Stimulation Of Nucleus Research Articles

Long-term ANT-DBS effects in pilocarpine-induced epileptic rats: A combined 9.4T MRI and histological study.

Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) appears to be effective against seizures in animals and humans however, its therapeutic mechanisms remain elusive. This study aimed to combine 9.4T multimodal magnetic resonance imaging (MRI) with histology to investigate the longitudinal effects of long-term ANT-DBS in pilocarpine-induced epileptic rats. Status epilepsy (SE) was induced by LiCl-pilocarpine injection in 11 adult male Sprague-Dawley rats. Four weeks after SE, chronic epileptic rats underwent either ANT-DBS (n=6) or sham-DBS (n=5) surgery. Electroencephalography (EEG) and spontaneous recurrent seizures (SRS) were recorded for 1 week. The T2-weighted image and images from resting-state functional MRI (rs-fMRI) were acquired at three states: before SE, at 4 weeks post-SE, and at 5 weeks post-DBS. Volumes of the hippocampal subregions and hippocampal-related functional connectivity (FC) were compared longitudinally. Finally, antibodies against neuronal nuclei (NeuN) and glial fibrillary acidic proteins were used to evaluate neuronal loss and astrogliosis in the hippocampus. Long-term ANT-DBS significantly reduced seizure generalization in pilocarpine-induced epileptic rats. By analyzing the gray matter volume using T2-weighted images, long-term ANT-DBS displayed morphometric restoration of the hippocampal subregions. Neuronal protection of the hippocampal subregions and inhibition of astrogliosis in the hippocampal subregions were observed in the ANT-DBS group. ANT-DBS caused reversible regulation of FC in the insula-hippocampus and subthalamic nucleus-hippocampus. Long-term ANT-DBS provides comprehensive protection of hippocampal histology, hippocampal morphometrics, and hippocampal-related functional networks.

The mortality of patients with Parkinson's disease with deep brain stimulation.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is effective in improving motor function in patients with Parkinson's disease (PD). This study aimed to investigate mortality associated with bilateral STN DBS in patients with PD and to assess the factors associated with mortality and causes of death after DBS. We reviewed the medical records of 257 patients with PD who underwent bilateral STN DBS at the Movement Disorder Center at Seoul National University Hospital between March 2005 and November 2018. Patients were evaluated preoperatively, at 3, 6, and 12 months after surgery and annually thereafter. The cause and date of death were obtained from interviews with caregivers or from medical certificates at the last follow-up. Of the 257 patients with PD, 48 patients (18.7%) died, with a median time of death of 11.2 years after surgery. Pneumonia was the most common cause of death. Older age of disease onset, preoperative falling score while on medication, and higher preoperative total levodopa equivalent daily dose were associated with a higher risk of mortality in time-dependent Cox regression analysis. These results confirm the mortality outcome of STN DBS in patients with advanced PD.

Analysis of deep brain stimulation of the subthalamic nucleus (STN-DBS) in patients with monogenic PRKN and LRRK2 forms of Parkinson's disease

IntroductionDeep brain stimulation of the subthalamic nucleus (STN-DBS) is the most common surgical treatment for Parkinson's disease (PD). Patient selection and genetic background can modify the response to this treatment. The objective of this study was to compare both clinical and pharmacologic response of STN-DBS between patients with monogenic forms of PD and non-mutation carriers with idiopathic PD. MethodsA retrospective analysis among 23 carriers of genetic mutations (8 PRKN and 15 LRRK2) and 74 patients with idiopathic PD was performed. The study included comparisons of Unified Parkinson's Disease Rating Scale (UPDRS) II and III scores, Schwab and England (S&E) scale values, Hoehn & Yahr (H&Y) stage scores, and equivalent doses of levodopa before and after the surgery (at 6 and 12 months) between both groups. ResultsThe mean age at the time in which STN-DBS was performed was 59.5 ± 8.6. Linear mixed models showed the absence of statistically significant differences between mutation and non-mutation carriers regarding levodopa doses (p = 0.576), UPDRS II (p = 0.956) and III (p = 0.512) scores, and S&E scale scores (0.758). The only difference between the two groups was observed with respect to H&Y stage in OFF medication/ON stimulation status being lower in genetic PD at 6 months after surgery (p = 0.030). ConclusionClinical and pharmacological benefit of bilateral STN-DBS is similar in PRKN and LRRK2 mutation carriers and patients with idiopathic PD.

Subthalamic stimulation modulates motor network in Parkinson's disease: recover, relieve and remodel.

Aberrant dynamic switches between internal brain states are believed to underlie motor dysfunction in Parkinson's disease. Deep brain stimulation of the subthalamic nucleus is a well-established treatment for the motor symptoms of Parkinson's disease, yet it remains poorly understood how subthalamic stimulation modulates the whole-brain intrinsic motor network state dynamics. To investigate this, we acquired resting-state functional magnetic resonance imaging time-series data from 27 medication-free patients with Parkinson's disease (mean age: 64.8 years, standard deviation: 7.6) who had deep brain stimulation electrodes implanted in the subthalamic nucleus, in both on and off stimulation states. Sixteen matched healthy individuals were included as a control group. We adopted a powerful data-driven modelling approach, known as a hidden Markov model, to disclose the emergence of recurring activation patterns of interacting motor regions (whole-brain intrinsic motor network states) via the blood oxygen level-dependent signal detected in the resting-state functional magnetic resonance imaging time-series data from all participants. The estimated hidden Markov model disclosed the dynamics of distinct whole-brain motor network states, including frequency of occurrence, state duration, fractional coverage and their transition probabilities. Notably, the data-driven decoding of whole-brain intrinsic motor network states revealed that subthalamic stimulation reshaped functional network expression and stabilized state transitions. Moreover, subthalamic stimulation improved motor symptoms by modulating key trajectories of state transition within whole-brain intrinsic motor network states. This modulation mechanism of subthalamic stimulation was manifested in three significant effects: recovery, relieving and remodelling effects. Significantly, recovery effects correlated with improvements in tremor and posture symptoms induced by subthalamic stimulation (P < 0.05). Furthermore, subthalamic stimulation was found to restore a relatively low level of fluctuation of functional connectivity in all motor regions to a level closer to that of healthy participants. Also, changes in the fluctuation of functional connectivity between motor regions were associated with improvements in tremor and gait symptoms (P < 0.05). These findings fill a gap in our knowledge of the role of subthalamic stimulation at the level of neural activity, revealing the regulatory effects of subthalamic stimulation on whole-brain inherent motor network states in Parkinson's disease. Our results provide mechanistic insight and explanation for how subthalamic stimulation modulates motor symptoms in Parkinson's disease.

Neuromodulation in Children with Drug-Resistant Epilepsy

AbstractThe introduction of neuromodulation was a revolutionary advancement in the antiseizure armamentarium for refractory epilepsy. The basic principle of neuromodulation is to deliver an electrical stimulation to the desired neuronal site to modify the neuronal functions not only at the site of delivery but also at distant sites by complex neuronal processes like disrupting the neuronal circuitry and amplifying the functions of marginally functional neurons. The modality is considered open-loop when electrical stimulation is provided at a set time interval or closed-loop when delivered in response to an incipient seizure. Neuromodulation in individuals older than 18 years with epilepsy has proven efficacious and safe. The use of neuromodulation is extended off-label to pediatric patients with epilepsy and the results are promising. Vagus nerve stimulation (VNS), responsive neurostimulation (RNS), and deep brain stimulation (DBS) are Food and Drug Administration-approved therapeutic techniques. The VNS provides retrograde signaling to the central nervous system, whereas DBS and RNS are more target specific in the central nervous system. While DBS is open-loop and approved for stimulation of the anterior nucleus of the thalamus, the RNS is closed-loop and can stimulate any cortical or subcortical structure. We will review different modalities and their clinical efficacy in individuals with epilepsy, with a focus on pediatric patients.

Relationship Between Iron Distribution in Deep Gray Matter Nuclei Measured by Quantitative Susceptibility Mapping and Motor Outcome After Deep Brain Stimulation in Patients With Parkinson's Disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor deficits in advanced Parkinson's disease (PD) patients, but the degree of motor improvement varies across individuals. PD pathology involves the changes of iron spatial distribution in the deep gray matter nuclei. To explore the relationship between the iron spatial distribution and motor improvement among PD patients who underwent STN-DBS surgery in three regions: substantia nigra (SN), STN, and dentate nucleus (DN). Prospective. Forty PD patients (49.7 ± 8.8 years, 22 males/18 females) who underwent bilateral STN-DBS. A 3 T preoperative three-dimensional spoiled bipolar-readout multi-echo gradient recalled echo and two-dimensional fast spin echo sequences. Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III) scores were assessed 2-3 days before and 6 months after STN-DBS. The first- and second-order texture features in regions of interest were measured on susceptibility maps. Intraclass correlation coefficient was used to determine the consistency of the region of interest volumes delineated by the two raters. Pearson or Spearman's correlation coefficients were used to assess the relationship between motor improvement after DBS and texture features. A P-value <0.05 was considered statistically significant. MDS-UPDRS III scores were reduced by 59.9% after STN-DBS in 40 PD patients. Motor improvement correlated with second-order texture parameters in the SN including angular second moment (r=-0.449), correlation (rho=0.326), sum of squares (r=0.402), sum of entropy (rho=0.421), and entropy (r=0.410). Additionally, DBS outcome negatively correlated with mean susceptibility values in the DN (r=-0.400). PD patients with a more homogeneous iron distribution throughout the SN or a higher iron concentration in the DN responded worse to STN-DBS. 2 TECHNICAL EFFICACY: Stage 1.

No effect of subthalamic deep brain stimulation on metacognition in Parkinson’s disease

Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a powerful treatment in Parkinson’s disease (PD), which provides a positive effect on motor symptoms although the way it operates on high cognitive processes such as metacognition remains unclear. To address this issue, we recorded electroencephalogram (EEG) of PD patients treated with STN-DBS that performed a reversal learning (RL) paradigm endowed with metacognitive self-assessment. We considered two stimulation conditions, namely DBS-ON (stimulation on) and DBS-OFF (stimulation off), and focused our EEG-analysis on the frontal brain region due to its involvement on high cognitive processes. We found a trend towards a significant difference in RL ability between stimulation conditions. STN-DBS showed no effect on metacognition, although a significant association between accuracy and decision confidence level held for DBS OFF, but not in the case of DBS ON. In summary, our study revealed no significant effect of STN-DBS on RL or metacognition.

Deep brain stimulation of the ventralis intermedius nucleus of the thalamus and posterior subthalamic area for Holmes’ tremor secondary to brainstem hemorrhage: A case report

Deep brain stimulation of the ventralis intermedius nucleus of the thalamus and posterior subthalamic area for Holmes’ tremor secondary to brainstem hemorrhage: A case report

Magnetoencephalography to measure the effect of contact point-specific deep brain stimulation in Parkinson’s disease: A proof of concept study

BackgroundDeep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for disabling fluctuations in motor symptoms in Parkinson’s disease (PD) patients. However, iterative exploration of all individual contact points (four in each STN) by the clinician for optimal clinical effects may take months. ObjectiveIn this proof of concept study we explored whether magnetoencephalography (MEG) has the potential to noninvasively measure the effects of changing the active contact point of STN-DBS on spectral power and functional connectivity in PD patients, with the ultimate aim to aid in the process of selecting the optimal contact point, and perhaps reduce the time to achieve optimal stimulation settings. MethodsThe study included 30 PD patients who had undergone bilateral DBS of the STN. MEG was recorded during stimulation of each of the eight contact points separately (four on each side). Each stimulation position was projected on a vector running through the longitudinal axis of the STN, leading to one scalar value indicating a more dorsolateral or ventromedial contact point position. Using linear mixed models, the stimulation positions were correlated with band-specific absolute spectral power and functional connectivity of i) the motor cortex ipsilateral tot the stimulated side, ii) the whole brain. ResultsAt group level, more dorsolateral stimulation was associated with lower low-beta absolute band power in the ipsilateral motor cortex (p = .019). More ventromedial stimulation was associated with higher whole-brain absolute delta (p = .001) and theta (p = .005) power, as well as higher whole-brain theta band functional connectivity (p = .040). At the level of the individual patient, switching the active contact point caused significant changes in spectral power, but the results were highly variable. ConclusionsWe demonstrate for the first time that stimulation of the dorsolateral (motor) STN in PD patients is associated with lower low-beta power values in the motor cortex. Furthermore, our group-level data show that the location of the active contact point correlates with whole-brain brain activity and connectivity. As results in individual patients were quite variable, it remains unclear if MEG is useful in the selection of the optimal DBS contact point.

Investigating the electrical stimulation of the subthalamic nucleus for the treatment of cortical stroke

Investigating the electrical stimulation of the subthalamic nucleus for the treatment of cortical stroke

Cerebellar gray matter alterations predict deep brain stimulation outcomes in Meige syndrome

BackgroundThe physiopathologic mechanism of Meige syndrome (MS) has not been clarified, and neuroimaging studies centering on cerebellar changes in MS are scarce. Moreover, even though deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been recognized as an effective surgical treatment for MS, there has been no reliable biomarker to predict its efficacy. ObjectiveTo characterize the volumetric alterations of gray matter (GM) in the cerebellum in MS and to identify GM measurements related to a good STN-DBS outcome. MethodsWe used voxel-based morphometry and lobule-based morphometry to compare the regional and lobular GM differences in the cerebellum between 47 MS patients and 52 normal human controls (HCs), as well as between 31 DBS responders and 10 DBS non-responders. Both volumetric analyses were achieved using the Spatially Unbiased Infratentorial Toolbox (SUIT). Further, we performed partial correlation analyses to probe the relationship between the cerebellar GM changes and clinical scores. Finally, we plotted the receiver operating characteristic (ROC) curve to select biomarkers for MS diagnosis and DBS outcomes prediction. ResultsCompared to HCs, MS patients had GM atrophy in lobule Crus I, lobule VI, lobule VIIb, lobule VIIIa, and lobule VIIIb. Compared to DBS responders, DBS non-responders had lower GM volume in the left lobule VIIIb. Moreover, partial correlation analyses revealed a positive relationship between the GM volume of the significant regions/lobules and the symptom improvement rate after DBS surgery. ROC analyses demonstrated that the GM volume of the significant cluster in the left lobule VIIIb could not only distinguish MS patients from HCs but also predict the outcomes of STN-DBS surgery with high accuracy. ConclusionMS patients display bilateral GM shrinkage in the cerebellum relative to HCs. Regional GM volume of the left lobule VIIIb can be a reliable biomarker for MS diagnosis and DBS outcomes prediction.

Reduced synaptic SV2A density in a porcine model of Parkinson’s disease and its modulation by deep brain stimulation of the subthalamic nucleus

Reduced synaptic SV2A density in a porcine model of Parkinson’s disease and its modulation by deep brain stimulation of the subthalamic nucleus

Effects of the combined treatment of bilateral subthalamic nucleus stimulation and levodopa on balance and mobility in Parkinson's disease.

<p>Background and purpose &ndash; To evaluate the efficacy of the combined therapy of bilateral subthalamic nucleus deep brain stimulation (STN-DBS) and dopaminergic medication on balance and mobility in patients with Parkinson&rsquo;s disease (PD).</p>. <p>Eighteen PD patients under bilateral STN-DBS stimulation therapy, were enrolled in this study. Unified Parkinson&rsquo;s Disease Rating Scale (UPDRS) was applied to assess the patients&rsquo; clinical characteristics. UPDRS part III postural instability/gait disorder (PIGD) scores (sum of items 3.9-3.13) and UPDRS part III postural stability item (item 3.12) were calculated separately. Patients were evaluated with Berg Balance Scale (BBS), Mini-Balance Evaluation Systems Test (Mini-BESTest), Timed Up and Go (TUG) test, dual-task TUG test, and Forward Functional Reach (FFR) Test in two conditions: Stimulation-ON (stim-ON)/Medication-ON (Med-ON) and Stimulation-OFF (Stim-OFF)/Med-ON.</p>. <p>The mean age of patients was 59.5&plusmn;9.1 (R: 41-71) years. The UPDRS part III total score and PIGD subsection score significantly improved after stimulation (p=0.001), but the postural instability item of the UPDRS part III did not change significantly (p=0.1). There were no significant differences between the Stim-ON/Med-ON and Stim-OFF/Med-ON conditions, in terms of total Mini-BESTest total scores, total BBS score, FFR test score (p&gt;0.05 for all of them). TUG test was significantly improved in the Stim-ON/Med-ON condition compared to Stim-OFF/Med-ON condition (p=0.03), but DT-TUG test did not change (p=0.1).&nbsp;</p>. <p>Combined bilateral STN-DBS and dopaminergic medication therapy had an additional improvement on motor symptoms and mobility performance, but not on balance and dual-task mobility.&nbsp;</p>.

Frequency specific effects on response selection in subthalamic nucleus stimulation for Parkinson’s disease

Frequency specific effects on response selection in subthalamic nucleus stimulation for Parkinson’s disease

Stimulation of the Presupplementary Motor Area Cluster of the Subthalamic Nucleus Predicts More Consistent Clinical Outcomes.

The development of diffusion tensor imaging and tractography has raised increasing interest in the functional targeting of deep brain stimulation of the subthalamic nucleus (STN) in Parkinson disease. To study, using deterministic tractography, the functional subdivisions of the STN and hyperdirect white matter connections located between the STN and the medial frontal cortex, especially the presupplementary motor area (preSMA), SMA, primary motor area (M1), and dorsolateral premotor cortex, and to study retrospectively whether this information correlates with clinical outcome. Twenty-two patients with Parkinson disease who underwent STN deep brain stimulation were analyzed. Using 3 T MR images, the medial frontal cortex was manually segmented into preSMA, SMA, M1, and dorsolateral premotor cortex, which were then used to determine the functional subdivisions of the lateral border of the STN. The intersectional quantities of the volume of activated tissue (VAT) and the hyperdirect white matter connections were calculated. The results were combined with clinical data including unilateral 12-month postoperative motor outcome and levodopa equivalent daily dose. Stimulated clusters of the STN were connected mostly to the cortical SMA and preSMA regions. Patients with primarily preSMA cluster stimulation (presmaVAT% ≥ 50%) had good responses to the treatment with unilateral motor improvement over 40% and levodopa equivalent daily dose reduction over 60%. Larger VAT was not found to correlate with better patient outcomes. Our study is the first to suggest that stimulating, predominantly, the STN cluster where preSMA hyperdirect pathways are located, could be predictive of more consistent treatment results.

Characteristics of Electroencephalogram in the Prefrontal Cortex during Deep Brain Stimulation of Subthalamic Nucleus in Parkinson's Disease under Propofol General Anesthesia.

Monitoring the depth of anesthesia by electroencephalogram (EEG) based on the prefrontal cortex is an important means to achieve accurate regulation of anesthesia for subthalamic nucleus (STN) deep brain stimulation (DBS) under general anesthesia in patients with Parkinson's disease (PD). However, no previous study has conducted an in-depth investigation into this monitoring data. Here, we aimed to analyze the characteristics of prefrontal cortex EEG during DBS with propofol general anesthesia in patients with PD and determine the reference range of parameters derived from the depth of anesthesia monitoring. Additionally, we attempted to explore whether the use of benzodiazepines in the 3 days during hospitalization before surgery impacted the interpretation of the EEG parameters. We included the data of 43 patients with PD who received STN DBS treatment and SedLine monitoring during the entire course of general anesthesia with propofol in a single center. Eighteen patients (41.86%) took benzodiazepines during hospitalization. We divided the anesthesia process into three stages: awake state before anesthesia, propofol anesthesia state, and shallow anesthesia state during microelectrode recording (MER). We analyzed the power spectral density (PSD) and derived parameters of the patients' prefrontal EEG, including the patient state index (PSI), spectral edge frequency (SEF) of the left and right sides, and the suppression ratio. The baseline characteristics, preoperative medication, preoperative frontal lobe image characteristics, preoperative motor and non-motor evaluation, intraoperative vital signs, internal environment and anesthetic information, and postoperative complications are listed. We also compared the groups according to whether they took benzodiazepines before surgery during hospitalization. The average PSI of the awake state, propofol anesthesia state, and MER state were 89.86 ± 6.89, 48.68 ± 12.65, and 62.46 ± 13.08, respectively. The preoperative administration of benzodiazepines did not significantly affect the PSI or SEF, but did reduce the total time of suppression, maximum suppression ratio, and the PSD of beta and gamma during MER. Regarding the occurrence of postoperative delirium and mini-mental state examination (MMSE) scores, there was no significant difference between the two groups (chi-square test, p = 0.48; Mann-Whitney U test, p = 0.30). For the first time, we demonstrate the reference range of the derived parameters of the depth of anesthesia monitoring and the characteristics of the prefrontal EEG of patients with PD in the awake state, propofol anesthesia state, and shallow anesthesia during MER. Taking benzodiazepines in the 3 days during hospitalization before surgery reduces suppression and the PSD of beta and gamma during MER, but does not significantly affect the observation of anesthesiologists on the depth of anesthesia, nor affect the postoperative delirium and MMSE scores.

Behavioral Reaction and c-fos Expression after Opioids Injection into the Pedunculopontine Tegmental Nucleus and Electrical Stimulation of the Ventral Tegmental Area

The pedunculopontine tegmental nucleus (PPN) regulates the activity of dopaminergic cells in the ventral tegmental area (VTA). In this study, the role of opioid receptors (OR) in the PPN on motivated behaviors was investigated by using a model of feeding induced by electrical VTA-stimulation (Es-VTA) in rats (male Wistar; n = 91). We found that the OR excitation by morphine and their blocking by naloxone within the PPN caused a change in the analyzed motivational behavior and neuronal activation. The opioid injections into the PPN resulted in a marked, dose-dependent increase/decrease in latency to feeding response (FR), which corresponded with increased neuronal activity (c-Fos protein), in most of the analyzed brain structures. Morphine dosed at 1.25/1.5 µg into the PPN significantly reduced behavior induced by Es-VTA, whereas morphine dosed at 0.25/0.5 µg into the PPN did not affect this behavior. The opposite effect was observed after the naloxone injection into the PPN, where its lowest doses of 2.5/5.0 μg shortened the FR latency. However, its highest dose of 25.0 μg into the PPN nucleus did not cause FR latency changes. In conclusion, the level of OR arousal in the PPN can modulate the activity of the reward system.

Subthalamic Nucleus Stimulation-Induced Local Field Potential Changes in Dystonia.

Subthalamic nucleus (STN) stimulation is an effective treatment for Parkinson's disease and induced local field potential (LFP) changes that have been linked with clinical improvement. STN stimulation has also been used in dystonia although the internal globus pallidus is the standard target where theta power has been suggested as a physiomarker for adaptive stimulation. We aimed to explore if enhanced theta power was also present in STN and if stimulation-induced spectral changes that were previously reported for Parkinson's disease would occur in dystonia. We recorded LFPs from 7 patients (12 hemispheres) with isolated craniocervical dystonia whose electrodes were placed such that inferior, middle, and superior contacts covered STN, zona incerta, and thalamus. We did not observe prominent theta power in STN at rest. STN stimulation induced similar spectral changes in dystonia as in Parkinson's disease, such as broadband power suppression, evoked resonant neural activity (ERNA), finely-tuned gamma oscillations, and an increase in aperiodic exponents in STN-LFPs. Both power suppression and ERNA localize to STN. Based on this, single-pulse STN stimulation elicits evoked neural activities with largest amplitudes in STN, which are relayed to the zona incerta and thalamus with changing characteristics as the distance from STN increases. Our results show that STN stimulation-induced spectral changes are a nondisease-specific response to high-frequency stimulation, which can serve as placement markers for STN. This broadens the scope of STN stimulation and makes it an option for other disorders with excessive oscillatory peaks in STN. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Automated deep brain stimulation programming based on electrode location: a randomised, crossover trial using a data-driven algorithm

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is highly effective in controlling motor symptoms in patients with Parkinson's disease. However, correct selection of stimulation parameters is pivotal to treatment success and currently follows a time-consuming and demanding trial-and-error process. We aimed to assess treatment effects of stimulation parameters suggested by a recently published algorithm (StimFit) based on neuroimaging data. This double-blind, randomised, crossover, non-inferiority trial was carried out at Charité - Universitätsmedizin, Berlin, Germany, and enrolled patients with Parkinson's disease treated with directional octopolar electrodes targeted at the STN. All patients had undergone DBS programming according to our centre's standard of care (SoC) treatment before study recruitment. Based on perioperative imaging data, DBS electrodes were reconstructed and StimFit was applied to suggest optimal stimulation settings. Patients underwent motor assessments using the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS-III) during OFF-medication and in OFF-stimulation and ON-stimulation states under both conditions, StimFit and SoC parameter settings. Patients were randomly assigned (1:1) to receive either StimFit-programmed DBS first and SoC-programmed DBS second, or SoC-programmed DBS first and StimFit-programmed DBS second. The allocation schedule was generated using a computerised random number generator. Both the rater and patients were masked to the sequence of SoC and StimFit stimulation conditions. All patients who participated in the study were included in the analysis. The primary endpoint of this study was the absolute mean difference between MDS-UPDRS-III scores under StimFit and SoC stimulation, with a non-inferiority margin of 5 points. The study was registered at the German Register for Clinical Trials (DRKS00023115), and is complete. Between July 10, 2020, and Oct 28, 2021, 35 patients were enrolled in the study; 18 received StimFit followed by SoC stimulation, and 17 received SoC followed by StimFit stimulation. Mean MDS-UPDRS-III scores improved from 47·3 (SD 17·1) at OFF-stimulation baseline to 24·7 (SD 12·4) and 26·3 (SD 12·4) under SoC and StimFit stimulation, respectively. Mean difference between motor scores was -1·6 (SD 7·1; 95% CI -4·0 to 0·9; superiority test psuperiority=0·20; n=35), establishing non-inferiority of StimFit stimulation at a margin of -5 points (non-inferiority test pnon-inferiority=0·0038). In six patients (17%), initial programming of StimFit settings resulted in acute side-effects and amplitudes were reduced until side-effects disappeared. Automated data-driven algorithms can predict stimulation parameters that lead to motor symptom control comparable to SoC treatment. This approach could significantly decrease the time necessary to obtain optimal treatment parameters. Deutsche Forschungsgemeinschaft through NeuroCure Clinical Research Center and TRR 295.

Deep Brain Stimulation in the Subthalamic Nucleus Can Improve Skilled Forelimb Movements and Retune Dynamics of Striatal Networks in a Rat Stroke Model.

Recovery of upper limb (UL) impairment after stroke is limited in stroke survivors. Since stroke can be considered as a network disorder, neuromodulation may be an approach to improve UL motor dysfunction. Here, we evaluated the effect of high-frequency stimulation (HFS) of the subthalamic nucleus (STN) in rats on forelimb grasping using the single-pellet reaching (SPR) test after stroke and determined costimulated brain regions during STN-HFS using 2-[18F]Fluoro-2-deoxyglucose-([18F]FDG)-positron emission tomography (PET). After a 4-week training of SPR, photothrombotic stroke was induced in the sensorimotor cortex of the dominant hemisphere. Thereafter, an electrode was implanted in the STN ipsilateral to the infarction, followed by a continuous STN-HFS or sham stimulation for 7 days. On postinterventional day 2 and 7, an SPR test was performed during STN-HFS. Success rate of grasping was compared between these two time points. [18F]FDG-PET was conducted on day 2 and 3 after stroke, without and with STN-HFS, respectively. STN-HFS resulted in a significant improvement of SPR compared to sham stimulation. During STN-HFS, a significantly higher [18F]FDG-uptake was observed in the corticosubthalamic/pallidosubthalamic circuit, particularly ipsilateral to the stimulated side. Additionally, STN-HFS led to an increased glucose metabolism within the brainstem. These data demonstrate that STN-HFS supports rehabilitation of skilled forelimb movements, probably by retuning dysfunctional motor centers within the cerebral network.