Mapping Subcortico-Cortical Coupling-A Comparison of Thalamic and Subthalamic Oscillations.

BACKGROUND: The ventral intermediate nucleus of the thalamus (VIM) is an effective target for deep brain stimulation in tremor patients. Despite its therapeutic importance, its oscillatory coupling to cortical areas has rarely been investigated in humans. OBJECTIVES: The objective of this study was to identify the cortical areas coupled to the VIM in patients with essential tremor. METHODS: We combined resting-state magnetoencephalography with local field potential recordings from the VIM of 19 essential tremor patients. Whole-brain maps of VIM-cortex coherence in several frequency bands were constructed using beamforming and compared with corresponding maps of subthalamic nucleus (STN) coherence based on data from 19 patients with Parkinson's disease. In addition, we computed spectral Granger causality. RESULTS: The topographies of VIM-cortex and STN-cortex coherence were very similar overall but differed quantitatively. Both nuclei were coupled to the ipsilateral sensorimotor cortex in the high-beta band; to the sensorimotor cortex, brainstem, and cerebellum in the low-beta band; and to the temporal cortex, brainstem, and cerebellum in the alpha band. High-beta coherence to sensorimotor cortex was stronger for the STN (P = 0.014), whereas low-beta coherence to the brainstem was stronger for the VIM (P = 0.017). Although the STN was driven by cortical activity in the high-beta band, the VIM led the sensorimotor cortex in the alpha band. CONCLUSIONS: Thalamo-cortical coupling is spatially and spectrally organized. The overall similar topographies of VIM-cortex and STN-cortex coherence suggest that functional connections are not necessarily unique to one subcortical structure but might reflect larger frequency-specific networks involving VIM and STN to a different degree. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Improved Outcomes and Therapy Longevity after Salvage Using a Novel Spinal Cord Stimulation System for Chronic Pain: Multicenter, Observational, European Case Series.

Spinal cord stimulation (SCS) is proven to effectively relieve chronic neuropathic pain. However, some implanted patients may face loss of efficacy (LoE) over time, and conversion to more recent devices may rescue SCS therapy. Recent SCS systems offer novel stimulation capabilities, such as temporal modulation and spatial neural targeting, and can be used to replace previous neurostimulators without changing existing leads. Our multicenter, observational, consecutive case series investigated real-world clinical outcomes in previously implanted SCS patients who were converted to a new implantable pulse generator. Data from 58 patients in seven European centers were analyzed (total follow-up 7.0 years, including 1.4 years after conversion). In the Rescue (LoE) subgroup (n = 51), the responder rate was 58.5% at the last follow-up, and overall pain scores (numerical rating scale) had decreased from 7.3 ± 1.7 with the previous SCS system to 3.5 ± 2.5 (p < 0.0001). Patients who converted for improved battery longevity (n = 7) had their pain scores sustained below 3/10 with their new neurostimulator. Waveform preferences were diverse and patient dependent (34.4% standard rate; 44.8% sub-perception modalities; 20.7% combination therapy). Our results suggest that patients who experience LoE over time may benefit from upgrading to a more versatile SCS system.

Patient profiling and outcome assessment in spinal cord stimulation for chronic back and/or leg pain (the PROSTIM study): a study protocol.

Spinal cord stimulation (SCS) is a well-established treatment option in the multidisciplinary approach to chronic back and leg pain. Nevertheless, careful patient selection remains crucial to provide the most optimal treatment and prevent treatment failure. We report the protocol for the PROSTIM study, an ongoing prospective, multicentric and observational clinical study (NCT05349695) that aims to identify different patient clusters and their outcomes after SCS. Patients are recruited in different centers in Europe. Analysis focuses on identifying significant patient clusters based on different health domains and the changes in biopsychosocial variables 6 weeks, 3 and 12 months after implantation. This study is the first to include a biopsychosocial cluster analysis to identify significant patient groups and their response to treatment with SCS.

What is the study about? Spinal cord stimulation (SCS) is a treatment for chronic back and leg pain, in which an electrical stimulation is delivered to the spinal cord in order to reduce pain experience. It is important to choose the right patients to make sure the treatment works well. The PROSTIM study is a research project in which we study patients selected to be treated with SCS. We want to understand how different groups of patients selected for this treatment do after getting SCS. The study includes patients in different European centers, following them for 6 weeks, 3 months and 1 year after getting SCS. This study is the first one to use a cluster analysis to group patients based on different aspects of their psychological and physical health and see how they respond differently to SCS treatment. Clinical Trial Registration: NCT05349695 (ClinicalTrials.gov).

Core patient-reported outcome measures for chronic pain patients treated with spinal cord stimulation or dorsal root ganglia stimulation.

BACKGROUND: Neurostimulation is a highly effective therapy for the treatment of chronic Intractable pain, however, due to the complexity of pain, measuring a subject's long-term response to the therapy remains difficult. Frequent measurement of patient-reported outcomes (PROs) to reflect multiple aspects of subjects' pain is a crucial step in determining therapy outcomes. However, collecting full-length PROs is burdensome for both patients and clinicians. The objective of this work is to identify the reduced set of questions from multiple validated PROs that can accurately characterize chronic pain patients' responses to neurostimulation therapies. METHODS: Validated PROs were used to capture pain, physical function and disability, as well as psychometric, satisfaction, and global health metrics. PROs were collected from 509 patients implanted with Spinal Cord Stimulation (SCS) or Dorsal Root Ganglia (DRG) neurostimulators enrolled in the prospective, international, post-market REALITY study (NCT03876054, Registration Date: March 15, 2019). A combination of linear regression, Pearson's correlation, and factor analysis were used to eliminate highly correlated questions and find the minimal meaningful set of questions within the predefined domains of each scale. RESULTS: The shortened versions of the questionnaires presented almost identical accuracy for classifying the therapy outcomes as compared to the validated full-length versions. In addition, principal component analysis was performed on all the PROs and showed a robust clustering of pain intensity, psychological factors, physical function, and sleep across multiple PROs. A selected set of questions captured from multiple PROs can provide adequate information for measuring neurostimulation therapy outcomes. CONCLUSIONS: PROs are important subjective measures to evaluate the physiological and psychological aspects of pain. However, these measures are cumbersome to collect. These shorter and more targeted PROs could result in better patient engagement, and enhanced and more frequent data collection processes for digital health platforms that minimize patient burden while increasing therapeutic benefits for chronic pain patients.

Neuroimaging-based analysis of DBS outcomes in pediatric dystonia: Insights from the GEPESTIM registry.

INTRODUCTION: Deep brain stimulation (DBS) is an established treatment in patients of various ages with pharmaco-resistant neurological disorders. Surgical targeting and postoperative programming of DBS depend on the spatial location of the stimulating electrodes in relation to the surrounding anatomical structures, and on electrode connectivity to a specific distribution pattern within brain networks. Such information is usually collected using group-level analysis, which relies on the availability of normative imaging resources (atlases and connectomes). Analysis of DBS data in children with debilitating neurological disorders such as dystonia would benefit from such resources, especially given the developmental differences in neuroimaging data between adults and children. We assembled pediatric normative neuroimaging resources from open-access datasets in order to comply with age-related anatomical and functional differences in pediatric DBS populations. We illustrated their utility in a cohort of children with dystonia treated with pallidal DBS. We aimed to derive a local pallidal sweetspot and explore a connectivity fingerprint associated with pallidal stimulation to exemplify the utility of the assembled imaging resources. METHODS: An average pediatric brain template (the MNI brain template 4.5-18.5 years) was implemented and used to localize the DBS electrodes in 20 patients from the GEPESTIM registry cohort. A pediatric subcortical atlas, analogous to the DISTAL atlas known in DBS research, was also employed to highlight the anatomical structures of interest. A local pallidal sweetspot was modeled, and its degree of overlap with stimulation volumes was calculated as a correlate of individual clinical outcomes. Additionally, a pediatric functional connectome of 100 neurotypical subjects from the Consortium for Reliability and Reproducibility was built to allow network-based analyses and decipher a connectivity fingerprint responsible for the clinical improvements in our cohort. RESULTS: We successfully implemented a pediatric neuroimaging dataset that will be made available for public use as a tool for DBS analyses. Overlap of stimulation volumes with the identified DBS-sweetspot model correlated significantly with improvement on a local spatial level (R = 0.46, permuted p = 0.019). The functional connectivity fingerprint of DBS outcomes was determined to be a network correlate of therapeutic pallidal stimulation in children with dystonia (R = 0.30, permuted p = 0.003). CONCLUSIONS: Local sweetspot and distributed network models provide neuroanatomical substrates for DBS-associated clinical outcomes in dystonia using pediatric neuroimaging surrogate data. Implementation of this pediatric neuroimaging dataset might help to improve the practice and pave the road towards a personalized DBS-neuroimaging analyses in pediatric patients.

Long-Term Follow-Up of Pediatric Patients with Dyskinetic Cerebral Palsy and Deep Brain Stimulation.

BACKGROUND: Deep brain stimulation (DBS) has been increasingly used in the management of dyskinetic cerebral palsy (DCP). Data on long-term effects and the safety profile are rare. OBJECTIVES: We assessed the efficacy and safety of pallidal DBS in pediatric patients with DCP. METHODS: The STIM-CP trial was a prospective, single-arm, multicenter study in which patients from the parental trial agreed to be followed-up for up to 36 months. Assessments included motor and non-motor domains. RESULTS: Of the 16 patients included initially, 14 (mean inclusion age 14 years) were assessed. There was a significant change in the (blinded) ratings of the total Dyskinesia Impairment Scale at 36 months. Twelve serious adverse events (possibly) related to treatment were documented. CONCLUSION: DBS significantly improved dyskinesia, but other outcome parameters did not change significantly. Investigations of larger homogeneous cohorts are needed to further ascertain the impact of DBS and guide treatment decisions in DCP. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Long-term safety of spinal cord stimulation systems in a prospective, global registry of patients with chronic pain.

Aim: The availability of long-term (>2 years) safety outcomes of spinal cord stimulation (SCS) remains limited. We evaluated safety in a global SCS registry for chronic pain. Methods: Participants were prospectively enrolled globally at 79 implanting centers and followed out to 3 years after device implantation. Results: Of 1881 participants enrolled, 1289 received a permanent SCS implant (1776 completed trial). The annualized rate of device explant was 3.5% (all causes), and 1.1% due to inadequate pain relief. Total incidence of device explantation >3 years was 7.6% (n = 98). Of these, 32 subjects (2.5%) indicated inadequate pain relief as cause for removal. Implant site infection (11 events) was the most common device-related serious adverse event (<1%). Conclusion: This prospective, global, real-world study demonstrates a high-level of safety for SCS with low rate of explant/serious adverse events. Clinical Trial Registration: NCT01719055 (ClinicalTrials.gov).

Alterations of resting-state networks of Parkinson's disease patients after subthalamic DBS surgery.

The implantation of deep brain stimulation (DBS) electrodes in Parkinson's disease (PD) patients can lead to a temporary improvement in motor symptoms, known as the stun effect. However, the network alterations induced by the stun effect are not well characterized. As therapeutic DBS is known to alter resting-state networks (RSN) and subsequent motor symptoms in patients with PD, we aimed to investigate whether the DBS-related stun effect also modulated RSNs. Therefore, we analyzed RSNs of 27 PD patients (8 females, 59.0 +- 8.7 years) using magnetoencephalography and compared them to RSNs of 24 age-matched healthy controls (8 females, 62.8 +- 5.1 years). We recorded 30 min of resting-state activity two days before and one day after implantation of the electrodes with and without dopaminergic medication. RSNs were determined by use of phase-amplitude coupling between a low frequency phase and a high gamma amplitude and examined for differences between conditions (i.e., pre vs post surgery). We identified four RSNs across all conditions: sensory-motor, visual, fronto-occipital, and frontal. Each RSN was altered due to electrode implantation. Importantly, these changes were not restricted to spatially close areas to the electrode trajectory. Interestingly, pre-operative RSNs corresponded better with healthy control RSNs regarding the spatial overlap, although the stun effect is associated with motor improvement. Our findings reveal that the stun effect induced by implantation of electrodes exerts brain wide changes in different functional RSNs.

Cortical network formation based on subthalamic beta bursts in Parkinson's disease.

Recent evidence suggests that beta bursts in subthalamic nucleus (STN) play an important role in Parkinsonian pathophysiology. We studied the spatio-temporal relationship between STN beta bursts and cortical activity in 26 Parkinson's disease (PD) patients undergoing deep brain stimulation (DBS) surgery. Postoperatively, we simultaneously recorded STN local field potentials (LFP) from externalized DBS leads and cortical activity using whole-brain magnetoencephalography. Event-related magnetic fields (ERF) were averaged time-locked to STN beta bursts and subjected to source localization. Our results demonstrate that ERF exhibiting activity significantly different from baseline activity were localized within areas functionally related to associative, limbic, and motor systems as well as regions pertinent for visual and language processing. Our data suggest that STN beta bursts are involved in network formation between STN and cortex. This interaction is in line with the idea of parallel processing within the basal ganglia-cortex loop, specifically within the functional subsystems of the STN (i.e., associative, limbic, motor, and the related cortical areas). ERFs within visual and language-related cortical areas indicate involvement of beta bursts in STN-cortex networks beyond the associative, limbic, and motor loops. In sum, our results highlight the involvement of STN beta bursts in the formation of multiple STN - cortex loops in patients with PD.

Neuronal oscillations predict deep brain stimulation outcome in Parkinson's disease.

BACKGROUND: Neuronal oscillations are linked to symptoms of Parkinson's disease. This relation can be exploited for optimizing deep brain stimulation (DBS), e.g. by informing a device or human about the optimal location, time and intensity of stimulation. Whether oscillations predict individual DBS outcome is not clear so far. OBJECTIVE: To predict motor symptom improvement from subthalamic power and subthalamo-cortical coherence. METHODS: We applied machine learning techniques to simultaneously recorded magnetoencephalography and local field potential data from 36 patients with Parkinson's disease. Gradient-boosted tree learning was applied in combination with feature importance analysis to generate and understand out-of-sample predictions. RESULTS: A few features sufficed for making accurate predictions. A model operating on five coherence features, for example, achieved correlations of r > 0.8 between actual and predicted outcomes. Coherence comprised more information in less features than subthalamic power, although in general their information content was comparable. Both signals predicted akinesia/rigidity reduction best. The most important local feature was subthalamic high-beta power (20-35 Hz). The most important connectivity features were subthalamo-parietal coherence in the very high frequency band (>200 Hz) and subthalamo-parietal coherence in low-gamma band (36-60 Hz). Successful prediction was not due to the model inferring distance to target or symptom severity from neuronal oscillations. CONCLUSION: This study demonstrates for the first time that neuronal oscillations are predictive of DBS outcome. Coherence between subthalamic and parietal oscillations are particularly informative. These results highlight the clinical relevance of inter-areal synchrony in basal ganglia-cortex loops and might facilitate further improvements of DBS in the future.

Anesthesia for deep brain stimulation system implantation: adapted protocol for awake and asleep surgery using microelectrode recordings.

PURPOSE: Deep brain stimulation (DBS), an effective treatment for movement disorders, usually involves lead implantation while the patient is awake and sedated. Recently, there has been interest in performing the procedure under general anesthesia (asleep). This report of a consecutive cohort of DBS patients describes anesthesia protocols for both awake and asleep procedures. METHODS: Consecutive patients with Parkinson's disease received subthalamic nucleus (STN) implants either moderately sedated or while intubated, using propofol and remifentanil. Microelectrode recordings were performed with up to five trajectories after discontinuing sedation in the awake group, or reducing sedation in the asleep group. Clinical outcome was compared between groups with the UPDRS III. RESULTS: The awake group (n = 17) received 3.5 mg/kg/h propofol and 11.6 µg/kg/h remifentanil. During recording, all anesthesia was stopped. The asleep group (n = 63) initially received 6.9 mg/kg/h propofol and 31.3 µg/kg/h remifentanil. During recording, this was reduced to 3.1 mg/kg/h propofol and 10.8 µg/kg/h remifentanil. Without parkinsonian medications or stimulation, 3-month UPDRS III ratings (ns = 16 and 52) were 40.8 in the awake group and 41.4 in the asleep group. Without medications but with stimulation turned on, ratings improved to 26.5 in the awake group and 26.3 in the asleep group. With both medications and stimulation, ratings improved further to 17.6 in the awake group and 15.3 in the asleep group. All within-group improvements from the off/off condition were statistically significant (all ps < 0.01). The degree of improvement with stimulation, with or without medications, was not significantly different in the awake vs. asleep groups (ps > 0.05). CONCLUSION: The above anesthesia protocols make possible an asleep implant procedure that can incorporate sufficient microelectrode recording. Together, this may increase patient comfort and improve clinical outcomes.

Directional Deep Brain Stimulation for Parkinson's Disease: Results of an International Crossover Study With Randomized, Double-Blind Primary Endpoint.

OBJECTIVE: Published reports on directional deep brain stimulation (DBS) have been limited to small, single-center investigations. Therapeutic window (TW) is used to describe the range of stimulation amplitudes achieving symptom relief without side effects. This crossover study performed a randomized double-blind assessment of TW for directional and omnidirectional DBS in a large cohort of patients implanted with a DBS system in the subthalamic nucleus for Parkinson's disease. MATERIALS AND METHODS: Participants received omnidirectional stimulation for the first three months after initial study programming, followed by directional DBS for the following three months. The primary endpoint was a double-blind, randomized evaluation of TW for directional vs omnidirectional stimulation at three months after initial study programming. Additional data recorded at three- and six-month follow-ups included stimulation preference, therapeutic current strength, Unified Parkinson's Disease Rating Scale (UPDRS) part III motor score, and quality of life. RESULTS: The study enrolled 234 subjects (62 ± 8 years, 33% female). TW was wider using directional stimulation in 183 of 202 subjects (90.6%). The mean increase in TW with directional stimulation was 41% (2.98 ± 1.38 mA, compared to 2.11 ± 1.33 mA for omnidirectional). UPDRS part III motor score on medication improved 42.4% at three months (after three months of omnidirectional stimulation) and 43.3% at six months (after three months of directional stimulation) with stimulation on, compared to stimulation off. After six months, 52.8% of subjects blinded to stimulation type (102/193) preferred the period with directional stimulation, and 25.9% (50/193) preferred the omnidirectional period. The directional period was preferred by 58.5% of clinicians (113/193) vs 21.2% (41/193) who preferred the omnidirectional period. CONCLUSION: Directional stimulation yielded a wider TW compared to omnidirectional stimulation and was preferred by blinded subjects and clinicians.

Motor Evoked Potentials Improve Targeting in Deep Brain Stimulation Surgery.

OBJECTIVES: One of the main challenges posed by the surgical deep brain stimulation (DBS) procedure is the successful targeting of the structures of interest and avoidance of side effects, especially in asleep surgery. Here, intraoperative motor evoked potentials (MEPs) might serve as tool to identify the pyramidal tract. We hypothesized that intraoperative MEPs are useful to define the distance to the pyramidal tract and reduce the occurrence of postoperative capsular side effects. MATERIALS AND METHODS: Motor potentials were evoked through both microelectrode and DBS-electrode stimulation during stereotactic DBS surgery on 25 subthalamic nuclei and 3 ventral intermediate thalamic nuclei. Internal capsule proximity was calculated for contacts on microelectrode trajectories, as well as for DBS-electrodes, and correlated with the corresponding MEP thresholds. Moreover, the predictivity of intraoperative MEP thresholds on the probability of postoperative capsular side effects was calculated. RESULTS: Intraoperative MEPs thresholds correlated significantly with internal capsule proximity, regardless of the stimulation source. Furthermore, MEPs thresholds were highly accurate to exclude the occurrence of postoperative capsular side effects. CONCLUSIONS: Intraoperative MEPs provide additional targeting guidance, especially in asleep DBS surgery, where clinical value of microelectrode recordings and test stimulation may be limited. As this technique can exclude future capsular side effects, it can directly be translated into clinical practice.

Quality of Life After Deep Brain Stimulation of Pediatric Patients with Dyskinetic Cerebral Palsy: A Prospective, Single-Arm, Multicenter Study with a Subsequent Randomized Double-Blind Crossover (STIM-CP).

BACKGROUND: Patients with dyskinetic cerebral palsy are often severely impaired with limited treatment options. The effects of deep brain stimulation (DBS) are less pronounced than those in inherited dystonia but can be associated with favorable quality of life outcomes even in patients without changes in dystonia severity. OBJECTIVE: The aim is to assess DBS effects in pediatric patients with pharmacorefractory dyskinetic cerebral palsy with focus on quality of life. METHODS: The method used is a prospective, single-arm, multicenter study. The primary endpoint is improvement in quality of life (CPCHILD [Caregiver Priorities & Child Health Index of Life with Disabilities]) from baseline to 12 months under therapeutic stimulation. The main key secondary outcomes are changes in Burke-Fahn-Marsden Dystonia Rating Scale, Dyskinesia Impairment Scale, Gross Motor Function Measure-66, Canadian Occupational Performance Measure (COPM), and Short-Form (SF)-36. After 12 months, patients were randomly assigned to a blinded crossover to receive active or sham stimulation for 24 hours each. Severity of dystonia and chorea were blindly rated. Safety was assessed throughout. The trial was registered at ClinicalTrials.gov, number NCT02097693. RESULTS: Sixteen patients (age: 13.4 ± 2.9 years) were recruited by seven clinical sites. Primary outcome at 12-month follow-up is as follows: mean CPCHILD increased by 4.2 ± 10.4 points (95% CI [confidence interval] -1.3 to 9.7; P = 0.125); among secondary outcomes: improvement in COPM performance measure of 1.1 ± 1.5 points (95% CI 0.2 to 1.9; P = 0.02) and in the SF-36 physical health component by 5.1 ± 6.2 points (95% CI 0.7 to 9.6; P = 0.028). Otherwise, there are no significant changes. CONCLUSION: Evidence to recommend DBS as routine treatment to improve quality of life in pediatric patients with dyskinetic cerebral palsy is not yet sufficient. Extended follow-up in larger cohorts will determine the impact of DBS further to guide treatment decisions in these often severely disabled patients. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Dopaminergic Modulation of Spectral and Spatial Characteristics of Parkinsonian Subthalamic Nucleus Beta Bursts.

In Parkinson's disease (PD), subthalamic nucleus (STN) beta burst activity is pathologically elevated. These bursts are reduced by dopamine and deep brain stimulation (DBS). Therefore, these bursts have been tested as a trigger for closed-loop DBS. To provide better targeted parameters for closed-loop stimulation, we investigate the spatial distribution of beta bursts within the STN and if they are specific to a beta sub-band. Local field potentials (LFP) were acquired in the STN of 27 PD patients while resting. Based on the orientation of segmented DBS electrodes, the LFPs were classified as anterior, postero-medial, and postero-lateral. Each recording lasted 30 min with (ON) and without (OFF) dopamine. Bursts were detected in three frequency bands: ±3 Hz around the individual beta peak frequency, low beta band (lBB), and high beta band (hBB). Medication reduced the duration and the number of bursts per minute but not the amplitude of the beta bursts. The burst amplitude was spatially modulated, while the burst duration and rate were frequency dependent. Furthermore, the hBB burst duration was positively correlated with the akinetic-rigid UPDRS III subscore. Overall, these findings on differential dopaminergic modulation of beta burst parameters suggest that hBB burst duration is a promising target for closed-loop stimulation and that burst parameters could guide DBS programming.

Real-World Outcomes Using a Spinal Cord Stimulation Device Capable of Combination Therapy for Chronic Pain: A European, Multicenter Experience.

Given the differing mechanisms thought to underlie therapeutic sub- and supra-perception-based neurostimulative modalities, Spinal Cord Stimulation (SCS) systems designed for combined delivery of these approaches may help improve analgesic outcomes and quality of life, and reduce treatment failures. This multicenter, observational case-series evaluated 188 patients with chronic back and/or leg pain implanted with an SCS device capable of sequential or simultaneous delivery of sub-perception and supra-perception stimulation programming (i.e., combination therapy) at 16 in Europe. Following implantation, patients were provided with an array of advanced supra-perception programs (e.g., paresthesia-based SCS using multiple independent current sources), and a custom set of sub-perception programs optimized with specific waveforms and/or field shapes. A mean overall pain score of 7.9 ± 1.7 (Standard Deviation (SD)) was reported pre-trial (Baseline). Overall pain was reduced by 4.4 ± 2.8 points (NRS) at 3-months (n = 117) and at 12 months post-implant (n = 90), respectively (p < 0.0001). Substantial quality-of-life (EQ-5D-5L) improvement as assessed at last follow-up was also observed (n = 60). These results suggest that an implanted SCS device capable of combination therapy, while also enabled with patient-specific waveform optimization and stimulation field targeting capabilities, can enable highly effective pain relief and improve quality of life in patients suffering with chronic pain.

Differential dopaminergic modulation of spontaneous cortico-subthalamic activity in Parkinson's disease.

Pathological oscillations including elevated beta activity in the subthalamic nucleus (STN) and between STN and cortical areas are a hallmark of neural activity in Parkinson's disease (PD). Oscillations also play an important role in normal physiological processes and serve distinct functional roles at different points in time. We characterised the effect of dopaminergic medication on oscillatory whole-brain networks in PD in a time-resolved manner by employing a hidden Markov model on combined STN local field potentials and magnetoencephalography (MEG) recordings from 17 PD patients. Dopaminergic medication led to coherence within the medial and orbitofrontal cortex in the delta/theta frequency range. This is in line with known side effects of dopamine treatment such as deteriorated executive functions in PD. In addition, dopamine caused the beta band activity to switch from an STN-mediated motor network to a frontoparietal-mediated one. In contrast, dopamine did not modify local STN-STN coherence in PD. STN-STN synchrony emerged both on and off medication. By providing electrophysiological evidence for the differential effects of dopaminergic medication on the discovered networks, our findings open further avenues for electrical and pharmacological interventions in PD.

Efficacy of different spinal cord stimulation paradigms for the treatment of chronic neuropathic pain (PARS-trial): study protocol for a double-blinded, randomized, and placebo-controlled crossover trial.

BACKGROUND: Spinal cord stimulation (SCS) is an effective method to treat neuropathic pain; however, it is challenging to compare different stimulation modalities in an individual patient, and thus, it is largely unknown which of the many available SCS modalities is most effective. Specifically, electrodes leading out through the skin would have to be consecutively connected to different, incompatible SCS devices and be tested over a time period of several weeks or even months. The risk of wound infections for such a study would be unacceptably high and blinding of the trial difficult. The PARS-trial seizes the capacity of a new type of wireless SCS device, which enables a blinded and systematic intra-patient comparison of different SCS modalities over extended time periods and without increasing wound infection rates. METHODS: The PARS-trial is designed as a double-blinded, randomized, and placebo-controlled multi-center crossover study. It will compare the clinical effectiveness of the three most relevant SCS paradigms in individual patients. The trial will recruit 60 patients suffering from intractable neuropathic pain of the lower extremities, who have been considered for SCS therapy and were already implanted with a wireless SCS device prior to study participation. Over a time period of 35 days, patients will be treated consecutively with three different SCS paradigms ("burst," "1 kHz," and "1.499 kHz") and placebo stimulation. Each SCS paradigm will be applied for 5 days with a washout period of 70 h between stimulation cycles. The primary endpoint of the study is the level of pain self-assessment on the visual analogue scale after 5 days of SCS. Secondary, exploratory endpoints include self-assessment of pain quality (as determined by painDETECT questionnaire), quality of life (as determined by Quality of Life EQ-5D-5L questionnaire), anxiety perception (as determined by the Hospital Anxiety and Depression Scale), and physical restriction (as determined by the Oswestry Disability Index). DISCUSSION: Combining paresthesia-free SCS modalities with wireless SCS offers a unique opportunity for a blinded and systematic comparison of different SCS modalities in individual patients. This trial will advance our understanding of the clinical effectiveness of the most relevant SCS paradigms. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00018929 . Registered on 14 January 2020.

Asleep Surgery May Improve the Therapeutic Window for Deep Brain Stimulation of the Subthalamic Nucleus.

OBJECTIVE: The effect of anesthesia type in terms of asleep vs. awake deep brain stimulation (DBS) surgery on therapeutic window (TW) has not been investigated so far. The objective of the study was to investigate whether asleep DBS surgery of the subthalamic nucleus (STN) improves TW for both directional (dDBS) and omnidirectional (oDBS) stimulation in a large single-center population. MATERIALS AND METHODS: A total of 104 consecutive patients with Parkinson's disease (PD) undergoing STN-DBS surgery (80 asleep and 24 awake) were compared regarding TW, therapeutic threshold, side effect threshold, improvement of Unified PD Rating Scale motor score (UPDRS-III) and degree of levodopa equivalent daily dose (LEDD) reduction. RESULTS: Asleep DBS surgery led to significantly wider TW compared to awake surgery for both dDBS and oDBS. However, dDBS further increased TW compared to oDBS in the asleep group only and not in the awake group. Clinical efficacy in terms of UPDRS-III improvement and LEDD reduction did not differ between groups. CONCLUSIONS: Our study provides first evidence for improvement of therapeutic window by asleep surgery compared to awake surgery, which can be strengthened further by dDBS. These results support the notion of preferring asleep over awake surgery but needs to be confirmed by prospective trials.

Directional Deep Brain Stimulation of the Thalamic Ventral Intermediate Area for Essential Tremor Increases Therapeutic Window.

OBJECTIVES: Deep brain stimulation (DBS) of the posterior subthalamic area (PSA) and the ventral intermediate thalamic nucleus (VIM) is a well-established therapy for essential tremor (ET), but it is frequently associated with side effects like dysarthria or gait ataxia. Directional DBS (dDBS) may be a way to activate fiber tracts more selectively. Is dDBS for ET superior to omnidirectional DBS (oDBS) regarding therapeutic window and clinically as effective as oDBS? MATERIALS AND METHODS: Ten patients with ET treated with PSA/VIM-DBS were recruited. Therapeutic window served as primary outcome parameter; clinical efficacy, volume of neuronal activation, and total electrical energy delivered (TEED) served as secondary outcome parameters. Therapeutic window was calculated for all three dDBS directions and for oDBS by determining therapeutic thresholds and side effect thresholds. Clinical efficacy was assessed by comparing the effect of best dDBS and oDBS on tremor and ataxia rating scales, and accelerometry. Volume of neural activation and TEED were also calculated for both paradigms. RESULTS: For best dDBS, therapeutic window was wider and therapeutic threshold was lower compared to oDBS. While side effect threshold did not differ, volume of neural activation was larger for dDBS. In terms of clinical efficacy, dDBS was as effective as oDBS. CONCLUSIONS: dDBS for ET widens therapeutic window due to reduction of therapeutic threshold. Larger volume of neural activation for dDBS at side effect threshold supports the notion of persistent directionality even at higher intensities. dDBS may compensate for slightly misplaced leads and should be considered first line for PSA/VIM-DBS.