Exploring adverse effects of deep brain stimulation: the need for personalized care and long-term monitoring.

Deep Brain Stimulation (DBS), an FDA-approved treatment for movement disorders such as Parkinson's Disease (PD), is increasingly used for various neurological and neuropsychiatric conditions. A recent systematic review and meta-analysis by Bahadori et al. highlighted a significant increase in Body Mass Index (BMI) among patients post-DBS, with most participants having PD. The study, however, noted moderate heterogeneity (I² = 67.566%) without thoroughly addressing its potential causes or proposing strategies to mitigate it. The review's limited patient diversity and short follow-up period also challenge its generalizability and long-term implications. In addition to BMI changes, DBS has been linked to motor, cognitive, and psychiatric side effects. Patients undergoing subthalamic nucleus (STN) stimulation, for example, face risks of motor complications, including speech and gait issues, while cognitive declines, particularly in verbal fluency and executive function, are also concerning. Psychiatric side effects such as depression, anxiety, and psychosis further complicate treatment outcomes. These findings underscore the importance of personalized treatment strategies, preoperative assessments, and ongoing patient education to minimize adverse effects and optimize the therapeutic potential of DBS.

Deep brain stimulation versus vagus nerve stimulation for the motor function of poststroke hemiplegia: study protocol for a multicentre randomised controlled trial.

INTRODUCTION: Deep brain stimulation (DBS) and vagus nerve stimulation (VNS) can improve motor function in patients with poststroke hemiplegia. No comparison study exists. METHODS AND ANALYSIS: This is a randomised, double-blind, controlled clinical trial involving 64 patients who had their first stroke at least 6 months ago and are experiencing poststroke limb dysfunction. These patients must receive necessary support at home and consent to participate. The aim is to evaluate the effectiveness and safety of DBS and VNS therapies. Patients are excluded if they have implantable devices that are sensitive to electrical currents, severe abnormalities in their lower limbs or are unable to comply with the trial procedures. The study has two parallel, distinct treatment arms: the Stimulation Group and the Sham Group. Initially, the Stimulation Group will undergo immediate electrical stimulation postsurgery, while the Sham Group will receive non-stimulation 1 month later. After 3 months, these groups will swap treatments, with the Stimulation Group discontinuing stimulation and the Sham Group initiating stimulation. Six months later, both groups will resume active stimulation. Our primary outcomes will meticulously assess motor function improvements, using the Fugl-Meyer Assessment, and safety, monitored by tracking adverse reaction rates. Furthermore, we will gain a comprehensive view of patient outcomes by evaluating secondary measures, including clinical improvement (National Institutes of Health Stroke Scale), surgical complications/side effects, quality of life (36-item Short Form Questionnaire) and mental health status (Hamilton Anxiety Rating Scale/Hamilton Depression Rating Scale). To ensure a thorough understanding of the long-term effects, we will conduct follow-ups at 9 and 12 months postsurgery, with additional long-term assessments at 15 and 18 months. These follow-ups will assess the sustained performance and durability of the treatment effects. The statistical analysis will uncover the optimal treatment strategy for poststroke hemiplegia, providing valuable insights for clinicians and patients alike. ETHICS AND DISSEMINATION: This study was reviewed and approved by the Ethical Committee of Chinese PLA General Hospital (S2022-789-01). The findings will be submitted for publication in peer-reviewed journals with online accessibility, ensuring adherence to the conventional scientific publishing process while clarifying how the research outcomes will be disseminated and accessed. TRIAL REGISTRATION NUMBER: NCT06121947.

Deep brain stimulation for Tourette's syndrome.

Tourette's syndrome is a neuropsychiatric disorder characterized by formidable motor and vocal tics. Many individuals also present with comorbid neuropsychiatric conditions. Though patients often benefit from pharmacological and behavioral therapies, a subset of individuals develop severe, treatment-resistant symptoms that might necessitate more invasive interventions, such as Deep Brain Stimulation (DBS). DBS, particularly targeting regions like the globus pallidus internus (GPi) and the centromedian-parafascicular complex (CM-Pf) of the thalamus, has demonstrated effectiveness in reducing tic severity and improving quality of life. This review outlines the mechanism, clinical efficacy, and long-term outcome of DBS in TS. Results from clinical studies reveal significant reductions in tics. However, success with DBS is variable depending on a number of factors, including target selection and electrode placement. The use of DBS has ethical considerations, which include risks to the surgical procedure, the need for full and complete informed consent, and questions about the implications of such treatment on cognitive and emotional growth. Long-term follow-up will be required to ensure appropriate patient outcomes and complication management. Additional research and ethical debate will be needed with advancing DBS technology to ensure responsible and equitable treatment. This paper narratively summarizes the surgical options available for TS, with a focus on the current status of DBS in the management of the disease.

Machine learning for the localization of Subthalamic Nucleus during deep brain stimulation surgery: a systematic review and Meta-analysis.

INTRODUCTION: Delineating subthalamic nucleus (STN) boundaries using microelectrode recordings (MER) and trajectory history is a valuable resource for neurosurgeons, aiding in the accurate and efficient positioning of deep brain stimulation (DBS) electrodes within the STN. Here, we aimed to assess the application of artificial intelligence, specifically Hidden Markov Models (HMM), in the context of STN localization. METHODS: A comprehensive search strategy was employed, encompassing electronic databases, including PubMed, EuroPMC, and MEDLINE. This search strategy entailed a combination of controlled vocabulary (e.g., MeSH terms) and free-text keywords pertaining to "artificial intelligence," "machine learning," "deep learning," and "deep brain stimulation." Inclusion criteria were applied to studies reporting the utilization of HMM for predicting outcomes in DBS, based on structured patient-level health data, and published in the English language. RESULTS: This systematic review incorporated a total of 14 studies. Various machine learning compared wavelet feature to proposed features in diagnosing the STN, with the HMM yielding a diagnostic odds ratio (DOR) of 838.677 (95% CI: 203.309-3459.645). Similarly, the K-Nearest Neighbors (KNN) model produced parameter estimates, including a diagnostic odds ratio of 25.151 (95% CI: 12.270-51.555). Meanwhile, the support vector machine (SVM) model exhibited parameter estimates, with a DOR of 13.959 (95% CI: 10.436-18.671). CONCLUSIONS: MER data demonstrates significant variability in neural activity, with studies employing a wide range of methodologies. Machine learning plays a crucial role in aiding STN diagnosis, though its accuracy varies across different approaches.

Letter to the Editor: "Efficacy of subthalamic deep brain stimulation programming strategies for gait disorders in Parkinson's disease: A systematic review and meta-analysis".

This letter provides valuable insights on the recently published article titled "Efficacy of Subthalamic Deep Brain Stimulation Programming Strategies for Gait Disorders in Parkinson's Disease: A Systematic Review and Meta-Analysis." While commending the authors comprehensive review, I suggest future research focus on standardizing gait disorder classifications, conducting long-term studies to assess the durability of DBS effects and exploring adaptive DBS systems for dynamic real-time programming. Additionally, integrating advanced neuroimaging techniques could enhance our understanding of neural connectivity changes post-DBS. These recommendations could significantly improve tailored interventions and outcomes for Parkinson's disease patients with gait disturbances.

Closed-Loop Deep Brain Stimulation With Reinforcement Learning and Neural Simulation.

Deep Brain Stimulation (DBS) is effective for movement disorders, particularly Parkinson's disease (PD). However, a closed-loop DBS system using reinforcement learning (RL) for automatic parameter tuning, offering enhanced energy efficiency and the effect of thalamus restoration, is yet to be developed for clinical and commercial applications. In this research, we instantiate a basal ganglia-thalamic (BGT) model and design it as an interactive environment suitable for RL models. Four finely tuned RL agents based on different frameworks, namely Soft Actor-Critic (SAC), Twin Delayed Deep Deterministic Policy Gradient (TD3), Proximal Policy Optimization (PPO), and Advantage Actor-Critic (A2C), are established for further comparison. Within the implemented RL architectures, the optimized TD3 demonstrates a significant 67% reduction in average power dissipation when compared to the open-loop system while preserving the normal response of the simulated BGT circuitry. As a result, our method mitigates thalamic error responses under pathological conditions and prevents overstimulation. In summary, this study introduces a novel approach to implementing an adaptive parameter-tuning closed-loop DBS system. Leveraging the advantages of TD3, our proposed approach holds significant promise for advancing the integration of RL applications into DBS systems, ultimately optimizing therapeutic effects in future clinical trials.

Real-world outcomes of Deep Brain Stimulation for dystonia treatment: Protocol for a prospective, multicenter, international registry.

INTRODUCTION: Deep Brain Stimulation (DBS) is an established therapeutic approach for the treatment of dystonia. However, to date, no large-scale or comprehensive DBS dystonia patient registry has been yet undertaken. Here, we describe the protocol for a world-wide registry of clinical outcomes in dystonia patients implanted with DBS. METHODS AND ANALYSIS: This protocol describes a multicenter, international clinical outcomes registry consisting of up to 200 prospectively enrolled participants at up to 40 different sites to be implanted with a constant-current, multiple independent current controlled (MICC) DBS device (Vercise DBS Systems, Boston Scientific) for treatment of dystonia. Key inclusion criteria for registry candidates include the following: understanding of study requirements and treatment procedures, a signed written informed consent form prior to participation, and meeting all criteria established in the locally applicable Instructions for Use (IFU) for the implanted DBS system. Key clinical endpoints include (but are not limited to) the evaluation of disease state (Burke-Fahn-Marsden Dystonia Rating Scale [BFMDRS], Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), quality of life (Short Form Health Survey-36, Short Form Health Survey-10), and treatment satisfaction (Clinical Global Impression of Change [CGI-Clinician; CGI-Subject; CGI-Caregiver]) at 6-months, 12-months, 2-years, and 3-years post-lead placement. Adverse events are documented and reported using structured questionnaires. PERSPECTIVES: Treatment of patients with dystonia using DBS has progressed considering recent technological advances. This international dystonia outcomes registry aims to collect and evaluate real-world clinical data derived from patients who have been implanted with a constant-current, MICC-equipped DBS system (with available directional capabilities), per standard of care.

Woodhouse-sakati syndrome with no reportable MRI findings: a case report.

BACKGROUND: Woodhouse-Sakati Syndrome (WSS) is a rare autosomal recessive condition caused by biallelic pathogenic variants in the DCAF17 gene, with fewer than 200 cases reported in the literature. Symptoms first emerge in middle-late adolescence with a spectrum of hypogonadal and progressive neurological features. CASE PRESENTATION: We present a case of WSS with no reportable T2-weighted, apparent diffusion coefficient mapping and susceptibility weighted MRI findings. This differs from cases reported in the current literature. Our patient developed abnormal movements in both legs, clumsiness of the hands, dysarthria, and swallowing difficulties. Moreover, she presented with alopecia manifesting as frontal and temporal balding, severe dystonia with painful dystonic spasms primarily in the left upper limb, as well as primary amenorrhea. She was not independently ambulatory on presentation, requiring wheelchair assistance. Genetic testing, the crucial test for a definitive diagnosis, was undertaken in Qatar and confirmed WSS. Treatment provided includes botulinum toxin injections and deep brain stimulation, providing better dystonia control, with progress in walking and strength exercises, and overall remarkable improvement. Intensive neurorehabilitation regimes were also deployed from admission, including physiotherapy, occupational therapy and speech and language therapy. CONCLUSION: This case adds to the current literature on WSS manifestations, with all previously reported cases having positive MRI findings, unlike our case.

A Patient-Centered Perspective on Changes in Personal Characteristics After Deep Brain Stimulation.

Importance: Deep brain stimulation (DBS) results in improvements in motor function and quality of life in patients with Parkinson disease (PD), which might impact a patient's perception of valued personal characteristics. Prior studies investigating whether DBS causes unwanted changes to oneself or one's personality have methodological limitations that should be addressed. Objective: To determine whether DBS is associated with changes in characteristics that patients with PD identify as personally meaningful. Design, Setting, and Participants: This cohort study assessed changes in visual analog scale (VAS) ratings reflecting the extent to which patients with PD manifested individually identified personal characteristics before and 6 and 12 months after DBS at a large academic medical center from February 21, 2018, to December 9, 2021. The VAS findings were tailored to reflect the top 3 individually identified personal characteristics the patient most feared losing. The VASs were scored from 0 to 10, with 0 representing the least and 10 the most extreme manifestation of the trait. Change scores were examined at the individual level. Content analysis was used to code the qualitative data. Qualitative and quantitative analyses were performed from January 12, 2019 (initial qualitative coding), to December 15, 2023. Exposure: Deep brain stimulation. Main Outcomes and Measures: The primary outcome variable was the mean VAS score for the top 3 personal characteristics. The secondary outcome was the incidence of meaningful changes on the patients' top 3 characteristics at the individual level. Results: Fifty-two of 54 dyads of patients with PD and their care partners (96.3%) were recruited from a consecutive series approved for DBS (36 patients [69.2%] were male and 45 care partners [86.5%] were female; mean [SD] age of patients, 61.98 [8.55] years). Two patients and 1 care partner were lost to follow-up. Increases in the mean VAS score (indicative of greater manifestation of [ie, positive changes in] specific characteristics) were apparent following DBS for ratings of both the patients (Wald χ2 = 16.104; P < .001) and care partners (Wald χ2 = 6.746; P < .001) over time. The slopes of the changes for both the patient and care partners were correlated, indicating agreement in observed changes over time. The individual level analyses indicated that scores for most patients and care partners remained the same or increased. Conclusions and Relevance: In this cohort study, participants reported greater (more positive) manifestations of individually identified, valued characteristics after DBS. These findings may be relevant to informing decision-making for patients with advanced PD who are considering DBS.

Beyond Pallidal or Subthalamic Deep Brain Stimulation to Treat Dystonia.

Deep brain stimulation of the subthalamic nucleus and globus pallidus internus is approved by the Food and Drug Administration for treating dystonia. Both targets have shown effectiveness in improving symptoms, but post-operative outcomes can vary significantly among patients. This variability has led researchers to explore alternative neuromodulation targets that might offer more consistent results. Emerging research has highlighted several promising new targets for DBS in dystonia. This review examines pre-clinical and clinical data on novel DBS targets for dystonia and explores non-invasive neuromodulation studies that shed light on the disease's underlying pathological circuitry.

Directional Stimulus-Evoked Pallidal Electrophysiology in Primary Dystonia.

Background: Deep brain stimulation for dystonia improves motor symptoms but variable and delayed responses challenge patient selection, targeting, and device programming. Case Report: Here we studied intracranial electrophysiology in a patient with primary dystonia and observed evoked resonant neural activity (ERNA) in the globus pallidus interna. These local stimulus-evoked potentials displayed refractory periods and paired-pulse facilitation at clinically relevant interstimulus intervals. Sensing from directional DBS contacts localized ERNA to an effective stimulation site in the ventral posterolateral portion of the pallidum. Discussion: To the best of our knowledge, this is the first observation of ERNA in the globus pallidus interna in a patient with primary dystonia. Stimulus-evoked activity could eventually guide both directional and adaptive stimulation for dystonia and other complex neuropsychiatric disorders.

Non-invasive temporal interference brain stimulation reduces preference on morphine-induced conditioned place preference in rats.

Long-term use of opioid drugs such as morphine can induce addiction in the central nervous system through dysregulation of the reward system of the brain. Deep brain stimulation (DBS) is a non-pharmacological technique capable of attenuating behavioral responses associated with opioid drug consumption and possesses the capability to selectively activate and target localized brain regions with a high spatial resolution. However, long-term implantation of electrodes in brain tissue may limit the effectiveness of DBS due to changes in impedance, position, and shape of the tip of the stimulation electrode and the risk of infection of nerve tissue around the implanted electrode. The main objective of the current study is to evaluate the effect of temporal interference (TI) brain stimulation on addictive behaviors of morphine-induced conditioned place preference (CPP) in rats. TI stimulation is a non-invasive technique used transcranially to modulate neural activity within targeted brain regions. It involves applying two high-frequency currents with slightly different frequencies, resulting in interference and targeted stimulation of different brain areas with the desired spatial resolution. The results indicated that TI stimulation with the amplitude of I 1 = I 2 = 0.5 mA, carrier frequency of 2 kHz, frequency difference of 25 Hz, ON-OFF stimulation frequency of 0.25 Hz, and total duration of 10 min in three consecutive days resulted in a significant reduction of morphine preference in the morphine-stimulation group in comparison with the morphine group (p < 0.001). These findings highlight the potential of TI stimulation as a modulatory intervention in mitigating the addictive properties of morphine and provide valuable insights into the therapeutic implications of this stimulation paradigm for treatment of opioid drugs in human subjects.

Structural connectivity modifications following deep brain stimulation of the subcallosal cingulate and nucleus accumbens in severe anorexia nervosa.

PURPOSE: Anorexia nervosa (AN) is a mental health disorder characterized by significant weight loss and associated medical and psychological comorbidities. Conventional treatments for severe AN have shown limited effectiveness, leading to the exploration of novel interventional strategies, including deep brain stimulation (DBS). However, the neural mechanisms driving DBS interventions, particularly in psychiatric conditions, remain uncertain. This study aims to address this knowledge gap by examining changes in structural connectivity in patients with severe AN before and after DBS. METHODS: Sixteen participants, including eight patients with AN and eight controls, underwent baseline T1-weigthed and diffusion tensor imaging (DTI) acquisitions. Patients received DBS targeting either the subcallosal cingulate (DBS-SCC, N = 4) or the nucleus accumbens (DBS-NAcc, N = 4) based on psychiatric comorbidities and AN subtype. Post-DBS neuroimaging evaluation was conducted in four patients. Data analyses were performed to compare structural connectivity between patients and controls and to assess connectivity changes after DBS intervention. RESULTS: Baseline findings revealed that structural connectivity is significantly reduced in patients with AN compared to controls, mainly regarding callosal and subcallosal white matter (WM) tracts. Furthermore, pre- vs. post-DBS analyses in AN identified a specific increase after the intervention in two WM tracts: the anterior thalamic radiation and the superior longitudinal fasciculus-parietal bundle. CONCLUSIONS: This study supports that structural connectivity is highly compromised in severe AN. Moreover, this investigation preliminarily reveals that after DBS of the SCC and NAcc in severe AN, there are WM modifications. These microstructural plasticity adaptations may signify a mechanistic underpinning of DBS in this psychiatric disorder.

A systematic review of deep brain stimulation for substance use disorders.

BACKGROUND: Pharmaco-psychiatric techniques remain the mainstay, first line treatments in substance use disorders (SUD), assisting in detoxification but largely ineffective at reducing dependence. The path to rehabilitation and freedom from addiction often proves uncertain and laborious for both patients and their significant others. Relapse rates for multiple substances of abuse are considerable and the number of SUD patients is on the increase worldwide. OBJECTIVE: To assess efficacy of deep brain stimulation (DBS) as a therapeutic solution for SUDs. METHODS: A systematic electronic database search of PubMed and EMBASE retrieved DBS addiction-focused studies on humans, of which a total of 26 (n = 71) from 2007 to 2023 were deemed eligible, including the first randomized controlled trial (RCT) in this field. This review was prospectively registered with PROSPERO: CRD42023411631. RESULTS: In addressing SUDs, DBS targeting primarily the nucleus accumbens (NAcc), with or without the anterior limb of the internal capsule, presented encouraging levels of efficacy in reducing cravings and consumption, followed by remission in some subjects, but still reporting relapses in 73.2% of patients. CONCLUSIONS: For treatment-refractory addictions DBS use seems limited to reducing cravings with a satisfactory degree of success, yet not clinically consistent in inducing abstinence, suggesting involvement of factors unaffected by DBS intervention. Furthermore, costs and the scale of the problem are such that DBS is unlikely to have a significant societal impact. Nevertheless, DBS may provide insight into the biology of addiction and is worthy of further research using increased methodological rigor, standardized outcome measures, and pre-established surgical protocols.

Deep Learning and fMRI-Based Pipeline for Optimization of Deep Brain Stimulation During Parkinson's Disease Treatment: Toward Rapid Semi-Automated Stimulation Optimization.

OBJECTIVE: Optimized deep brain stimulation (DBS) is fast becoming a therapy of choice for the treatment of Parkinson's disease (PD). However, the post-operative optimization (aimed at maximizing patient clinical benefits and minimizing adverse effects) of all possible DBS parameter settings using the standard-of-care clinical protocol requires numerous clinical visits, which substantially increases the time to optimization per patient (TPP), patient cost burden and limit the number of patients who can undergo DBS treatment. The TPP is further elongated in electrodes with stimulation directionality or in diseases with latency in clinical feedback. In this work, we proposed a deep learning and fMRI-based pipeline for DBS optimization that can potentially reduce the TPP from ~1 year to a few hours during a single clinical visit. METHODS AND PROCEDURES: We developed an unsupervised autoencoder (AE)-based model to extract meaningful features from 122 previously acquired blood oxygenated level dependent (BOLD) fMRI datasets from 39 a priori clinically optimized PD patients undergoing DBS therapy. The extracted features are then fed into multilayer perceptron (MLP)-based parameter classification and prediction models for rapid DBS parameter optimization. RESULTS: The AE-extracted features of optimal and non-optimal DBS were disentangled. The AE-MLP classification model yielded accuracy, precision, recall, F1 score, and combined AUC of 0.96 ± 0.04, 0.95 ± 0.07, 0.92 ± 0.07, 0.93 ± 0.06, and 0.98 respectively. Accuracies of 0.79 ± 0.04, 0.85 ± 0.04, 0.82 ± 0.05, 0.83 ± 0.05, and 0.70 ± 0.07 were obtained in the prediction of voltage, frequency, and x-y-z contact locations, respectively. CONCLUSION: The proposed AE-MLP models yielded promising results for fMRI-based DBS parameter classification and prediction, potentially facilitating rapid semi-automated DBS parameter optimization. Clinical and Translational Impact Statement-A deep learning-based pipeline for semi-automated DBS parameter optimization is presented, with the potential to significantly decrease the optimization duration per patient and patients' financial burden while increasing patient throughput.

Utilizing diffusion tensor imaging as an image biomarker in exploring the therapeutic efficacy of forniceal deep brain stimulation in a mice model of Alzheimer's disease.

Objective.With prolonged life expectancy, the incidence of memory deficits, especially in Alzheimer's disease (AD), has increased. Although multiple treatments have been evaluated, no promising treatment has been found to date. Deep brain stimulation (DBS) of the fornix area was explored as a possible treatment because the fornix is intimately connected to memory-related areas that are vulnerable in AD; however, a proper imaging biomarker for assessing the therapeutic efficiency of forniceal DBS in AD has not been established.Approach.This study assessed the efficacy and safety of DBS by estimating the optimal intersection volume between the volume of tissue activated and the fornix. Utilizing a gold-electroplating process, the microelectrode's surface area on the neural probe was increased, enhancing charge transfer performance within potential water window limits. Bilateral fornix implantation was conducted in triple-transgenic AD mice (3 × Tg-AD) and wild-type mice (strain: B6129SF1/J), with forniceal DBS administered exclusively to 3 × Tg-AD mice in the DBS-on group. Behavioral tasks, diffusion tensor imaging (DTI), and immunohistochemistry (IHC) were performed in all mice to assess the therapeutic efficacy of forniceal DBS.Main results.The results illustrated that memory deficits and increased anxiety-like behavior in 3 × Tg-AD mice were rescued by forniceal DBS. Furthermore, forniceal DBS positively altered DTI indices, such as increasing fractional anisotropy (FA) and decreasing mean diffusivity (MD), together with reducing microglial cell and astrocyte counts, suggesting a potential causal relationship between revised FA/MD and reduced cell counts in the anterior cingulate cortex, hippocampus, fornix, amygdala, and entorhinal cortex of 3 × Tg-AD mice following forniceal DBS.Significance.The efficacy of forniceal DBS in AD can be indicated by alterations in DTI-based biomarkers reflecting the decreased activation of glial cells, suggesting reduced neural inflammation as evidenced by improvements in memory and anxiety-like behavior.