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.

Prosody matters: Preserved prominence marking strategies in people with Parkinson's disease independent of motor status.

While many studies focus on segmental variation in Parkinsonian speech, little is known about prosodic modulations reflecting the ability to adapt to communicative demands in people with Parkinson's disease (PwPD). This type of prosodic modulation is important for social interaction, and it involves modifications in speech melody (intonational level) and articulation of consonants and vowels (segmental level). The present study investigates phonetic cues of prosodic modulations with respect to different focus structures in mild dysarthric PwPD as a function of levodopa. Acoustic and kinematic speech parameters of 25 PwPD were assessed in two motor conditions. Speech production data from PwPD were collected before (medication-OFF) and after levodopa intake (medication-ON) by means of 3-D electromagnetic articulography. On the acoustic level, intensity, pitch, and syllable durations were analyzed. On the kinematic level, movement duration and amplitude were investigated. Spatio-temporal modulations of speech parameters were examined and compared across three different prosodic focus structures (out-of-focus, broad focus, contrastive focus) to display varying speech demands. Overall, levodopa had beneficial effects on motor performance, speech loudness, and pitch modulation. Acoustic syllable durations and kinematic movement durations did not change, revealing no systematic effects of motor status on the temporal domain. In contrast, there were spatial modulations of the oral articulators: tongue tip movements were smaller and lower lip movements were larger in amplitude under levodopa, reflecting a more agile and efficient articulatory movement under levodopa. Thus, respiratory-phonatory functions and consonant production improved, while syllable duration and tongue body kinematics did not change. Interestingly, prominence marking strategies were comparable between the medication conditions under investigation, and in fact, appear to be preserved in mild dysarthric PwPD.

Preoperative motor deficits and depressive symptoms predict quality of life in patients with Parkinson's disease at different time points after surgery for subthalamic stimulation: a retrospective study.

BACKGROUND: While subthalamic nucleus deep brain stimulation (STN-DBS) improves the quality of life (QoL) of patients with Parkinson's disease (PD), the clinical parameters that predict this improvement remain debated. This retrospective study explored whether preoperative motor, cognitive, and affective parameters predict QoL or its components at 6 and 12 months after STN-DBS surgery. METHODS: QoL was assessed with the Parkinson's Disease Questionnaire-39 (PDQ-39) before (baseline), at 6 months (N = 90) and 12 months (N = 63) after STN-DBS surgery. Changes in the PDQ-39 and its subdomains were analysed with Wilcoxon signed-rank tests. In total, seven motor, cognitive, and affective parameters recorded at baseline were used in multiple linear regressions to predict QoL and its subdomains. RESULTS: QoL had improved significantly at six months post STN-DBS surgery. After 12 months, this effect remained significant but was less pronounced. At both time points, significant improvements in mobility, activities of daily living, stigma, and bodily discomfort were present. Correlation and linear regression analyses showed that preoperative QoL status and changes in QoL at 6 and 12 months after surgery were driven by preoperative dopaminergic medication, as well as motor (UPDRS-III medOFF and PIGD-subscore medOFF) and affective (HADS anxiety and depression) symptoms. In contrast, preoperative cognitive performance did not predict QoL at any time point. CONCLUSION: Data show that preoperative motor and affective symptoms drive both QoL baseline status and changes in QoL after STN-DBS surgery. Thus, these clinical parameters need to be assessed appropriately to provide comprehensive presurgical advice to patients suffering from PD.

Progressive Supranuclear Palsy: Subcortical Tau Depositions Are Associated with Cortical Perfusion in Frontal and Limbic Regions.

 In progressive supranuclear palsy (PSP), subcortical tau and cortical perfusion can be assessed using the tracer [18F]PI-2620. We investigated if subcortical tau (globus pallidus internus, dentate nucleus) and frontal/limbic perfusion correlate in a cohort of 32 PSP patients. Tau in subcortical regions showed significant negative correlation with perfusion in limbic cortex. Perfusion in frontal regions was negatively associated with tau in both subcortical regions, but the significance threshold was only passed for the dentate nucleus. A reason could be a diaschisis-like phenomenon; that is, subcortical tau could lead to reduced connectivity to frontal regions and, thereby, to decreased perfusion.

In a study of 32 patients with progressive supranuclear palsy (PSP), we used a molecular imaging tracer called [18F]PI-2620 to measure two things: the presence of a protein called tau in deep brain areas (specifically, the globus pallidus internus and dentate nucleus) and the function of the brain's cortex by assessing blood flow (perfusion). We found that higher amounts of tau in these deep brain areas were associated with reduced blood flow in the limbic cortex, which is involved in emotion regulation. Also, the frontal areas of the brain showed reduced blood flow related to tau in these deep brain regions. However, this connection was statistically significant only for the dentate nucleus. This study suggests that the buildup of tau protein in deeper brain areas can disrupt function in parts of the brain's cortex, highlighting the damaging role of tau in PSP.

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.