Motor neglect: issues and prospects

Although the motor and sensory components of the neglect syndrome appear as dependent on a unitary attentional process, the clinical observation of pure motor neglect raises the possibility of segregation between attentional and intentional neural mechanisms. Neuroanatomical evidence suggests a separate role for the anterior and posterior cingulum. The anterior cingulum mainly projects to the supplementary motor area, the superior premotor area and the prefrontal granular cortex whereas the posterior cingulum mainly controls the inferior parietal lobule. The role of the intralaminar thalamic nuclei, together with the frontostriatal loops is considered. Behavioral neurology should strengthen its analytical approach in order to dissociate, by appropriate testing, the separate operations which contribute to relate perception and action. Several new hypotheses are presented.     

Motor neglect of thalamic origin: report on two cases (author's transl)

Two cases of thalamic lesions with motor neglect are presented. The syndrome of motor neglect was complete in those cases with a) underutilization of left limbs, but good utilization upon verbal orders, b) loss of placement reaction, c) weakness of movement when hand was approaching the target, d) weakness of motor reaction to nociceptive stimuli. Those cases confirm that motor neglect exists after thalamic lesions and bring pathologic clues for topographic discussion. Motor neglect seems to be a particular case of partial unilateral neglect throwing some doubt on the hypothesis of a global trouble of hemispheric activation. Prevalence of left motor neglects suggests some linkage between propositional motility and language. One may suppose that in the right hemisphere language is able to have a vicarious action when spontaneous activation is lost; at the opposite, in the left hemisphere language and motility would be too linked to let this dissociation be generally possible.     

The functional anatomy of frontal lobe neglect in the monkey: Behavioral and quantitative 2-deoxyglucose studies

A syndrome of hemisensory neglect follows damage to frontal association areas in monkeys and humans. To study the syndrome we removed frontal association cortex from the right hemisphere of macaque monkeys. After operation, behavioral testing showed conditional deficits in visual, somatosensory, and motor responses contralateral to the lesion. Brains of animals were studied with [¹⁴C]2-deoxyglucose autoradiography to evaluate functional neuroanatomical changes. Ipsilateral striatal and selected thalamic and midbrain nuclei exhibited depression of glucose utilization (10 to 60%). No consistent glucose utilization changes appeared in cortex or in primary motor or sensory pathways. Brains from unoperated control animals did not exhibit these changes, nor did brains from operated animals with behavioral recovery from neglect. We conclude that the symptoms of frontal lobe neglect in the monkey are the result of dysfunction within a widely distributed system of subcortical centers. The distribution of the dysfunction provides an explanation for some of the clinical features of neglect.     

Thalamic afferents to prefrontal cortices from ventral motor nuclei in decision‐making

The focus of this literature review is on the three interacting brain areas that participate in decision‐making: basal ganglia, ventral motor thalamic nuclei, and medial prefrontal cortex, with an emphasis on the participation of the ventromedial and ventral anterior motor thalamic nuclei in prefrontal cortical function. Apart from a defining input from the mediodorsal thalamus, the prefrontal cortex receives inputs from ventral motor thalamic nuclei that combine to mediate typical prefrontal functions such as associative learning, action selection, and decision‐making. Motor, somatosensory and medial prefrontal cortices are mainly contacted in layer 1 by the ventral motor thalamic nuclei and in layer 3 by thalamocortical input from mediodorsal thalamus. We will review anatomical, electrophysiological, and behavioral evidence for the proposed participation of ventral motor thalamic nuclei and medial prefrontal cortex in rat and mouse motor decision‐making.     

Thalamic neglect

Three patients with right thalamic hemorrhage showed contralateral neglect and limb akinesia. They also had anosognosia, visuospatial disorders, and emotional flattening. In animals, neglect can be induced by lesions along a cortico-limbic-reticular loop including the intralaminar thalamic nuclei. We propose that an activation defect is responsible not only for the neglect and akinesia, but also for the visuospatial and emotional defects usually associated with right-hemisphere cortical dysfunction.     

Topographical connections of the substantia nigra pars reticulata to higher-order thalamic nuclei in the rat

The substantia nigra pars reticulata (SNR) is the ventral subdivision of the substantia nigra and contains mostly GABAergic neurons. The present study explores whether the SNR relates to all dorsal thalamic nuclei equally or just to a particular group of nuclei, such as first or higher-order nuclei. Injections of biotinylated dextran amine (BDA) were made into the SNR of 10 male adult rats. The distribution of anterogradely labelled axon terminals in the thalamic nuclei was documented. The projections of the SNR to the thalamic nuclei were exclusively to some motor higher-order, but not to first-order thalamic relays. There were bilateral projections to the ventromedial (VM), parafascicular (PF), centromedian (CM) and paracentral (PC) nuclei and unilateral projections to the centrolateral (CL), mediodorsal (MD) and thalamic reticular nucleus (Rt). Labelled axon terminals in the thalamic nuclei ranged from numerous to sparse in VM, PF, CM, CL, PC, MD and Rt. Further, injections into the SNR along its rostral-caudal axis showed specific topographical connections with the thalamic nuclei. The rostral SNR injections showed labelled axon terminals of VM, PF, CL, PC, CM, MD and Rt. Caudal SNR injections showed labelling of VM, PF, PC, CM and MD. All injections showed labelled axons and terminals in the zona incerta. The nigrothalamic GABAergic neurons can be regarded as an important system for the regulation of motor activities. The SNR is in a position to influence large areas of the neocortex by modulating some of the motor higher-order thalamic nuclei directly or indirectly via Rt.     

Motor neglect.

Motor neglect is characterised by an underutilisation of one side, without defects of strength, reflexes or sensibility. Twenty cases of frontal, parietal and thalamic lesions causing motor neglect, but all without sensory neglect, are reported. It is proposed that the cerebral structures involved in motor neglect are the same as those for sensory neglect and for the preparation of movement. As in sensory neglect, the multiplicity of the structures concerned suggests that this interconnection is necessary to maintain a sufficient level of activity. Predominance of left sided neglect by right sided lesions suggests that the left hemisphere is dominant for deliberate activity; hemispheric dominance could be applied to sensory neglect where conscious awareness would play the role of deliberate activity.     

Fatal familial insomnia: clinical and pathologic study of five new cases.

In 1986, we reported two anatomoclinical observations of a familial condition that we called "fatal familial insomnia" (FFI). We now present the pedigree as well as the clinical and neuropathologic findings in five new subjects. The pedigree includes 288 members from six generations. Men and women are affected in a pattern consistent with an autosomal dominant inheritance. The age of onset of the disease varies between 37 and 61 years; the course averages 13 months with a range of 7 to 25 months. Progressive insomnia (polygraphically proven in two cases); autonomic disturbances including hyperhidrosis, hyperthermia, tachycardia, and hypertension; and motor abnormalities including ataxia, myoclonus, and pyramidal dysfunction, were present in every case, but with variable severity and time of presentation. Sleep and autonomic disorders were the earliest signs in two subjects, motor abnormalities were dominant in one, and others had intermediate clinical patterns. Pathologically, all the cases had severe atrophy of the anterior ventral and mediodorsal thalamic nuclei. Other thalamic nuclei were less severely and inconsistently affected. In addition, most of the cases had gliosis of the cerebral cortex, a moderate degree of cerebellar atrophy with "torpedoes," and severe atrophy of the inferior olivary nuclei. One case also showed spongy degeneration of the cerebral cortex. We conclude that all the lesions were primary, and that FFI is a multisystem disease in which the different structures are primarily affected with different severity. The insomnia appears to correlate best with the major thalamic pathology. The possibility that FFI belongs to the group identified as prion diseases or diseases transmitted by unconventional agents is examined.     

The functional connectivity of intralaminar thalamic nuclei in the human basal ganglia

Projections of the centromedian‐parafasicularis neurons of the intralaminar thalamus are major inputs of the striatum. Their functional role in the activity of human basal ganglia (BG) is not well known. The aim of this work was to study the functional connectivity of intralaminar thalamic nuclei with other BG by using the correlations of the BOLD signal recorded during “resting” and a motor task. Intralaminar nuclei showed a marked functional connectivity with all the tested BG, which was observed during “resting” and did not change with the motor task. As regards the intralaminar nuclei, BG connectivity was much lower for the medial dorsal nucleus (a thalamic nucleus bordering the intralaminar nuclei) and for the default mode network (although intralaminar nuclei showed a negative correlation with the default mode network). After the “regression” of intralaminar nuclei activity (partial correlation), the functional connectivity of the caudate and putamen nuclei with other BG decreased (but not with the primary sensorimotor cortex). Present data provide evidence that intralaminar nuclei are not only critical for striatal activity but also for the global performance of human BG, an action involving subcortical BG loops more than cortico‐subcortical loops. The high correlation found between BG suggest that, similarly to that reported in other brain centers, the very‐slow frequency fluctuations are relevant for the functional activity of these centers. Hum Brain Mapp 36:1335–1347, 2015. © 2014 Wiley Periodicals, Inc .     

Neural circuits and functional organization of the striatum

The basal ganglia and motor thalamic nuclei are functionally and anatomically divided into the sensorimotor, supplementary motor, premotor, associative and limbic territories. There exist both primary segregated basal ganglia-thalamocortical loops and convergence of functionally related information from different cortical areas onto these cortical basal gaglia-thalamocortical loops. The basal ganglia-thalamocortical loop arising from the sensorimotor area, supplementary motor area (SMA), premotor area and cingulate motor area provides distinct segregated subloops through the functionally distict stritial, pallidal and thalamic regions with partial overlap. The subthalamic nucleus (STN) is also topographically organized. The ventrolateral part of the caudal 2/3 levels of the medial pallidal segment (GPi) projects to the primary motor area via the oral part of the ventral lateral thalamic nucleus (VLo) (Voa, Vop by Hassler's nomenclature). The thalamic relay nuclei of the GPi projection to SMA are identified in the transitional zoe of the VApc (parvicellular part of the anterior ventral nucleus)-VLo and in the rostromedical part of the VLo. The thalamic nuclei relaying the cingulate subloop are not yet clearly defined. The supplementary motor subloop appears to be divided into the pre-SMA and SMA proper subloops. The premotor area is also divided into the dorsal premotor area subloop and the ventral premotor area subloop. It is suggested that the limbic loop consists of a number of subloops in the monkey as indicated by Haber et al. [67] and in rats [64]. We review here the microcircuitry of the striatum, as well as the convergence and integration between the functionally segregated loops. Finally, we discuss the functional implications of stritial connections.

     

Two whisker motor areas in the rat cortex: Evidence from thalamocortical connections

In primates, the motor cortex consists of at least seven different areas, which are involved in movement planning, coordination, initiation, and execution. However, for rats, only the primary motor cortex has been well described. A rostrally located second motor area has been proposed, but its extent, organization, and even definitive existence remain uncertain. Only a rostral forelimb area (RFA) has been definitively described, besides few reports of a rostral hindlimb area. We have previously proposed existence of a second whisker area, which we termed the rostral whisker area (RWA), based on its differential response to intracortical microstimulation compared with the caudal whisker area (CWA) in animals under deep anesthesia (Tandon et al. [2008] Eur J Neurosci 27:228). To establish that RWA is distinct from the caudally contiguous CWA, we determined sources of thalamic inputs to the two proposed whisker areas. Sources of inputs to RFA, caudal forelimb area (CFA), and caudal hindlimb region were determined for comparison. The results show that RWA and CWA can be distinguished based on differences in their thalamic inputs. RWA receives major projections from mediodorsal and ventromedial nuclei, whereas the major projections to CWA are from the ventral anterior, ventrolateral, and posterior nuclei. Moreover, the thalamic nuclei that provide major inputs to RWA are the same as for RFA, and the nuclei projecting to CWA are same as for CFA. The results suggest that rats have a second rostrally located motor area with RWA and RFA as its constituents. J. Comp. Neurol. 522:528–545, 2014. © 2013 Wiley Periodicals, Inc.     

Thalamostriatal and cerebellothalamic pathways in a songbird,the Bengalese finch

The thalamostriatal system is a major network in the mammalian brain, originating principally from the intralaminar nuclei of thalamus. Its functions remain unclear, but a subset of these projections provides a pathway through which the cerebellum communicates with the basal ganglia. Both the cerebellum and basal ganglia play crucial roles in motor control. Although songbirds have yielded key insights into the neural basis of vocal learning, it is unknown whether a thalamostriatal system exists in the songbird brain. Thalamic nucleus DLM is an important part of the song system, the network of nuclei required for learning and producing song. DLM receives output from song system basal ganglia nucleus Area X and sits within dorsal thalamus, the proposed avian homolog of the mammalian intralaminar nuclei that also receives projections from the cerebellar nuclei. Using a viral vector that specifically labels presynaptic axon segments, we show in Bengalese finches that dorsal thalamus projects to Area X, the basal ganglia nucleus of the song system, and to surrounding medial striatum. To identify the sources of thalamic input to Area X, we map DLM and cerebellar‐recipient dorsal thalamus (DT_CbN). Surprisingly, we find both DLM and dorsal anterior DT_CbN adjacent to DLM project to Area X. In contrast, the ventral medial subregion of DT_CbN projects to medial striatum outside Area X. Our results suggest the basal ganglia in the song system, like the mammalian basal ganglia, integrate feedback from the thalamic region to which they project as well as thalamic regions that receive cerebellar output.     

Functional anatomy of thalamus and basal ganglia

THALAMUS: The human thalamus is a nuclear complex located in the diencephalon and comprising of four parts (the hypothalamus, the epythalamus, the ventral thalamus, and the dorsal thalamus). The thalamus is a relay centre subserving both sensory and motor mechanisms. Thalamic nuclei (50-60 nuclei) project to one or a few well-defined cortical areas. Multiple cortical areas receive afferents from a single thalamic nucleus and send back information to different thalamic nuclei. The corticofugal projection provides positive feedback to the "correct" input, while at the same time suppressing irrelevant information. Topographical organisation of the thalamic afferents and efferents is contralateral, and the lateralisation of the thalamic functions affects both sensory and motoric aspects. Symptoms of lesions located in the thalamus are closely related to the function of the areas involved. An infarction or haemorrhage thalamic lesion can develop somatosensory disturbances and/or central pain in the opposite hemibody, analgesic or purely algesic thalamic syndrome characterised by contralateral anaesthesia (or hypaesthesia), contralateral weakness, ataxia and, often, persistent spontaneous pain. BASAL GANGLIA: Basal ganglia form a major centre in the complex extrapyramidal motor system, as opposed to the pyramidal motor system (corticobulbar and corticospinal pathways). Basal ganglia are involved in many neuronal pathways having emotional, motivational, associative and cognitive functions as well. The striatum (caudate nucleus, putamen and nucleus accumbens) receive inputs from all cortical areas and, throughout the thalamus, project principally to frontal lobe areas (prefrontal, premotor and supplementary motor areas) which are concerned with motor planning. These circuits: (i) have an important regulatory influence on cortex, providing information for both automatic and voluntary motor responses to the pyramidal system; (ii) play a role in predicting future events, reinforcing wanted behaviour and suppressing unwanted behaviour, and (iii) are involved in shifting attentional sets and in both high-order processes of movement initiation and spatial working memory. Basal ganglia-thalamo-cortical circuits maintain somatotopic organisation of movement-related neurons throughout the circuit. These circuits reveal functional subdivisions of the oculomotor, prefrontal and cingulate circuits, which play an important role in attention, learning and potentiating behaviour-guiding rules. Involvement of the basal ganglia is related to involuntary and stereotyped movements or paucity of movements without involvement of voluntary motor functions, as in Parkinson's disease, Wilson's disease, progressive supranuclear palsy or Huntington's disease. The symptoms differ with the location of the lesion. The commonest disturbances in basal ganglia lesions are abulia (apathy with loss of initiative and of spontaneous thought and emotional responses) and dystonia, which become manifest as behavioural and motor disturbances, respectively.     

Afferent projections to the parafascicular thalamic nucleus of the rat, as shown by the retrograde transport of wheat germ agglutinin

Afferent projections to the parafascicular nucleus of the rat have been mapped using the retrograde transport of unconjugated wheat germ agglutinin and immunohistochemistry using very short survival times. Retrogradely labelled neurones were found in laminae V and V1 of primary motor cortex, lamina V1 of primary somatosensory cortex, and deep laminae of gustatory cortex; in the reticular thalamic nucleus and zona incerta; and in the caudate-putamen, entopeduncular nucleus, mesencephalic reticular formation and pretectum. Additional label was found in the laterodorsal tegmental nucleus, nucleus tegmenti pedunculopontinus, dorsal and ventral parabrachial nuclei, vestibular nuclei and the lateral cervical, medial and interpositus nuclei of the cerebellum. These results are discussed in the context of the connections of parafascicular nucleus with the motor system, particularly the basal ganglia. Of particular interest are inputs from laterodorsal tegmental nucleus, nucleus reticularis of thalamus, mesencephalic reticular formation, nucleus tegmenti pedunculopontinus, primary motor cortex and deep cerebellar nuclei. These indicate that the parafascicular nucleus lies at an interface between the reticular activating system on the one hand, and the motor system on the other. This result thus enlarges on present concepts of the parafascicular nucleus. Comparison of afferent projections to a variety of non-specific thalamic nuclei, the parafascicular, paraventricular and mediodorsal thalamic nuclei, indicate a remarkable set of topographic parallels from cortical, reticular thalamic, hypothalamic and brainstem sites. These comparisons provide clues as to the organisational principles of these non-specific thalamic nuclei, particularly in the context of the reticular activating system.     

Corticothalamic projections from layer V cells in rat are collaterals of long-range corticofugal axons

The vast majority of corticothalamic (CT) axons projecting to sensory-specific thalamic nuclei arise from layer VI cells but intralaminar and associative thalamic nuclei also receive, to various degrees, a cortical input from layer V pyramidal cells. It is also well established that all long-range corticofugal projections reaching the brainstem and spinal cord arise exclusively from layer V neurons. These observations raise the possibility that the CT input from layer V cells may be collaterals of those long-range axons projecting below thalamic level. The thalamic projections of layer V cells were mapped at a single cell level following small microiontophoretic injections of biocytin performed in the motor, somatosensory and visual cortices in rats. Camera lucida reconstruction of these CT axons revealed that they are all collaterals of long-range corticofugal axons. These collaterals do not give off axonal branches within the thalamic reticular nucleus and they arborize exclusively within intralaminar and associative thalamic nuclei where they form small clusters of varicose endings. As layer V cells are involved in motor commands everywhere in the neocortex, these CT projections and their thalamic targets should be directly involved in the central organization of motor programs.     

Afferent connections to the diencephalon in the marsupial phalanger and question of sensory convergence in the "posterior group" of the thalamus

The various afferent pathways terminating in the thalamus of the marsupial phalanger have been investigated with the Nauta techniques, with a view to determining the extent of overlap and convergence of these pathways. If this had proved to be extensive, it would have lent support to the views of some authors that, in primitive and generalized mammals, the relay nuclei are in the process of differentiating out of a single archetypical, multi-modal nucleus. However, the amount of overlap between the various afferent pathways in this animal is no greater than in the cat and monkey; in the case of the ventral nuclear complex, despite the presence of a common sensory and motor cortical representation, the overlap between the somatic sensory and cerebellar pathways is probaly less than in the higher mammals. The question, therefore, arises as to whether differentiation of certain thalamic nuclei may precede that of the cortical area with which they are connected. The results furnish evidence for the homologies of the posterior group of thalamic nuclei in other mammals, but the limited amount of overlap of afferent pathways occurring in the posterior group is not necessarily indicative of its being the common precursor of all the sensory relay nuclei.     

Diffuse thalamic degeneration in fatal familial insomnia. A morphometric study

A morphometric investigation disclosed most thalamic nuclei severely degenerated in two patients with fatal familial insomnia. Associative and motor nuclei lost 90% neurons, and limbic–paralimbic, intralaminar and reticular nuclei lost 60%. These findings point to the disorganization of most thalamic circuits as a condition necessary for the sleep–wake rhythm being affected.     

An investigation of thalamic nuclei volumes and the intrinsic thalamic structural network based on motor subtype in drug naïve patients with Parkinson's disease

IntroductionThis study aimed to investigate the alterations in thalamic nuclei volumes and the intrinsic thalamic structural network in patients with de novo Parkinson's disease (PD) based on their predominant symptoms.MethodsWe enrolled 65 patients with de novo PD (44 patients with tremor-dominant [TD] subtype and 21 patients with postural instability and gait disturbance [PIGD] subtype) and 20 healthy controls. All subjects underwent three-dimensional T1-weighted magnetic resonance imaging. The thalamic nuclei were segmented using the FreeSurfer program.ResultsWe obtained volumetric differences in the thalamic nuclei of each subtype of PD in comparison of healthy control. Volumes of the right and left suprageniculate nuclei were significantly increased, whereas that of the left parafascicular nucleus was decreased in patients with the TD subtype. Volumes of the right and left suprageniculate nuclei and right ventromedial nucleus were significantly increased, whereas those of the right and left parafascicular nuclei volumes were decreased in patients with the PIGD subtype. The measures of the intrinsic thalamic global network were not different between patients with TD PD and healthy controls. However, in patients with the PIGD subtype, the global and local efficiencies were significantly increased compared to healthy controls. Moreover, although there were no differences in thalamic volume and intrinsic thalamic global network between patients with the TD and PIGD variants, we identified significant differences in the intrinsic thalamic local network between the two groups.ConclusionsAlterations in thalamic nuclei volumes and the intrinsic thalamic network in patients with PD differed based on their predominant symptoms. These findings might be related to the underlying pathogenesis and suggest that PD is a heterogeneous syndrome.     

Anatomical evidence for segregated focal groupings of efferent cells and their terminal ramifications in the cerebellothalamic pathway of the monkey

Patterns of termination of the cerebellothalamic pathway were investigated using anterograde tracing techniques. The thalamic projections from each of the deep cerebellar nuclei are topographically organized in two and possibly in three dimensions. First, the caudo-rostral cerebellar nuclear dimension is mapped onto the mediolateral dimension within the cell-sparse ventral lateral thalamic region (VPLo, VLc, VLps, and nucleus X). By correlating this topographic ordering with the previously established lamellar organization of the cell-sparse thalamic region a somatotopy is inferred within the deep cerebellar nuclei, with caudal body parts represented anteriorly and rostral body parts represented posteriorly in each nucleus. A second topography consists of the mapping of the mediolateral dimension of the dentate and interpositus nuclei onto the ventrodorsal dimension of the lamellae in the thalamus. Since the thalamic connections with motor cortex predict a somatotopic organization with distal body parts ventral and axial parts dorsal in thalamus, each cerebellar nucleus should, therefore, represent axial body parts laterally and distal parts medially. A third mapping dimension is shown for the dentatothalamic projection: dorsal parts of the dentate nucleus project posteriorly within the cell-sparse thalamic region, and ventral parts project anteriorly. The significance of this as regards representation of the body is not known. Subsidiary foci of terminations within the cell-sparse thalamic region are visible following tritiated amino acid injections into each of the deep cerebellar nuclei. Following dentate injections these foci appear as anteroposteriorly elongated, rod-like aggregations of terminations which are similar to the rod-like aggregations of thalamocortical relay cells which have been demonstrated following focal injections of horseradish peroxidase into the motor cortex. The interpositothalamic and the fastigiothalamic terminations are elongated and appear as focal clusters in all planes of section. The interpositothalamic clusters are distributed within posterodorsally curving planar sheets. An anterograde double labeling technique, using a combination of the autoradiographic technique with the axonal degeneration technique, was used to investigate the interrelations of the terminations from different nuclei and from different parts of the same nucleus. Rods from different parts of the dentate nucleus terminate independently of one another. Dentatothalamic rods and interpositothalamic clusters, though interdigitating within the same thalamic region, do not overlap. This topographic and modular organization of the cerebellothalamic pathway suggests that the cerebellar input may reflect both the somatotopic and the columnar organization of the motor cortex.     

Differential projections from the mediodorsal and centrolateral thalamic nuclei to the frontal cortex in rats

The aim of the present study was to investigate afferent projections from the medial thalamic nuclei (MT) to the frontal cortical areas using a single small iontophoretic injection of biotinylated dextran amine (BDA) and analysis of the anterogradely labeled fibers and varicosities. Projections from the mediodorsal (MD) nuclei were found primarily and extensively in the anterior cingulate cortex (ACC), whereas those from the centrolateral (CL) thalamic nucleus were found in the frontal motor cortex. The density of terminals in the ACC was high in layers II and III and sparse in layer I. The majority of projected fibers from the CL were found at a high density in layer V, with a moderate density in the superficial layers. The differential projection patterns were topographically organized in the medial prefrontal cortex and sensory motor cortex. These findings support the results of our previous electrophysiological studies suggesting that neurons in the medial thalamic nuclei relay nociceptive information to the limbic or sensory motor cortical areas. The present results agree with the current notion that the medial thalamo-frontal cortical network circuitry plays an important role in processing the emotional aspect of nociception.