What type of neuron in the thalamus communicates sensory information to the cerebral cortex?

Abstract

The somatic sensory system is one of the phylogenetically oldest sensory systems, evolving before the specialized senses of vision and hearing. This complex system provides information on the spatial limits of the organism by communicating information about the body to the brain through distinct receptors and pathways. For the most part, information arises from the body surface, although vital sensory information is also relayed from the muscles, internal organs, and blood vessels. By providing a continuous source of information on the body conditions and interactions with the external world, these pathways allow for rapid perception of threatening as well as pleasing stimuli. Neurological diseases of diverse causes may affect this somatosensory system, and understanding the underlying anatomy is a useful tool for localizing the pathological processes within the nervous system.

Somatic sensory system: proprioception and touch

The somatic sensory system mediates a number of sensations that are transduced by receptors in the skin or muscle. One important subsystem uses skin receptors to mediate the sensation of touch, and the other subsystem uses receptors in muscles, tendons, and joints to mediate proprioception – the ability to sense the position of our own limbs and body parts in space. For both of these subsystems, somatic sensations begin from activity detected by specific receptors on afferent nerve fibers whose processes branch within skin or muscle. These afferent nerve fibers conduct the signal to cell bodies that reside within the dorsal root ganglia for the body or within the cranial nerve ganglia for the head. These afferent fibers conduct the action potentials past the cell bodies in the ganglia until they reach their synaptic terminals in the target structures within the CNS.

Within the skin and muscle, specialized sensory receptor cells called mechanoreceptors typically encapsulate the afferent fibers used for touch and proprioception. For touch, the skin contains four morphologically different mechanoreceptor cells (Zimmerman et al., 2014). Meissner corpuscles are found in the tips of the dermal papillae, close to the skin surface. Merkel cells are found in the epidermis. Ruffini corpuscles are found in the next layer of skin, the dermis, and pacinian corpuscles are found deep in the dermis or even the subcutaneous layer. For proprioception, other types of mechanoreceptors provide information about the position of limbs and other body parts in space. The three receptors and their functions are: (1) muscle spindles that are found in striated muscles and provide information about changes in muscle length; (2) Golgi tendon organs that are found in tendons and provide information about changes in muscle tension; and (3) joint receptors that give signals when joint movements come close to range limits (Proske and Gandevia, 2012).

Tactile sensory information gathered by the mechanoreceptors in the skin of the body enters the spinal cord through the dorsal roots and ascends ipsilaterally through the dorsal column to the lower medulla. In the lower medulla, axons carrying information originating from the upper body synapse onto neurons in the cuneate nucleus subdivision of the dorsal column nuclei, while axons from the lower body synapse onto neurons in the gracile nucleus. The axons exiting from the dorsal column nuclei, called the internal arcuate fibers, decussate (cross over) and form the medial lemniscus which project to the ventral posterior lateral nucleus of the thalamus, which in turn send their axons to the primary somatosensory cortex (SI) as well as to the secondary somatosensory cortex (SII) (Fig. 4.5). Cutaneous mechanoreceptor information from afferents originating in the face enters the spinal cord by a separate set of neurons that are located in the trigeminal ganglion. The central processes of trigeminal ganglion cells enter the brainstem at the pons and synapse with neurons in the trigeminal brainstem complex. From here information is sent to the ventral posterior medial nucleus of the thalamus, where it is then sent to the SI and SII regions of the cerebral cortex.

Proprioceptive sensory information travels along a very similar central pathway as tactile information. However, a few important differences exist that underlie the importance of proprioceptive information in motor reflexes. When proprioceptive afferents originating from the lower body first enter the spinal cord, they separate into two branches. One branch synapses onto neurons in the dorsal and ventral horns of the sacral region of the spinal cord to mediate reflexes such as the knee-jerk reflex (see below). The other branch synapses with neurons in Clarke's nucleus in the lumbar region of the spinal cord. These neurons send axons that travel up to the cerebellum, with collaterals branching off to synapse with neurons in the dorsal column nuclei. The cerebellum requires this proprioceptive information to properly regulate voluntary movements. The proprioceptive neurons in the dorsal column nuclei then send axons along a similar route as tactile information, with neural signals traveling to the ventral posterior lateral nucleus of the thalamus and from there to the SI and SII regions of the cerebral cortex. Proprioceptive afferents originating from the upper body enter the spinal cord at higher regions than afferents from the lower body, but follow a similar route to the dorsal column nuclei and cerebellum.

SI processes both tactile and proprioceptive sensory information. SI is located in the postcentral gyrus of the cerebral cortex and contains four distinct regions, called Brodmann's areas 3a, 3b, 1, and 2. Each of these distinct regions contains its own complete representation of the body using the same topographic organization that is shown in the homunculus. Tactile sensory information is processed mainly in areas 3b and 1, whereas proprioceptive information is processed in area 3a. Neurons in area 2 process both types of sensory information. However, many interconnections exist between the four areas of the SI. All regions of SI send projections to SII, where sensory information is further processed before being sent to limbic structures such as the amygdala and hippocampus. Area 2 in the SI also sends projections to the parietal cortex, specifically areas 5 and 7, which in turn send projections to the primary motor and premotor areas of the frontal lobe. This pathway is critical for integrating sensory and motor information for the execution of voluntary movements.

6.16.5 Overview

This account has been a survey of multiple ways in which a particular somatosensory system can be special. Most somatic sensory systems have been considered to be mechanosensory; so other bodily ubiquitous forms of energy transduction into neural signals can be considered special. The familiar triad of energy transductions that occur in free nerve endings would, in this view, constitute the basis of one general sensory modality, mechanosensory, and two special modalities, nociceptive and thermosensory (thermosensory is often divided into two submodalities, sensation of warmth and of cold).

We have seen in Section 6.16.2.1 that current work on the role of TRP channels in thermal and nociceptive transduction in free nerve endings suggests a common cellular mechanism for touch, heat, cold, and painful sensation and that the distinction between these modalities is based on distinctive ranges of sensitivities that overlap and together comprise a continuous spectrum of sensed energy alterations. This in turn points the way toward considering these various modalities as a single modality that is present in most body tissues of animals and perhaps plants and other life forms as well. The nociceptive modality is at least as ubiquitous as the mechanosensory, such that pain is allotted a volume of its own in this series of handbook volumes.

We have included the generally distributed thermosensitive systems here as specialized somatosensory systems largely because they are not treated elsewhere in the series. Within the thermal modality there is at least one truly specialized apparatus – that of the heat-sensitive pit organs found in crotaline and some boid snakes, described in Section 6.16.2.4.3

Another form of specialization is represented by the electrosensory apparatus of the monotreme mammals, discussed in Section 6.16.3.5. In this case, in a restricted taxonomic grouping, a truly specialized system has evolved, but it works in concert with the general mechanoreceptive system with which it shares the same trigeminal-to-cerebral-cortical pathway and associated brain processing regions.

The remainder of the specialized systems we described were elaborations and variations in mechanosensory capabilities. One set of these specialties are those that take advantage of peripheral structures, in many cases developed to serve other vital functions such as alimentation and locomotion, to increase the range of mechanical recognition of environmental features and events. This was done by attaching mechanoreceptive nerve endings to such structures as lips, limbs, barbels of fishes, feathers of birds, and hairs of mammals. A great deal of scientific attention has been paid to vibrissae, mammalian hairs that have become specialized for mechanoreceptive functions. We classify these spatial range-extending specialties as telemechanosensory – touching at a distance.

An alternative type of specializations we call endoreceptive. They consist of unusual concentrations of receptors within certain regions of skin, such as lips of the oral cavity.

Both telemechanoreceptive and endomechanoreceptive specialties include brain elaborations and expansions to process the increased amount of information delivered by the specialized receptive interfaces with the environment.

Many systems incorporate both telemechanoreceptive and endomechanoreceptive properties. Among these we have considered the hands of raccoons, the tails of some New World monkeys, the trunks of elephants, and the stars of star-nosed moles. Significantly, all of these enhanced sensory surfaces are also mechanically prehensile, revealing the collaborative nature of motor and sensory specialization of particular body parts.

Our selection, and that of science in general, of specialized somatosensory systems is in no way exhaustive. Those presented here are certain instances of sensory system evolution that have caught the attention of astute observers. They constitute an instructive exhibit of the evolutionary possibilities that have been realized in variations and additions to basic sensory equipment.

4.27.5 Overview

This account has been a survey of multiple ways in which a particular somatosensory system can be special. Most somatic sensory systems have been considered to be mechanosensory; so other bodily ubiquitous forms of energy transduction into neural signals can be considered special. The familiar triad of energy transductions that occur in free nerve endings would, in this view, constitute the basis of one general sensory modality, mechanosensory, and two special modalities, nociceptive and thermosensory (thermosensory is often divided into two submodalities, sensation of warmth and of cold).

We have seen in Section Receptor Structure and Function that current work on the role of TRP channels in thermal and nociceptive transduction in free nerve endings suggests a common cellular mechanism for touch, heat, cold, and painful sensation and that the distinction between these modalities is based on distinctive ranges of sensitivities that overlap and together comprise a continuous spectrum of sensed energy alterations. This in turn points the way toward considering these various modalities as a single modality that is present in most body tissues of animals and perhaps plants and other life forms as well. The nociceptive modality is at least as ubiquitous as the mechanosensory, such that pain is allotted a volume of its own (volume 5).

We have included the generally distributed thermosensitive systems here as specialized somatosensory systems largely because they are not treated elsewhere in the series. Within the thermal modality there is at least one truly specialized apparatus – that of the heat-sensitive pit organs found in crotaline and some boid snakes, described in Section Role in Behavior.

Another form of specialization is represented by the electrosensory apparatus of the monotreme mammals, discussed in Section Comparison of the Trigeminal Electrosensory System of Monotremes with the Octavolateral Electrosensory Systems of Fishes. In this case, in a restricted taxonomic grouping, a truly specialized system has evolved, but it works in concert with the general mechanoreceptive system with which it shares the same trigeminal-to-cerebral-cortical pathway and associated brain processing regions.

The remainder of the specialized systems we described were elaborations and variations in mechanosensory capabilities. One set of these specialties are those that take advantage of peripheral structures, in many cases developed to serve other vital functions such as alimentation and locomotion, to increase the range of mechanical recognition of environmental features and events. This was done by attaching mechanoreceptive nerve endings to such structures as lips, limbs, barbels of fishes, feathers of birds, and hairs of mammals. A great deal of scientific attention has been paid to vibrissae, mammalian hairs that have become specialized for mechanoreceptive functions. We classify these spatial range-extending specialties as telemechanosensory – touching at a distance.

An alternative type of specializations we call endoreceptive. They consist of unusual concentrations of receptors within certain regions of skin, such as lips of the oral cavity.

Both telemechanoreceptive and endomechanoreceptive specialties include brain elaborations and expansions to process the increased amount of information delivered by the specialized receptive interfaces with the environment.

Many systems incorporate both telemechanoreceptive and endomechanoreceptive properties. Among these we have considered the hands of raccoons, the tails of some New World monkeys, the trunks of elephants, and the stars of star-nosed moles. Significantly, all of these enhanced sensory surfaces are also mechanically prehensile, revealing the collaborative nature of motor and sensory specialization of particular body parts.

Our selection, and that of science in general, of specialized somatosensory systems is in no way exhaustive. Those presented here are certain instances of sensory system evolution that have caught the attention of astute observers. They constitute an instructive exhibit of the evolutionary possibilities that have been realized in variations and additions to basic sensory equipment.

SENSORY SYSTEMS AND THEIR ROLE AS POSTURE MODULATORS

Three sensory systems are involved in modulating the postural control mechanism: the visual system, the vestibular system and the somatic sensory system. The visual sensory system imparts information concerning the body's vertical orientation to the horizon as well as providing a mechanism for distance or depth perception. This information is mapped to the occipital portion of the cerebral cortex. Age-related changes in the visual system include alterations in visual acuity and depth perception. Visual acuity in the newborn is difficult to measure but has been reported to be 20/400 at birth. By 3 years it is between 20/30 and 20/20. Generally, there is little pupillary accommodation in newborns. Convergence is present and, under controlled conditions, infants between 8 and 10 weeks can track an object across approximately 180° (Olitsky & Nelson 2000). Both acuity and depth perception can affect postural stability, especially during movement-based activities. Depth perception involves taking a two-dimensional image and converting it into three dimensions (Wurtz & Kandel 2000). The ocular dominance columns of visual cortex segregate from each other at 4 months, and binocular depth perception emerges. Monocular depth perception relies more on experience than binocular depth perception and appears later.

Although visual acuity and depth perception are immature functions in young infants, movement and posture are visually triggered. For example, at 3 days of age, newborns will orient their eyes to a visual stimulus and track it as it moves, even though muscle synergies are too immatureto support coordinated head movement (Shumway-Cook & Woollacott 2000). By 2 months of age, early signs of postural control can be recognized. An infant lying on her back will turn her head to look at something, and an infant lying on his stomach will begin to lift his head. These are visually triggered activities. Studies confirm that infants rely heavily on visual input in early postural control (Butterworth & Cicchetti 1978); however, vestibular and somatosensory inputs also have a role in maintaining balance (Woollacott et al 1987). By 2.5 months, visual fixation contributes to significant improvements in antigravity reflexes and the infant will respond to perturbations of balance with head control movements.

Visually activated muscle synergies precede those activated by the somatic sensory system. This suggests that the visual system maps to the motor system earlier than the proprioceptive system. Observations of the influence of visual cues on early posture and balance control confirm this hypothesis; infants under 1 year will sway in response to visual stimuli (Lee & Aronson 1974). Ten-month-old infants will make postural adjustments to optic flow while sitting. By 12 months, they will make postural adjustments while standing (Shumway-Cook & Woollacott 2000). In general, visual input appears to weigh more heavily than somatosensory cues when an individual is attempting a new task. Once the task becomes more automated, somatosensory input takes over (Lee & Aronson 1974) and visually triggered reflexes lessen.

The second system involved with posture is the vestibular system. The vestibular system supplies information regarding the direction of gravity and head motion in the sagittal, coronal and horizontal planes. Its information is mapped through the brainstem and onto the insular portion of the cerebral cortex. Each vestibular apparatus is located in the petrous portion of the temporal bone and is completely formed by 9.5 weeks of gestation (Fig. 9.1). The vestibular nuclei are functional by 21 weeks. Each vestibular apparatus is composed of three semicircular canals placed 90° from each other in superior, posterior and horizontal positions. The ampulla of each canal is lined with specialized hair cells, each of which is covered with many stereocilia and a single kinocilium that extend into the lumen of the canal. The canals are filled with endolymph. Movement of the head produces a relative movement of the endolymph located within the semicircular canals. The stereocilia of the hair cells are bent as they pass through the endolymph, like seaweed by a wave (Fig. 9.2). When the stereocilia are bent towards the kino-cilium, the cell depolarizes. There is an increase in the release of neurotransmitter, and an increase in the rate of firing. When the stereocilia are bent away from the kinocilium, the cell hyperpolarizes and the release of neurotransmitteris decreased, as is the firing rate. The signal from the vestibu-lar hair cells travels to the vestibular nuclear complex, four distinct nuclei with different architecture and functions. The lateral vestibular nucleus influences the extensors of the legs and flexors of the arms, and is involved with upright stance. This is termed the vestibulospinal reflex. The medial and superior nuclei mediate the vestibulo-ocular reflex. Signals from cells in these nuclei trigger the abducens and oculomotor nuclei, and the eyes are moved at an equal velocity but in an opposite direction to the movement of the head (Fig. 9.3). Fibers originating in the superior vestibular nucleus also terminate on motor neurons of the cervical musculature and influence neck position through the vestibulocollic reflex. The vestibulo-ocular reflex is intact at birth and, along with the vestibulocollic and vestibulospinal reflexes, will influence head and neck posture in the young infant. These three reflexes affect paraspinal muscle tone and can be used in specific muscle energy techniques for treatment of upper cervical somatic dysfunction (Goodridge & Kuchera 1997). Conversely, individuals with uncorrected visual acuity problems may develop increased tone in the upper cervical musculature, presumably through the same mechanism. As we pass through middle age, degeneration of the hair cells within the vestibular labyrinth organ affects the vestibular contribution to posture and balance.

The third system, the somatic sensory system, receives information from the skin, muscles and connective tissues of the body. This information is mapped onto the parietal portion of the cerebral cortex. Muscle afferent fibers are proprioceptive in function and relate information about change in spatial position. When these fibers are triggered by rapid tendon or muscle stretch, the resulting muscle contraction provides a quickly adaptive response to sudden positional change. Joint afferent fibers provide information regarding alterations in the relationship of joint surfaces. This includes changes in the orientation of the head to the neck and spine, and changes in the orientation of the limbs (appendicular skeleton) to the trunk (axial skeleton). Joint afferent fibers carry information about spatial relationships to the central nervous system. Many of these proprio-ceptors are located in the connective tissues of the cervical spine. The proprioceptive information from the cervical spine can actually override positional information from the eyes and vestibular system. Cutaneous afferent fibers carry information concerning pressure from the skin. Of particular importance to upright posture is information from the skin on the soles of the feet. Pressure on the plantar surface elicits a reflex movement of the foot towards the stimulus, and this increases tone in the extensor muscles of the limb and pelvis. In addition, neural signals concerning shearing forces on the skin of the plantar surface supply data on body motion to the central nervous system.

Alterations in the function of the somatosensory system may impede postural stability. For example, distortions in the proprioceptive information from diseased joints such as an arthritic knee (Barrett et al 1991) or spondylitic vertebrae will affect the individual's perception of position. Proprioceptive information can be altered by changes in joint mobility and gliding, increase in cervical lordosis and compression of vertebral disk spaces (Alexander et al 1992). This phenomena is not limited to joint proprioceptors. Diseases affecting cutaneous afferent fibers, such as diabetic neuro-pathy, will interfere with information about motion coming from the soles of the feet (Simoneau et al 1994). One study done by Woollacott et al (1998) suggests that children with spastic diplegia have altered postural strategies secondary to the altered biomechanical relationships rather than the neurological pathology (see Ch. 16). Although the effects of altered biomechanical relationships on posture have not been studied extensively, clinical experience suggests a significant relationship between the two. In addition to the potential for altered proprioception, alterations in position sense require adaptations in movement strategies which are often difficult for the disabled or deconditioned patient, further compromising stability.

Posture is an expression of the integration of information from these three sensory systems: visual, vestibular and somatosensory. There appears to be a certain amount of redundancy between the systems, which allows for masking of deficits. However, when two systems are stressed, underlying dysfunctions are unmasked and balance is compromised.

Insensitivity to Chemical Irritants

The body vibrissae of the naked mole-rat act as very sensitive touch detectors. In contrast, another aspect of this species’ somatic sensory system is extremely insensitive: its response to chemical irritants. Both the skin and the upper respiratory tract of naked mole-rats are completely insensitive to specific irritants, including acid, ammonia, and capsaicin (the spicy ‘hot’ compound found in chili peppers). At least one aspect of this insensitivity appears to be quite adaptive, since naked mole-rats are exposed to acidic conditions every day in their burrows.

As mentioned earlier in this encyclopedia entry, naked mole-rats have a very unusual combination of ecological and social characteristics. They are fully subterranean, extremely social, and they live in colonies with many individuals. In other words, naked mole-rats live in large numbers in very tight quarters and in very poorly ventilated spaces where respiration depletes oxygen and increases carbon dioxide (CO2) to extremely high levels. Usually, these conditions would challenge an animal’s ability to extract oxygen from the air and to maintain an appropriate acid–base balance. Also mentioned earlier, naked mole-rats have adaptive mechanisms to help deal with these challenges, including hemoglobin with a very high affinity for O2, and blood with a high capacity to buffer CO2.

Breathing high levels of CO2 not only challenges the body’s ability to maintain an appropriate acid–base balance, it also induces pain in the eyes and nose due to the formation of acid on the surface of those tissues as they come into contact with CO2. To give some perspective, the concentration of CO2 in room air is about 0.03%, and CO2 levels in naked mole-rat tunnels is about 2%. Higher concentrations (∼5%) have been measured in their nest chambers in the laboratory, and it is likely that concentrations are much higher in their natural nest chambers in Africa.

Recent experiments have shown that naked mole-rats have sensory adaptations that make them insensitive to stimulation of the nerve fibers that normally respond to high levels of CO2, and other specific chemical irritants such as capsaicin and ammonia. The nerve fibers that respond to these irritants belong to a class of fibers called C-fibers. They are small in diameter, unmyelinated, and they release neuropeptides, notably Substance P and calcitonin gene-related peptide, onto their targets in the central nervous system. These are the nerve fibers that convey the stinging, burning sensation we experience when sniffing ammonia fumes or rubbing our eyes after handling hot chili peppers, and the neuropeptides they release are thought to be critical in signaling the unpleasant quality of irritants.

Remarkably, naked mole-rats naturally lack these neuropeptides from the C-fibers innervating their eyes and nose (and skin, described below). Behaviorally, the animals show no signs of irritation or discomfort from applying capsaicin solution to their nostrils, whereas in mice, capsaicin induces vigorous rubbing of the nose. Naked mole-rats also fail to avoid strong ammonia fumes. When placed in an arena with sponges that are saturated with ammonia or water, naked mole-rats spend as much time in close proximity to the ammonia as they do to the water. Rats and mice tested in the same procedure enthusiastically avoid the ammonia. These data, and a schematic of the testing arena, are shown in Figure 5. Interestingly, naked mole-rats do show an aversion to a different irritant, nicotine fumes, which act on a population of sensory fibers that are distinct from classical C-fibers.

The remarkable insensitivity that naked mole-rats display is not limited to their eyes and nose, but it extends to their skin as well. Naked mole-rats show no response to capsaicin solution or acidic saline (the strength of lemon juice) injected into the skin of the foot. The same irritants cause rubbing and scratching at the injection site in humans and vigorous licking in rats and mice. Responses of naked mole-rats and mice to capsaicin and acidic saline are shown in Figure 6. It is noteworthy that naked mole-rats do not have a complete loss of neuropeptides as their viscera appear to retain the full complement.

Surprisingly, physiological studies revealed that naked mole-rat C-fibers themselves respond to capsaicin. This finding suggested that the lack of neuropeptides, which would normally be released onto spinal neurons, acted to ‘disconnect’ the C-fibers from the central nervous system, preventing the brain from sensing irritation. To test this hypothesis, one of the missing neuropeptides was introduced into the spinal circuitry using two techniques. The first was gene therapy, where Substance P was introduced into the nerve fibers of the foot. This was done by applying a transgenic virus engineered to carry the DNA for Substance P. The second technique involved directly infusing Substance P into the spinal cord at the level where nerve fibers from the foot enter. In both cases, the introduction of Substance P caused naked mole-rats to respond behaviorally to capsaicin: after treatment, the animals licked at the injection site similarly to rats and mice.

Physiological studies also revealed another surprise. In contrast to their response to capsaicin, C-fibers in naked mole-rats were completely unresponsive to acidic saline. Consistent with this finding, introducing Substance P had no effect on acid insensitivity behavior – the mole-rats remain impervious to acidic saline injection.

Anatomical studies revealed yet another anomaly about the C-fibers of naked mole-rats. C-fibers in naked mole-rats have an unusual pattern of connectivity in the spinal cord. Almost half of the cells in the deep dorsal horn of the spinal cord receive direct (monosynaptic) connections from capsaicin-sensitive C-fibers, whereas in other species, almost all capsaicin-sensitive C-fibers terminate in the superficial dorsal horn. The significance of this unusual connection pattern is not clear, but it suggests that whatever signals might be conveyed from the C-fibers might not follow the usual irritant pathways once they reach the spinal cord.

Taken together, it appears that the C-fiber system of naked mole-rats has multiple mechanisms that make the system insensitive to specific irritants. Again, the working hypothesis is that these mechanisms are adaptations that have evolved for living under high CO2, and therefore acidic, conditions that would otherwise cause chronic irritation of the eyes and nose. It is unclear if there are adaptive advantages to insensitivity in the skin. The extension of insensitivity to the skin may be an epiphenomenon. The trigeminal C-fibers that innervate the eyes and nose have a similar physiology and are developmentally orthologous to C-fiber sensory afferents in the dorsal root ganglia, which innervate the rest of the body. It is only speculation at this time, but it may be that adaptive changes in trigeminal C-fibers are necessarily reiterated in dorsal root ganglia C-fibers.

Nasal Trigeminal Nerves and Solitary Chemoreceptive Cells

Inhaled chemicals may neurogenically stimulate not only the OE in the main chamber and accessory olfactory organs, but also chemoreceptors of nasal trigeminal nerves, which are part of the somatic sensory system for the eyes, nose, and mouth. Trigeminal chemoreceptors are present throughout the nasal epithelium lining the rodent and human nasal cavity. Stimulation of trigeminal nerve fibers produces sensations described as irritating, painful, burning, cooling, tingling, stinging, or pungent. Chemical stimulation of these sensory nerves may also result in protective reflexes causing increased secretions (e.g., nasal mucus), decreased respiration rate (e.g., apnea), and reduction in the nasal airways due to vascular congestion and mucosal swelling. Nasal trigeminal nerve fibers that respond to irritants release neuropeptides, such as substance P and calcitonin gene-related peptides, and are presumably polymodal nociceptors. They mediate irritant responses through TRP channels (e.g., TrpV1 and TrpA1), acid-sensing ion channels (ASICs), and other ion channels. Nasal trigeminal nerve fibers ramify repeatedly in the nasal mucosa, and their intraepithelial nerve endings extend close to the airway surface, just below the apical tight junctions connecting epithelial cells. Interestingly, some of these trigeminal nerve fibers in rodent nasal epithelium, predominantly in RE lining the proximal nasal airways, are intimately associated and synapse with solitary chemoreceptive cells (SCCs), distinct nonciliated epithelial cells with loose apical microvilli. These epithelial cells are morphologically distinct from brush cells, also found in RE, that have a stiff tuft of apical microvilli. In contrast to nasal trigeminal nerves, SCCs express elements of the taste transduction cascade, including Tas1R and Tas2 receptor molecules, α-gustducin, PLC-β2, and TrpM5. They detect inhaled irritants and other xenobiotic substances that trigger trigeminally mediated airway reflexes. SCCs in rodents are located in nasal, laryngeal, and tracheobronchial airways. In the nasal airways, they are only found in the nasal epithelium.

Nasal Nerves and Blood Vessels

Inhaled chemicals may neurogenically stimulate not only the OE in the main chamber and accessory olfactory organs, but also chemoreceptors of nasal trigeminal nerves, which are part of the somatic sensory system for the eyes, nose, and mouth. Trigeminal chemoreceptors are present throughout the nasal epithelium lining the murine and human nasal cavities. Simulation of trigeminal nerve fibers produces sensations described as irritating, painful, burning, cooling, tingling, stinging, or pungent. Chemical stimulation of these sensory nerves may also result in protective reflexes causing increased secretions (e.g., nasal mucus), decreased respiration rate (e.g., apnea), and reduction in the nasal airways due to vascular congestion and mucosal swelling. Nasal trigeminal nerve fibers that respond to irritants release neuropeptides, such as substance P and calcitonin gene-related peptides (CGRP), and are presumably polymodal nocioceptors.

Nasal trigeminal nerve fibers ramify repeatedly in the nasal mucosa, and their intraepithelial nerve endings extend close to the airway surface, just below the apical tight junctions connecting epithelial cells. Interestingly, some of these trigeminal nerve fibers in the murine nasal epithelium, predominantly in the RE lining the proximal nasal airways, are intimately associated with and synapse with solitary chemoreceptive cells (SCCs), distinct non-ciliated epithelial cells with loose apical microvilli. These epithelial cells are morphologically distinct from brush cells, also found in the RE, that have a stiff tuft of apical microvilli. SCCs express elements of the taste transduction cascade, including Tas1R and Tas2 receptor molecules, α-gustducin, PLCβ2, and TrpM5. They detect inhaled irritants and other xenobiotic substances that trigger trigeminal mediated airway reflexes. SCCs in mice are located in the nasal, laryngeal, and tracheobronchial airways, but only in the nasal epithelium due to their synapse with trigeminal nerve fibers. In contrast to the nasal SCCs that rely on taste receptors, the free trigeminal nerve endings in the nasal epithelium mediate irritant responses through transient receptor potential cation channels (TRP; e.g., TrpV1, TrpA1), and other ion channels. Therefore, free trigeminal nerve fibers and SCCs respond to different chemical agents.

The subepithelial lamina propria of the nasal mucosa has a rich and complex network of blood vessels, with each of the epithelial regions receiving blood from a separate arterial supply. A unique feature of the nasal vasculature is the large venous sinusoids (i.e., capacitance vessels, venous erectile tissue, or “swell bodies”) that are distributed throughout the mucosa. These blood vessels are well developed in specific sites of the anterior or proximal aspects of the nasal passages. Capacitance vessels have dense adrenergic innervations, and the congestion and constriction of these vascular structures are regulated by the sympathetic nerve supply to the nose. Congestion of blood in these vessels can change mucosal thickness, resulting in an altering of nasal airflow patterns and increased nasal resistance.

Thalamic Firing Patterns in Chronic Pain

Thalamic neuronal activity was recorded during procedures to implant electrodes in the thalamus for the treatment of chronic pain secondary to spinal cord injury or amputation. Activity was also recorded in patients with essential tremor and no abnormality of the somatic sensory system during intervals without tremor.

Figure 3.2 shows an example of recordings and responses to stimulation in the thalamus of a patient with neuropathic pain following a T8 spinal cord transaction.118 In the 15 mm lateral plane (Figure 3.2A, upper) the receptive fields (RFs) and projected fields were all referred to the hand, a part of the representational homunculus, which is above the level of the transaction. The next trajectory (Figure 3.2B upper) was in the 17 mm lateral plane, where the representation of the leg is usually found, relative to the hand representation.87

In this plane input from the periphery was interrupted by a traumatic spinal cord lesion. Along this trajectory many cells did not have RFs. Those that did have RFs had RFs on the chest wall. This is a larger representation of the chest wall than normal where it usually forms a sliver above the large representation of the extremities. The neurons with chest wall RFs were located at sites where microstimulation-evoked sensations located in the anesthetic lower extremities. Therefore, activity at the borderzone of the sensory loss may be referred to lower extremity, which is consistent with clinical and QST studies of SCI central pain.119

In the case of patients with spinal cord injury, the part of the thalamus representing the painful area at and below the level of the spinal cord injury (Figure 3.2B upper) was identified by electrophysiological activity (Figure 3.2B lower).118 In particular, the activity of neurons in this area was characterized by the absence of cells with RFs and the presence of thalamic microstimulation evoked sensations (Projected Fields, PFs) in the anesthetic part of the body.

In describing the spike train, we have determined the firing rate, the burst rate, and the pre-burst interspike interval, as in previous studies.103,118,120 The primary event rate was calculated by including all spikes occurring outside bursts plus the first spike in each burst. Therefore, the primary event rate is a measure of the rate of spikes occurring between bursts.91,121 The pre-burst ISI was interpreted as an inhibitory event, which can indicate the type of GABAergic conductance. We have repeatedly validated, illustrated and published these techniques and these burst criteria in our prior studies.103,118,120

In these subjects, most neurons located in the part of the region of Vc representing the anesthetic part of the body were in the I category as characterized by burst firing rates which were 10 X greater than control (see Table 3 in Reference118). Single spike firing rates between bursts were not different between control subjects and different thalamic areas representing the parts of the body below and above the spinal transection. In patients with spinal cord transaction, the pre-burst silent periods were 2.6 X greater than in control patients (movement disorders).

In patients with chronic pain following amputations, the region of Vc was divided into those representing the stump or the phantom.120 Thalamic areas representing the stump were identified by receptive fields and projected fields representing the stump. Areas representing the phantom were identified by the absence of receptive fields and the presence of projected fields on the phantom. In the representation of the stump and phantom, burst rates were 2.5 X greater than control while firing rates were not different and the pre-burst silent period was 2.3 X longer (see Table 1 in Reference120).

In patients with neuropathic pain, like that occurring in patients with spinal cord lesions or amputation, the nervous system injury seems to lead to sensitization of the STT-thalamocortical pathway.122 In such patients, electrical microstimulation in Vc and in the region inferior and posterior to Vc evokes pain sensations more commonly, and non-painful cold less commonly than in patients without neuropathic pain.95,123 Stimulation of this region evoked pain more commonly in patients with hyperalgesia in the setting of neuropathic pain than in those without hyperalgesia.69,72,76 Therefore, sensitization of this pathway may lead to the ongoing pain and hyperalgesia of central pain syndromes.

In summary, neurons with the I category firing pattern (Figure 3.1) are more likely to respond to the laser,124 to change category when the cognitive task changes.125 Furthermore, I firing pattern is associated with inhibitory events of GABAb duration leading to LTS bursts. This change in inhibitory events, possibly related to GABA receptors, could be the result of anatomical distribution of receptors, or of activity changes in pathways innervating the neuron.126–129

I category firing is also more common in the representation of the painful part of the body in the patients with neuropathic pain.118,120 In this population, pre-burst inhibitions are much longer, perhaps consistent with a GABAb conductance. Therefore, I category firing in thalamic modules may be a gate which enables both the response to the painful laser, and the transmission of that response to the cortex.105,130

Thalamic structures are likely modules to interact with the SI module of the pain network based on their involvement in densely inter-connected thalamo-cortical assemblies.114,131 Cortico-cortical synchrony and GRC may be related to thalamic modules by mechanisms including: divergent pathways, or common input from the thalamus to the cortex, or afferent volleys traversing the thalamus, or intrinsic thalamic oscillations.132–134

The neurons with I category firing pattern are more likely to respond to the laser,124 and to change category when the cognitive task changes.125 Therefore, I category firing may be a thalamic carrier signal which switches with changes in cognitive task,125 and so enables both the response to the painful laser,124 and the transmission of that response to the cortex. Furthermore, the I firing pattern is associated with inhibitory events of GABAb duration leading to LTS bursts, which might be exploited by therapies targeting thalamic GABAergic transmission or LTS channels.135–137

Connections

The prefrontal cortex is connected with many other cerebral structures. Its extrinsic connectivity has certain peculiarities that distinguish it from other neocortical regions. They are as follows:

Reciprocal connections with anterior and dorsal nuclei of the thalamus; the prominent links of the prefrontal cortex with the nucleus medialis dorsalis are conventionally used as the criterion for the definition of this cortex in all species.

Reciprocal connections with several sensory processing areas of posterior association cortex; afferent inputs from various sensory systems (somatic, visual, auditory, and olfactory) arrive in the prefrontal cortex, which therefore may be considered cortex of polymodal sensory convergence and association.

Reciprocal connections with limbic formations, especially the hypothalamus, the amygdala, and the hippocampus, which are known to be involved in certain aspects of emotion, motivation, and memory.

Efferent connections to subcortical structures involved in motor control, such as the basal ganglia; further, through the basal ganglia, the cerebellum, and the thalamus, the prefrontal cortex has indirect connective access to the neighboring motor areas of the frontal lobe.

In addition, the prefrontal cortex, as in other associative regions of the neocortex, is reciprocally connected with diencephalic and mesencephalic nuclei and reticular formations with diffuse cortical projection. As in other regions, some afferent (corticocortical) connections in the prefrontal cortex have been noted to terminate in columnar transcortical patterns of distribution.