Physio F1 - Somatosensory System PDF

PHYSIO F1 - THE SOMATOSENSORY SYSTEM Somatosensory system mediates a range of sensations: touch, pressure, vibration, limb position, heat, cold, itch, and pai, transduced by receptors within the skin, muscles, or joints and conveyed to a variety of CNS targets. It can be divided into functionally...

PHYSIO F1 - THE SOMATOSENSORY SYSTEM Somatosensory system mediates a range of sensations: touch, pressure, vibration, limb position, heat, cold, itch, and pai, transduced by receptors within the skin, muscles, or joints and conveyed to a variety of CNS targets. It can be divided into functionally distinct subsystems with distinct sets of peripheral receptors and central pathways: -​ one subsystem transmits information from cutaneous mechanoreceptors and mediates the sensations of fine touch, vibration, and pressure -​ another subsystem originates in specialized receptors that are associated with muscles, tendons, and joints and is responsible for proprioception -​ the third subsystem arises from receptors that supply information about painful stimuli and changes in temperature as well as non-discriminative (or sensual) touch 1.​ Functions of the somatosensory system It has 3 major functions: ​ Proprioception: experience of posture and movement of our body. It is possible thanks to receptors in skeletal muscles, joints & skin. ​ Exteroception: sense of the direct interaction between our body and the external world. It is perceived through receptors in the skin and consists in extraction of physical features of the object and the environment. ​ Interoception: perception of our internal state, sense of function of the major organs or viscera. It is perceived through receptors in the viscera and consists in the perception of our internal state. 2.​ Somatosensory afferents Somatosensory afferents differ significantly in their response properties and these differences, taken together, define distinct classes of afferents, each of which makes unique contributions to somatic sensation. a.​ Axon diameter Axon diameter is one factor that differentiates classes of somatosensory afferents. -​ The largest-diameter sensory afferents (designated Ia) are those that supply the sensory receptors in the muscles. -​ Most of the information subserving touch is conveyed by slightly smaller diameter fibers (Aβ afferents), -​ Information about pain and temperature is conveyed by even smaller diameter fibers (Aδ and C).  b.​ Receptive field size Another distinguishing feature of sensory afferents is the size of the receptive field—for cutaneous afferents, the area of the skin surface over which stimulation results in a significant change in the rate of action potentials. A given region of the body surface is served by sensory afferents that vary significantly in the size of their receptive fields: the size of the receptive field is largely a function of the branching characteristics of the afferent within the skin smaller arborizations result in smaller receptive fields. Moreover, there are systematic regional variations in the average size of afferent receptive fields that reflect the density of afferent fibers supplying the area. The receptive fields in regions with dense innervation (fingers, lips, toes) are relatively small compared with those in the forearm or back that are innervated by a smaller number of afferent fibers. c.​ Temporal dynamics Sensory afferents are further differentiated by the temporal dynamics of their response to sensory stimulation. -​ Some afferents fire rapidly when a stimulus is first presented, then fall silent in the presence of continued stimulation (rapidly adapting afferents) -​ others generate a sustained discharge in the presence of an ongoing stimulus (slowly adapting afferents).  3.​ The sense of touch The sense of touch is take by the cutaneous mechanosensory afferents (first order neurones) into the spinal cord and from here it is conveyed to the CNS through: -​ Dorsal column medial leminiscus pathway: from lower body, upper body and posterior head (lateral) -​ Trigeminal pathway: from face (medial) Second order neurons from both pathways synapse in the VP complex of the thalamus, divided into: -​ VPM nucleus: receives projections from the trigeminal lemniscus (information from the face) -​ VPL nucleus: receives projections from the medial leminiscus (information from the body and posterior head) This allows the VP complex to contain a complete representation of the somatic sensory periphery. The VP complex shows a craniocaudal-mediolateral somatotopy gradient. The division of the information arriving in the nuclei is not sharp, but there is a gradient: in the lateral most part there are information from the lower body, moving medially there is the trunk and the head and in the overlapping there are fingers and face; the uppermost part is devoted to the face. Therefore, the ventral posterior nucleus proper (VPM-VPL) receives the cutaneous information conveyed by the trigeminal lemniscus axons and the medial lemniscus axons (DCML). More recently additive nuclei have been found in the VP complex: -​ the ventral posterior superior (VPS) receives mainly proprioception -​ the ventral posterior inferior (VPI) receives mainly interoception I.​ 1° somatosensory cortex 1.​ Primary somatosensory cortex – Brodmann areas The majority of the axons arising from neurons in the ventral posterior complex of the thalamus project to cortical neurons located in layer 4 of the primary somatosensory cortex. The primary somatosensory cortex in humans is located in the postcentral gyrus of the parietal lobe and comprises four distinct regions, or fields, known as Brodmann’s areas 3a, 3b, 1, and 2. The different areas of S1 receive different inputs from the periphery and are involved in different functional aspect (from ventral to dorsal): -​ Area 3a: o​ inputs from muscle stretch receptors o​ primarily detects changes in the length of the muscle (proprioception) -​ Area 3b: o​ inputs from SA1 fibers (Merkel receptors) an RA1 fibers (Meissner receptors). o​ Detects the detail of surface texture. o​ It is very small and has part of the excitatory and inhibitory areas overlapped. -​ Area 1: o​ inputs from RA1 & RA2 fibers (Pacinian corpuscles). o​ Detects details of surface texture (like 3b)  -​ Area 2: o​ inputs of tactile and proprioceptive information, o​ detect size and shape of the object. o​ It is the most integrative region, important for complicate movements (e.g., grabbing an object). In area 2 the region of overlapping is more complex because the receptive fields of excitatory presynaptic neurons are aligned, the motion direction of the stimulus is detected and touch info becomes increasingly more abstract. Specific neurons in area 2 can also encode motion, direction, and orientation of tactile stimulus: -​ Motion-sensitive neuron responds to stroking the skin in all directions -​ Direction-sensitive neuron responds strongly to motion toward the ulnar side of the palm but fails to respond to motion in the opposite direction -​ Orientation-sensitive neuron responds better to motion across a finger (ulnar-radial) than to motion along the finger (distal proximal) but does not distinguish ulnar from radial nor proximal from distal directions. Since the different Brodmann areas receive different types of information, each of them has its own specific connection with the thalamus: -​ Area 3a receives information from the VPS -​ Area 3b receives information from VPL and VPM -​ Area 1 receives information from VPL and VPM -​ Area 2 receives information from VPS Nissl staining allows to identify the different layers of the cortex by staining the Nissl bodies in the soma of the neurons. Relation between intensity of staining and density of neurons in different areas provides an architectonical classification of different areas in the brain. 2.​ Somatosensory neurons in primary somatosensory cortex There are 3 features of somatosensory neurons in primary somatosensory cortex: a.​ Receptive field size with respect to the periphery The receptive fields of neurons in S-1 are larger with respect to the receptive field in the periphery and integrate inputs from hundreds of sensory nerve fibers. The receptive field of a neuron in area 3b represents a composite of inputs from 300 to 400 sensory nerve fibers. The size of receptive fields changes also among neurons in the different Brodmann areas. For example, neurons in the area 3b have a receptive field that is way smaller than the ones of neurons in area 2. This can be explained considering that area 3b detect details of the texture while area 2 is involved in determining more general features such as the shape of the object.  b.​ The lateral Inhibition Receptive field of Cortical neurons usually have a central excitatory zone surrounded by an inhibitory zone. This means that a deformation of the skin in the central zone leads to stimulus that reaches the cortex while the deformation of the skin in the peripheral region leads to a firing at the level of the first-order neuron but in its process through the dorsal column nuclei, the thalamus and at the cortical level the stimulus is inhibited to increase the firing rate of the neurons in the central region. This is important to limit the spread of excitation allowing a winner-take-all-strategy that increases tactile acuity. The inhibitory activity is generated in the dorsal column nuclei, thalamus, and cortex by connections through interneurons. The shape of the central excitatory region and its related inhibitory zone are different within primary somatosensory areas and allow to detect different functional aspects. e.g., the specific shape of the central excitatory zone of the receptive field of neurons in area 2 allows detecting edges and different types of motion that could not be caught through the receptive fields of area 3B c.​ Organization in functional columns Vernon Benjamin Mountcastle discovered that neurons in the somatosensory cortex are organized into functionally specialized columns. Penetrating with electrodes in the receptive fields of monkey’s brain he detected the presence of different vertical columns that received information from different types of neurons. For example, it is possible distinguish columns that receive information from fast adapting neurons and columns that receive from slow adapting ones. 4.​ Cortical layers -​ Layer I: receives from other brain areas (posterior parietal cortex, frontal motor areas, limbic areas, medial temporal lobe) and project into layers II and III. -​ Layers II – III: horizontal connections with neighbour columns and other cortical regions (complex signal integration). -​ Layer IV: third order neurons from the thalamus synapse in layer IV of the cortex, there is a complex interaction between the columns as they project in the deeper and superficial layers. -​ Layer V: receives from layers II and III and project to subcortical structures including basal ganglia, pontine and brainstem nuclei, spinal cord and the dorsal column nuclei. -​ Layer VI: projects to the thalamus. 5.​ Somatotopic organization of the cortical columns The cortical columns (the organization of neurons in the somatosensory cortex) in the somatosensory cortex are arranged in a somatotopic organization. This means that vertical columns detecting different types of stimuli from the same region of the body are localized near to each other. The different body parts are arranged in a medio-lateral fashion. From medial to lateral the primary somatosensory cortex receives information from lower limbs, trunk, upper limbs, head and face. 6.​ Cortical magnification Cortical magnification refers to the fact that the cortical surface for each body part is closely correlated with the innervation density and thus the spatial acuity of the receptors in the skin. In other words, different body parts have a different number of receptors and the size of the primary somatosensory cortex involved in encoding the information coming from a specific area is directly related to the number of receptors in that specific area. Areas of cerebral cortex are not proportional to the spatial topography of the skin but rather the amount of sensitivity in each body part. The Homunculus is an ideal representation of the human being that allows to understand how the cortical areas related to different parts of the body vary in size. Each part of the body is represented in proportion to its importance to the sense of touch. Cortical areas representing lips, tongue and fingers are the areas with the greatest magnification Fingers e.g., by performing this technique in monkeys it has been possible to study the differences in the cortical columns of the hand. Despite the distinct columnar organization, fingers representation seems to be highly overlapped. The fingers are represented in a continuum and the horizontal connections between the receptive fields of the fingers are probably important when manipulating a specific surface because allow to have a continuum sensation when it passes between fingers. It is also possible to notice that this topography reflects the functional organization among fingers. -​ Indeed, D3 to D5 are more overlapped, -​ But, D1 (thumb) and D2 (index) are more distinct. This organization reflects the higher importance of D1 and D2 in the role of touch. These studies suggest that not only the size of the cortical areas relative to the different body parts is important but also their relationships. In support of this Jhon Cast also performed a study on the continuity between hand and mouth cortical areas that seems to play an important role for complex behaviours such as hand mouth interaction (feeding). II.​ Higher somatosensory cortex 1.​ Secondary somatosensory cortex complex (PV/SII) The primary somatosensory cortex is important in the passive touch, but the higher somatosensory cortex became crucial in active touch. The flow of somatosensory information from primary to higher somatosensory areas contributes to cognitive action (object discrimination) and support motor act (object manipulation) The first higher somatosensory cortex is the secondary somatosensory cortex complex. The secondary somatosensory cortex complex is localized in the dorsal bank of the lateral fissure. This complex is composed of -​ SII proper -​ Parietal Ventral area (PV). These two areas have different granularities.  b.​ SII proper SII proper receives information from: -​ Area 3B -​ Area 1 -​ VP complex nuclei (in particular, the inferior one that sends deep somatic information and the superior one for proprioception). SII if compared with PV has a thalamic input that is more like primary somatosensory cortex. In SII, the receptive field are combined and bilateral. Among the combined-type receptive fields, two tendencies of RF convergence were found: -​ the distal parts of the limbs (i.e., hand and foot) and the mouth are interconnected -​ the trunk RFs extend continuously toward the distal parts of the limb and head to cover the entire body surface c.​ Area PV In area PV the thalamic inputs are quite different from SII since it receives from non-sensory thalamic areas. It receives information from: -​ Area 3B  -​ Area 3A -​ Mediodorsal nucleus of the thalamus -​ Centrolateral nucleus of the thalamus It has strong connections with premotor area and with frontal eye field. The mediodorsal nucleus is related to the limbic system and so it’s important for tactile memory and attention. The centrolateral nucleus receives from the basal ganglia and from the limbic and prelimbic areas thus suggesting the involvement of area PV in other cognitive functions still related to memory. The involvement of area PV in cognitive functions related to memory has been shown through an experiment conducted on monkeys: The monkeys were trained to receive a tactile stimulus on the tip of the finger with a specific frequency and after 2 seconds a second stimulus with different frequency of vibration. The monkeys were trained to make a choice depending on the relationship between the two frequencies. If the second was higher than the first they had to do one thing, if the second was lower they had to do something else. During delay period the neurons continued to discharge even if the monkeys didn’t receive any type of tactile stimulus. This activity was associated to the encoding of memory signals that were important for the following task (take the right decision). 2.​ Parietal rostral area (PR) Recently it has been discovered another area called the parietal rostral area. It is located just anterior to PV. This area receives from PV and other somatosensory areas and is activated only during active touch. In this area are localized specific neurons that do not have a specific receptive field or somatosensory function but discharges mainly Lduring movement of the hand exploring or grasping. Lllllplll  3.​ Posterior parietal cortex The posterior parietal cortex (PPC) involves Broadmann areas 5 and 7. These areas play a role in sensory guidance of voluntary movement rather than in discriminative touch. -​ Area 5 (SPL) receives inputs from sensory and non-sensory thalamic nuclei. -​ Area 7 (IPL) which is in the inferior parietal lobe, receives information mainly from non-sensory thalamic nuclei, which are: o​ the lateral posterior nucleus (LP) o​ anterior and medial pulvinar nuclei (respectively PuA and PuM) Get These non-sensory thalamic nuclei are selectively connected (send and receive info) with a variety of higher order areas: -​ temporal cortex -​ cingulate cortex -​ prefrontal cortex LP and PuM projections thus, may convey highly processed sensory and/or goal related information to PPC areas. Brodmann’s areas 5 and 7 of the cerebral cortex (located in parietal cortex behind somatosensory area I), play important roles in deciphering deeper meanings of the sensory information in the somatosensory areas. Therefore, these areas are called somatosensory association areas. The somatosensory association area combines information arriving from multiple points in the primary somatosensory area to decipher its meaning. This occurrence also fits with the anatomical arrangement of the neuronal tracts that enter the somatosensory association area because it receives signals from: -​ somatosensory area I -​ ventrobasal nuclei of the thalamus -​ other areas of the thalamus  -​ visual cortex -​ auditory cortex a.​ Somatosensory modality in the posterior parietal lobe: the case of Broadman’s area 7 and visuo-tactile neurons. Some neurons in the posterior parietal cortex are not just unimodal neurons (respond to stimuli in one sensory modality) but they can also be bimodal. In the ventral intraparietal areas (VIP, a region of the posterior parietal cortex) neurons are bimodal, being stimulated by both visual and tactile stimulation. e.g., in an experiment on monkeys, it was found that the same neurons in this region discharge after tactile stimulation alone and after visual stimulation alone. There is thus some sort of correspondence between tactile and receptive field. To note: this visual information does not depend on retinotopic or retinocentric stimulation, or in general eye movement - it is completely anchored to the somatosensory receptive field. This is an example of integration between somatosensory info and sensory info of other nature. b.​ Visuo-tactile receptive fields in area 5 can extend their space: the case of tool use. Another great example of multisensory information integration comes from a study of Azuki Iriki. Recording from the superior parietal lobe, the scientist found somatosensory neurons that had both a tactile receptive field (RF) covering the whole hand, and a visual receptive field around the hand. A monkey was trained to use a tool and after learning how to use the tool the visual receptive field expanded also to the tool: the visuo-tactile neurons adapted and followed the increased motor ability of the monkey. x  4.​ Somatosensory modality in the inferior parietal lobe Neurons in the inferior parietal lobe are of different types: -​ somatosensory, -​ visual, -​ motor. In the parietal lobe also complex and non-complex receptive fields (RFs) are intermingled and present a somatotopic organization. Orofacial RFs are the most anterior ones, hand and trunk RFs are located in PG, which is the most posterior area of the inferior parietal lobe in monkeys. 5.​ Somatosensory receptive field in area 5 Thalamic inputs arriving in area 5 are very similar to those arriving in S1, though area 5 also receives info from non-sensory thalamic nuclei. Receptive fields in area 5 are complex, they cover different body parts: -​ these RFs are involved in different portions of the forelimb, such as knuckles, wrist, and elbow (A in picture). -​ RFs can also be bilateral (B in picture), -​ can cover multiple digits (C in picture), -​ can cover relatively large portions of the palm of the hand (D in picture). All these features increase the complexity of RFs of these neurons. Neurons in area 5 respond to manipulation of joints (passive joint movement), of muscles and taps on portions of skin: in these neurons an integration of proprioceptive and tactile information happens, similarly to what occurs in area 2, but in this case the complexity is increased, with bilateral RFs that include different body parts. Area 5 presents a somatotopy. 6.​ Projection neurons in area 5 and 7 DEFINITION Mountcastle discovered some neurons in areas 5 and 7 that were defined as projection neurons: these neurons, instead of having a clear proprioceptive or somatosensory RF, were particularly active when the monkey was exploring the space around itself to look for food or objects. The discharge of projection neurons is highly dependent on the goal of the behaviour rather than on the tactile or proprioceptive stimulus. In this area no neurons were activated by passive stimuli. The graph reports the firing of projection neurons. Letter D indicates the moment of contact between the object and the hand. The discharge of neurons is intense in the two upper graphs: it starts even before the contact between hand and object, indicating an action with a goal. In the lower graph the discharge is less intense and happens only after hand-object contact, indicating a goal-free action. Indeed, projection neurons in somatosensory PPC fire before contact with the object. This precontact firing is caused by synapses of neurons from motor areas with projection neurons, when planned actions are carried out. In this way, projection neurons are provided with information on planned actions, allowing them to compare planned and actual neural responses to tactile stimuli. This essentially allows sensory prediction of the action before the action is actually performed. This kind of integration is useful to correct movements that are carried out in a different way with respect to the movement originally planned. Therefore, these somatosensory areas are able to integrate visual information and motor information with somatosensory information. MICROSTIMULATION Studies were conducted that used microstimulation of neurons. -​ When the motor cortex is excited with microstimulation involuntary movements are performed. -​ If instead an electrode is used to have microstimulation in the somatosensory area of the parietal lobe, no motor outputs are expected. T o​ This outcome however, is only partially true, since there are a lot of connections between somatosensory areas of the parietal lobe and motor areas. If areas 1, 2, 5, and 7 are stimulated with high intensity, it is possible to cause somatotopic movements. MOUVEMENT TYPE AND SOMATOTOPY Moreover, it was found that there is high correspondence between movement type (the one caused by stimulation) and somatotopy and often there is also correspondence between RFs and type of movements. e.g., intracortical stimulation of somatosensory neurons with RF in digit one (D1) causes twitch in digit one. Intracortical stimulation of multisensory neurons evoke specific behaviours rather than simple movements: for example stimulation in area 5 causes a precision grip. 7.​ Lesions of somatosensory areas Lesions in SI (lesions classified as A) in humans cause severe difficulties in simple tactile tests. The clinical outcome in monkeys is that the monkey is still able to move but isn’t able to pick up food from a funnel. Lesions in PPC (lesions classified as B/C) in humans cause: -​ mild difficulties in simple tactile tests -​ severe difficulties in complex tactile recognition tasks. This clinical outcome is called stereognosis - patients are not able to recognize an object only with touch, they also need sight to recognize it. -​ kinematic defects: patients are not able to interact correctly with objects. This kind of clinical outcome is called tactile apraxia (apraxia is a complex condition with many features but for the sake of simplicity it can be used in this context). In monkeys these lesions cause: -​ moderate deficits in simple tactile test -​ wrong directioning of hands when grabbing objects -​ wrong object pre-shaping with hands (when having to grab a small object the hand approaches the object with the fingers wide open as if it had to grab a big object) These two last points are due to problems in integrating multisensory information. Lesions in SII in humans cause: -​ severe problems in complex tactile discrimination tasks, similarly to what happend in PPC. -​ the impairment seems to be more cognitive than sensorimotor (lesions in PPC caused an impairment that was more sensorimotor). In monkeys the same lesions cause: -​ deficits in object discrimination -​ impaired learning of new discrimination skills Two scientists, Melvin Goodale and David Milner finally concluded that there are 2 somatosensory streams, similarly to what happens in the visual system. -​ The more ventral one includes SII, PV, parieto-rostral area, and is involved in cognitive touch (recognition and assignment of names to objects, which allows us to remember them). -​ The PPC and dorsal parietal areas bordering the intraparietal sulcus, which are more dorsal, are instead related to somatosensory info, motor info and info of different sensory origin. Therefore, the dorsal stream has a role in sensorimotor guidance (guiding movement). 8.​ Tonic and phasic responses in the somatosensory cortex Study conducted by Pietro Avanzini on humans. The patient has implanted electrodes recording cerebral activity (similarly to the monkeys). When the median nerve is stimulated, there is a huge activation of the cortex after about 20-30 milliseconds (the time for the evoked somatosensory potential in S1): the activity is recorded in the posterior parietal lobe, in the intraparietal lobe as well as in motor and premotor areas. After 40-50 ms the activity spreads but it is found in more or less the same areas. After more than 100 ms, activity is only recorded in regions located in the posterior part of the Sylvian fissure. The activity registered in higher somatosensory cortices is electrophysiologically different from that registered in primary somatosensory cortex. Indeed, in the primary somatosensory cortex, responses are phasic: a spike of activity is observed at 20 ms, while a drastic drop occurs after 50 ms; this response is coherent with the discriminative aspects of touch. On the other hand, in somatosensory area S2 (SII-PV) and in the posterior insular cortex the registered activity (blue in the graph) is lower in magnitude and is tonic, lasting for several seconds: this activity therefore may be related to the awareness or experience of the somatosensory information. The tibial nerve and the trigeminal nerve also show this response. [Remembering the somatotopic organization: the cortical representation of the lower limb (tibial nerve) on the somatosensory cortex is medial, whereas the representation of the face (trigeminal nerve) is lateral.] Technique reflecting the somatotopic activation of the tibial, trigeminal and median nerve. The activity is also registered in motor areas, suggesting that motor areas also receive somatosensory information. The primary motor cortex has many neurons involved in proprioception; when it comes to the primary somatosensory cortex, area 3a, the rostral-most part of the primary somatosensory cortex (at the edge of the primary motor cortex), is involved in proprioception. The tonic and the phasic responses are also found in other body parts representation. Indeed, tonic organization does not depend on the type of effector (the effector may be the hand, the arm, the lower limb etc. - it makes no difference): in all cases this type of electrophysiological activity is recorded in the higher somatosensory area S2 and in the posterior insular cortex. III.​ Nociception and pain The relatively unspecialized nerve cell endings that initiate the sensation of pain are called nociceptors. They arise from cell bodies in dorsal root ganglia (or in the trigeminal ganglion) that send one axonal process to the periphery and the other into the spinal cord or brainstem. The axons associated with nociceptors, conduct relatively slowly, being only lightly myelinated or, more commonly, unmyelinated. Accordingly, axons conveying information about pain fall into either  -​ the Aδ group of myelinated axons, which conduct at 5 to 30 m/s, -​ the C fiber group of unmyelinated axons, which conduct at velocities generally less than 2 m/s. Thus, even though the conduction of all nociceptive information is relatively slow, pain pathways can be either fast or slow. In general, two categories of pain perception have been described: a sharp first pain and a more delayed, diffuse, and longer-lasting sensation that is generally called second pain. The faster-conducting Aδ nociceptors are now known to fall into two main classes. -​ Type I Aδ fibers respond to dangerously intense mechanical and chemical stimulation but have relatively high heat thresholds, -​ type II Aδ fibers have complementary sensitivities—that is, much lower thresholds for heat but very high thresholds for mechanical stimulation. Thus, the Aδ system has specialized pathways for the transmission of heat and mechanical nociceptive stimuli. Most of the slower-conducting, unmyelinated C-fiber nociceptors respond to all forms of nociceptive stimuli—thermal, mechanical, and chemical—and are therefore said to be polymodal. However, C-fiber nociceptors are also heterogeneous, with subsets that respond preferentially to heat or chemical stimulation rather than mechanical stimulation. Further subtypes of C-fiber nociceptors are especially responsive to chemical irritants, acidic substances, or cold. A specific receptor is associated with the sensation of noxious heat. The threshold for perceiving a thermal stimulus as noxious is around 43°C (110°F), and this pain threshold corresponds with the sensitivity of sub-types of Aδ- and C-fiber nociceptive endings. The so-called vanilloid receptor (TRPV1), found in both C and Aδ fibers, is a member of the larger family of transient receptor potential (TRP) channels. Structurally, TRP channels resemble voltage-gated potassium or cyclic nucleotide-gated channels, having six transmembrane do- mains with a pore between domains 5 and 6. Under resting conditions, the pore of the channel is closed. In the open, ac- tivated state, these receptors allow an influx of sodium and calcium that initiates the generation of action potentials in the nociceptive fibers. The receptors responsible for the transduction of me- chanical and chemical forms of nociceptive stimulation are less well understood. Several different candidates for mechanotransducers have been identified, including other members of the TRP family (TRPV4), a rapidly adapting ion channel called Piezo2, and some members of the ASIC (acid-sensing ion channels) family. 1.​ Central pain pathways Pathways responsible for pain originate with other sensory neurons in dorsal root ganglia, and the central axons of nociceptive nerve cells enter the spinal cord via the dorsal roots. When these centrally projecting axons reach the dorsal horn of the spinal cord, they branch into ascending and descending collaterals, forming the dorsolateral tract of Lissauer. Axons in Lissauer’s tract typically run up and down for one or two spinal cord segments before they penetrate the gray matter of the dorsal horn. Once within the dorsal horn, the axons give off branches that contact second-order neurons located in Rexed’s laminae I, II, and V. Laminae I and V contain projection neurons whose axons travel to brainstem and thalamic targets. There are interneurons in all laminae of the spinal cord. These afferent terminations are organized in a lamina-specific fashion: -​ C fibers terminate exclusively in Rexed’s laminae I and II, -​ Aδ fibers terminate in laminae I and V. A subset of the lamina V neurons receive converging inputs from nociceptive and non-nociceptive afferents. These multimodal lamina V neurons are called wide-dynamic-range neurons. Some of them receive visceral sensory input as well, making them a likely substrate for referred pain (i.e., pain that arises from damage to visceral organs but is misperceived as coming from a somatic location). The axons of the second-order neurons in laminae I and V of the dorsal horn of the spinal cord cross the midline and ascend to the brainstem and thalamus in the anterolateral (also called ventrolateral) quadrant of the contralateral half of the spinal cord. For this reason, the neural pathway that conveys pain and temperature information to higher centers is often referred to as the anterolateral system. The crossing point for information conveyed by the anterolateral system lies within the spinal cord: (1)​ first-order neurons terminate in the dorsal horn, (2)​ second-order neurons in the dorsal horn send their axons across the midline and ascend on the contralateral side of the cord (in the anterolateral column) to their targets in the thalamus and brainstem. 2.​ Parallel pain pathway One component of the anterolateral system, the spinothalamic tract, mediates the sensory–discriminative aspects of pain: -​ the location, -​ intensity, -​ quality of the noxious stimulation. These aspects of pain are thought to depend on information coming from laminae I and V-VII of the spinal cord, relayed through the ventral posterior lateral nucleus (VPL) to neurons in the primary and secondary somatosensory cortex. Although axons from the anterolateral system overlap those from the dorsal column system in the ventral posterior nuclei, these axons contact different classes of relay neurons, so that nociceptive information remains segregated up to the level of cortical circuits. The spinoreticular tract (from laminae VII and VIII) and the spinomesencephalic tract (from laminae I-V), convey information about the affective–motivational aspects of pain: -​ the unpleasant feeling, -​ the fear and anxiety, -​ the autonomic activation that accompany exposure to a noxious stimulus (the classic fight-or-flight response). Targets of these projections include -​ several subdivisions of the reticular formation, -​ the periaqueductal gray, -​ the deep layers of the superior colliculus, -​ the parabrachial nucleus in the rostral pons. The parabrachial nucleus processes and relays second pain signals to -​ the amygdala, -​ hypothalamus, -​ a distinct set of thalamic nuclei, the medial thalamic nuclei. These medial thalamic nuclei, which also receive input from anterolateral system axons, play an important role in transmitting nociceptive signals to both the anterior cingulate cortex and to the insula. Together with the amygdala and hypothalamus, which are also interconnected with the cingulate cortex and insula, these limbic forebrain structures elaborate affective-motivational aspects of pain. The broad array of areas whose activity is associated with the experience of pain—somatosensory cortex, insular cortex, amygdala, and anterior cingulate cortex—is referred as the pain matrix. The presentation of a painful stimulus results in the activation of both primary somatosensory cortex and anterior cingulate cortex. Changes in intensity of a painful stimulus are accompanied by changes in the activity of neurons in somatosensory cortex, with little change in the activity of cingulate cortex, whereas changes in unpleasantness of the painful stimulus are highly correlated with changes in the activity of neurons in cingulate cortex 7.​ Pain and temperature pathways for the face Information about noxious and thermal stimulation of the face originates from first-order neurons located in the trigeminal ganglion and from ganglia associated with cranial nerves VII, IX, and X. After entering the pons, these small myelinated and unmyelinated trigeminal fibers descend to the medulla, forming the spinal trigeminal tract and terminate in two subdivisions of the spinal trigeminal nucleus: the pars interpolaris and pars caudalis. Axons from the second-order neurons in these two trigeminal subdivisions cross the midline and terminate in a variety of targets in the brainstem and thalamus. These targets can be grouped into those that mediate the discriminative aspects of pain and those that mediate the affective–motivational aspects: -​ the discriminative aspects of facial pain are thought to be mediated by projections to the contralateral VPM nucleus (via the trigeminothalamic tract) and projections from the VPM to primary and secondary somatosensory cortex. -​ Affective–motivational aspects are mediated by connections to various targets in the reticular formation and parabrachial nucleus, as well as by the medial nuclei of the thalamus, which supply the cingulate and insular regions of cortex. 8.​ Nociception – summary of thalamic nuclei and primary somatosensory cortex The VP complex receives information from the spinothalamic pathway: -​ the VPL receives projections from the spinothalamic pathway, carrying information coming from the body (lower and upper limbs, and trunk) -​ the VPM receives projections from the trigeminothalamic pathway carrying information coming from the face. Nociceptive information also reaches the medial nuclear group of the thalamus, comprehending the central lateral nucleus and the intralaminar complex nucleus. Information reaching the medial nuclear group is related to the affective and motivational aspect of nociception: these nuclei are involved in creating the psychological/cognitive experience related to nociceptors’ activity - pain. The primary somatosensory cortex receives information coming from the lateral nuclear group, encoding for pain and temperatures; however, there are areas of the brain that seem to be more activated by nociceptive stimuli: these are the cingulate and insular cortices. 9.​ Pain modulation In order to modulate pain, it is needed the activation of descending pain-modulating pathways that project to the dorsal horn of the spinal cord (as well as to the spinal trigeminal nucleus) and regulate the transmission of information to higher centers. One of the major brainstem regions that produce this effect is located in the periaqueductal gray matter of the midbrain. Both the cingulate and the insular cortex are able to modulate nociceptive information and pain experience through descending information to the periaqueductal gray matter (PAG) in the brainstem. Animal (mouses and monkeys) studies show that the mechanical or electrical stimulation of the PAG elicits profound and selective analgesia with no interphase with other sensory modality - it is specifically related to nociception. The PAG indeed has connections with specific regions of the rostroventral medulla, in particular with the Locus Coeruleus, which is a part of the noradrenergic system and inhibits the activity of projection neurons in laminae I and V (where the spinothalamic pathway begins); it also has connection with the Nucleus Raphe Magnus, which is part of the serotonergic system - it inhibits the activity of projection neurons in laminae I, II and V.  a.​ Peripheral regulation of pain perception Pain perception can also be peripherally regulated. This discovery is due to Patrick Wall and Ronald Melzack in 1960. The projection neuron in the spinal cord receives 3 functional inputs coming from the periphery: -​ information from C fibers, which elicit the activity of the projection neuron while inhibiting the activity of the inhibitory interneuron -​ inhibitory interneuron inhibits firing of the projection neuron -​ A-beta fibers also synapse with the inhibitory neuron with the effect of stimulating the firing of this neuron, therefore indirectly reducing the firing rate of the projection neuron. This is the gate control theory. 10.​C-tactile afferents Recently it has been discovered that there is a class of C fibers that encode not solely nociceptive information (that are high-threshold) but also light, gentle touch. This class of C fibers are known as the “C tactile fibers”; they are low threshold mechanoreceptors and are mainly present in hairy skin. A hypothesis suggests that these fibers encode for gentle touch, that, like pain, has a corresponding autonomic response but with a positive valence. These fibers project to the posterior part of the insular cortex, which also encodes nociceptive information. C-tactile fibers may be involved in pain modulation which seems like a promising application in the future. 11.​Social pain The cingulate and the insular cortex aren’t only active during the encoding of nociceptive information, but also in the encoding of visual nociceptive information: they play a role in “social pain”. -​ The anterior cingulate cortex is located in the deep portion of the medial frontal lobe and is involved in processing the emotional state associated with pain. -​ The insular cortex is involved in processing information about the internal state of the body (interoception) and contributes to the autonomic component of pain processing. Both areas are active during the observation of painful stimuli in others - there is a vicarious activity of these two areas. a.​ The insular cortex in pain AD (Bud) Craig, neurophysiologist, studied the property of neurons in the insular cortex encoding for both somatosensory and nociceptive information and found that nociceptive information is also topographically organized in an posterior-to-anterior fashion (with the foot posterior, the hand more anterior and the face being the anterior-most). A recent model based on his studies suggests that the spinal and the cranial afferents to the insular cortex represent the ascending part of the sympathetic and parasympathetic nervous system. For this reason, the insula integrates the nociceptive information with autonomic and arousal responses. Social touch and social pain Interaction with other people is very important for humans. This study was conducted by Christian Keysers in 2004. It was an FMRI study in which the subject was placed in the tunnel of the functional magnetic resonance imaging machine and was touched on the leg. The dorsal part of the primary somatosensory cortex and the secondary somatosensory cortex were activated. Then a video of another person touching their own leg was shown to the subject: the activity in SI almost completely disappeared, while SII/VP were still active, and it was anatomically overlapping with the activity registered during the actual touch of the leg of the subject. Somatosensory stimulation therefore resonates between people. Red represents the areas of common activation (when observing others in pain and experiencing pain oneself) which include the anterior insula and the middle cingulate cortex. Green represents the self-related responses in the posterior insula, primary somatosensory cortex and in large parts of the medial and anterior cingulate cortex. Pain in the self and pain in others greatly overlaps in the middle cingulate cortex and in the anterior insular cortex. Present works provide strong meta-analytic evidence that bilateral anterior insula and a region at the border of the anterior medial cingulate cortex constitute a core network for pain empathy. Hypotheses suggest that these areas are involved in feeling empathy for others.