Radiosurgical thalamotomy for essential tremor: state of the art, current challenges and future directions.

INTRODUCTION: Essential tremor (ET) is the most frequent movement disorder, affecting up to 5% of adults > 65 years old. In 30-50% of cases, optimal medical management provides insufficient tremor relief and surgical options are considered. Thalamotomy is a time-honored intervention, which can be performed using radiofrequency (RF), stereotactic radiosurgery (SRS), or magnetic resonance-guided focused ultrasounds (MRgFUS). While the latter has received considerable attention in the last decade, SRS has consistently been demonstrated as an effective and well-tolerated option. AREAS COVERED: This review discusses the evidence on SRS thalamotomy for ET. Modern workflows and emerging techniques are detailed. Current outcomes are analyzed, with a specific focus on tremor reduction, complications and radiological evolution of the lesions. Challenges for the field are highlighted. EXPERT OPINION: SRS thalamotomy improves tremor in > 80% patients. The efficacy appears comparable to other modalities, including DBS, RF and MRgFUS. Side effects result mostly from idiosyncratic hyper-responses to radiation, which occur in up to 10% of treatments, are usually self-resolving, and are symptomatic in < 4% of patients. Future research should focus on accumulating more data on bilateral treatments, collecting long-term outcomes, refining targeting, and improving lesion consistency.

Auditory oddball responses in the human subthalamic nucleus and substantia nigra pars reticulata.

The auditory oddball is a mainstay in research on attention, novelty, and sensory prediction. How this task engages subcortical structures like the subthalamic nucleus and substantia nigra pars reticulata is unclear. We administered an auditory OB task while recording single unit activity (35 units) and local field potentials (57 recordings) from the subthalamic nucleus and substantia nigra pars reticulata of 30 patients with Parkinson's disease undergoing deep brain stimulation surgery. We found tone modulated and oddball modulated units in both regions. Population activity differentiated oddball from standard trials from 200 ms to 1000 ms after the tone in both regions. In the substantia nigra, beta band activity in the local field potential was decreased following oddball tones. The oddball related activity we observe may underlie attention, sensory prediction, or surprise-induced motor suppression.

Subthalamic and pallidal neurons are modulated during externally cued movements in Parkinson's disease.

External sensory cues can reduce freezing of gait in people with Parkinson's disease (PD), yet the role of the basal ganglia in these movements is unclear. We used microelectrode recordings to examine modulations in single unit (SU) and oscillatory local field potentials (LFP) during auditory-cued rhythmic pedaling movements of the feet. We tested five blocks of increasing cue frequencies (1 Hz, 1.5 Hz, 2 Hz, 2.5 Hz, and 3 Hz) in 24 people with PD undergoing deep brain stimulation surgery of the subthalamic nucleus (STN) or globus pallidus internus (GPi). Single unit firing and beta band LFPs (13-30 Hz) in response to movement onsets or cue onsets were examined. We found that the timing accuracy of foot pedaling decreased with faster cue frequencies. Increasing cue frequencies also attenuated firing rates in both STN and GPi neurons. Peak beta power in the GPi and STN showed different responses to the task. GPi beta power showed persistent suppression with fast cues and phasic modulation with slow cues. STN beta power showed enhanced beta synchronization following movement. STN beta power also correlated with rate of pedaling. Overall, we showed task-related responses in the GPi and STN during auditory-cued movements with differential roles in sensory and motor control. The results suggest a role for both input and output basal ganglia nuclei in auditory rhythmic pacing of gait-like movements in PD.

Postoperative cerebellar mutism syndrome is an acquired Autism-like network disturbance.

BACKGROUND: Cerebellar mutism syndrome (CMS) is a common and debilitating complication of posterior fossa tumour surgery in children. Affected children exhibit communication and social impairments that overlap phenomenologically with subsets of deficits exhibited by children with Autism spectrum disorder (ASD). Although both CMS and ASD are thought to involve disrupted cerebro-cerebellar circuitry, they are considered independent conditions due to an incomplete understanding of their shared neural substrates. METHODS: In this study, we analyzed post-operative cerebellar lesions from 90 children undergoing posterior fossa resection of medulloblastoma, 30 of whom developed CMS. Lesion locations were mapped to a standard atlas, and the networks functionally connected to each lesion were computed in normative adult and paediatric datasets. Generalizability to ASD was assessed using an independent cohort of children with ASD and matched controls (n=427). RESULTS: Lesions in children who developed CMS involved the vermis and inferomedial cerebellar lobules. They engaged large-scale cerebellothalamocortical circuits with a preponderance for the prefrontal and parietal cortices in the paediatric and adult connectomes, respectively. Moreover, with increasing connectomic age, CMS-associated lesions demonstrated stronger connectivity to the midbrain/red nuclei, thalami and inferior parietal lobules and weaker connectivity to prefrontal cortex. Importantly, the CMS-associated lesion network was independently reproduced in ASD and correlated with communication and social deficits, but not repetitive behaviours. CONCLUSIONS: Our findings indicate that CMS-associated lesions result in an ASD-like network disturbance that occurs during sensitive windows of brain development. A common network disturbance between CMS and ASD may inform improved treatment strategies for affected children.

Deep brain stimulation for substance use disorder: a systematic review and meta-analysis.

Objective: Substance use disorder (SUD) is a significant public health issue with a high mortality rate. Deep brain stimulation (DBS) has shown promising results in treating SUD in certain cases. In this study, we conducted a meta-analysis to evaluate the efficacy of DBS in the treatment of SUD and reduction of relapse rates. Methods: We performed a thorough and methodical search of the existing scientific literature, adhering to the PRISMA guidelines, to identify 16 original studies that fulfilled our inclusion criteria. We used the evidence levels recommended by the Oxford Centre for Evidence-Based Medicine to assess bias. The R version 4.2.3 software was utilized to calculate the mean effect size. We estimated study heterogeneity by employing tau2 and I2 indices and conducting Cochran's Q test. Results: The results showed that DBS treatment resulted in a significant improvement in the clinical SUD scales of patients, with an average improvement of 59.6%. The observed relapse rate was 8%. The meta-analysis estimated a mean effect size of 55.9 [40.4; 71.4]. Heterogeneity analysis showed a large degree of heterogeneity among the included studies. Subgroup and meta-regression analysis based on age and SUD type suggested that DBS may be more effective for patients above 45 years of age, and for alcohol and opioid addiction compared to nicotine addiction. Conclusion: The current literature suggests that DBS has a moderate effect on SUD symptoms. However, the limited number of studies and small sample size indicate that more research is needed to better understand the factors that influence its effectiveness.

Investigation of neurophysiologic and functional connectivity changes following glioma resection using magnetoencephalography.

Background: In patients with glioma, clinical manifestations of neural network disruption include behavioral changes, cognitive decline, and seizures. However, the extent of network recovery following surgery remains unclear. The aim of this study was to characterize the neurophysiologic and functional connectivity changes following glioma surgery using magnetoencephalography (MEG). Methods: Ten patients with newly diagnosed intra-axial brain tumors undergoing surgical resection were enrolled in the study and completed at least two MEG recordings (pre-operative and immediate post-operative). An additional post-operative recording 6-8 weeks following surgery was obtained for six patients. Resting-state MEG recordings from 28 healthy controls were used for network-based comparisons. MEG data processing involved artifact suppression, high-pass filtering, and source localization. Functional connectivity between parcellated brain regions was estimated using coherence values from 116 virtual channels. Statistical analysis involved standard parametric tests. Results: Distinct alterations in spectral power following tumor resection were observed, with at least three frequency bands affected across all study subjects. Tumor location-related changes were observed in specific frequency bands unique to each patient. Recovery of regional functional connectivity occurred following glioma resection, as determined by local coherence normalization. Changes in inter-regional functional connectivity were mapped across the brain, with comparable changes in low to mid gamma-associated functional connectivity noted in four patients. Conclusion: Our findings provide a framework for future studies to examine other network changes in glioma patients. We demonstrate an intrinsic capacity for neural network regeneration in the post-operative setting. Further work should be aimed at correlating neurophysiologic changes with individual patients' clinical outcomes.

Deep Brain Stimulation of the Globus Pallidus Internus and Externus in Multiple System Atrophy.

BACKGROUND: Multiple system atrophy with parkinsonism (MSA-P) is a progressive condition with no effective treatment. OBJECTIVE: The aim of this study was to describe the safety and efficacy of deep brain stimulation (DBS) of globus pallidus pars interna and externa in a cohort of patients with MSA-P. METHODS: Six patients were included. Changes in Movement Disorders Society Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III), Parkinson's Disease Questionnaire (PDQ-39) scores, and levodopa equivalent daily dose were compared before and after DBS. Electrode localization and volume tissue activation were calculated. RESULTS: DBS surgery did not result in any major adverse events or intraoperative complications. Overall, no differences in MDS-UPDRS III scores were demonstrated (55.2 ± 17.6 preoperatively compared with 67.3 ± 19.2 at 1 year after surgery), although transient improvement in mobility and dyskinesia was reported in some subjects. CONCLUSIONS: Globus pallidus pars interna and externa DBS for patients with MSA-P did not result in major complications, although it did not provide significant clinical benefit as measured by MDS-UPDRS III. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Utilization, surgical populations, centers, coverages, regional balance, and their influential factors of deep brain stimulation for Parkinson's disease: a large-scale multicenter cross-sectional study from 1997 to 2021.

BACKGROUND: Deep brain stimulation (DBS) is an emerging and effective therapy for Parkinson's disease (PD). However, little is known about its utilization, surgical populations, centers, coverages, regional balance, and influential factors. MATERIALS AND METHODS: This large-scale multicenter cross-sectional study was conducted using a national census involving 74 Chinese centers. National DBS populations and centers for PD were investigated in 1997-2021, and regional sociodemographic features, surgical populations, related resources, and insurance policies in 2020 were explored. RESULTS: Since the first DBS surgery in 1997, a total of 38 122 PD patients from 349 centers underwent DBS by 2021, which covered 1.118% (1.108-1.129) of patients and 0.954% (0.933-0.976) of centers. Significant upward trends in the annual surgical population and coverages were observed with rapid climbing rates, while the annual surgical centers and their coverage showed two growth peaks in 2002-2006 and 2010-2018, correlating with clinical approvals and new technologies. A total of 103 070 (51 165-154 975) PD patients [2.088% (1.351-2.825) coverage] and 603 (72-1134) centers [1.356% (1.126-1.586) coverage] are predicted to conduct DBS by 2030. The new remotely programmed DBS technology was recoded as the first application in 2015 and rapidly increased to 2771 (47.39%, 46.11-48.67) patients with 10 507 remote programming sessions annually in 2021. Provinces in the eastern and central regions had better economic status, more surgical patients, higher insurance affordability, and more related resources than those in the western and northeastern regions. Higher gross domestic product per capita ( ß =5.041, 3.324-6.758 and ß =0.008, 0.004-0.012; all P <0.001) and more functional neurosurgery doctors ( ß =3.596, 0.353-6.839; P =0.031 and ß =0.010, 0.002-0.017; P =0.013) positively influenced surgical populations and coverages, while higher insurance levels ( ß =128.888, 64.702-193.075; P <0.001) positively influenced surgical coverages. CONCLUSION: Although surgical populations, centers, and coverages of DBS for PD have rapidly improved and are predicted to show future increases, this is still insufficient to cover potential eligible patients. Regionally imbalanced health coverage should be given attention to promote coordinated development.

Predictors of Future Deep Brain Stimulation Surgery in de novo Parkinson's Disease.

Background: Deep brain stimulation (DBS) surgery is offered to a subset of Parkinson's disease (PD) patients. It is unclear if there are features at diagnosis that predict future DBS surgery. Objective: To assess predictors of eventual DBS surgery in de novo PD patients. Methods: Subjects from the Parkinson's Progression Marker Initiative (PPMI) database with newly diagnosed, sporadic PD (n = 416) were identified and stratified by their eventual DBS status (DBS+, n = 43; DBS-, n = 373). A total of 50 baseline clinical, imaging, and biospecimen features were extracted for each subject and cross-validated lasso regression was used for feature reduction. Multivariate logistic regression assessed their relationship with DBS status and a receiver operating characteristic curve evaluated model performance. Linear mixed effect models assessed disease progression over 4 years in DBS+ and DBS- patients. Results: Age at symptom onset, Hoehn and Yahr (H&Y) stage, tremor score, and ratio of CSF Tau to amyloid-beta 1-42 (Tau: Ab) were identified as important baseline features for predicting DBS surgery. Each independently predicted DBS surgery (area under the curve = 0.83). DBS- patients had faster memory decline (P < 0.05), while DBS+ patients had faster decline in H&Y stage (P < 0.001) and motor scores (P < 0.05) prior to surgery. Conclusion: The identified features may be used for early identification of patients who may be surgical candidates during the course of their disease. Disease progression in these groups reflects surgical eligibility criteria, with DBS- patients having more rapid decline in memory while DBS+ patients experienced a faster decline in motor scores prior to DBS surgery.

Essential Tremor - Deep Brain Stimulation vs. Focused Ultrasound.

INTRODUCTION: Essential Tremor (ET) is one of the most common tremor syndromes typically presented as action tremor, affecting mainly the upper limbs. In at least 30-50% of patients, tremor interferes with quality of life, does not respond to first-line therapies and/or intolerable adverse effects may occur. Therefore, surgery may be considered. AREAS COVERED: In this review, the authors discuss and compare unilateral ventral intermedius nucleus deep brain stimulation (VIM DBS) and bilateral DBS with Magnetic Resonance-guided Focused Ultrasound (MRgFUS) thalamotomy, which comprises focused acoustic energy generating ablation under real-time MRI guidance. Discussion includes their impact on tremor reduction and their potential complications. Finally, the authors provide their expert opinion. EXPERT OPINION: DBS is adjustable, potentially reversible and allows bilateral treatments; however, it is invasive requires hardware implantation, and has higher surgical risks. Instead, MRgFUS is less invasive, less expensive, and requires no hardware maintenance. Beyond these technical differences, the decision should also involve the patient, family, and caregivers.

Advances in Technical Aspects of Deep Brain Stimulation Surgery.

BACKGROUND: Deep brain stimulation has become an established technology for the treatment of patients with a wide variety of conditions, including movement disorders, psychiatric disorders, epilepsy, and pain. Surgery for implantation of DBS devices has enhanced our understanding of human physiology, which in turn has led to advances in DBS technology. Our group has previously published on these advances, proposed future developments, and examined evolving indications for DBS. SUMMARY: The crucial roles of structural MR imaging pre-, intra-, and post-DBS procedure in target visualization and confirmation of targeting are described, with discussion of new MR sequences and higher field strength MRI enabling direct visualization of brain targets. The incorporation of functional and connectivity imaging in procedural workup and their contribution to anatomical modelling is reviewed. Various tools for targeting and implanting electrodes, including frame-based, frameless, and robot-assisted, are surveyed, and their pros and cons are described. Updates on brain atlases and various software used for planning target coordinates and trajectories are presented. The pros and cons of asleep versus awake surgery are discussed. The role and value of microelectrode recording and local field potentials are described, as well as the role of intraoperative stimulation. Technical aspects of novel electrode designs and implantable pulse generators are presented and compared.

Optimal deep brain stimulation sites and networks for stimulation of the fornix in Alzheimer's disease.

Deep brain stimulation (DBS) to the fornix is an investigational treatment for patients with mild Alzheimer's Disease. Outcomes from randomized clinical trials have shown that cognitive function improved in some patients but deteriorated in others. This could be explained by variance in electrode placement leading to differential engagement of neural circuits. To investigate this, we performed a post-hoc analysis on a multi-center cohort of 46 patients with DBS to the fornix (NCT00658125, NCT01608061). Using normative structural and functional connectivity data, we found that stimulation of the circuit of Papez and stria terminalis robustly associated with cognitive improvement (R = 0.53, p < 0.001). On a local level, the optimal stimulation site resided at the direct interface between these structures (R = 0.48, p < 0.001). Finally, modulating specific distributed brain networks related to memory accounted for optimal outcomes (R = 0.48, p < 0.001). Findings were robust to multiple cross-validation designs and may define an optimal network target that could refine DBS surgery and programming.

Persistent synaptic inhibition of the subthalamic nucleus by high frequency stimulation.

BACKGROUND: Deep brain stimulation (DBS) provides symptomatic relief in a growing number of neurological indications, but local synaptic dynamics in response to electrical stimulation that may relate to its mechanism of action have not been fully characterized. OBJECTIVE: The objectives of this study were to (1) study local synaptic dynamics during high frequency extracellular stimulation of the subthalamic nucleus (STN), and (2) compare STN synaptic dynamics with those of the neighboring substantia nigra pars reticulata (SNr). METHODS: Two microelectrodes were advanced into the STN and SNr of patients undergoing DBS surgery for Parkinson's disease (PD). Neuronal firing and evoked field potentials (fEPs) were recorded with one microelectrode during stimulation from an adjacent microelectrode. RESULTS: Inhibitory fEPs could be discerned within the STN and their amplitudes predicted bidirectional effects on neuronal firing (p = .013). There were no differences between STN and SNr inhibitory fEP dynamics at low stimulation frequencies (p > .999). However, inhibitory neuronal responses were sustained over time in STN during high frequency stimulation but not in SNr (p < .001) where depression of inhibitory input was coupled with a return of neuronal firing (p = .003). INTERPRETATION: Persistent inhibitory input to the STN suggests a local synaptic mechanism for the suppression of subthalamic firing during high frequency stimulation. Moreover, differences in the resiliency versus vulnerability of inhibitory inputs to the STN and SNr suggest a projection source- and frequency-specificity for this mechanism. The feasibility of targeting electrophysiologically-identified neural structures may provide insight into how DBS achieves frequency-specific modulation of neuronal projections.

Lesion network mapping of ectopic craniopharyngioma identifies potential cause of psychosis: a case report.

We report the case of a patient with craniopharyngioma who demonstrated ectopic spread to the right temporal lobe and concurrent local recurrence, 10 years after her initial diagnosis. The patient additionally demonstrated new-onset psychotic symptoms of uncertain etiology during her admission. Lesion network mapping identified the ectopic lesion as a putative cause for her psychosis. These findings were substantiated after the resection of the ectopic lesion and subsequent resolution of her psychiatric symptoms. This report adds to the rare accounts of ectopic craniopharyngioma, while highlighting the utility of network-based analyses in peri-operative tumor evaluation and the assessment of atypical neuropsychiatric phenomena.

Ipsilateral and axial tremor response to focused ultrasound thalamotomy for essential tremor: clinical outcomes and probabilistic mapping.

BACKGROUND: MR-guided focused ultrasound (MRgFUS) thalamotomy has been shown to be a safe and effective treatment for essential tremor (ET). OBJECTIVE: To investigate the effects of MRgFUS in patients with ET with an emphasis on ipsilateral-hand and axial tremor subscores. METHODS: Tremor scores and adverse effects of 100 patients treated between 2012 and 2018 were assessed at 1 week, 3, 12, and 24 months. A subgroup analysis of ipsilateral-hand tremor responders (defined as patients with ≥30% improvement at any time point) and non-responders was performed. Correlations and predictive factors for improvement were analysed. Weighted probabilistic maps of improvement were generated. RESULTS: Significant improvement in axial, contralateral-hand and total tremor scores was observed at all study visits from baseline (p<0.0001). There was no significant improvement in ipsilateral subscores. A subset of patients (n=20) exhibited group-level ipsilateral-hand improvement that remained significant through all follow-ups (p<0.001). Multivariate regression analysis revealed that higher baseline scores predict better improvement in ipsilateral-hand and axial tremor. Probabilistic maps demonstrated that the lesion hotspot for axial improvement was situated more medially than that for contralateral improvement. CONCLUSION: MRgFUS significantly improved axial, contralateral-hand and total tremor scores. In a subset of patients, a consistent group-level treatment effect was observed for ipsilateral-hand tremor. While ipsilateral improvement seemed to be less directly related to lesion location, a spatial relationship between lesion location and axial and contralateral improvement was observed that proved consistent with the somatotopic organisation of the ventral intermediate nucleus. TRIAL REGISTRATION NUMBERS: NCT01932463, NCT01827904, and NCT02252380.

Psychiatric surgery: The legal landscape.

More than most or even any other medical intervention, surgery for the relief of severe psychiatric illness is tied up in complex ethical issues and, inevitably, legal considerations. The latter may vary considerably from one jurisdiction to the next, and even within countries. Even though political considerations may play a role in regulating psychiatric surgery, and enacted policies may not necessarily be based on the best available evidence, neurosurgeons and psychiatrists must be aware of the restrictions that may be placed on the type of procedures they can perform. Nonetheless, despite the seemingly arbitrary differences in policy that exist around the world, governmental agencies take their responsibilities for protecting the public as a serious matter. Practitioners can influence public decision-making by adhering to the legal and ethical requirements of their region, and by amassing evidence that can help to inform well-meaning government officials as to the best practices of psychiatric surgery. This chapter will describe the medicolegal environment affecting the practice of psychiatric surgery in the United States, Canada, and Brazil.

Functional tremor developing after successful MRI-guided focused ultrasound thalamotomy for essential tremor.

OBJECTIVE: To describe a case of functional tremor occurring after a successful MR-guided focused ultrasound thalamotomy (MRgFUS) for essential tremor. METHODS: A 71-year-old right-handed man with essential tremor was referred to us for consideration of deep brain stimulation surgery for worsening bilateral upper limb tremor after a successful left MRgFUS for essential tremor. RESULTS: On clinical exam, signs compatible with a functional tremor were noted, including entertainability and suppressibility. Electrophysiological studies were consistent with essential tremor and superimposed tremor fulfilling the laboratory-supported criteria for functional tremor. DISCUSSION: We describe the first reported case of a functional movement disorder occurring after successful MRgFUS procedure for essential tremor. Recognising this entity and its development after such therapeutic interventions is essential to avoid further unnecessary invasive therapies.