Theta frequency deep brain stimulation in the subthalamic nucleus improves working memory in Parkinson's disease.

Most research in Parkinson's disease focuses on improving motor symptoms. Yet, up to 80% of patients present with non-motor symptoms that often have a large impact on patients' quality of life. Impairment in working memory, a fundamental cognitive process, is common in Parkinson's disease. While deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor symptoms in Parkinson's disease, its impact on cognitive functions is less well studied. Here, we examine the effect of DBS in the theta, beta, low and high gamma frequency on working memory in 20 Parkinson's disease patients with bilateral STN-DBS. A linear mixed effects model demonstrates that STN-DBS in the theta frequency improves working memory performance. This effect is frequency-specific and was absent for beta and gamma frequency stimulation. Further, this effect is specific to cognitive performance, as theta frequency DBS did not affect motor function. A non-parametric cluster-based permutation analysis of whole-brain normative structural connectivity shows that working memory enhancement by theta frequency stimulation is associated with higher connectivity between the stimulated subthalamic area and the right middle frontal gyrus. Again, this association is frequency- and task-specific. These findings highlight the potential of theta frequency STN-DBS as a targeted intervention to improve working memory in patients with Parkinson's disease.

Diffusion tensor imaging in pediatric patients with dystonia.

BACKGROUND: Childhood-onset dystonia is often progressive and severely impairs a child´s life. The pathophysiology is very heterogeneous and treatment responses vary in patients with dystonia. Factors influencing treatment effects remain to be elucidated. We hypothesize that differences in brain connectivity and fiber coherence contribute to the heterogeneity in treatment response among pediatric patients with inherited and acquired dystonia. METHODS: Twenty patients with childhood-onset dystonia were retrospectively recruited including twelve patients with inherited or idiopathic, and eight patients with acquired dystonia (mean age 10 years; 8 female/12 male). Fiber density between the internal part of the globus pallidus and selective target regions, as well as the diffusion measures of fractional anisotropy (FA) and mean diffusivity (MD) were analyzed and compared between different etiologies. RESULTS: Patients with acquired dystonia presented higher fiber density to the premotor cortex and putamen and lower FA values in the thalamus compared to patients with inherited/idiopathic dystonia. MD in the premotor cortex was higher in patients with acquired dystonia, while it was lower in the thalamus. CONCLUSION: Diffusion MRI reveals microstructural and network alterations in patients with dystonia of different etiologies.

One side effect: two networks? Lateral and posteromedial stimulation spreads induce dysarthria in subthalamic deep brain stimulation for Parkinson's disease.

BACKGROUND: Stimulation-induced dysarthria (SID) is a troublesome and potentially therapy-limiting side effect of deep brain stimulation of the subthalamic nucleus (STN-DBS) in patients with Parkinson's disease (PD). To date, the origin of SID, and especially whether there is an involvement of cerebellar pathways as well as the pyramidal tract, remains a matter of debate. Therefore, this study aims to shed light on structural networks associated with SID and to derive a data-driven model to predict SID in patients with PD and STN-DBS. METHODS: Randomised, double-blinded monopolar reviews determining SID thresholds were conducted in 25 patients with PD and STN-DBS. A fibre-based mapping approach, implementing the calculation of fibr-wise ORs for SID, was employed to identify the distributional pattern of SID in the STN's vicinity. The ability of the data-driven model to classify stimulation volumes as 'causing SID' or 'not causing SID' was validated by calculating receiver operating characteristics (ROC) in an independent out-of-sample cohort comprising 14 patients with PD and STN-DBS. RESULTS: Local fibre-based stimulation maps showed an involvement of fibres running lateral and posteromedial to the STN in the pathogenesis of SID, independent of the investigated hemisphere. ROC analysis in the independent out-of-sample cohort resulted in a good fit of the data-driven model for both hemispheres (area under the curve (AUC)left=0.88, AUCright=0.88). CONCLUSIONS: This study reveals an involvement of both, cerebello-thalamic fibres, as well as the pyramidal tract, in the pathogenesis of SID in STN-DBS. The results may impact future postoperative programming strategies to avoid SID in patients with PD and STN-DBS TRIAL REGISTRATION NUMBER: DRKS00023221; German Clinical Trials Register (DRKS) Number.

General Algorithm Applicability in Determining DBS Lead Orientation: Adapting 2D and 3D X-Ray Techniques for SenSightTM Leads.

INTRODUCTION: With recent advancements in deep brain stimulation (DBS), directional leads featuring segmented contacts have been introduced, allowing for targeted stimulation of specific brain regions. Given that manufacturers employ diverse markers for lead orientation, our investigation focuses on the adaptability of the 2017 techniques proposed by the Cologne research group for lead orientation determination. METHODS: We tailored the two separate 2D and 3D X-ray-based techniques published in 2017 and originally developed for C-shaped markers, to the dual-marker of the Medtronic SenSight™ lead. In a retrospective patient study, we evaluated their feasibility and consistency by comparing the degree of agreement between the two methods. RESULTS: The Bland-Altman plot showed favorable concordance without any noticeable systematic errors. The mean difference was 0.79°, with limits of agreement spanning from 21.4° to -19.8°. The algorithms demonstrated high reliability, evidenced by an intraclass correlation coefficient of 0.99 (p < 0.001). CONCLUSION: The 2D and 3D algorithms, initially formulated for discerning the circular orientation of a C-shaped marker, were adapted to the marker of the Medtronic SenSight™ lead. Statistical analyses revealed a significant level of agreement between the two methods. Our findings highlight the adaptability of these algorithms to different markers, achievable through both low-dose intraoperative 2D X-ray imaging and standard CT imaging.

Thalamic deep brain stimulation for tourette syndrome increases cortical beta activity.

BACKGROUND: Deep brain stimulation (DBS) of the thalamus can effectively reduce tics in severely affected patients with Tourette syndrome (TS). Its effect on cortical oscillatory activity is currently unknown. OBJECTIVE: We assessed whether DBS modulates beta activity at fronto-central electrodes. We explored concurrent EEG sources and probabilistic stimulation maps. METHODS: Resting state EEG of TS patients treated with thalamic DBS was recorded in repeated DBS-on and DBS-off states. A mixed linear model was employed for statistical evaluation. EEG sources were estimated with eLORETA. Thalamic probabilistic stimulation maps were obtained by assigning beta power difference scores (DBS-on minus DBS-off) to stimulation sites. RESULTS: We observed increased beta power in DBS-on compared to DBS-off states. Modulation of cortical beta activity was localized to the midcingulate cortex. Beta modulation was more pronounced when stimulating the thalamus posteriorly, peaking in the ventral posterior nucleus. CONCLUSION: Thalamic DBS in TS patients modulates beta frequency oscillations presumably important for sensorimotor function and relevant to TS pathophysiology.

A Retrospective Comparison of Multiple Approaches to Anatomically Informed Contact Selection in Subthalamic Deep Brain Stimulation for Parkinson's Disease.

Background: Conventional deep brain stimulation (DBS) programming via trial-and-error warrants improvement to ensure swift achievement of optimal outcomes. The definition of a sweet spot for subthalamic DBS in Parkinson's disease (PD-STN-DBS) may offer such advancement. Objective: This investigation examines the association of long-term motor outcomes with contact selection during monopolar review and different strategies for anatomically informed contact selection in a retrospective real-life cohort of PD-STN-DBS. Methods: We compared contact selection based on a monopolar review (MPR) to multiple anatomically informed contact selection strategies in a cohort of 28 PD patients with STN-DBS. We employed a commercial software package for contact selection based on visual assessment of individual anatomy following two predefined strategies and two algorithmic approaches with automatic targeting of either the sensorimotor STN or our previously published sweet spot. Similarity indices between chronic stimulation and contact selection strategies were correlated to motor outcomes at 12 months follow-up. Results: Lateralized motor outcomes of chronic DBS were correlated to the similarity between chronic stimulation and visual contact selection targeting the dorsal part of the posterior STN (rho = 0.36, p = 0.007). Similar relationships could not be established for MPR or any of the other investigated strategies. Conclusions: Our data demonstrates that a visual contact selection following a predefined strategy can be linked to beneficial long-term motor outcomes in PD-STN-DBS. Since similar correlations could not be observed for the other approaches to anatomically informed contact selection, we conclude that clear definitions and prospective validation of any approach to imaging-based DBS-programming is warranted.

Electrophysiological sweet spot mapping in deep brain stimulation for Parkinson's disease patients.

BACKGROUND: Subthalamic deep brain stimulation (STN-DBS) is a well-established therapy to treat Parkinson's disease (PD). However, the STN-DBS sub-target remains debated. Recently, a white matter tract termed the hyperdirect pathway (HDP), directly connecting the motor cortex to STN, has gained interest as HDP stimulation is hypothesized to drive DBS therapeutic effects. Previously, we have investigated EEG-based evoked potentials (EPs) to better understand the neuroanatomical origins of the DBS clinical effect. We found a 3-ms peak (P3) relating to clinical benefit, and a 10-ms peak (P10) suggesting nigral side effects. Here, we aimed to investigate the neuroanatomical origins of DBS EPs using probabilistic mapping. METHODS: EPs were recorded using EEG whilst low-frequency stimulation was delivered at all DBS-contacts individually. Next, EPs were mapped onto the patients' individual space and then transformed to MNI standard space. Using voxel-wise and fiber-wise probabilistic mapping, we determined hotspots/hottracts and coldspots/coldtracts for P3 and P10. Topography analysis was also performed to determine the spatial distribution of the DBS EPs. RESULTS: In all 13 patients (18 hemispheres), voxel- and fiber-wise probabilistic mapping resulted in a P3-hotspot/hottract centered on the posterodorsomedial STN border indicative of HDP stimulation, while the P10-hotspot/hottract covered large parts of the substantia nigra. CONCLUSION: This study investigated EP-based probabilistic mapping in PD patients during STN-DBS, revealing a P3-hotspot/hottract in line with HDP stimulation and P10-hotspot/hottract related to nigral stimulation. Results from this study provide key evidence for an electrophysiological measure of HDP and nigral stimulation.

Engaging dystonia networks with subthalamic stimulation.

Deep brain stimulation is a viable and efficacious treatment option for dystonia. While the internal pallidum serves as the primary target, more recently, stimulation of the subthalamic nucleus (STN) has been investigated. However, optimal targeting within this structure and its complex surroundings have not been studied in depth. Indeed, multiple historical targets that have been used for surgical treatment of dystonia are directly adjacent to the STN. Further, multiple types of dystonia exist, and outcomes are variable, suggesting that not all types would profit maximally from the exact same target. Therefore, a thorough investigation of the neural substrates underlying effects on dystonia symptoms is warranted. Here, we analyze a multi-center cohort of isolated dystonia patients with subthalamic implantations (N = 58) and relate their stimulation sites to improvement of appendicular and cervical symptoms as well as blepharospasm. Stimulation of the ventral oral posterior nucleus of thalamus and surrounding regions was associated with improvement in cervical dystonia, while stimulation of the dorsolateral STN was associated with improvement in limb dystonia and blepharospasm. This dissociation was also evident for structural connectivity, where the cerebellothalamic, corticospinal and pallidosubthalamic tracts were associated with improvement of cervical dystonia, while hyperdirect and subthalamopallidal pathways were associated with alleviation of limb dystonia and blepharospasm. Importantly, a single well-placed electrode may reach the three optimal target sites. On the level of functional networks, improvement of limb dystonia was correlated with connectivity to the corresponding somatotopic regions in primary motor cortex, while alleviation of cervical dystonia was correlated with connectivity to the recently described 'action-mode' network that involves supplementary motor and premotor cortex. Our findings suggest that different types of dystonia symptoms are modulated via distinct networks. Namely, appendicular dystonia and blepharospasm are improved with modulation of the basal ganglia, and, in particular, the subthalamic circuitry, including projections from the primary motor cortex. In contrast, cervical dystonia was more responsive when engaging the cerebello-thalamo-cortical circuit, including direct stimulation of ventral thalamic nuclei. These findings may inform DBS targeting and image-based programming strategies for patient-specific treatment of dystonia.

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

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

Mapping dysfunctional circuits in the frontal cortex using deep brain stimulation.

Frontal circuits play a critical role in motor, cognitive and affective processing, and their dysfunction may result in a variety of brain disorders. However, exactly which frontal domains mediate which (dys)functions remains largely elusive. We studied 534 deep brain stimulation electrodes implanted to treat four different brain disorders. By analyzing which connections were modulated for optimal therapeutic response across these disorders, we segregated the frontal cortex into circuits that had become dysfunctional in each of them. Dysfunctional circuits were topographically arranged from occipital to frontal, ranging from interconnections with sensorimotor cortices in dystonia, the primary motor cortex in Tourette's syndrome, the supplementary motor area in Parkinson's disease, to ventromedial prefrontal and anterior cingulate cortices in obsessive-compulsive disorder. Our findings highlight the integration of deep brain stimulation with brain connectomics as a powerful tool to explore couplings between brain structure and functional impairments in the human brain.

Deep Brain Stimulation for Obsessive-Compulsive Disorder: Optimal Stimulation Sites.

BACKGROUND: Deep brain stimulation (DBS) is a promising treatment option for treatment-refractory obsessive-compulsive disorder (OCD). Several stimulation targets have been used, mostly in and around the anterior limb of the internal capsule and ventral striatum. However, the precise target within this region remains a matter of debate. METHODS: Here, we retrospectively studied a multicenter cohort of 82 patients with OCD who underwent DBS of the ventral capsule/ventral striatum and mapped optimal stimulation sites in this region. RESULTS: DBS sweet-spot mapping performed on a discovery set of 58 patients revealed 2 optimal stimulation sites associated with improvements on the Yale-Brown Obsessive Compulsive Scale, one in the anterior limb of the internal capsule that overlapped with a previously identified OCD-DBS response tract and one in the region of the inferior thalamic peduncle and bed nucleus of the stria terminalis. Critically, the nucleus accumbens proper and anterior commissure were associated with beneficial but suboptimal clinical improvements. Moreover, overlap with the resulting sweet- and sour-spots significantly estimated variance in outcomes in an independent cohort of 22 patients from 2 additional DBS centers. Finally, beyond obsessive-compulsive symptoms, stimulation of the anterior site was associated with optimal outcomes for both depression and anxiety, while the posterior site was only associated with improvements in depression. CONCLUSIONS: Our results suggest how to refine targeting of DBS in OCD and may be helpful in guiding DBS programming in existing patients.