The role of the motor thalamus in deep brain stimulation for essential tremor.

The advent of next-generation technology has significantly advanced the implementation and delivery of Deep Brain Stimulation (DBS) for Essential Tremor (ET), yet controversies persist regarding optimal targets and networks responsible for tremor genesis and suppression. This review consolidates key insights from anatomy, neurology, electrophysiology, and radiology to summarize the current state-of-the-art in DBS for ET. We explore the role of the thalamus in motor function and describe how differences in parcellations and nomenclature have shaped our understanding of the neuroanatomical substrates associated with optimal outcomes. Subsequently, we discuss how seminal studies have propagated the ventral intermediate nucleus (Vim)-centric view of DBS effects and shaped the ongoing debate over thalamic DBS versus stimulation in the posterior subthalamic area (PSA) in ET. We then describe probabilistic- and network-mapping studies instrumental in identifying the local and network substrates subserving tremor control, which suggest that the PSA is the optimal DBS target for tremor suppression in ET. Taken together, DBS offers promising outcomes for ET, with the PSA emerging as a better target for suppression of tremor symptoms. While advanced imaging techniques have substantially improved the identification of anatomical targets within this region, uncertainties persist regarding the distinct anatomical substrates involved in optimal tremor control. Inconsistent subdivisions and nomenclature of motor areas and other subdivisions in the thalamus further obfuscate the interpretation of stimulation results. While loss of benefit and habituation to DBS remain challenging in some patients, refined DBS techniques and closed-loop paradigms may eventually overcome these limitations.

Human Motor Thalamus Reconstructed in 3D from Continuous Sagittal Sections with Identified Subcortical Afferent Territories.

Classification and delineation of the motor-related nuclei in the human thalamus have been the focus of numerous discussions for a long time. Difficulties in finding consensus have for the most part been caused by paucity of direct experimental data on connections of individual nuclear entities. Kultas-Ilinsky et al. (2011) showed that distribution of glutamic acid decarboxylase isoform 65 (GAD65), the enzyme that synthesizes inhibitory neurotransmitter γ-aminobutyric acid, is a reliable marker that allows to delineate connectionally distinct nuclei in the human motor thalamus, namely the territories innervated by nigral, pallidal, and cerebellar afferents. We compared those immunocytochemical staining patterns with underlying cytoarchitecture and used the latter to outline the three afferent territories in a continuous series of sagittal Nissl-stained sections of the human thalamus. The 3D volume reconstructed from the outlines was placed in the Talairach stereotactic coordinate system relative to the intercommissural line and sectioned in three stereotactic planes to produce color-coded nuclear maps. This 3D coordinate-based atlas was coregistered to the Montreal Neurological Institute (MNI-152) space. The current report proposes a simplified nomenclature of the motor-related thalamic nuclei, presents images of selected histological sections and stereotactic maps illustrating topographic relationships of these nuclei as well as their relationship with adjacent somatosensory afferent region. The data are useful in different applications such as functional MRI and diffusion tractography. The 3D dataset is publicly available under an open license and can also be applicable in clinical interventions in the thalamus.

Development of the human motor-related thalamic nuclei during the first half of gestation, with special emphasis on GABAergic circuits.

This study analyzed the expression of differentiation markers (Calbindin D28K: CaBP; parvalbumin: PARV; calretinin: CalR), gamma-aminobutyric acid (GABA) markers (GABA, glutamic acid decarboxylases: GAD65, GAD67; and GABA transporters: GAT1, GAT3), and other markers (neurotensin: NT, and neurofilament-specific protein: SMI32) in the human thalamus at 8-23 gestation weeks (g.w.), focusing on the motor-related nuclei. From 8-13 g.w. mainly CaBP was expressed in the cells while fiber bundles traversing the thalamus in addition to CaBP expressed all GABA markers except GAD67. CaBP and PARV expression patterns in different nuclei changed over the time course studied, whereas NT was expressed consistently along the anterior-lateral curvature of the thalamus. CalR and SMI were detectable at 23 g.w. in the ventral parts of the dorsal thalamus. Most remarkably, punctate GAD65 immunoreactivity in the neuropil was confined to the nigro- and pallidothalamic afferent receiving nuclei from 16 to about 21 g.w., overlapping with that of CaBP in some of these nuclei (subdivisions of the ventral anterior and mediodorsal nuclei) and with PARV in others (centromedian nucleus). During this period, GAD65 immunoreactivity can be considered a marker of the basal ganglia afferent receiving territory in the motor thalamus. GAD67-positive local circuit neurons were first detected at 12-13 g.w. in the thalamic nuclei outside the basal ganglia afferent receiving territory. In the ventral anterior and centromedian nuclei, GAD-containing local circuit neurons were not conspicuous even at 22-23 g.w. The cells of the reticular nucleus expressed GAD67 and PARV from 12 g.w. on starting in the lateral-posterior regions. By 23 g.w., both markers were expressed in about two-thirds of the nucleus except for its most medial-anterior part. The results imply spatially and temporally differential expression of GABA and differentiation markers in the developing human thalamus.

Reevaluation of the primary motor cortex connections with the thalamus in primates.

Six injections (approximately 1 mm in diameter) of biotinylated dextran amine (BDA) were placed in different locations of the primary motor cortex of the rhesus monkey. Anterograde and retrograde labeling patterns in the thalamus were charted and individual labeled axons traced in continuous serial sections. Both anterograde and retrograde labeling in the thalamus was extensive, spanning several millimeters mediolaterally and including ventral lateral, ventral anterior, centromedian, and centrolateral nuclei. Paracentral, mediodorsal, lateral posterior, and medial pulvinar nuclei were also labeled. Two basic types of corticothalamic axons were identified: small to medium-width, type 1 axons that formed large terminal fields with small boutons, and thick, type 2 axons that formed small terminal fields with large boutons. Within each group, subtypes were identified based on specific features of the axons and terminals: two subtypes of type 1 axons and four subtypes of type 2 axons. The results revealed multiple modes of corticothalamic connectivity: sparsely distributed type 1 axons, dense plexuses of type 1 axons, type 2 axon terminal fields either singly or in clusters, and mixed plexuses of type 1 and type 2 axons. Only some cells in the plexuses were retrogradely labeled; some plexuses did not contain any labeled neurons, and many retrogradely labeled neurons were in the regions devoid of anterograde labeling. These connectivity patterns differed between thalamic nuclei. The results revealed much more complex relationships between M1 and thalamus than were previously thought to exist. It is suggested that this connectivity is neither of exclusively a feedback nature nor perfectly reciprocal but is subserved by a multitude of channels, most likely originating from different populations of cortical neurons, and feeding into a variety of functionally different neuronal networks, with each processing specific information.

Posterior parietal cortex projections to the ventral lateral and some association thalamic nuclei in Macaca mulatta.

The study focused on projections from the posterior parietal cortex (PPC) to the ventral lateral thalamic nucleus (VL) and three thalamic association nuclei, mediodorsal (MD), lateral posterior (LP) and pulvinar. For light microscopic analysis small biotinylated dextran amine (BDA) or biocytin injections were placed in midrostral and dorsal portions of the inferior parietal lobule (IPL), respectively. The distribution of anterograde and retrograde labeling was charted, and representative axons and terminal fields were reconstructed in the sagittal plane to examine their features. Two types of fibers were identified--those of thin diameter forming diffuse terminal fields with small boutons, and thick fibers forming focal terminal fields with large boutons. Area PFG injection of BDA resulted in labeling of both types of fibers in LP, MD, and pulvinar, whereas only fibers of the first type were found in VL. Biocytin injection in area Opt resulted in preferential labeling of large fibers terminating in LP and pulvinar. Further electron microscopic analysis of labeled boutons in VL and LP, following a large wheat germ agglutinin conjugated horseradish peroxidase injection in the middle of IPL, confirmed the existence of small and large corticothalamic boutons and their different termination sites: the small boutons formed synapses on distal dendrites while the large boutons were found close to somata of thalamocortical projection neurons, on the dendrites of local circuit neurons and in complex synaptic arrangements, such as glomeruli. The results demonstrate that projections from small loci of the PPC to functionally and connectionally different thalamic nuclei differ anatomically, implying a different functional impact on these diverse targets.

Surgery of the motor thalamus: problems with the present nomenclatures.

The literature on thalamic surgery is difficult to read because different nomenclatures are in use. Neurosurgeons mostly use the stereotactic atlas of Schaltenbrand with Hassler's nomenclature of the thalamus. Neuroanatomists use different nomenclatures for the primate thalamus. The cytoarchitectonic definition of nuclei is difficult in the motor thalamus, and it would be best to define the nuclei based on their subcortical afferents. However, tracing studies are not available in humans. Thus, human thalamic nomenclature is based entirely on cytoarchitectonic subdivisions and transfer of knowledge by analogy from monkey to man. Problems arise when trying to transfer the detailed knowledge from monkey to the human brain. By doing so, different authors have come to different conclusions concerning the subcortical afferents of Hassler's motor nuclei, which inevitably leads to confusion when attempting neurophysiological interpretations of the surgical data. The present review draws attention to the discrepancies and open questions in the literature. There is a need to better define the limits of the sensory and cerebellar afferent receiving thalamic nuclei as well as those of the cerebellar and pallidal afferent receiving territories in humans.

Motor thalamic circuits in primates with emphasis on the area targeted in treatment of movement disorders.

The ventral region of the motor thalamus that receives cerebellar afferents has been and still is the target of stereotactic interventions for movement disorders. According to Hassler, this area includes ventro-oralis posterior (Vop) and ventral intermedius (Vim) nuclei, although some investigators believe that Vop is associated with the pallidothalamic pathway. We sought to correlate our experimental data on distribution of nigral, pallidal, and cerebellar afferents to the monkey thalamus with Hassler's motor thalamic parcelations. We concluded that Hassler's parcelations retained their value, although some adjustments were needed to relate them to the current neuroanatomic data; particularly, the cerebellothalamic zone that represents the monkey ventral lateral nucleus (VL) corresponds topographically to Hassler's Vop, Vim, and most of Voi. Electron microscopic tracing studies have shown very complex circuitry in this region of the monkey thalamus, as the cerebellar and cortical afferents innervating it are engaged in complex synapses with thalamocortical projection neurons, and this interaction is strongly modulated by local circuit neurons and the input from the reticular thalamic nucleus, which are both inhibitory and gamma-aminobutyric acid (GABA)ergic. Spinothalamic afferents also reach the VL, but this input is less studied in the monkey. The circuitry subserving the activity of thalamocortical projection neurons in the VL should be considered while interpreting the functional data obtained in stereotactic surgery.