GPi/GPe borderland- a potential sweet spot for deep brain stimulation for chorea in Huntington's disease?

BACKGROUND: Pallidal deep brain stimulation (GPi-DBS) has been considered as an effective treatment option for medication-refractory Huntington's disease (HD). OBJECTIVES: To identify stimulation-dependent effects on motor symptoms and to determine if these alterations are associated with the local impact of DBS on different pallidal parcellations. METHODS: We prospectively evaluated the effects of bilateral GPi-DBS within one year in 5 HD patients. We evaluated the effects of GPi-DBS on choreatic symptoms and UHDRS. Electrode placement in the pallidum was localized, and the local impact of DBS was estimated. RESULTS: The chorea subscore (p < 0.001) and UHDRS total motor score was significantly reduced postoperatively (p = 0.019). Pallidal DBS did not improve other motor symptoms. Activation of the lateral GPi/GPe was associated with improvement in choreatic symptoms (p = 0.048; r = 0.90). CONCLUSIONS: Our findings indicate that stimulation of the lateral GPi has a stable effect on choreatic symptoms. The modulation of the electrical field is relevant for motor outcome.

Bilateral Globus Pallidus Externus Deep Brain Stimulation for the Treatment of Refractory Tourette Syndrome: An Open Clinical Trial.

OBJECTIVES: We have previously proposed that Tourette syndrome (TS) is the clinical expression of the hyperactivity of globus pallidus externus (GPe) and various cortical areas. This study was designed to test this hypothesis by verifying the efficacy and safety of bilateral GPe deep brain stimulation (DBS) for treating refractory TS. MATERIALS AND METHODS: In this open clinical trial, 13 patients were operated on. Target coordinates (center of GPe) were obtained by direct visualization. Physiological mapping was performed with macrostimulation and microrecording. Primary and secondary outcome measures were, respectively, responder and improvement rates of TS and comorbidities, according to pre- and postoperative scores on the following assessment instruments: Yale Global Tic Severity Scale, Yale-Brown Obsessive Compulsive Scale, Beck Depression Inventory/Hamilton Depression Rating Scale, Beck Anxiety Inventory/Hamilton Anxiety Rating Scale, and Concentrated Attention test. RESULTS: Intraoperative stimulation (100 Hz/5.0V) did not produce any adverse effects or impact on tics. Microrecording revealed bursting cells discharging synchronously with tics in the central part of the dorsal half of GPe. Patients were followed up for a mean of 61.46±48.50 months. Responder rates were 76.9%, 75%, 71.4%, 71.4%, and 85.7%, respectively, for TS, obsessive-compulsive disorder (OCD), depression, anxiety, and attention deficit hyperactivity disorder. Mean improvements among responders in TS, OCD, depression, and anxiety were 77.4%, 74.7%, 89%, and 84.8%, respectively. After starting stimulation, tic improvement was usually delayed, taking up to ten days to manifest. Afterward, it increased over time, usually reaching its maximum at approximately one year postoperatively. The best stimulation parameters were 2.3V to 3.0V, 90 to 120 µsec, and 100 to 150 Hz, and the most effective contacts were the two dorsal ones. Two complications were registered: reversible impairment of previous depression and transient unilateral bradykinesia. CONCLUSIONS: Bilateral GPe-DBS proved to be low risk and quite effective for treating TS and comorbidities, ratifying the pathophysiological hypothesis that led to this study. Moreover, it compared favorably with DBS of other targets currently in use.

Deep brain stimulation and stereotactic-assisted brain graft injection targeting fronto-striatal circuits for Huntington's disease: an update.

INTRODUCTION: Huntington's Disease as progressive neurological disorders associated with motor, behavioral, and cognitive impairment poses a therapeutic challenge in case of limited responsiveness to established therapeutics. Pallidal deep brain stimulation and neurorestorative strategies (brain grafts) scoping to modulate fronto-striatal circuits have gained increased recognition for the treatment of refractory Huntington's disease (HD). AREAS COVERED: A review (2000-2022) was performed in PubMed, Embase, and Cochrane Library covering clinical trials conceptualized to determine the efficacy and safety of invasive, stereotactic-guided deep-brain stimulation and intracranial brain-graft injection targeting the globus pallidus and adjunct structures (striatum). EXPERT OPINION: Stereotactic brain-grafting strategies were performed in few HD patients with inconsistent findings and mild-to-moderate clinical responsiveness with a recently published large, randomized-controlled trial (NCT00190450) yielding negative results. We identified 19 in-human DBS trials (uncontrolled) targeting the globus pallidus internus/externus along with randomized-controlled trial pending report (NCT02535884). We did not detect any significant changes in the UHDRS total score after restorative injections, while in contrast, the use of deep-brain stimulation resulted in a significant reduction of chorea. GPi-DBS should be considered in cases where selective chorea is present. However, both invasive therapies remain experimental and are not ready for the implementation in clinical use.

Induction of Ticlike Involuntary Movements in Rats by Striatotomy and Subsequent Neurochemical Sensitization.

OBJECTIVE: It has been proposed that Tourette syndrome is associated with dysfunction in widespread cortical areas and globus pallidus externus hyperactivity secondary to dopaminergic hyperactivity and serotonergic/dynorphinergic hypoactivity. The main objective of this study was to test this hypothesis by developing an animal model of Tourette syndrome via striatotomy, followed by administration of drugs that mimic the neurotransmitter environment, so as to induce globus pallidus externus hyperactivity. METHODS: Rats were assigned to 3 groups: stereotactic striatotomy (STT) and striatal sham -lesion (SHAM) groups, treated with anterior and posterior striatum procedures in both hemispheres, and a group of nonoperated animals (NAIVE). Postoperatively, all rodents were blindly administered 3 drug protocols: levodopa/benserazide; levodopa/benserazide/ergotamine/naloxone (MIX); and saline. The animals were filmed at the peak action of these drugs. The videos were evaluated by a single blinded researcher. RESULTS: Six types of involuntary movements (IMs) were observed: cephalic, trunk jerks, oromandibular, forepaw jerks, dystonic, and locomotive. The number of animals with IM and the mean number of IM after both levodopa/benserazide and MIX was significantly higher in the STT compared with the SHAM and NAIVE groups. In the SHAM and NAIVE, MIX was superior to levodopa/benserazide in the induction of IM. In the STT, MIX was superior to levodopa/benserazide in the induction of trunk jerks. Appendicular IM were more common after posterior than after anterior striatotomy. CONCLUSIONS: These results show that striatotomy, followed by administration of levodopa/benserazide alone or associated with ergotamine and naloxone, is efficacious in inducing IM, supporting the hypothesis that led to this study.

Precise targeting of the globus pallidus internus with quantitative susceptibility mapping for deep brain stimulation surgery.

OBJECTIVE: The goal of this study was to demonstrate the use of quantitative susceptibility mapping (QSM)-based images to precisely localize the globus pallidus internus (GPi) for deep brain stimulation (DBS) planning and to enhance postsurgical visualization of the DBS lead positions. METHODS: Presurgical T1-weighted (T1w), T2-weighted (T2w), and QSM images as well as postsurgical CT images were obtained in 29 patients with Parkinson's disease. To enhance the contrast within the GP, a hybrid contrast was created by linearly combining T1w and QSM images. Contrast-to-noise ratios (CNRs) of the GPi on T1w, T2w, QSM, and hybrid images were compared. The CNR differences were tested using the 1-way ANOVA method. The visualization of the DBS lead position was demonstrated by merging the postsurgical CT with presurgical MR images. RESULTS: The hybrid images yield the best CNRs for GPi depiction and the visualization of the postsurgical DBS lead position was significantly improved. CONCLUSIONS: QSM-based images allow for confident localization of borders of the GPi that is superior to T1w and T2w images. High-contrast hybrid images can be used for precisely directed DBS targeting, e.g., GPi DBS for the treatment of advanced Parkinson's disease.

Reduced volumes of the external and internal globus pallidus in male heroin addicts: a postmortem study.

Deep brain stimulation (DBS) of the globus pallidus internus was recently proposed as a potential new treatment target for opioid addiction. DBS requires computer-assisted-3D planning to implant the stimulation electrode precisely. As volumes of brain regions may differ in addiction compared to healthy controls, our aim was to investigate possible volume differences in addicts compared to healthy controls. Volumes of the globus pallidus externus (PE) and internus (PI) in heroin addicts (n = 14) and healthy controls (n = 12) were assessed using morphometry of serial whole-brain sections. Total brain volume was larger in the heroin group (mean 1479 ± 62 cm3 vs. mean 1352 ± 103 cm3), as the heroin group was more than 10 years younger (p = 0.001). Despite larger mean whole brain volume, the mean relative volume of the PE and PI was smaller in addicted subjects compared to healthy controls (PE 0.658 ± 0.183 × 10-3 vs. 0.901 ± 0.284 × 10-3; ANOVA F(1, 24) = 6.945, p = 0.014, η2 = 0.224; PI 0.253 ± 0.095 × 10-3 vs. 0.345 ± 0.107 × 10-3; ANOVA F(1, 24) = 5.374, p = 0.029, η2 = 0.183). These findings were not significantly confounded by age, duration of autolysis, and fixation time. Our results provide further evidence for structural and not only functional deficits of the globus pallidus in addiction. In the context of previous studies, our findings support the idea of shared pathophysiological processes between comorbid depression and impulsivity in opioid addiction.

Microsurgical anatomy of the subthalamic nucleus: correlating fiber dissection results with 3-T magnetic resonance imaging using neuronavigation.

OBJECTIVE: Despite the extensive use of the subthalamic nucleus (STN) as a deep brain stimulation (DBS) target, unveiling the extensive functional connectivity of the nucleus, relating its structural connectivity to the stimulation-induced adverse effects, and thus optimizing the STN targeting still remain challenging. Mastering the 3D anatomy of the STN region should be the fundamental goal to achieve ideal surgical results, due to the deep-seated and obscure position of the nucleus, variable shape and relatively small size, oblique orientation, and extensive structural connectivity. In the present study, the authors aimed to delineate the 3D anatomy of the STN and unveil the complex relationship between the anatomical structures within the STN region using fiber dissection technique, 3D reconstructions of high-resolution MRI, and fiber tracking using diffusion tractography utilizing a generalized q-sampling imaging (GQI) model. METHODS: Fiber dissection was performed in 20 hemispheres and 3 cadaveric heads using the Klingler method. Fiber dissections of the brain were performed from all orientations in a stepwise manner to reveal the 3D anatomy of the STN. In addition, 3 brains were cut into 5-mm coronal, axial, and sagittal slices to show the sectional anatomy. GQI data were also used to elucidate the connections among hubs within the STN region. RESULTS: The study correlated the results of STN fiber dissection with those of 3D MRI reconstruction and tractography using neuronavigation. A 3D terrain model of the subthalamic area encircling the STN was built to clarify its anatomical relations with the putamen, globus pallidus internus, globus pallidus externus, internal capsule, caudate nucleus laterally, substantia nigra inferiorly, zona incerta superiorly, and red nucleus medially. The authors also describe the relationship of the medial lemniscus, oculomotor nerve fibers, and the medial forebrain bundle with the STN using tractography with a 3D STN model. CONCLUSIONS: This study examines the complex 3D anatomy of the STN and peri-subthalamic area. In comparison with previous clinical data on STN targeting, the results of this study promise further understanding of the structural connections of the STN, the exact location of the fiber compositions within the region, and clinical applications such as stimulation-induced adverse effects during DBS targeting.

The role of the human globus pallidus in Huntington's disease.

Huntington's disease (HD) is characterized by pronounced pathology of the basal ganglia, with numerous studies documenting the pattern of striatal neurodegeneration in the human brain. However, a principle target of striatal outflow, the globus pallidus (GP), has received limited attention in comparison, despite being a core component of the basal ganglia. The external segment (GPe) is a major output of the dorsal striatum, connecting widely to other basal ganglia nuclei via the indirect motor pathway. The internal segment (GPi) is a final output station of both the direct and indirect motor pathways of the basal ganglia. The ventral pallidum (VP), in contrast, is a primary output of the limbic ventral striatum. Currently, there is a lack of consensus in the literature regarding the extent of GPe and GPi neurodegeneration in HD, with a conflict between pallidal neurons being preserved, and pallidal neurons being lost. In addition, no current evidence considers the fate of the VP in HD, despite it being a key structure involved in reward and motivation. Understanding the involvement of these structures in HD will help to determine their involvement in basal ganglia pathway dysfunction in the disease. A clear understanding of the impact of striatal projection loss on the main neurons that receive striatal input, the pallidal neurons, will aid in the understanding of disease pathogenesis. In addition, a clearer picture of pallidal involvement in HD may contribute to providing a morphological basis to the considerable variability in the types of motor, behavioral, and cognitive symptoms in HD. This review aims to highlight the importance of the globus pallidus, a critical component of the cortical-basal ganglia circuits, and its role in the pathogenesis of HD. This review also summarizes the current literature relating to human studies of the globus pallidus in HD.

Anatomy of the subthalamic nucleus, with correlation of deep brain stimulation [RETRACTED].

OBJECT The goal in this study was to examine the cadaveric anatomy of the subthalamic nucleus (STN) and to analyze the implications of the findings for deep brain stimulation (DBS) surgery. METHODS Five formalin-fixed human cerebrums were dissected using the Klingler fiber dissection technique. Digital photographs of the dissections were fused to obtain an anaglyphic image. RESULTS The STN was located posteroinferior to the anterior corticospinal fibers, posterosuperior to the substantia nigra, and anteromedial to the red nucleus, lenticular fasciculus, and thalamic fasciculus. The subthalamic region is ventral to the thalamus, medial to the internal capsule, and lateral and caudal to the hypothalamus. The nuclei found within the subthalamic region include the STN. The relationship between the STN and surrounding structures, which are not delineated sharply, is described. CONCLUSIONS The fiber dissection technique supports the presence of the subthalamic region as an integrative network in humans and offers the potential to aid in understanding the impacts of DBS surgery of the STN in patients with Parkinson disease. Further research is needed to define the exact role of the STN in the integrative process.

Deep brain stimulation for Tourette syndrome.

Tourette syndrome is a neuropsychiatric disorder characterized by motor and vocal tics, often associated with behavioral disorders, with typical onset in early childhood. In most patients, the symptoms decrease spontaneously when adulthood is reached, or can be treated with behavioral therapy or medication. Only a small proportion of patients are candidates for surgical treatment. In 1999, thalamic deep brain stimulation (DBS) was introduced for intractable Tourette syndrome. Since then, a diversity of targets have been used, located mainly at the level of the medial part of the thalamus, in the globus pallidus internus (anteromedial limbic and posteroventrolateral motor part), the globus pallidus externus, and the internal capsule/nucleus accumbens. The pathophysiology of Tourette syndrome is still a matter of considerable debate. Current knowledge of cortical-basal ganglia-thalamocortical circuits provides explanations for the beneficial effects of DBS on tics. Inclusion and exclusion criteria have been formulated to identify good candidates for DBS. Because of the small number of patients, there is a strong need for multicenter double-blind trials with standard protocols.

Surgery for Tourette syndrome.

Tourette syndrome is a chronic neuropsychiatric disorder characterized by motor and vocal tics. In the majority of cases, tics are associated by behavioral disorders such as obsessive-compulsive behavior. First symptoms typically appear in early childhood. Mostly symptoms disappear when adulthood is reached. Treatment options consist of behavioral therapy and medication. In refractory cases, surgery may be an option. In the past, several attempts have been made to treat therapy-refractory patients through neurosurgical ablative procedures. In 1999, deep brain stimulation was introduced as a novel treatment option for patients with intractable Tourette syndrome. Up until now, five brain areas have been used or suggested as potential target areas for deep brain stimulation in Tourette syndrome. In the majority of the published cases, there is a clear effect on tics but most studies consist of only a limited number of patients. A strict patient selection is absolutely mandatory. There is a need for double-blinded multicenter trials with inclusion of more patients.

Evolution and rebirth of functional stereotaxy in the subthalamus.

The first human stereotactic surgery based on intracerebral landmarks and Cartesian coordinates was performed in 1947. With this followed the publication of a number of stereotactic frames and atlases. The intercommissural line joining the anterior and posterior commissures was to define stereotactic coordinate systems used in movement disorders and other functional neurosurgical procedures. Initially the target for Parkinson disease was the globus pallidus internus (GPi), but many investigators soon turned to the thalamus or parts of the subthalamus, but not the subthalamic nucleus. Microelectrode recording was introduced in 1961. With the apparent clinical efficacy of L-DOPA in 1965 interest in stereotactic surgery for Parkinson disease declined. The failure of prolonged, consistent pharmacologic management of bradykinesia and tremor, the side effects of dyskinesias, and the fading therapeutic success of medical treatment of movement disorders led to a resurgence of interest in the surgical management of movement disorders. With advances in understanding of the functional anatomy of the corticobasal ganglia circuit, advances in brain imaging, more sophisticated electrophysiologic recordings, and the use of deep brain stimulation as a reversible lesion, stereotactic surgery returned as a viable option for the treatment of movement disorders. The posterior medial part of the globus pallidus, ventral intermediate nucleus of the thalamus, and the subthalamus, its nuclei and pathways, are sites for interrupting pathophysiologic circuits. Not only has this been applied to movement disorders, but to epilepsy, chronic pain, and behavioral disorders.