Optimal deep brain stimulation sites and networks for cervical vs. generalized dystonia.

Dystonia is a debilitating disease with few treatment options. One effective option is deep brain stimulation (DBS) to the internal pallidum. While cervical and generalized forms of isolated dystonia have been targeted with a common approach to the posterior third of the nucleus, large-scale investigations regarding optimal stimulation sites and potential network effects have not been carried out. Here, we retrospectively studied clinical results following DBS for cervical and generalized dystonia in a multicenter cohort of 80 patients. We model DBS electrode placement based on pre- and postoperative imaging and introduce an approach to map optimal stimulation sites to anatomical space. Second, we investigate which tracts account for optimal clinical improvements, when modulated. Third, we investigate distributed stimulation effects on a whole-brain functional connectome level. Our results show marked differences of optimal stimulation sites that map to the somatotopic structure of the internal pallidum. While modulation of the striatopallidofugal axis of the basal ganglia accounted for optimal treatment of cervical dystonia, modulation of pallidothalamic bundles did so in generalized dystonia. Finally, we show a common multisynaptic network substrate for both phenotypes in the form of connectivity to the cerebellum and somatomotor cortex. Our results suggest a brief divergence of optimal stimulation networks for cervical vs. generalized dystonia within the pallidothalamic loop that merge again on a thalamo-cortical level and share a common whole-brain network.

Pallidal Beta Activity Is Linked to Stimulation-Induced Slowness in Dystonia.

BACKGROUND: Pallidal deep brain stimulation (DBS) effectively alleviates symptoms in dystonia patients, but may induce movement slowness as a side-effect. In Parkinson's disease, hypokinetic symptoms have been associated with increased beta oscillations (13-30 Hz). We hypothesize that this pattern is symptom-specific, thus accompanying DBS-induced slowness in dystonia. METHODS: In 6 dystonia patients, pallidal rest recordings with a sensing-enabled DBS device were performed and tapping speed was assessed using marker-less pose estimation over 5 time points following cessation of DBS. RESULTS: After cessation of pallidal stimulation, movement speed increased over time (P < 0.01). A linear mixed-effects model revealed that pallidal beta activity explained 77% of the variance in movement speed across patients (P = 0.01). CONCLUSIONS: The association between beta oscillations and slowness across disease entities provides further evidence for symptom-specific oscillatory patterns in the motor circuit. Our findings might help DBS therapy improvements, as DBS-devices able to adapt to beta oscillations are already commercially available. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Surgical Site Infections Associated With Implanted Pulse Generators for Deep Brain Stimulation: Meta-Analysis and Systematic Review.

OBJECTIVES: The aim of this study was to identify and systematically analyze relevant literature on surgical site infections (SSIs) associated with implantable pulse generator (IPG) procedures for deep brain stimulation (DBS). MATERIALS AND METHODS: In compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we conducted a systematic review and meta-analyses of 58 studies that reported SSI rates of 11,289 patients and 15,956 IPG procedures. A meta-analysis of proportions was performed to estimate the pooled proportion of SSIs across DBS procedures in general and to estimate the proportion of SSIs that occur at the IPG pocket. Moreover, a meta-analysis of odds ratio (OR) was conducted on those studies that reported their results of applying topical vancomycin powder during closure of the IPG wound. Results are presented as rates and OR with 95% CIs. RESULTS: The pooled proportion of SSIs was 4.9% (95% CI, 4.1%-6.1%) among all DBS procedures. The dominant SSI localization was the IPG pocket in 61.2% (95% CI, 53.4%-68.5%). A trend toward a beneficial effect of vancomycin powder over standard wound closure was found with an OR of 0.46 (95% CI, 0.21-1.02). Most studies (79.1%) that reported their treatment strategy in case of SSI had a strict protocol of removal of the IPG, followed by antimicrobial treatment and reimplantation of the IPG once the SSI had been eradicated. CONCLUSIONS: The IPG pocket was identified as the main site of SSI after DBS procedures. Most studies recommend complete IPG removal, antimicrobial treatment, and reimplantation of an IPG once the SSI has been eradicated. Future studies are needed to clarify the role of alternative approaches (eg, topical vancomycin powder) in the prevention of SSI associated with IPG.

StimFit-A Data-Driven Algorithm for Automated Deep Brain Stimulation Programming.

BACKGROUND: Finding the optimal deep brain stimulation (DBS) parameters from a multitude of possible combinations by trial and error is time consuming and requires highly trained medical personnel. OBJECTIVE: We developed an automated algorithm to identify optimal stimulation settings in Parkinson's disease (PD) patients treated with subthalamic nucleus (STN) DBS based on imaging-derived metrics. METHODS: Electrode locations and monopolar review data of 612 stimulation settings acquired from 31 PD patients were used to train a predictive model for therapeutic and adverse stimulation effects. Model performance was then evaluated within the training cohort using cross-validation and on an independent cohort of 19 patients. We inverted the model by applying a brute-force approach to determine the optimal stimulation sites in the target region. Finally, an optimization algorithm was established to identify optimal stimulation parameters. Suggested stimulation parameters were compared to the ones applied in clinical practice. RESULTS: Predicted motor outcome correlated with observed outcome (R = 0.57, P < 10-10 ) across patients within the training cohort. In the test cohort, the model explained 28% of the variance in motor outcome differences between settings. The stimulation site for maximum motor improvement was located at the dorsolateral border of the STN. When compared to two empirical settings, model-based suggestions more closely matched the setting with superior motor improvement. CONCLUSION: We developed and validated a data-driven model that can suggest stimulation parameters leading to optimal motor improvement while minimizing the risk of stimulation-induced side effects. This approach might provide guidance for DBS programming in the future. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The Contribution of Subthalamic Nucleus Deep Brain Stimulation to the Improvement in Motor Functions and Quality of Life.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) effectively treats motor symptoms and quality of life (QoL) of advanced and fluctuating early Parkinson's disease. Little is known about the relation between electrode position and changes in symptom control and ultimately QoL. OBJECTIVES: The relation between the stimulated part of the STN and clinical outcomes, including the motor score of the Unified Parkinson's Disease Rating Scale (UPDRS) and the quality-of-life questionnaire, was assessed in a subcohort of the EARLYSTIM study. METHODS: Sixty-nine patients from the EARLYSTIM cohort who underwent DBS, with a comprehensive clinical characterization before and 24 months after surgery, were included. Intercorrelations of clinical outcome changes, correlation between the affected functional parts of the STN, and changes in clinical outcomes were investigated. We further calculated sweet spots for different clinical parameters. RESULTS: Improvements in the UPDRS III and Parkinson's Disease Questionnaire (PDQ-39) correlated positively with the extent of the overlap with the sensorimotor STN. The sweet spots for the UPDRS III (x = 11.6, y = -13.1, z = -6.3) and the PDQ-39 differed (x = 14.8, y = -12.4, z = -4.3) ~3.8 mm. CONCLUSIONS: The main influence of DBS on QoL is likely mediated through the sensory-motor basal ganglia loop. The PDQ sweet spot is located in a posteroventral spatial location in the STN territory. For aspects of QoL, however, there was also evidence of improvement through stimulation of the other STN subnuclei. More research is necessary to customize the DBS target to individual symptoms of each patient. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Probabilistic sweet spots predict motor outcome for deep brain stimulation in Parkinson disease.

OBJECTIVE: To investigate whether functional sweet spots of deep brain stimulation (DBS) in the subthalamic nucleus (STN) can predict motor improvement in Parkinson disease (PD) patients. METHODS: Stimulation effects of 449 DBS settings in 21 PD patients were clinically and quantitatively assessed through standardized monopolar reviews and mapped into standard space. A sweet spot for best motor outcome was determined using voxelwise and nonparametric permutation statistics. Two independent cohorts were used to investigate whether stimulation overlap with the sweet spot could predict acute motor outcome (10 patients, 163 settings) and long-term overall Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) improvement (63 patients). RESULTS: Significant clusters for suppression of rigidity and akinesia, as well as for overall motor improvement, resided around the dorsolateral border of the STN. Overlap of the volume of tissue activated with the sweet spot for overall motor improvement explained R2 = 37% of the variance in acute motor improvement, more than triple what was explained by overlap with the STN (R2 = 9%) and its sensorimotor subpart (R2 = 10%). In the second independent cohort, sweet spot overlap explained R2 = 20% of the variance in long-term UPDRS-III improvement, which was equivalent to the variance explained by overlap with the STN (R2 = 21%) and sensorimotor STN (R2 = 19%). INTERPRETATION: This study is the first to predict clinical improvement of parkinsonian motor symptoms across cohorts based on local DBS effects only. The new approach revealed a distinct sweet spot for STN DBS in PD. Stimulation overlap with the sweet spot can predict short- and long-term motor outcome and may be used to guide DBS programming. ANN NEUROL 2019;86:527-538.

Pallidal and thalamic neural oscillatory patterns in tourette's syndrome.

OBJECTIVE: Aberrant oscillatory activity has been hypothesized to play a role in the pathophysiology of Tourette's syndrome (TS). Deep brain stimulation (DBS) has recently been established as an effective treatment for severe TS. Modulation of symptom-specific oscillations may underlie the mechanism of action of DBS and could be used for adaptive neuromodulation to improve therapeutic efficacy. The objective of this study was to demonstrate a pathophysiological association of pallidal and thalamic local field potentials (LFPs) with TS. METHODS: Nine medication-refractory TS patients were included in the study. Intracerebral LFPs were recorded simultaneously from bilateral pallidal and thalamic DBS electrodes. Spectral and temporal dynamics of pallidal and thalamic oscillations were characterized and correlated with preoperative Yale Global Tic Severity Scale (YGTSS) scores. RESULTS: Peaks of activity in the theta (3-12Hz) and beta (13-35Hz) were present in pallidal and thalamic recordings from all patients (3 women/6 men; mean age, 29.8 years) and coupled through coherence across targets. Presence of prolonged theta bursts in both targets was associated with preoperative motor tic severity. Total preoperative YGTSS scores (mean, 38.1) were correlated with pallidal and thalamic LFP activity using multivariable linear regression (R² = 0.96; p = 0.02). INTERPRETATION: Our findings suggest that pallidothalamic oscillations may be implicated in the pathophysiology of TS. Furthermore, our results highlight the utility of multisite and -spectral oscillatory features in severely affected patients for future identification and clinical use of oscillatory physiomarkers for adaptive stimulation in TS. Ann Neurol 2018;84:505-514.

Motor Cortical Plasticity Relates to Symptom Severity and Clinical Benefit From Deep Brain Stimulation in Cervical Dystonia.

OBJECTIVE: To investigate the relationship between motor cortical plasticity, intracortical inhibition, and clinical response to pallidal deep brain stimulation (DBS) in patients with cervical dystonia (CD). MATERIALS AND METHODS: Response to paired associative stimulation (PAS) and short interval intracortical inhibition (SICI) were assessed in patients with CD before and after three months of DBS and correlated with severity of dystonic symptoms as assessed by Toronto-Western-Spasmodic Torticollis Rating Scale (TWSTRS) severity score. Relations of electrophysiological parameters with clinical improvement were explored with correlation analysis. RESULTS: Patients with higher levels of plasticity before surgery showed higher symptom severity (R = 0.83, p = 0.008) but had also the larger clinical benefit following DBS (R = 0.88, p = 0.003). This correlation was independent from preoperative (preOP) TWSTRS motor score as revealed by partial correlation analysis. Intracortical inhibition was not altered in CD and not related to clinical outcome after DBS. CONCLUSIONS: Our findings indicate that a high degree of preOP plasticity is associated with higher symptom severity, underlining the role of abnormal plasticity in the pathophysiology of dystonia. At the same time individual degree of plasticity may drive reestablishment of normal motor programs, leading to better clinical outcome with DBS. The latter suggests that individual PAS-response may indicate the susceptibility for neuromodulatory processes as an important factor for clinical DBS effects. It might therefore serve as a neurophysiological marker to predict outcome and guide patient selection.

Multiple input algorithm-guided Deep Brain stimulation-programming for Parkinson's disease patients.

Technological advances of Deep Brain Stimulation (DBS) within the subthalamic nucleus (STN) for Parkinson's disease (PD) provide increased programming options with higher programming burden. Reducing the effort of DBS optimization requires novel programming strategies. The objective of this study was to evaluate the feasibility of a semi-automatic algorithm-guided-programming (AgP) approach to obtain beneficial stimulation settings for PD patients with directional DBS systems. The AgP evaluates iteratively the weighted combination of sensor and clinician assessed responses of multiple PD symptoms to suggested DBS settings until it converges to a final solution. Acute clinical effectiveness of AgP DBS settings and DBS settings that were found following a standard of care (SoC) procedure were compared in a randomized, crossover and double-blind fashion in 10 PD subjects from a single center. Compared to therapy absence, AgP and SoC DBS settings significantly improved (p = 0.002) total Unified Parkinson's Disease Rating Scale III scores (median 69.8 interquartile range (IQR) 64.6|71.9% and 66.2 IQR 58.1|68.2%, respectively). Despite their similar clinical results, AgP and SoC DBS settings differed substantially. Per subject, AgP tested 37.0 IQR 34.0|37 settings before convergence, resulting in 1.7 IQR 1.6|2.0 h, which is comparable to previous reports. Although AgP long-term clinical results still need to be investigated, this approach constitutes an alternative for DBS programming and represents an important step for future closed-loop DBS optimization systems.

Six Action Steps to Address Global Disparities in Parkinson Disease: A World Health Organization Priority.

Importance: The Global Burden of Disease study conducted between 1990 and 2016, based on a global study of 195 countries and territories, identified Parkinson disease (PD) as the fastest growing neurological disorder when measured using death and disability. Most people affected by PD live in low- and middle-income countries (LMICs) and experience large inequalities in access to neurological care and essential medicines. This Special Communication describes 6 actions steps that are urgently needed to address global disparities in PD. Observations: The adoption by the 73rd World Health Assembly (WHA) of resolution 73.10 to develop an intersectoral global action plan on epilepsy and other neurological disorders in consultation with member states was the stimulus to coordinate efforts and leverage momentum to advance the agenda of neurological conditions, such as PD. In April 2021, the Brain Health Unit at the World Health Organization convened a multidisciplinary, sex-balanced, international consultation workshop, which identified 6 workable avenues for action within the domains of disease burden; advocacy and awareness; prevention and risk reduction; diagnosis, treatment, and care; caregiver support; and research. Conclusions and Relevance: The dramatic increase of PD cases in many world regions and the potential costs of PD-associated treatment will need to be addressed to prevent possible health service strain. Across the board, governments, multilateral agencies, donors, public health organizations, and health care professionals constitute potential stakeholders who are urged to make this a priority.

Pallidal DBS for dystonia in the age of personalized medicine.

In response to the correspondence by Albanese and co-workers, we discuss etiology as a factor predicting outcome of pallidal DBS in dystonia, reanalysing our dataset on causes of non-response to pallidal DBS in isolated dystonia by looking only at patients with a diagnosis of idiopathic dystonia at time of surgery.