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.

Nutritional Formulation for Patients with Angelman Syndrome: A Randomized, Double-Blind, Placebo-Controlled Study of Exogenous Ketones.

BACKGROUND: Angelman syndrome (AS) patients often respond to low glycemic index therapy to manage refractory seizures. These diets significantly affect quality of life and are challenging to implement. These formulations may have benefits in AS even in the absence of biomarkers suggesting ketosis. OBJECTIVES: We aimed to compare an exogenous medical food ketone formulation (KF) with placebo for the dietary management of AS. METHODS: This randomized, double-blind, placebo-controlled, crossover clinical trial was conducted in an academic center from 15 November, 2018 to 6 January, 2020. Thirteen participants with molecularly confirmed AS aged 4-11 y met the criteria and completed the 16-wk study. The study consisted of four 4-wk phases: a baseline phase, a blinded KF or placebo phase, a washout phase, and the crossover phase with alternate blinded KF or placebo. Primary outcomes were safety and tolerability rated by retention in the study and adherence to the formulation. Additional secondary outcomes of safety in this nonverbal population included blood chemistry, gastrointestinal health, seizure burden, cortical irritability, cognition, mobility, sleep, and developmental staging. RESULTS: Data were compared between the baseline, KF, and placebo epochs. One participant exited the trial owing to difficulty consuming the formulation. Adverse events included an increase in cholesterol in 1 subject when consuming KF and a decrease in albumin in 1 subject when consuming placebo. Stool consistency improved with KF consumption, from 6.04 ± 1.61 at baseline and 6.35 ± 1.55 during placebo to 4.54 ± 1.19 during KF (P = 0.0027). Electroencephalograph trends showed a decrease in Δ frequency power during the KF arm and event-related potentials suggested a change in the frontal memory response. Vineland-3 showed improved fine motor skills in the KF arm. CONCLUSIONS: The exogenous KF appears safe. More data are needed to determine the utility of exogenous ketones as a nutritional approach in children with AS.This trial was registered at clinicaltrials.gov as NCT03644693.

A comparative evaluation of telehealth and direct assessment when screening for spasticity in residents of two long-term care facilities.

OBJECTIVE: To evaluate the performance of telehealth as a screening tool for spasticity compared to direct patient assessment in the long-term care setting. DESIGN: Cross-sectional, observational study. SETTING: Two long-term care facilities: a 140-bed veterans' home and a 44-bed state home for individuals with intellectual and developmental disabilities. SUBJECTS: Sixty-one adult residents of two long-term care facilities (aged 70.1 ± 16.2 years) were included in this analysis. Spasticity was identified in 43% of subjects (Modified Ashworth Scale rating mode = 2). Contributing diagnoses included traumatic brain injury, spinal cord injury, birth trauma, stroke, cerebral palsy, and multiple sclerosis. MAIN MEASURES: Movement disorders neurologists conducted in-person examinations to determine whether spasticity was present (reference standard) and also evaluated subjects with spasticity using the Modified Ashworth Scale. Telehealth screening examinations, facilitated by a bedside nurse, were conducted remotely by two teleneurologists using a three-question screening tool. Telehealth screening determinations of spasticity were compared to the reference standard determination to calculate sensitivity, specificity, and the area under the curve (AUC) in receiver operating characteristics. Teleneurologist agreement was evaluated using Cohen's kappa. RESULTS: Teleneurologist 1 had a specificity of 89% and sensitivity of 65% to identify the likely presence of spasticity (n = 61; AUC = 0.770). Teleneurologist 2 showed 100% specificity and 82% sensitivity (n = 16; AUC = 0.909). There was almost perfect agreement between the two examiners at 94% (kappa = 0.875, 95% CI: 0.640-1.000). CONCLUSION: Telehealth may provide a useful, efficient method of identifying residents of long-term care facilities that likely need referral for spasticity evaluation.

Action Control Deficits in Patients With Essential Tremor.

OBJECTIVES: Essential tremor (ET) is a movement disorder characterized by action tremor which impacts motor execution. Given the disrupted cerebellar-thalamo-cortical networks in ET, we hypothesized that ET could interfere with the control mechanisms involved in regulating motor performance. The ability to inhibit or stop actions is critical for navigating many daily life situations such as driving or social interactions. The current study investigated the speed of action initiation and two forms of action control, response stopping and proactive slowing in ET. METHODS: Thirty-three ET patients and 25 healthy controls (HCs) completed a choice reaction task and a stop-signal task, and measures of going speed, proactive slowing and stop latencies were assessed. RESULTS: Going speed was significantly slower in ET patients (649 ms) compared to HCs (526 ms; F(1,56) = 42.37; p <.001; η 2 = .43), whereas proactive slowing did not differ between groups. ET patients exhibited slower stop signal reaction times (320 ms) compared to HCs (258 ms, F(1,56) = 15.3; p <.00; η 2 = .22) and more severe motor symptoms of ET were associated with longer stopping latencies in a subset of patients (Spearman rho = .48; p <.05). CONCLUSIONS: In line with previous studies, ET patients showed slower action initiation. Additionally, inhibitory control was impaired whereas proactive slowing remained intact relative to HCs. More severe motor symptoms of ET were associated with slower stopping speed, and may reflect more progressive changes to the cerebellar-thalamo-cortical network. Future imaging studies should specify which structural and functional changes in ET can explain changes in inhibitory action control. (JINS, 2019, 25, 156-164).

Motivational Sensitivities Linked to Impulsive Motor Errors in Parkinson's Disease.

OBJECTIVES: We investigated how broad motivational tendencies are related to the expression and suppression of action impulses in Parkinson's disease (PD). METHODS: Sixty-nine participants with PD completed a Simon response conflict task and Behavioral Inhibition System (BIS) and Behavioral Activation System (BAS) scales based on Gray's (1987) reinforcement sensitivity theory. Analyses determined relationships between BIS, BAS, and the susceptibility to making impulsive action errors and the proficiency of inhibiting interference from action impulses. RESULTS: BIS scores correlated positively with rates of impulsive action errors, indicating that participants endorsing low BIS tendencies were much more susceptible to acting on strong motor impulses. Analyses of subgroups with high versus low BIS scores confirmed this pattern and ruled out alternative explanations in terms of group differences in speed-accuracy tradeoffs. None of the scores on the BIS or BAS scales correlated with reactive inhibitory control. CONCLUSIONS: PD participants who endorse diminished predilection toward monitoring and avoiding aversive experiences (low BIS) show much greater difficulty restraining fast, impulsive motor errors. Establishing relationships between motivational sensitivities and cognitive control processes may have important implications for treatment strategies and positive health outcomes in participants with PD, particularly those at risk for falling and driving difficulties related to impulsive reactions. (JINS, 2018, 24, 128-138).

Confined Thalamic Deep Brain Stimulation in Refractory Essential Tremor.

BACKGROUND: Thalamic ventral intermediate nucleus (VIM) deep brain stimulation (DBS) is an effective therapy for medication-refractory essential tremor (ET). However, 13-40% of patients with an initially robust tremor efficacy lose this benefit over time despite reprogramming attempts. At our institution, a cohort of ET patients with VIM DBS underwent implantation of a second anterior (ventralis oralis anterior; VOA) DBS lead to permit "confined stimulation." We sought to assess whether confined stimulation conferred additional tremor capture compared to VIM or VOA stimulation alone. METHODS: Seven patients participated in a protocol-based programming session during which a video-recorded Fahn-Tolosa-Marin Part A (FTM-A) tremor rating scale was used in the following 4 DBS states: off stimulation, VIM stimulation alone, VOA stimulation alone, and dual lead (confined) stimulation. RESULTS: The average (SD) baseline FTM-A off score was 17.6 (4.0). VIM stimulation alone lowered the average FTM-A total score to 6.9 (4.0). Confined stimulation further attenuated the tremor, reducing the total score to 5.7 (2.8). CONCLUSIONS: Confined thalamic DBS can provide additional symptomatic benefits in patients with unsatisfactory tremor control from VIM or VOA stimulation alone.

Parkinson's Disease Subtypes Show Distinct Tradeoffs Between Response Initiation and Inhibition Latencies.

OBJECTIVES: In unpredictable situations, individuals often show tradeoffs between response initiation and inhibition speeds. We tested the hypothesis that Parkinson's disease (PD) motor subtypes differentially impact tradeoffs between these two action-oriented processes. We predicted that, compared to tremor dominant (TD) patients, predominant postural instability and gait dysfunction (PIGD) patients would show exacerbated tradeoffs between response initiation and inhibition in situations requiring the sudden potential need to interrupt an action. METHODS: Fifty-one PD patients (subdivided into PIGD [n=27] and TD [n=24]) and 21 healthy controls (HCs) completed a choice reaction task to establish baseline response initiation speed between groups. Subsequently, participants completed a stop-signal task which introduced an occasional, unpredictable stop stimulus. We measured changes in initiation speed in preparation of an unpredictable stop (i.e., proactive slowing) and inhibition latency (i.e., stop-signal reaction time). RESULTS: Compared to HCs, PD patients showed slower response initiation speeds in the choice reaction task. All groups showed proactive slowing in the stop-signal task but the magnitude was considerably larger in PIGD patients, almost twice as large as TD patients. PD patients, irrespective of motor subtype, showed longer inhibition latencies than HCs. CONCLUSIONS: PIGD and TD subtypes both showed exacerbated response inhibition deficits. However, PIGD patients showed much more pronounced proactive slowing in situations with an expected yet unpredictable need to stop action abruptly. This suggests that PIGD is accompanied by exaggerated tradeoffs between response initiation and inhibition processes to meet situational action demands. We discuss putative neural mechanisms and clinical implications of these findings. (JINS, 2017, 23, 665-674).

Generalized motor inhibitory deficit in Parkinson's disease patients who freeze.

Freezing of gait is a disabling symptom of Parkinson's disease (PD) that involves failure to initiate and continue motor activity appropriately. PD disrupts fronto-basal ganglia circuitries that also implement the inhibition of responses, leading to the hypothesis that freezing of gait may involve fundamental changes in both initiation and inhibition of motor actions. We asked whether PD patients who show freezing of gait show selective deficits in their ability to inhibit upper and lower extremity reactions. We compared older healthy controls, older PD controls without freezing of gait, and older PD participants with freezing of gait, in stop-signal tasks that measured the initiation (go trials) and inhibition (stop trials) of both hand and foot responses. When only go trials were presented, all three groups showed similar initiation speeds across lower and upper extremity responses. When stop-signal trials were introduced, both PD groups slowed their reactions nearly twice as much as healthy controls. While this adjustment helped PD controls stop their actions as quickly as healthy controls, PD patients with freezing showed significantly delayed inhibitory control of both upper and lower extremities. When anticipating the need to stop their actions urgently, PD patients show greater adjustments (i.e., slowing) to reaction speed than healthy controls. Despite these proactive adjustments, PD patients who freeze show marked impairments in inhibiting both upper and lower extremity responses, suggesting that freezing may involve a fundamental disruption to the brain's inhibitory control system.

The optimal pallidal target in deep brain stimulation for dystonia: a study using a functional atlas based on nonlinear image registration.

BACKGROUND: Deep brain stimulation (DBS) of the globus pallidus internus is established as efficacious for dystonia, yet the optimal target within this structure is not well defined. Published evidence suggests that spatial normalization provides a better estimate of DBS lead location than traditional methods based on standard stereotactic coordinates. METHODS: We retrospectively reviewed our pallidal implanted dystonia population. Patient imaging scans were morphed into an MRI atlas using a nonlinear image registration algorithm. Active contact locations were projected onto the atlas and clusters analyzed for the degree of variance in two groups: (1) good and poor responders and (2) cervical (CD) and generalized dystonia (GD). RESULTS: The average active contact location between CD and GD good responders was distinct but not significantly different. The mean active contact for CD poor responders was significantly different from CD responders and GD poor responders in the dorsoventral direction. CONCLUSIONS: A normalized imaging space is arguably more accurate in visualizing postoperative leads. Despite some separation between groups, this data suggests there was not an optimal pallidal target for common dystonia patients. Degrees of variance overlapped due to a large degree of individual target variation. Patient selection may ultimately be the key to maximizing patient outcomes.

The factors involved in deep brain stimulation infection: a large case series.

BACKGROUND: Deep brain stimulation (DBS) is a proven treatment for various movement disorders resistant to medical management. Complications such as postsurgical infection can negate benefits and increase patient morbidity. We sought to better define risk factors for infection. METHODS: We performed a review of DBS cases at our institution from January 1996 to June 2011. Information on multiple metrics including surgical complications, procedural complications and infection were entered into a secure online database. RESULTS: A total of 447 patients received DBS surgery. Twenty-six (5.82%) developed infection sometime after DBS surgery with 9 (2.01%) developing infection within 30 days after the final staged surgery. Operating surgeon (p = 0.012), scalp erosion (p = 0.0001), surgical incision opening time (0.0001) and number of individuals in the operating room (0.0027) were significant in the cumulative infection group. CONCLUSION: The 30-day infection rate was comparably low to other published studies. Several factors were noted to be significant in the cumulative infection group, but none in the 30-day infection group. Further understanding of infection risk factors is important to optimize patient selection and standardize infection-preventative techniques.

60-Hz frequency effect on gait in Parkinson's disease with subthalamic nucleus deep brain stimulation.

OBJECTIVE: Gait dysfunction is common in advancing Parkinson's disease and has a disappointing response to dopamine replacement and subthalamic nucleus deep brain stimulation programming parameters. Low-frequency stimulation, less than 130 Hz in combination with increased voltage, has been shown to decrease freezing episodes and number of steps with little impact on overall performance measured by the Unified Parkinson's Disease Rating Scale. This was in the setting of delivering the same total energy, which required both a change in voltage and frequency. We wanted to determine if the benefit came from low frequency alone. MATERIALS AND METHODS: We enrolled 20 Parkinson's patients who were at least three months in postbilateral subthalamic deep brain stimulation and reported gait changes. Subjects held their Parkinson's medications overnight, and following a baseline evaluation, they were randomly assigned to both 60 and 130 Hz stimulation in a blinded fashion with all other parameters held constant. Each subject was set at each frequency twice during the study, with a 60-min stimulation interval prior to each gait evaluation. RESULTS: There was no significant difference between the two frequencies, with the primary outcome measure of stride length. Two of the 20 patients reported a significant subjective improvement in their gait with no statistical difference in their outcomes. There also was less tremor control at 60 Hz. CONCLUSION: We were unable to demonstrate improved gait with lower frequency stimulation as suggested by prior studies. This may have been because of the decreased energy delivered from the lower frequency and unchanged voltage.

Neurologist consistency in interpreting information provided by an interactive visualization software for deep brain stimulation postoperative programming assistance.

INTRODUCTION: Postoperative programming in deep brain stimulation (DBS) therapy for movement disorders can be challenging and time consuming. Providing the neurologist with tools to visualize the electrode location relative to the patient's anatomy along with models of tissue activation and statistical data can therefore be very helpful. In this study, we evaluate the consistency between neurologists in interpreting and using such information provided by our DBS programming assistance software. METHODS: Five neurologists experienced in DBS programming were each given a dataset of 29 leads implanted in 17 patients. For each patient, probabilistic maps of stimulation response, anatomical images, models of tissue activation volumes, and electrode positions were presented inside a software framework called CRAnialVault Explorer (CRAVE) developed in house. Consistency between neurologists in optimal contact selection using the software was measured. RESULTS: With only the efficacy map, the average consistency among the five neurologists with respect to the mode and mean of their selections was 97% and 95%, respectively, while these numbers were 93% and 89%, respectively, when both efficacy and an adverse effect map were used simultaneously. Fleiss' kappa statistic also showed very strong agreement among the neurologists (0.87 when using one map and 0.72 when using two maps). CONCLUSION: Our five neurologists demonstrated high consistency in interpreting information provided by the CRAVE interactive visualization software for DBS postoperative programming assistance. Three of our five neurologists had no prior experience with the software, which suggests that the software has a short learning curve and contact selection is not dependent on familiarity with the program tools.

Improving Medication Management for Inpatients with a Secondary Diagnosis of Parkinson Disease.

ABSTRACT: Patients who have Parkinson disease require individualized medication regimens to optimize care. A review of the medication management of patients admitted to a tertiary care hospital with a secondary diagnosis of Parkinson disease found significant departures from the patients' home regimen. Medication regimens are often altered by health care teams unfamiliar with Parkinson disease-specific care in order to conform to standard hospital medication orders and administration times, potentially resulting in increased patient falls, delirium, and mortality.A nurse-led multidisciplinary team consisting of pharmacy, nursing, informatics, neurology, and quality personnel implemented a quality improvement (QI) project between July 2020 and July 2022 to identify patients with Parkinson disease, including those with a secondary diagnosis and those undergoing deep brain stimulation, and customize medication management in order to reduce length of stay, mortality, falls, falls with harm, and 30-day readmissions. The QI project team also evaluated patient satisfaction with medication management.Among patients with a secondary diagnosis of Parkinson disease, the proportion who had medication histories conducted by a pharmacy staff member increased from a baseline of 53% to more than 75% per month. For all patients with Parkinson disease, those whose medication history was taken by a pharmacy staff member had orders matching their home regimen 89% of the time, whereas those who did not had orders matching the home regimen only 40% of the time. Among patients with a secondary diagnosis of Parkinson disease, the length-of-stay index decreased from a baseline of 1 to 0.94 and observed-to-expected mortality decreased from 1.03 to 0.78. The proportion of patients experiencing a fall decreased from an average of 5% to 4.08% per quarter, while the proportion of patients experiencing a fall with harm decreased from an average of 1% to 0.75% per quarter. The rate of 30-day readmissions decreased from 10.81% to 4.53% per quarter. Patient satisfaction scores were 1.95 points higher for patients who had medication histories taken by pharmacy than for those who did not (5 versus 3.05).

Randomized Controlled Comparative Effectiveness Trial of Risk Model-Guided Clinical Decision Support for Suicide Screening.

Suicide prevention requires risk identification, appropriate intervention, and follow-up. Traditional risk identification relies on patient self-reporting, support network reporting, or face-to-face screening with validated instruments or history and physical exam. In the last decade, statistical risk models have been studied and more recently deployed to augment clinical judgment. Models have generally been found to be low precision or problematic at scale due to low incidence. Few have been tested in clinical practice, and none have been tested in clinical trials to our knowledge. Methods: We report the results of a pragmatic randomized controlled trial (RCT) in three outpatient adult Neurology clinic settings. This two-arm trial compared the effectiveness of Interruptive and Non-Interruptive Clinical Decision Support (CDS) to prompt further screening of suicidal ideation for those predicted to be high risk using a real-time, validated statistical risk model of suicide attempt risk, with the decision to screen as the primary end point. Secondary outcomes included rates of suicidal ideation and attempts in both arms. Manual chart review of every trial encounter was used to determine if suicide risk assessment was subsequently documented. Results: From August 16, 2022, through February 16, 2023, our study randomized 596 patient encounters across 561 patients for providers to receive either Interruptive or Non-Interruptive CDS in a 1:1 ratio. Adjusting for provider cluster effects, Interruptive CDS led to significantly higher numbers of decisions to screen (42%=121/289 encounters) compared to Non-Interruptive CDS (4%=12/307) (odds ratio=17.7, p-value <0.001). Secondarily, no documented episodes of suicidal ideation or attempts occurred in either arm. While the proportion of documented assessments among those noting the decision to screen was higher for providers in the Non-Interruptive arm (92%=11/12) than in the Interruptive arm (52%=63/121), the interruptive CDS was associated with more frequent documentation of suicide risk assessment (63/289 encounters compared to 11/307, p-value<0.001). Conclusions: In this pragmatic RCT of real-time predictive CDS to guide suicide risk assessment, Interruptive CDS led to higher numbers of decisions to screen and documented suicide risk assessments. Well-powered large-scale trials randomizing this type of CDS compared to standard of care are indicated to measure effectiveness in reducing suicidal self-harm. ClinicalTrials.gov Identifier: NCT05312437.

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.

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.

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.

Predicting Motor Responsiveness to Deep Brain Stimulation with Machine Learning.

Deep brain stimulation is a complex movement disorder intervention that requires highly invasive brain surgery. Clinicians struggle to predict how patients will respond to this treatment. To address this problem, we are working toward developing a clinical tool to help neurologists predict deep brain stimulation response. We analyzed a cohort of 105 Parkinson's patients who underwent deep brain stimulation at Vanderbilt University Medical Center. We developed binary and multicategory models for predicting likelihood of motor symptom reduction after undergoing deep brain stimulation. We compared the performances of our best models to predictions made by neurologist experts in movement disorders. The strongest binary classification model achieved a 10-fold cross validation AUC of 0.90, outperforming the best neurologist predictions (0.56). These results are promising for future clinical applications, though more work is necessary to validate these findings in a larger cohort and taking into consideration broader quality of life outcome measures.

Early subthalamic nucleus deep brain stimulation in Parkinson's disease reduces long-term medication costs.

INTRODUCTION: Subthalamic nucleus (STN) deep brain stimulation (DBS) is recognized as a safe and effective treatment in mid- and advanced-staged Parkinson's disease (PD) that decreases the need for PD medications and their associated costs. This study reports medication costs from the only clinical trial to evaluate DBS in patients with early-stage PD and projects costs through advanced-stage disease. METHODS: The DBS in early-stage PD pilot was a prospective, single-blind clinical trial that randomized 30 patients with early-stage PD 1:1 to receive bilateral STN-DBS plus optimal drug therapy (ODT) or ODT alone. Subjects who completed the trial participated in an observational follow-up study and were evaluated annually for five years after randomization. PD medication data collected at each study visit were used to calculate and project medication costs (n = 28). RESULTS: Five-year cumulative medication cost reduction with early DBS+ODT was $28,246. Mean annual medication cost for early DBS+ODT subjects was 2.4 times lower than early ODT subjects (ß = 2.4, 95%CI:1.5-3.7, p = 0.0004). Early DBS+ODT is projected to reduce cumulative medication costs by $104,958 over 15 years of disease duration. CONCLUSION: DBS in early-stage PD may provide long-term medication cost reduction compared to standard care.