Pain syndromes and the parietal lobe

Handbook of Clinical Neurology, Vol. 151 (3rd series) The Parietal Lobe G. Vallar and H.B. Coslett, Editors https://doi.org/10.1016/B978-0-444-63622-5.00010-3 Copyright © 2018 Elsevier B.V. All rights reserved

Chapter 10

Pain syndromes and the parietal lobe LUIS GARCIA-LARREA1,2* AND FRANÇOIS MAUGUIÈRE1,3 NeuroPain Laboratory, Lyon Centre for Neuroscience, Inserm U1028 and University Claude Bernard, Lyon, France

1

Center for the Evaluation and Treatment of Pain, H^ opital Neurologique, Hospices Civils de Lyon, Lyon, France

2

Functional Neurology Service, H^opital Neurologique, Hospices Civils de Lyon, Lyon, France

3

Abstract Pain was considered to be integrated subcortically during most of the 20th century, and it was not until 1956 that focal injury to the parietal opercular-insular cortex was shown to produce selective loss of pain senses. The parietal operculum and adjacent posterior insula are the main recipients of spinothalamic afferents in primates. The innermost operculum appears functionally associated with the posterior insula and can be segregated histologically, somatotopically and neurochemically from the more lateral S2 areas. The Posterior Insula and Medial Operculum (PIMO) encompass functional networks essential to initiate cortical nociceptive processing. Destruction of this region selectively abates pain sensations; direct stimulation generates acute pain, and epileptic foci trigger painful seizures. Lesions of the PIMO have also high potential to develop central pain with dissociated loss of pain and temperature. The PIMO region behaves as a somatosensory area on its own, which handles phylogenetically old somesthetic capabilities based on thinly myelinated or unmyelinated inputs. It integrates spinothalamic-driven information – not only nociceptive but also innocuous heat and cold, crude touch, itch, and possibly viscero-somatic interoception. Conversely, proprioception, graphesthesia or stereognosis are not processed in this area but in S1 cortices. Given its anatomo-functional properties, thalamic connections, and tight relations with limbic and multisensory cortices, the region comprising the inner parietal operculum and posterior insula appears to contain a third somatosensory cortex contributing to the spinothalamic attributes of the final perceptual experience.

A WOUNDED LIEUTENANT On March 13, 1915, during the First World War, a French lieutenant was hit in the head by a Mauser bullet, causing a fracture in the left parietal region. Upon recovery from transient right hemiplegia, he was left with sensory troubles in the right arm and leg that had not been described previously in the medical literature. Less than 1 year later, Dejerine and Mouzon (1915) reported his case to the French Neurological Society, in what became the first description of a focal cerebral lesion entailing the selective loss of pain and temperature sensations, plus partially tickle and vibration. The authors were puzzled by this case:

since sensibility is affected in a way totally different to that commonly encountered in monoplegia or hemiplegia of cortical origin. ... Pain, temperature and vibration, which were respected in our [previous] reports, are on the contrary very much altered in this case, while the other modes of sensibility are almost entirely intact (light contact, tactile identification, localisation and discrimination; sense of segmental attitudes, of pressure, of weight; stereognostic perception; motor coordination. In 1915 this new “parietal” condition appeared as a mirror image of the classic parietal sensory syndrome, identified at the beginning of the 20th century

*Correspondence to: Luis Garcia-Larrea, H^opital Neurologique, 59 Bd Pinel, 69003 Lyon, France. Tel: +33-472357888, E-mail: [email protected]

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(Verger, 1900; Dejerine, 1914) and characterized by loss of positional sense, discriminative tact, and stereognosis with retention of touch, temperature, and pain. Although the Dejerine–Mouzon syndrome was considered as a “parietal” syndrome, pathologic examination of the patient’s brain was never available, and the exact cortical origin of his sensory dissociation remained a mystery.

IS THE CORTEX INVOLVED IN PAIN SENSATION? In line with Hitzig (1900), who had stated categorically that pain sensation was formed subcortically, Head and Holmes (1911), in their monumental work on sensory disturbances from brain lesions, suggested that pain was integrated in the thalamus, and that cortical damage produced at most a temporary loss in pain sensation. Following such influential work, physiologic views on nociception during the first half of the last century remained largely dominated by the idea that the cortex was not involved in the perception of pain (Foerster, 1927). A number of reports, however, mostly emerging from the analysis of war wounds, progressively contradicted these views. Karl Kleist (1922, 1934) in Germany, and Pieron (1923) in France reviewed their wartime experiences with cortical injury and reported cases that had demonstrated hypoalgesia as the predominant, or exclusive, sensory disturbance. In parallel, case reports were being reported with definite alteration of pain sensation from cortical lesions, usually quite extensive, but sparing the thalamus on pathologic examination (Guillain and Bertrand, 1932; Davison and Schick, 1935). In 1951 John Marshall described a series of 10 patients with cortical injuries sustained in World War II and resulting in permanent alteration of pain sensibility. He was one of the first to conclude that “the cortex is intimately concerned with appreciation of pain.” Despite such accumulated clinical evidence, no distinct pathologic analysis could determine a cortical focus responsible for isolated pain and temperature alterations, until Biemond (1956), in a beautifully precise paper, described 2 patients presenting with selective loss of pain and temperature sense, but preserved proprioception and tactile discrimination, following lesions involving selectively the parietal opercular and insular cortices. In contrast to Dejerine and Mouzon’s case, one of Biemond’s patients also developed neuropathic pain contralateral to the lesion, and the pain was so terrible as to lead the patient to commit suicide: Dejerine–Mouzon syndrome had acquired the stature of central poststroke pain.

POSTSTROKE PAIN AND SOMATOSENSORY DEFICITS The history of poststroke pain started in 1906, when Dejerine and Roussy described what they called “thalamic syndrome,” based on the postmortem findings of 3 patients who developed pain following thalamic stroke. Their description indicated “mild hemiplegia without contractures, persistent hemianaesthesia with impaired deep sensation, mild hemiataxia, astereognosis, and in addition ... severe, persisting, paroxysmal, often intolerable pain.” Despite Dejerine and Roussy reporting that pain was an inconstant feature of the syndrome, the label “thalamic pain” was rapidly ascribed to pain following all types of supratentorial stroke, whether or not it involved the thalamus. The prevailing notions at that time were indeed: (1) that noxious influxes were integrated at thalamic level, and inhibited via corticothalamic connexions; and (2) that the dorsal column and medial lemniscus proprioceptive system exerted inhibitory influences upon the pain-conducting system, and loss of this inhibition was the main cause of central pain (Head and Holmes, 1911; Foerster, 1927; Riddoch, 1938; Nathan et al., 1986; Schott et al., 1986). The increasing number of cases with “pseudothalamic pain” linked to cortical lesions was therefore interpreted within this framework (Davison and Schick, 1935; Lhermitte and de Ajuriaguerra, 1935; Riddoch, 1938) and considered to entail some kind of “disinhibition pain.” These ideas were not clearly contradicted until the end of the 1980s, when systematic study of patients with central lesions at spinal, brainstem, thalamic, and suprathalamic level established that central pain was associated with spinothalamic involvement (indicated by impairment of pinprick and thermal sensation), while injury of the dorsal column proprioceptive pathways was not essential (Beric et al., 1988; Boivie et al., 1989; Vestergaard et al., 1995; Schott, 1996). Most importantly, it also became progressively clearer that, while superficial parietal lesions disturbed position sense and stereognosis without impairing pain sensations, only cortical lesions involving the deep parietal lobes were able to disturb pain perception and generate central pain. Such deep parietal lesions were consistently reported to include the parietal operculum and the posterior insula (Bassetti et al., 1993; Takeda, 2004; Kim, 2007). Cortical terminations of the spinothalamic system transmitting pain must therefore reach directly deep cortical areas, in the insula and suprasylvian operculum, as Biemond (1956) had suggested more than 30 years before.

PAIN SYNDROMES AND THE PARIETAL LOBE

THE CORTICAL TARGETS OF THE SPINOTHALAMIC SYSTEM IN PRIMATES While the thalamic targets of the spinothalamic system have been analyzed since the 1960s (e.g., Mehler, 1966), the main projections of this system to the cerebral cortex in primates have only been determined recently, using electrophysiology in humans and tracer studies in nonhuman primates. Dum and his colleagues (2009) injected herpesvirus within laminae I, V, and VII of the spinal dorsal horn of macaques, from which the essential portion of spinothalamic system arises, allowing the virus to be transported rostrally and infect second-order (thalamic) and third-order (cortical) neurons receiving spinothalamic projections. The vast majority of spinothalamic cortical targets were found in the posterior insular cortex (
40%), in the medial parietal operculum (
30%), and in the midcingulate cortex (
24%). These areas have also been noted as being the sources of the earliest cortical responses to thermo-nociceptive stimuli in humans, either through source reconstruction of scalp electroencephalogram (EEG) signals, or after subdural and intracortical recordings (Lenz et al., 1988a, b; Frot et al., 1999, 2008; Treede et al., 2000; Garcia-Larrea et al., 2003). The same regions have also been described in functional imaging studies (positron emission tomography scan or functional magnetic resonance imaging (fMRI)) as being the areas most frequently activated by noxious stimuli, whether thermal or mechanical (Peyron et al., 2000; Apkarian et al., 2005; Garcia-Larrea and Peyron, 2013). Given the respective functional aspects of these different areas, networks within the midcingulate were considered to support essentially the motor concomitants of nociception, including orienting, withdrawal, and vocalization (e.g., Vogt, 2016), whereas afferents to the posterior insula and parietal operculum were thought to contribute to sensory aspects of spinothalamic processing. Almost at the same time, intracranial recordings in humans showed that the timing of operculoinsular and midcingulate responses to nociceptive stimuli was virtually identical, at least in their early phases (Frot et al., 2008), providing further evidence that lateral sensory and medial motor nociceptive systems were activated in parallel by spinothalamic input, rather than sequentially, as had been previously considered.

THE POSTERIOR DORSAL INSULA/MEDIAL PARIETAL OPERCULUM AS A FUNCTIONAL UNIT Evidence for different functional areas within the parietal operculum of mammals, especially primates, has accumulated since the 1990s, leading to functional

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segmentation and redefinition of a cortex that was sometimes loosely labeled “S2” (Krubitzer and Kaas, 1990; Krubitzer and Calford, 1992; Burton et al., 1995; Krubitzer et al., 1995; Qi et al., 2002; see review in Kaas and Collins, 2003). Four distinct areas with their own somatotopic representations have been described in monkeys, two in the lateral parietal operculum (S2 proper and parietal ventral area, or PV), and two in its medial part (caudal and rostral ventral somatosensory (VS) areas) (Kaas and Collins, 2003; Coq et al., 2004). In humans, histologic examination of 10 postmortem brains also identified four distinct opercular regions, labeled OP1 to OP4 by Eickhoff and colleagues (2006a, b). Two of these areas are lateral in the operculum (OP1 and OP4) and correspond to S2 proper (¼ OP1) and PV (¼ OP4) (see Figure 3 in Eickhoff et al., 2006b). The two medial regions, contiguous with the insula, appear as the human equivalents of the monkey’s VS area ( ¼ human OP3) and retroinsular vestibular cortex (
human OP2) (Eickhoff et al., 2006b, 2007; Gallay et al., 2012). An intimate macro- and microscopic relationship exists between the medial operculum and the adjacent posterior insula in both human and nonhuman primates, to the point that the two areas can be said to represent a functional unit. Thus, the two medial opercular areas extend into the insular domain beyond the circular sulcus (Kurth et al., 2010; Gallay et al., 2012), and the somatotopic representation in the inner operculum (OP3 in humans, VS in monkeys) follows an anteroposterior axis similar to that observed in the posterior insula, and different from the mediolateral somatotopy observed in the lateral operculum (Krubitzer et al., 1995; Disbrow et al., 2000; Brooks et al., 2005; Mazzola et al., 2009). The inner operculum–insular commonalities are also neurochemical, as has been highlighted by the study of human opioid receptors, which show a mediolateral gradient with highest receptor density in the insula and adjacent medial operculum, steeply decreasing toward its lateral side (Baumg€artner et al., 2006). Higher myelination and enhanced staining for parvalbumin, SMI-32, and acethylcholinesterase have also suggested a commonalty between the posterior dorsal insula and VS opercular regions (Gallay et al., 2012). Therefore, the innermost operculum can be segregated histologically, somatotopically, and neurochemically from the more lateral S2/PV areas, and appears functionally associated with the posterior insula, of which it forms the dorsal border. The assertion that the primate posterior insular cortex contains “a sensory representation of small-diameter afferent activity” (Craig, 2002), although generally correct, should include the medial operculum, which contains a representation of thin afferents too. In what

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follows, this region will be labeled with the acronym PIMO, for posterior insular and medial operculum (Garcia-Larrea, 2012a). The following sections will discuss functional data in human beings, showing that such a functional PIMO area is likely to contain networks devoted to the initial sensory processing of nociceptive input.

IS THE PRIMARY SOMATOSENSORY CORTEX INVOLVED IN NOCICEPTIVE PROCESSING? Although Chung et al. (1986) reported that half of VPL projecting neurons could be nociceptive, most other studies in monkeys and humans found only 6–12% of neurons with nociceptive properties in the cutaneous ventral posterior lateral (VPL) core that projects to the primary sensory area S1 (Casey and Morrow, 1983; Lenz et al., 1993a, b; Apkarian and Shi, 1994). Classic studies from Kenshalo and Isensee (1983) and Gingold et al. (1991) estimated that less than 24% of the total input to S1 was nociceptive, and more recently, Dum et al. (2009) found that only 6% of all spinothalamic ascending input had its third neuron in S1. This is consistent with clinical data in humans, since lesions involving exclusively S1, while creating impressive discriminative sensory loss (stereognosis, position sense, two-point discrimination) do not entail sizeable deficits in pain and temperature sensations (e.g. Verger, 1900; Dejerine, 1914; Bassetti et al., 1993; Kim, 2007), and direct electric stimulation of S1 rarely, if ever, creates pain (see below). Nociceptive-responding units are not evenly distributed within S1: they are very scarce in area 3b and predominate in areas 1 and 3a (Kenshalo and Isensee, 1983; Tommerdahl et al., 1996; Kenshalo et al., 2000; Whitsel et al., 2009), which in humans lie respectively in the crown and the depth of the postcentral gyrus. Focal nociceptive responses from areas 1–2 were suggested by early magnetoencephalogram (MEG) and subdural EEG data in humans (Ploner et al., 1999; Kanda et al., 2000; Inui et al., 2003; Ohara et al., 2004; Ogino et al., 2005). A more recent study (Frot et al., 2013) shed light on this issue by recording intracortical EEG responses to innocuous and noxious stimuli from 30 different S1 sites. Nociceptive responses in area 3b were recorded in only half of cases, whereas they were systematically obtained when electrode tracks reached the crown of the postcentral gyrus, consistent with an origin in somatosensory areas 1–2. Therefore, while a selective representation of thermal nociceptive information appears to exist in human S1, it is of much lesser extent than the nonnociceptive one. Notably, area 3b, which responds massively

to nonnoxious Ab activation, was much less involved in the processing of noxious heat. When present, S1 responses to noxious heat occurred at latencies comparable to those observed in the suprasylvian opercular region of the same patients, suggesting a parallel, rather than hierarchic, processing of noxious inputs in S1 and the PIMO (Ploner et al., 1999; Inui et al., 2003; Frot et al., 2013). This is in contrast to the cortical processing of nonnoxious somatosensory stimuli in anthropoid primates, including humans, in whom serial activation from S1 to the opercular area has been abundantly demonstrated (Garraghty et al., 1991; Allison et al., 1992; Hari et al., 1993; Mauguière et al., 1997; Bradley et al., 2016). Thus, while studies in monkeys and humans confirm that S1 receives a fraction of spinothalamic input, functional anatomy and clinical data indicate that this input is weak, and relegates S1 to a subordinate role in nociceptive processing. Despite such paucity of nociceptive neurons, there is some evidence supporting a role for S1 in the handling of nociceptive input. For instance, twothirds of the S1 neurons responding to noxious thermal stimulation in monkeys enhanced their discharge in response to graded-intensity increases; their activity was correlated with detection speed (Kenshalo et al., 1988). This suggests that these neurons may be involved in the encoding process by which monkeys perceived the intensity of noxious thermal stimuli. It is also important to remember that in most instances of real life, noxious and nonnoxious peripheral afferents are simultaneously activated. Since nociceptive and nonnociceptive S1 neurons share cortical columns (Kenshalo et al., 2000), the initial S1 activation by nonnoxious afferents may enhance the spatial localization of noxious input reaching the cortex subsequently. Therefore, although its contribution is minor and its damage is unable to create significant deficits, S1 can participate in the encoding of intensity and location of noxious stimuli, in particular when they activate concomitantly nonnoxious afferents.

STIMULATING THE CORTEX TO PRODUCE PAIN Perisurgical stimulation of the parietal cortex: the Penfield legacy Wilfred Graves Penfield and his colleagues were the first to use direct cortical stimulation for intraoperative cortical functional mapping in the context of epilepsy surgery. Between his first description of the functional organization of the sensorimotor strip in 1947 (Rasmussen and Penfield, 1947) and his last published Gold Medal lecture given at the Royal Society of Medicine in 1968, W. Penfield produced an exhaustive functional map of

PAIN SYNDROMES AND THE PARIETAL LOBE the human cortex based on electric stimulation while patients are conscious. Somatic pain was virtually absent from the list of elementary responses to stimulation of the somatosensory cortex, including the primary and secondary somatosensory areas and the insula (Penfield and Faulk, 1955). Only 11 of the 800 cortical locations in the primary sensorimotor cortex were reported to elicit pain when stimulated (Penfield and Boldrey, 1937). Later on, Penfield and Jasper (1954) noted that some pricking or tingling sensations evoked by stimulation of the somatosensory areas were occasionally reported as “unpleasant” by patients. They considered however that the degree of pain was so slight “as to cause one to wonder if the use of the term is not a misnomer.” The notion that pain cannot be produced by focal stimulation of a localizable area of the human cortex prevailed for many years after the seminal studies of the Montreal School. The complexity of the cortical network activated by painful stimuli in more recent neuroimaging studies led researchers to question the existence of a cortical primary pain area receiving specific nociceptive inputs from the periphery, which could play the same role as other primary sensory areas for visual, auditory, or nonpainful somatic sensations. The main reason why Penfield and his colleagues failed to elicit pain responses more often by stimulating the human cortex is that they stimulated using exclusively surface electrodes during surgical procedures. Therefore their access to the PIMO was limited in time and possible only after surgical removal of the outer part of the frontoparietal operculum. This limitation is illustrated by the map of insular somatosensory responses drawn by Penfield and Faulk (1955), which left almost unexplored the upper and caudal part of the insula where most pain responses can be obtained by electric stimulation through electrodes chronically implanted in the PIMO cortex.

Discovering the pain-eliciting properties of the PIMO cortex The pain-eliciting properties of the PIMO cortex in humans was discovered in the past 25 years by means of stimulations delivered through multicontact electrodes implanted perpendicular to the midsagittal plane, and exploring the opercular and insular cortices along a single trajectory (Isnard et al., 2004). These electrodes, which can be left in place chronically up to 15 days, are increasingly used in the context of epilepsy surgery for localizing the area that produces focal epileptic seizures in the perisylvian cortex; they also permit functional mapping by cortical electric stimulations delivered through two adjacent contacts. The epilepsy surgery context in which cortical stimulations are used entails some limitations regarding

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physiologic studies. Firstly, only the minimal number of electrodes that are useful to diagnosis can be implanted; this implies that the spatial resolution of the mapping in each individual is low, and pooling interindividual data is necessary to draw topographic functional maps based on depth electrode data. Secondly, the trajectory of electrode tracts is guided by hypotheses based on the most probable location of the epileptogenic zone, and is also constrained by the anatomy of blood vessels that are particularly dense in the anterior part of lateral fissure, with the result that the rostral inferior insula is rarely or never explored. Thirdly, responses to stimulations can be considered as reflecting normal physiology only on the condition that they have been obtained in cortical areas that are not involved in the epileptogenic process and do not show hyperexcitability to peripheral inputs or local electric fields produced by stimulation. Painful sensations in response to direct electric stimulation of the PIMO cortex have been reported in the posterior insula by Ostrowsky et al. (2000, 2002) and in the medial parietal operculum by Mazzola et al. (2006) (Fig. 10.1). Qualities of the evoked pain are described as burning, stinging, and disabling sensations or an electric shock. Pain intensity varies from mild to intolerable but is not related to pain threshold intensity. Pain disappears as soon as the stimulation is interrupted in most cases, it is located contralateral to the stimulation site or bilaterally when midline parts of the body are involved, and it affects larger areas of the body after stimulation of the insula (face, upper limb, half of the body) than of the medial operculum, suggesting that receptive fields for nociceptive input are more extended in the insular than in the adjacent opercular cortex (Mazzola et al., 2006). Reviewing responses to stimulations in 4160 sites scattered all over the human cortical mantle in 164 patients, Mazzola et al. (2012) reported that sites where stimulation produced pain were exclusively concentrated in the medial parietal operculum and the insular cortex. All patients who reported a painful sensation in response to cortical stimulation also had spontaneous behavioral manifestations of pain, including facial pain expressions, verbal complaints such as shouts and cries, movements to avoid the stimulus, and/or vegetative changes such as facial pallor or rubefaction. In the insula all contacts where pain responses were obtained at very low current intensities were concentrated in the dorsal posterior insula. The descriptive terms used by patients to qualify their pain (burning, electric shock, painful pins and needles, stinging, crushing, or cramp sensation) were similar after stimulation of medial parietal operculum and insula, and there was no significant difference between these two regions in terms of pain intensity. Interestingly, 75% of the 128 stimulations of the primary

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Fig. 10.1. Differential encoding of noxious and nonnoxious thermal stimuli in the posterior insular and medial operculum. (A) Operculoinsular sites evoking pain and thermal perceptions in humans. Upper part: axial slices; lower part: coronal slices. Sites where stimulation induced nonnoxious thermal sensations (in green) were situated in the inner operculum, while those evoking pain (in red) tended to concentrate more medially, in the posterior insula. (Adapted from Mazzola L, Isnard J, Mauguie`re F (2006) Somatosensory and pain responses to stimulation of the second somatosensory area (SII) in humans. A comparison with SI and insular responses. Cereb Cortex 16: 960–968, with permission from Oxford University Press.) (B) Intracortical evoked potentials to thermal laser stimuli recorded from the posterior insula (black squares) and the inner operculum (black crosses). In the lower part, responses from 8 consecutive subjects are superimposed. Sizeable responses at low thermal intensities could be obtained from opercular sites (left), but not from the insula (right), which only responded when intensity approached the subjective pain threshold. (Adapted from Frot M, Magnin M, Mauguie`re F, et al. (2007) Human SII and posterior insula differently encode thermal laser stimuli. Cereb Cortex 17: 610–620, with permission from Oxford University Press.)

somatosensory cortex evoked paresthesiae in restricted body areas that were never reported as painful and were exclusively contralateral to stimulations in the limbs and mostly bilateral in the face or trunk. In spite of large and overlapping projection fields of pain responses on the skin surface, there is some blurred somatotopic organization of pain in the PIMO cortex (Mazzola et al., 2006, 2009). However, this somatotopic representation is obtained by pooling, at the group level, pain responses in patients who each have a very limited number of insular contacts, and merits confirmation by increasing the spatial sampling of insular stimulation sites in the same individual – a condition that is rarely justifiable in the clinical context of epilepsy surgery. Although pain responses to cortical stimulation are exclusively obtained in the PIMO cortex, they represent only 10–12% of responses reported by patients after stimulation of this cortical region (Afif et al., 2010; Mazzola et al., 2012). The first reason for this intriguing observation is probably technical. Stimulations used in the context of presurgical functional mapping are set at threshold intensities and do not aim to produce pain responses. Therefore stimulations are never repeated at

higher current intensity in sites where any type of nonpainful sensation has been obtained. The question whether increasing the stimulus intensity might induce a pain response in a site where a nonpainful somatic response has been elicited cannot be addressed for obvious ethical reasons. The second reason for the rarity of pain responses to cortical stimulation might be that focal cortical stimulation of the operculoinsular region is per se insufficient to consistently reproduce the global experience of pain but can only initiate the aversive sensation qualified as pain in some privileged circumstances. Isnard et al. (2011) have reported the case of a patient with a cortical dysplasia of the posterior insula who experienced spontaneous painful epileptic seizures, and in whom ictal fast lowvoltage activity and repetitive spiking in the lesion area produced a pain sensation that could be reproduced by focal stimulation (see below). The high-frequency ( 40 Hz) energy of the signal recorded by intracortical electrodes also increased in parietal operculum, midcingulate gyrus, and more anterior insular segments during seizures, and spikes in the posterior insula preceded by 80 ms those recorded in these regions. This suggests that

PAIN SYNDROMES AND THE PARIETAL LOBE the experience of pain can be triggered by the posterior insular cortex but also depends on the subsequent activation of a network of cortical areas. This interpretation is in line with Penfield’s statement that “experiential responses” to cortical stimulation reflect activation of distributed cortical areas distant from, but interconnected with, the stimulation site (Penfield, 1968).

Painful epileptic seizures and the parietal lobe Painful somatosensory seizures (PSS), during which patients complain of acute and intense pain (burning sensation, pricking ache, throbbing pain, or muscle-tearing sensation), affecting part of the body, most often contralateral to the epileptic focus, have a very low prevalence and represent only 1.5% of all somatosensory seizures (Mauguière and Courjon, 1978). Ictal pain has often been interpreted as part of a Jacksonian seizure contralateral to an epileptic focus located in the central cortex, involving a restricted somatotopic region and often concomitant to somatosensory aura and motor symptoms with the same distribution as the painful sensation (Whitty, 1953; Wilkinson, 1973; Young and Blume, 1983). It has long been accepted that PSS originate from primary or secondary somatosensory areas (Young and Blume, 1983; Blume et al., 1992; Siegel et al., 1999). Alternative origins have been proposed in the supplementary motor area (Fried et al., 1991), cingulate gyrus (Roebling and Lerche, 2009), and inferior parietal lobule (Yamamoto et al., 2003). These hypotheses were all based on scalp-recorded EEG activity or cortical surface recordings (Young and Blume, 1983; Young et al., 1986; Blume et al., 1992; Nair et al., 2001) without direct exploration of the PIMO cortex. However, in two recent series of parietal lobe epilepsy, including ictal stereotactic intracerebral EEG recording in one, pain is never mentioned as a symptom of seizures originating in the S1 area (Kim et al., 2004; Bartolomei et al., 2011). Montavont et al. (2015) reported data from ictal stereotactic intracerebral EEG recordings and cortical stimulation in PIMO cortex in 5 patients with PSS. The common feature they observed in all recorded PSS was that the onset of the seizure discharge was located in the upper posterior quadrant of the insula and in the medial parietal operculum when patients experienced ictal pain, with various patterns. The seizure activity might first involve the parietal operculum before spreading to the insula, or the reverse, and might also involve concomitantly both of these two areas. Three clinical features were consistently observed in all seizures: (1) pain intensity was much higher than that of unpleasant and nonpainful paresthesiae produced by stimulation of the S1 area; (2) pain did not show the characteristic spread, as reported by Jackson, in seizures of the central region;

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and (3) pain affected large somatotopic territories up to half of the body, that was very similar to that of somatosensory and pain sensations evoked by direct stimulation of the operculoinsular cortex. It is noteworthy that S1 and midcingulate gyrus were secondarily involved by the PSS discharge, but neither pain onset nor pain duration correlated in time with discharges in S1 or cingulate gyrus. Thus, among the cortical pain matrix areas, only the PIMO cortex was able to trigger the “experience” of pain during a seizure and can thus be viewed as the pain symptomatogenic area of PSS.

LESIONS IN THE PIMO ENTAIL SELECTIVE DEFICITS IN PAIN AND TEMPERATURE SENSATIONS While the first clinical description of a selective loss of pain sensation comes from 1915 (Dejerine and Mouzon), neuropathologic analysis of this syndrome was not available until the middle of the 20th century. As described above, Biemond (1956) was the first to report 2 patients with selective loss of pain and temperature sensation in whom a posterior insular lesion was demonstrated anatomically; since then, a number of reports have abundantly confirmed that lesions involving the posterior insula and medial parietal operculum can give rise to selective pain and temperature deficits while respecting proprioception and discriminative touch (Obrador et al., 1957; Greenspan and Winfield, 1992; Bassetti et al., 1993; Horiuchi et al., 1996; Greenspan et al., 1999; Birklein et al., 2005; Kim, 2007; GarciaLarrea et al., 2010), and this region is indeed the only one where focal lesions have been described to selectively abolish or attenuate pain sensation (see review in Garcia-Larrea, 2012b) (Fig. 10.2). A study in epileptic patients showed that highfrequency inhibitory posterosuperior insular stimulation had the potential to decrease thermal nociception (Denis et al., 2015). In contradistinction to this, lesions concerning exclusively the anterior insula or the frontoinsular operculum were never associated with pain or temperature deficits in the detailed study of Greenspan et al. (1999). Also, lesions involving exclusively the lateral parietal operculum (S2I proper, or S2/PV) have been reported to produce global hypaesthesia, or a cheiro-oral syndrome with preserved pain sensation (Bogousslavsky et al., 1991; Bowsher et al., 2004), and lesions disconnecting the anterior from the posterior insula were reported to dampen emotional reactions to pain, but preserve recognition of nociceptive stimuli (Berthier et al., 1988). It is therefore widely acknowledged now that the posterior operculoinsular region is the only brain area where focal lesions have been consistently documented to abolish selectively thermal and thermoalgesic

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Fig. 10.2. (A) Examples of lesions generating selective loss of pain and temperature sensations, and central operculoinsular (parasylvian) pain. High-resolution magnetic resonance imaging (MRI) demonstrates systematic involvement of the posterior insula and the medial part of the adjacent parietal operculum (the posterior insular and medial operculum (PIMO) area) in each of the patients. In the top row, the left images (MRI) show an ischemic lesion involving the posterodorsal part of the left insula and its adjacent operculum. The positron emission tomography scan image of the same patient (study of opioid receptors with 11 C-diprenorphine) shows evidence of metabolic diaschisis, with receptor loss in regions wider than the anatomic lesion, extending to the mid-anterior insula and even to the ipsilateral thalamus. (B and C) Laser-evoked potentials (LEPs) and sympathetic skin responses (L-SSR) are suppressed following nociceptive-specific stimulation contralateral to the opercular lesion (red traces) as compared with stimulation of the ipsilateral limbs (black traces). (D) In contrast, somatosensory evoked potentials (SEPs) to nonnociceptive electric stimuli, reflecting activity in primary somatosensory areas, remain normal and symmetric. Such dissociation between spinothalamic (LEPs, L-SSR) and lemniscal responses (SEPs) in focal cortical lesions suggests operculoinsular involvement with high potential of developing thermo-nociceptive sensory loss, and subsequently central pain. (Reproduced from Garcia-Larrea L (2012b) Insights gained into pain processing from patients with focal brain lesions. Neurosci Lett 520: 188–191, with permission.)

sensations in humans, and is therefore likely to contain networks specifically devoted to the sensory processing of thermal and noxious inputs.

THE OPERCULOINSULAR REGION AND CENTRAL PAIN Since the late 1980s and the seminal work of Jurgen Boivie, it is generally acknowledged that central pain is associated with spinothalamic involvement, while injury of the proprioceptive dorsal column pathways is not essential (Boivie et al., 1989; Boivie, 2006). At all levels of central somatosensory processing, lesions

inducing selective spinothalamic sensory loss have a high potential of developing central pain: at spinal and brainstem levels, these lesions are mainly represented by syringomyelia and dissociated brainstem syndromes, while in the cerebral cortex lesions inducing selective spinothalamic loss are located in the PIMO. Admittedly, many cases of poststroke pain arise in the context of extended lesions involving both the operculoinsular and the primary and second somatosensory areas, resulting in nondissociated sensory loss (e.g., Hamby, 1961). However, central pain is exceptional when cortical lesions are restricted to lateral somatosensory regions (S1 and S2 proper) (Bassetti et al., 1993; Kim, 2007),

PAIN SYNDROMES AND THE PARIETAL LOBE and its development in global somatosensory syndromes is thought to depend on injury to the operculoinsular region. On clinical grounds, operculoinsular pain (parasylvian pain) is a distinct central pain syndrome that can be clinically suspected and objectively diagnosed with combined radiologic and electrophysiologic methods (Garcia-Larrea et al., 2010). In particular, the recording of evoked potentials to electric and thermal (laser) stimuli may establish the specific alteration of spinothalamic responses and the preservation of lemniscal-related potentials, which represent the neurophysiologic signature of the syndrome (Fig. 10.2). As is the case for other lesions in the spinothalamic pathways, sensory involvement is not a sufficient condition for central pain to develop, and only around half of cases with a PIMO stroke develop a pain syndrome (e.g., Bassetti et al., 1993; Cereda et al., 2002; Bowsher et al., 2004; Bowsher, 2006; Kim, 2007). This is consistent with rates of central pain following spinothalamic lesions in spinal cord and brainstem, which range from 30% to 70% (see review in Boivie, 2006), and suggests that operculoinsular pain should be seen as the cortical variant of central pain due to a selective spinothalamic system lesions, such as pain following syringomyelia or lateral medullar (Wallenberg) syndrome. Electrophysiology and functional imaging have suggested some functional segregation within the PIMO region; the posterior insula is more likely activated by painful thermal stimuli and the medial operculum responds to stimuli of lower energy (Frot et al., 2007; Fig. 10.1). Also, direct cortical stimulation evoked pain more frequently when addressed to the posterior insula, while nonpainful warm sensations tend to appear when the inner operculum is stimulated (Mazzola et al., 2012; Fig. 10.1). However, clinical lesions, even minute, rarely concentrate exclusively on one part of this small and convoluted region, and the respective role of its subareas in the development of central pain cannot be ascertained at this point. The term parietal pseudothalamic pain has been used to describe central poststroke pain after cortical lesions (Schmahmann and Leifer, 1992; Schott, 1996). This term is however clearly inappropriate, since most patients with genuine thalamic pain do not exhibit dissociated sensory loss, which is the key feature of operculoinsular pain. Indeed, although spinothalamic involvement is one essential feature of patients with thalamic poststroke pain (Vartiainen et al., 2016), such involvement is most often not dissociated and involves also the lemniscal projections (Graff-Radford et al., 1985; Bogousslavsky et al., 1988; Mauguière and Desmedt, 1988; Shintani, 1998; Kim, 2007). In sharp contrast, virtually 100% of reported cases of focal opercular-insular lesions involved exclusively spinothalamic projections, as indicated by

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dissociated sensory loss of pain and temperature, with preservation of proprioception and discriminative touch. Although spinothalamic and lemniscal projections partially converge in VPL, ventral posterior medial (VPM) and ventral posterior inferior (VPI) nuclei (Apkarian and Hodge, 1989; Willis and Westlund, 1997), they break up again in their respective projections to the cortex, lemniscal axons mostly projecting to the postcentral gyrus, and spinothalamic afferents mostly targeting the posterior insula and medial parietal operculum (Dum et al., 2009). These two regions are separated enough to allow clearly distinct syndromes to emerge, and only the operculoinsular syndrome is definitely prone to develop central neuropathic pain. The recent description of a central pain syndrome with thermonociceptive deficit in 2 patients who had a posterior operculoinsulectomy for epilepsy (Denis et al., 2015) underscores the outstanding importance of this region as one containing networks essential for thermal sensation and pain.

THE PIMO AREA IS MORE THAN A SENSORY CORTEX FOR PAIN The privileged relationship of the PIMO region with pain-related processing has led some investigators to claim that this region represents a “primary area for pain.” However, this area is also involved in the processing of other sensory inputs, and during the last 15 years it has been considered to contain primary networks for a number of sensibilities, including thermo-sensation, painful and nonpainful pricking sensations, emotional touch, mechanical and heat pain, and protopathic feelings subserving interoception. While each of these claims may be founded on sound experimental data, none of them captures the whole functional complexity of the PIMO region.

The PIMO as a thermo-sensory area Thermal stimuli significantly activate the PIMO, and induce linear hemodynamic changes with both increasing and decreasing nonnoxious temperatures (Coghill et al., 1999; Craig et al., 2000; Maihofner et al., 2002; Hua et al., 2005). Focal lesions in the PIMO can suppress not only pain but also thermal perceptions (Greenspan et al., 1999; Kim, 2007, Garcia-Larrea et al., 2010; Fig. 10.2), and stimulation of the operculoinsular region in awake humans elicits nonnoxious warm and painful heat sensations in a comparable proportion of cases, with stimuli evoking nonpainful warmth concentrating in the medial operculum and those yielding pain in the posterior dorsal insula (Fig. 10.1). This is in accordance with studies of evoked potentials to thermal laser stimuli, where the opercular region was able to encode low levels of thermal change (Chen et al., 2006; Frot et al., 2007),

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whereas the posterior insula tended to respond only when thermal stimuli had almost reached the subjective pain threshold (Frot et al., 2007).

Nonnoxious mechano-sensation in the PIMO Nonpainful tingling, light touch, and feelings of pulsation, vibration, or slight electric current were produced by direct stimulation of the medial parietal operculum and the posterior insula in 35% of cases (Mazzola et al., 2006, 2012). Single-unit recordings in monkeys have also shown responses to gentle mechanic activation in the dorsal posterior insula and adjacent operculum (Robinson and Burton, 1980; Schneider et al., 1993; Coq et al., 2004), and injury to the PIMO in humans often modifies significantly the tactile thresholds (Greenspan and Winfield, 1992; Schmahmann and Leifer, 1992; Greenspan et al., 1999; Garcia-Larrea et al., 2010). A dual tactile innervation exists in humans, based respectively on fast-conducting Ab fibers and slowconducting C-afferents responding to light touch. C-fiber tactile sensations are carried by the spinothalamic tract (STT) via synapses in lamina I and III–V (Zhang et al., 1991; Craig, 2002), and may be relayed to the PIMO by the posterior and suprageniculate limitans thalamic nuclei (Apkarian and Shi, 1994). In patients totally deprived of Ab fibers, stimulation of C-tactile afferents activated the posterior insula, but not the primary somatosensory cortex or S2 in the lateral operculum (Olausson et al., 2002, 2008). Comparison of tactile activation of the forearm (where Ab and C-tactile afferents coexist) and the palm (devoid of C-tactile afferents) suggested that the most posterior part of the insula is a selective target for C-driven touch afferents (Olausson et al., 2002; Bj€ ornsdotter et al., 2009). C-driven touch is often considered the support for emotional, sensual, or social touch (Olausson et al., 2010; Morrison et al., 2011). However, C-afferents can evoke tactile sensations devoid of any particular pleasantness, such as those elicited by punctate Von Frey filaments (Cole et al., 2006), and direct stimulation of the posterior insula evokes tactile sensations of pulsation, vibration, or electric current, which are not described as particularly pleasant (see above). “Emotional touch” is not specifically triggered by C-afferents, since tickle can be induced after complete interruption of the STTs (Nathan, 1990), and sensual tactile sensations can be derived from regions devoid of C-tactile fibres, such as the palm of the hand, as beautifully described by Honore de Balzac (“the kiss she allowed me to lay upon her hand, (...) only the back and never the palm, as though she drew the line of sensual emotions there”: De Balzac, 1836). Thus, although the notion of a C-driven tactile system

projecting to the PIMO can be proposed with confidence, the pleasant character of such sensations is clearly context-dependent.

Itching and the PIMO Itching, or the sensation associated with the desire to scratch, depends on activation of A and C-thin afferents, and is transmitted rostrally via the STT (Jeffry et al., 2011). All STT neurons responding to itching also respond to mechanical pain, and two-thirds respond to noxious or nonnoxious heat (Davidson et al., 2014). Section of the STT by anterolateral cordotomy simultaneously abolishes itch and pain (Nathan, 1990), patients with congenital insensitivity to pain also lack itch sensations (Indo, 2010), and the same neurologic illnesses that cause neuropathic pain can also, or instead, cause neuropathic itch (see review in Oaklander, 2011). Such intimate relations between itch and pain make the existence of itch-related projections to the PIMO highly plausible, and indeed, most fMRI and EEG/MEG studies have shown itch-related activations within the PIMO areas (e.g., Drzezga et al., 2001; Leknes et al., 2007; Mochizuki et al., 2007, 2009; Vierow et al., 2009). Despite the close association between itch and pain, the two experiences are subjectively distinct and may even be inversely related: for instance, itching often emerges as a side-effect of opioid analgesics, and can be reduced by nociceptive scratching. Also, itching sensations have not been described to our knowledge following intracranial stimulation of the PIMO.

Interoception and the PIMO As defined by Sherrington (1948), interoception refers to “stimuli that originate inside the body,” and comprises all sensations coming from the gastrointestinal, urinary, or reproductive tracts, circulatory or respiratory systems. This generic term includes such dissimilar feelings as hunger and thirst, air hunger, sexual arousal and orgasm, nausea, and urge to void. Although it has been proposed to redefine interoception as including “temperature, pain, itch and other somatic feelings” (Craig, 2002), such an all-inclusive definition betrays the etymology of the word, contradicts the very notion of internalness (i.e., “coming or acting from within”), and should not replace the classic definition (see Lenz et al., 2004). Visceral afferents reach the central nervous system via two pathways involving respectively the vagus and the splanchnic nerves. Vagal afferents reach the nucleus of the solitary tract, itself projecting to a large number of targets in the brainstem, hypothalamus, and limbic forebrain (amygdala and anterior insula) (see reviews by J€anig, 1996; Rinaman, 2010). Although most vagal inputs bypass sensory areas and never reach consciousness (J€anig, 1996), they can lead to cortical arousal

PAIN SYNDROMES AND THE PARIETAL LOBE and are associated with regulatory reflexes inducing conscious sensations, such as nausea. The second visceral path reaches the dorsal horn via the splanchnic nerves, where it converges with exteroceptive afferents in laminae I, V, and X (Tattersall et al., 1986), and ascends both within the STT and a postsynaptic dorsal column pathway (Willis and Westlund, 1997). Interoceptive units in monkeys are mainly found in the midinsula rather than its posterior part (Zhang et al., 1999), and in the meta-analysis of Kurth et al. (2010), the region specific to human interoceptive processing was not in the posterior but in the midinsula. Interoceptive sensations, such as air hunger or urge to void, tend to activate the mid- and anterior insula (Banzett et al., 2000; Kuhtz-Buschbeck et al., 2005), and direct electric stimulation in humans entails visceral feelings at locations rostral to those eliciting general somatosensory or pain sensations (Isnard et al., 2004; Stephani et al., 2011). The contention that the posterior insula contains a primary image of visceral afferents (Craig, 2002; Mayer et al., 2009) is inconsistent with the evidence reviewed above. One hypothesis to be confirmed is that anterior and midinsular activity depend on vagal afferents, bypassing somatosensory cortices and projecting via the nucleus of the solitary tract to anterior insular segments (Rinaman, 2010), while the posterior insula might represent one target of viscerosomatic input carried exclusively by splanchnic pathways. While the insula is commonly activated by visceral interoceptive stimuli, the activation of parietal opercular areas is less consistent (Mayer et al., 2009). Also, visceral perceptions in humans are clearly more prevalent after insular than opercular stimulation (Mazzola et al., 2006, 2009), and in both rat and monkey the percentage of neurons responding to interoceptive changes in the medial parietal operculum was much smaller than in the adjacent midinsula (Zhang et al., 1999). There may exist, therefore, a functional segregation within posterior insula and medial operculum, which is reminiscent of that observed in its response to thermal stimuli (see above).

THE PIMO CONTAINS A DISTINCT SOMATOSENSORY PROCESSOR OF PRIMITIVE SOMATOSENSORY ATTRIBUTES Based on anatomic plausibility, activation by appropriate stimuli, lesion-induced deficits, and perceptions induced by in situ stimulation, the previous sections illustrate how the PIMO networks integrate not only nociceptive stimuli, but also a number of nonnoxious sensations, including heat, cold, touch, itch, and visceral feelings. Sensory modalities processed in the PIMO do not cover the whole spectrum of somatosensory abilities,

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since proprioception, graphesthesia, and stereognosis are not primarily processed in this area (Kim, 2007). The PIMO region behaves as a somatosensory area on its own, and appears as the cortical target of a distinct system for somatosensory processing, mainly depending on spinothalamic ascending projections. The somatic modalities converging in the PIMO have several points in common. Firstly, the neural machinery ensuring their transmission relies upon thin Ad and C-fibres in the periphery, and the spinothalamic system in the spinal cord. Secondly, the outer, most lateral portions of the parietal operculum appear to be largely excluded from this somatosensory input. Indeed, while lesions affecting the PIMO generate deficits identical to those encountered after injury to spinothalamic pathways (see above), lesions restricted to the lateral operculum do not entail selective spinothalamic symptoms (Bogousslavsky et al., 1991; Bowsher et al., 2004). Moreover, C-driven “sensual” tact and itching, which consistently activate the PIMO, spare the lateral operculum (see above), whereas Ab tactile stimuli, which somatotopically activate the lateral operculum, hardly activate its medial part (Eickhoff et al., 2007). Phylogenetic evidence suggests that sensory attributes handled in the PIMO are among the oldest somesthetic capabilities of living organisms. The most conspicuous PIMO role is the processing of rudimentary mechanic, thermal, and noxious inputs, which are essential for survival and must have developed before discriminative tact, stereognosis, and proprioception appeared (Smith and Lewin, 2009). Invertebrates (Annelida) such as the leech possess segmental ganglia containing touch, pressure, and noxious cells (Nicholls and Baylor, 1968; Pastor et al., 1996). The latter respond to strong mechanic, chemical, or thermal stimuli, and lower their threshold for repeated activation, just like mammalian nociceptors. Wide-dynamic-range neurons responding to both low and high stimulus intensities are present in Mollusca such as Aplyssia (Walters et al., 1983), and all these primitive senses in invertebrates are conveyed by unmyelinated fibers. In vertebrates, the evolution pursues from an unmyelinated nervous system in the sea lamprey (which displays both mechanic and heat sensitivity) to fishes, where myelinated nociceptors are first observed (Smith and Lewin, 2009). The pathways conducting such rudimentary sensations also appear as precursors of the spinothalamic system. Certain reptiles have projections analogous to the mammalian neo- and paleospinothalamic tracts, while such connections have not been described in teleost fishes and they may exist in some amphibians and not in others (Kevetter and Willis, 1984; Sneddon, 2009). In the masurpial phallanger the ascending nociceptive system is interrupted in the brainstem (Clezy et al., 1961), whereas in the opossum 2% of anterolateral fibers

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reach the thalamus, and the proportion of direct fibers reaching the thalamic VPL/VPI increases with phylogenetic progression (Mehler, 1966). Thus, a somatosensory system based on unmyelinated or thinly myelinated inputs appears to have preceded that of large-diameter myelinated fibers. Physical disjointing of their respective cortical targets may have developed in parallel with the progressive “operculation” of the insular cortex, which is situated entirely on the hemisphere surface in hedgehogs and rabbits, partly covered by adjacent formations in carnivores and prosimians, and wholly “operculated” only in primates and cetaceans (see review in Nieuwenhuys, 2012). The insula is a phylogenetically conservative telencephalic part that has preserved most of its functions in species ranging from rodents to primates. Therefore, it may have undergone the operculation process while keeping its main functions, including that of cortical recipient of somatosensory input conveyed by the spinothalamic system.

SUBAREAS WITHIN THE PIMO: MULTIPLE PRIMARY CORTICES? Cortical lesions, even millimetric, restricted to the PIMO area tend to simultaneously alter thermal, tactile, and pain thresholds (Greenspan et al., 1999; Birklein et al., 2005; Kim, 2007; Garcia-Larrea et al., 2010). In monkeys, the same neuron in the posterior insula could respond to noxious and nonnoxious stimuli (Robinson and Burton, 1980), and in at least one human case electric stimulation in the insula generated first a cold sensation and later a painful electric-like shock (Ostrowsky et al., 2002). Despite such obvious convergence, both intracortical stimulation and intracortical evoked potentials in humans suggest some modal segregation, whereby nonnoxious thermal encoding tends to concentrate in the medial parietal operculum, whereas pain and viscerosensitive responses predominate in the adjacent dorsal posterior insula (Mazzola et al., 2006; Frot et al., 2007) (Fig. 10.2). Segregation is not solely cortical: a study of 63 patients with lesions of ascending spinothalamic pathways found separable deficits of touch, sharpness, innocuous warmth/cold, mechanic and heat pain, suggesting partially independent representation of these submodalities even in ascending pathways (Bowsher, 2005). Functional parting in insula and parietal operculum would bear resemblance to that in S1, where neurons of different submodalities are distributed differentially in postcentral areas 3a, 3b, 1, and 2 (see Chapter 4). Interestingly, the concept of a “S1” cortex has survived, despite the fact that area 3b may be considered as a “primary cortex” for discriminative tact, area 2 for joint position sense, and area 3a for muscle stretch

perception (see reviews in Kaas and Collins, 2003; Mountcastle, 2005). The “S1” concept survived because it reflects a functional unit of essentially tactile processing receiving input from the dorsal column–medial lemniscus system through the ventrocaudal thalamus. In this line, the PIMO area includes another functional unit receiving input from spinothalamic channels through thalamic relays essentially different from, and posterior to, the VPL/VPM complex. As in S1, it might be possible to separate within the PIMO different functional subareas, in particular a more internal part concerned predominantly with noxious, C-tactile, and (perhaps) viscerosomatic stimuli, and a more external one in the inner operculum, where nonnoxious thermal and pressure stimuli are preferentially processed. However, the whole system appears to share a common functional role as the first sensory cortical recipient of the most primitive somatic inputs (Kim, 2007). Between the PIMO and S1, the lateral operculum containing the S2/VP areas appears to participate in both systems, receiving both dorsal column-lemniscal afferents (direct and through S1) and spinothalamic input via the VPI (Pollin and Albe-Fessard, 1979; Dykes et al., 1981; Dum et al., 2009).

CONCLUSIONS In addition to enhancing our knowledge of central pain syndromes, the study of the PIMO region has contributed significantly to our understanding of the cortical integration of spinothalamic signals. As a primary projection area of the spinothalamic system, the PIMO appears involved in the cortical processing of all kind of spinothalamic signals, including thermo-nociception, C-driven touch, itch, and (in part) visceral interoception. Each of the somatosensory cortical areas, via its pattern of extrinsic connections and intrinsic operations, contributes “a particular attribute to the final perceptual image” (Mountcastle, 2005, p.382). Given its particular anatomofunctional properties, thalamic connections, and tight relations with limbic and multisensory cortices, the region comprising the posterior insula and medial parietal operculum deserves to be considered as a third somatosensory cortex contributing to the spinothalamic attributes of the final perceptual experience.

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