The Somatosensory Thalamus and Associated Pathways

6.07 The Somatosensory Thalamus and Associated Pathways J H Kaas, Vanderbilt University, Nashville, TN, USA ª 2008 Elsevier Inc. All rights reserved.

6.07.1 6.07.2 6.07.3 6.07.3.1 6.07.4 6.07.5 6.07.6 6.07.7 6.07.8 6.07.9 References

Introduction Somatosensory Afferents and Afferent Pathways Somatosensory Relay Nuclei of the Medulla and Upper Spinal Cord The Dorsal Column–Trigeminal Complex The Nuclei of the Somatosensory Thalamus, Their Spinal Cord and Brainstem Somatosensory Inputs, and Their Cortical Projections The Ventroposterior Nucleus The Ventroposterior Superior Nucleus The Ventroposterior Inferior Nucleus Other Nuclei: The Anterior Pulvinar, the Lateral Posterior Nucleus, the Posterior Group, the Ventroposterior Parvocellular Nucleus, and the Ventromedial Posterior Nucleus Cortical Projections to the Somatosensory Thalamus and Dorsal Column Nuclei

118 119 120 122 125 126 131 133 135 136 136

Glossary anterior pulvinar A subdivision of the pulvinar complex of the dorsal thalamus that is somatosensory rather than visual in function. The anterior pulvinar receives inputs from areas of the somatosensory cortex and projects back to areas of the somatosensory cortex. dorsal column–trigeminal complex A group of three main subnuclei in the lower brainstem and upper spinal cord that receives cutaneous receptor afferents from the body, via the dorsal columns of the spinal cord, and from the head, via the trigeminal nerve. The complex projects to the ventroposterior nucleus (VP) of the contralateral thalamus. The subnuclei, often called nuclei, include the gracile nucleus for the lower body, the cuneate nucleus for the upper body and forelimb, and the trigeminal nucleus for the face and mouth. dorsal root ganglia The structures that contain the cell bodies of afferents that course in peripheral nerves and enter the spinal cord via the dorsal roots of peripheral nerves. dorsal thalamus A major component of the diencephalon, which also includes the epithalamus, ventral thalamus, hypothalamus, and pretectum. The dorsal thalamus, the division that is largest in mammals, receives ascending sensory pathways and projects to the neocortex.

low-threshold mechanoreceptor afferents Four types of low-threshold mechanoreceptors subserve the glabrous skin. The type I class is a slowly adapting afferent (SA-I) that is activated by receptors called Merkel disks, which respond to light pressure. The type II class (SA-II) is activated by Ruffini corpuscles that respond to skin stretch. The type I rapidly adapting afferent (RA-I) is activated by Meissner corpuscles and signals changes in skin indentation. The rapidly adapting type II (RA-II) or Pacinian afferent stems from Pacinian corpuscles that respond to vibration. thalamic nucleus A collection of neurons and glia in the thalamus that is united by a common function. A nucleus is typically identified as a group of cells that is distinguished from adjoining groups of cells by differences in the sizes and packing of neurons. Many other histological characteristics are used to distinguish nuclei. Each nucleus should also have a distinct set of connections with the neocortex and other structures, and have neurons that have a distinct set of physiological response characteristics. ventroposterior nucleus A nucleus in the thalamus that receives somatosensory afferents from the contralateral brainstem, systematically represents the cutaneous receptors of the contralateral body, and projects to the primary somatosensory cortex.

117

118 The Somatosensory Thalamus and Associated Pathways

6.07.1 Introduction This chapter describes structures in the early stages of processing in the somatosensory system. The focus is on the ascending sensory inputs to the somatosensory thalamus, the organization of the somatosensory thalamus, and the relay of somatosensory information from the thalamus to the cortex. Most of this description concentrates on what is known about the somatosensory system of anthropoid primates (monkeys, apes, and humans), as this information is most relevant to understanding how somatosensory information is processed in the human brain. Because the types of studies of somatosensory systems that can be conducted using apes and humans are limited, much of the data discussed here comes from investigations on monkeys. Thus, it is important to remember that many features of even the early stages of processing in somatosensory systems are variable across species. The somatosensory system of humans resembles those of monkeys, while being different in many ways. In addition, there are approximately 4500 species of mammals, now divided into six superorders. This impressive radiation of mammalian species has resulted in a number of distinctly different specializations of somatosensory systems (see Chapters The Evolution of Parietal Areas Involved in Hand Use in Primates and Specialized Somatosensory Systems), of which only a few have been studied in any detail. While an extensive comparative approach is not possible here, observations on the somatosensory systems of some of the more fully studied nonprimate mammals are included. The parts of the somatosensory system of primates covered in this review are depicted schematically in Figure 1. In brief, peripheral nerve afferents related to receptors in the skin, muscles, and joints of each side of the body enter the spinal cord and lower brainstem where they branch to terminate locally in the dorsal horn of the spinal cord. Other branches of these afferents ascend in the ipsilateral dorsal columns or join the trigeminal pathways to terminate in the dorsal column–trigeminal nucleus complex or proprioceptive nuclei in the upper spinal cord and lower brainstem. Neurons in these nuclei send axons across the midline to form the medial lemniscus, a pathway that terminates in the ventroposterior complex of the contralateral thalamus. In addition, a small proportion of these neurons, largely neurons representing afferents devoted to the teeth and tongue, project into the ipsilateral medial lemniscus to the

ipsilateral thalamus. Thus, parts of the oral cavity become represented in both the ipsilateral and the contralateral ventroposterior complex, as well as in the cortex. Another source of somatosensory information to the ventroposterior complex is from the spinothalamic pathway. Afferents that terminate in the dorsal horn of the spinal cord, and the equivalent part of the trigeminal nuclei of the lower brainstem, synapse on neurons that send axons across the midline to form the ventrolateral spinothalamic pathway that terminates in several subdivisions of the contralateral somatosensory thalamus. Thalamic neurons in the ventroposterior complex send axons to subdivisions of the anterior parietal cortex and other somatosensory areas such as the second somatosensory area (S2). In anthropoid primates, the anterior parietal cortex consists of the architectonic fields 3a, 3b, 1, and 2 of Brodmann K. (1909). Each of these fields receives a different pattern of projections from the somatosensory thalamus, and each contains a separate, complete representation of peripheral nerve afferents, mainly those from the contralateral half of the body. Thus, each area represents the contralateral body, from tail (if present) to tongue, in a mediolateral sequence across the cortex. The representations of ipsilateral afferents from the tongue and teeth activate the lateral extremes of these representations. Another thalamic nucleus, the anterior pulvinar of primates, receives inputs from areas of the somatosensory cortex, and contains neurons that project back to areas of the somatosensory cortex. Descriptions of the somatosensory thalamus and cortex of cats and rats, and other well-studied nonprimate mammals, differ from those of anthropoid primates in that several subdivisions of the somatosensory thalamus and cortex are not recognized, or they have different names. In the thalamus, for example, the anterior pulvinar and the ventroposterior inferior nuclei (VPI) are not generally recognized, and the question that arises is whether these nuclei have emerged only in primates, have been named differently in other mammals, or have not been identified in other mammals. Likewise, in the cortex of anthropoid primates, four parallel representations exist in the anterior parietal cortex (areas 3a, 3b, 1, and 2), but only area 3b appears to correspond to the primary somatosensory area, S1, as commonly defined in other mammals. Are the other areas (3a, 1, and 2) unrecognized, differently named, or a derivation of anthropoid primates? Thus, descriptions and discussions of especially the organization of the

The Somatosensory Thalamus and Associated Pathways

119

Anterior parietal cortex areas 3a, 3b, 1, 2

h

5b 7a

Vision

Cere bra l

em

re he

5a

us s ulc al nt r Ce

Posterior parietal cortex

isp

7b

Frontal lobe Lateral parietal cortex (in lateral sulcus) areas S2, PV

Ventroposterior complex of the thalamus Dorsal column nuclei Dorsal root neuron rent axon Affe

Encapsulated receptor complex

Dorsal root ganglion Peripheral nerve Spinal cord

Figure 1 The basic components of the somatosensory system shown on a posterolateral view of a primate brain. Afferents subserving receptors in the skin, muscles, and joints travel in peripheral nerves to enter the spinal cord or brainstem to send axon branches into the dorsal column nuclei or divisions of the trigeminal complex. Neurons in these nuclei send axons to the ventroposterior nucleus (VP) and the ventroposterior superior nucleus (VPS) of the ventroposterior complex of the contralateral thalamus. Neurons in VP and VPS project to areas 3a, 3b, 1, and 2 of the anterior parietal cortex. Information from the anterior parietal cortex is distributed further to areas of the lateral parietal cortex, including the second somatosensory area (S2), the parietal ventral area (PV), the parietal rostral area (PR), and the ventral somatosensory area (VS). Other projections from the anterior and lateral parietal cortex spread somatosensory information to subdivisions of the posterior parietal cortex, shown here as divided into the classical areas of Brodmann K. (1909) numbered 5a, 5b, 7a, and 7b for general locations (this cortex is now known to be more complexly organized). Other afferents (see Figure 2) terminate in the dorsal horn of the spinal cord where neurons contribute to the contralateral spinothalamic tract, which terminates in the ventroposterior inferior nucleus (VPI) where neurons project to areas of the anterior and lateral parietal cortex. From Kaas, J. H. 2004. Somatosensory System. In: The Human Nervous System, 2nd edn. (eds. G. Paxinos and J. K. Mai), pp. 1059–1092. Elsevier Academic Press.

thalamus and cortex that go beyond our focus on primates and include other well-studied mammals are complicated by species differences in the appearances and names of brain structures.

6.07.2 Somatosensory Afferents and Afferent Pathways Because several other chapters in this volume (see Chapters Cutaneous Mechanisms of Tactile Perception: Morphological and Chemical Organization of the Innervation to the Skin, Merkel Cells, Physiological Responses of Sensory Afferents in Glabrous and Hairy Skin of Humans and Monkeys, and Physiological Characteristics of Second-Order Somatosensory Circuits in Spinal Cord and Brainstem) review the functional

organization of the peripheral somatosensory system, only a brief overview is necessary here (also see Kaas, J. H., 2004). Our main focus is on the lowthreshold mechanoreceptors of the glabrous and hairy skin, as these provide the input that is critical for making fine tactile discriminations and tactile recognition. However, afferents from joint and muscle receptors for proprioception are equally important, as object recognition and localization by touch depend on knowing the articulation of the digits relative to each other, and the relationship between activity from cutaneous and proprioceptors. Low-threshold afferents from the glabrous skin include the slowly adapting type I (SA-I) subserved by Merkel cells, rapidly adapting type I (RA-1) from Meissner corpuscles, slowly adapting type II (SA-II) with Ruffini-like receptors, and rapidly adapting type II, emanating from Pacinian corpuscles. Hairy skin

120 The Somatosensory Thalamus and Associated Pathways

afferents are similar, except that RA-I and SA-I receptors are also found in hair follicles around shafts of hairs where hair movement disturbs the base. Merkel cell receptors for SA-I afferents may be aggregated in touch domes or spots, and RA-II Pacinian receptors are found in deeper tissues rather than the skin. Other cutaneous afferents include the wide dynamic range (WDR) and other more slowly conducting afferents that respond to touch and more intense stimuli, and contribute to the spinothalamic pathway. In deeper tissues, the muscle spindle receptor afferents are very important for proprioception, perhaps aided by afferents from Ruffini and Golgi types of receptors in and around joints. Afferents from peripheral receptors combine to form small nerve fascicles that join other fascicles and motor efferent axons to form peripheral nerves that then segregate afferents from efferents as they approach the spinal cord to form the dorsal sensory and ventral motor roots, as sensory afferents enter the spinal cord (and brainstem) and motor neuron axons leave. Afferents entering the spinal cord terminate locally on neurons in the ipsilateral dorsal horn of the spinal cord to form an elongated representation of the ipsilateral half of the body (e.g., Florence, S. L. et al., 1988; 1989). Terminations of the axon arbors of different classes of afferents distribute differently over the layers of the dorsal horn, maintaining a segregation of types of information. The low-threshold mechanoreceptors and muscle spindle receptor afferents also branch to send a collateral toward the brainstem to terminate either in the dorsal horn at higher levels or in the dorsal column–trigeminal complex of the lower brainstem (Figure 2). These collaterals contribute to the dorsal (posterior) column and dorsolateral column afferent pathways. WDR, nociceptive, and temperature-sensitive afferents terminate locally in the dorsal horn of the spinal cord on neurons that send axons across the midline of the spinal cord to ascend in the ventrolateral white matter to form the spinothalamic pathway, known as a relay of information about pain, temperature, and crude touch (Willis, W. D. and Coggeshall, R. E., 2004). Primary afferents from oral and facial structures course in the trigeminal (fifth cranial) nerve to branch and terminate in the principal trigeminal nucleus (combining with the dorsal column nuclei to form a complete representation of the tactile receptors of the ipsilateral body surface), the mesencephalic trigeminal nucleus for muscle spindle afferents, and the spinal trigeminal nucleus for WDR and other afferents.

Second-order neurons in the spinal trigeminal nucleus send axons to the opposite ascending spinothalamic pathway. Thus, afferents entering the brainstem sort themselves to terminate with similar types in nuclei with second-order neurons that project contralaterally to form the medial lemniscus or spinothalamic pathways to the somatosensory thalamus. In addition to neurons in the dorsal horn of the spinal cord that contribute to the spinothalamic tract, a long column of neurons outside the dorsal horn that extends from about the fourth cervical segment to the caudal medulla is known as the lateral cervical nucleus (Kaas, J. H., 2004). In humans, the lateral cervical nucleus is usually only a rudimentary structure, but it may contain up to 8000 neurons in cats where it is well developed. The lateral cervical nucleus receives a wide range of somatosensory inputs, and projects via the spinocervicothalamic pathway to the contralateral somatosensory thalamus to terminate in the septal regions of VP (Broman, J. and Zhang, M., 1996) in conjunction with spinothalamic tract terminations.

6.07.3 Somatosensory Relay Nuclei of the Medulla and Upper Spinal Cord A collection of nuclei in the lower brainstem and upper spinal cord receive inputs from ipsilateral low-threshold mechanoreceptors and project to the contralateral ventroposterior complex of the thalamus (Figure 2). By tradition, several nuclei have been distinguished and named in this complex, but such subdivisions are best considered subnuclei, that is, parts of a functional system differing mainly in what parts of the body they represent, rather than nuclei that are devoted to distinct functions. Thus, the gracile, cuneate, and principal trigeminal nuclei all receive inputs from the low-threshold mechanoreceptors of the skin, and represent the hindlimb, the trunk and forelimb, and face plus oral cavity in a mediolateral sequence of subnuclei in the lower brainstem and upper spinal cord (e.g., Johnson, J. I. et al., 1968; Xu, J. and Wall, J. T., 1996). Some investigators even distinguish a more medial cell group as Bischoff’s nucleus (e.g., Johnson, J. I. et al., 1968), a midline cell group that receives afferent inputs from the tail (Qi, H.-X. and Kaas, J. H., 2006). These subnuclei combine to form a functional unit, the dorsal column–trigeminal complex. However, there are other nuclei or subnuclei associated with the complex, as inputs from muscle spindle and joint

The Somatosensory Thalamus and Associated Pathways

Anterior parietal CS

Postparietal 5+7

2

1

121

Cortex 3b

c

4

PV

VPS VPM Face

To cerebellum

VS r

S2

3a

VPL VP Hand

PR

Lateral parietal cortex

Foot

Thalamus VPI

External cuneate N. Muscle spindle receptor inputs

Gracile N. Cuneate N. Trigeminal N.

RA + SA inputs

Medulla Spinothalamic tract

Dorsal root ganglion Receptors

Spinal cord

Left

Right

Figure 2 A more detailed schematic of components of the somatosensory system of anthropoid primates. Afferents from low-threshold, rapidly adapting (RA), and slowly adapting (SA) mechanoreceptors in the skin enter the spinal cord and brainstem to send branches that terminate in the gracile and cuneate nuclei (N) of the principal nucleus of the trigeminal nuclear complex, to synapse on neurons that project via the medial lemniscus nucleus (VP), where the ventroposterior lateral division (VPL) represents the foot, trunk, and hand, and the ventroposterior medial division (VPM) represents the face and oral structures. Afferents from muscle spindle receptors enter the spinal cord or brainstem to send branches to the external cuneate nucleus and other nuclei that project via the medial lemniscus to the contralateral ventroposterior superior nucleus (VPS). Other afferents terminate in the dorsal horn of the spinal cord or its equivalent in the trigeminal nuclear complex where neurons project via the contralateral spinothalamic tract to the ventroposterior inferior (VPI) nucleus. Arrows indicate projections of the three thalamic nuclei to the Brodmann K. (1909) areas of the anterior parietal cortex (3a, 3b, 1, and 2), and the lateral parietal cortex (ventral somatosensory area, VS, with caudal and rostral divisions, c and r, second somatosensory area (S2), parietal ventral area (PV), and parietal rostral area (PR)). Arrows also denote cortical connections that further distribute somatosensory information from the anterior parietal cortex, including a projection from area 3a to area 4 of the motor cortex. The bend in the cortical sheet corresponds to the central sulcus (CS). From Kaas, J. H. 2004. Somatosensory System. In: The Human Nervous System, 2nd edn. (eds. G. Paxinos and J.K. Mai), 1059–1092. Elsevier Academic Press.

receptor afferents terminate separately in several cell groups that relay to a separate nucleus of the contralateral ventroposterior thalamus, the ventroposterior superior nucleus (VPS) (Figure 2). Thus, two small medullary nuclei, termed X and Z by Pompeiano O. and Brodal A. (1957), receive inputs from muscle spindle afferents of the lower limb, the

external cuneate nucleus is activated by muscle spindle afferents from the trunk and upper limb, while the mesencephalic trigeminal nucleus receives muscle spindle afferents from the face. These cell groups form a second functional unit in the lower brainstem that relays proprioceptive information to the contralateral thalamus.

122 The Somatosensory Thalamus and Associated Pathways

6.07.3.1 The Dorsal Column–Trigeminal Complex The sensory inputs to the subnuclei of the medullary complex that represent the forelimb, trunk, and hindlimb travel in the dorsal (posterior) columns of the spinal cord, while the inputs from the face and oral cavity course both dorsally and caudally after entering the midpontine brainstem to innervate the principal nucleus and other subnuclei of the trigeminal complex. The two major divisions of the dorsal column pathway are the gracile tract that carries information from the lower limb, lower trunk, and tail (if present) and the cuneate tract subserving the upper limb, upper trunk, and neck. The axons in the dorsal columns include the ascending branches of large, myelinated dorsal root fibers that enter the spinal cord at various levels while subserving adjoining skin regions. As the branches enter the dorsal columns from lower to higher spinal cord levels, the branches at higher levels add to the pathways laterally, resulting in a rough somatotopic pattern from medial to lateral across the dorsal columns (Whitsel, B. L. et al., 1972). A further refinement of this pattern occurs as the terminations of these axons sort themselves somatotopically in the dorsal column nuclei. Other axons in the dorsal columns originate from spinal cord neurons in the dorsal horn that either course in the dorsal column for several spinal cord segments to exit or continue to terminate in dorsal column nuclei or associated nuclei. Thus, the dorsal column pathway contains both branches of peripheral nerve axons, and axons that originate in second- or higher-order neurons of the dorsal horn of the spinal cord. The gracile and cuneate tracts contain mixtures of functional classes of axons (Whitsel, B. L. et al., 1972). At lower spinal cord levels, the gracile tract contains a mixture of cutaneous afferents and muscle spindle afferents. The muscle spindle afferents leave at higher levels to innervate proprioceptive nuclei for the lower limb. The remaining afferents appear to be largely of the rapidly adapting RA-I type, but the smaller numbers of RA-II (Pacinian) and SA-I afferents likely course in this pathway as well to terminate in the gracile nucleus. The fate of the SA-II afferents, sensitive to skin stretch and thereby joint movement, is uncertain, but they may enter and then leave the tract to join with muscle spindle afferents to contribute to proprioception (McCloskey, P. I., 1978). The cuneate tract also contains a mixture of axonal branches of cutaneous and muscle spindle afferents,

with the muscle spindle afferents separating to terminate in the external (proprioceptive) cuneate nucleus. Complete lesions of the dorsal column in humans produce major defects in their ability to detect the speed and direction of moving contacts on the skin, but simple contacts can be felt and roughly localized (Nathan, P. W. et al., 1986; see Mountcastle, V. B., 2005, for review). The ability to judge the position and movement of the limbs is also greatly impaired, as there can be a major loss of the afferents carrying proprioceptive information. Thus, monkeys and humans with such lesions tend to not use the affected limb, and are impaired in the positioning and control of finger and hand movements (Glendenning, D. S. et al., 1992; Cooper, B. Y. et al., 1993). The subnuclei of the dorsal column–trigeminal complex are organized somewhat differently from each other. However, all are elongated in the rostrocaudal dimension (Figure 2), and are largely composed of discrete clusters of cells separated from each other by a matrix of axons and glia. The cell clusters or nests have long been recognized (e.g., Cajal, S. R. Y., 1911). These clusters express higher levels of the inhibitory neurotransmitter, GABA, the calcium-binding proteins calbindin and parvalbumin, the activity-dependent enzyme nitric oxide synthase, and brain-derived neurotropic factor (Strata, F. et al., 2003) than the surrounding neuropil. In addition, the cell clusters express higher levels of the metabolic enzyme, cytochrome oxidase (CO), which is commonly used as a histological marker for these nuclei (Figure 3). Thus, the cell clusters are centers of metabolic activity in the nuclei where neurotransmitters are released and high levels of synaptic activity occur. While the majorities of neurons in the clusters are excitatory and project to the contralateral thalamus, roughly 30% of the neurons are inhibitory, and have local connections within the nuclei where they constrain the sizes of receptive fields (Schwark, H. D. et al., 1999; Wang, X. and Wall, J. T., 2006). Areas of the somatosensory cortex also project to the cell clusters, and these inputs appear to modulate the response properties of the relay neurons (Willis, W. D. and Coggeshall, R. E., 2004; Wang, X. and Wall, J. T., 2005). The segregation of neurons into small clusters that are activated by a similar input may be a reflection of developmental mechanisms that isolate particular groups of neurons so that other axons are less likely to inadvertently grow into an inappropriate cluster (Massey, J. M. et al., 2006). The cell

The Somatosensory Thalamus and Associated Pathways

(a) PTH

D1 D2 D3 D4

Galago D5 PH

T1 T5 T4

(b)

123

Owl monkey

T5

T3 T2

T4

T3 T2

Hand Hand

T1

05-32

04-54 (c)

Squirrel monkey

Macaque

(d)

D2 D3 D4 D5 D1

T5 T4

T5 T4 T3

T3 T2 T1

T2 T1 Hand Hand

D5 D4 D3 D2

D M

02-42

D1

03-31

Figure 3 The gracile and cuneate nuclei of (a) a prosimian primate, galago; (b) a New World owl monkey; (c) a New World squirrel monkey; and (d) an Old World macaque monkey. The transverse brainstem sections through the rostral third of the nuclei have been processed for cytochrome oxidase (CO) to reveal CO-dense ovals or islands of tissue that are densely packed with neurons and surrounded by CO-light septa that have few neurons. The CO-dense modules for each primate receive slowly adapting (SA) or rapidly adapting (RA) afferents from different body parts so that collectively they represent the trunk, limbs, and tail, with afferents from the face and oral structures terminating in the principal nucleus of the trigeminal complex (not shown). In each section, dorsal (D) is up and medial (M) is to the right. Note that the toes of the foot (TI–T5) are represented in a mediolateral sequence in the more medial gracile nucleus, while the digits of the hand (D1–D5) are represented in a lateromedial sequence in the more lateral cuneate nucleus. CO-dense cell clusters activated from the thenar pad (Pth) and hyperthenarpad (PH) of the hand are also shown for the galago. The detailed organization of the cuneate nucleus in owl monkeys has not yet been determined. Dorsal (D) and medial (M) are indicated by arrows. Scale bar ¼ 0.5 mm. From Qi, H.-X. and Kaas, J. H. 2006. The organization of primary afferent projections to the gracile nucleus of the dorsal column system of primates. J. Comp. Neurol. 499, 183–217.

clusters are most prominent in the central parts of the nuclei. While these isolated groups of neurons are activated by afferents from the same body part, they may also be receiving a different class of inputs from that body part. In the cuneate nucleus of cats, at least, microelectrode recordings have revealed a mosaic of restricted locations where cell neurons are activated by rapidly adapting type I inputs, Pacinian type II inputs, or slowly adapting inputs, probably type I (Dykes, R. W. et al., 1982). This type of evidence is consistent with the premise that three or four of the major types of cutaneous mechanoreceptor afferents terminate in the nuclei of the dorsal column–trigeminal complex, and that separate groups of cells are

activated by each class of input. Nevertheless, the inputs are organized overall into a somatotopic pattern. The patches of dense expression of CO that correspond to cell clusters are shown for four species of primates in Figure 3. The figure also indicates the clusters that are innervated by afferents from different parts of the hand in the cuneate nucleus, and the foot in the gracile nucleus. These patterns of representation were determined by injecting tracers into restricted portions of the skin, which were then transported by afferents from the skin to terminations in cell clusters (Florence, S. L. et al., 1988; 1989; 1991; Strata, F. et al., 2003; Qi, H.-X. and Kaas, J. H., 2006).

124 The Somatosensory Thalamus and Associated Pathways

Note that the digits are represented in order from lateral to medial by a series of CO-dense patches in the cuneate nucleus (not shown for the owl monkey, as the relevant experiments have not been done in this primate). Curiously, the glabrous hand is represented ventral to that of the digits in New World monkeys and dorsal to the hand in Old World monkeys (and probably in humans), while parts of the hand are represented both dorsal and ventral to that of the digits in prosimian galagos. In other mammals, the dorsal representation of the digits is often represented with a part of the dorsal and ventral hand (see Florence, S. L. et al., 1991). Because the pattern of organization of the cuneate nucleus in prosimian galagos (Figure 3(a)) resembles patterns seen in other mammals, rather than the patterns seen in monkeys, it is likely that the organization of the cuneate in galagos reflects a primitive pattern of organization for this nucleus. Differences across primate taxa may relate to the increased use of the digits as a sensory surface in macaques, and to a lesser extent squirrel and owl monkeys, over prosimian galagos. As the dorsal column nuclei are elongated rostrocaudally, a fuller appreciation of the somatotopic organization of these nuclei can be obtained by examining a series of transverse sections. In Figure 4, the gracile nucleus of a prosimian galago is color coded across a series of spinal cord and brainstem sections to show the overall somatotopic organization, and to show that the same body part is represented over most or all of the nucleus. Thus, the representations of the tail, foot, lower leg, and upper leg form a mediolateral sequence, while the representation of each of these skin surfaces is disjunctively focused within separated cell clusters along the rostrocaudal length of the nucleus. Results from other primates are similar, with a certain amount of species-specific variation. The reasons for separate clusters of neurons being activated by inputs from the same body part are not clear, but separate clusters could relate to different classes of afferent inputs, as noted above. The representation of skin receptors in the gracile nucleus seems to be more discontinuous and complex than in the cuneate nucleus. The trigeminal component of the dorsal column– trigeminal nuclear group is more complex than the gracile and cuneate nuclei, as the trigeminal complex has been traditionally divided into five sensory nuclei: the principal sensory nucleus (Pr5), three spinal nuclei (oralis (Sp5o), interpolaris (SP5i), caudalis (Sp5c)), and

AP Xd XII Cu

Gr Gr

Cu

Gr

Cu

ECu ECu Tri Tri

R

Cu

Gr

D

Tri Gr

M

Cu

Tail

Cu Foot Lower leg Upper leg

Tri

Gr

Tri

Cu

Gr Cu

Tri Tri

pyr

Figure 4 The somatotopic organization of the gracile nucleus in monkeys shown on a rostral (R) to caudal (C) series of brain sections through the dorsal column nuclei. Note that the tail, foot, lower leg, and upper leg are represented in a mediolateral sequence. A more lateral representation of the trunk joins the gracile with the cuneate nucleus for the forelimb. On the individual brain sections, the gracile nucleus (Gr), the cuneate nucleus (Cu), the trigeminal nuclear complex (Tri), and the external cuneate nucleus (ECu) are outlined. The locations of the pyramidal tracts (Pyr), motor nucleus of the twelfth cranial nerve (XII), and dorsal nucleus of the tenth nerve (Xd) and area postrema (AP) are shown for reference. From Qi, H.-X. and Kaas, J. H. 2006. The organization of primary afferent projections to the gracile nucleus of the dorsal column system of primates. J. Comp. Neurol. 499, 183–217.

the mesencephalic nucleus (Me5) for proprioception. Together they form a long column of cells that extends from the rostral pons to the upper segments of the cervical spinal cord (Waite, P. M. E. and Ashwell, K. W. S., 2004). The principal nucleus receives low-threshold mechanoreceptor afferents from the ipsilateral face and mouth, and it is the trigeminal component of the dorsal column–trigeminal complex. Neurons in the principal nucleus project across the midline to join the contralateral medial lemniscus and ascend to terminate in the ventroposterior medial subnucleus of VP. The principal nucleus is somatotopically organized (Kerr, F. W. L. et al., 1968; Florence, S. L. and Lakshman, S., 1995; May, P. J. and Porter, J. D., 1998) and has the CO-dense patches of cells that also characterize the dorsal column nuclei (Noriega, A. L. and Wall, J. T., 1991).

The Somatosensory Thalamus and Associated Pathways

The three spinal trigeminal nuclei all appear to contain separate representations of inputs from the face and oral cavity. CO patches found in the principal nucleus are not evident in the spinal nuclei in primates, but patches representing vibrissae of the face can be found in nucleus interpolaris and nucleus caudalis of rodents and cats (see Noriega, A. L. and Wall, J. T., 1991, for review). These nuclei are analogous to cells located in the dorsal horn of the spinal cord and cells in the proprioceptive nuclei for the lower body. As such, they contribute to the relay of muscle spindle afferent information to the contralateral thalamus, as well as a relay of mechanoreceptor, WDR, and nociceptive afferent information via the trigeminal contribution to the spinothalamic tract. In addition to the contralateral projections from neurons in the trigeminal complex, both the principal and the spinal nuclei of the complex project ipsilaterally to the ventroposterior thalamus (Ganchrow, D., 1978; Jones, E. G. et al., 1986). This ipsilateral component of a bilateral projection seems to be species variable, being large in sheep and small or absent in rats (Bombardieri, R. A. et al., 1975). Across species, the ipsilateral relay is largely of inputs from the mouth, but ipsilateral inputs from the side of the head and lips are also observed in sheep (Cobral, R. J. and Johnson, J. I., 1971). In monkeys, the ipsilateral projections from the principal nucleus relay information from periodontal receptors that are responsive to light touch on the teeth and from cutaneous receptors on the tongue and inner cheek (Bombardieri, R. A. et al., 1975; Jones, E. G. et al., 1986). Other types of information are relayed from the spinal nuclei. The mesencephalic trigeminal nucleus is another component of the trigeminal complex. The neurons of this nucleus are unique in that they are the cell bodies of peripheral nerve afferents. Instead of being located in the dorsal root ganglia for peripheral nerves, as for the cell bodies of other peripheral nerve afferents, these cell bodies are located within the central nervous system, mainly in the pons of the upper brainstem (Waite, P. M. E. and Ashwell, K. W. S., 2004). The cell bodies are of several types, mainly the pseudounipolar type that is characteristic of dorsal root ganglion cells, but also bipolar and multipolar neurons (Luo, P. et al., 1991). The afferents of these cell bodies conduct proprioceptive impulses from muscle spindle receptors in the jaw muscles and from periodontal mechanoreceptors (see Luo, P. et al., 1991, for review). The central projections of the cell bodies of the mesencephalic trigeminal nucleus terminate in the principal trigeminal nucleus

125

(Luo, P. et al., 1991; 1995), which in turn, relays proprioceptive information to the contralateral (and possibly ipsilateral) ventroposterior complex (e.g., Williams, M. N. et al., 1994). Thus, most or all of the second-order neurons in the principal trigeminal nucleus that are responsive to proprioceptive inputs are activated by first-order afferent neurons with cell bodies in the mesencephalic trigeminal nucleus. The trigeminal complex also includes a motor nucleus (Mo5) with cells projecting to muscles of the face and tongue. Some of the inputs to Mo5 are from Me5. The supratrigeminal nucleus and the intertrigeminal nucleus are additional motor nuclei associated with the trigeminal complex (Waite, P. M. E. and Ashwell, K. W. S., 2004).

6.07.4 The Nuclei of the Somatosensory Thalamus, Their Spinal Cord and Brainstem Somatosensory Inputs, and Their Cortical Projections The somatosensory thalamus of primates includes three major nuclei (Figure 2): VP, VPS, and VPI. VP is the main relay of tactile information to the somatosensory cortex, and is a nucleus that has been identified in all studied mammals. VPS relays information from deep receptors in muscles and joints to the cortex. This nucleus has not been recognized as such in mammals other than primates, but a homologue likely exists in all or most mammals. VPI has spinothalamic inputs and projects broadly to somatosensory cortical areas. As for VPS, VPI is not generally recognized in nonprimate mammals, but has been recognized in squirrels, raccoons, and cats (Herron, P., 1983; Herron, P. and Dykes, R. W., 1986; Krubitzer, L. A. and Kaas, J. H., 1987). In addition to these three nuclei, the anterior pulvinar of primates is associated with somatosensory processing as it has reciprocal connections with the somatosensory cortex. Another subdivision of the pulvinar complex, the medial pulvinar, has connections with posterior parietal cortical fields involved in generating visually directed reaching and grasping and multisensory integration, which suggests that this nucleus is involved in higher-order functions. The lateral posterior nucleus, a less well-defined structure, also has connections with subdivisions of the posterior parietal cortex. However, in cats and a number of other mammals, components of the visual pulvinar have been included in the lateral posterior nucleus or

126 The Somatosensory Thalamus and Associated Pathways

complex. In most mammals, one or more nuclei have been defined as belonging to the posterior complex (Po), which has somatosensory and multisensory functions. Finally, the ventromedial posterior nucleus, VMpo, has been proposed as a nucleus involved in the sensation of pain and temperature (Craig, A. D. et al., 1994), and the parvocellular ventroposterior medial nucleus (VPMpc) is involved in relaying information about both touch and taste to the cortex (Kaas, J. H. et al., 2006). The focus here is on the three main nuclei of the VP complex: VP, VPS, and VPI.

6.07.5 The Ventroposterior Nucleus VP is a basic subdivision of the mammalian thalamus (Welker, W. I., 1973; Jones, E. G., 2007) that is easily identified by its densely packed, darkly stained neurons (Figure 5(b)) and its ventral location just posterior to the motor thalamus in coronal brain sections stained for cell bodies (Nissl stain). Neurons in VP express high levels of the metabolic enzyme CO (Figure 5(a)), and the calcium-binding protein parvalbumin (Rausell, E. et al., 1992). In contrast, VP expresses very little of the calcium-binding protein calbindin (Figure 5(c)). These are some of the histochemical features that distinguish VP from the adjacent thalamic nuclei in primates: VPS and VPI. Neurons in VPS and VPI are less densely packed and less darkly stained for Nissl substance, and express less CO and more calbindin. The histological features that distinguish VP are also present in other primary sensory nuclei of the thalamus (the lateral geniculate nucleus and the ventral nucleus of the medial geniculate complex). The distinction between the VP and the VPS is less pronounced in macaque monkeys (see Figure 7) (e.g., Paxinos, G. et al., 2000) and humans (e.g., Morel, A. et al., 1997), where VPS more closely resembles VP in cytoarchitecture than in prosimian galagos (Figure 5) and New World monkeys (Figure 6; Krubitzer, L. A. and Kaas, J. H., 1992). Thus, most early studies of the connections and physiology of VP in macaques did not distinguish between VP and VPS and combined results from both nuclei. The clear architectonic distinctions between VP and VPS in prosimian primates and New World monkeys reflect major differences in the functional properties of neurons in the two structures, and in their patterns of cortical connections. These anatomical and functional differences are also

found in macaque monkeys. Thus, there are reasons for distinguishing VP from VPS in all primates. Another characteristic of VP is that the nucleus is divided into separate masses of cells by narrow cellpoor bands or septa (Figures 5–7). The most conspicuous of these across species is the band that separates the more medial part of VP representing the face from the more lateral part representing the body. These two divisions of VP, the ventroposterior medial division (VPM) and the ventroposterior lateral division (VPL), are typically distinguished as two nuclei separated by a prominent septum called the arcuate lamina, but they are more accurately considered major divisions of VP. Other septa are species variable, but common. In primates, a more lateral septum is present that separates the representations of the forelimb from the hindlimb, and often a narrow, less apparent septum separates a narrow band of cells on the lateral margin of VP, representing the tail from more medial cells representing the hindlimb. In favorable preparations, even septa separating representations of the digits of the hand are apparent in the subnucleus devoted to the hand. In the medial division of VP (VPM), other septa are apparent as they separate groups of cells devoted to different parts of the face and mouth. These septa are also apparent in brain sections processed for CO, myelin, or parvalbumin. Septa are especially numerous in VPM of macaque monkeys (Rausell, E. and Jones, E. G., 1991), although the assignment of specific cell clusters to parts of the face and mouth representations has not been fully determined. Septa separating cell groups that represent distinct body parts, or even individual facial whiskers of some rodents, commonly occur at different levels of the somatosensory system, including the dorsal column–trigeminal complex, the VP of the thalamus, and the primary somatosensory cortex (Welker, W. I., 1973; Killackey, H. and Rhoades, R. W., 1995). These segregating septa may emerge in development as a consequence of perturbations in the balance of target-selection factors by axons based on neural activity patterns and position-dependent attractions (Kaas, J. H. and Catania, K. C., 2002). The septa correspond to discontinuities or disruptions in the distribution of receptors in the skin, and these segregating septa are determined by the body form, including the separation of fingers and the isolation of receptors at the base of each protruding sensory hair from those for other hairs. The sizes of the segregated cell clusters in the thalamus and elsewhere vary according to the number and sizes of the afferents they subserve.

The Somatosensory Thalamus and Associated Pathways

In addition, the cell clusters often have places where they merge with other clusters, as groups of peripheral receptors are usually not completely isolated from each other. Receptor populations for the fingers, for example, are isolated from each other except where the fingers join the palm at their base. These isolated cell clusters in the somatosensory brainstem, thalamus, and cortex are not equivalent to the classical cortical columns (Mountcastle, V. B., 1997), which correspond to alternating patches of cortical neurons that are activated by one class of peripheral afferent or another (e.g., Sur, M. et al., 1984). Although there are clear disruptions in the continuity of the somatotopy in VP, the overall pattern is consistent across mammals (Welker, W. I., 1973). From medial to lateral, the representation transitions from mouth to face, forelimb, hindlimb, and tail. When they have been demonstrated, the representations of the ipsilateral tongue and teeth are most medial (Bombardieri, R. A. et al., 1975; Jones, E. G. et al., 1986). The distal limbs are represented ventrally, or ventrorostrally, and the proximal limbs and trunk are represented dorsally. This somatotopy is portrayed in more detail for VP of the squirrel monkey in Figure 8. Note that the digits of the hand and the toes of the foot (1–5) are represented in order from medial to lateral in the subnuclei devoted to the hand and foot. Moreover, the digit and toe tips are represented ventrally, while the bases are represented dorsally. In detail, the representations are complicated by separating septa and by folds in the continuous parts of the representation (Kaas, J. H. et al., 1984). In addition, there is likely to be a segregation of clusters of neurons activated by the SA-I class of peripheral afferents from those activated by the RA-I class (Dykes, R. W. et al., 1981; Zhang, H. Q. et al., 2001). Thus, VP likely contains at least two interdigitated maps of the cutaneous receptors of the contralateral body: one for RA receptors and one for SA receptors (see Sur, M. et al., 1984 for cortex). As in other parts of the somatosensory system, the representations of body parts in VP are proportional to receptor density, so that, for example, the distal phalanges of the digits with high concentrations of afferents have proportionally larger representations than those of the proximal phalanges with fewer afferents. Lee C. C. and Woolsey C. N. (1975) have called this a peripheral scaling factor. In rare instances, the representation of important sensory surfaces can be greater than that predicted by the proportional representation of peripheral afferents.

127

Such an overrepresentation has been called afferent magnification (Catania, K. C. and Kaas, J. H., 1997). The major activating inputs to VP are from the SA-I and RA-I afferents relayed from the dorsal column–trigeminal complex via the medial lemniscus (Figure 2; Smith, R. L., 1975; Berkley, K., 1980; Kalil, K., 1981; Asanuma, H. et al., 1983). Neurons responding to Pacinian (RA-II) inputs have been detected along the ventral margin of the nucleus (Dykes, R. W. et al., 1981), but their distribution within VP is uncertain. Possibly SA-II afferents also activate VP neurons, but this is unknown. As SA-II afferents may contribute to a sense of digit position (McCloskey, P. I., 1974), they seem functionally more related to VPS, which is involved in proprioception. A few neurons in VP are activated by WDR afferents (e.g., Kenshalo, D. R. J. et al., 1980). These neurons respond to light tactile stimuli, but respond with increasing magnitude as the stimulus intensity increases into the painful range. These neurons in the WDR category likely correspond to the small neurons in the septal regions of VP that have spinothalamic inputs (Rausell, E. et al., 1992). Because some of these septal regions merge ventrally with VPI, which also has spinothalamic inputs and histologically resembles VP septal zones, one interpretation of the VP septa is that they are extensions of VPI (Krubitzer, L. A. and Kaas, J. H., 1992; Wilson, P. et al., 1999). However, VP appears to receive most of its spinothalamic inputs from WDR neurons in layer 5 of the dorsal horn of the spinal cord, while VPI also receives inputs from the nociceptive neurons of layer 1 (Craig, A. D., 2006). A few neurons in VP are responsive to afferents that innervate the bladder, colon, and esophagus, and most of these were WDR or nociceptive, also often responding to afferents from skin (Bru¨ggemann, J. et al., 1994). In addition, spinothalamic axons terminate in a number of small patches along the rostral and caudal borders of VP (Stepniewska, I. et al., 2003). These patches seem to be at least partly outside of VP (Figure 9). In summary, SA-I and RA-I inputs dominate VP, but other inputs are expressed as well. In humans, electrical stimulation of neurons in VP generally results in a feeling of numbness or tingling in some skin location, rather than touch (e.g., Davis, K. D. et al., 1996; Lenz, F. A. et al., 1998), and localized lesions of VP are followed by persistent numbness in some skin region (e.g., Domino, E. F. et al., 1965). The inputs to VP of other mammals, judging from the well-studied cats and rats, appear to be similar to those of primates in that the dominating

128 The Somatosensory Thalamus and Associated Pathways

somatosensory input is from the dorsal column–trigeminal complex. In rats, dorsal column nuclei project densely to VP (Lund, R. D. and Webster, K. E., 1967a), while spinothalamic afferents terminate along the caudal and rostral borders of VP, and more sparsely within VP (Lund, R. D. and Webster, K. E., 1967b; Ma, W. et al., 1986). Spinothalamic

afferents from lamina 1 of the dorsal horn of the spinal cord, which carry nociceptive and thermoreceptive information, terminate at the caudal margin of VP (Gauriau, C. and Bernard, J. F., 2004), possibly in a separate nucleus, as in VPMpo of primates (Craig, A. D., 2007). In cats, the dominant inputs to VP are from the dorsal column–trigeminal complex

(a) Cytochrome oxidase

D VPMpc

M

(b) Nissl

VPMpc (c) Calbindin

VPS

VPL

VPM

VPI

VPMpc

The Somatosensory Thalamus and Associated Pathways

(Berkley, K., 1980), while the spinothalamic afferents project mainly to the ventral border of VP (Craig, A. D. and Burton, H., 1985) in VPI (Herron, P. and Dykes, R. W., 1986). As for other thalamic nuclei, VP includes both relay neurons projecting to the cortex and about 30% interneurons with connections within the nucleus (e.g., Spreafico, R. et al., 1983; Chmielowska, J. and Pons, T. P., 1995). The interneurons are inhibitory GABAergic neurons. Curiously, rats and possibly other rodents have very few (1%) GABAergic neurons in VP (Harris, R. M. and Hendrickson, A. E., 1987), and inhibitory functions in the nucleus largely depend on inputs from GABAergic neurons in the thalamic reticular nucleus. These reticular nucleus neurons are activated by collaterals of VP relay neurons projecting to S1, and by cortical neurons in S1, which also provide feedback to VP (Descheˆnes, M. et al., 1998). Besides inputs to VP from the somatosensory sector of the reticular nucleus (Crabtree, J. W., 1996), VP and other thalamic nuclei receive modulatory inputs from the ascending dorsal tegmental cholinergic system and from other diffusely organized modulatory systems (Sherman, S. M. and Guillery, R. W., 2006; Jones, E. G., 2007). In all mammals, the major cortical projections of VP are to S1 (see Krubitzer, L. A. and Kaas, J. H., 1987, for review), which corresponds to area 3b of primates (Kaas, J. H., 1982). In most mammals, VP also projects to two adjoining areas, S2 and the parietal ventral somatosensory area, PV (see Krubitzer, L. A. and Kaas, J. H., 1987). This allows S2 and PV to be activated in parallel with S1.

129

Therefore, S2 and PV can be activated via VP after lesions of S1 (Garraghty, P. E. et al., 1991). However, anthropoid primates (monkeys, apes, and humans), as well as raccoons, appear to have lost most of their VP inputs to S2 (Friedman, D. P. and Murray, E. A., 1986; Krubitzer, L. A. and Kaas, J. H., 1992; Disbrow, E. et al., 2002; see Herron, P., 1983 for raccoons). In macaque monkeys, lesions of the anterior parietal cortex (area 3a, 3b, 1, and 2) result in a loss of 94% of the non-GABA-containing projection neurons, leaving few neurons to project to other areas, including S2 (Chmielowska, J. and Pons, T. P., 1995). Thus, S1 (3b) lesions deactivate S2 and PV in these mammals (Burton, H. et al., 1990; Garraghty, P. E. et al., 1990b; Pons, T. P. et al., 1992). Across species, the major VP inputs to S1 (3b) are to layer 4 (e.g., Jones, E. G., 1975), where they have a powerful activating influence. In addition, the small cells in the septa of VP that are related to spinothalamic input project to the more superficial layers of area 3b (Rausell, E. and Jones, E. G., 1991; Jones, E. G., 1998), and possibly play a modulatory role. Some of these cells also project to other areas including S2 and PV (Stevens, R. T. et al., 1993). In anthropoid primates, VP has additional projections to two other areas of the anterior parietal cortex: area 1 (the posterior cutaneous field) and area 2 (the deep receptor field of the anterior parietal cortex). While architectonic fields 3a, 3b, 1, and 2 were once all considered to be parts of S1 in primates, there has been long-standing evidence that each of these fields is functionally distinct and contains a separate representation of the contralateral body (see below). In keeping with the functional distinctions between

Figure 5 Architectonic features of the nuclei of the ventroposterior complex of a prosimian primate (galago). In the lower panel (c), showing a coronal brain section, processed for the calcium-binding protein calbindin (Cb), the two major divisions of the ventroposterior nucleus (VP), the ventroposterior lateral (VPL) and the ventroposterior medial (VPM) subnuclei, correspond to the Cb-light central region. Just ventral to VP, the ventroposterior inferior nucleus (VPI) is characterized by neurons and neural processes that express moderate levels of Cb, as does the ventromedially located ventroposterior medial parvocellular nucleus (VPMpc) for taste, touch, and other functions. In the middle panel (b), an adjacent brain section was processed for Nissl substance to reveal the cell bodies of neurons. VP is characterized by densely packed, large neurons that are darkly stained. Groups of neurons within VP are separated from each other by lightly stained, cell-poor septa. The most notable septum separates VPL from VPM, but other septa are visible as well, including a septum in the middle of VPL that separates more lateral neurons representing the foot from more lateral neurons representing the hand. VPMpc has slightly smaller neurons, while VPI and ventroposterior superior nucleus (VPS) both have smaller, more scattered neurons so that the nuclei are less darkly stained. In the upper panel (a), both VP and VPMpc express moderate to dense levels of the metabolic enzyme, cytochrome oxidase (CO). Within VP, a CO-light septum separates VPL from VPM, and several CO-light septa are apparent in VPM. A septum in the middle of VPL is faintly visible. VPI expresses very little CO, while CO is faintly expressed in VPS. These architectonic distinctions, especially evident in some primates such as galagos, provide part of the evidence that VP, VPI, and VPS are separate nuclei within the ventroposterior complex. From Kass, J. H., Qi, H.-X., and Iyengar, S. 2006. Cortical network for representing the teeth and tongue in primates. Anat. Rec. 288A, 182–190.

130 The Somatosensory Thalamus and Associated Pathways

(a) Nissl

Cytochrome oxidase

Marmoset

LD

MD

LP IL

VPS

CM

PA VPS

VPL VPM

VPL

VPI

VPM VPI

LGN (b) CO

LD MD

LP IL PA

CM

VPS

Figure 7 A coronal brain section through the somatosensory thalamus of a two-month-old macaque monkey that has been processed for cytochrome oxidase (CO). Note that the ventroposterior nucleus (VP) (ventroposterior lateral (VPL) and ventroposterior medial (VPM)) densely expresses CO, and a septum separating VPM from VPL is prominent. Ventroposterior superior nucleus (VPS) expresses only slightly less CO than VP. Because VPS is also only slightly less darkly stained in Nissl preparations than VP of macaque monkeys, the two nuclei were considered to be a single nucleus, VP, in early studies. Ventroposterior inferior nucleus (VPI) expresses little CO.

VPL VPM VPI LGN

1 mm

Figure 6 The architectonic subdivisions of the somatosensory thalamus of a marmoset, a small New World monkey. (a) A Nissl-stained section showing cell bodies. (b) An adjacent section processed for cytochrome oxidase (CO). Arrows mark the same two blood vessels for aligning the two sections. Note the darker cells and denser expression of CO in ventroposterior nucleus (VP) (ventroposterior lateral (VPL) and ventroposterior medial (VPM)). A cell-poor, CO-light septum separates VPL from VPM. The Nissl-stained cells in the ventroposterior superior nucleus (VPS) are notably lighter than those in VP, but darker than in the ventroposterior inferior nucleus (VPI) of galagos, making the boundary between VP and VPS less obvious. However, the expression of CO is notably less in VPS than in VP. VPI is less darkly stained than VP in both preparations. The locations of the anterior pulvinar (PA) and the lateral posterior nucleus (LP), both with somatosensory functions, are indicated. The lateral dorsal (LD) nucleus, the intralaminar nucleus (IL), the center median nucleus (CM), the medial dorsal nucleus (MD), and the lateral geniculate nucleus (LGN) are labeled for reference. From Qi, H.-X., Lyon, D. C., and Kaas, J. H. 2002. Cortical and thalamic connections of the parietal ventral somatosensory area in marmoset monkeys (Callithrix jacchus). J. Comp. Neurol. 443, 168–182.

areas 3b, 1, and 2, which can be considered successively higher levels of cortical processing (e.g., Felleman, D. J. and Van Essen, D. C., 1991), VP projects less densely to area 1, and the axons of the neurons projecting to area 1 are thinner, and more slowly conducting than those projecting to area 3b. Further, the terminations of these axons in area 1 are in layer 3 rather than layer 4 (Jones, E. G., 1975). Locations in VP project to somatotopically matched locations in all parts of both the representations in area 3b and in area 1 (Lin, C.-S. et al., 1979; Nelson, R. J. and Kaas, J. H., 1981; Mayner, L. and Kaas, J. H., 1986; Darian-Smith, C. et al., 1990; Krubitzer, L. A. and Kaas, J. H., 1992). More neurons in VP project to area 3b than to area 1 (Nelson, R. J. and Kaas, J. H., 1981), and it is possible that only the RA-I class of VP relay cells projects to area 1. However, perhaps as many as 20% of VP neurons project via collaterals to both areas 3b and 1 (Cusick, C. G. et al., 1985). In addition, parts of area 2 and even area 5 that are most responsive to cutaneous stimuli, those representing the glabrous hand and face, receive sparse inputs from VP, at least in macaque monkeys (Pons, T. P. and Kaas, J. H., 1985). Finally, a few neurons in VP of macaques project to the part of area 5 that is responsive to light tactile stimuli on the forelimb (Pons, T. P. and Kaas, J. H., 1985).

The Somatosensory Thalamus and Associated Pathways

131

Squirrel monkey thalamus

il

G

Ta

Distal

Forearm Shoulder

Forearm

lp

D4

D3

Neck

Hindlimb

Do rsa

T i T5 p

VP T4 T3 T5 T2 e D5 s Ventral prox Ba l Chest ea Hindlimb lut

D1 D2 Ear Chin

rl

m

ro

x Dorsal trunk

Lo

we

Craniu

ip

Face

T4 T3 Foot

Dorsal prox T2

T 1

D5

D4

D3

Upper lip

D2

Upper

VPL

Tongue

Teeth

Hand

Lower

D1

VPM

D

R M

Figure 8 The somatotopic organization of the ventroposterior (VP) nucleus of squirrel monkeys. This 3D rendition is viewed from the back. The medial division of VP, the ventroposterior medial (VPM) subnucleus, devotes large territories to the lips, teeth, and tongue. A most medial portion also represents the ipsilateral teeth and tongue (not shown). A septum separates VPM from the lateral division, ventroposterior lateral nucleus (VPL). A septum within VPL separates the more medial representation of the hand from the more lateral representation of the foot. The tail is represented most laterally. A dorsal cap of VP represents the limbs, trunk, and cranium. Note that digits (D1–D5) and toes (T1–T5) are represented in order. Adapted from Kaas, J. H., Nelson, R. J., Sur, M., Dykes, R. W., and Merzenich, M. M. 1984. The somatotopic organization of the ventroposterior thalamus of the squirrel monkey, Saimiri sciureus. J. Comp. Neurol. 226, 111–140.

6.07.6 The Ventroposterior Superior Nucleus The VPS forms a dorsal cap on the VP of primates. Although the region had long been recognized as having a concentration of inputs from receptors in deep tissues, muscles, and joints, in contrast to VP proper where inputs relayed from cutaneous receptors predominate, traditionally, the VPS region was usually included in VPL (e.g., Poggio, G. F. and Mountcastle, V. B., 1963). VPS was distinguished as a separate nucleus after the results of extensive microelectrode recording experiments were related to thalamic architecture in squirrel monkeys (Kaas, J. H. et al., 1984). The results indicated that VPS is architectonically distinct from VP, and that each nucleus contains a separate representation of the contralateral body with VPS devoted to muscle spindle receptors, while VP is devoted to cutaneous receptors. In general, VPS has neurons that are less darkly stained in Nissl preparations, and less densely packed than neurons in VP. Further, VPS expresses less CO (Krubitzer, L. A. and Kaas, J. H., 1992) and less acetylcholinesterase (Pons, T. P. and Kaas, J. H.,

1985) than does VP. VPS also expresses more calbindin and less parvalbumin (Figure 5). Inputs to VPS are from neurons in brainstem and upper spinal cord nuclei, such as the external cuneate nucleus. These inputs are activated by muscle spindle afferents and they send axons into the contralateral medial lemniscus (Berkley, K., 1980; Boivie, J. and Boman, K., 1981). Recordings in VPS, previously recognized as a rostral cap of VP (Maendly, R. et al., 1981) or an anterodorsal shell of VP (Friedman, D. P. and Jones, E. G., 1981), indicate that the vast majority of neurons are activated by muscle spindle receptors (Wiesendanger, M. and Miles, T. S., 1982). VPS projects to areas 3a and 2 (Jones, E. G. et al., 1979; Friedman, D. P. and Jones, E. G., 1980; 1981; Cusick, C. G. et al., 1985; Pons, T. P. and Kaas, J. H., 1985; Darian-Smith, C. et al., 1990; Akbarian, S. et al., 1992; Darian-Smith, C. and Darian-Smith, I., 1993; Huffman, K. J. and Krubitzer, L. A., 2001). Possibly as many as 40% of the relay neurons in VPS project via collaterals to somatotopically matched locations in both area 3b and area 2 (Cusick, C. G. et al., 1985), as both of these fields contain systematic tail-to-tongue representations of deep receptors in mediolateral

132 The Somatosensory Thalamus and Associated Pathways

(a)

(b)

Figure 9 Parasagittal brain sections through the somatosensory thalamus after being processed for axon terminals labeled with wheatgerm agglutinin conjugated to horseradish peroxidase (WGA–HRP). In panel (a), an injection of WGA–HRP into the cervical spinal cord of a macaque monkey labeled patches of terminals along the rostral (left) and caudal borders of the ventroposterior nucleus, VP. Other patches of labeled terminals are in divisions of the posterior nuclei caudal to VP. In panel (b), an injection of WGA–HRP was placed in the contralateral dorsal column nuclei and VP was densely labeled. A few patches of labeled terminals were rostral to VP in the motor thalamus. In both panels, VP is outlined. (a) From Stepniewska, I., Sakai, S. T., Qi, H.-X., and Kaas, J. H. 2003. Distribution of somatosensory pathways in relation to thalamic neurons relaying information to the motor and premotor cortex in the macaque monkey. Soc. Neurosci. Abstr. 29, 60.16.

sequences that parallel those of areas 3b and 1 (e.g., Kaas, J. H. et al., 1979; Pons, T. P. et al., 1985; Huffman, K. J. and Krubitzer, L. A., 2001; Krubitzer, L. A. et al., 2004). As expected from the more extensive evidence from monkeys, an orderly representation of deep receptors has been described as just rostrodorsal to the representation of cutaneous receptors in VP of humans (Lenz, F. A. et al., 1990; Ohye, C. et al., 1993; Seike, M., 1993). This human VPS represents receptors activated by movements of the jaw, digits, arm, and leg in a mediolateral sequence. Human VPS is located in a region of thalamus that has been variously identified, but most recently termed anterior VP or anterior VPL (Morel, A. et al., 1997). Rather than an anterior or anterodorsal division of VP, the evidence for distinctly different inputs and outputs, as well as histological differences, justifies distinguishing the region as a separate nucleus in the ventroposterior complex, VPS. There is also evidence for VPS in nonprimate mammals, although the nucleus may not be well differentiated. However, a problem in identifying VPS in nonprimates is that the cortical targets of VPS in primates, areas 3a and 2, often have not been identified. However, in all mammals, it appears that the primary somatosensory cortex, S1 or area 3b, is bordered rostrally by a narrow zone of the cortex that likely subserves proprioception and is also, based on position and function, a likely homologue of area 3a (Krubitzer, L. A. et al., 2004; Kaas, J. H., 2007b). In rodents, the evidence for area 3a is most clear for squirrels, although there is supporting evidence from rats. In both rodents, S1 is histologically very distinct in preparations of sections cut parallel to the surface of the flattened cortex as a highly granular zone (packed with densely stained, small neurons) that also expresses high levels of CO and myelin (Krubitzer, L. A. and Kaas, J. H., 1987; Jain, N. et al., 2003). The cortex along the rostral border of this S1 has been called dysgranular cortex (Chapin, J. K. and Lin, C. S., 1984), as layer 4 is less pronounced than in S1. In squirrels and rats, part of this dysgranular zone protrudes caudally between the representatives of the face and the forelimb in S1. The larger size of this protrusion of area 3a into S1 of squirrels made it a suitable target for injection of tracers that revealed the connections of the dysgranular cortex (Gould, H. J. et al., 1989). The thalamic inputs to this dysgranular cortex were largely from a thalamic zone along the dorsal border of VP that has been referred to by

The Somatosensory Thalamus and Associated Pathways

various names, but in rodents is called the posterior nucleus with medial (POm) and lateral (POl) divisions (e.g., Jones, E. G., 2007). More recently, Francis J. T. et al. (2003) used the results of microelectrode recordings to divide the somatosensory thalamus of rats into a middle zone of VP that responds to cutaneous somatosensory stimuli and a rostral subnucleus of VP that responded mainly to proprioceptive inputs. Furthermore, projections from the external cuneate nucleus in rats (Mantle-St. John, L. A. and Tracey, D. J., 1987), which carry muscle spindle information, terminate in the same rostrodorsal region of the somatosensory thalamus. Thus, rodents have a thalamic nucleus for proprioception that has been variously considered a subnucleus of VP or a rostrodorsal capping nucleus of VP, just as has VPS of primates. The nucleus projects to the dysgranular cortex that appears to be a homologue of area 3a of primates. Other evidence comes from experiments in carnivores. Most notably, in raccoons, microelectrode recordings from the somatosensory thalamus identified a distinct zone of proprioceptive neurons responsive to receptors in muscles, tendons, and joints that were located rostrodorsal to the zone responsive to cutaneous stimulation (Wiener, S. I. et al., 1987). As the functionally distinct zones were architectonically similar, they were termed cutaneous and kinesthetic divisions of VP (termed Vb for ventrobasal nucleus), although the kinesthetic division of VP was described as having less cell density (Wiener, S. I. et al., 1987). The kinesthetic thalamic zone projects to a 3a-like strip of the dysgranular cortex rostral to S1 (Doetsch, G. S. et al., 1988; Feldman, S. H. and Johnson, J. I., 1988). In cats, the situation is similar, as a rostrodorsal cap on VP has been identified as a proprioceptive nucleus with inputs from muscle spindle receptors (Andersson, S. A. et al., 1966; Maendly, R. et al., 1981; Wiesendanger, M. and Miles, T. S., 1982; Kniffki, K.-D. and Mizumura, K., 1983). This thalamic region, which Dykes R. W. et al. (1986) called the ventroposterior oralis nucleus (VPO), appears to correspond to VPS of monkeys. In cats, the cortex between S1 (area 3b) and the primary motor cortex (M1) has long been considered to be area 3a on architectonic grounds (Hassler, R. and Muhs-Clement, K., 1964). This 3a of cats is activated by receptors in muscles and joints (e.g., Dykes, R. W. et al., 1980) and it receives projections from VPO (Dykes, R. W. et al., 1986; Zheng, A.-H. et al., 1986). Thus, at least in carnivores and rodents, there is evidence of a proprioceptive nucleus in the

133

thalamus that is in the relative position of VPS of primates and projects to area 3a or a 3a-like area, as does VPS of primates. A difference is that VPS of moneys also projects to area 2, a subdivision of the somatosensory cortex that may not exist in nonprimate mammals (Kaas, J. H., 2004; 2007a), although the cortex caudal to S1 has been classified as area 1–2 (presumably, a composite of areas 1 and 2) in some instances. An area 2 is sometimes distinguished in the somatosensory cortex of cats, although this appears to be a misidentification, as some investigators distinguish areas 3b, 1, and 2 within a single area 3b body representation (see for review, Felleman, J. D. et al., 1983). In a detailed reinvestigation of the organization of the somatosensory cortex of cats, Myasinkov A. A. et al. (1994) found evidence for two representations of body receptors in the cortex caudal to S1 (they identified S1 as area 3b), with neither corresponding to previously proposed areas 1 and 2, and neither activated by deep receptors. Even in prosimian primates, there is no clear evidence for an area 2, and the cortex caudal to S1 (area 3b) in the position of area 1 is not very responsive to cutaneous stimuli in anesthetized animals, so there are uncertainties even about area 1 (e.g., Wu, C. W.-H. and Kaas, J. H., 2003). Furthermore, the presence of an area 2 has been questioned for some New World monkeys (Padberg, J. et al., 2005), further complicating the use of projections to area 2, as well as those to area 3a, in identifying VPS. Presently, the evidence suggests that a nucleus responsive to proprioceptive inputs, termed VPS here, is segregated from VP in a wide range of mammals, and this nucleus projects to a proprioceptive zone of the cortex at the rostral border of S1 that is recognized as area 3a in primates and cats, but is variously recognized and named in other mammals. The comparative evidence suggests that area 2, as a secondary target of VPS, emerged with the evolution of anthropoid primates (Kaas, J. H., 2007a), although an area 2 with a mixed representation of deep and cutaneous receptors is not clearly present in all investigated New World anthropoids.

6.07.7 The Ventroposterior Inferior Nucleus VPI was first distinguished by Crouch R. L. (1934) in macaque monkeys, where it was described as a cellsparse region ventral to VP. Jones E. G. (2007)

134 The Somatosensory Thalamus and Associated Pathways

considered VPI to be distinct only in the brains of primates, although the nucleus is obvious in the brains of raccoons (Herron, P. et al., 1997), carnivores with specialized hand use, as in primates. The neurons in VPI are smaller and less densely stained in Nissl preparations than neurons in VP, and VPI expresses less CO and parvalbumin, and more calbindin than VP (Figures 5–7; also see Rausell, E. and Jones, E. G., 1991; Krubitzer, L. A. and Kaas, J. H., 1992). The septal regions that separate the subnuclei of VP are almost identical in histological appearance with VPI proper, and spinothalamic inputs and projections to superficial cortical layers are shared, so it seemed parsimonious to include these septal regions with the main body of VPI as a single nucleus (Krubitzer, L. A. and Kaas, J. H., 1992; also see Wilson, P. et al., 1999). However, there is evidence that the sources of spinothalamic inputs to VPI proper and the septal regions of VP are somewhat different, with the WDR neurons of lamina 5 of the dorsal horn of the spinal cord projecting to septa within VP, and both lamina 5 and nociceptive neurons in lamina 1 projecting to VPI proper (Craig, A. D. and Zhang, E. T., 2006). Thus, there are also arguments for not including septal regions of VP in VPI. In monkeys, the major source of sensory information to VPI is from the spinothalamic tract, including inputs from the spinal trigeminal nuclei (Mehler, W. R. et al., 1960; Boivie, J., 1980; Burton, H. and Craig, A. D., 1983; Mantyh, P. W., 1983; Apkarian, A. V. and Hodge, C. J., 1989; Ralston, H. J. and Ralston, D. D., 1992). There have been suggestions for a relay of Pacinian afferents, as well (Dykes, R. W. et al., 1981; Herron, P. and Dykes, R. W., 1986), but this seems unlikely as the small cells of VPI and their superficial cortical projections seem incongruent with a lowthreshold, rapidly conducting pathway for a Pacinian RA-II subsystem. In addition, Pacinian afferents would relay from dorsal column nuclei rather than from spinothalamic neurons. Some inputs may be from vestibular nuclei, but they are sparse (Deecke, L. et al., 1974; Lang, W. et al., 1979). Recordings indicate that VPI contains a somatotopic representation of afferents from the contralateral body that parallels the representation in VP, and that the major activating input is from WDR peripheral nerve afferents (Craig, A. D., 2007). In monkeys, the major cortical projections of VPI are to higher-order somatosensory areas, S2 and PV (Friedman, D. P. and Murray, E. A., 1986; Krubitzer, L. A. and Kaas, J. H., 1992; Disbrow, E.

et al., 2002; Qi, H.-X. et al., 2002; Coq, J. O. et al., 2004). VPI projects much less densely to other somatosensory areas, such as 3b and 1. Projections to areas 3b and 1 also come from neurons in the embedded septal regions of VP (Penny, G. R. et al., 1982; Rausell, E. and Jones, E. G., 1991). The VPI projections and septal neuron projections are to the superficial layers of the somatosensory cortex, rather than layer 4, and thus are likely to be modulatory instead of driving. This supposition is supported by the observations that S2 and PV, with dense VPI inputs, depend on areas 3a and 3b for activation (Garraghty, P. E. et al., 1990a; Pons, T. P. et al., 1992), and that neurons in S2 and PV respond vigorously to light tactile stimulation (see Coq, J. O. et al., 2004, for review), while VPI neurons do not. In addition to being recognized in primates, VPI has been described as a distinct nucleus in both cats and raccoons (see Herron, P., 1983; Craig, A. D. and Burton, H., 1985). As in primates, VPI of these carnivores consists of a narrow band of small cells that are lightly stained in Nissl preparations. VPI is just ventral to VP, and the septal regions in VP have lightly stained cells, as in VPI, and are continuous with VPI. Spinothalamic terminations terminate both in VPI proper and in and around VP septal zones (e.g., Berkley, K., 1980; Craig, A. D. and Burton, H., 1985). VPI is larger and more distinct in raccoons, and it appears to receive denser spinothalamic inputs. As in monkeys, there is evidence that Pacinian inputs activate neurons in VPI of cats and raccoons (Herron, P. and Dykes, R. W., 1986), but others place the Pacinian-responsive neurons in ventral VP (Fisher, G. R. et al., 1983). In raccoons, Herron P. (1983) showed for the first time in a convincing manner that VPI projects strongly to S2, although there was some evidence for this from an earlier study in cats (Rinvik, E., 1968). Later studies more conclusively demonstrated VPI projections to S2 in cats (Herron, P. and Dykes, R. W., 1986). In rats, there is not much of a region ventral to VP that can be identified as VPI (Jones, E. G., 2007), and spinothalamic axons terminate mainly on the rostral and caudal borders of VP (McAllister, J. P. and Wells, J., 1981). However, in squirrels, a small, thin VPI that contains small, lightly stained (Nissl) neurons has been identified (Krubitzer, L. A. and Kaas, J. H., 1987). While no connections were demonstrated between S2 and this VPI, connections with PV were found. A few connections with S1 were also revealed. In conclusion, most of the evidence for the existence of VPI comes from studies on primates,

The Somatosensory Thalamus and Associated Pathways

although a comparable region of the thalamus has been identified in raccoons, cats, and squirrels. It is not certain from the limited attempts to identify and characterize VPI if the nucleus is a basic component of the mammalian thalamus, although usually not a very distinctive part, or if a nucleus with similar histological characteristics and connections arose independently in primates, carnivores, and some rodents. The main function of VPI seems to be to relay modulating influences based on spinothalamic inputs activated by WDR afferents, to cortical areas S2 and PV, and to a lesser extent S1 and bordering somatosensory fields. The suggestions of Pacinian inputs to VPI deserve further study, but the limited evidence is open to the interpretation that the Pacinian-like thalamic cells are in ventral VP rather than VPI.

6.07.8 Other Nuclei: The Anterior Pulvinar, the Lateral Posterior Nucleus, the Posterior Group, the Ventroposterior Parvocellular Nucleus, and the Ventromedial Posterior Nucleus A number of other thalamic nuclei contribute to somatosensory function in primates and other mammals. In monkeys, the anterior (oral) pulvinar, which has been identified only in primates, has widespread interconnections with somatosensory areas of anterior, posterior, and lateral subdivisions of the parietal cortex (e.g., Pons, T. P. and Kaas, J. H., 1985; Cusick, C. G. and Gould, H. J. I., 1990; Padberg, J. and Krubitzer, L. A., 2006). As the anterior pulvinar receives inputs from the somatosensory cortex and it projects back to the somatosensory cortex, the anterior pulvinar spreads activity (Sherman, S. M. and Guillery, R. W., 2006) across somatosensory areas, possibly coordinating activities in several areas, rather than providing an additional source of sensory information. Another subdivision of the pulvinar complex, the medial pulvinar, has connections with areas of the posterior parietal cortex that are multisensory or somatosensory, as well as areas of cingulate and the frontal cortex (see Stepniewska, I. et al., 2004, for review). These nuclei of the primate thalamus have no obvious homologues in nonprimates. The lateral posterior nucleus or region in primates also has interconnections with regions of the posterior and lateral parietal cortex (see Padberg, J. and Krubitzer, L. A., 2006). Comparisons with

135

nonprimates are complicated by the common use of the term lateral posterior complex or nucleus to refer to part of or all of the visual pulvinar. Thus, different parts of the thalamus are called lateral posterior across taxa. Another region, the Po is also defined somewhat differently across species. In rats, the posterior nucleus is divided into medial and lateral nuclei. Both receive a mixture of somatosensory inputs from the brainstem and spinal cord and are interconnected with S1 and S2, and possibly other areas of the somatosensory cortex (see Groenewegen, H. J. and Witter, M. P., 2004). Similar nuclei, POm and POl, have been described in cats, where POl is mainly involved in processing auditory information, while POm has connections with the somatosensory areas of the cortex (Jones, E. G., 2007). A more caudal region of the thalamus is defined as the posterior complex in primates, where connections are with the somatosensory and multisensory cortex of the lateral fissure (Burton, H. and Jones, E. G., 1976). A nucleus in the medioventral margin of VP, VPMpc (also known as the basal ventral medial nucleus, VMb) is sometimes referred to as the thalamic taste nucleus, although it receives inputs relayed from cutaneous and other somatosensory afferents in addition to those for gustation. In primates, VPMpc projects to the representation of the tongue in S1 (area 3b) and to a gustatory region, area G, in the cortex of the rostral part of the lateral sulcus (Kaas, J. H. et al., 2006; Iyengar, S. et al., 2007). Similar connections are likely in other mammals (Lundy, R. F. and Norgren, R., 2004). Finally, Craig A. D. et al. (1994) have identified a region of the posterolateral thalamus of monkeys as the posterior ventral medial nucleus (VMpo). This nucleus, on the medial margin of VP just caudal to VPMpc, receives trigeminothalamic and spinothalamic inputs from nociceptive second-order neurons (Craig, A. D., 2004; 2007) and projects to the dorsal anterior insular cortex in the lateral sulcus. The nucleus is identified in part by its dense calbindinpositive fiber plexus. Craig A. D. (2004) regarded VMpo as novel to primates, and proposed that this relay in rats and cats involves VPI and VP (also see Zhang, X. et al., 2006). This interpretation of the significance of VMpo has been criticized by Willis W. D. et al. (2002) for ignoring the nociceptive inputs to VP of primates that relay to S1 and S2. Jones E. G. (2007) has argued against the concept of VMpo. The proposal of Craig A. D. et al. (1994) has

136 The Somatosensory Thalamus and Associated Pathways

provoked some thought and support, as well as disagreement, and further study is needed.

6.07.9 Cortical Projections to the Somatosensory Thalamus and Dorsal Column Nuclei Cortical projections to the thalamus are obviously important in the functions of the somatosensory thalamus, as they are many times more numerous than the thalamocortical connections. These connections emerge from pyramidal neurons in layers 5 and 6, with the projections from layer 6 being denser while having smaller terminal endings. The less abundant projections from layer 5 terminate in the thalamus with large endings. The layer 6 projections are postulated to have weak, modulatory effects, while the layer 5 projections are considered to be feedforward, driving connections (Sherman, S. M. and Guillery, R. W., 2006). This laminar pattern of projections exists across cortical areas and mammalian species, with most thalamic nuclei receiving a mixture of layer 5 and layer 6 projections (Rouiller, E. M. and Welker, W. I., 2000). However, in rats, the S1 projection to VP originates entirely from layer 6 neurons (Killackey, H. P. and Sherman, S. M., 2003). The cortical projections to the somatosensory thalamus largely follow the general pattern that areas project back to the same thalamic regions that project to them. But thalamic nuclei also receive projections from somatotopically mismatched parts of a field, or fields without input from that nucleus. The layer 5 and 6 projections to the thalamus are excitatory, and they terminate on both relay neurons and inhibitory interneurons (see Li, L. and Ebner, F. F., 2007). Thalamic neurons may be influenced indirectly via cortical projections to the thalamic reticular nucleus, which has GABAergic inhibitory neurons projecting to the thalamus (Crabtree, J. W., 1996). The corticothalamic projections to relay nuclei appear to alter the receptive field characteristics of projection neurons, sometimes by increasing the selectivity of these neurons according to behavioral state. For example, Li L. and Ebner F. F. (2007) found that microstimulation of neurons in the S1 cortex of rats rotates the angle of the directional selectivity for whisker movements of VPM neurons toward the direction that cortical neurons prefer. Cortical projections also help constrain the sizes of receptive field for VP neurons. When activity of neurons in S1 (area 3b) of macaque monkeys was suppressed, the

receptive fields of neurons in VP increased in size (Ergenzinger, E. R. et al., 1998). Similar results have been obtained in rats (Krupa, D. J. et al., 1999; Chowdhury, S. A. et al., 2004). Other cortical projections, especially those to the intrinsic nuclei such as the anterior pulvinar, may activate relay neurons so that information is transferred from one cortical area to another via the thalamus (Sherman, S. M. and Guillery, R. W., 2006). The somatosensory cortex also projects to the contralateral dorsal column–trigeminal complex (Rustioni, A. and Sotelo, C., 1974; Wise, S. P. and Jones, E. G., 1977; Weinberg, R. J. et al., 1990; Lue, J.-H. et al., 1997; Martinez-Lorenzana, G., et al., 2001; ). One of the suggested functions of these cortical inputs is to activate intrinsic inhibitory neurons to selectively constrain the sizes of receptive fields for neurons in the nuclear complex (Wang, X. and Wall, J. T., 2005).

References Akbarian, S., Gru¨sser, O. J., and Guldin, W. O. 1992. Thalamic connections of the vestibular cortical fields in the squirrel monkey (Saimiri sciureus). J. Comp. Neurol. 326, 423–441. Andersson, S. A., Landgren, G., and Wolsk, D. 1966. The thalamic relay and cortical projection of group I muscle afferents from the forelimb of the cat. J. Physiol. 183, 576–591. Apkarian, A. V. and Hodge, C. J. 1989. Primate spinothalamic pathways. III. Thalamic terminations of the dorsolateral and ventral spinothalamic pathways. J. Comp. Neurol. 288, 493–511. Asanuma, H., Thach, W. T., and Jones, E. G. 1983. Distribution of cerebellar terminations and their relation to other afferent terminations in the ventral lateral thalamic region of the monkey. Brain Res. Rev. 5, 237–265. Berkley, K. 1980. Spatial relationships between the terminations of somatic sensory and motor pathways in the rostral brainstem of cats and monkeys. I. Ascending somatic sensory inputs to lateral diencephalon. J. Comp. Neurol. 193, 283–317. Boivie, J. 1980. Thalamic projections from lateral cervical nucleus in monkey. A degeneration study. Brain Res. 198, 13–26. Boivie, J. and Boman, K. 1981. Termination of a separate (proprioceptive?) cuneothalamic tract from external cuneate nucleus in monkey. Brain Res. 224, 235–246. Bombardieri, R. A., Johnson, J. I., and Campos, G. B. 1975. Species differences in mechanosensory projections from the mouth to the ventrobasal thalamus. J. Comp. Neurol. 163, 41–64. Brodman, K. 1909. Vergleichende Lokalisationslehre der Grosshirnrhinde. Barth. Broman, J. and Zhang, M. 1996. The cerviothalamic tract terminates in Cat-301-sparse regions of the cat VPL. Neuroreport 7, 1493–1496. Bru¨ggemann, J., Shi, T., and Apkarian, A. V. 1994. Squirrel monkey lateral thalamus. II. Viscerosomatic convergent

The Somatosensory Thalamus and Associated Pathways representation of urinary bladder, colon, and esophagus. J. Neurosci. 14, 6796–6914. Burton, H. and Craig, A. D. 1983. Spinothalamic Projections in Cat, Raccoon and Monkey: A Study Based on Anterograde Transport of Horseradish Peroxidase. In: Somatosensory Integration in the Thalamus (eds. G. Macchi, A. Rustioni, and R. Spreafico), pp. 17–41. Elsevier. Burton, H. and Jones, E. G. 1976. The posterior thalamic region and its cortical projection in New World and Old World monkeys. J. Comp. Neurol. 168, 249–302. Burton, H., Sathian, K., and Shao, D. H. 1990. Altered responses to cutaneous stimuli in the second somatosensory cortex following lesions of the postcentral gyrus in infant and juvenile macaques. J. Comp. Neurol. 291, 395–414. Cajal, S. R. Y. 1911. Histology of the Nervous System. (trans. N. Swanson and L. W. Swanson) Oxford University Press. Catania, K. C. and Kaas, J. H. 1997. Somatosensory fovea in the star-nosed mole: behavioral use of the star in relation to innervation patterns and cortical representation. J. Comp. Neurol. 387, 215–233. Chapin, J. K. and Lin, C. S. 1984. Mapping the body representation in the SI cortex of anesthetized and awake rats. J. Comp. Neurol. 229, 199–213. Chmielowska, J. and Pons, T. P. 1995. Patterns of thalamocortical degeneration after ablation of somatosensory cortex in monkeys. J. Comp. Neurol. 360, 377–392. Chowdhury, S. A., Grek, K. A., and Rasmusson, D. D. 2004. Changes in corticothalamic modulation of receptive fields during peripheral injury-induced reorganization. Proc. Natl. Acad. Sci. U. S. A. 101, 7135–7140. Cobral, R. J. and Johnson, J. I. 1971. The organization of mechanoreceptive projections in the ventrobasal thalamus of the sheep. J. Comp. Neurol. 141, 17–36. Cooper, B. Y., Glendenning, D. S., and Vierck, C. J. 1993. Finger movement deficits in the stumptail macaque following lesions of the fasciculus cuneatus. Somatosens. Mot. Res. 10, 17–29. Coq, J. O., Qi, H.-X., Collins, C. E., and Kaas, J. H. 2004. Anatomical and functional organization of somatosensory areas of the lateral fissure of the New World titi monkey (Callicebus moloch). J. Comp. Neurol. 476, 363–387. Crabtree, J. W. 1996. Organization in the somatosensory section of the cat’s thalamic reticular nucleus. J. Comp. Neurol. 366, 207–222. Craig, A. D. 2004. Distribution of trigeminothalamic and spinothalamic lamina. I. Terminations in the macaque monkey. J. Comp. Neurol. 477, 119–148. Craig, A. D. 2006. Retrograde analyses of spinothalamic projections in the macaque monkey: input to ventral posterior nuclei. J. Comp. Neurol. 499, 965–978. Craig, A. D. 2007. Evolution of Pain Pathways. In: Evolution of Nervous Systems in Mammals (eds. J. H. Kaas and L. A. Krubitzer), pp. 227–235. Elsevier. Craig, A. D. and Burton, H. 1985. The distribution and topographical organization in the thalamus of anterogradelytransported horseradish peroxidase after spinal injection in cat and raccoon. Exp. Brain Res. 58, 227–254. Craig, A. D. and Zhang, E. T. 2006. Retrograde analyses of spinothalamic projections in the macaque monkey: input to posterolateral thalamus. J. Comp. Neurol. 499, 953–964. Craig, A. D., Bushnell, M. C., Zhang, E. T., and Blomqvist, A. 1994. A thalamic nucleus specific for pain and temperature sensation. Nature 372, 770–773. Crouch, R. L. 1934. The nuclear configuration of the thalamus of Macacus rhesus. J. Comp. Neurol. 59, 451–485. Cusick, C. G. and Gould, H. J. I. 1990. Connections between area 3b of the somatosensory cortex and subdivisions of the

137

ventroposterior nuclear complex and the anterior pulvinar nucleus in squirrel monkeys. J. Comp. Neurol. 292, 83–102. Cusick, C. G., Steindler, D. A., and Kaas, J. H. 1985. Corticocortical and collateral thalamocortical connections of postcentral somatosensory cortical areas in squirrel monkeys: a double-labeling study with radiolabeled wheatgerm agglutinin and wheat germ agglutinin conjugated to horseradish peroxidase. Somatosens. Res. 3, 1–31. Darian-Smith, C. and Darian-Smith, I. 1993. Thalamic projections to areas 3a, 3b and 4 in the sensorimotor cortex of the mature and infant macaque monkey. J. Comp. Neurol. 335, 173–199. Darian-Smith, C., Darian-Smith, I., and Cheema, S. S. 1990. Thalamic projections to sensorimotor cortex in the macaque monkey. Use of multiple retrograde fluorescent tracers. J. Comp. Neurol. 299, 17–46. Davis, K. D., Kiss, Z. H. T., Tasker, R. R., and Destrovsky, J. O. 1996. Thalamic relay site for cold perception in humans. J. Neurophysiol. 81, 1970–1973. Deecke, L., Schwarz, D. W. F., and Fredickson, V. M. 1974. Nucleus ventroposterior inferior (VPI) as the vestibular thalamic relay in the rhesus monkey. I. Field potential investigation. Exp. Brain Res. 20, 88–100. Descheˆnes, M., Veinante, P., and Zhang, Z. W. 1998. The organization of corticothalamic projections: reciprocity versus parity. Brain Res. Rev. 28, 286–308. Disbrow, E., Litinas, E., Recanzone, G. H., Slutsky, D. A., and Krubitzer, L. A. 2002. Thalamocortical connections of the parietal ventral area (PV) and the second somatosensory area (S2) in macaque monkeys. Thalamus Relat. Syst. 1, 289–302. Doetsch, G. S., Standage, G. P., Johnston, K. W., and Lin, C.-S. 1988. Thalamic connections of two functional subdivisions of the somatosensory forepaw cerebral cortex of the raccoon. J. Neurosci. 8, 1873–1886. Domino, E. F., Matsuoka, S., Waltz, J., and Cooper, I. S. 1965. Effects of cryogenic thalamic lesions on the somesthetic evoked response in man. Electroencephalogr. Clin. Neurophysiol. 53, 143–165. Dykes, R. W., Herron, P., and Lin, C.-S. 1986. Ventroposterior thalamic regions projecting to cytoarchitectonic areas 3a and 3b in the cat. J. Neurophysiol. 56, 1521–1541. Dykes, R. W., Rasmussen, D. D., and Hoeltzell, P. B. 1980. Organization of primary somatosensory cortex in the cat. J. Neurophysiol. 43, 1527–1546. Dykes, R. W., Rasmussen, D. D., Survetavan, D., and Rehman, M. B. 1982. Submodality segregation and receptive field sequences in cuneate, gracile, and external cuneate nuclei of the cat. J. Neurophysiol. 47, 389–416. Dykes, R. W., Sur, M., Merzenich, M. M., Kaas, J. H., and Nelson, R. J. 1981. Regional segregation of neurons responding to quickly adapting, slowly adapting, deep and Pacinian receptors within thalamic ventroposterior lateral and ventroposterior inferior nuclei in the squirrel monkey (Saimiri sciureus). Neuroscience 6, 1687–1692. Ergenzinger, E. R., Glasier, M. M., Hahm, J. O., and Pons, T. P. 1998. Cortically induced thalamic plasticity in the primate somatosensory system. Nat. Neurosci. 1, 226–229. Feldman, S. H. and Johnson, J. I. 1988. Kinesthetic cortical area anterior to primary somatic sensory cortex in the raccoon (Procyon lotor). J. Comp. Neurol. 277, 80–95. Felleman, D. J. and Van Essen, D. C. 1991. Distributed hierarchical processing in the primate cerebral cortex. Cereb. Cortex 1, 1–47. Felleman, J. D., Nelson, R. J., Sur, M., and Kaas, J. H. 1983. Representations of the body surface in areas 3b and 1 of postcentral parietal cortex of cebus monkeys. Brain Res. 268, 15–26.

138 The Somatosensory Thalamus and Associated Pathways Fisher, G. R., Freeman, B., and Rowe, M. J. 1983. Organization of parallel projections from Pacinian afferent fibers to somatosensory cortical areas I and II in the cat. J. Neurophysiol. 49, 75–97. Florence, S. L. and Lakshman, S. 1995. Topography of primary afferent projections in the trigeminal sensory nuclei of rats. Acta Neurobiol. Exp. 55, 193–200. Florence, S. L., Wall, J. T., and Kaas, J. H. 1988. The somatotopic pattern of afferent projections from the digits to the spinal cord and cuneate nucleus in macaque monkeys. Brain Res. 452, 388–392. Florence, S. L., Wall, J. T., and Kaas, J. H. 1989. Somatotopic organization of inputs from the hand to the spinal gray and cuneate nucleus of monkeys with observations on the cuneate nucleus of humans. J. Comp. Neurol. 286, 48–70. Florence, S. L., Wall, J. T., and Kaas, J. H. 1991. Central projections from the skin of the hand in squirrel monkeys. J. Comp. Neurol. 311, 563–578. Francis, J. T., Xu, S., Rodriguez, D., and Chapin, J. K. 2003. Mapping the ventroposterior lateral thalamus: Cutaneous and proprioceptive representations. Soc. Neurosci. Abstrs. 60.5. Friedman, D. P. and Jones, E. G. 1980. Focal projection of electrophysiologically defined groupings of thalamic cells on the monkey somatic sensory cortex. Brain Res. 191, 249–252. Friedman, D. P. and Jones, E. G. 1981. Thalamic input to areas 3a and 2 in monkeys. J. Neurophysiol. 45, 59–85. Friedman, D. P. and Murray, E. A. 1986. Thalamic connectivity of the second somatosensory area and neighboring somatosensory fields of the lateral sulcus of the macaque. J. Comp. Neurol. 252, 348–373. Ganchrow, D. 1978. Intratrigeminal and thalamic projections of nucleus caudalis in the squirrel monkey (Saimiri sciureus): a degeneration and autoradiographic study. J. Comp. Neurol. 178, 281–312. Garraghty, P. E., Florence, S. L., and Kaas, J. H. 1990a. Ablations of areas 3a and 3b of monkey somatosensory cortex abolish cutaneous responsivity in area 1. Brain Res. 528, 165–169. Garraghty, P. E., Florence, S. L., Tenhula, W. N., and Kaas, J. H. 1991. Parallel thalamic activation of the first and second somatosensory areas in prosimian primates and tree shrews. J. Comp. Neurol. 311, 289–299. Garraghty, P. E., Pons, T. P., and Kaas, J. H. 1990b. Ablations of areas 3b (S-I proper) and 3a of somatosensory cortex in marmosets deactivate the second and parietal ventral somatosensory areas. Somatosens. Mot. Res. 7, 125–135. Gauriau, C. and Bernard, J. F. 2004. A comparative reappraisal of projections from the superficial laminae of the dorsal horn in the rat: the forebrain. J. Comp. Neurol. 468, 24–56. Glendenning, D. S., Cooper, B. Y., Vierck, C. J., and Leonard, C. M. 1992. Altered precision grasping in stumptail macaques after fasciculus cuneatus lesions. Somatosens. Mot. Res. 9, 61–73. Gould, H. J., Whitworth, R. H., and LeDoux, M. S. 1989. Thalamic and extrathalamic connections of the dysgranular unresponsive zone in the grey squirrel (Sciurus carolinensis). J. Comp. Neurol. 287, 38–63. Groenewegen, H. J. and Witter, M. P. 2004. Thalamus. In: The Rat Nervous System (ed. G. Paxinos), pp. 407–453. Elsevier. Harris, R. M. and Hendrickson, A. E. 1987. Local circuit neurons in the rat ventrobasal thalamus – a GABA immunocytochemical study. Neuroscience 21, 229–236. Hassler, R. and Muhs-Clement, K. 1964. Architektonischer aufbau des sensomotorischen und parietalen cortex der katze. J. Hirnforsch. 6, 377–420.

Herron, P. 1983. The connections of cortical somatosensory areas I and II with separate nuclei in the ventroposterior thalamus in the raccoon. Neuroscience 8, 243–257. Herron, P. and Dykes, R. W. 1986. The ventroposterior inferior nucleus in the thalamus of cats: a relay nucleus in the Pacinian pathway to somatosensory cortex. J. Neurophysiol. 56, 1475–1497. Herron, P., Baskerville, K. A., Chang, H. T., and Doetsch, G. S. 1997. Distribution of neurons immunoreactive for parvalbumin and calbindin in the somatosensory thalamus of the raccoon. J. Comp. Neurol. 388, 120–129. Huffman, K. J. and Krubitzer, L. A. 2001. Area 3a: topographic organization and cortical connections in marmoset monkeys. Cereb. Cortex 11, 849–867. Iyengar, S., Qi, H.-X., Jain, N., and Kaas, J. H. 2007. Cortical and thalamic connections of the representations of the teeth and tongue in the somatosensory cortex of New World monkeys. J. Comp. Neurol. 501, 95–120. Jain, N., Diener, P. S., Coq, J. O., and Kaas, J. H. 2003. Patterned activity via spinal dorsal quadrant inputs is necessary for the formation of organized somatosensory maps. J. Neurosci. 23, 10321–10330. Johnson, J. I., Welker, W. I., and Pubols, B. H. 1968. Somatotopic organization of raccoon dorsal column nuclei. J. Comp. Neurol. 132, 1–44. Jones, E. G. 1975. Lamination and differential distribution of thalamic afferents within the sensory-motor complex of the squirrel monkey. J. Comp. Neurol. 160, 167–203. Jones, E. G. 1998. Viewpoint: the core and matrix of thalamic organization. Neuroscience 85, 331–345. Jones, E. G. 2007. The Thalamus, 2nd edn. Cambridge University Press. Jones, E. G., Schwark, H. D., and Callahan, P. A. 1986. Extent of the ipsilateral representation in the ventral posterior medial nucleus of the monkey thalamus. Exp. Brain Res. 63, 310–320. Jones, E. G., Wise, S. P., and Coulter, J. C. 1979. Differential thalamic relationships of sensory-motor and parietal cortical fields in monkeys. J. Comp. Neurol. 183, 833–882. Kaas, J. H. 1982. The Somatosensory Cortex and Thalamus in Galago. In: The Lesser Bush Baby (Galago) as an Animal Model: Selected Topics (ed. E. E. Haines), pp. 169–181. CRC Press. Kaas, J. H. 2004. Somatosensory System. In: The Human Nervous System, 2nd edn. (eds. G. Paxinos and J. K. Mai), pp. 1059–1092. Elsevier Academic Press. Kaas, J. H. 2007a. The Evolution of Sensory and Motor Systems in Primates. In: The Evolution of Primate Nervous Systems (eds. J. H. Kaas and T. M. Preuss), pp. 35–57. Elsevier. Kaas, J. H. 2007b. The Evolution of the Dorsal Thalamus in Mammals. In: The Evolution of Nervous Systems in Mammals (eds. J. H. Kaas and L. A. Krubitzer), pp. 500–516. Elsevier. Kaas, J. H. and Catania, K. C. 2002. How do features of sensory representations develop? Bioessays 24, 334–343. Kaas, J. H., Nelson, R. J., Sur, M., Dykes, R. W., and Merzenich, M. M. 1984. The somatotopic organization of the ventroposterior thalamus of the squirrel monkey, Saimiri sciureus. J. Comp. Neurol. 226, 111–140. Kaas, J. H., Nelson, R. J., Sur, M., Lin, C. S., and Merzenich, M. M. 1979. Multiple representations of the body within the primary somatosensory cortex of primates. Science 204, 521–523. Kaas, J. H., Qi, H.-X., and Iyengar, S. 2006. Cortical network for representing the teeth and tongue in primates. Anat. Rec. 288A, 182–190. Kalil, K. 1981. Projections of the cerebellar and dorsal column nuclei upon the thalamus of the rhesus monkey. J. Comp. Neurol. 195, 25–50.

The Somatosensory Thalamus and Associated Pathways Kenshalo, D. R. J., Giesler, G. J., Leonard, R. B., and Willis, W. P. 1980. Responses of neurons in primate ventral posterior lateral nucleus to noxious stimuli. J. Neurophysiol. 43, 1594–1614. Kerr, F. W. L., Kruger, L., Schwassmann, H. O., and Stern, R. 1968. Somatotopic organization of mechanoreceptor units in the trigeminal nuclear complex of the macaque. J. Comp. Neurol. 134, 127–144. Killackey, H. and Rhoades, R. W. 1995. The formation of a cortical somatotopic map. Trends Neurosci. 18, 202–407. Killackey, H. P. and Sherman, S. M. 2003. Corticothalamic projections from the rat primary somatosensory cortex. J. Neurosci. 23, 7381–7384. Kniffki, K.-D. and Mizumura, K. 1983. Responses of neurons in VPL and VPL-VL region of the cat to algesic stimulation of muscle and tendon. J. Neurophysiol. 49, 649–661. Krubitzer, L. A. and Kaas, J. H. 1987. Thalamic connections of three representations of the body surface in somatosensory cortex of gray squirrels. J. Comp. Neurol. 265, 549–580. Krubitzer, L. A. and Kaas, J. H. 1992. The somatosensory thalamus of monkeys: cortical connections and a redefinition of nuclei in marmosets. J. Comp. Neurol. 319, 1–18. Krubitzer, L. A., Huffman, K. J., Disbrow, E., and Recanzone, G. 2004. Organization of area 3a in macaque monkeys: contributions to the cortical phenotype. J. Comp. Neurol. 471, 97–111. Krupa, D. J., Ghazanfar, A. A., and Nicolelis, M. A. L. 1999. Immediate thalamic sensory plasticity depends on corticothalamic feedback. Proc. Natl. Acad. Sci. U. S. A. 96, 8200–8205. Lang, W., Bu¨ttner-Ennever, J. A., and Bittner, U. 1979. Vestibular projections to monkey thalamus: an autoradiographic study. Brain Res. 177, 3–17. Lee, C. C. and Woolsey, C. N. 1975. A proportional relationship between peripheral innervation and cortical neuron number in the somatosensory system of the mouse. Brain Res. 99, 349–353. Lenz, F. A., Garonzik, I. M., Zirh, T. A., and Dougherty, P. M. 1998. Neuronal activity in the region of the thalamic principal sensory nucleus (ventralis caudalis) in patients with pain following amputations. Neuroscience 86, 1065–1081. Lenz, F. A., Kwan, H. C., Dostrovsky, J. O., Tasker, R. R., Murphy, J. T., and Lenz, Y. E. 1990. Single unit analysis of the human ventral thalamic nuclear group: activity correlated with movement. Brain 113, 1795–1821. Li, L. and Ebner, F. F. 2007. Cortical modulation of spatial and angular tuning maps in the rat thalamus. J. Neurosci. 27, 167–179. Lin, C.-S., Merzenich, M. M., Sur, M., and Kaas, J. H. 1979. Connections of areas 3b and 1 of the parietal somatosensory strip with the ventroposterior nucleus in the owl monkey, Aotus trivirgatus. J. Comp. Neurol. 185, 355–372. Lue, J.-H., Lai, S.-M., Wang, T.-J., Shieh, J.-Y., and Wen, C.-Y. 1997. Synaptic relationships between corticocuneate terminals and glycine-immunoreactive neurons in the rat cuneate nucleus. Brain Res. 771, 167–171. Lund, R. D. and Webster, K. E. 1967a. Thalamic afferents from the dorsal column nuclei. an experimental anatomical study in the rat. J. Comp. Neurol. 130, 301–312. Lund, R. D. and Webster, K. E. 1967b. Thalamic afferents from the spinal cord and trigeminal nuclei. An experimental anatomical study in the rat. J. Comp. Neurol. 130, 313–328. Lundy, R. F. and Norgren, R. 2004. Gustatory System. In: The Rat Nervous System (ed. G. Paxinos), pp. 891–921. Elsevier. Luo, P., Wang, B. R., Peng, Z. Z., and Li, J. S. 1991. Morphological characteristics and terminating patterns of masseteric neurons of the mesencephalic trigeminal nucleus

139

in the rat: an intracellular horseradish peroxidase labeling study. J. Comp. Neurol. 303, 286–299. Luo, P., Wong, R., and Dessem, D. 1995. Ultrastructural basis for synaptic transmission between jaw-muscle spindle afferents and trigeminothalamic neurons in the rostral trigeminal sensory nuclei of the rat. J. Comp. Neurol. 363, 109–128. Ma, W., Peschanski, M., and Besson, J. M. 1986. The overlap of spinothalamic and dorsal column nuclei projections in the ventrobasal complex of the rat thalamus: a double anterograde labeling study using light microscopy analysis. J. Comp. Neurol. 245, 531–540. Maendly, R., Ru¨egg, D. G., Wiesendanger, M., Wiesendanger, R., Lagowska, J., and Hess, B. 1981. Thalamic relay for group I muscle afferents of forelimb nerves in the monkey. J. Neurophysiol. 46, 901–917. Mantle-St. John, L. A., and Tracey, D. J. 1987. Somatosensory nuclei in the brainstem of the rat: independent projections to the thalamus and cerebellum. J. Comp. Neurol. 255, 259–271. Mantyh, P. W. 1983. The spinothalamic tract in the primate: a re-examination using wheatgerm agglutinin conjugated to horseradish peroxidase. Neuroscience 9, 847–862. Martinez-Lorenzana, G., Machin, R., and Avendano, C. 2001. Definite segregation of cortical neurons projecting to the dorsal column nuclei in the rat. Neuroreport 12, 413–416. Massey, J. M., Hubscher, C. H., Wagoner, M. R., Decker, J. A., Amps, J., Silver, J., and Onifer, S. M. 2006. Chondroitinase ABC digestion of the perineuronal net promotes functional collateral sprouting in the cuneate nucleus after cervical spinal cord injury. J. Neurosci. 26, 4406–4414. May, P. J. and Porter, J. D. 1998. The distribution of primary afferent terminals from the eyelids of macaque monkeys. Exp. Brain Res. 123, 368–381. Mayner, L. and Kaas, J. H. 1986. Thalamic projections from electrophysiologically defined sites of body surface representations in areas 3b and 1 of somatosensory cortex of Cebus monkeys. Somatosens. Res. 4, 13–29. McAllister, J. P. and Wells, J. 1981. The structural organization of the ventral posterolateral nucleus in the rat. J. Comp. Neurol. 197, 271–301. McCloskey, P. I. 1974. Muscular and cutaneous mechanisms in the estimation of the weights of grasped objects. Neuropsychologia 12, 513–529. McCloskey, P. I. 1978. Kinesthetic sensibility. Physiol. Rev. 58, 763–820. Mehler, W. R., Feferman, M. E., and Nauta, W. J. H. 1960. Ascending axon degeneration following anterolateral cordotomy. An experimental study in the monkey. Brain 83, 718–750. Morel, A., Magnin, M., and Jeanmonod, D. 1997. Multiarchitectonic and stereotactic atlas of the human thalamus. J. Comp. Neurol. 387, 588–630. Mountcastle, V. B. 1997. The columnar organization of the neocortex. Brain 120, 701–722. Mountcastle, V. B. 2005. The Sensory Hand. Harvard University Press. Myasinkov, A. A., Dykes, R. W., and Avendano, C. 1994. Cytoarchitecture and responsiveness of the medial ansate region of the cat primary somatosensory cortex. J. Comp. Neurol. 349, 401–427. Nathan, P. W., Smith, M. C., and Cook, A. W. 1986. Sensory effects in man of lesions of the posterior columns and of some other afferent pathways. Brain 109, 1003–1041. Nelson, R. J. and Kaas, J. H. 1981. Connections of the ventroposterior nucleus of the thalamus with the body surface representations in cortical areas 3b and 1 of the cynomolgus macaque (Macaca fascicularis). J. Comp. Neurol. 199, 29–64.

140 The Somatosensory Thalamus and Associated Pathways Noriega, A. L. and Wall, J. T. 1991. Parcellated organization in the trigeminal and dorsal column nuclei of primates. Brain Res. 565, 188–194. Ohye, C., Shihazaki, T., Hirai, T., Kawashima, Y., Hirato, M., and Matsumura, K. 1993. Tremor-mediated thalamic zone studied in humans and in monkeys. Stereotact. Funct. Neurosurg. 6, 12–23. Padberg, J. and Krubitzer, L. A. 2006. Thalamocortical connections of anterior and posterior parietal cortical areas in New World titi monkeys. J. Comp. Neurol. 497, 416–435. Padberg, J., Disbrow, E., and Krubitzer, L. 2005. The organization and connections of anterior and posterior parietal cortex in titi monkeys: do New World monkeys have an area 2? Cereb. Cortex 12, 1938–1963. Paxinos, G., Huang, X. F., and Toya, A. W. 2000. The Rhesus Monkey Brain. Academic Press. Penny, G. R., Itoh, K., and Diamond, I. T. 1982. Cells of different sizes project to different layers of the somatic cortex in the cat. Brain Res. 242, 55–65. Poggio, G. F. and Mountcastle, V. B. 1963. The functional properties of ventrobasal thalamic neurons studied in unanesthetized monkeys. J. Neurophysiol. 26, 775–806. Pompeiano, O. and Brodal, A. 1957. Spino-vestibular fibers in the cat. An experimental study. J. Comp. Neurol. 108, 353–378. Pons, T. P. and Kaas, J. H. 1985. Connections of area 2 of somatosensory cortex with the anterior pulvinar and subdivisions of the ventroposterior complex in macaque monkeys. J. Comp. Neurol. 240, 16–36. Pons, T. P., Garraghty, P. E., Cusick, C. G., and Kaas, J. H. 1985. A sequential representation of the occiput, arm, forearm and hand across the rostrocaudal dimension of areas 1, 2 and 5 in macaque monkeys. Brain Res. 335, 350–353. Pons, T. P., Garraghty, P. E., and Mishkin, M. 1992. Serial and parallel processing of tactual information in somatosensory cortex of rhesus monkeys. J. Neurophysiol. 68, 518–527. Qi, H.-X. and Kaas, J. H. 2006. The organization of primary afferent projections to the gracile nucleus of the dorsal column system of primates. J. Comp. Neurol. 499, 183–217. Qi, H.-X., Lyon, D. C., and Kaas, J. H. 2002. Cortical and thalamic connections of the parietal ventral somatosensory area in marmoset monkeys (Callithrix jacchus). J. Comp. Neurol. 443, 168–182. Ralston, H. J. and Ralston, D. D. 1992. The primate dorsal spinothalamic tract: evidence for a specific termination in the posterior nuclei (Po/SG) of the thalamus. Pain 48, 107–118. Rausell, E. and Jones, E. G. 1991. Chemically distinct compartments of the thalamic VPM nucleus in monkeys relay principal and spinal trigeminal pathways to different layers of the somatosensory cortex. J. Neurosci. 11, 226–237. Rausell, E., Bae, C. S., Vinuela, A., Huntlery, G. W., and Jones, E. G. 1992. Calbindin and parvalbumin cells in monkey VPL thalamic nucleus: distribution, laminar cortical projections, and relations to spinothalamic terminations. J. Neurosci. 12, 4088–4111. Rinvik, E. 1968. The re-evaluation of the cytoarchitecture of the ventral nuclear complex of the cat’s thalamus on the basis of corticothalamic connections. Brain Res. 8, 237–254. Rouiller, E. M. and Welker, W. I. 2000. A comparative analysis of the morphology of corticothalamic projections in mammals. Brain Res. 53, 727–741. Rustioni, A. and Sotelo, C. 1974. Synaptic organization of the nucleus gracilis of the cat. Experimental identification of dorsal root fibers and cortical afferents. J. Comp. Neurol. 155, 441–468. Schwark, H. D., Tennison, C. F., Ilyinsky, O. B., and Fuchs, J. L. 1999. Inhibitory influences on receptive field size in the dorsal column nuclei. Exp. Brain Res. 126, 439–442.

Seike, M. 1993. A study of the area of distribution of the deep sensory neurons of the human ventral thalamus. Stereotact. Funct. Neurosurg. 61, 12–23. Sherman, S. M. and Guillery, R. W. 2006. Exploring the Thalamus and Its Role in Cortical Function. MIT Press. Smith, R. L. 1975. Axonal projections and connections of the principal sensory trigeminal nucleus in the monkey. J. Comp. Neurol. 163, 347–376. Spreafico, R., Schmechel, D. E., Ellis, L. C., and Rustioni, A. 1983. Cortical relay neurons and interneurons in the N. ventralis posterolateralis of cats: a horseradish peroxidase, electron-microscopic, Golgi and immuno-cytochemical study. Neuroscience 9, 491–509. Stepniewska, I., Collins, C. E., and Kaas, J. H. 2004. Connection patterns of dorsolateral visual cortex in macaques suggest the dorsal and ventral boundaries of V4. Cereb. Cortex 15, 809–822. Stepniewska, I., Sakai, S. T., Qi, H.-X., and Kaas, J. H. 2003. Distribution of somatosensory pathways in relation to thalamic neurons relaying information to the motor and premotor cortex in the macaque monkey. Soc. Neurosci. Abstr. 29, 60.16. Stevens, R. T., London, S. M., and Apkarian, A. V. 1993. Spinothalamocortical projections to the secondary somatosensory cortex (S-II) in squirrel monkey. Brain Res. 63, 241–246. Strata, F., Coq, J. O., and Kaas, J. H. 2003. The chemo- and somatotopic architecture of the Galago cuneate and gracile nuclei. Neuroscience 116, 831–850. Sur, M., Wall, J. T., and Kaas, J. H. 1984. Modular distribution of neurons with slowly adapting and rapidly adapting responses in area 3b of somatosensory cortex in monkeys. J. Neurophysiol. 51, 724–744. Waite, P. M. E. and Ashwell, K. W. S. 2004. The Trigeminal Sensory System. In: The Human Nervous System (eds. G. Paxinos and J. K. Mai), pp. 1093–1124. Elsevier. Wang, X. and Wall, J. T. 2005. Cortical influences on sizes and rapid plasticity of tactile receptive fields in the dorsal column nuclei. J. Comp. Neurol. 489, 241–248. Wang, X. and Wall, J. T. 2006. Cortical influences on rapid brainstem plasticity. Brain Res. 1095, 73–84. Weinberg, R. J., Pierce, J. P., and Rustioni, A. 1990. Single fiber studies of ascending input to the cuneate nucleus of cats: I. Morphometry of primary afferent fibers. J. Comp. Neurol. 300, 113–133. Welker, W. I. 1973. Principles of organization of the ventrobasal complex in mammals. Brain Behav. Evol. 7, 253–336. Whitsel, B. L., Petrucelli, L. M., Ha, H., and Dryer, D. A. 1972. The resorting of spinal afferents as antecedent to the body representation in the postcentral gyrus. Brain Behav. Evol. 5, 303–342. Wiener, S. I., Johnson, J. I., and Ostapoff, E.-M. 1987. Demarcations of the mechanosensory projection zones in the raccoon thalamus, shown by cytochrome oxidase, acetylcholinesterase, and Nissl stains. J. Comp. Neurol. 258, 509–526. Wiesendanger, M. and Miles, T. S. 1982. Ascending pathway of low-threshold muscle afferents to the cerebral cortex and its possible role in motor control. Physiol. Rev. 62, 1234–1270. Williams, M. N., Zahm, D. S., and Jacquin, M. F. 1994. Differential foci and synaptic organization of the principal and spinotrigeminal projections to the thalamus in the rat. Eur. J. Neurosci. 6, 429–453. Willis, W. D. and Coggeshall, R. E. 2004. Sensory Mechanisms of the Spinal Cord. Kluwer Academic. Willis, W. D., Zhang, X., Honda, C. N., and Giesler, J., Jr. 2002. A critical review of the role of the proposed VMpo nucleus in pain. J. Pain 3, 79–94.

The Somatosensory Thalamus and Associated Pathways Wilson, P., Kitchener, P. D., and Snow, P. J. 1999. Cutaneous receptive field organization in the ventral posterior nucleus of the thalamus in the common marmoset. J. Neurophysiol. 82, 1865–1875. Wise, S. P. and Jones, E. G. 1977. Cells of origin and terminal distribution of descending projections of the rat somatic sensory cortex. J. Comp. Neurol. 175, 129–158. Wu, C. W.-H. and Kaas, J. H. 2003. Somatosensory cortex of prosimian galagos: physiological recording, cytoarchitecture, and corticocortical connections of anterior parietal cortex and cortex of the lateral sulcus. J. Comp. Neurol. 457, 263–292. Xu, J. and Wall, J. T. 1996. Cutaneous representations of the hand and other body parts in the cuneate nucleus of a primate, and some relationships to previously described

141

cortical representations. Somatosens. Mot. Res. 13, 187–197. Zhang, X., Davidson, S., and Giesler, G. J. J. 2006. Thermally identified subgroups of marginal zone neurons project to distinct regions of the ventral posterior lateral nucleus in rats. J. Neurosci. 26, 5215–5223. Zhang, H. Q., Murray, G. M., Coleman, G. T., Turman, A. B., Zang, S. P., and Rowe, M. J. 2001. Functional characteristics of the parallel SI and SII projecting neurons of the thalamic ventroposterior nucleus in the marmoset. J. Neurophysiol. 85, 1805–1822. Zheng, A.-H., Wu, C.-P., and Xi, M.-C. 1986. Thalamic projection to motor area and area 3a of the cat cerebral cortex. Brain Res. 380, 389–393.