, IRD, Inserm, Paris, France. 7. ONG Aprosam, San Pedro, Côte d'Ivoire. 8. Université Félix Houphouët-Boigny, Département de Dermatologie et Infectiologie, UFR des Sciences Médicales, Abidjan, Cote D'Ivoire

Table 1 . Prevalence of STIs at inclusion

 1

	n/N	prevalence	[95% CI]

Table 2 . Incidence of STIs during follow-up cases/py incidence [95% CI]

 2

	Syndromic STIs


Mélanie Plazy

Marcellin Nouaman

Valentine Becquet

Aline Agoua

Clémence Zébago

Hervé Dao

Patrick Zonhoulou

Serge Coffie

Joseph Eholié

Larmarange

Clémence

Delays to PrEP initiation among female sex workers in Côte d'Ivoire (ANRS 12381 PRINCESSE project)

Presented at AIDS 2022 -The 24th International AIDS Conference

Introduction

The cross-sectional PrEP-CI study, conducted in 2016 among female sex workers (FSW) in Côte d'Ivoire, showed that this key population was still particularly vulnerable:

• FSW are highly exposed to HIV • In the San Pedro area, the HIV incidence was estimated at 3.2% • Condom use for HIV prevention is not systematic. Even though a large majority of FSW (87%) declared regularly use condoms, 59% disclosed having had at least one sexual intercourse without condom in the week before the study.

In the same time, the oral pre-exposure prophylaxis (PrEP), recommended by the WHO, is an effective tool for HIV prevention as long as it is taken with good adherence. Yet, several studies showed that the implementation of PrEP can be sub-optimal in women, including FSW.

Objective

To describe the delays to initiation of oral PrEP among FSW in Côte d'Ivoire.

Methods

ANRS 12381 PRINCESSE project

• Objectif: evaluate the implementation of a comprehensive and community-based care offer among FSW aged ≥18 years in the San Pedro region. • Study area: region with farming businesses (coffee and cocoa in urban zones, and palm oil and hevea in rural areas), thus leading to a high degree of labor migration among men.

• Study design: single-arm interventional cohort, implemented since end-2019 (still on-going).

• Intervention: comprehensive sexual and reproductive health care package, including PrEP, offered through a mobile clinic operating on 10 prostitution sites (visited every two weeks), and a fixed-clinic (in the APROSAM NGO in San Pedro).

• PrEP delivrance: all HIV-FSW are eligible; PrEP initiation is possible after verifying the creatinine level (determined with a biological assessment; results valid for one month)

Analysis plan for this study

• Study population: FSW who were HIV-and hepatitis B virus-negative (HBsAg-), included until 30/04/2022. • Analysis:

•

Poster #EPC171

Results

Study population: N = 349 HIV-/AgHBS-(on 412 FSW in the cohort).

Description of PrEP initiation

Conclusion

Despite strong PrEP interest among FSW, PrEP initiation remained suboptimal among FSW in the PRINCESSE project. First explanatory analyses of qualitative interviews and discussions with field's teams suggested several barriers to PrEP initiation (such as high FSW mobility, FSW's perception of a burdensome follow-up, mobile clinic fidelity not optimal with about 20% of time when the mobile clinic could not go to prostitution sites because of rainy season or lack of professional). This highlighted the challenge of implementing oral PrEP in this key population, and the need to continue adapting models of care and developing appropriate and effective HIV prevention tools for such population.

  Description of the different steps between inclusion in the PRINCESSE project and PrEP initiation (= 1 st PrEP prescription), or the end of the follow-up • For each step, percentages are given functions of the previous step. • Description of time between FSW's interest for PrEP and PrEP initiation. • Description of reasons of not initiating PrEP. • Description of probability of PrEP initiation since PrEP interest: Kaplan-Meier curve censored on 31/05/2022 (an analysis censored at the date of the last visit was also conducted).Delays to PrEP initiation among female sex workers in Côte d'Ivoire(ANRS 12381 PRINCESSE project)

  1. Bordeaux Population Health Research Center, Université de Bordeaux, Inserm UMR 1219, IRD EMR 271 -Bordeaux (France), 2. PAC-CI -Abidjan (Côte d'Ivoire), 3. Département de Santé Publique, UFR d'Odonto-Stomatologie, Université Félix Houphouet-Boigny -Abidjan (Côte d'Ivoire), 4. Ined -Paris (France), 5. Ceped, Université Paris Cité, IRD, Inserm -Paris (France), 6. ONG Aprosam -San-Pédro (Côte d'Ivoire), 7. Département de Dermatologie et Infectiologie, UFR des Sciences Médicales, Université Félix Houphouet-Boigny -Abidjan (Côte d'Ivoire).

Probability of PrEP initiation since PrEP interest

				IQR: Inter-Quartile Range
	Temporality of PrEP initiation visit
	• 21 initiated PrEP the same day as the
	PrEP interest (biological assessment
	done in a previous visit)
	• 168 initiated PrEP in the visit following
	the interest (median delay since
	interest: 3 weeks [IQR: 2-6])
	• 31 initiated PrEP later (median delay:
	18 weeks [IQR: 12-42], either because
	they were temporarly not interested in
	PrEP (n = 4), or because they came
	back late)
			39% at 1 month
			55% at 3 months
	0 4 8 12	24	36	52
			Weeks since PrEP interest

Photo: V. Becquet Photo: V. Becquet


Mélanie Plazy

Marcellin N Nouaman

Valentine Becquet

Aline Agoua

Clémence Zébago

Hervé Dao

Patrick Zonhoulou

Serge Coffie

Joseph Eholié

Larmarange

Retards à l'initiation de la PrEP orale chez les travailleuses du sexe en Côte d'Ivoire (projet ANRS 12381 PRINCESSE)

teaching and research institutions in France or abroad, or from public or private research centers.

• Les TS en Côte d'Ivoire sont fortement exposées au VIH. A San Pedro, l'incidence du VIH a été estimée à 3,2 %.

• L'utilisation du préservatif comme moyen de prevention du VIH n'est pas systématique.

Si une grande majorité des TS (87%) déclare utiliser le préservatif régulièrement, 59 % ont eu au moins un rapport sexuel sans préservatif au cours de la semaine précédant l'enquête.

La prophylaxie pré-exposition (PrEP) orale, recommandée par l'OMS, est efficace quand elle est prise correctement. Cependant, sa mise en oeuvre peut être sous-optimale dans certaines populations, notamment les femmes.

OBJECTIF

  Population Health Research Center, Université de Bordeaux, Inserm UMR 1219, IRD EMR 271 -Bordeaux (France), 2. PAC-CI -Abidjan (Côte d'Ivoire), 3. Département de Santé Publique, UFR d'Odonto-Stomatologie, Université Félix Houphouet-Boigny -Abidjan (Côte d'Ivoire), 4. Ined -Paris (France), 5. Ceped, Université Paris Cité, IRD, Inserm -Paris (France), 6. ONG Aprosam -San-Pédro (Côte d'Ivoire), 7. Département de Dermatologie et Infectiologie, UFR des Sciences Médicales, Université Félix Houphouet-Boigny -Abidjan (Côte d'Ivoire).CONTEXTE L'étude PrEP-CI conduite en 2016 auprès de travailleuses du sexe (TS) en Côte d'Ivoire avait montré que cette population était toujours vulnérable.

  Décrire et documenter les retards à l'initiation de la PrEP orale au sein du projet PRINCESSE, une cohorte mobile de santé sexuelle et communautaire à destination des TS de la région de San Pedro en Côte d'Ivoire. Projet ANRS 12381 PRINCESSE : • Objectif : évaluer la mise en oeuvre d'une offre de soins globale et communautaire auprès des TS de ≥18 ans dans la région de San Pedro. • Schéma d'étude : cohorte interventionnelle mono-bras, dont les inclusions ont débuté le 26/11/2019 (toujours en cours). • Intervention : offre globale de soins en santé sexuelle et reproductive au sein d'une clinique mobile se déplaçant sur 10 sites prostitutionnels (chaque site étant visité toutes les deux semaines) et d'une clinique fixe. • Organisation de la PrEP : proposée à toutes les TS VIH-; l'initiation est possible après vérification du taux de créatinine (déterminé via un bilan biologique ; résultats valables un mois). Plan d'analyse de la présente étude : • Population d'étude : TS VIH-et séronégatives au virus de l'hépatite B (AgHBs-) incluses jusqu'au 28/02/2022. • Analyse réalisée : description de ce qu'il s'est passé entre l'intérêt exprimé pour la PrEP et l'initiation (= prescription) de la PrEP (ou la fin de suivi) : les pourcentages sont donnés par rapport à l'étape précédente. La probabilité d'initiation de la PrEP après avoir exprimé son intérêt est décrite via une courbe de Kaplan-Meier censurée au 05/03/2022. intérêt exprimé pour la PrEP, son initiation reste sous-optimale parmi les TS de PRINCESSE. Les premières analyses exploratoires et discussions avec les équipes sur le terrain suggèrent plusieurs obstacles (mobilité des TS, intérêt mal perçu pour la PrEP, lourdeur du suivi, fidélité des sorties de la clinique mobile), et confirment la nécessité de trouver des solutions adaptées pour rendre la PrEP effective chez les TS. Voir aussi CO16.4 de Becquet et al. Vendredi 8 avril à 15h45 sur les représentations du corps des TS et CO5.3 de Nouaman et al. Jeudi 7 avril à 11h40 sur l'incidence des IST chez les TS. RESULTATS RESULTATS (suite) Raisons de non-initiation de la PrEP • 79 jamais revenues • 29 revenues trop tard (donc nécessite un nouveau bilan) • 5 n'étant plus intéressées • 1 diagnostic VIH+ >93 % même jour que inclusion >99 % même jour que présentation de la PrEP Délai médian de l'initiation depuis intérêt : 3,3 semaines [IIQ = 2 ; 8] Temporalité de la visite d'initiation de la PrEP • 20 TS ont initié la PrEP le jour même de l'intérêt exprimé (bilan biologique réalisé lors d'une précédente visite) • 159 lors de la visite suivant l'intérêt (délai médian depuis l'intérêt : 3 semaines [IIQ : 2-6]) • 30 lors d'une visite ultérieure (délai médian : 19 semaines (11-45], soit parce qu'elles n'étaient temporairement plus intéressées (n=4), soit parce qu'elles sont revenues tardivement) Durée du travail du sexe (années) 2 [0-5] Lieu(x) de travail au cours du dernier mois Maison