Differences of the medial lemniscus and spinothalamic tract according to the cortical termination areas: A diffusion tensor tractography study.

We investigated differences of the medial lemniscus and its thalamocortical pathway (ML), and the spinothalamic tract and its thalamocortical pathway (STT) according to the cortical termination areas. We found that the ML and STT terminated in the motor cortex and the somatosensory cortex. The ML may be closely related to the motor cortex for motor planning and execution, while the STT may be closely related to the cerebral cortex for somatosensory function and motor execution.

Termination differences in the primary sensorimotor cortex between the medial lemniscus and spinothalamic pathways in the human brain.

The medial lemniscus (ML) and its thalamocortical pathway is responsible for proprioception, in contrast, the spinothalamic tract (ST) and its thalamocortical pathway is the neural tract for pain and body temperature. Therefore, the ML pathway plays a crucial role in skillful movements and may be more linked to motor function than the ST pathway. We investigated the differences in the distribution of the primary motor cortex (M1) and the primary somatosensory cortex (S1) between the ML and ST pathways. Adults (mean age: 40.4 years, range: 21-61 years) were recruited for this study. The seed masks for the ML and ST pathways were given on the color map of the medulla according to the known anatomy and waypoint masks were placed on the ventro-postero-lateral nucleus of the thalamus. The volume of ML pathway did not show any difference between the M1 (10.94) and S1 (13.02) (p>0.05). By contrast, the mean voxel number of the ST pathway in the M1 (18.25) and S1 (27.38) showed significant difference between the M1 and S1 (p<0.05). As for relative voxel number percentage of the M1 compared to the S1, the ML pathway (84%) was significantly higher than ST pathway (67%) (p<0.05). We found that more neural fibers of the ML pathway were terminated in the M1 relative to the S1 compared to the SLP, and this may be linked to the inherent execution of movements of the M1.

Clustering probabilistic tractograms using independent component analysis applied to the thalamus.

The connectivity information contained in diffusion tensor imaging (DTI) has previously been used to parcellate cortical and subcortical regions based on their connectivity profiles. The aim of the current study is to investigate the utility of a novel approach to connectivity based parcellation of the thalamus using probabilistic tractography and independent component analysis (ICA). We use ICA to identify spatially coherent tractograms as well as their underlying seed regions, in a single step. We compare this to seed-based tractography results and to an established and reliable approach to parcellating the thalamus based on the dominant cortical connection from each thalamic voxel (Behrens et al., 2003a,b). The ICA approach identifies thalamo-cortical pathways that correspond to known anatomical connections, as well as parcellating the underlying thalamus in a spatially similar way to the connectivity based parcellation. We believe that the use of such a multivariate method to interpret the complex datasets created by probabilistic tractography may be better suited than other approaches to parcellating brain regions.

Quantitative analysis of spinothalamic tract neurons in adult and developing mouse.

Understanding the development of nociceptive circuits is important for the proper treatment of pain and administration of anesthesia to prenatal, newborn, and infant organisms. The spinothalamic tract (STT) is an integral pathway in the transmission of nociceptive information to the brain, yet the stage of development when axons from cells in the spinal cord reach the thalamus is unknown. Therefore, the retrograde tracer Fluoro-Gold was used to characterize the STT at several stages of development in the mouse, a species in which the STT was previously unexamined. One-week-old, 2-day-old and embryonic-day-18 mice did not differ from adults in the number or distribution of retrogradely labeled STT neurons. Approximately 3,500 neurons were retrogradely labeled from one side of the thalamus in each age group. Eighty percent of the labeled cells were located on the side of the spinal cord contralateral to the injection site. Sixty-three percent of all labeled cells were located within the cervical cord, 18% in thoracic cord, and 19% in the lumbosacral spinal cord. Retrogradely labeled cells significantly increased in diameter over the first postnatal week. Arborizations and boutons within the ventrobasal complex of the thalamus were observed after the anterograde tracer biotinylated dextran amine was injected into the neonatal spinal cord. These data indicate that, whereas neurons of the STT continue to increase in size during the postnatal period, their axons reach the thalamus before birth and possess some of the morphological features required for functionality.

Identification of spinothalamic tract and its related thalamocortical fibers in human brain.

Little is known about the spinothalamic tract (STT) and its related thalamocortical fibers. In the current study, we attempted to identify the STT and related thalamocortical fibers in the human brain, using diffusion tensor tractography (DTT). We recruited 23 healthy volunteers for this study. Diffusion tensor images (DTIs) were scanned using 1.5-T, and the STT and medial lemniscus (ML) were obtained using FMRIB software. Normalized DTI tractography was reconstructed using the Montreal Neurological Institute (MNI) echo-planar imaging (EPI) template supplied with the SPM. The STT began at the posterolateral medulla and ascended to the ventral posterior-lateral (VPL) nucleus of the thalamus, through the pontine tegmentum posterolateral to the ML, and through the mesencephalic tegmentum posterior to the ML. STT-related thalamocortical fibers originated from the VPL nucleus of the thalamus and ascended through the posterior limb of the internal capsule and the posterior portion of the corona radiata, terminating at the primary somatosensory cortex. We identified the STT and its related thalamocortical fibers using DTT. These results would be helpful in the clinical field and also in research on somatosensory function in the human brain.

The spinothalamic system targets motor and sensory areas in the cerebral cortex of monkeys.

Classically, the spinothalamic (ST) system has been viewed as the major pathway for transmitting nociceptive and thermoceptive information to the cerebral cortex. There is a long-standing controversy about the cortical targets of this system. We used anterograde transneuronal transport of the H129 strain of herpes simplex virus type 1 in the Cebus monkey to label the cortical areas that receive ST input. We found that the ST system reaches multiple cortical areas located in the contralateral hemisphere. The major targets are granular insular cortex, secondary somatosensory cortex and several cortical areas in the cingulate sulcus. It is noteworthy that comparable cortical regions in humans consistently display activation when subjects are acutely exposed to painful stimuli. We next combined anterograde transneuronal transport of virus with injections of a conventional tracer into the ventral premotor area (PMv). We used the PMv injection to identify the cingulate motor areas on the medial wall of the hemisphere. This combined approach demonstrated that each of the cingulate motor areas receives ST input. Our meta-analysis of imaging studies indicates that the human equivalents of the three cingulate motor areas also correspond to sites of pain-related activation. The cingulate motor areas in the monkey project directly to the primary motor cortex and to the spinal cord. Thus, the substrate exists for the ST system to have an important influence on the cortical control of movement.

A quantitative study of spinothalamic neurons in laminae I, III, and IV in lumbar and cervical segments of the rat spinal cord.

The major ascending outputs from superficial spinal dorsal horn consist of projection neurons in lamina I, together with neurons in laminae III-IV that express the neurokinin 1 receptor (NK1r) and have dendrites that enter the superficial laminae. Some neurons in each of these populations belong to the spinothalamic tract, which conveys nociceptive information via the thalamus to cortical areas involved in pain. A projection from the cervical superficial dorsal horn to the posterior triangular nucleus (PoT) has recently been identified. PoT is at the caudal end of the thalamus and was not included in injection sites in many previous retrograde tracing studies. We have injected various tracers (cholera toxin B subunit, Fluoro-Gold, and fluorescent latex microspheres) into the thalamus to estimate the number of spinothalamic neurons in each of these two populations, and to investigate their projection targets. Most lamina I and lamina III/IV NK1r-immunoreactive spinothalamic neurons in cervical and lumbar segments could be labeled from injections centered on PoT. Our results suggest that there are 90 lamina I spinothalamic neurons per side in C7 and 15 in L4 and that some of those in C7 only project to PoT. We found that 85% of the lamina III/IV NK1r-immunoreactive neurons in C6 and 17% of those in L5 belong to the spinothalamic tract, and these apparently project exclusively to the caudal thalamus, including PoT. Because PoT projects to second somatosensory and insular cortices, our results suggest that these are major targets for information conveyed by both these populations of spinothalamic neurons.

The contribution of neuroimaging techniques to the understanding of supraspinal pain circuits: implications for orofacial pain.

The aim of this article was to give an overview of the current knowledge of supraspinal pain mechanisms derived from neuroimaging studies, and to present data related to chronic orofacial pain disorders. The available studies implied that the anterior cingulate cortex plays a role in the emotional-affective component of pain, as well as in pain-related attention and anxiety. The somatosensory cortices may be involved in encoding spatial, temporal, and intensity aspects of noxious input. The insula may mediate both affective and sensory-discriminative aspects of the pain experience. The thalamus appears to be a multifunctional relay system. The prefrontal cortex has been implied in the pain-related attention processing; it does not have intensity encoding properties. Chronic pain conditions were associated with increased activity in the somatosensory cortices, anterior cingulate cortex, and the prefrontal cortex, and with decreased activity in the thalamus. Few neuroimaging studies used experimental stimuli to the trigeminal system or included orofacial pain patients. However, the available studies appeared to be in agreement with those using stimuli to other body parts and those concerning other chronic pain conditions. Overall, the available data suggest that chronic (orofacial) pain states may be related to a dysfunctional brain network and may involve a compromised descending inhibitory control system. The somatosensory cortices, anterior cingulate cortex, thalamus, and prefrontal cortex may play a vital role in the pathophysiology of chronic pain and should be the main focus of future neuroimaging studies in chronic pain patients.

A comparative reappraisal of projections from the superficial laminae of the dorsal horn in the rat: the forebrain.

Projections to the forebrain from lamina I of spinal and trigeminal dorsal horn were labeled anterogradely with Phaseolus vulgaris-leucoagglutinin (PHA-L) and/or tetramethylrhodamine-dextran (RHO-D) injected microiontophoretically. Injections restricted to superficial laminae (I/II) of dorsal horn were used primarily. For comparison, injections were also made in deep cervical laminae. Spinal and trigeminal lamina I neurons project extensively to restricted portions of the ventral posterolateral and posteromedial (VPL/VPM), and the posterior group (Po) thalamic nuclei. Lamina I also projects to the triangular posterior (PoT) and the ventral posterior parvicellular (VPPC) thalamic nuclei but only very slightly to the extrathalamic forebrain. Furthermore, the lateral spinal (LS) nucleus, and to a lesser extent lamina I, project to the mediodorsal thalamic nucleus. In contrast to lamina I, deep spinal laminae project primarily to the central lateral thalamic nucleus (CL) and only weakly to the remaining thalamus, except for a medium projection to the PoT. Furthermore, the deep laminae project substantially to the globus pallidus and the substantia innominata and more weakly to the amygdala and the hypothalamus. Double-labeling experiments reveal that spinal and trigeminal lamina I project densely to distinct and restricted portions of VPL/VPM, Po, and VPPC thalamic nuclei, whereas projections to the PoT appeared to be convergent. In conclusion, these experiments indicate very different patterns of projection for lamina I versus deep laminae (III-X). Lamina I projects strongly onto relay thalamic nuclei and thus would have a primary role in sensory discriminative aspects of pain. The deep laminae project densely to the CL and more diffusely to other forebrain targets, suggesting roles in motor and alertness components of pain.

Position of spinothalamic tract axons in upper cervical spinal cord of monkeys.

Percutaneous upper cervical cordotomy continues to be performed on patients suffering from several types of severe chronic pain. It is believed that the operation is effective because it cuts the spinothalamic tract (STT), a primary pathway carrying nociceptive information from the spinal cord to the brain in humans. In recent years, there has been controversy regarding the location of STT axons within the spinal cord. The aim of this study was to determine the locations of STT axons within the spinal cord white matter of C2 segment in monkeys using methods of antidromic activation. Twenty lumbar STT cells were isolated. Eleven were classified as wide dynamic range neurons, six as high-threshold cells, and three as low-threshold cells. Eleven STT neurons were recorded in the deep dorsal horn and nine in superficial dorsal horn. The axons of the examined neurons were located at antidromic low-threshold points (<30 microA) within the contralateral lateral funiculus of C2. All low-threshold points were located ventral to the denticulate ligament, within the lateral half of the ventral lateral funiculus (VLF). None were found in the dorsal half of the lateral funiculus. The present findings support our previous suggestion that STT axons migrate ventrally as they ascend the length of the spinal cord. Also, the present findings indicate that surgical cordotomies that interrupt the VLF in C2 likely disrupt the entire lumbar STT.

Locations of spinothalamic tract axons in cervical and thoracic spinal cord white matter in monkeys.

The spinothalamic tract (STT) is the primary pathway carrying nociceptive information from the spinal cord to the brain in humans. The aim of this study was to understand better the organization of STT axons within the spinal cord white matter of monkeys. The location of STT axons was determined using method of antidromic activation. Twenty-six lumbar STT cells were isolated. Nineteen were classified as wide dynamic range neurons and seven as high-threshold cells. Fifteen STT neurons were recorded in the deep dorsal horn (DDH) and 11 in superficial dorsal horn (SDH). The axons of 26 STT neurons were located at 73 low-threshold points (<30 microA) within the lateral funiculus from T(9) to C(6). STT neurons in the SDH were activated from 33 low-threshold points, neurons in the DDH from 40 low-threshold points. In lower thoracic segments, SDH neurons were antidromically activated from low-threshold points at the dorsal-ventral level of the denticulate ligament. Neurons in the DDH were activated from points located slightly ventral, within the ventral lateral funiculus. At higher segmental levels, axons from SDH neurons continued in a position dorsal to those of neurons in the DDH. However, axons from neurons in both areas of the gray matter were activated from points located in more ventral positions within the lateral funiculus. Unlike the suggestions in several previous reports, the present findings indicate that STT axons originating in the lumbar cord shift into increasingly ventral positions as they ascend the length of the spinal cord.

Neuroanatomy of the pain system and of the pathways that modulate pain.

We review many of the recent findings concerning mechanisms and pathways for pain and its modulation, emphasizing sensitization and the modulation of nociceptors and of dorsal horn nociceptive neurons. We describe the organization of several ascending nociceptive pathways, including the spinothalamic, spinomesencephalic, spinoreticular, spinolimbic, spinocervical, and postsynaptic dorsal column pathways in some detail and discuss nociceptive processing in the thalamus and cerebral cortex. Structures involved in the descending analgesia systems, including the periaqueductal gray, locus ceruleus, and parabrachial area, nucleus raphe magnus, reticular formation, anterior pretectal nucleus, thalamus and cerebral cortex, and several components of the limbic system are described and the pathways and neurotransmitters utilized are mentioned. Finally, we speculate on possible fruitful lines of research that might lead to improvements in therapy for pain.

[Some useful basics of functional anatomy for a better understanding of the pain phenomenon]. / Quelques rappels d'anatomie fonctionnelle utiles à la compréhension du phénomène douloureux.

Cannot simply be considered as a nociception phenomenon: it is more complex than a simple transmission system that conveys this information to the cerebral cortex. It is mainly a psychological event. Numerous regulating and inhibiting effects on incoming pain signals exist, for the most part located in spinal and thalamic areas; only half of these are morphine-dependent. Knowledge of these allows a better approach to chronic pain, using not only medication but also other techniques such as physiotherapy and music therapy analgesia.

Primate spinothalamic pathways: III. Thalamic terminations of the dorsolateral and ventral spinothalamic pathways.

The termination sites of the dorsolateral (DSTT) and ventral (VSTT) spinothalamic pathways were determined by using anterograde transport of horseradish peroxidase from the lumbar spinal cord in primates. One animal had no spinal cord lesion, while of two other animals, one received a midthoracic dorsolateral funiculus lesion, and the other received a midthoracic ventral quadrant lesion contralateral to the injection. The thalamic label in the animal with no spinal cord lesion was much less than the label in the two animals with spinal lesions. Moreover, in the animals with spinal lesions, HRP-labeled cells were found within the thalamus. Therefore, the remaining six animals received ipsilateral hemisections and bilateral dorsal column lesions, irrespective of the contralateral lesions. The thalamic label in the animals without contralateral lesions were assumed to represent the total spinothalamic input to the diencephalon. In these animals, label was located mainly in suprageniculate and pulvinar oralis, caudal and oral divisions of ventral posterior lateral nucleus, the lateral half of ventral posterior inferior nucleus, and zona incerta, while in the medial thalamus label was primarily in two distinct bands in medial dorsal nucleus and in the posterior dorsal portion of central lateral nucleus. Scattered lighter labeling was found in other thalamic nuclei. The pattern of terminal labeling observed in the ventral posterior lateral region was arranged in patches, while elsewhere in the thalamus a more uniform labeling pattern was observed. The thalamic label in animals with contralateral ventral quadrant lesions represented the terminations of the DSTT, while the label in animals with contralateral dorsolateral funiculus lesions represented VSTT terminations. The labeling pattern was similar between these two groups. However, there were small differences between them. These results indicate that DSTT and VSTT terminations largely overlap and innervate the lateral and medial thalamamus.

Organization of the spinocervicothalamic pathway in the rat.

We used silver degeneration techniques to examine the termination of the spinocervical and cervicothalamic tracts in rats. Lesions of the dorsal portion of the lateral funiculus (DLF) of the spinal cord produced degeneration of a relatively small number of ascending fibers that were seen within the most lateral portion of the DLF rostral to the lesion. Within the lateral cervical nucleus, the degeneration was more extensive mediolaterally and of a finer caliber. Such labeling is attributable to the degeneration of fine fibers and terminals. Degenerating processes could be seen in apposition to neurons in the lateral cervical nucleus. At all levels of the cord, the lateral spinal nucleus was devoid of terminal labeling following lesions of the DLF. No terminal degeneration could be seen within the DLF at levels rostral to the lateral cervical nucleus. Lesions of the DLF at either midcervical or lower thoracic levels produced degeneration throughout the lateral cervical nucleus. This finding suggests that the lateral cervical nucleus of the rat is not somatotopically organized. Lesions of the lateral cervical nucleus produced degeneration of a small number of fibers within the contralateral midbrain and thalamus. Within the mesencephalon, degenerating fibers and terminals were seen primarily in the intercollicular region and the deep layers of the superior colliculus. Less degeneration was found in the lateral portion of the central gray. Within the diencephalon, a small area of termination was located in the ventromedial part of the rostral portion of the medial geniculate nucleus. A prominent termination was present in a restricted area within the caudal fourth of the ventrobasal complex.

Topographic organization of convergent projections to the thalamus from the inferior colliculus and spinal cord in the rat.

The purpose of this study was to identify thalamic areas receiving convergent sensory inputs from acoustic and spinal projection systems in the rat. The topographic distribution of afferents to the thalamus from the inferior colliculus and spinal cord was examined by using WGA-HRP as an anterograde axonal tracer. Following injections in the inferior colliculus, terminal labeling was present in ventral, medial, and dorsal divisions of the medial genicuate body (MGB) and in adjacent areas of the posterior thalamus, including the posterior limitans nucleus, the posterior intralaminar nucleus, the marginal zone, the peripeduncular region, the lateral or parvicellular part of the subparafascicular nucleus, and a region intercalated between the posterior limitans nucleus and the suprageniculate nucleus. In the caudal thalamus spinal projections remained in the reticular formation medial to the collicular terminal field. At intermediate levels of the MG, however, the spinal projection began to overlap the collicular field, terminating in the medial division of the MG and in the posterior intralaminar nucleus, the marginal zone, the lateral subparafascicular nucleus, and the area between the suprageniculate and posterior limitans nuclei. More rostrally, the convergent field expanded to include aspects of the dorsal MG division. The extent to which afferent projections to the thalamus from the inferior colliculus and spinal cord converge is thus graded in the caudorostral plane, with the greatest overlap occurring at the level of the rostral third of the MGB. These observations identify potential areas of acoustic and somesthetic integration and may account for observations of neuronal plasticity in the thalamus in response to the pairing of acoustic and somesthetic inputs.

A retrograde double label tracing technique using horseradish peroxidase and the fluorescent dye 4'-,6-diamidino-2-phenylindole 2HC1 (DAPI).

Retrograde transport of HRP and the fluorescent dye DAPI were used to double label spinothalamic tract cells with dual projections to thalamus and cerebellum. Cells containing both retrograde tracers were found in the intermediate gray zone and in the lateral spinal nucleus of the rat lumbosacral spinal cord. Double labeled cells were easily identified by the presence of granular HRP reaction, product and the blue fluorescence of DAPI. The use of HRP and DAPI provides an effective double labeling technique for the localization of neurons with nonoverlapping projections in the central and/or peripheral nervous system.