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.

Deep brain stimulation of symptom-specific networks in Parkinson's disease.

Deep Brain Stimulation can improve tremor, bradykinesia, rigidity, and axial symptoms in patients with Parkinson's disease. Potentially, improving each symptom may require stimulation of different white matter tracts. Here, we study a large cohort of patients (N = 237 from five centers) to identify tracts associated with improvements in each of the four symptom domains. Tremor improvements were associated with stimulation of tracts connected to primary motor cortex and cerebellum. In contrast, axial symptoms are associated with stimulation of tracts connected to the supplementary motor cortex and brainstem. Bradykinesia and rigidity improvements are associated with the stimulation of tracts connected to the supplementary motor and premotor cortices, respectively. We introduce an algorithm that uses these symptom-response tracts to suggest optimal stimulation parameters for DBS based on individual patient's symptom profiles. Application of the algorithm illustrates that our symptom-tract library may bear potential in personalizing stimulation treatment based on the symptoms that are most burdensome in an individual patient.

Long-Term Follow-Up of Unilateral Deep Brain Stimulation Targeting the Caudal Zona Incerta in 13 Patients with Parkinsonian Tremor.

INTRODUCTION: Deep brain stimulation (DBS) is an established treatment for Parkinson's disease (PD) and other movement disorders. The ventral intermediate nucleus of the thalamus is considered as the target of choice for tremor disorders, including tremor-dominant PD not suitable for DBS in the subthalamic nucleus (STN). In the last decade, several studies have shown promising results on tremor from DBS in the posterior subthalamic area (PSA), including the caudal zona incerta (cZi) located posteromedial to the STN. The aim of this study was to evaluate the long-term effect of unilateral cZi/PSA-DBS in patients with tremor-dominant PD. METHODS: Thirteen patients with PD with medically refractory tremor were included. The patients were evaluated using the motor part of the Unified Parkinson Disease Rating Scale (UPDRS) off/on medication before surgery and off/on medication and stimulation 1-2 years (short-term) after surgery and at a minimum of 3 years after surgery (long-term). RESULTS: At short-term follow-up, DBS improved contralateral tremor by 88% in the off-medication state. This improvement persisted after a mean of 62 months. Contralateral bradykinesia was improved by 40% at short-term and 20% at long-term follow-up, and the total UPDRS-III by 33% at short-term and by 22% at long-term follow-up with stimulation alone. CONCLUSIONS: Unilateral cZi/PSA-DBS seems to remain an effective treatment for patients with severe Parkinsonian tremor several years after surgery. There was also a modest improvement on bradykinesia.

Concurrent decoding of distinct neurophysiological fingerprints of tremor and bradykinesia in Parkinson's disease.

Parkinson's disease (PD) is characterized by distinct motor phenomena that are expressed asynchronously. Understanding the neurophysiological correlates of these motor states could facilitate monitoring of disease progression and allow improved assessments of therapeutic efficacy, as well as enable optimal closed-loop neuromodulation. We examined neural activity in the basal ganglia and cortex of 31 subjects with PD during a quantitative motor task to decode tremor and bradykinesia - two cardinal motor signs of PD - and relatively asymptomatic periods of behavior. Support vector regression analysis of microelectrode and electrocorticography recordings revealed that tremor and bradykinesia had nearly opposite neural signatures, while effective motor control displayed unique, differentiating features. The neurophysiological signatures of these motor states depended on the signal type and location. Cortical decoding generally outperformed subcortical decoding. Within the subthalamic nucleus (STN), tremor and bradykinesia were better decoded from distinct subregions. These results demonstrate how to leverage neurophysiology to more precisely treat PD.

Optogenetic Globus Pallidus Stimulation Improves Motor Deficits in 6-Hydroxydopamine-Lesioned Mouse Model of Parkinson's Disease.

Excessive inhibition of the external globus pallidus (GPe) by striatal GABAergic neurons is considered a central mechanism contributing to motor symptoms of Parkinson's disease (PD). While electrophysiological findings support this view, behavioral studies assessing the beneficial effects of global GPe activations are scarce and the reported results are controversial. We used an optogenetic approach and the standard unilateral 6-hydroxydopamine nigrostriatal dopamine (DA) lesion model of PD to explore the effects of GPe photostimulation on motor deficits in mice. Global optogenetic GPe inhibition was used in normal mice to verify whether it reproduced the typical motor impairment induced by DA lesions. GPe activation improved ipsilateral circling, contralateral forelimb akinesia, locomotor hypoactivity, and bradykinesia in 6-OHDA-lesioned mice at ineffective photostimulation parameters (532 nm, 5 Hz, 3 mW) in normal mice. GPe photoinhibition (450 nm, 12 mW) had no effect on locomotor activity and forelimb use in normal mice. Bilateral photoinhibition (450 nm, 6 mW/side) reduced directed exploration and improved working memory performances indicating that recruitment of GPe in physiological conditions may depend on the behavioral task involved. Collectively, these findings shed new light on the functional role of GPe and suggest that it is a promising target for neuromodulatory restoration of motor deficits in PD.

The Sequence Effect Worsens Over Time in Parkinson's Disease and Responds to Open and Closed-Loop Subthalamic Nucleus Deep Brain Stimulation.

BACKGROUND: The sequence effect is the progressive deterioration in speech, limb movement, and gait that leads to an inability to communicate, manipulate objects, or walk without freezing of gait. Many studies have demonstrated a lack of improvement of the sequence effect from dopaminergic medication, however few studies have studied the metric over time or investigated the effect of open-loop deep brain stimulation in people with Parkinson's disease (PD). OBJECTIVE: To investigate whether the sequence effect worsens over time and/or is improved on clinical (open-loop) deep brain stimulation (DBS). METHODS: Twenty-one people with PD with bilateral subthalamic nucleus (STN) DBS performed thirty seconds of instrumented repetitive wrist flexion extension and the MDS-UPDRS III off therapy, prior to activation of DBS and every six months for up to three years. A sub-cohort of ten people performed the task during randomized presentations of different intensities of STN DBS. RESULTS: The sequence effect was highly correlated with the overall MDS-UPDRS III score and the bradykinesia sub-score and worsened over three years. Increasing intensities of STN open-loop DBS improved the sequence effect and one subject demonstrated improvement on both open-loop and closed-loop DBS. CONCLUSION: Sequence effect in limb bradykinesia worsened over time off therapy due to disease progression but improved on open-loop DBS. These results demonstrate that DBS is a useful treatment of the debilitating effects of the sequence effect in limb bradykinesia and upon further investigation closed-loop DBS may offer added improvement.

A systematic review of local field potential physiomarkers in Parkinson's disease: from clinical correlations to adaptive deep brain stimulation algorithms.

Deep brain stimulation (DBS) treatment has proven effective in suppressing symptoms of rigidity, bradykinesia, and tremor in Parkinson's disease. Still, patients may suffer from disabling fluctuations in motor and non-motor symptom severity during the day. Conventional DBS treatment consists of continuous stimulation but can potentially be further optimised by adapting stimulation settings to the presence or absence of symptoms through closed-loop control. This critically relies on the use of 'physiomarkers' extracted from (neuro)physiological signals. Ideal physiomarkers for adaptive DBS (aDBS) are indicative of symptom severity, detectable in every patient, and technically suitable for implementation. In the last decades, much effort has been put into the detection of local field potential (LFP) physiomarkers and in their use in clinical practice. We conducted a research synthesis of the correlations that have been reported between LFP signal features and one or more specific PD motor symptoms. Features based on the spectral beta band (~ 13 to 30 Hz) explained ~ 17% of individual variability in bradykinesia and rigidity symptom severity. Limitations of beta band oscillations as physiomarker are discussed, and strategies for further improvement of aDBS are explored.

A non-contact system for intraoperative quantitative assessment of bradykinesia in deep brain stimulation surgery.

BACKGROUND AND OBJECTIVE: Deep brain stimulation (DBS) is an effective treatment for a number of neurological diseases, especially for the advanced stage of Parkinson's disease (PD). Objective assessment of patients' motor symptoms is crucial for accurate electrode targeting and treatment. Existing approaches suffer from subjective variability or interference with voluntary motion. This work is aimed to establish an objective assessment system to quantify bradykinesia in DBS surgery. METHODS: Based on the analysis of the requirements for intraoperative assessment, we developed a system with non-contact measurement, online movement feature extraction, and interactive data analysis and visualization. An optical sensor, Leap Motion Controller (LMC), was taken to detect hand movement in three clinical tasks. A graphic user interface was designed to process, compare and visualize the collected data and assessment results online. Quantified movement features include amplitude, frequency, velocity, their decrement and variability, etc. Technical validation of the system was performed with a motion capture system (Mocap), with respect to data-level and feature-level accuracy and reliability. Clinical validation was conducted with 20 PD patients for intraoperative assessments in DBS surgery. Treatment responses with respect to the bradykinesia movement features were analyzed. Single case analysis and group statistical analysis were performed to examine the differences between preoperative and intraoperative performance, and the correlation between the clinical ratings and the quantified assessment was analyzed. RESULTS: For the movements measured by LMC and Mocap, the average Pearson's correlation coefficient was 0.986, and the mean amplitude difference was 2.11 mm. No significant difference was found for all movement features quantified by LMC and Mocap. For the clinical tests, key movement features showed significant differences between the preoperative baseline and intraoperative performance when the brain stimulation was ON. The assessment results were significantly correlated with the MDS-UPDRS clinical ratings. CONCLUSIONS: The proposed non-contact system has established itself as an objective intraoperative assessment, analysis, and visualization tool for DBS treatment of Parkinson's disease.

Characterization and localization of upper and lower extremity motor improvements in STN DBS for Parkinson's disease.

INTRODUCTION: Subthalamic deep brain stimulation (STN DBS) may have differential effects on cardinal motor signs of Parkinson's disease (PD) in the upper and lower extremities. In addition, sites of maximally effective DBS for each sign and extremity may be distinct. Our study seeks to elucidate these structure-function relationships. METHODS: We applied an ordinary least squares linear regression model to measure motor effects of STN DBS on upper (UE) and lower (LE) extremity tremor, rigidity, and bradykinesia. We then applied an atlas-independent electrical-field model to identify sites of maximally effective stimulation for each sign and each extremity. Distances between sites and statistical power to resolve differences were calculated. RESULTS: In our study population (n = 78 patients), STN DBS improved all cardinal motor signs (ß = 0.64, p < .05). Improvement magnitudes were tremor > rigidity > bradykinesia. Effects of STN DBS on UE versus LE signs were statistically equal for tremor and bradykinesia, but greater for UE rigidity than LE rigidity (ß = 0.19, p < .05). UE maximal-effect loci were lateral, anterior, and dorsal to LE loci, but were not statistically resolved, despite sufficient statistical power to resolve differences of ≤0.48 mm (p < .05) between maximally effective loci of stimulation. CONCLUSION: STN DBS produces differential effects on UE and LE rigidity, but not for tremor or bradykinesia. This finding is not explained by distinct UE and LE loci of maximally effective stimulation. Instead, we hypothesize that downstream effects of STN DBS on motor networks and limb biomechanics are responsible for observed differences in UE and LE responses.

Comparative Analysis of Acute Levodopa Challenge Test and the Outcomes of Deep Brain Stimulation in Parkinson's Disease.

BACKGROUND: We study the correlation between the preoperative levodopa challenge test and the efficacy of deep brain stimulation (DBS) surgery in Parkinson's disease (PD). METHODS: Fifty patients with PD who underwent DBS treatment in our hospital from October 2016 to October 2017 were enrolled in this study. Using the Unified Parkinson Disease Rating Scale-III (UPDRS-III) as an indicator, we analyzed the improvement in motor symptoms on the levodopa challenge test and by DBS surgery. We also discussed the correlation between the effects of the levodopa challenge test and DBS surgery. RESULTS: There was no correlation between the results of the levodopa challenge test and DBS surgery. There was a linear correlation between muscle rigidity and bradykinesia, whereas the linear correlation between other symptoms was weak. CONCLUSION: The levodopa challenge test can be used as a screening tool for patients undergoing DBS surgery, and can predict the degree of improvement in muscle rigidity and bradykinesia surgery. However, the prediction of the degree of improvement of total motor symptoms is poor.

Treatment of unexplained coma and hypokinetic-rigid syndrome in a patient with COVID-19.

The COVID-19 pandemic has dealt a devastating blow to healthcare systems globally. Approximately 3.2% of patients infected with COVID-19 require invasive ventilation during the course of the illness. Within this population, 25% of patients are affected with neurological manifestations. Among those who are affected by severe neurological manifestations, some may have acute cerebrovascular complications (5%), impaired consciousness (15%) or exhibit skeletal muscle hypokinesis (20%). The cause of the severe cognitive impairment and hypokinesis is unknown at this time. Potential causes include COVID-19 viral encephalopathy, toxic metabolic encephalopathy, post-intensive care unit syndrome and cerebrovascular pathology. We present a case of a 60 year old patient who sustained a prolonged hospitalization with COVID-19, had a cerebrovascular event and developed a persistent unexplained encephalopathy along with a hypokinetic state. He was treated successfully with modafinil and carbidopa/levodopa showing clinical improvement within 3-7 days and ultimately was able to successfully discharge home.

A walking dance to improve gait speed for people with Parkinson disease: a pilot study.

Aim: To determine the effectiveness of a targeted dance intervention to improve walking speed for people with Parkinson disease (PD) by increasing motor motivation. Materials & methods: 11 participants with PD participated in a 6-week pilot study in which they learned a contemporary dance composed of walking steps and designed to mimic everyday walking. 1 h classes occurred twice-weekly. Results: Pre- and post-intervention assessments revealed a significant increase in gait speed (t9 = 3.30; p = 0.009), cadence (t9 = 2.345; p = 0.044), and stride length (t9 = 3.757; p = 0.005), and a significant decrease (improvement) in single support time variability (t9 = -2.744; p = 0.022). There were no significant changes in other measures of gait variability nor in motor symptoms, mood and anxiety, extent of life-space mobility, or quality of life. No adverse events were reported. Conclusion: Joywalk provides preliminary evidence that a targeted physical intervention for people with PD may specifically counter bradykinesia.

Acute effects of adaptive Deep Brain Stimulation in Parkinson's disease.

BACKGROUND: Beta-based adaptive Deep Brain Stimulation (aDBS) is effective in Parkinson's disease (PD), when assessed in the immediate post-implantation phase. However, the potential benefits of aDBS in patients with electrodes chronically implanted, in whom changes due to the microlesion effect have disappeared, are yet to be assessed. METHODS: To determine the acute effectiveness and side-effect profile of aDBS in PD compared to conventional continuous DBS (cDBS) and no stimulation (NoStim), years after DBS implantation, 13 PD patients undergoing battery replacement were pseudo-randomised in a crossover fashion, into three conditions (NoStim, aDBS or cDBS), with a 2-min interval between them. Patient videos were blindly evaluated using a short version of the Unified Parkinson's Disease Rating Scale (subUPDRS), and the Speech Intelligibility Test (SIT). RESULTS: Mean disease duration was 16 years, and the mean time since DBS-implantation was 6.9 years. subUPDRS scores (11 patients tested) were significantly lower both in aDBS (p=<.001), and cDBS (p = .001), when compared to NoStim. Bradykinesia subscores were significantly lower in aDBS (p = .002), and did not achieve significance during cDBS (p = .08), when compared to NoStim. Two patients demonstrated re-emerging tremor during aDBS. SIT scores of patients who presented stimulation-induced dysarthria significantly worsened in cDBS (p = .009), but not in aDBS (p = .407), when compared to NoStim. Overall, stimulation was applied 48.8% of the time during aDBS. CONCLUSION: Beta-based aDBS is effective in PD patients with bradykinetic phenotypes, delivers less stimulation than cDBS, and potentially has a more favourable speech side-effect profile. Patients with prominent tremor may require a modified adaptive strategy.

Wearable technology to assess bradykinesia and immobility in patients with severe depression undergoing electroconvulsive therapy: A pilot study.

The psychomotor retardation that may be seen in major depression represents an interesting parallel to bradykinesia, a core feature of Parkinson's disease. Psychomotor retardation has been correlated with the severity of depression and is a predictor of response to electroconvulsive therapy (ECT). Psychomotor retardation has typically been assessed by subjective clinical judgement including clinical rating scales. Gross activity levels have also been measured with actigraphy previously. The Parkinson's KinetiGraph (PKG) was developed to assess bradykinesia, dyskinesia and tremor in Parkinson's disease and allows for an objective assessment of motor symptoms over time. It has not been used previously to assess motor symptoms in depression. The aim of the current pilot study was to use the PKG to objectively measure both bradykinesia and immobility in depressed inpatients undergoing ECT before, during and at the end of therapy and review correlations with depressive symptomatology and treatment response. The majority of patients (9/12) had PKG defined bradykinesia at baseline and 7/9 of these improved with ECT. All patients with bradykinesia who remitted clinically demonstrated improvements in bradykinesia scores. PKG defined immobility was present at baseline in 11/12 total patients and improved in the majority of these patients (9/11) post ECT. Correlations between clinically assessed melancholia and PKG measures were significant (r = 0.701, p 0.011 at baseline to rs = 0.655, p 0.021 at end). A strong association between bradykinesia and immobility scores and depression severity was not seen. The PKG is a potentially useful wearable technology to objectively assess motor symptoms in depression.

Analyzing the effects of PDSAFEx™ on the motor symptoms of Parkinson's disease: A retrospective study.

BACKGROUND: The cardinal motor symptoms of Parkinson's disease (PD) include postural instability, bradykinesia, tremor and rigidity. The overall Unified Parkinson's Disease Rating Scale (UPDRS-III) indicates, the gold-standard treatment for PD (dopaminergic-therapy) is very effective in improving these symptoms. However, recent research indicated that 2 of the 4 cardinal symptoms of PD (balance and tremor) remain unimproved by dopaminergic-therapy. This prompts the investigation of other alternative and adjunct treatments such as exercise rehabilitation. Unfortunately, like drug studies, exercise studies often focus on overall symptom improvement yet fail to monitor changes to specific symptoms. This may be problematic for individuals with different symptomatic phenotypes. If tremor/balance were the main concern, then adjunct therapies may be critically important when these symptoms may be dopa-resistant. Thus, it is important for all therapies to examine individual symptomatic-improvement. Interestingly, recent studies show PDSAFEx™ (a sensory integration therapy) to have a significantly improve motor symptoms in comparison to traditional exercise (14). Yet, the effects of PDSAFEx™ on individual PD symptoms is unknown. OBJECTIVE: To explore the effects of PDSAFEx™ on PD symptoms in adjunct to medications. METHODS: UPDRS-III scores of 229 cases were retrospectively examined and analysed in SPSS using Wilcoxon pairs singed-rank test to evaluate specific symptom-improvements. RESULTS: PDSAFEx™ was confirmed to improve overall motor symptoms (p = 0.0001), but more importantly a significant improvement to tremor (p < 0.00001) and balance (p < 0.00001) were also identified. CONCLUSIONS: These findings suggest that PDSAFEx™ is an important adjunct to medications, since it is able to address all four cardinal symptoms of PD.

Connectivity-based selection of optimal deep brain stimulation contacts: A feasibility study.

BACKGROUND: The selection of optimal deep brain stimulation (DBS) parameters is time-consuming, experience-dependent, and best suited when acute effects of stimulation can be observed (e.g., tremor reduction). OBJECTIVES: To test the hypothesis that optimal stimulation location can be estimated based on the cortical connections of DBS contacts. METHODS: We analyzed a cohort of 38 patients with Parkinson's disease (24 training, and 14 test cohort). Using whole-brain probabilistic tractography, we first mapped the cortical regions associated with stimulation-induced efficacy (rigidity, bradykinesia, and tremor improvement) and side effects (paresthesia, motor contractions, and visual disturbances). We then trained a support vector machine classifier to categorize DBS contacts into efficacious, defined by a therapeutic window ≥2 V (threshold for side effect minus threshold for efficacy), based on their connections with cortical regions associated with efficacy versus side effects. The connectivity-based classifications were then compared with actual stimulation contacts using receiver-operating characteristics (ROC) curves. RESULTS: Unique cortical clusters were associated with stimulation-induced efficacy and side effects. In the training dataset, 42 of the 47 stimulation contacts were accurately classified as efficacious, with a therapeutic window of ≥3 V in 31 (66%) and between 2 and 2.9 V in 11 (24%) electrodes. This connectivity-based estimation was successfully replicated in the test cohort with similar accuracy (area under ROC = 0.83). CONCLUSIONS: Cortical connections can predict the efficacy of DBS contacts and potentially facilitate DBS programming. The clinical utility of this paradigm in optimizing DBS outcomes should be prospectively tested, especially for directional electrodes.

Multiple stimulation parameters influence efficacy of deep brain stimulation in parkinsonian mice.

Deep brain stimulation (DBS) is used to treat multiple neuropsychiatric disorders, including Parkinson's Disease (PD). Despite widespread clinical use, its therapeutic mechanisms are unknown. Here, we developed a mouse model of subthalamic nucleus (STN) DBS for PD, to permit investigation using cell type-specific tools available in mice. We found that electrical STN DBS relieved bradykinesia, as measured by movement velocity. In addition, our model recapitulated several hallmarks of human STN DBS, including rapid onset and offset, frequency dependence, dyskinesia at higher stimulation intensity, and associations between electrode location, therapeutic benefit, and side effects. We used this model to assess whether high frequency stimulation is necessary for effective STN DBS, or if low frequency stimulation can be effective when paired with compensatory adjustments in other parameters. We found that low frequency stimulation, paired with greater pulse width and amplitude, relieved bradykinesia. Moreover, a composite metric incorporating pulse width, amplitude, and frequency predicted therapeutic efficacy better than frequency alone. We found a similar relationship between this composite metric and movement speed in a retrospective analysis of human data, suggesting correlations observed in the mouse model may extend to human patients. Together, these data establish a mouse model for elucidating mechanisms of DBS.

The Use of Data from the Parkinson's KinetiGraph to Identify Potential Candidates for Device Assisted Therapies.

Device-assisted therapies (DAT) benefit people with Parkinsons Disease (PwP) but many referrals for DAT are unsuitable or too late, and a screening tool to aid in identifying candidates would be helpful. This study aimed to produce such a screening tool by building a classifier that models specialist identification of suitable DAT candidates. To our knowledge, this is the first objective decision tool for managing DAT referral. Subjects were randomly assigned to either a construction set (n = 112, to train, develop, cross validate, and then evaluate the classifier's performance) or to a test set (n = 60 to test the fully specified classifier), resulting in a sensitivity and specificity of 89% and 86.6%, respectively. The classifier's performance was then assessed in PwP who underwent deep brain stimulation (n = 31), were managed in a non-specialist clinic (n = 81) or in PwP in the first five years from diagnosis (n = 22). The classifier identified 87%, 92%, and 100% of the candidates referred for DAT in each of the above clinical settings, respectively. Furthermore, the classifier score changed appropriately when therapeutic intervention resolved troublesome fluctuations or dyskinesia that would otherwise have required DAT. This study suggests that information from objective measurement could improve timely referral for DAT.

Deep brain stimulation: Connectivity profile for bradykinesia alleviation.

OBJECTIVE: Subthalamic deep brain stimulation may alleviate bradykinesia in Parkinson patients. Research suggests that this stimulation effect may be mediated by brain networks like the corticocerebellar loop. This study investigated the connectivity between stimulation sites and cortical and subcortical structures to identify connections for effective stimulation. METHODS: We retrospectively investigated 21 patients with Parkinson disease with bilateral subthalamic deep brain stimulation. Stimulation effectiveness in reducing bradykinesia, tremor, and rigidity was evaluated for each electrode contact in brain hemispheres contralateral to the affected hemibody. Dysarthric side effects were also examined. Probabilistic tractography based on diffusion-weighted imaging was performed in individual patient-specific brains using electrode contacts as seeds. Connectivity profiles of contacts with effective and noneffective stimulation were compared. RESULTS: Connectivity profiles of effective and noneffective contacts differed. Moreover, the connectivity profile for bradykinesia differed from that for rigidity, tremor, or dysarthria. Regarding bradykinesia, effective contacts were significantly more often connected with the ipsilateral superior cerebellar peduncle and the ipsilateral dentate nucleus, which correspond to the ipsilateral portion of the cerebellothalamocortical pathway. Rigidity was mitigated by stimulation of ascending brainstem and intralaminar thalamic connections. Tremor alleviation was related to connections with the internal capsule (anterior limb) and the pallidum. Dysarthric side effects were associated with connections to the supplementary motor area and the decussating cerebellothalamocortical pathway. INTERPRETATION: Whereas bradykinesia seems to be mitigated by stimulation of the ascending, ipsilateral cerebellothalamocortical pathway, stimulation of the descending corticopontocerebellar pathway may be ineffective. Rigidity, tremor, and dysarthric side effects seem to be influenced by different neural networks. ANN NEUROL 2019;85:852-864.

Dual threshold neural closed loop deep brain stimulation in Parkinson disease patients.

BACKGROUND: Closed loop deep brain stimulation (clDBS) in Parkinson's disease (PD) using subthalamic (STN) neural feedback has been shown to be efficacious only in the acute post-operative setting, using externalized leads and stimulators. OBJECTIVE: To determine feasibility of neural (N)clDBS using the clinical implanted neurostimulator (Activa™ PC + S, FDA IDE approved) and a novel beta dual threshold algorithm in tremor and bradykinesia dominant PD patients on chronic DBS. METHODS: 13 PD subjects (20 STNs), on open loop (ol)DBS for 22 ±â€¯7.8 months, consented to NclDBS driven by beta (13-30 Hz) power using a dual threshold algorithm, based on patient specific therapeutic voltage windows. Tremor was assessed continuously, and bradykinesia was evaluated after 20 min of NclDBS using a repetitive wrist flexion-extension task (rWFE). Total electrical energy delivered (TEED) on NclDBS was compared to olDBS using the same active electrode. RESULTS: NclDBS was tolerated for 21.67 [21.10-26.15] minutes; no subject stopped early. Resting beta band power was measurable and similar between tremor and bradykinesia dominant patients. NclDBS improved bradykinesia and tremor while delivering only 56.86% of the TEED of olDBS; rWFE velocity (p = 0.003) and frequency (p < 0.001) increased; tremor was below 0.15 rad/sec for 95.4% of the trial and averaged 0.26 rad/sec when present. CONCLUSION: This is the first study to demonstrate that STN NclDBS is feasible, efficacious and more efficient than olDBS in tremor and bradykinesia dominant PD patients, on long-term DBS, using an implanted clinical neurostimulator and driven by beta power with a novel dual threshold algorithm, based on customized therapeutic voltage windows.