Download The Thalamic Projections of the Spinothalamic Tract

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The Nociceptive Thalamus: A Brief History
Luis Garcia-Larreaa,b and Michel Magnina
a
Central Integration of Pain Laboratory (NeuroPain), Center for Research in Neurosciences
of Lyon, INSERM U1028, Lyon, France; bCenter for Assessment and Treatment of Pain,
Neurological Hospital, Lyon, France
The Thalamic Projections
of the Spinothalamic Tract
Although J.W. Mott [70] had speculated that the “fasciculus spino-thalamicus” ended up in the ventral and lateral thalamus, the credit for the initial
description of the thalamic termination of spinothalamic fibers in humans
should go to Quensel [74], who in 1898 used the Marchi method to trace
the degeneration of spinal fibers to the “nucleus externus thalami” in the
brain of a patient who had suffered from a spinal lesion. His description
was soon followed by others [36,46], and these papers led to the notion,
which prevailed until the late 1950s, that the spinothalamic fibers terminated exclusively in the ventroposterolateral nucleus (VPL), overlapping
with fibers from the dorsal column medial lemniscus (e.g., [10,55,87]).
The notion that the thalamic recipients of the human “pain ascending systems” were not concentrated in the VPL nucleus, but included
other important thalamic targets, started to emerge in the mid-1950s,
thanks to the work of William Mehler. Using the Nauta staining method
Headache and Pain
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after anterolateral cordotomies in human and non-human primates, Mehler was able to describe profuse degenerating terminals within the posterobasal thalamus, in regions variously described as the “outlying caudal
part of the ventro-posterior-lateral nucleus” [64,65], “magnocellular medial geniculate” [89], “suprageniculate nucleus,” or “posterior nuclear group”
[73]. Thus, in 1965 Mehler could state that “neurological and clinical neurophysiological observations cast serious doubt on the classical notion that
the principal VPL and VPM thalamic nuclei represent significant neural
relays” of the nociceptive system [65]. Paradoxically, this conclusion was
not inconsistent with Quensel’s notion that the spinal projections ended
“in the most posterior region (hinteren Teilen) of the nucleus externus
thalami” [74]. This posterobasal thalamic region also corresponded to the
site where Hassler had reported being able to elicit selective localized pain
by electrical stimulation in humans [43], a site named by this same author
as “porta thalami.” By the end of the 1960s, all “early modern” investigators
were in agreement that there was a dense zone of spinothalamic termination at the caudal pole of the ventral posterior complex, although different
terminologies and atlases prevented them from reaching an agreement
on terminology (review in [56]). Although Mehler also observed spinothalamic degenerating fibers throughout the VPL nucleus, these fibers
appeared to form sparse “bursts” of degeneration—an “archipelago-like”
structure different from both the profuse more posterior spinothalamic
terminations and the homogeneous terminations of the VPL medial lemniscal afferents [65,66]. Lastly, Mehler’s experiments also described degenerating spinothalamic fibers in the medial thalamus. These fibers appeared
to be collaterals of those targeting the ventrobasal thalamus, which were
given off at right angles at the mesencephalic level, entered the thalamus
via the internal medullary lamina, and terminated in the parafascicularis,
mediodorsal, and central lateral nuclei.
Thus, by the 1970s it was already clear that the thalamic projections of the spinothalamic system were not concentrated on a single
nucleus, not even on a single circumscribed region, but rather included at least three separate areas: (1) a relatively sparse projection to the
principal somatosensory (VPL/VPM) nuclei; (2) a denser projection at
the caudal pole of the ventral posterior complex (VPI and posterior-suprageniculate complex in modern terminology [23]); and (3) a medial
The Nociceptive Thalamus
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projection to the parafascicularis, mediodorsal nuclei, and central lateral
intralaminar nuclei.
Cellular and Synaptic Differences
in the Thalamus Between Nociceptive
and Non-Nociceptive Afferent Systems
In subsequent years, research showed that input from lemniscal and spinothalamic systems reached different cell types in the thalamus, even in
nuclei where they converged anatomically. Thus, in the VPL/VPM nuclei,
medial lemniscal neurons projected to large and medium-sized cells that
were immunoreactive for parvalbumin, topographically arranged in “rods,”
and connected with middle cortical layers in S1 (primary somatosensory
cortex), whereas spinothalamic axons (including those from the trigeminal nucleus caudalis) projected to small cells distributed between rods,
with different immunoreactivity (parvalbumin-negative and calbindinpositive) and weak reactivity to cytochrome oxydase (CO) [79,80]. The
latter type of recipient cell appeared to be specifically associated with
the spinothalamic tract (STT), as other thalamic regions receiving high
concentrations of spinothalamic terminations (e.g., the ventral posterior
inferior nucleus, posterior-suprageniculate complex, and anterior pulvinar nucleus) had identical characteristics in terms of cell size, and histochemical or immunoreactive properties. This anatomical picture led
E.G. Jones and his group to conclude that “the small-celled, CO-weak,
calbindin-positive zones (…) appear to form part of a wider system of
small thalamic neurons unconstrained by traditional nuclear boundaries
that are preferentially the targets of spinothalamic and caudal trigeminal
inputs” [79].
The intrinsic arrangement of synaptic terminals also differentiates lemniscal and spinothalamic projections to their thalamic targets.
For instance, a common form of contact of lemniscal thalamic terminals
consists of three interacting cell types, called a “triad.” In this particular
arrangement, sensory terminals make synaptic contact with both a thalamocortical relay cell dendrite and a local GABAergic interneuron, which
itself is in contact with the same relay cell [12,42]. The “triadic synapse,”
first described in the visual system (the lateral geniculate nucleus), appears
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to function as a unit allowing rapid inhibition of the thalamocortical cell’s
discharge, resulting from the release of inhibitory transmitter by the excitation of the interneuron through the same afferent. This kind of triadic arrangement seems to be very prevalent in thalamic terminals from
the medial lemniscus system, as one study showed that more than 65%
of lemniscus axon terminals formed synaptic contacts with dendrites of
thalamocortical relay neurons and also with the dendritic appendages of
GABAergic interneurons [78]. In this same study, the synaptic contacts of
spinothalamic terminals were mostly devoid of triads, and in more than
95% of cases these terminals were found to form simple axodendritic synapses with relay cells, without contacting with GABAergic interneurons.
Thus, the thalamic synaptic relationships of nociceptive terminals appear
to be fundamentally different from those of non-nociceptive afferents.
Such functional differentiation of afferent classes by their synaptic structure is also common in other sensory systems, and for instance has been
shown to discriminate retinal terminals contacting X-type cells in the lateral geniculate from those that contact Y-type neurons [92,93]. The low
probability of spinothalamic afferents to contact GABAergic interneurons
indicates a smaller possibility of local modulation in the STT, as compared
with the medial lemniscal afferent input [76].
The Question of Pain Specificity
in the Posterior Thalamus
Neurons projecting to the thalamus via the spinothalamic (or caudal trigeminothalamic) system are located in the marginal zone (lamina I) and
neck (laminae IV–VI) of the dorsal horn. The cells in lamina I are activated
specifically by noxious stimuli (nociceptive-specific, or NS cells), whereas
neurons of deeper laminae respond in a graded fashion to innocuous and
painful stimuli and are termed wide-dynamic-range (WDR) cells. Mehler’s
work could not distinguish STT projections arising from different laminae
of the spinal cord dorsal horn, and it remained possible that degenerating
axons of lamina I fibers had a different thalamic region of termination than
those from deeper laminae. At the beginning of the 1990s, cumulative anatomical work had led to the general view that spinothalamic projections,
including those from lamina I, were extensive rather than concentrated,
The Nociceptive Thalamus
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and that they reached different thalamic domains including lateral, posterior, and intralaminar nuclei [e.g., 1,3,8]. Gingold and coworkers [35] studied terminal STT-like structures in the thalamus of squirrel monkeys after
spinal injections of wheat germ agglutinin-horseradish peroxidase (WGAHRP). They suggested that the ventral posterior lateral (VPL), ventral posterior inferior (VPI), and central lateral (CL) nuclei, combined, receive
almost 90% of spinothalamic inputs from the cervical enlargement. These
authors were unable, however, to determine the precise origin of STT afferents to each nucleus within the dorsal horn. One year later, Ralston and
Ralston [77] published their finding of combined anterograde transport
of WGA-HRP with selective cordotomies, offering the conclusion that
the more dorsal aspect of the spinothalamic pathway, thought to contain
many axons from lamina I, projected primarily to the posterior/suprageniculate group (PO/SG). Stimulation to this region, which lies posterior to
the VPL/VPM nuclei, was also found to elicit thermal and pain sensations
in humans [57,61]. Shortly afterward, Craig and colleagues [21] used anterograde tracing coupled with single-unit recordings to study the thalamic projections of lamina I neurons, and claimed to have found that their
site of termination was a very restricted region of the posterior thalamus,
with only some sparse additional projections to the mediodorsal nucleus
and still weaker input to the ventral posterior group. In a series of papers
that included technically sound and highly detailed studies, Craig and
his colleagues posited the existence of a specific thermosensory nucleus
within this region, which they claimed could be characterized by cytoarchitectonic, immunostaining, and synaptology methods, and which
they labeled “ventromedial posterior nucleus” (VMpo) [7,9,20,21]. Three
very strong conclusions were put forward from these studies: (1) that the
VMpo represented “a specific thalamic nucleus for pain and temperature
in both monkey and human”; (2) that a lesion of the VMpo underlay the
analgesia and thermanesthesia of the thalamic pain syndrome; and (3)
that central pain in humans was explained by selective injury to the VMpo
nucleus, or to the spinal pathway leading to it. Such lesions would supposedly disinhibit a medial thalamic pathway responsible for central pain
and cold allodynia (reviewed in [14]). The proposal that VMpo was “the”
specific primate thalamic nucleus for pain and temperature was combined
with the assertion that the largest somatosensory nuclei (VPL/VPM)
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receive very few afferent lamina I axons. Indeed, the introduction to some
of their key papers does not even mention the VPL/VPM as receiving
any lamina I projections [9]. This omission was highly controversial, especially in the light of previous studies from other groups, in particular
W.D. Willis, F.E. Lenz, and E.G. Jones (e.g., [90]). Not surprisingly, Craig’s
postulates set off a lively controversy both among neuroanatomists and
pain clinicians, which lasted most of the first decade of the 21st century,
with some aspects remaining in contention. The two following sections
describe the anatomical and clinical implications, as well as the current
state of this controversy.
“The VMpo Anatomical Affair”
Craig et al.’s views on spinothalamic projections to the thalamus were contested rapidly and vividly by a number of specialists in thalamic anatomy.
The most substantial criticisms concerned (1) the anatomical credibility
of a separate nucleus in the zone regarded as crucial by Craig, and (2) the
particular synaptology of spinothalamic afferents in this particular zone.
Concerning synaptology, Craig’s group reported that about 60% of labeled
STT boutons in the VMpo exhibited a “triadic” arrangement with relay
cell dendrites [7]. However, as commented above, previous work on STT
terminals had shown that synaptic triads were typical of lemniscal thalamic afferents, but very rare in STT projections to thalamic relay neurons. Indeed, Ralston and Ralston [78] found that STT terminals contacted GABAergic interneurons and formed triads in only 4% of all synaptic
appositions (1% in single sections), the other 96–99% being contacts with
the dendrites of projection neurons. This discrepancy was very surprising;
it cast some doubt on the reliability of the supposed STT/triad connection, and was underscored in a swift and elegant manner in a commentary
article by H.J. Ralston [75]. More scathingly critical papers on other anatomical aspects of the VMpo were to follow soon.
Graziano and Jones [37] analyzed the terminal arbors of lamina I
fibers projecting to the calbindin-immunoreactive zone identified by Craig
and his colleagues as the “primary thalamic relay” for these fibers, and thus
for pain. They did not confirm the specificity of such a zone, nor the existence of an identifiable nucleus; rather, they reported that the densest region of calbindin immunoreactivity was “part of a more extensive region
The Nociceptive Thalamus
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lying within the medial tip of the VPM nucleus.” They further indicated
that fiber terminations of lamina I projections were widespread and not
restricted to this calbindin-rich zone and that the lamina I arising fibers
were not themselves calbindin immunoreactive. The injections in lamina
I described by Craig et al. [21] were considered “too small and too limited
in rostrocaudal extent” to permit projections to other thalamic sites to
be ruled out, and incapable of labeling a sufficient number of cells to reveal the widespread pattern of projections from lamina I to the thalamus
[49,75,91]. Graziano and Jones [37] baldly considered that their findings
“disproved the existence of VMpo as an independent thalamic pain nucleus or as a specific relay in the ascending pain system.” Not surprisingly,
the above conclusions were strongly disputed by Craig [16,17], who suggested that a difference in the specific calbindin antibodies used by each
group (monoclonal versus polyclonal) might underlie the discrepancies.
This explanation was considered unlikely, however, since Western blot
analysis of both antibodies showed that they were directed against identical epitopes [37,49].
This very hot discussion tapered off somewhat in the following
years. The amount of data challenging the VMpo as a separate and lamina I-specific recipient nucleus became more and more important (e.g.
[50,56]), and in parallel, Craig’s views on such specificity also tended to
smooth out. Thus, consecutive papers from Craig’s group in cats and
monkeys demonstrated lamina I projections reaching lateral and medial
thalamic regions outside the “VMpo” zone, including the parafascicularis
and mediodorsal nuclei, the habenula, the zona incerta, the VPI, and the
VPL/VPM complex [15,16,18,19]. The putative anatomical location of the
“VMpo” also changed a little in subsequent articles (compare [9], [21],
and [18]). The prevailing view among thalamic experts in 2013 is that the
VMpo region does not constitute a differentiated nucleus on its own, but
rather a region included within the posterior complex and adjacent nuclei
(PO/SG), which is a major recipient of spinothalamic axons [26,56].
Even if the notion of a “VMpo” nucleus as principal thalamic relay
for noxious information does not seem to have resisted the passing of
time, several interesting epiphenomena were driven by the controversy
that it was able to launch. One was that it prompted extensive literature
reviews and meta-analyses by a number of experts, which helped to refine
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and reconstruct the anatomy of the nociceptive thalamus (e.g., [50,56]).
Also, Craig et al.’s work underscored the relatively limited importance of
the VPL/VPM nucleus in the processing of nociceptive-specific information, in line with Mehler’s thoughts in the 1960s (see the beginning of
this chapter). Indeed, the anatomical projection study of Apkarian and
Shi [3] had already suggested a proportion of less than 10% of nociceptive cells in VPL, contrasting with 50% in VPI and 40% in the posterior
group, and coupled stimulation and recording studies by Lenz and coworkers [60,61] had also shown that only 6% of recorded neurons in the
cutaneous core of the human principal sensory nucleus had greater responses to noxious than innocuous heat. Even in the studies of Willis and
his coworkers [90,91], the proportion of retrograde-labeled neurons in
lamina I after VPL/VPM injections, although described as “numerous,”
represented only 12–25% of labeled neurons, while the contribution of
neurons in deep laminae amounted to 80%. A more recent study from
Craig [18] found only 8% of lamina I neurons labeled following injections
to be restricted to VPL, this percentage increasing to 21% when injections impinged on the VPI and PO regions. It has now become clear that
lamina I projections to VPL, although they do exist, represent a minority
of STT projections. Last and surely not least, the stress put by Craig on
“labeled” versus “multimodal” STT lines has prompted renewed interest
in functionally differentiable components within the primate STT. Modality segregation of nociceptive inputs had already been suggested in
stimulation studies by Lenz and coworkers [58,61], since thalamic neurons responding to painful mechanical stimulation were located within
the core of the human Vc (VPL), while thermal/pain sensations were
elicited primarily by stimulation within, or in the border of, the posterior-inferior thalamus. The sites where thermal pain was evoked were
consistent with the posterior nuclear (PO) group, lateral to, but not far
from, the putative location of the “VMpo” subregion (see Fig. 2 in ref.
[9]). A parsimonious interpretation of these data is therefore (1) that the
“VMpo” area is not a distinct nucleus but a region included in the PO/SG
nuclear group [26,50,56,75], and (2) that this region receives substantial
thermal input from lamina I, while input to the principal somatosensory
nucleus (VPL) from lamina I would be scarce and perhaps of essentially
mechanical origin.
The Nociceptive Thalamus
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Thalamic Nuclei and Central Pain
In parallel to their anatomical views, Craig et al. considered their “VMpo
finding” as crucial to explain the pathogenesis of central pain in humans.
They considered that lesions of the VMpo could explain the thermoanesthesia observed in patients with thalamic syndrome, since the “VMpo”
location corresponded “to the area in which infarcts cause anesthesia and
thermoanalgesia (…) and can lead to central pain.” In this perspective,
central pain was explained by “injury to a cool-signaling pathway through
VMpo, which disinhibits a nociceptive medial thalamic pathway producing central pain and cold allodynia” [13]. This concept was not merely to
be added to other central pain pathogeneses, but, in Craig’s view, provided
“a concrete explanation for central pain” [9,21; review in 14].
This putative explanation was, however, very rapidly dismissed by
the majority of clinical work on central pain patients. Greenspan et al.
[40] evaluated quantitatively the sensory abnormalities in 13 patients with
central poststroke pain (CPSP). They showed that, contrary to Craig’s hypothesis, cold hypoesthesia was neither necessary nor sufficient for cold
allodynia to develop. For instance, while 11 of 13 patients exhibited cold
hypoesthesia, only 2 of them had cold allodynia. And inversely, the most
dramatic case of cold allodynia occurred in a patient who had normal detection thresholds for cold. In central syndromes due to spinal lesions,
both Ducreux et al. [25] and Hatem et al. [45] showed that cold hypoesthesia could not discriminate between patients with or without neuropathic pain. Also, a number of authors specifically examined Craig’s central hypothesis, namely that thalamic lesions must include the region of
the VMpo to result in loss of cold sensibility, cold allodynia, and CPSP.
Montes and coworkers [68] performed an extensive study of a patient
with a focal thalamic lesion and central pain who could be followed up for
several years. The thalamic lesion, precisely localized using 3D magnetic
resonance imaging along with Morel’s human thalamic atlas [69], involved
the VPL and to a lesser extent the VPM, VPI, and pulvinar anterior nuclei,
but did not extend posteriorly and ventrally enough to include the putative location of the “VMpo.” Central pain in this patient coexisted with
hypoesthesia for all sensory modes, including cold, as well as very important and drug-resistant allodynic symptoms, including cold allodynia, underscoring that both central pain and cold allodynia could develop in the
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absence of injury to the region described as the “VMpo nucleus.” Similar
results were reported by Kim and coworkers [53], who examined four patients with thalamic strokes and CPSP and/or dysesthesias. Lesions could
affect the VPL (Vc) exclusively or might also involve more posterior nuclei
(Vc portae and pulvinar anterior), but never reached the “VMpo.” More
recently, it was reported that the thalamic region where lesions had the
maximal likelihood of causing pain was situated at the junction between
the VPL and pulvinar anterior nuclei [84], demonstrating once again that
lesions involving the lateral-posterior thalamus outside the “VMpo” region are sufficient to produce central pain.
Despite the fact that a specific link between the “VMpo” and central pain could be dismissed, the anatomical-clinical controversy promoted healthy efforts that helped to clarify relations between thalamic lesions,
sensory deficits, and central pain. For instance, in the study of Montes and
her coworkers [68], somatosensory evoked potentials showed that a lesion centered in the VPL greatly attenuated lemniscal responses (reducing
them by 67%), to a much greater extent than those mediated exclusively
by the STT (with a reduction of only 33%). This finding led the authors to
conclude that, although the VPL was involved in thermoalgesic transmission in humans, many of the spinothalamocortical volleys do not transit
through the VPL, supporting the existence of pain-processing loci more
posteriorly in the human thalamus. The paucity of the VPL’s contribution
to thermal processing was also put forward by Kim and coworkers [53],
who noted, using quantitative sensory testing, that cold and warm hypoesthesia were not observed in the smallest VPL lesion, and that thermal sensory loss needed a relatively important volume of the VPL to be destroyed.
All these results are consistent with the known distribution of STT projections to VPL, which form sparse (“archipelago-like”) clusters very different
from the dense and profuse posterior spinothalamic terminations in most
posterior (PO/SG) nuclei (e.g. [65]).
Spinothalamic Projections to the Cortex
Given the extensive thalamic distribution of STT afferents, it is expected
that the cortical projections of the corresponding relay thalamic cells are
also widely distributed, rather than concentrated to the S1 areas, as is the
The Nociceptive Thalamus
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case with the lemniscal system. A number of cortical regions receiving input from thalamic STT recipients were determined during the 1980s and
1990s, in particular: (1) S1, receiving afferents from VPL/VPM [35]; (2) the
parietal operculum/S2, with major afferents from the VPI (and to a small
extent from VPL) [27,85]; (3) the insular and retroinsular cortices, interconnected with PO/SG and pulvinar nuclei [27,71]; and (4) the cingulate
cortex, connected with the intralaminar and mediodorsal nuclei [44,82].
Such descriptions could not determine the relative importance of each of
these connections, relative to the whole STT system, and could not prove
that STT ascending information was actually relayed to each of the cortical targets described. Therefore, the actual cortical targets of the spinothalamic system (STS) remained the subject of considerable controversy
during the last decade, in particular among defendants of a significant role
of the primary somatosensory cortex (S1, areas 1–3) and those who minimized or excluded its participation (see e.g. [14,91].
This controversy was partially solved by comprehensive quantitative analyses on the cortical projections of the primate STS by Dum,
Levinthal, and Strick [26]. These authors injected a strain of herpes virus
(H129 of HSV1) into lower cervical segments of the spinal cord, at multiple depths consistent with those of laminae I, V, and VII, from which
the essential spinothalamic axons arise in monkeys [2]. Using this technique, the virus is taken up by first-order neurons at the injection site and
transported in the anterograde direction to the thalamus. There, it moves
trans-synaptically to infect second-order thalamic neurons, the cortical
projections of which transport the virus to the cerebral cortex, where it
trans-synaptically infects third-order neurons. The neurons labeled in
the thalamus with this method corresponded well to the thalamic STT
targets described in previous sections, with major labeling in VPI, VPL,
CL, mediodorsal nuclei, and the PO/SG complex, and also clusters in pulvinar anterior, ventrolateral, and midline nuclei. The projections of such
spinothalamic neurons reached essentially three areas in the contralateral hemisphere: 41% of the labeled neurons were found in the posterior
granular insular cortex, 29% in the medial portion of the parietal operculum (considered to contain S2), and 24% in the motor subregions of the
mid-cingulate cortex. The remaining 6% of the neurons were distributed
between the somatomotor region (Brodmann areas 1–4), and posterior
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parietal areas 7 and 5. Thus, more than 90% of the STS projections to the
primate cortex were distributed within just three cortical areas, namely
the posterior granular insula, the medial part of S2, and the motor midcingulate regions. This cortical distribution is in accordance with electrophysiological recordings in humans, which have shown that the earliest
cortical responses to nociceptive-specific (laser) stimulation arise precisely from the posterior insula, medial parietal operculum, and mid-cingulate
cortex [28,31,33,59], with some additional contribution of S1/M1 and posterior parietal cortices [5,30]. Responses from operculoinsular areas are
thought to sustain sensory spinothalamic processing, while those from the
motor cingulate cortex support orienting and withdrawal reactions driven
by noxious stimuli. As expected from parallel projections from thalamus
to cortex, the initial operculoinsular, S1/M1, and mid-cingulate responses
have been shown to start simultaneously in human intracortical recordings [30,31]. The different cortical targets can, however, be differentially
modulated by physiological changes, and for instance the motor-orienting
cingulate responses are much more drastically attenuated during sleep
compared with the sensory insular and opercular potentials [6].
The specificity of the operculoinsular region as a spinothalamic
receptive area has received abundant corroboration by clinical and experimental studies in humans. A substantial number of reports have demonstrated that posterior insular and opercular lesions give rise to selective
spinothalamic deficits, but preserve discriminative touch and proprioception [4,34,39,41,47,54] (review in [32]). This finding contrasts markedly with focal lesions of the primary sensory cortex S1, which, since the
first description of the “cortical parietal syndrome” by Verger [86], are
known to preserve spinothalamic-type (pain and temperature) sensations
[4,54,86]. Moreover, the opercular and insular cortex is the only cortical
region where focal electrical stimulation can elicit pain sensations in humans [63], and where an epileptogenic lesion can produce purely painful
seizures [48]. Direct stimulation of S1, in contrast, rarely, if ever, produces
pain (e.g., [72]), in accordance with the paucity of nociceptive-specific
neurons found in this area [51] or in the VPL nucleus [3,18,90] (but see
contrasting results in [35]). Thus, while studies in both monkeys and humans confirm that S1 receives STS input, functional anatomy and clinical
data indicate that this input is relatively weak, and tend to relegate S1 “to a
The Nociceptive Thalamus
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subordinate role in nociceptive processing” [26]. It is likely, however, that
in environmental conditions (in the absence of a lesion), S1 does participate in the encoding of the intensity of a noxious stimulus (e.g. [52]), since
noxious stimuli in real life most commonly activate nociceptive and nonnociceptive afferents simultaneously.
Specialization of Spinothalamic Receiving
Areas: Labeled Lines or Network Properties?
While the posterior insula and the parietal operculum are both cortical
reception areas for STS projections, their functional role in the processing
of noxious inputs may not be identical. For instance, in humans, cortical
stimuli evoking nonpainful warm or cold sensations tend to concentrate
in the medial operculum, while those eliciting acute pain predominate in
the posterior dorsal insula [62,63]. Also, intracortical evoked potentials
in humans showed that the opercular region was able to encode low levels of thermal change, whereas the posterior insula responded only when
stimuli had almost reached the subjective pain threshold [11,29]. “Labeled
lines” conducting different spinothalamic submodalities could explain
such functional differences, and in this vein, Craig has suggested that the
STS input to the posterior insula would originate from nociceptive-specific neurons in lamina I, whereas input to S2 in the operculum would derive
primarily from WDR neurons in lamina V [14,18]. Explaining functional
segregation by labeled lines shows, however, obvious limits as well. For instance, single-unit recording in monkeys failed to discover any differences
in response properties in the posterior insula and its adjacent operculum
[81,83], and there is much evidence of convergence of autonomic and somatosensory input both in the insula proper and in thalamic units projecting to the insula [94]. Spinothalamic neurons responding to mechanical
pain and thermal heat also respond to itching in primates [22,24]. Segregation of submodalities in sensory cortices may therefore not rely uniquely
on the intrinsic properties of individual “labeled” neurons, but also (or
predominantly) on stimulus timing and network properties. Accordingly,
discrimination of noxious from innocuous stimuli has been suggested
to rely on temporal network dynamics and reverberation within thalamocortical loops [88], and timing and duration of thalamic and insular
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activity were the most conspicuous differences between itch- and painrelated sensations in humans [67]. The posterior insula has a much more
extended connectivity pattern than the opercular region and S2, and this
distinction may also sustain their functional differences. In particular,
the massive amount of afferent input to the insula may entail greater
background activity than in the operculum, therefore obstructing the
precise encoding of low-energy stimuli that barely emerge from background noise. This feature might explain why posterior insula networks
are biased toward nociception [29], despite the fact that approximately
70% of primate insular neurons can respond to non-noxious somatic inputs too [81]. In summary, without denying the existence of labeled lines
for sensory information, afferent signals generated in the periphery need
not be obligatorily “carried through” to the cerebral cortex in labeledline systems (review in [38]). The cortex can create segregation by its
internal properties, and network activity rather than intrinsic attributes
of individual neurons can tune a region toward one functional significance or another.
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Correspondence to: Luis Garcia-Larrea, MD, PhD, Center for Assessment and
Treatment of Pain, Neurological Hospital, 59 Bd. Pinel, 69003 Lyon, France.
Email: [email protected].