Structural Connectivity Patterns of Side Effects Induced by Subthalamic Deep Brain Stimulation for Parkinson's Disease.

Background: Tractography based on diffusion-weighted magnetic resonance imaging (DWI) models the structural connectivity of the human brain. Deep brain stimulation (DBS) targeting the subthalamic nucleus is an effective treatment for advanced Parkinson's disease, but may induce adverse effects. This study investigated the relationship between structural connectivity patterns of DBS electrodes and stimulation-induced side effects. Materials and Methods: Twenty-one patients with Parkinson's disease treated with bilateral subthalamic DBS were examined. Overall, 168 electrode contacts were categorized as inducing or noninducing depending on their capability for inducing side effects such as motor effects, paresthesia, dysarthria, oculomotor effects, hyperkinesia, and other complications as assessed during the initial programming session. Furthermore, the connectivity of each contact with target regions was evaluated by probabilistic tractography based on DWI. Finally, stimulation sites and structural connectivity patterns of inducing and noninducing contacts were compared. Results: Inducing contacts differed across the various side effects and from those mitigating Parkinson's symptoms. Although contacts showed a largely overlapping spatial distribution within the subthalamic region, they could be distinguished by their connectivity patterns. In particular, inducing contacts were more likely connected with supplementary motor areas (hyperkinesia, dysarthria), frontal cortex (oculomotor), fibers of the internal capsule (paresthesia), and the basal ganglia-thalamo-cortical circuitry (dysarthria). Discussion: Side effects induced by DBS seem to be associated with distinct connectivity patterns. Cerebellar connections are hardly associated with side effects, although they seem relevant for mitigating motor symptoms in Parkinson's disease. A symptom-specific, connectivity-based approach for target planning in DBS may enhance treatment outcomes and reduce adverse effects. Impact statement Tractography based on diffusion-weighted magnetic resonance imaging has become a prominent technique for investigating the connectivity of human brain networks in vivo. However, the relationship between structural connections and brain function is still hardly known. The present study examined the relationship between adverse behavioral effects induced by deep brain stimulation (DBS) and tractography patterns in individual brains. The results suggest that DBS-based side effects depend on the structural connections of electrode contacts rather than their location. Network-based target planning in DBS may improve treatment by avoiding side effects. Moreover, the adopted approach may serve as a paragon for investigating structure/function relationships.

A multicenter, open-label, controlled trial on acceptance, convenience, and complications of rechargeable internal pulse generators for deep brain stimulation: the Multi Recharge Trial.

OBJECTIVE: Rechargeable neurostimulators for deep brain stimulation have been available since 2008, promising longer battery life and fewer replacement surgeries compared to non-rechargeable systems. Long-term data on how recharging affects movement disorder patients are sparse. This is the first multicenter, patient-focused, industry-independent study on rechargeable neurostimulators. METHODS: Four neurosurgical centers sent a questionnaire to all adult movement disorder patients with a rechargeable neurostimulator implanted at the time of the trial. The primary endpoint was the convenience of the recharging process rated on an ordinal scale from "very hard" (1) to "very easy" (5). Secondary endpoints were charge burden (time spent per week on recharging), user confidence, and complication rates. Endpoints were compared for several subgroups. RESULTS: Datasets of 195 movement disorder patients (66.1% of sent questionnaires) with Parkinson's disease (PD), tremor, or dystonia were returned and included in the analysis. Patients had a mean age of 61.3 years and the device was implanted for a mean of 40.3 months. The overall convenience of recharging was rated as "easy" (4). The mean charge burden was 122 min/wk and showed a positive correlation with duration of therapy; 93.8% of users felt confident recharging the device. The rate of surgical revisions was 4.1%, and the infection rate was 2.1%. Failed recharges occurred in 8.7% of patients, and 3.6% of patients experienced an interruption of therapy because of a failed recharge. Convenience ratings by PD patients were significantly worse than ratings by dystonia patients. Caregivers recharged the device for the patient in 12.3% of cases. Patients who switched from a non-rechargeable to a rechargeable neurostimulator found recharging to be significantly less convenient at a higher charge burden than did patients whose primary implant was rechargeable. Age did not have a significant impact on any endpoint. CONCLUSIONS: Overall, patients with movement disorders rated recharging as easy, with low complication rates and acceptable charge burden.

Deep brain stimulation: Connectivity profile for bradykinesia alleviation.

OBJECTIVE: Subthalamic deep brain stimulation may alleviate bradykinesia in Parkinson patients. Research suggests that this stimulation effect may be mediated by brain networks like the corticocerebellar loop. This study investigated the connectivity between stimulation sites and cortical and subcortical structures to identify connections for effective stimulation. METHODS: We retrospectively investigated 21 patients with Parkinson disease with bilateral subthalamic deep brain stimulation. Stimulation effectiveness in reducing bradykinesia, tremor, and rigidity was evaluated for each electrode contact in brain hemispheres contralateral to the affected hemibody. Dysarthric side effects were also examined. Probabilistic tractography based on diffusion-weighted imaging was performed in individual patient-specific brains using electrode contacts as seeds. Connectivity profiles of contacts with effective and noneffective stimulation were compared. RESULTS: Connectivity profiles of effective and noneffective contacts differed. Moreover, the connectivity profile for bradykinesia differed from that for rigidity, tremor, or dysarthria. Regarding bradykinesia, effective contacts were significantly more often connected with the ipsilateral superior cerebellar peduncle and the ipsilateral dentate nucleus, which correspond to the ipsilateral portion of the cerebellothalamocortical pathway. Rigidity was mitigated by stimulation of ascending brainstem and intralaminar thalamic connections. Tremor alleviation was related to connections with the internal capsule (anterior limb) and the pallidum. Dysarthric side effects were associated with connections to the supplementary motor area and the decussating cerebellothalamocortical pathway. INTERPRETATION: Whereas bradykinesia seems to be mitigated by stimulation of the ascending, ipsilateral cerebellothalamocortical pathway, stimulation of the descending corticopontocerebellar pathway may be ineffective. Rigidity, tremor, and dysarthric side effects seem to be influenced by different neural networks. ANN NEUROL 2019;85:852-864.

Probabilistic vs. deterministic fiber tracking and the influence of different seed regions to delineate cerebellar-thalamic fibers in deep brain stimulation.

This study compared tractography approaches for identifying cerebellar-thalamic fiber bundles relevant to planning target sites for deep brain stimulation (DBS). In particular, probabilistic and deterministic tracking of the dentate-rubro-thalamic tract (DRTT) and differences between the spatial courses of the DRTT and the cerebello-thalamo-cortical (CTC) tract were compared. Six patients with movement disorders were examined by magnetic resonance imaging (MRI), including two sets of diffusion-weighted images (12 and 64 directions). Probabilistic and deterministic tractography was applied on each diffusion-weighted dataset to delineate the DRTT. Results were compared with regard to their sensitivity in revealing the DRTT and additional fiber tracts and processing time. Two sets of regions-of-interests (ROIs) guided deterministic tractography of the DRTT or the CTC, respectively. Tract distances to an atlas-based reference target were compared. Probabilistic fiber tracking with 64 orientations detected the DRTT in all twelve hemispheres. Deterministic tracking detected the DRTT in nine (12 directions) and in only two (64 directions) hemispheres. Probabilistic tracking was more sensitive in detecting additional fibers (e.g. ansa lenticularis and medial forebrain bundle) than deterministic tracking. Probabilistic tracking lasted substantially longer than deterministic. Deterministic tracking was more sensitive in detecting the CTC than the DRTT. CTC tracts were located adjacent but consistently more posterior to DRTT tracts. These results suggest that probabilistic tracking is more sensitive and robust in detecting the DRTT but harder to implement than deterministic approaches. Although sensitivity of deterministic tracking is higher for the CTC than the DRTT, targets for DBS based on these tracts likely differ.

IL-7 receptor α expressing B cells act proinflammatory in collagen-induced arthritis and are inhibited by sympathetic neurotransmitters.

OBJECTIVES: The sympathetic nervous system (SNS) as well as the interleukin (IL)-7/IL-7 receptor (IL-7R) system play a role in the pathogenesis of arthritis. However, the target cells and mechanisms involved are not fully resolved. The goal of this study was to determine if B cells are influenced by IL-7 and to investigate the possible interplay between the SNS and the IL-7/IL-7R system on B cells in arthritis. METHODS: Collagen type II-induced arthritis (CIA) in DBA1 mice. ELISA to determine specific anti-CII antibodies. Fluorescence activated cell sorting (FACS) analysis to determine IL-7R+ cells and intracellular phosphorylated signal transducer and activator of transcription 5 (pSTAT5). Immunohistochemistry to show IL-7R+ B cells in rheumatoid arthritis (RA) and osteoarthritis (OA) synovial tissue. RESULTS: IL-7 stimulated IL-7R+ mature B cells act proinflammatory (increased clinical score, increased anticollagen type II antibodies) after cell transfer in CIA. The sympathetic neurotransmitter norepinephrine abrogates this effect. Expression of IL-7Rα is increased when B cells are activated (anti-CD40 or lipopolysaccharide) in vitro and stimulating the IL-7R induces intracellular accumulation of pSTAT5. α- And ß-adrenergic agonists show no influence on expression levels of IL-7R on activated B cells; however, intracellular IL-7R downstream signalling is abrogated via the ß2-adreonceptor (ß2AR) agonist terbutaline. IL-7R and ß2AR are also expressed on B cells in synovial tissue from RA and OA patients. CONCLUSIONS: These data indicate that IL7R+ B cells have a proinflammatory role in arthritis which can be inhibited by the sympathetic neurotransmitter norepinephrine via inhibition of IL-7R signalling.