Target-Specific Effects of Deep Brain Stimulation for Tourette Syndrome: A Systematic Review and Meta-Analysis

Background: Extended research has pointed to the efficacy of deep brain stimulation (DBS) in treatment of patients with treatment-refractory Tourette syndrome (TS). The four most commonly used DBS targets for TS include the centromedian nucleus–nucleus ventrooralis internus (CM-Voi) and the centromedian nucleus–parafascicular (CM-Pf) complexes of the thalamus, and the posteroventrolateral (pvIGPi) and the anteromedial portion of the globus pallidus internus (amGPi). Differences and commonalities between those targets need to be compared systematically.Objective: Therefore, we evaluated whether DBS is effective in reducing TS symptoms and target-specific differences.Methods: A PubMed literature search was conducted according to the PRISMA guidelines. Eligible literature was used to conduct a systematic review and meta-analysis.Results: In total, 65 studies with 376 patients were included. Overall, Yale Global Tic Severity Scale (YGTSS) scores were reduced by more than 50 in 69% of the patients. DBS also resulted in significant reductions of secondary outcome measures, including the total YGTSS, modified Rush Video-Based Tic Rating Scale (mRVRS), Yale-Brown Obsessive Compulsive Scale (YBOCS), and Becks Depression Inventory (BDI). All targets resulted in significant reductions of YGTSS scores and, with the exception of the CM-Pf, also in reduced YBOCS scores. Interestingly, DBS of pallidal targets showed increased YGTSS and YBOCS reductions compared to thalamic targets. Also, the meta-analysis including six randomized controlled and double-blinded trials demonstrated clinical efficacy of DBS for TS, that remained significant for GPi but not thalamic stimulation in two separate meta-analyses.Conclusion: We conclude that DBS is a clinically effective treatment option for patients with treatment-refractory TS, with all targets showing comparable improvement rates. Future research might focus on personalized and symptom-specific target selection.

Case Report: Embedding “Digital Chronotherapy” Into Medical Devices—A Canine Validation for Controlling Status Epilepticus Through Multi-Scale Rhythmic Brain Stimulation

Circadian and other physiological rhythms play a key role in both normal homeostasis and disease processes. Such is the case of circadian and infradian seizure patterns observed in epilepsy. However, these rhythms are not fully exploited in the design of active implantable medical devices. In this paper we explore a new implantable stimulator that implements chronotherapy as a feedforward input to supplement both open-loop and closed-loop methods. This integrated algorithm allows for stimulation to be adjusted to the ultradian, circadian and infradian patterns observed in patients through slowly-varying temporal adjustments of stimulation and algorithm sub-components, while also enabling adaption of stimulation based on immediate physiological needs such as a breakthrough seizure or change of posture. Embedded physiological sensors in the stimulator can be used to refine the baseline stimulation circadian pattern as a “digital zeitgeber,” i.e., a source of stimulus that entrains or synchronizes the subject's natural rhythms. This algorithmic approach is tested on a canine with severe drug-resistant idiopathic generalized epilepsy exhibiting a characteristic diurnal pattern correlated with sleep-wake cycles. Prior to implantation, the canine's cluster seizures evolved to status epilepticus (SE) and required emergency pharmacological intervention. The cranially-mounted system was fully-implanted bilaterally into the centromedian nucleus of the thalamus. Using combinations of time-based modulation, thalamocortical rhythm-specific tuning of frequency parameters as well as fast-adaptive modes based on activity, the canine experienced no further SE events post-implant as of the time of writing (7 months). Importantly, no significant cluster seizures have been observed either, allowing the reduction of rescue medication. The use of digitally-enabled chronotherapy as a feedforward signal to augment adaptive neurostimulators could prove a useful algorithmic method in conditions where sensitivity to temporal patterns are characteristics of the disease state, providing a novel mechanism for tailoring a more patient-specific therapy approach.

Network Substrates of Centromedian Nucleus Deep Brain Stimulation in Generalized Pharmacoresistant Epilepsy

Deep brain stimulation (DBS), specifically thalamic DBS, has achieved promising results to reduce seizure severity and frequency in pharmacoresistant epilepsies, thereby establishing it for clinical use. The mechanisms of action are, however, still unknown. We evidenced the brain networks directly modulated by centromedian (CM) nucleus-DBS and responsible for clinical outcomes in a cohort of patients uniquely diagnosed with generalized pharmacoresistant epilepsy. Preoperative imaging and long-term (2–11 years) clinical data from ten generalized pharmacoresistant epilepsy patients (mean age at surgery = 30.8 ± 5.9 years, 4 female) were evaluated. Volume of tissue activated (VTA) was included as seeds to reconstruct the targeted network to thalamic DBS from diffusion and functional imaging data. CM-DBS clinical outcome improvement (> 50%) appeared in 80% of patients and was tightly related to VTAs interconnected with a reticular system network encompassing sensorimotor and supplementary motor cortices, together with cerebellum/brainstem. Despite methodological differences, both structural and functional connectomes revealed the same targeted network. Our results demonstrate that CM-DBS outcome in generalized pharmacoresistant epilepsy is highly dependent on the individual connectivity profile, involving the cerebello-thalamo-cortical circuits. The proposed framework could be implemented in future studies to refine stereotactic implantation or the parameters for individualized neuromodulation.

Damage to the central nucleus of the thalamus via atypical Holmes tremor: a case report

Holmes tremor (HT) is a rare symptomatic movement disorder characterized by a combination of resting, postural, and action tremors. HT is usually caused by lesions in the brain stem, thalamus, and cerebellum, and the pathogenesis is believed to be related to the nigrostriatal pathway and/or the cerebello–thalamo–cortical pathway. Many medications have been used to treat HT with various degrees of effectiveness. We herein present a case involving an elderly woman who developed atypical HT 23 months after cerebral hemorrhage. The atypical HT manifested as a tremor of the right limb with involuntary flexion of the distal five fingers of the right upper limb. Imaging findings suggested the existence of an old hemorrhage in the left thalamus. Specifically, diffusion tensor imaging data of the whole brain and multimodal three-dimensional medical imaging revealed significant white matter microstructural changes in the centromedian nucleus of the left thalamus. Treatment with high-dose oral levodopa was not efficient, but the symptoms gradually decreased in severity and disappeared 1 month after switching to oral clonazepam treatment.

Connectivity Patterns of Deep Brain Stimulation Targets in Patients with Gilles de Tourette Syndrome

Since 1999, several targets for deep brain stimulation (DBS) in Gilles de la Tourette syndrome (GTS) have emerged showing similar success rates. Studies using different tractography techniques have identified connectivity profiles associated with a better outcome for individual targets. However, GTS patients might need individualized therapy. The objective of this study is to analyze the connectivity profile of different DBS targets for GTS. We identified standard target coordinates for the centromedian nucleus/nucleus ventro-oralis internus (CM/Voi), the CM/parafascicular (CM-Pf) complex, the anteromedial globus pallidus internus (amGPi), the posteroventral GPi (pvGPi), the ventral anterior/ventrolateral thalamus (VA/VL), and the nucleus accumbens/anterior limb of the internal capsule (Nacc/ALIC). Probabilistic tractography was performed from the targets to different limbic and motor areas based on patient-specific imaging and a normative connectome (HCP). Our analysis showed significant differences between the connectivity profiles of standard DBS targets (p < 0.05). Among all targets, the pvGPi showed the strongest connection to the sensorimotor cortex, while the amGPi showed the strongest connection to the prefrontal cortex in patient-specific imaging. Differences were observed between the connectivity profiles when using probabilistic tractography based on patient data and HCP. Our findings showed that the connectivity profiles of different DBS targets to major motor and limbic areas differ significantly. In the future, these differences may be considered when planning DBS for GTS patients employing an individualized approach. There were compelling differences in connectivity profiles when using different tractography techniques.

Modulation of Fibers to Motor Cortex during Thalamic DBS in Tourette Patients Correlates with Tic Reduction

Probabilistic tractography in Tourette syndrome (TS) patients have shown an alteration in the connectivity of the primary motor cortex and supplementary motor area with the striatum and thalamus, suggesting an abnormal connectivity of the cortico-striatum-thalamocortical-pathways in TS. Deep brain stimulation (DBS) of the centromedian nucleus–nucleus ventrooralis internus (CM-Voi complex) in the thalamus is an effective treatment for refractory TS patients. We investigated the connectivity of activated fibers from CM-Voi to the motor cortex and its correlation between these projections and their clinical outcome. Seven patients with TS underwent CM-Voi-DBS surgery and were clinically evaluated preoperatively and six months postoperatively. We performed diffusion tensor imaging to display the activated fibers projecting from the CM-Voi to the different motor cortex regions of interest. These analyses showed that the extent of tic reduction during DBS is associated with the degree of stimulation-dependent connectivity between CM-Voi and the motor cortex, and in particular, an increased density of projections to the presupplementary motor area (preSMA). Non-responder patients displayed the largest amount of active fibers projecting into cortical areas other than motor cortex compared to responder patients. These findings support the notion that an abnormal connectivity of thalamocortical pathways underlies TS, and that modulation of these circuits through DBS could restore the function and reduce symptoms.