Objective Inhibitory control deficits are a hallmark of Parkinson’s disease (PD), particularly in patients with L-DOPA-induced dyskinesias (LID), but the cortical mechanisms underlying impaired inhibition remain poorly understood. We used transcranial magnetic stimulation and electroencephalography (TMS-EEG) to investigate cortical dynamics during a Go/NoGo task in PD patients with and without LID, compared with healthy volunteers. Methods Thirty-six PD patients (18 LID-PD, 18 nLID-PD) and 20 healthy volunteers performed a Go/NoGo task during TMS-EEG, which assessed functional connectivity between the supplementary motor area (SMA) and primary motor cortex (M1), and cortical reactivity through TMS-evoked potentials. Results Healthy volunteers exhibited task-dependent modulation of SMA–M1 connectivity, with increased theta-band coupling during NoGo trials and gamma-band coupling during Go trials; this pattern was absent in both PD groups, particularly in those with dyskinesias. TMS-evoked potentials revealed enhanced N100 responses during NoGo trials in healthy volunteers, reduced in non-dyskinetic patients and absent in dyskinetic ones. SMA–M1 gamma connectivity correlated with motor performance and clinical severity. During post-TMS epochs, healthy volunteers showed context-dependent alpha/beta modulation that was disrupted in PD patients. Conclusions SMA–M1 communication and cortical inhibitory processing are impaired in PD, especially in patients with dyskinesias. Significance SMA dysfunction may represent a biomarker and therapeutic target for inhibitory deficits in PD.
Objective Deep brain stimulation of the superolateral branch of the medial forebrain bundle (slMFB-DBS) has shown promising therapeutic effects in treatment-resistant depression and obsessive–compulsive disorder. Here, we explore for the first time the electrophysiological connectivity between the stimulation target and cortical sites in humans. Methods Electrophysiological responses to single slMFB-DBS pulses were mapped in 7 patients using epidural electrocorticography (ECoG; n = 4) or high-density electroencephalography (EEG; n = 3) over 11 sessions. Electrooculography (EOG) was simultaneously recorded, given that oculomotor side-effects are common after slMFB-DBS. Results Cortical evoked potentials were observed in 5 of 7 patients, with consistent latencies across modalities and prefrontal EEG topographies. In one patient, screening a broad parameter space demonstrated clear modulation of ECoG responses by DBS parameters. EOG activity consistent with oculomotor nerve co-activation was present in 6 of 7 patients, yet differed in timing and morphology from cortical responses. Conclusion This work shows effective connectivity between the slMFB-DBS target and the prefrontal cortex via ECoG and EEG, complementing existing structural connectivity data. Significance This is the first exploratory study demonstrating electrophysiological connectivity between the slMFB-DBS target and the prefrontal cortex in humans, opening the door to future studies which should systematically address their robustness and suitability for objective, biomarker-guided slMFB-DBS.
Objective To assess the feasibility and sensitivity of a revised stimulation-free motor unit number estimate (REMUNE) for detecting motor unit (MU) loss in amyotrophic lateral sclerosis (ALS). Methods Eighteen ALS patients and twelve healthy controls underwent up to six assessments over one year. High-density surface EMG was recorded bilaterally from clinically relevant hand and lower-leg muscles during stable contractions across ten force levels. MU decomposition used blind source separation, following a novel REMUNE algorithm. In ALS patients, ALS functional rating scale-revised scores and motor unit number index were recorded in parallel. Results REMUNE was lower in ALS than controls after adjusting for age and gender (24.9 vs. 52.1, p=0.006; -52%). This difference persisted when only strong ALS muscles were analysed (26.0 vs. 56.1, p=0.027; -54%; strength data available only at first visits). Within ALS, weak muscles produced lower REMUNE values than strong ones (15.5 vs 26.0, p=0.003; -40%). An age-related decline in REMUNE was observed across all participants (-0.85 units/year, p=0.014). REMUNE remained stable over time in ALS muscles (p=0.997). Conclusions REMUNE distinguished ALS from healthy muscles and captured strength-dependent MU loss. Significance REMUNE’s sensitivity to presymptomatic MU loss highlights its potential as an early diagnostic aid and trial stratification tool.
