A Novel Closed-Loop Electrical Brain Stimulation Device Featuring Wireless Low-Energy Ultrasound Power and Communication.

OBJECTIVES: This study aimed to indicate the feasibility of a prototype electrical neuromodulation system using a closed-loop energy-efficient ultrasound-based mechanism for communication, data transmission, and recharging. MATERIALS AND METHODS: Closed-loop deep brain stimulation (DBS) prototypes were designed and fabricated with ultrasonic wideband (UsWB) communication technology and miniaturized custom electronics. Two devices were implanted short term in anesthetized Göttingen minipigs (N = 2). Targeting was performed using preoperative magnetic resonance imaging, and locations were confirmed postoperatively by computerized tomography. DBS systems were tested over a wide range of stimulation settings to mimic minimal, typical, and/or aggressive clinical settings, and evaluated for their ability to transmit data through scalp tissue and to recharge the DBS system using UsWB. RESULTS: Stimulation, communication, reprogramming, and recharging protocols were successfully achieved in both subjects for amplitude (1V-6V), frequency (50-250 Hz), and pulse width (60-200 µs) settings and maintained for ≥six hours. The precision of pulse settings was verified with <5% error. Communication rates of 64 kbit/s with an error rate of 0.05% were shown, with no meaningful throughput degradation observed. Time to recharge to 80% capacity was <9 minutes. Two DBS systems also were implanted in the second test animal, and independent bilateral stimulation was successfully shown. CONCLUSIONS: The system performed at clinically relevant implant depths and settings. Independent bilateral stimulation for the duration of the study with a 4F energy storage and full rapid recharge were achieved. Continuous function extrapolates to six days of continuous stimulation in future design iterations implementing application specific integrated circuit level efficiency and 15F storage capacitance. UsWB increases energy efficiency, reducing storage requirements and thereby enabling device miniaturization. The device can enable intelligent closed-loop stimulation, remote system monitoring, and optimization and can serve as a power/data gateway to interconnect the intrabody network with the Internet of Medical Things.

Focused stimulation of dorsal versus ventral subthalamic nucleus enhances action-outcome learning in patients with Parkinson's disease.

Deep brain stimulation of the subthalamic nucleus is an effective treatment for the clinical motor symptoms of Parkinson's disease, but may alter the ability to learn contingencies between stimuli, actions and outcomes. We investigated how stimulation of the functional subregions in the subthalamic nucleus (motor and cognitive regions) modulates stimulus-action-outcome learning in Parkinson's disease patients. Twelve Parkinson's disease patients with deep brain stimulation of the subthalamic nucleus completed a probabilistic stimulus-action-outcome task while undergoing ventral and dorsal subthalamic nucleus stimulation (within subjects, order counterbalanced). The task orthogonalized action choice and outcome valence, which created four action-outcome learning conditions: action-reward, inhibit-reward, action-punishment avoidance and inhibit-punishment avoidance. We compared the effects of deep brain stimulation on learning rates across these conditions as well as on computed Pavlovian learning biases. Dorsal stimulation was associated with higher overall learning proficiency relative to ventral subthalamic nucleus stimulation. Compared to ventral stimulation, stimulating the dorsal subthalamic nucleus led to a particular advantage in learning to inhibit action to produce desired outcomes (gain reward or avoid punishment) as well as better learning proficiency across all conditions providing reward opportunities. The Pavlovian reward bias was reduced with dorsal relative to ventral subthalamic nucleus stimulation, which was reflected by improved inhibit-reward learning. Our results show that focused stimulation in the dorsal compared to the ventral subthalamic nucleus is relatively more favourable for learning action-outcome contingencies and reduces the Pavlovian bias that could lead to reward-driven behaviour. Considering the effects of deep brain stimulation of the subthalamic nucleus on learning and behaviour could be important when optimizing stimulation parameters to avoid side effects like impulsive reward-driven behaviour.

Progressive Multifocal Encephalopathy Holmes Tremor Successfully Treated with Bilateral Deep Brain Stimulation.

Background: We report a patient with bilateral HT treated with DBS. Case report: A 58-year-old man diagnosed with HIV/AIDS and progressive multifocal leukoencephalopathy (PML) presented with 20 years of bilateral arm tremor refractory to therapy. DBS was implanted on the left ventral intermediate nucleus and posterior subthalamic area (VIM/PSA). One year later, a right VIM/PSA DBS was implanted. At twelve months, there were no significant side-effects. With his DBS turned off and on, the Fahn-Tolosa-Marin scale was rated 82 and 58, respectively. Discussion: To our knowledge, this is the first report of bilateral DBS VIM/PSA treating HT with no significant side effects. Highlights: We report a successful treatment using deep brain stimulation of bilateral Holmes tremor that was caused by progressive multifocal encephalopathy. The patient achieved 30% improvement in tremor control with a meaningful improvement in his activities of daily living.

Spinal Cord Stimulation for Parkinson's Disease: A Systematic Review and Meta-Analysis of Pain and Motor Outcomes.

BACKGROUND: Spinal cord stimulation (SCS) has been investigated as a potential therapeutic option for managing refractory symptoms in patients with Parkinson's disease (PD). OBJECTIVE: This systematic review and meta-analysis aimed to evaluate the safety and efficacy of SCS in PD. METHOD: A comprehensive literature search was conducted on PubMed and Web of Science to identify SCS studies reporting Unified Parkinson Disease Rating Scale-III (UPDRS-III) or Visual Analogue Scale (VAS) score changes in PD cohorts with at least 3 patients and a follow-up period of at least 1 month. Treatment effect was measured as the mean change in outcome scores and analyzed using an inverse variance random-effects model. The risk of bias was assessed using the Newcastle-Ottawa Scale and funnel plots. RESULTS: A total of 11 studies comprising 76 patients were included. Nine studies involving 72 patients reported an estimated decrease of 4.43 points (95% confidence interval [CI]: 2.11; 6.75, p < 0.01) in UPDRS-III score, equivalent to a 14% reduction. The axial subscores in 48 patients decreased by 2.35 points (95% CI: 1.26; 3.45, p < 0.01, 20% reduction). The pooled effect size of five studies on back and leg pain VAS scores was calculated as 4.38 (95% CI: 2.67; 6.09, p < 0.001), equivalent to a 59% reduction. CONCLUSIONS: Our analysis suggests that SCS may provide significant motor and pain benefits for patients with PD, although the results should be interpreted with caution due to several potential limitations including study heterogeneity, open-label designs, small sample sizes, and the possibility of publication bias. Further research using larger sample sizes and placebo-/sham-controlled designs is needed to confirm effectiveness.

Long-term outcomes of mesial temporal laser interstitial thermal therapy for drug-resistant epilepsy and subsequent surgery for seizure recurrence: a multi-centre cohort study.

BACKGROUND: Magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) is a minimally invasive alternative to surgical resection for drug-resistant mesial temporal lobe epilepsy (mTLE). Reported rates of seizure freedom are variable and long-term durability is largely unproven. Anterior temporal lobectomy (ATL) remains an option for patients with MRgLITT treatment failure. However, the safety and efficacy of this staged strategy is unknown. METHODS: This multicentre, retrospective cohort study included 268 patients consecutively treated with mesial temporal MRgLITT at 11 centres between 2012 and 2018. Seizure outcomes and complications of MRgLITT and any subsequent surgery are reported. Predictive value of preoperative variables for seizure outcome was assessed. RESULTS: Engel I seizure freedom was achieved in 55.8% (149/267) at 1 year, 52.5% (126/240) at 2 years and 49.3% (132/268) at the last follow-up ≥1 year (median 47 months). Engel I or II outcomes were achieved in 74.2% (198/267) at 1 year, 75.0% (180/240) at 2 years and 66.0% (177/268) at the last follow-up. Preoperative focal to bilateral tonic-clonic seizures were independently associated with seizure recurrence. Among patients with seizure recurrence, 14/21 (66.7%) became seizure-free after subsequent ATL and 5/10 (50%) after repeat MRgLITT at last follow-up≥1 year. CONCLUSIONS: MRgLITT is a viable treatment with durable outcomes for patients with drug-resistant mTLE evaluated at a comprehensive epilepsy centre. Although seizure freedom rates were lower than reported with ATL, this series represents the early experience of each centre and a heterogeneous cohort. ATL remains a safe and effective treatment for well-selected patients who fail MRgLITT.

Ogilvie's syndrome after paddle spinal cord stimulator implantation: An experience report.

Spinal cord stimulation (SCS) is an emerging technology to treat chronic pain from complex regional pain syndrome (CPRS) neuropathy and post-laminectomy syndrome. A rarely reported postoperative complication of SCS paddle implantation is abdominal pain that can result from thoracic radiculopathy. Ogilvie's syndrome (OS) is a disorder characterized by acute dilatation of the colon in the absence of an anatomic lesion that obstructs the flow of intestinal contents, which has seldom been observed after spine surgery. Here, we describe the case of a 70-year-old male who developed OS after SCS paddle implantation resulting in cecal perforation and multi-system organ failure with lethal outcome. We discuss the pathophysiology, present a method measuring the spinal canal to cord ratio (CCR) to prevent the risk of thoracic radiculopathy and OS after paddle SCS implantation, and propose suggestions for management and treatment of this condition.

Evidence for Thalamic Responsive Neurostimulation in Treatment of Adult and Pediatric Epilepsy.

Responsive neurostimulation (RNS) has well-established efficacy in patients with identifiable seizure foci. Emerging evidence suggests the feasibility of expanding this treatment to patients with nonfocal or multifocal epileptic profiles with thalamic targeting. Our institution performed two successful implantations of thalamic RNS (tRNS) targeting the centromedian nucleus of the thalamus (CMT), and 1-year postoperative outcomes are provided. Additionally, a literature review of all reported tRNS was conducted. Publications were excluded if they did not include demographic data and/or epilepsy outcomes at follow-up. In the literature, 19 adult and 3 pediatric cases were identified. These cases were analyzed for outcome, indications, previous operations, and surgical practice variations. Both of our patients had failed multiple previous pharmacological and neurosurgical interventions for epilepsy. Case #1 underwent tRNS with bilateral CMT stimulation. Case #2 underwent tRNS with simultaneous right CMT and right insular stimulation, although an additional lead was placed in the left CMT and left capped for potential future use. Each has achieved ≥90% reduction in seizure burden and approach seizure freedom. 71% of patients in the literature review had multifocal, bilateral, or cryptogenic seizure onset. Three patients were implanted for Lennox Gastaut (2 of 3 are pediatric). 16 patients underwent an average of 1.6 failed procedures prior to successful tRNS implantation. Taken together, the 21 adult patients reviewed have experienced an average seizure reduction of 77% at the latest follow-up. 95% of the adult patients reported in the literature experienced >50% reduction in seizure activity following tRNS and 52% experienced ≥90% reduction in seizure burden following tRNS. Pediatric patients have experienced 70-100% improvement.

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.

Feasibility of Transcranial Motor Evoked Potentials and Electromyography during MRI-Guided Laser Interstitial Thermal Therapy for Glioblastoma.

BACKGROUND: Intraoperative neuromonitoring (IONM) is routinely used during neurosurgical procedures. Magnetic resonance imaging (MRI)-guided laser interstitial thermal therapy (LITT) is increasingly being used in patients with various brain lesions. Use of IONM (transcranial motor evoked potential [TcMEP] and electromyography [EMG]) during LITT of a brain lesion has not been described previously. METHODS: In this report, we describe a 70-year-old man who presented with motor weakness in whom imaging revealed a left thalamic lesion. Due to the difficulty in accessing the lesion and proximity to the motor tracts, patient was offered MRI-guided LITT using TcMEP and EMG. RESULTS: The patient underwent satisfactory ablation of the lesion with successful recording of the TcMEP and EMG. Technical nuances related to the set-up and procedure is discussed in this report. No procedure-related complications were encountered. CONCLUSIONS: We describe the first report of safety and feasibility of TcMEP and EMG during MRI-guided LITT for left thalamic glioblasatoma. This report paves the way for further prospective investigations regarding the utility of this technique for eloquent brain tumors.

A new paradigm for investigating real-world social behavior and its neural underpinnings.

Eye tracking and other behavioral measurements collected from patient-participants in their hospital rooms afford a unique opportunity to study natural behavior for basic and clinical translational research. We describe an immersive social and behavioral paradigm implemented in patients undergoing evaluation for surgical treatment of epilepsy, with electrodes implanted in the brain to determine the source of their seizures. Our studies entail collecting eye tracking with other behavioral and psychophysiological measurements from patient-participants during unscripted behavior, including social interactions with clinical staff, friends, and family in the hospital room. This approach affords a unique opportunity to study the neurobiology of natural social behavior, though it requires carefully addressing distinct logistical, technical, and ethical challenges. Collecting neurophysiological data synchronized to behavioral and psychophysiological measures helps us to study the relationship between behavior and physiology. Combining across these rich data sources while participants eat, read, converse with friends and family, etc., enables clinical-translational research aimed at understanding the participants' disorders and clinician-patient interactions, as well as basic research into natural, real-world behavior. We discuss data acquisition, quality control, annotation, and analysis pipelines that are required for our studies. We also discuss the clinical, logistical, and ethical and privacy considerations critical to working in the hospital setting.

Effects of deep brain stimulation target on the activation and suppression of action impulses.

OBJECTIVE: Deep brain stimulation (DBS) is an effective treatment to improve motor symptoms in Parkinson's disease (PD). The Globus Pallidus (GPi) and the Subthalamic Nucleus (STN) are the most targeted brain regions for stimulation and produce similar improvements in PD motor symptoms. However, our understanding of stimulation effects across targets on inhibitory action control processes is limited. We compared the effects of STN (n = 20) and GPi (n = 13) DBS on inhibitory control in PD patients. METHODS: We recruited PD patients undergoing DBS at the Vanderbilt Movement Disorders Clinic and measured their performance on an inhibitory action control task (Simon task) before surgery (optimally treated medication state) and after surgery in their optimally treated state (medication plus their DBS device turned on). RESULTS: DBS to both STN and GPi targets induced an increase in fast impulsive errors while simultaneously producing more proficient reactive suppression of interference from action impulses. CONCLUSIONS: Stimulation in GPi produced similar effects as STN DBS, indicating that stimulation to either target increases the initial susceptibility to act on strong action impulses while concomitantly improving the ability to suppress ongoing interference from activated impulses. SIGNIFICANCE: Action impulse control processes are similarly impacted by stimulating dissociable nodes in frontal-basal ganglia circuitry.

Combined Responsive Neurostimulation and Focal Resection for Super Refractory Status Epilepticus: A Systematic Review and Illustrative Case Report.

OBJECTIVE: Super-refractory status epilepticus (SRSE) is a neurologic emergency with high mortality and morbidity. Although medical algorithms typically are effective, when they do fail, options may be limited, and neurosurgical intervention should be considered. METHODS: We report a case of SRSE treated acutely with responsive neurostimulation (RNS) and focal surgical resection after intracranial monitoring. We also conducted a systematic review of the literature for neurosurgical treatment of SRSE (e.g., neurostimulation). Only published manuscripts were considered. RESULTS: Our patient's seizure semiology consisted of left facial twitching with frequent evolution to bilateral tonic-clonic convulsions. Stereoelectroencephalography and grid monitoring identified multiple seizure foci. The patient underwent right RNS placement with cortical strip leads over the lateral primary motor and premotor cortex as well as simultaneous right superior temporal and frontopolar resection. Status epilepticus resolved 21 days after surgical resection and placement of the RNS. The systematic review revealed 15 case reports describing 17 patients with SRSE who underwent acute neurosurgical intervention. There were 3 patients with SRSE with RNS placement as a single modality, all of whom experienced cessation of SE. Four patients with SRSE received vagus nerve stimulation (3 as a single modality and 1 with combined corpus callosotomy), of whom 1 had SE recurrence at 2weeks. Two patients with SRSE received deep brain stimulation, and the remaining 8 underwent surgical resection; none had recurrence of SE. CONCLUSIONS: RNS System placement with or without resection can be a viable treatment option for select patients with SRSE. Early neurosurgical intervention may improve seizure outcomes and reduce complications.

Developing Predictor Models of Postoperative Verbal Fluency After Deep Brain Stimulation Using Preoperative Neuropsychological Assessment.

BACKGROUND: Deep brain stimulation (DBS) for Parkinson disease provides significant improvement of motor symptoms but can also produce neurocognitive side effects. A decline in verbal fluency (VF) is among the most frequently reported side effects. Preoperative factors that could predict VF decline have yet to be identified. OBJECTIVE: To develop predictive models of DBS postoperative VF decline using a machine learning approach. METHODS: We used a prospective database of patients who underwent neuropsychological and VF assessment before both subthalamic nucleus (n = 47, bilateral = 44) and globus pallidus interna (n = 43, bilateral = 39) DBS. We used a neurobehavioral rating profile as features for modeling postoperative VF. We constructed separate models for action, semantic, and letter VF. We used a leave-one-out scheme to test the accuracy of the predictive models using median absolute error and correlation with actual postoperative scores. RESULTS: The predictive models were able to predict the 3 types of VF with high accuracy ranging from a median absolute error of 0.92 to 1.36. Across all three models, higher preoperative fluency, digit span, education, and Mini-Mental State Examination were predictive of higher postoperative fluency scores. By contrast, higher frontal system deficits, age, Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease scored by the patient, disease duration, and Behavioral Inhibition/Behavioral Activation Scale scores were predictive of lower postoperative fluency scores. CONCLUSION: Postoperative VF can be accurately predicted using preoperative neurobehavioral rating scores above and beyond preoperative VF score and relies on performance over different aspects of executive function.

Essential tremor impairs the ability to suppress involuntary action impulses.

Essential tremor (ET) is a movement disorder characterized primarily by action tremor which affects the regulation of movements. Disruptions in cerebello-thalamocortical networks could interfere with cognitive control over actions in ET, for example, the ability to suppress a strong automatic impulse over a more appropriate action (conflict control). The current study investigated whether ET impacts conflict control proficiency. Forty-one ET patients and 29 age-matched healthy controls (HCs) performed a conflict control task (Simon task). Participants were instructed to give a left or right response to a spatially lateralized arrow (direction of the arrow). When the action signaled by the spatial location and direction of the arrow were non-corresponding (induced conflict), the inappropriate action impulse required suppression. Overall, ET patients responded slower and less accurately compared to HCs. ET patients were especially less accurate on non-corresponding conflict (Nc) versus corresponding (Cs) trials. A focused analysis on fast impulsive response rates (based on the accuracy rate at the fastest reaction times on Nc trials) showed that ET patients made more fast errors compared to HCs. Results suggest impaired conflict control in ET compared to HCs. The increased impulsive errors seen in the ET population may be a symptom of deficiencies in the cerebello-thalamocortical networks, or, be caused by indirect effects on the cortico-striatal pathways. Future studies into the functional networks impacted by ET (cortico-striatal and cerebello-thalamocortical pathways) could advance our understanding of inhibitory control in general and the cognitive deficits in ET.

Enhanced Interplay of Neuronal Coherence and Coupling in the Dying Human Brain.

The neurophysiological footprint of brain activity after cardiac arrest and during near-death experience (NDE) is not well understood. Although a hypoactive state of brain activity has been assumed, experimental animal studies have shown increased activity after cardiac arrest, particularly in the gamma-band, resulting from hypercapnia prior to and cessation of cerebral blood flow after cardiac arrest. No study has yet investigated this matter in humans. Here, we present continuous electroencephalography (EEG) recording from a dying human brain, obtained from an 87-year-old patient undergoing cardiac arrest after traumatic subdural hematoma. An increase of absolute power in gamma activity in the narrow and broad bands and a decrease in theta power is seen after suppression of bilateral hemispheric responses. After cardiac arrest, delta, beta, alpha and gamma power were decreased but a higher percentage of relative gamma power was observed when compared to the interictal interval. Cross-frequency coupling revealed modulation of left-hemispheric gamma activity by alpha and theta rhythms across all windows, even after cessation of cerebral blood flow. The strongest coupling is observed for narrow- and broad-band gamma activity by the alpha waves during left-sided suppression and after cardiac arrest. Albeit the influence of neuronal injury and swelling, our data provide the first evidence from the dying human brain in a non-experimental, real-life acute care clinical setting and advocate that the human brain may possess the capability to generate coordinated activity during the near-death period.

The American Society for Stereotactic and Functional Neurosurgery Position Statement on Laser Interstitial Thermal Therapy for the Treatment of Drug-Resistant Epilepsy.

Magnetic resonance image-guided laser interstitial thermal therapy (MRgLITT) is a novel tool in the neurosurgical armamentarium for the management of drug-resistant epilepsy. Given the recent introduction of this technology, the American Society for Stereotactic and Functional Neurosurgery (ASSFN), which acts as the joint section representing the field of stereotactic and functional neurosurgery on behalf of the Congress of Neurological Surgeons and the American Association of Neurological Surgeons, provides here the expert consensus opinion on evidence-based best practices for the use and implementation of this treatment modality. Indications for treatment are outlined, consisting of failure to respond to, or intolerance of, at least 2 appropriately chosen medications at appropriate doses for disabling, localization-related epilepsy in the setting of well-defined epileptogenic foci, or critical pathways of seizure propagation accessible by MRgLITT. Applications of MRgLITT in mesial temporal lobe epilepsy and hypothalamic hamartoma, along with its contraindications in the treatment of epilepsy, are discussed based on current evidence. To put this position statement in perspective, we detail the evidence and authority on which this ASSFN position statement is based.

Incidence of repeat procedures and healthcare utilization following surgery, radiosurgery, and percutaneous procedures in elderly patients with trigeminal neuralgia.

OBJECTIVE: Management of trigeminal neuralgia (TN) in elderly patients poses significant challenges. The impact of different treatment modalities (surgery, radiosurgery [RS], and percutaneous techniques [PTs]) on healthcare utilization is not well defined in the management of TN in elderly patients. The aim of this study was to compare the long-term healthcare utilization metrics of different interventions in the management of elderly patients with TN. METHODS: The MarketScan database was queried using the International Classification of Diseases, Ninth Revision and Current Procedural Terminology, from 2000 to 2016. TN patients ≥ 65 years of age managed using surgery, RS, and PTs with at least 5 years of follow-up after the index procedure were included. Outcomes analyzed were hospital admissions, outpatient services, and medication refills. RESULTS: Of 993 patients, 43% (n = 430) underwent RS, 44% (n = 432) had PTs, and only 13% (n = 131) underwent surgery for TN. Overall, the median age of patients was 74 years old, 64% were females, 90% had Medicare insurance, and 17% had an Elixhauser index ≥ 3. Patients in the surgery group were younger (median age 71 years) with a higher comorbidity index (≥ 3; 24%) compared with patients undergoing RS and PTs (13% and 17%, respectively). At 1, 2, and 5 years after the index procedure, 41%, 48%, and 57% of patients in the PT cohort underwent any repeat procedure compared with 11%, 18%, and 29% for the RS cohort, and 6%, 9%, and 11% for the surgical cohort, respectively. Also, patients in the PT cohort incurred 1.8, 1.9, and 2.0 times the combined payment at 1, 2, and 5 years, respectively, compared with the surgery cohort. Similarly, patients who underwent RS for TN incurred 1.4, 1.5, and 1.5 times the combined payment at 1, 2, and 5 years, respectively, compared with the surgery cohort. At 5 years after the index procedure, combined payments for the PT cohort were $79,753 (IQR $46,013, $144,064) compared with $61,016 (IQR $27,114, $117,097) for the RS cohort and $41,074 (IQR $25,392, $87,952) for the surgery cohort (p < 0.0001). CONCLUSIONS: PTs followed by RS were the common procedures used in the majority of elderly patients with TN. However, surgery for TN resulted in durable control with the least need for reoperations up to 5 years after the index procedure, followed by RS and PTs. PTs for TN resulted in the highest utilization of healthcare resources and need for reoperations at all time points. These findings should be considered in clinical decision-making when selecting appropriate treatment modalities in elderly patients with TN.

BDNF rs6265 Genotype Influences Outcomes of Pharmacotherapy and Subthalamic Nucleus Deep Brain Stimulation in Early-Stage Parkinson's Disease.

INTRODUCTION: The efficacy of pharmacotherapy and deep brain stimulation of the subthalamic nucleus in treating Parkinson's disease motor symptoms is highly variable and may be influenced by patient genotype. The relatively common (prevalence about one in three) and protein-altering rs6265 single nucleotide polymorphism (C > T) in the gene BDNF has been associated with different clinical outcomes with levodopa. OBJECTIVE: We sought to replicate this reported association in early-stage Parkinson's disease subjects and to examine whether a difference in clinical outcomes was present with subthalamic nucleus deep brain stimulation. MATERIALS AND METHODS: Fifteen deep brain stimulation and 13 medical therapy subjects were followed for 24 months as part of the Vanderbilt DBS in Early Stage PD clinical trial (NCT00282152, FDA IDE #G050016). Primary outcome measures were the Unified Parkinson's Disease Rating Scale (UPDRS) and Parkinson's Disease Questionnaire-39. RESULTS: Outcomes with drug therapy in subjects carrying the rs6265 T allele were significantly worse following 12 months of treatment compared to C/C subjects (UPDRS: +20 points, p = 0.019; PDQ-39: +16 points, p = 0.018). In contrast, rs6265 genotype had no effect on overall motor response to subthalamic nucleus deep brain stimulation at any time point; further, rs6265 C/C subjects treated with stimulation were associated with worse UPDRS part II scores at 24 months compared to medical therapy. CONCLUSIONS: Genotyping for the rs6265 polymorphism may be useful for predicting long-term response to drug therapy and counseling Parkinson's disease patients regarding whether to consider earlier subthalamic nucleus deep brain stimulation. Validation in a larger cohort of early-stage Parkinson's disease subjects is warranted.

Targeting for stereotactic radiosurgical thalamotomy based on tremor treatment response.

OBJECTIVE: Stereotactic radiosurgery (SRS) treats severe, medically refractory essential tremor and tremor-dominant Parkinson disease. However, the optimal target for SRS treatment within the thalamic ventral intermediate nucleus (VIM) is not clearly defined. This work evaluates the precision of the physician-selected VIM target, and determines the optimal SRS target within the VIM by correlation between early responders and nonresponders. METHODS: Early responders and nonresponders were assessed retrospectively by Elements Basal Ganglia Atlas autocontouring of the VIM on the pre-SRS-treatment 1-mm slice thickness T1-weighted MRI and correlating the center of the post-SRS-treatment lesion. Using pre- and posttreatment diffusion tensor imaging, the fiber tracking package in the Elements software generated tremor-related tracts from autosegmented motor cortex, thalamus, red nucleus, and dentate nucleus. Autocontouring of the VIM was successful for all patients. RESULTS: Among 23 patients, physician-directed SRS targets had a medial-lateral target range from +2.5 mm to -2.0 mm from the VIM center. Relative to the VIM center, the SRS isocenter target was 0.7-0.9 mm lateral for 6 early responders and 0.9-1.1 mm medial for 4 nonresponders (p = 0.019), and without differences in the other dimensions: 0.2 mm posterior and 0.6 mm superior. Dose-volume histogram analyses for the VIM had no significant differences between responders and nonresponders between 20 Gy and 140 Gy, mean or maximum dose, and dose to small volumes. Tractography data was obtained for 4 patients. CONCLUSIONS: For tremor control in early responders, the Elements Basal Ganglia Atlas autocontour for the VIM provides the optimal SRS target location that is 0.7-0.9 mm lateral to the VIM center.

Noninvasive Thalamotomy for Refractory Tremor by Frameless Radiosurgery.

PURPOSE: We sought to determine whether a more widely accessible, noninvasive, frameless approach to radiosurgical thalamotomy would improve objective measures of refractory essential or parkinsonian tremor without added toxicity compared with reports of frame-based radiosurgery. METHODS AND MATERIALS: We conducted a single-arm pilot observational prospective trial of adult patients with essential or parkinsonian tremor from 2013 to 2019 and report results at 1-year follow-up. Patients were treated with frameless unilateral radiosurgical ablation of the thalamic ventral intermediate nucleus to a maximum dose of 160 Gy. Treatment response was measured by the Fahn-Tolosa-Marin (FTM) tremor rating scale and the Quality of Life in Essential Tremor or Parkinson's Disease Questionnaire obtained before treatment and at 3, 6, 9, and 12 months. RESULTS: Thirty-three patients, including 23 with essential tremor and 10 with Parkinson's disease, were enrolled. Overall treatment response rate per FTM was 83% (15 of 18) at 6 months. There was a marked improvement in tremor, with an average total FTM reduction of 21% at 3 months (from 46 to 30 points; P = .003) and 41% at 6 months (from 46 to 24 points; P = .001). At 6 months, functional decline had regressed by 54% (from 15 to 7 points; P = .001). Quality of life improved by 57% (P = .001) at 6 months in patients with essential tremor, and patients with Parkinson's disease had unchanged quality of life. At 1-year follow-up, grade 2 neurologic adverse events were observed in 6% (2 of 33) of patients without any grade ≥ 3 events. CONCLUSION: Noninvasive, frameless radiosurgical thalamotomy may be a feasible treatment for patients with refractory tremor and demonstrates short-term safety at 1-year follow-up. This pilot study provides promising preliminary descriptions of efficacy, and definitive estimates of long-term safety and benefit require further study with longer follow-up.