Ventral intermediate nucleus of the thalamus, dentatorubrothalamic tract, and caudal zona incerta: stimulation of which structure provides ongoing tremor control in patients with essential tremor?

OBJECTIVE: Essential tremor (ET) is the most common movement disorder. Deep brain stimulation (DBS) targeting the ventral intermediate nucleus (VIM) is known to improve symptoms in patients with medication-resistant ET. However, the clinical effectiveness of VIM-DBS may vary, and other targets have been proposed. The authors aimed to investigate whether the same anatomical structure is responsible for tremor control both immediately after VIM-DBS and at later follow-up evaluations. METHODS: Of 68 electrodes from 41 patients with ET, the authors mapped the distances of the active contact from the VIM, the dentatorubrothalamic tract (DRTT), and the caudal zona incerta (cZI) and compared them using Friedman's ANOVA and the Wilcoxon signed-rank follow-up test. The same distances were also compared between the initially planned target and the final implantation site after intraoperative macrostimulation. Finally, the comparison among the three structures was repeated for 16 electrodes whose active contact was changed after a mean 37.5 months follow-up to improve tremor control. RESULTS: After lead implantation, the VIM was statistically significantly closer to the active contact than both the DRTT (p = 0.008) and cZI (p < 0.001). This result did not change if the target was moved based on intraoperative macrostimulation. At the last follow-up, the active contact distance from the VIM was always significantly less than that of the cZI (p < 0.001), but the distance from the DRTT was reduced and even less than the distance from the VIM. CONCLUSIONS: In patients receiving VIM-DBS, the VIM itself is the structure driving the anti-tremor effect and remains more effective than the cZI, even years after implantation. Nevertheless, the role of the DRTT may become more important over time and may help sustain the clinical efficacy when the habituation from the VIM stimulation ensues.

Quantitative susceptibility mapping and a nonlinearly transformed atlas for targeting the ventral intermediate nucleus of the thalamus in a patient with tremor and thalamic hypertrophy: illustrative case.

BACKGROUND: The ventral intermediate nucleus (Vim) of the thalamus is a surgical target for treating various types of tremor. Because it is difficult to visualize the Vim using standard magnetic resonance imaging, the structure is usually targeted based on the anterior and posterior commissures. This standard targeting method is practical in most patients but not in those with thalamic asymmetry. The authors examined the usefulness of quantitative susceptibility mapping (QSM) and transformed Vim atlas images to estimate the Vim localization in a patient with tremor and significant thalamic hypertrophy. OBSERVATIONS: A 51-year-old right-handed female had experienced a predominant left-hand action tremor for 6 years. Magnetic resonance imaging showed significant hypertrophy of the right thalamus and caudal shift of the thalamic ventral border. The authors referred to the QSM images to localize the decreased susceptibility area within the lateral ventral thalamic nuclei to target the Vim. In addition, the nonlinearly transformed Vim atlas images complemented the imaging-based targeting. The radiofrequency thalamotomy at the modified Vim target relieved the tremor completely. LESSONS: A combination of QSM and nonlinear transformation of the thalamic atlas can be helpful in the targeting method of the Vim for tremor patients with thalamic asymmetry.

Deep brain stimulation does not modulate resting-state functional connectivity in essential tremor.

While the effectiveness of deep brain stimulation in alleviating essential tremor is well-established, the underlying mechanisms of the treatment are unclear. Essential tremor, as characterized by tremor during action, is proposed to be driven by a dysfunction in the cerebello-thalamo-cerebral circuit that is evident not only during motor actions but also during rest. Stimulation effects on resting-state functional connectivity were investigated by functional MRI in 16 essential tremor patients with fully implanted deep brain stimulation in the caudal zona incerta during On-and-Off therapeutic stimulation, in a counterbalanced design. Functional connectivity was calculated between different constellations of sensorimotor as well as non-sensorimotor regions (as derived from seed-based and data-driven approaches), and compared between On and Off stimulation. We found that deep brain stimulation did not modulate resting-state functional connectivity. The lack of modulation by deep brain stimulation during resting-state, in combination with previously demonstrated effects on the cerebello-thalamo-cerebral circuit during motor tasks, suggests an action-dependent modulation of the stimulation in essential tremor.

Ventral Intermediate Nucleus of the Thalamus versus Posterior Subthalamic Area: Network Meta-Analysis of DBS Target Site Efficacy for Essential Tremor.

BACKGROUND: Deep brain stimulation (DBS) targeting the ventral intermediate nucleus (Vim) of the thalamus or the posterior subthalamic area (PSA) are effective treatments for essential tremor (ET). However, their relative efficacy is unknown. OBJECTIVE: Here, we present the first systematic review and network meta-analysis, examining the efficacy of Vim versus PSA DBS for treating medically refractory ET. METHODS: We included all primary studies that reported validated Fahn-Tolosa-Marin Tremor Rating Scale (FTM-TRS) scores pre-/postimplantation or on-/off-stimulation postimplantation, for patients receiving either Vim or PSA DBS. The primary outcome was FTM-TRS score reduction; the secondary outcome was percent reduction in score. We categorized all outcomes as short-term (≤12 months) or long-term (>12 months). RESULTS: For pre-/postimplantation comparisons, 19 and 11 studies met inclusion criteria for short- and long-term follow-ups, respectively. For on-/off-stimulation tremor score comparisons, 8 studies met inclusion criteria for short-term follow-up. Network meta-analysis of pre-/postimplantation tremor scores showed greater tremor reduction with PSA implantation short-term (absolute tremor reduction: PSA: -30.94 [95% confidence interval (CI): -34.93, -26.95]; Vim: -26.26 [95% CI: -33.39, -19.12]; relative tremor reduction: PSA: 63.3% [95% CI: 61.8%-64.8%]; Vim: 57.8% [95% CI: 56.5%-59.0%]). However, there was no difference in efficacy between PSA and Vim DBS when comparing tremor on-versus off-stimulation at short-term follow-up or pre- versus postimplantation tremor reduction long-term. CONCLUSION: Our systematic review highlighted both heterogeneity in scoring systems used and lack of transparency in reporting total scores, limiting direct comparison across studies. We found a modestly superior efficacy with PSA stimulation in the short term, but no difference in tremor reduction long-term.

Glutamatergic Neurons in the Caudal Zona Incerta Regulate Parkinsonian Motor Symptoms in Mice.

Parkinson's disease (PD) is the second most common and fastest-growing neurodegenerative disorder. In recent years, it has been recognized that neurotransmitters other than dopamine and neuronal systems outside the basal ganglia are also related to PD pathogenesis. However, little is known about whether and how the caudal zona incerta (ZIc) regulates parkinsonian motor symptoms. Here, we showed that specific glutamatergic but not GABAergic ZIcVgluT2 neurons regulated these symptoms. ZIcVgluT2 neuronal activation induced time-locked parkinsonian motor symptoms. In mouse models of PD, the ZIcVgluT2 neurons were hyperactive and inhibition of their activity ameliorated the motor deficits. ZIcVgluT2 neurons monosynaptically projected to the substantia nigra pars reticulata. Incerta-nigral circuit activation induced parkinsonian motor symptoms. Together, our findings provide a direct link between the ZIc, its glutamatergic neurons, and parkinsonian motor symptoms for the first time, help to better understand the mechanisms of PD, and supply a new important potential therapeutic target for PD.

Glutamatergic Neurons in the Caudal Zona Incerta Regulate Parkinsonian Motor Symptoms in Mice / 神经科学通报·英文版

Parkinson's disease (PD) is the second most common and fastest-growing neurodegenerative disorder. In recent years, it has been recognized that neurotransmitters other than dopamine and neuronal systems outside the basal ganglia are also related to PD pathogenesis. However, little is known about whether and how the caudal zona incerta (ZIc) regulates parkinsonian motor symptoms. Here, we showed that specific glutamatergic but not GABAergic ZIc

Deep brain stimulation in the caudal zona incerta modulates the sensorimotor cerebello-cerebral circuit in essential tremor.

Essential tremor is effectively treated with deep brain stimulation (DBS), but the neural mechanisms underlying the treatment effect are poorly understood. Essential tremor is driven by a dysfunctional cerebello-thalamo-cerebral circuit resulting in pathological tremor oscillations. DBS is hypothesised to interfere with these oscillations at the stimulated target level, but it is unknown whether the stimulation modulates the activity of the cerebello-thalamo-cerebral circuit during different task states (with and without tremor) in awake essential tremor patients. To address this issue, we used functional MRI in 16 essential tremor patients chronically implanted with DBS in the caudal zona incerta. During scanning, the patients performed unilateral tremor-inducing postural holding and pointing tasks as well as rest, with contralateral stimulation turned On and Off. We show that DBS exerts both task-dependent as well as task-independent modulation of the sensorimotor cerebello-cerebral regions (p â€‹≤ â€‹0.05, FWE cluster-corrected for multiple comparisons). Task-dependent modulation (DBS â€‹× â€‹task interaction) resulted in two patterns of stimulation effects. Firstly, activity decreases (blood oxygen level-dependent signal) during tremor-inducing postural holding in the primary sensorimotor cortex and cerebellar lobule VIII, and activity increases in the supplementary motor area and cerebellar lobule V during rest (p â€‹≤ â€‹0.05, post hoc two-tailed t-test). These effects represent differences at the effector level and may reflect DBS-induced tremor reduction since the primary sensorimotor cortex, cerebellum and supplementary motor area exhibit less motor task-activity as compared to the resting condition during On stimulation. Secondly, task-independent modulation (main effect of DBS) was observed as activity increase in the lateral premotor cortex during all motor tasks, and also during rest (p â€‹≤ â€‹0.05, post hoc two-tailed t-test). This task-independent effect may mediate the therapeutic effects of DBS through the facilitation of the premotor control over the sensorimotor circuit, making it less susceptible to tremor entrainment. Our findings support the notion that DBS in essential tremor is modulating the sensorimotor cerebello-cerebral circuit, distant to the stimulated target, and illustrate the complexity of stimulation mechanisms by demonstrating task-dependent as well as task-independent actions in cerebello-cerebral regions.

A Case Report of Multitrack Recording of Posterior Subthalamic Nucleus, Caudal Zona Incerta, and Prelemniscal Radiation: Which Is Most Effective for Bradykinesia?

Deep brain stimulation (DBS) of the posterior subthalamic nucleus (pSTN), caudal zona incerta (cZI), and prelemniscal radiation (Raprl) has been shown to improve Parkinsonian motor symptoms. We herein report neurophysiological and functional differences among the cZI, Raprl, and pSTN in a 68-year-old male patient with Parkinson's disease (PD). The stereotactic implantation of DBS electrodes in the right STN was performed. Thereafter, a transfrontal trajectory for the left cZI was planned for left side implantation, with the expectation that the electrode entered the pSTN in the case of a posterior brain shift. In the implantation of the DBS lead in the cZI, three microelectrodes were simultaneously placed in an array with the central, medial, and anterior positions placed 2 mm apart to delineate the cZI, Raprl, and pSTN, respectively. A maximal reduction in bradykinesia was obtained from the stimulation of the pSTN at the lowest voltage thresholds, and the voltage threshold for abolishing tremors was lower in the Raprl and cZI than in the pSTN. The left DBS lead was implanted in the pSTN because right-sided bradykinesia was more severe than tremor. The multitrack recording of cZI, Raprl, and pSTN might broaden target selection depending on patients' symptoms.

Voice Tremor Response to Deep Brain Stimulation in Relation to Electrode Location in the Posterior Subthalamic Area.

BACKGROUND: Deep brain stimulation of the motor thalamus or the posterior subthalamic area (PSA) shows promising results for patients with voice tremor, although only for about 50% of patients. There are indications that voice tremor requires more focused stimulation within the target area compared with hand tremor. The objective of the present study was to determine the most efficient location for reducing voice tremor within the PSA. METHODS: Thirty-seven patients with essential tremor were evaluated off stimulation and in a set of experimental conditions with unilateral stimulation at increasing amplitude levels. Two listeners performed blinded assessments of voice tremor from recordings of sustained vowel productions. RESULTS: Twenty-five patients (68%) had voice tremor. Unilateral stimulation reduced voice tremor for the majority of patients, and only 6 patients had poor outcomes. Contacts yielding efficient voice tremor reduction were deeper relative to the midcommissural point (MCP) and more posterior relative to the posterior tip of the subthalamic nucleus (pSTN) (zMCP = -3.1, ypSTN = -0.2) compared with poor contacts (zMCP = -0.7, ypSTN = 1.0). High-amplitude stimulation worsened voice tremor for 7 patients and induced voice tremor in 2 patients. Hand tremor improved to a greater extent than voice tremor, and improvements could be seen throughout the target area. CONCLUSIONS: Our results indicate that efficient voice tremor reduction can be achieved by stimulating contacts located in the inferior part of the PSA, close or slightly posterior to the pSTN. We observed cases in which voice tremor was induced by high-amplitude stimulation.

Unilateral Left Deep Brain Stimulation of the Caudal Zona Incerta Is Equally Effective on Voice Tremor as Bilateral Stimulation: Evidence from 7 Patients with Essential Tremor.

BACKGROUND/AIMS: Deep brain stimulation (DBS) is less effective on voice tremor than arm tremor, and it is generally assumed that successful voice tremor treatment requires bilateral DBS and possibly more precise thalamic stimulation. However, recent findings suggest that these assumptions should be reconsidered. OBJECTIVES: To evaluate whether unilateral DBS targeting the caudal zona incerta (cZi) may be sufficient to alleviate voice tremor in patients with essential tremor, or whether bilateral stimulation is needed. METHODS: Seven patients with voice tremor off stimulation were evaluated during bilateral stimulation using their clinical settings, and during unilateral left stimulation in iterations with increasing stimulation amplitude. Two expert listeners assessed voice tremor severity in all samples in a blinded procedure. RESULTS: Six patients had comparable or better effects with unilateral left stimulation compared to bilateral stimulation. For the seventh patient, unilateral DBS at a slightly higher amplitude achieved similar results as bilateral DBS. Overall, high-amplitude stimulation did not appear to be beneficial on voice tremor. CONCLUSIONS: Unilateral left and bilateral cZi-DBS had comparable effects on voice tremor in the investigated group of 7 patients. This finding suggests that the assumption that bilateral DBS is required to treat voice tremor may need to be reconsidered.

Connectivity derived thalamic segmentation in deep brain stimulation for tremor.

The ventral intermediate nucleus (VIM) of the thalamus is an established surgical target for stereotactic ablation and deep brain stimulation (DBS) in the treatment of tremor in Parkinson's disease (PD) and essential tremor (ET). It is centrally placed on a cerebello-thalamo-cortical network connecting the primary motor cortex, to the dentate nucleus of the contralateral cerebellum through the dentato-rubro-thalamic tract (DRT). The VIM is not readily visible on conventional MR imaging, so identifying the surgical target traditionally involved indirect targeting that relies on atlas-defined coordinates. Unfortunately, this approach does not fully account for individual variability and requires surgery to be performed with the patient awake to allow for intraoperative targeting confirmation. The aim of this study is to identify the VIM and the DRT using probabilistic tractography in patients that will undergo thalamic DBS for tremor. Four male patients with tremor dominant PD and five patients (three female) with ET underwent high angular resolution diffusion imaging (HARDI) (128 diffusion directions, 1.5 mm isotropic voxels and b value = 1500) preoperatively. Patients received VIM-DBS using an MR image guided and MR image verified approach with indirect targeting. Postoperatively, using parallel Graphical Processing Unit (GPU) processing, thalamic areas with the highest diffusion connectivity to the primary motor area (M1), supplementary motor area (SMA), primary sensory area (S1) and contralateral dentate nucleus were identified. Additionally, volume of tissue activation (VTA) corresponding to active DBS contacts were modelled. Response to treatment was defined as 40% reduction in the total Fahn-Tolosa-Martin Tremor Rating Score (FTMTRS) with DBS-ON, one year from surgery. Three out of nine patients had a suboptimal, long-term response to treatment. The segmented thalamic areas corresponded well to anatomically known counterparts in the ventrolateral (VL) and ventroposterior (VP) thalamus. The dentate-thalamic area, lay within the M1-thalamic area in a ventral and lateral location. Streamlines corresponding to the DRT connected M1 to the contralateral dentate nucleus via the dentate-thalamic area, clearly crossing the midline in the mesencephalon. Good response was seen when the active contact VTA was in the thalamic area with highest connectivity to the contralateral dentate nucleus. Non-responders had active contact VTAs outside the dentate-thalamic area. We conclude that probabilistic tractography techniques can be used to segment the VL and VP thalamus based on cortical and cerebellar connectivity. The thalamic area, best representing the VIM, is connected to the contralateral dentate cerebellar nucleus. Connectivity based segmentation of the VIM can be achieved in individual patients in a clinically feasible timescale, using HARDI and high performance computing with parallel GPU processing. This same technique can map out the DRT tract with clear mesencephalic crossing.

Swallowing safety in Parkinson's disease after zona incerta deep brain stimulation.

OBJECTIVES: The objective of this study was to examine swallowing function in patients with Parkinson's disease before and after caudal zona incerta deep brain (cZI DBS) surgery. The aims were to examine the effect of cZI DBS on swallowing safety regarding liquid and solid food, as well as to identify the effect of cZI DBS on body mass index (BMI) and specific items from part II of the Unified Parkinson's Disease Rating Scale (UPDRS). MATERIALS AND METHODS: The median age of the 14 patients was 57 years (range 46-71), with a median disease duration of 6 years (range 2-13). The present sample is an extension of a previous report, into which six additional patients have been added. Fiber endoscopic examinations of swallowing function, measures of BMI, and evaluation of UPDRS part II items were made before and 12 months after surgery, with and without activated DBS. RESULTS: There were no significant changes due to cZI DBS regarding penetration/aspiration, pharyngeal residue or premature spillage (p > .05). Median BMI increased by +1.1 kg/m2 12 months after surgery (p = .01, r = .50). All reported specific symptoms from the UPDRS part II were slight or mild. A significant improvement regarding handling of utensils was seen 12 months postoperatively (p = .03, r = -.42). CONCLUSIONS: Caudal zona incerta DBS was found not to have a negative impact on swallowing safety. A significant increase in postoperative weight was observed, and speech seemed to be slightly negatively affected, whereas handling of utensils was improved with cZI DBS.

Dystonic tics induced by deep brain stimulation of the posterior subthalamic area for essential tremor.

OBJECTIVE The posterior subthalamic area (PSA) is a promising target of deep brain stimulation (DBS) for medication-refractory essential tremor (ET). This case series describes a novel adverse effect manifesting as dystonic tics in patients with ET undergoing DBS of the PSA. METHODS Six patients with ET received electrode implants for DBS of the dorsal and caudal zona incerta subregions of the PSA. RESULTS Five of the 6 patients developed dystonic tics soon after clinical programming. These tics were of varying severity and required reduction of the electrical stimulation amplitude. This reduction resolved tic occurrence without significantly affecting ET control. Dystonic tics were not observed in 39 additional patients who underwent DBS of the same brain regions for controlling non-ET movement disorders. CONCLUSIONS The pathophysiology of tic disorders is poorly understood and may involve the basal ganglia and related cortico-striato-thalamo-cortical circuits. This series is the first report of DBS-induced tics after stimulation of any brain target. Although the PSA has not previously been implicated in tic pathophysiology, it may be a candidate region for future studies.

Swallowing Quality of Life After Zona Incerta Deep Brain Stimulation.

OBJECTIVES: The management of Parkinson's disease (PD) has been improved, but management of signs like swallowing problems is still challenging. Deep brain stimulation (DBS) alleviates the cardinal motor symptoms and improves quality of life, but its effect on swallowing is not fully explored. The purpose of this study was to examine self-reported swallowing-specific quality of life before and after caudal zona incerta DBS (cZI DBS) in comparison with a control group. METHODS: Nine PD patients (2 women and 7 men) completed the self-report Swallowing Quality of Life questionnaire (SWAL-QOL) before and 12 months after cZI DBS surgery. The postoperative data were compared to 9 controls. Median ages were 53 years (range, 40-70 years) for patients and 54 years (range, 42-72 years) for controls. RESULTS: No significant differences were found between the pre- or postoperative scores. The SWAL-QOL total scores did not differ significantly between PD patients and controls. The PD patients reported significantly lower scores in the burden subscale and the symptom scale. CONCLUSIONS: Patients with PD selected for cZI DBS showed good self-reported swallowing-specific quality of life, in many aspects equal to controls. The cZI DBS did not negatively affect swallowing-specific quality of life in this study.

Case Study of Image-Guided Deep Brain Stimulation: Magnetic Resonance Imaging-Based White Matter Tractography Shows Differences in Responders and Nonresponders.

BACKGROUND: The caudal zona incerta (cZI) is an increasingly popular deep brain stimulation (DBS) target for the treatment of tremor-predominant disease. The dentatorubrothalamic tract (DRTT) is a white matter fiber bundle that traverses the cZI and can be identified using diffusion-weighted magnetic resonance imaging fiber tractography to ascertain its precise course. In this report, we compare 2 patient cases of cZI DBS, a responder and a nonresponder. CASE DESCRIPTION: Patient 1 (responder) is a 65-year-old man with medically refractory Parkinson disease who underwent bilateral DBS lead placement in the cZI. Postoperatively he demonstrated >90% reduction in baseline tremor and was not limited by stimulation side effects. Postoperative imaging showed correct lead placement in the cZI. Tractography revealed a DRTT within the field of stimulation, bilaterally. Patient 2 (nonresponder) is a 61-year-old man with medically refractory Parkinson disease who also underwent bilateral DBS lead placement in the cZI. He initially demonstrated >90% reduction in baseline tremor but developed disabling dystonia of his left leg and significant slurring of his speech in the months after surgery. Postoperative imaging showed bilateral lead placement in the cZI. Right-sided electrode revision was recommended and resulted in relief of tremor and reduced dystonic side effects. Tractography analysis of the original leads revealed a DRTT with an atypical anterior trajectory and a location outside the field of stimulation. Tractography analysis of the revised lead showed a DRTT within the field of stimulation. CONCLUSIONS: Preoperative diffusion-weighted magnetic resonance imaging fiber tractography imaging of the DRTT has the potential to improve and individualize DBS planning.

Drowning hazard with deep brain stimulation: case report.

The caudal zona incerta target within the posterior subthalamic area is an investigational site for deep brain stimulation (DBS) in Parkinson disease (PD) and tremor. The authors report on a patient with tremor-predominant PD who, despite excellent tremor control and an otherwise normal neurological examination, exhibited profound difficulty swimming during stimulation. Over the last 20 years, anecdotal reports have been received of 3 other patients with PD who underwent thalamic or pallidal lesioning or DBS surgery performed at the authors' center and subsequently drowned. It may be that DBS puts patients at risk for drowning by specifically impairing their ability to swim. Until this finding can be further examined in larger cohorts, patients should be warned to swim under close supervision soon after DBS surgery.

Word-level intelligibility after caudal zona incerta stimulation for Parkinson's disease.

OBJECTIVES: To investigate the effect of caudal zona incerta-deep brain stimulation (cZi-DBS) on word-level speech intelligibility in patients with Parkinson's disease, under both an optimal listening condition and a simulated more naturalistic listening condition. MATERIALS AND METHODS: Spoken single words were extracted from read samples collected from 10 bilaterally implanted patients with PD pre- and post-cZi-DBS. Intelligibility was assessed through a transcription task performed by 32 naive listeners under two listening conditions: (i) with low-amplitude conversational speech added as background and (ii) with no added background noise. The listeners' responses were scored in terms of agreement with the intended words. RESULTS: Post-operatively, the total intelligibility score was significantly lower when cZi stimulation was switched on compared with off, for both listening conditions (with and without added background noise). Intelligibility was also significantly lower on stimulation compared with preoperative recordings, but only when assessed in the listening condition without background noise. The listening condition with added background noise resulted in significantly lower intelligibility scores compared with the no added noise condition for all stimulation conditions. CONCLUSIONS: The results of this study indicate that cZi-DBS in patients with PD can be detrimental to word-level speech intelligibility.

The anatomy of the caudal zona incerta in rodents and primates.

The caudal zona incerta is the target of a recent modification of established procedures for deep brain stimulation (DBS) for Parkinson's disease and tremor. The caudal zona incerta contains a number of neuronal populations that are distinct in terms of their cytoarchitecture, connections, and pattern of immunomarkers and is located at a position where a number of major tracts converge before turning toward their final destination in the forebrain. However, it is not clear which of the anatomical features of the region are related to its value as a target for DBS. This paper has tried to identify features that distinguish the caudal zona incerta of rodents (mouse and rat) and primates (marmoset, rhesus monkey, and human) from the remainder of the zona incerta. We studied cytoarchitecture, anatomical relationships, the pattern of immunomarkers, and gene expression in both of these areas. We found that the caudal zona incerta has a number of histological and gene expression characteristics that distinguish it from the other subdivisions of the zona incerta. Of particular note are the sparse population of GABA neurons and the small but distinctive population of calbindin neurons. We hope that a clearer appreciation of the anatomy of the region will in the end assist the interpretation of cases in which DBS is used in human patients.