Neuroanatomical considerations for optimizing thalamic deep brain stimulation in Tourette syndrome.

OBJECTIVE: Deep brain stimulation (DBS) of the centromedian thalamic nucleus has been reportedly used to treat severe Tourette syndrome, yielding promising outcomes. However, it remains unclear how DBS electrode position and stimulation parameters modulate the specific area and related networks. The authors aimed to evaluate the relationships between the anatomical location of stimulation fields and clinical responses, including therapeutic and side effects. METHODS: The authors collected data from 8 patients with Tourette syndrome who were treated with DBS. The authors selected the active contact following threshold tests of acute side effects and gradually increased the stimulation intensity within the therapeutic window such that acute and chronic side effects could be avoided at each programming session. The patients were carefully interviewed, and stimulation-induced side effects were recorded. Clinical outcomes were evaluated using the Yale Global Tic Severity Scale, the Yale-Brown Obsessive-Compulsive Scale, and the Hamilton Depression Rating Scale. The DBS lead location was evaluated in the normalized brain space by using a 3D atlas. The volume of tissue activated was determined, and the associated normative connective analyses were performed to link the stimulation field with the therapeutic and side effects. RESULTS: The mean follow-up period was 10.9 ± 3.9 months. All clinical scales showed significant improvement. Whereas the volume of tissue activated associated with therapeutic effects covers the centromedian and ventrolateral nuclei and showed an association with motor networks, those associated with paresthesia and dizziness were associated with stimulation of the ventralis caudalis and red nucleus, respectively. Depressed mood was associated with the spread of stimulation current to the mediodorsal nucleus and showed an association with limbic networks. CONCLUSIONS: This study addresses the importance of accurate implantation of DBS electrodes for obtaining standardized clinical outcomes and suggests that meticulous programming with careful monitoring of clinical symptoms may improve outcomes.

Delineation of the nucleus centre median by proton density weighted magnetic resonance imaging at 3 T.

OBJECTIVE: To demonstrate that proton density weighted magnetic resonance imaging (MRI) at 3 T accomplishes delineation of the centre median (CM) complex from surrounding thalamic tissue and may improve targeting accuracy in stereotactic neurosurgery. METHODS: Five healthy subjects (1 man, 4 women; age range 22-35 years) underwent high-resolution MRI at 3 T with different imaging parameters in order to optimize the direct visualization of the CM. RESULTS: In healthy subjects, the CM complex of the thalamus can be reliably contrasted on axially oriented slices by means of proton density weighted turbo-spin-echo MRI. An in-plane resolution of at least 0.6 x 0.6 mm2 is crucial at a slice thickness between 2 and 3 mm. Effective suppression of head motion is essential. CONCLUSION: MRI-based delineation of the CM could have therapeutic potential to facilitate target determination for neuromodulation in stereotactic neurosurgery.

Preliminary study in patients with obsessive-compulsive disorder treated with electrical stimulation in the inferior thalamic peduncle.

OBJECTIVE: Deep brain stimulation has been used in the treatment of refractory obsessive-compulsive disorder (OCD). Our principal objective was to determine the safety and effectiveness of deep brain stimulation of the inferior thalamic peduncle in the treatment of refractory OCD. METHODS: An open protocol was performed from March 2003 to April 2007 in 5 patients with OCD refractory to conventional treatments. Bilateral stereotactic implantation of tetrapolar electrodes was aimed at the inferior thalamic peduncle and corroborated by electrophysiological responses and magnetic resonance imaging. All patients were off stimulation for 1 month after implantation. In the on-stimulation period, parameters were set at 5 V, 450 microseconds, 130 Hz in bipolar and continuous mode. Clinical changes were evaluated every 3 months for 12 months by means of the Yale-Brown Obsessive Compulsive Scale and the Global Assessment of Functioning scale. Statistical significance was assessed by the Friedman and Wilcoxon tests. RESULTS: The mean Yale-Brown Obsessive Compulsive Scale score decreased from 35 to 17.8 (P < 0.001), and the mean Global Assessment of Functioning scale score improved from 20% to 70% (P < 0.0001). The neuropsychological battery did not show significant changes, and there were no side effects related to electrical stimulation in the chronic period. CONCLUSION: We conclude that inferior thalamic peduncle stimulation is a safe procedure and may be an effective alternative in the treatment of those OCD cases refractory to conventional treatments.

Roles of the thalamic CM-PF complex-Basal ganglia circuit in externally driven rebias of action.

The centromedian (CM)-parafascicular (PF) nuclear complex in the primate thalamus has reciprocal and specific connections with the basal ganglia. It has been argued that the thalamic CM-PF complex has a role in pain processing and attention. However, the functional relationship of this complex with the basal ganglia, which is considered to have a role in goal-directed movement, has not been well characterized. Here we present a hypothetical view that the thalamic CM-PF complex-basal ganglia circuit plays complementary roles in response bias. The basal ganglia are involved in creating 'reward-based pre-action bias', which facilitates the selection and execution of an action associated with a higher value. In contrast, when an action with a lower value is unexpectedly requested, the CM-PF induces an 'externally driven rebiasing' process in the striatum that aborts the pre-action bias and assists selecting and executing actions appropriate for unexpected situations. This model provides a framework for how the thalamic CM-PF complex and the basal ganglia function together in general for unexpected situations.

The primate centromedian-parafascicular complex: anatomical organization with a note on neuromodulation.

In addition to the cerebral cortex, the striatum receives excitatory input from the thalamus. The centromedian (centre median, CM) and parafascicular (Pf) nuclei are an important source of thalamostriatal projections. Anterograde tract-tracing indicates the CM-Pf complex provides dense afferents to the matrix compartment of the striatum. Whereas CM projects to the entire sensorimotor territory of the striatum, the Pf provides complementary input to the entire associative sector. The Pf also provides lighter input to the nucleus accumbens. Both CM and Pf provide light to moderately dense inputs to other components of the basal ganglia in a largely complementary manner, covering motor or associative-limbic territories of the subthalamic nucleus, globus pallidus and ventral midbrain. In turn, the CM and Pf receive mainly segregated input from parallel motor and associative-limbic circuits of the basal ganglia. The CM and Pf may therefore be considered important participants in parallel processing of motor and associative-limbic information in the basal ganglia. Connections of the CM and Pf with other thalamic nuclei suggest they also participate in integrative functions within the thalamus. In addition, inputs from the brainstem reticular core, reciprocal connections with the cerebral cortex and reticular thalamic nucleus suggest a role in state-dependant information processing. Consideration of the differential connections of the CM and Pf, and better understanding of their role in pathophysiology, may eventually lead to development of an important new target for relief of a variety of neurological and psychiatric disorders.

GABAergic and non-GABAergic thalamic, hypothalamic and basal forebrain projections to the ventral oral pontine reticular nucleus: their implication in REM sleep modulation.

The ventral part of the oral pontine reticular nucleus (vRPO) is a demonstrated site of brainstem REM-sleep generation and maintenance. The vRPO has reciprocal connections with structures that control other states of the sleep-wakefulness cycle, many situated in the basal forebrain and the diencephalon. Some of these connections utilize the inhibitory neurotransmitter GABA. The aim of the present work is to map the local origin of the basal forebrain and diencephalon projections to the vRPO whether GABAergic or non-GABAergic. A double-labelling technique combining vRPO injections of the neuronal tracer, cholera-toxin (CTB), with GAD-immunohistochemistry, was used for this purpose in adult cats. All of the numerous CTB-positive neurons in the reticular thalamic and dorsocaudal hypothalamic nuclei were double-labelled (CTB/GAD-positive) neurons. Approximately 15%, 14% and 16% of the CTB-positive neurons in the zona incerta and the dorsal and lateral hypothalamic areas are, respectively, CTB/GAD-positive neurons. However, only some double-labelled neurons were found in other hypothalamic nuclei with abundant CTB-positive neurons, such as the paraventricular nucleus, perifornical area and H1 Forel field. In addition, CTB-positive neurons were abundant in the central amygdaline nucleus, terminal stria bed nuclei, median preoptic nucleus, medial and lateral preoptic areas, dorsomedial and ventromedial hypothalamic nuclei, posterior hypothalamic area and periventricular thalamic nucleus. The GABAergic and non-GABAergic connections described here may be the morphological pillar through which these prosencephalic structures modulate, either by inhibiting or by exciting, the vRPO REM-sleep inducing neurons during the different sleep-wakefulness cycle states.

Expression of the mRNAs encoding for the vesicular glutamate transporters 1 and 2 in the rat thalamus.

Vesicular glutamate transporters (VGLUTs) are responsible for glutamate trafficking and for the subsequent regulated release of this excitatory neurotransmitter at the synapse. Three isoforms of the VGLUT have been identified, now known as VGLUT1, VGLUT2, and VGLUT3. Both VGLUT1 and VGLUT2 have been considered definitive markers of glutamatergic neurons, whereas VGLUT3 is expressed in nonglutamatergic neurons such as cholinergic striatal interneurons. It is widely believed that VGLUT1 and VGLUT2 are expressed in a complementary manner at the cortical and thalamic levels, suggesting that these glutamatergic neurons fulfill different physiological functions. In the present work, we analyzed the pattern of VGLUT1 and VGLUT2 mRNA expression at the thalamic level by using single and dual in situ hybridization. In accordance with current beliefs, we found significant expression of VGLUT2 mRNA in all the thalamic nuclei, while moderate expression of VGLUT1 mRNA was consistently found in both the principal relay and the association thalamic nuclei. Interestingly, individual neurons within these nuclei coexpressed both VGLUT1 and VGLUT2 mRNAs, suggesting that these individual thalamic neurons may have different ways of trafficking glutamate. These results call for a reappraisal of the previously held concept regarding the mutually exclusive distribution of VGLUT transporters in the central nervous system.

Connections of the zona incerta to the reticular nucleus of the thalamus in the rat.

This study demonstrated that there is a pathway from the zona incerta to the thalamic reticular nucleus. Injections of horseradish peroxidase or Fluorogold were made, using stereotaxic coordinates, into the rostral, intermediate or caudal regions of the thalamic reticular nucleus of adult Sprague-Dawley rats. The results show that the different regions of the thalamic reticular nucleus have distinct patterns of connections with the sectors of the zona incerta. In terms of the relative strength of the connections, injections made into the rostral regions of the thalamic reticular nucleus showed the highest number of labelled cells within the rostral and ventral sectors of the zona incerta; injections made into the intermediate regions of the thalamic reticular nucleus showed labelled cells in the dorsal and ventral sectors; while injections to the caudal regions of the thalamic reticular nucleus showed only a few labelled cells in the caudal sector of the zona incerta. Previous studies have shown that the zona incerta projects to the higher order thalamic nuclei but not first order thalamic nuclei. The labelling observed in the present study may represent collaterals of zona incerta to higher order thalamic nuclei projections.

Magnetic resonance imaging of mediodorsal, pulvinar, and centromedian nuclei of the thalamus in patients with schizophrenia.

BACKGROUND: Postmortem and magnetic resonance imaging (MRI) data have suggested volume reductions in the mediodorsal (MDN) and pulvinar nuclei (PUL) of the thalamus. The centromedian nucleus (CMN), important in attention and arousal, has not been previously studied with MRI. METHODS: A sample of 41 patients with schizophrenia (32 men and 9 women) and 60 healthy volunteers (45 men and 15 women) underwent assessment with high-resolution 1.2-mm thick anatomical MRI. Images were differentiated to enhance the edges and outline of the whole thalamus, and the MDN, PUL, and CMN were outlined on all slices by a tracer masked to diagnostic status. RESULTS: Significantly smaller volumes of the MDN and PUL were found in patients with schizophrenia compared with controls. Volume relative to brain size was reduced in all 3 nuclei; differences in relative reduction did not differ among the nuclei. The remainder of the thalamic volume (whole thalamus minus the volume of the 3 delineated nuclei) was not different between schizophrenic patients and controls, indicating that the volume reduction was specific to these nuclei. Volume relative to brain size was reduced in all 3 nuclei and remained significant when only patients who had never been exposed to neuroleptic medication (n = 15) were considered. For the MDN, women had larger relative volumes than men among controls, but men had larger volumes than women among schizophrenic patients. CONCLUSIONS: Three association regions of the thalamus that have reciprocal connectivity to schizophrenia-associated regions of the cortex have significantly smaller volumes on MRI in patients with schizophrenia.

Corticothalamic and thalamocortical pathfinding in the mouse: dependence on intermediate targets and guidance axis.

Recently, increasing attention has been paid to the study of intermediate targets and their relay guidance role in long-range pathfinding. In the present study, mechanisms of corticothalamic and thalamocortical pathfinding were investigated in C57BL/6 mice using in vitro DiI labeling and in vivo cholera toxin labeling. Specifically, three important intermediate targets, the subplate, ganglionic eminence, and reticular thalamic nucleus, were studied for their role in corticothalamic and thalamocortical pathfinding. The results show that the neuroepithelium of the ganglionic eminence is a source of pioneer neurons and pioneer fibers. Through radial and tangential migration, these pioneer neurons and fibers can approach the differentiating field of the ganglionic eminence, the subplate and thalamic reticular nucleus to participate in the formation of these three intermediate targets. Furthermore, the subplate, ganglionic eminence and thalamic reticular nucleus are linked by pioneer neurons and fibers to form a guidance axis. The guidance axis and the three important intermediate targets provide an ideal environment of contact guidance and chemical guidance for the corticothalamic and thalamocortical pathfinding. The concept of a "waiting time" in the subplate and the thalamic reticular nucleus is likely due to the expression of a guidance effect, so that the thalamocortical and corticothalamic projections can be deployed spatially and temporally to the subplate and thalamic reticular nucleus before these projections enter their final destinations, the neocortex and thalamus.

Morphological evidence for a vestibulo-thalamo-striatal pathway via the parafascicular nucleus in the rat.

We observed by anterograde and retrograde tracing techniques that projection fibers originating from the medial vestibular nucleus (MVe) of the rat terminated in the dorsal two-thirds of the lateral part of the parafascicular thalamic nucleus (PF), where neurons sending their axons to the dorsolateral part of the striatum existed. It was further revealed that the vestibular fibers made asymmetrical synaptic contacts mainly with dendrites and additionally with soma of the striatum-projecting PF neurons. These data suggest that output signals from the MVe may be transmitted disynaptically to the striatal neurons via the PF neurons.