Differential Responses to Low- and High-Frequency Subthalamic Nucleus Deep Brain Stimulation on Sensor-Measured Components of Bradykinesia in Parkinson's Disease.

INTRODUCTION: The current approach to assessing bradykinesia in Parkinson's Disease relies on the Unified Parkinson's Disease Rating Scale (UPDRS), which is a numeric scale. Inertial sensors offer the ability to probe subcomponents of bradykinesia: motor speed, amplitude, and rhythm. Thus, we sought to investigate the differential effects of high-frequency compared to low-frequency subthalamic nucleus (STN) deep brain stimulation (DBS) on these quantified facets of bradykinesia. METHODS: We recruited advanced Parkinson's Disease subjects with a chronic bilateral subthalamic nucleus (STN) DBS implantation to a single-blind stimulation trial where each combination of medication state (OFF/ON), electrode contacts, and stimulation frequency (60 Hz/180 Hz) was assessed. The Kinesia One sensor system was used to measure upper limb bradykinesia. For each stimulation trial, subjects performed extremity motor tasks. Sensor data were recorded continuously. We identified STN DBS parameters that were associated with improved upper extremity bradykinesia symptoms using a mixed linear regression model. RESULTS: We recruited 22 subjects (6 females) for this study. The 180 Hz STN DBS (compared to the 60 Hz STN DBS) and dopaminergic medications improved all subcomponents of upper extremity bradykinesia (motor speed, amplitude, and rhythm). For the motor rhythm subcomponent of bradykinesia, ventral contacts yielded improved symptom improvement compared to dorsal contacts. CONCLUSION: The differential impact of high- and low-frequency STN DBS on the symptoms of bradykinesia may advise programming for these patients but warrants further investigation. Wearable sensors represent a valuable addition to the armamentarium that furthers our ability to conduct objective, quantitative clinical assessments.

Why are clinical trials of deep brain stimulation terminated? An analysis of clinicaltrials.gov.

Background: Although deep brain stimulation (DBS) has established uses for patients with movement disorders and epilepsy, it is under consideration for a wide range of neurologic and neuropsychiatric conditions. Objective: To review successful and unsuccessful DBS clinical trials and identify factors associated with early trial termination. Methods: The ClinicalTrials.gov database was screened for all studies related to DBS. Information regarding condition of interest, study aim, trial design, trial success, and, if applicable, reason for failure was collected. Trials were compared and logistic regression was utilized to identify independent factors associated with trial termination. Results: Of 325 identified trials, 79.7% were successful and 20.3% unsuccessful. Patient recruitment, sponsor decision, and device issues were the most cited reasons for termination. 242 trials (74.5%) were interventional with 78.1% successful. There was a statistically significant difference between successful and unsuccessful trials in number of funding sources (p = 0.0375). NIH funding was associated with successful trials while utilization of other funding sources (academic institutions and community organizations) was associated with unsuccessful trials. 83 trials (25.5%) were observational with 84.0% successful; there were no statistically significant differences between successful and unsuccessful observational trials. Conclusion: One in five clinical trials for DBS were found to be unsuccessful, most commonly due to patient recruitment difficulties. The source of funding was the only factor associated with trial success. As DBS research continues to grow, understanding the current state of clinical trials will help design successful future studies, thereby minimizing futile expenditures of time, cost, and patient engagement.

An Institutional Experience of Directional Deep Brain Stimulation and a Review of the Literature.

INTRODUCTION: Directional deep brain stimulation (dDBS) has been suggested to have a similar therapeutic effect when compared with the traditional omnidirectional DBS, but with an improved therapeutic window that yields optimized clinical effect owing to the ability to better direct, or "steer," electric current. We present our single-center, retrospective analysis of our experience in the use of dDBS in patients with movement disorders and provide a review of the literature. MATERIALS AND METHODS: We identified all patients with Parkinson disease (PD) and essential tremor (ET) who received a dDBS system between 2018 and 2022 and retrospectively examined characteristics of their longitudinal treatment. A total of 70 leads were identified across 42 patients (28 PD, 14 ET). RESULTS: Three types of systems were implemented (single-segment activation, 45.2% of patients; multiple independent current control, 50.0%; and local field potential sensing-enabled, 4.7%). The subthalamic nucleus or globus pallidus internus was targeted in PD, and the ventral intermediate nucleus of the thalamus in ET. Across the entire cohort (n = 70 leads), at initial programming, 54.2% of leads (n = 38) were programmed using directional stimulation. At the most recent reprogramming, 58.6% of leads (n = 41) implemented directionality. In patients with PD, the average decrease in levodopa-equivalent daily dose at six months after implantation was 35.4% ± 39.2%. Despite the ability to steer current to relieve stimulation-induced side effects, ten leads in six patients required surgical revision owing to electrode malposition. CONCLUSIONS: We show wide adaptability and implementation of directional stimulation, adding to the growing compendium of real-world uses of dDBS therapy. We used directionality to improve clinical response in both patients with PD and patients with ET and found that its programming flexibility was used at high rates long after implantation and initial programming. In patients with PD, dDBS led to a significant reduction in dopaminergic medication, suggesting sustained clinical improvement. Nonetheless, accurate surgical placement remains necessary to ensure optimal clinical outcomes.

Differential spatiotemporal gait effects with frequency and dopaminergic modulation in STN-DBS.

Objective: The spatiotemporal gait changes in advanced Parkinson's disease (PD) remain a treatment challenge and have variable responses to L-dopa and subthalamic deep brain stimulation (STN-DBS). The purpose of this study was to determine whether low-frequency STN-DBS (LFS; 60 Hz) elicits a differential response to high-frequency STN-DBS (HFS; 180 Hz) in spatiotemporal gait kinematics. Methods: Advanced PD subjects with chronic STN-DBS were evaluated in both the OFF and ON medication states with LFS and HFS stimulation. Randomization of electrode contact pairs and frequency conditions was conducted. Instrumented Stand and Walk assessments were carried out for every stimulation/medication condition. LM-ANOVA was employed for analysis. Results: Twenty-two PD subjects participated in the study, with a mean age (SD) of 63.9 years. Significant interactions between frequency (both LFS and HFS) and electrode contact pairs (particularly ventrally located contacts) were observed for both spatial (foot elevation, toe-off angle, stride length) and temporal (foot speed, stance, single limb support (SLS) and foot swing) gait parameters. A synergistic effect was also demonstrated with L-dopa and both HFS and LFS for right SLS, left stance, left foot swing, right toe-off angle, and left arm range of motion. HFS produced significant improvement in trunk and lumbar range of motion compared to LFS. Conclusion: The study provides evidence of synergism of L-dopa and STN-DBS on lower limb spatial and temporal measures in advanced PD. HFS and LFS STN-DBS produced equivalent effects among all other tested lower limb gait features. HFS produced significant trunk and lumbar kinematic improvements.

Improving Medication Regimen Recommendation for Parkinson's Disease Using Sensor Technology.

Parkinson's disease medication treatment planning is generally based on subjective data obtained through clinical, physician-patient interactions. The Personal KinetiGraph™ (PKG) and similar wearable sensors have shown promise in enabling objective, continuous remote health monitoring for Parkinson's patients. In this proof-of-concept study, we propose to use objective sensor data from the PKG and apply machine learning to cluster patients based on levodopa regimens and response. The resulting clusters are then used to enhance treatment planning by providing improved initial treatment estimates to supplement a physician's initial assessment. We apply k-means clustering to a dataset of within-subject Parkinson's medication changes-clinically assessed by the MDS-Unified Parkinson's Disease Rating Scale-III (MDS-UPDRS-III) and the PKG sensor for movement staging. A random forest classification model was then used to predict patients' cluster allocation based on their respective demographic information, MDS-UPDRS-III scores, and PKG time-series data. Clinically relevant clusters were partitioned by levodopa dose, medication administration frequency, and total levodopa equivalent daily dose-with the PKG providing similar symptomatic assessments to physician MDS-UPDRS-III scores. A random forest classifier trained on demographic information, MDS-UPDRS-III scores, and PKG time-series data was able to accurately classify subjects of the two most demographically similar clusters with an accuracy of 86.9%, an F1 score of 90.7%, and an AUC of 0.871. A model that relied solely on demographic information and PKG time-series data provided the next best performance with an accuracy of 83.8%, an F1 score of 88.5%, and an AUC of 0.831, hence further enabling fully remote assessments. These computational methods demonstrate the feasibility of using sensor-based data to cluster patients based on their medication responses with further potential to assist with medication recommendations.

Machine Learning's Application in Deep Brain Stimulation for Parkinson's Disease: A Review.

Deep brain stimulation (DBS) is a surgical treatment for advanced Parkinson's disease (PD) that has undergone technological evolution that parallels an expansion in clinical phenotyping, neurophysiology, and neuroimaging of the disease state. Machine learning (ML) has been successfully used in a wide range of healthcare problems, including DBS. As computational power increases and more data become available, the application of ML in DBS is expected to grow. We review the literature of ML in DBS and discuss future opportunities for such applications. Specifically, we perform a comprehensive review of the literature from PubMed, the Institute for Scientific Information's Web of Science, Cochrane Database of Systematic Reviews, and Institute of Electrical and Electronics Engineers' (IEEE) Xplore Digital Library for ML applications in DBS. These studies are broadly placed in the following categories: (1) DBS candidate selection; (2) programming optimization; (3) surgical targeting; and (4) insights into DBS mechanisms. For each category, we provide and contextualize the current body of research and discuss potential future directions for the application of ML in DBS.

Optimizing Clinical Assessments in Parkinson's Disease Through the Use of Wearable Sensors and Data Driven Modeling.

The emergence of motion sensors as a tool that provides objective motor performance data on individuals afflicted with Parkinson's disease offers an opportunity to expand the horizon of clinical care for this neurodegenerative condition. Subjective clinical scales and patient based motor diaries have limited clinometric properties and produce a glimpse rather than continuous real time perspective into motor disability. Furthermore, the expansion of machine learn algorithms is yielding novel classification and probabilistic clinical models that stand to change existing treatment paradigms, refine the application of advance therapeutics, and may facilitate the development and testing of disease modifying agents for this disease. We review the use of inertial sensors and machine learning algorithms in Parkinson's disease.

Diagnosis, treatment, and clinical outcomes in 43 cases with cerebrotendinous xanthomatosis.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a rare disorder due to defective sterol 27-hydroxylase causing a lack of chenodeoxycholic acid (CDCA) production and high plasma cholestanol levels. OBJECTIVES: Our objective was to review the diagnosis and treatment results in 43 CTX cases. METHODS: We conducted a careful review of the diagnosis, laboratory values, treatment, and clinical course in 43 CTX cases. RESULTS: The mean age at diagnosis was 32 years; the average follow-up was 8 years. Cases had the following conditions: 53% chronic diarrhea, 74% cognitive impairment, 70% premature cataracts, 77% tendon xanthomas, 81% neurologic disease, and 7% premature cardiovascular disease. The mean serum cholesterol concentration was 190 mg/dL; the mean plasma cholestanol level was 32 mg/L (normal <5.0 mg/L), which decreased to 6.0 mg/L (-81%) with CDCA therapy generally given as 250 mg orally 3 times daily. Of those tested on treatment, 63% achieved cholestanol levels of <5.0 mg/L; 91% had normal liver enzyme levels; none had significant liver problems after dose adjustment. Treatment improved symptoms in 57% at follow-up, but 20% with advanced disease continued to deteriorate. In the United States, CDCA has been approved for gallstone dissolution, but not for CTX despite long-term efficacy and safety data. CONCLUSIONS: Health care providers seeing young patients with tendon xanthomas and relatively normal cholesterol levels, especially those with cataracts and learning problems, should consider the diagnosis of CTX so they can receive treatment. CDCA should receive regulatory approval to facilitate therapy for the prevention of the complications of the disease.

Improvement of Post-hypoxic Myoclonus with Bilateral Pallidal Deep Brain Stimulation: A Case Report and Review of the Literature.

BACKGROUND: Post-hypoxic myoclonus (PHM) is a syndrome that occurs when a patient has suffered hypoxic brain injury. The myoclonus is usually multifocal and generalized, often stemming from both cortical and subcortical origins. In severe cases, pharmacological treatments with antiepileptic medications may not satisfactorily control the myoclonus. METHODS: We present a case of a 23-year-old male with chronic medication refractory PHM following a cardiopulmonary arrest related to an asthmatic attack who improved with bilateral globus pallidus internus (GPi) deep brain stimulation (DBS). We review the clinical features of PHM, as well as the preoperative and postoperative Unified Myoclonus Rating Scale scores and DBS programming parameters in this patient and compare them with the three other published PHM-DBS cases in the literature. RESULTS: This patient experienced an alleviation of myoclonic jerks at rest and a 39% reduction in action myoclonus with improvement in both positive and negative myoclonus with bilateral GPi-DBS. High frequency stimulation (130 Hz) with amplitudes >2.5 V were needed for the therapeutic response. DISCUSSION: We demonstrate a robust improvement in a medication refractory PHM patient with bilateral GPi-DBS, and suggest that it is a viable therapeutic option for debilitating post-hypoxic myoclonus.

Stratifying Parkinson's Patients With STN-DBS Into High-Frequency or 60 Hz-Frequency Modulation Using a Computational Model.

OBJECTIVE: High frequency stimulation (HFS) of the subthalamic nucleus (STN) is a well-established therapy for Parkinson's disease (PD), particularly the cardinal motor symptoms and levodopa induced motor complications. Recent studies have suggested the possible role of 60 Hz stimulation in STN-deep brain stimulation (DBS) for patients with gait disorder. The objective of this study was to develop a computational model, which stratifies patients a priori based on symptomatology into different frequency settings (i.e., high frequency or 60 Hz). METHODS: We retrospectively analyzed preoperative MDS-Unified Parkinson's Disease Rating Scale III scores (32 indicators) collected from 20 PD patients implanted with STN-DBS at Mount Sinai Medical Center on either 60 Hz stimulation (ten patients) or HFS (130-185 Hz) (ten patients) for an average of 12 months. Predictive models using the Random Forest classification algorithm were built to associate patient/disease characteristics at surgery to the stimulation frequency. These models were evaluated objectively using leave-one-out cross-validation approach. RESULTS: The computational models produced, stratified patients into 60 Hz or HFS (130-185 Hz) with 95% accuracy. The best models relied on two or three predictors out of the 32 analyzed for classification. Across all predictors, gait and rest tremor of the right hand were consistently the most important. CONCLUSIONS: Computational models were developed using preoperative clinical indicators in PD patients treated with STN-DBS. These models were able to accurately stratify PD patients into 60 Hz stimulation or HFS (130-185 Hz) groups a priori, offering a unique potential to enhance the utilization of this therapy based on clinical subtypes.

Isolated Focal Dystonia as a Disorder of Large-Scale Functional Networks.

Isolated focal dystonias are a group of disorders with diverse symptomatology but unknown pathophysiology. Although recent neuroimaging studies demonstrated regional changes in brain connectivity, it remains unclear whether focal dystonia may be considered a disorder of abnormal networks. We examined topology as well as the global and local features of large-scale functional brain networks across different forms of isolated focal dystonia, including patients with task-specific (TSD) and nontask-specific (NTSD) dystonias. Compared with healthy participants, all patients showed altered network architecture characterized by abnormal expansion or shrinkage of neural communities, such as breakdown of basal ganglia-cerebellar community, loss of a pivotal region of information transfer (hub) in the premotor cortex, and pronounced connectivity reduction within the sensorimotor and frontoparietal regions. TSD were further characterized by significant connectivity changes in the primary sensorimotor and inferior parietal cortices and abnormal hub formation in insula and superior temporal cortex, whereas NTSD exhibited abnormal strength and number of regional connections. We suggest that isolated focal dystonias likely represent a disorder of large-scale functional networks, where abnormal regional interactions contribute to network-wide functional alterations and may underline the pathophysiology of isolated focal dystonia. Distinct symptomatology in TSD and NTSD may be linked to disorder-specific network aberrations.

Case Study of Image-Guided Deep Brain Stimulation: Magnetic Resonance Imaging-Based White Matter Tractography Shows Differences in Responders and Nonresponders.

BACKGROUND: The caudal zona incerta (cZI) is an increasingly popular deep brain stimulation (DBS) target for the treatment of tremor-predominant disease. The dentatorubrothalamic tract (DRTT) is a white matter fiber bundle that traverses the cZI and can be identified using diffusion-weighted magnetic resonance imaging fiber tractography to ascertain its precise course. In this report, we compare 2 patient cases of cZI DBS, a responder and a nonresponder. CASE DESCRIPTION: Patient 1 (responder) is a 65-year-old man with medically refractory Parkinson disease who underwent bilateral DBS lead placement in the cZI. Postoperatively he demonstrated >90% reduction in baseline tremor and was not limited by stimulation side effects. Postoperative imaging showed correct lead placement in the cZI. Tractography revealed a DRTT within the field of stimulation, bilaterally. Patient 2 (nonresponder) is a 61-year-old man with medically refractory Parkinson disease who also underwent bilateral DBS lead placement in the cZI. He initially demonstrated >90% reduction in baseline tremor but developed disabling dystonia of his left leg and significant slurring of his speech in the months after surgery. Postoperative imaging showed bilateral lead placement in the cZI. Right-sided electrode revision was recommended and resulted in relief of tremor and reduced dystonic side effects. Tractography analysis of the original leads revealed a DRTT with an atypical anterior trajectory and a location outside the field of stimulation. Tractography analysis of the revised lead showed a DRTT within the field of stimulation. CONCLUSIONS: Preoperative diffusion-weighted magnetic resonance imaging fiber tractography imaging of the DRTT has the potential to improve and individualize DBS planning.

Improvement of Isolated Myoclonus Phenotype in Myoclonus Dystonia after Pallidal Deep Brain Stimulation.

BACKGROUND: Myoclonus-dystonia is a condition that manifests predominantly as myoclonic jerks with focal dystonia. It is genetically heterogeneous with most mutations in the epsilon sarcoglycan gene (SGCE). In medically refractory cases, deep brain stimulation (DBS) has been shown to provide marked sustainable clinical improvement, especially in SGCE-positive patients. We present two patients with myoclonus-dystonia (one SGCE positive and the other SGCE negative) who have the isolated myoclonus phenotype and had DBS leads implanted in the bilateral globus pallidus internus (GPi). METHODS: We review their longitudinal Unified Myoclonus Rating Scale scores along with their DBS programming parameters and compare them with published cases in the literature. RESULTS: Both patients demonstrated complete amelioration of all aspects of myoclonus within 6-12 months after surgery. The patient with the SGCE-negative mutation responded just as well as the patient who was SGCE positive. High-frequency stimulation (130 Hz) with amplitudes greater than 2.5 V provided therapeutic benefit. DISCUSSION: This case series demonstrates that high frequency GPi-DBS is effective in treating isolated myoclonus in myoclonus-dystonia, regardless of the presence of SGCE mutation.

Neural correlates of abnormal sensory discrimination in laryngeal dystonia.

Aberrant sensory processing plays a fundamental role in the pathophysiology of dystonia; however, its underpinning neural mechanisms in relation to dystonia phenotype and genotype remain unclear. We examined temporal and spatial discrimination thresholds in patients with isolated laryngeal form of dystonia (LD), who exhibited different clinical phenotypes (adductor vs. abductor forms) and potentially different genotypes (sporadic vs. familial forms). We correlated our behavioral findings with the brain gray matter volume and functional activity during resting and symptomatic speech production. We found that temporal but not spatial discrimination was significantly altered across all forms of LD, with higher frequency of abnormalities seen in familial than sporadic patients. Common neural correlates of abnormal temporal discrimination across all forms were found with structural and functional changes in the middle frontal and primary somatosensory cortices. In addition, patients with familial LD had greater cerebellar involvement in processing of altered temporal discrimination, whereas sporadic LD patients had greater recruitment of the putamen and sensorimotor cortex. Based on the clinical phenotype, adductor form-specific correlations between abnormal discrimination and brain changes were found in the frontal cortex, whereas abductor form-specific correlations were observed in the cerebellum and putamen. Our behavioral and neuroimaging findings outline the relationship of abnormal sensory discrimination with the phenotype and genotype of isolated LD, suggesting the presence of potentially divergent pathophysiological pathways underlying different manifestations of this disorder.

Early Use of 60 Hz Frequency Subthalamic Stimulation in Parkinson's Disease: A Case Series and Review.

BACKGROUND: Deep brain stimulation (DBS) is effective in treating the segmental symptoms of Parkinson's disease (PD) as well as axial symptoms that are levodopa responsive. PD patients on chronic DBS who develop axial symptoms and gait disturbances several years later oftentimes are refractory to high frequency stimulation (HFS). Several studies report benefit produced by low frequency subthalamic nucleus (STN) stimulation in such patients, though the sustainability of the effects has been mixed. OBJECTIVE: To report the clinical outcomes of a series of patients with Parkinson's disease and levodopa responsive axial and gait disturbances who were switched to 60 Hz stimulation within one year of their DBS surgery. METHODS: A retrospective review of 5 patients, whose severe pre-DBS, levodopa responsive gait disorders worsened on HFS STN-DBS and were subsequently switched to 60 Hz stimulation within 1 year of their surgery. RESULTS: The median age of this cohort was 66 years with median disease duration of 14 years. Four of 5 patients' experienced acute worsening of their axial and gait UPDRS III scores on HFS. All patients' gait disorder improved with 60 Hz along with amelioration of their segmental symptoms and reduction of their levodopa induced dyskinesia. The median time on HFS prior to switching to 60 Hz was two months. Stimulation through the ventral contacts was utilized in all patients with relatively modest changes achieved in levodopa equivalent daily dose. CONCLUSION: This case series demonstrates the clinical efficacy of utilizing low frequency (60 Hz) STN stimulation early in the DBS programming course in more advanced PD patients with levodopa responsive gait disturbance and freezing of gait. Activation of a broader stimulation field likely contributed to both axial and segmental symptom improvement while possibly aiding in the reduction of dyskinesia.

Pseudobulbar laughter as a levodopa off phenomenon exacerbated by subthalamic deep brain stimulation.

Pseudobulbar affect is a common symptom in neurodegenerative diseases and can also result from lesions in cortical, subcortical and brainstem regions. In Parkinson's disease (PD), pseudobulbar affect (PBA) can occur as a wearing off phenomenon, manifested usually as crying without emotionality. In addition, subthalamic (STN) deep brain stimulation (DBS) has been reported to induce PBA in PD patients with no prior history of such episodes. We present a case of inappropriate laughter lacking mirth as a levodopa OFF phenomenon in a patient with PD, whose laughter also worsened with STN-DBS in his non-medicated state. Levodopa ameliorated his PBA both with and without stimulation. The case demonstrates pseudobulbar laughter as a levodopa OFF phenomenon that is also exacerbated by STN-DBS.

Reply to: Hemichorea Associated with CASPR2 Antibody.

This letter was written in reply to this letter to the editor: Vynogradova I, Savitski V, Heckmann JG. Hemichorea associated with CASPR2 antibody. Tremor Other Hyperkinet Mov. 2014; 4. doi: 10.7916/D8VM49C5. The above letter to the editor was written in response to this article: Ramdhani RA, Frucht SJ. Isolated Chorea Associated with LGI1 Antibody. Tremor Other Hyperkinet Mov. 2014; 4. doi: 10.7916/D8MG7MFC.