Cortical pain. Clinical, electrophysiologic and topographic study of 12 cases

Vascular lesions of the cerebral cortex sparing the thalamus (MRI or CT with reconstructions) may be accompanied by burning or constrictive pain which suggests thalamic pain as it affects one half of the body and is associated with induced pain. Summation hyperpathia is rare; allodynia is more common and sometimes isolated (2 cases). Cortical pain may be paroxysmal, and in 3 of our patients it progressed like a jacksonian seizure. The territory of pain is also the site of global or spinothalamic hypoaesthesia (5 cases). Early SEPs are abolished or of low amplitude (8 cases). The lesion is located in area SI or extends to the thalamo-parietal radiations; in 11 out of 12 patients it was located in the minor hemisphere. Two physiopathological theories are discussed: hyperactivity of the intralaminar thalamus relieved from cortical inhibition, or denervation hyperactivity related to the cortical or subcortical lesion.     

Evoked response studies of the thalamic pain syndrome

Human and animal studies have suggested that the occurrence of thalamic pain (hyperpathia) is not simply a manifestation of a functional deficit in the major lemniscal pathway mediated through the ventral posterior (VP) thalamic nucleus. More effective relief of this pain has occurred following stereotaxic lesions of the centromedianum (CM) than after lesions restricted to VP. Median nerve stimulation has evoked abnormal contralateral somatosensory evoked responses (SER) in patients with lesions of VP. In this study the SERs evoked by contra-lateral stimulation in two patients with thalamic pain secondary to infarction were normal. These results support the hypothesis that thalamic pain can be caused by thalamic lesions sparing VP. The minor change noted in the ipsilateral SER when the abnormal hand was stimulated was consistent with a lesion involving CM or adjacent nonspecific thalamic nuclei.     

Crosstalk between the two sides of the thalamus through the reticular nucleus: A retrograde and anterograde tracing study in the rat

In order to investigate the possible routes linking the thalamus in the two sides of the brain, the connections of the reticular nucleus (RT), the major component of the ventral thalamus, with contralateral dorsal thalamic nuclei were systematically investigated in the adult rat. This study was performed with several tract-tracing techniques: single and double retrograde labeling with fluorescent tracers, and anterograde tracing with biocytin. Retrograde tracing was also combined with immunocytochemistry to provide additional criteria for the identification of labeled RT neurons. The data obtained with the retrograde transport of one fluorescent tracer showed that RT neurons project to contralateral dorsal thalamic domains. In particular, retrograde labeling findings indicated that the anterior intralaminar nuclei, as well as the ventromedial (VM) nucleus, are preferential targets of the contralateral RT projections. Commissural neurons were concentrated in two portions of RT: its rostral part, including the rostral pole, which projects to the contralateral central lateral (CL) and paracentral (Pc) nuclei, and the ventromedial sector of the middle third of RT, which projects to the contralateral VM and posterior part of CL and Pc. The double retrograde labeling study of the bilateral RT–intralaminar connection indicated that at least part of the commissural RT cells bifurcate bilaterally to symmetrical portions of the anterior intralaminar nuclei. The targets of the RT commissural system inferred from the retrograde labeling data were largely confirmed by anterograde tracing. Moreover, it was shown that RT fibers cross the midline in the intrathalamic commissure. The present data demonstrate that bilateral RT connections with the dorsal thalamus provide a channel for interthalamic crosstalk. Through these bilateral connections with thalamic VM and intralaminar neurons, RT could influence the activity of wide territories of the cerebral cortex and basal ganglia of both hemispheres. © 1993 Wiley-Liss, Inc.     

Thalamic components of the ascending vestibular system

A combined anatomical and physiological approach was used to identify the thalamic nuclei that relay vestibular activity to the cerebral cortex at short latency in the cat. For the anatomical experiments, electrical stimulation was applied to the vestibular nerve, the cortical sites showing maximal amplitude responses were defined, and horseradish peroxidase was injected in these sites. Two days later, the animals were killed and brain sections were processed to localize enzyme reaction products in thalamic neurons. After either anterior suprasylvian injection or posterior cruciate region injection, most labeled neurons were in the ventral posterolateral nucleus. A few labeled neurons were found in the intralaminar and posterior groups of nuclei. In separate physiological experiments, responses to vestibular nerve stimulation and cerebral cortical stimulation were recorded from the thalamus. Short-latency (<3.5 ms), large-amplitude evoked potentials from vestibular nerve stimulation and antidromic field potentials from cortical stimulation were recorded within the ventral basal complex and the most rostral portions of the posterior group of thalamic nuclei. These data indicate that neurons in the ventral basal complex and the region between the ventral basal complex and the posterior group relay vestibular activity to both the anterior suprasylvian and posterior cruciate regions of the cerebral cortex.     

Basal forebrain cholinergic and noncholinergic projections to the thalamus and brainstem in cats and monkeys

The projections of basal forebrain neurons to the thalamus and the brainstem were investigated in cats and primates by using retrograde transport techniques and choline acetyltransferase (ChAT) immunohistochemistry. In a first series of experiments, the lectin wheat germ-agglutinin conjugated with horseradish peroxidase (WGA-HRP) was injected into all major sensory, motor, intralaminar, and reticular (RE) thalamic nuclei of cats and into the mediodorsal (MD) and pulvinar-lateroposterior thalamic nuclei of macaque monkeys. In cats numerous neurons of the vertical and horizontal limbs of the diagonal band nucleus and the substantia innominata (SI), including its rostromedial portion termed the ventral pallidum (VP), were retrogradely labeled after WGA-HRP injections in the rostral pole of the RE complex, the MD, and anteroventral/anteromedial (AV/AM) thalamic nuclei. Fewer retrogradely labeled cells were observed in the same areas after injections in the ventromedial (VM) thalamic nucleus, and none or very few after other thalamic injections. After RE, MD, and AV/AM injections, 7-20% of all retrogradely labeled cells in the basal forebrain were also ChAT positive, while none of the retrogradely labeled neurons following VM injections displayed ChAT immunoreactivity. The basal forebrain projection to the MD nucleus was shown to arise principally from VP in both cats and macaque monkeys. In a second series of experiments performed in cats, injections of WGA-HRP in the brainstem peribrachial (PB) area comprising the pedunculopontine nucleus led to retrograde labeling of a moderate number of neurons in the lateral part of the VP, SI, and preoptic area (POA), only a few of which displayed ChAT immunoreactivity. In addition, a large number of retrogradely labeled cells were observed in the bed nuclei of the anterior commissure and stria terminalis after PB injections. In a third series of experiments, the use of the retrograde double-labeling method with fluorescent tracers in squirrel monkeys allowed us to identify a significant number of basal forebrain neurons sending axon collaterals to both the RE thalamic nucleus and PB brainstem area, while no double-labeled neurons were disclosed after injections confined to the ventral anterior/ventral lateral (VA/VL) thalamic nuclei and PB area or following injections in the cerebral cortex and PB area. Our findings reveal the existence of cholinergic and noncholinergic basal forebrain projections to the thalamus and the brainstem in both cats and macaque monkeys. We suggest that these projections may play a crucial role in the control of thalamic functions in mammals.     

Thalamostriatal neurons with collateral projection onto the rostral reticular thalamic nucleus: anatomical study in the rat by retrograde axonal transport of iron-dextran and horseradish peroxidase

Injection of horseradish peroxidase (HRP) into the head of the reticular thalamic nucleus (RT) of rats having undergone large cortical and striatal lesions, led to the labeling of thalamic neurons in medial thalamic nuclei. After injection of iron-dextran into the corpus striatum and HRP into the rostral RT of intact rats, double-labeled neurons were observed in the medial thalamus, mainly in the central lateral nucleus.     

Thalamic connectivity of the primary motor cortex of normal and reeler mutant mice

Reeler, an autosomal recessive mutation in mice, causes cytoarchitectonic abnormalities of the cerebral cortex, which are characterized by malposition of neurons. Retrograde and anterograde transport of horseradish peroxidase (HRP) was employed to examine the reciprocal connectivity between the hindlimb area of the primary motor cortex (MI) and thalamus of normal and reeler mutant mice. In the normal mouse, most of the cells labelled after HRP injection into the hindlimb area of MI were located in the ventrolateral nucleus, the lateral division of the ventrobasal nucleus, the central lateral, paracentral and central intralaminar nuclei, and the medial division of the posterior complex. HRP reaction product anterogradely transported was also observed in the same nuclei and in the thalamic reticular nucleus. In the reeler mutant mouse, retrogradely labelled neurons and anterogradely labelled terminals were again found in the nuclei referred to above, and the distribution pattern and morphology of HRP-filled neurons were also similar to those of normal controls. The present results suggest therefore that the normal reciprocal connectivity between MI (hindlimb representation) and thalamus is preserved in the reeler mouse. That is to say, dislocated cortical neurons appropriately project to their target nuclei of the thalamus, and conversely, thalamic neurons send their axons precisely to their target cortical areas of the radially disorganized cortex.     

Locus coeruleus modulation of the motor thalamus: Inhibition in nuclei ventralis lateralis and ventralis anterior

Single-cell recordings were made from 693 cells in thalamic nuclei ventralis lateralis and ventralis anterior (VL-VA). Cells were identified as thalamocortical projection cells by antidromic firing from motor cortex or classified according to responsiveness to stimulation of the brachium conjunctivum (BC), entopeduncular nucleus, and motor cortx. Only 14% of the cells tested responded to entopeduncular nucleus stimulation, whereas BC and motor cortex (orthodromic) stimulation each evoked responses in 31% of the VL-VA cells tested. The most common sources of convergent input to VL-VA cells were motor cortex and BC. In 30% of the VL-VA population tested, spontaneous firing was inhibited by stimulation of the locus coeruleus (LC). This inhibition had a long latency to onset which varied from cell to cell (100 to 1000 ms or more) and a long duration (mean = 1183 ms). The inhibition of spontaneous firing by LC was associated with a variable effect upon BC-evoked excitatory responses in VL-VA cells. In some cases, BC evoked responses were suppressed, but not abolished. In other cells, the excitatory response to BC was unaffected despite complete cessation of VL-VA cell spontaneous firing after LC stimulation. The inhibitory action of LC was not limited to any class of VL-VA cells, but occurred most frequently in neurons receiving an input from the BC. The LC inhibition of VL-VA is not related to changes in systemic blood pressure or an action at the level of the cerebellar cortex. However, LC also produces inhibitory and excitatory effects in centrum medianum neurons, which could account for some of the long-latency responses observed in VL-VA. This electrophysiological study of the action of locus coeruleus upon cellular activity in the motor thalamus argues against involvement in phasic movement and associated postural adjustments. Rather, the locus coeruleus projection to thalamus has properties which suggest a role in longer-term tonic regulation of motor activity.     

Allodynia in the flank after thalamic stroke.

Lesions responsible for thalamic pain are often thought to involve the ventral posteromedial nucleus and ventral posterolateral nucleus of the thalamus. We describe two patients with allodynia and hyperpathia in the contralateral flank caused by a small lesion in the posteroventral part of the thalamus. When considered with the literature, involvement of the ventral posteroinferior nucleus may be responsible for this unique post-stroke pain syndrome.     

Early and specific expression of monocyte chemoattractant protein-1 in the thalamus induced by cortical injury

For many years it has been known that retrograde degeneration of thalamic neurons occurs following damage to the cerebral cortex, however, the molecular mechanisms which control this process are unknown. Recent studies have demonstrated microglial activation in thalamic nuclei well before the onset of retrograde neuronal cell death. Activated monocytes and microglia synthesize factors detrimental to neuronal survival as well as phagocytose damaged and dying neurons. Our previous studies demonstrated that monocyte chemoattractant protein-1 (MCP-1), a β chemokine which attracts cells of monocytic origin to sites of injury, is rapidly expressed in the brain following visual cortical lesions. The present study examined the expression of MCP-1 messenger RNA and protein in the thalamus following a visual cortical lesion. Aspiration lesions of visual cortex were made in adult mice. At specific times after lesion, brains were harvested and dissected into specific regions. MCP-1 message as detected using northern analysis was absent in uninjured brain, but was elevated in the ipsilateral thalamus as rapidly as 1 h following the lesion. In situ hybridization localized MCP-1 message to subpial glial cells of the lateral geniculate nucleus (LGN) of the ipsilateral thalamus after injury. ELISA showed that MCP-1 protein levels were significantly elevated in the ipsilateral thalamus at 6 h, peaked at 12 h, and remained above baseline levels for at least 1 week post lesion. In addition, anti-GFAP staining demonstrated activated astrocytes localized to the ipsilateral LGN at 24 and 72 h after injury. The early expression and regional localization of MCP-1 mRNA and protein strongly suggest that MCP-1 is a critical molecule in the regulation of thalamic retrograde neuronal degeneration.     

Some aspects of the organization of the thalamic reticular complex.

Anatomical methods which depend upon the anterograde axonal transport of isotopically labeled neuronal proteins or the retrograde axonal transport of the enzyme, horseradish peroxidase, have been used to elucidate the relationships between the reticular complex and the dorsal thalamus and cerebral cortex. Injections of tritiated amino acids in the dorsal thalamus or cerebral cortex in rats, cats and monkeys, show that as the bundles of thalamo-cortical and cortico-thalamic fibers joining a particular dorsal thalamic nucleus to its associated area of the cerebral cortex traverse the reticular complex, they each give rise to a dense zone of terminals occupying a sector of the reticular complex which is relatively constant for that dorsal thalamic nucleus and cortical area. However, because of the wide extent of the dendritic fields of the reticular cells and the degree of overlap between the sectors of the complex subtended by adjacent dorsal thalamic nuclei and adjacent cortical areas, it is likely that the reticular complex samples thalamo-cortical and cortico-thalamic activity in a somewhat unspecific manner. Fibers passing to the reticular complex from the intralaminar nuclei of the thalamus appear to be associated with the projection from the intralaminar nuclei to the striatum. Injections of tritiated amino acids in the reticular complex itself and injections of horseradish peroxidase in various other parts of the brain show that the only efferent pathway from the reticular complex terminates in the nuclei of the dorsal thalamus. The reticular complex does not appear to send fibers to other components of the ventral thalamus nor to the cerebral cortex.     

The neurobiology of thalamic amnesia: Contributions of medial thalamus and prefrontal cortex to delayed conditional discrimination

Although medial thalamus is well established as a site of pathology associated with global amnesia, there is uncertainty about which structures are critical and how they affect memory function. Evidence from human and animal research suggests that damage to the mammillothalamic tract and the anterior, mediodorsal (MD), midline (M), and intralaminar (IL) nuclei contribute to different signs of thalamic amnesia. Here we focus on MD and the adjacent M and IL nuclei, structures identified in animal studies as critical nodes in prefrontal cortex (PFC)-related pathways that are necessary for delayed conditional discrimination. Recordings of PFC neurons in rats performing a dynamic delayed non-matching-to position (DNMTP) task revealed discrete populations encoding information related to planning, execution, and outcome of DNMTP-related actions and delay-related activity signaling previous reinforcement. Parallel studies recording the activity of MD and IL neurons and examining the effects of unilateral thalamic inactivation on the responses of PFC neurons demonstrated a close coupling of central thalamic and PFC neurons responding to diverse aspects of DNMTP and provide evidence that thalamus interacts with PFC neurons to give rise to complex goal-directed behavior exemplified by the DNMTP task.     

Differential Calcium Binding Protein Immunoreactivity Distinguishes Classes of Relay Neurons in Monkey Thalamic Nuclei

The distributions of neurons displaying immunoreactivity for two calcium binding proteins, parvalbumin and 28Kd calbindin, were studied in the thalamus of M. fascicularis. Colocalization experiments were carried out to determine the extent to which parvalbumin- and calbindin-like immunoreactivity was found in the same cells and the extent to which either was localized in GABAergic interneurons. Anterograde and retrograde tracing experiments involving the fluorescent tracer, fast blue, were also used to determine that cells expressing the calcium binding proteins projected upon the cerebral cortex. In the dorsal thalamus, nuclei are distinguished by different patterns of parvalbumin-like and calbindin-like immunoreactivity. In certain nuclei, for example the lateral dorsal and anterior pulvinar, neurons express immunoreactivity for only one of the calcium binding proteins. In others, neurons in different layers, for example the dorsal lateral geniculate nucleus, or in different compartments, for example the intralaminar nuclei, express immunoreactivity for either parvalbumin or calbindin; in other nuclei, for example the ventral group, neurons are mixed and immunoreactivity for parvalbumin and calbindin is commonly colocalized. In the ventral thalamus and epithalamus, similar patterns are observed. Colocalization of parvalbumin- and GABA-immunoreactivity is found in all cells of the reticular nucleus but only in certain cells in selected nuclei of the dorsal thalamus, namely the dorsal lateral geniculate and magnocellular medial geniculate. No calbindin-positive cells are also GABA-positive. Most parvalbumin and/or calbindin positive cells in the dorsal thalamus project to the cerebral cortex, as indicated by the retrograde tracing studies, and many parvalbumin positive fibres entering the cerebral cortex could also be shown to contain fast blue anterogradely transported from a thalamic injection. Most of the major sensory and motor pathways entering the dorsal thalamus express parvalbumin immunoreactivity. The optic tract also expresses calbindin immunoreactivity but most other calbindin positive fibres entering the thalamus ascend in the midbrain tegmentum. The differential distributions of parvalbumin and calbindin implied by these results suggest that thalamic cells belonging to different functional systems and projecting differentially upon the cerebral cortex can be distinguished by differential expression of these or closely related calcium binding proteins. This may yield clues to their differential responsivity to afferent driving.     

Calcitonin gene-related peptide (CGRP) immunoreactivity in the afferents to the caudate-putamen and perirhinal cortex of rats

The posterior caudate-putamen and perirhinal cortex are innervated by fibers immunoreactive to calcitonin gene-related peptide (CGRP). We investigated the origins of these fibers by using immunohistochemistry combined with lesion experiments and fluorescent dye tracers. Lesions of the posterior thalamus surrounding the medial geniculate nucleus, in which groups of CGRP-like immunoreactive (CGRP-LI) cells exist, decreased the number of ipsilaterally CGRP-LI fibers in the posterior caudate-putamen and partly in the perirhinal cortex. Some of CGRP-LI neurons in several posterior thalamic nuclei surrounding the medial geniculate nucleus were labeled with both Fast blue injected into the posterior caudate-putamen and fluoro-gold administered into the anterior perirhinal cortex. Our results indicate that CGRP-LI cells in the posterior thalamus, such as posterior intralaminar, lateral subparafascicular and subparafascicular nuclei, project either separately or simultaneously to innervate the posterior caudate-putamen and perirhinal cortex.     

Immunohistochemical study of glutaminase-containing neurons in the cerebral cortex and thalamus of the rat

In an attempt to identify glutamatergic neurons, the cerebral cortex and thalamus of the rat were examined immunohistochemically by using a monoclonal antibody against phosphate-activated glutaminase (PAG), a major synthetic enzyme of transmitter glutamate in the central nervous system. In both the neocortex and mesocortex, pyramidal cells in layers V and VI showed intense PAG-like immunoreactivity (PAG-LI), whereas neuronal cell bodies in layers I-IV showed weak PAG-LI. At the deep border of layer VI, neurons with horizontally elongated cell bodies showed PAG-LI. In the pyriform and entorhinal cortices, neurons with intense to moderate PAG-LI were seen in layer II as well as in the deeper layers. In the hippocampal formation, pyramidal cells in CA1, CA2, and CA3 and polymorphic cells in CA4 showed PAG-LI; PAG-LI was most intense in pyramidal cells of CA3. Fine granules with weak PAG-LI were also seen on and/or within the cell bodies of granule cells in the dentate gyrus. In the thalamus, neurons with PAG-LI were distributed in all nuclei, although regional differences were observed in the distribution pattern of neurons with PAG-LI and in the intensity of PAG-LI in individual neurons. The largest neurons in each thalamic nucleus showed intense PAG-LI; these were considered to be projection neurons. In addition to perikaryal labeling, many fine, PAG-like immunoreactive granules were distributed in the neuropil of both the cerebral cortex and thalamic nuclei. Some of these fine granules with PAG-LI in the neuropil were assumed to represent fiber terminals with PAG-LI, because the distribution pattern of the deposits in the primary somatosensory and primary visual cortices resembled that of thalamocortical fiber terminals. Glutamate is rather ubiquitous in the mammalian central nervous system, and it is still debatable whether the monoclonal antibody to PAG from brain mitochondria can distinguish transmitter-related glutaminase from the other metabolism-related ones. In the present study, however, large neurons in the thalamic nuclei, as well as pyramidal neurons in the cerebral cortex, showed PAG-LI most intensely, supporting the assumption that projection neurons of the cerebral cortex and thalamus are primarily glutamatergic.     

Expression of cholecystokinin and somatostatin genes in the human thalamus.

The cholecystokinin (CCK) gene is expressed in thalamocortical and thalamo-striatal neurons of the rat. In the cat, this peptide is found in some intralaminar and midline nuclei, whereas somatostatin (SRIF) is expressed in the reticular nucleus of the cat but not in rat. Since the putative neurotransmitters used by thalamic neurons are still incompletely known, especially in humans, we investigated the expression of the CCK and SRIF genes in the human thalamus by using hybridization histochemistry. CCK mRNA was found in many neurons, located in several nuclei of the dorsal thalamus. They were especially numerous and widespread in the nuclei associated with the internal thalamic lamina. They formed a continuum in the basal medial thalamus, from the central-medial nucleus, through the centre median/parafascicular complex to the limitans and suprageniculate nuclei. In addition, neurons with CCK mRNA were found medially and laterally to the mediodorsal nucleus, in the midline and intralaminar nuclei. Only rare neurons with CCK mRNA were found in other nuclei (e.g., in the ventral group of nuclei). SRIF mRNA was found in many neurons of the reticular nucleus, but not in the dorsal thalamus. Neurochemical features of the human thalamus, for the genes studied here, resemble those found in the cat. SRIF may play a role in modulating dorsal thalamic impulses, which may be conveyed through CCK innervation to the striatum and, partly, to the cortex.     

Afferent connections of the anterior thalamus in rabbits

This study was designed to determine whether axons of cholinergic dorsal tegmental neurons terminate on cells in the anterior thalamus in rabbits as in other species, and to localize projecting tegmental cells for future studies of their contributions to anterior thalamic learning-relevant neuronal activity. The distribution of retrogradely labeled neurons was examined following injections of wheat germ agglutinin horseradish peroxidase (WGA-HRP) centered in the anterior ventral (AV) thalamic nucleus. The results confirm past findings in rabbits indicating projections to anterior thalamus from the mammillary nuclei, the posterior cingulate cortex, presubiculum and postsubiculum. Demonstrated for the first time in rabbits were projections from the lateral dorsal and the pedunculopontine tegmental nuclei, locus coeruleus, dorsal raphe nucleus, Gudden's dorsal tegmental nucleus, pretectum and reticular thalamic nucleus.     

The organization of thalamic connections

Connections ascending to the thalamus. Contrary to classical opinion, all thalamic nuclei receive extrathalamic afferents. Segregation or convergence within a topographically defined nucleus represent two modalities of thalamic afferents. In addition, certain topographically organized thalamic afferents possess "privileged" or primary "targets" in the thalamic nucleus while others possess supplementary "targets" in other thalamic nuclei (see cerebellar, pallidal and spinothalamic projections). Ascending connections from several brain stem structures can converge on the same nucleus or diverge to several thalamic nuclei. Thalamic connections with the telencephalon. Methods for determining axonal transport have demonstrated that all thalamic nuclei, with the exception of the reticular nucleus and the ventral part of the lateral geniculate body, project towards the cerebral cortex. Four nuclear complexes can be recognized in the cat as a function of the different modalities of localization, concentration and lamination of the projections towards the cortex and the central grey nuclei. In general, the thalamocortical connections have reciprocal ipsilateral corticothalamic projections originating in the infragranular layers of the cerebral cortex. The reticular nucleus and the ventral part of the lateral geniculate body, which is not projected to the cerebral cortex, are exceptions. Each cortical area receives a "privileged" connection from a thalamic nucleus and a supplementary connection- from one or several other thalamic nuclei. The "privileged" connections usually pass to the fourth and third layers of the neocortex, and sometimes also to the first layer. In contrast, the supplementary connections pass to different superficial or deep cortical layers. Each nucleus is formed of subunits which possess different hodologic and topographic characteristics as a function of the nucleus considered. Convergence or divergence of thalamocortical and corticothalamic projections on the different thalamic nuclei, as well as the laminar distribution of efferents in the cerebral cortex, are related strictly to the hodologic organization of different cellular subunits constituting the nuclei. Concentration or diffusion of thalamic projections on cerebral cortex is related more to the single or multiple projection of cell populations belonging to a thalamic nucleus than to widespread collateralization of thalamocortical axons.