Claudia Ammann

Background: In Parkinson's disease, motor dysfunction largely reflects dopamine‐dependent pathophysiological alterations and compensatory mechanisms that progress over time and are partially reversible with dopaminergic treatment. Our recent cross‐sectional observations suggest that disinhibition of the primary motor cortex—assessed with short‐interval intracortical inhibition (SICI) using transcranial magnetic stimulation—does not correlate with clinical motor features, does not progress across disease stages, and instead correlates with olfactory dysfunction, a common prodromal and dopamine‐independent feature. Objective: We aimed to provide longitudinal evidence for or against the hypothesis that motor cortex disinhibition is dissociated from clinical motor features in Parkinson's disease. Methods: We compared SICI across three cohorts (total n = 95 patients): (1) baseline and 2‐year follow‐up (n = 43), with concurrent motor assessment and ¹⁸ F‐DOPA positron emission tomography (PET) imaging (n = 24); (2) before and after levodopa administration (n = 30); and (3) before and after focused ultrasound subthalamotomy (n = 22). We also included a pooled healthy control group (n = 75) from two previously published studies. Bayesian statistics was applied to formally assess evidence for the presence or the absence of an effect. Results: SICI was expectedly reduced, with very strong to extreme Bayesian evidence, in patients compared with control subjects. We found evidence that cortical disinhibition did not worsen with clinically evident disease progression confirmed with ¹⁸ F‐DOPA PET and did not improve following a clinically effective dose of levodopa or subthalamotomy. Moreover, changes in SICI did not correlate with changes in motor features across cohorts. Conclusions: These findings provide longitudinal evidence that motor cortex disinhibition is largely dissociated from clinical motor features in Parkinson's disease. © 2026 International Parkinson and Movement Disorder Society.

Background and Objectives: Unilateral Magnetic Resonance-guided Focused Ultrasound subthalamotomy (FUS-STN) has been shown to improve the cardinal motor features of Parkinson’s disease (PD). Whether this effect is sustained is not known. This study aims to report the long-term outcome of PD patients treated with unilateral FUS-STN. Methods: We conducted a prospective, open-label study of asymmetrical PD patients who underwent unilateral FUS-STN. All patients were evaluated up to 36 months after treatment. The primary outcome was the difference from baseline to 36 months after FUS-STN in the score of the Movement Disorders Society-Unified Rating scale (MDS-UPDRS) motor part (III) for the treated hemibody in the off-medication state. The safety outcome included all adverse events occurring during follow-up. Secondary outcomes were the change in the MDS-UPDRS III score on-medication; sub-scores of rigidity, bradykinesia, tremor, and axial features; total MDS-UPDRS III; and the MDS-UPDRS part IV. Functional disability and quality of life were assessed using the MDS-UPDRS II and the PDQ39, respectively. Patient impression of change and satisfaction with the treatment were self-assessed. The Wilcoxon signed-rank test with subsequent Bonferroni’s correction was used for data analysis. Results: Thirty-two PD patients were evaluated 36 months after treatment. The mean (±SD) age at baseline was 56.0±10.1 years, with a mean disease duration of 6.8±2.8 years. The MDS-UPDRS III score for the treated hemibody off-medication was improved by 52.3% from baseline to 3 years (score reduction from 19.0±3.2 to 8.9±3.3, 95% confidence interval [95CI] 8.7 to 11.6, PP<0.001). The MDS-UPDRS II, IV, and PDQ39 scores and levodopa dose were equivalent to those at baseline. Discussion: The benefit of unilateral FUS-STN on PD motor features is sustained in the long term. FUS-STN contributes to better clinical control over several years of evolution. NCT02912871/03454425. Classification of Evidence: This study provides Class IV evidence on the utility of focused ultrasound unilateral subthalamotomy in the treatment of people with Parkinson9s disease.

One common neuropsychiatric complication in patients with Parkinson’s disease treated with dopamine replacement therapy is impulse control disorders. A proportion of patients under dopamine agonist exhibit excessive desire towards appetitive cues accompanied by lost control over behaviour in forms of pathological gambling, hypersexuality or binge eating. The balance between enhanced desire towards sexual cues and cognitive control changes has been hypothesized to be biased toward the former in individuals with hypersexuality and impulse control disorders. Yet, some studies report no behavioural differences in cognitive control differences between impulsive patients and general Parkinson’s disease, suggesting possible functional changes along the mesocorticolimbic cortico-subcortical circuitry. Here, we provide evidence for this hypothesis by comparing the neurobiological substrate of sexual disturbance over response inhibition associated to medication states in Parkinson’s disease patients with a specific subtype of impulse control disorders (i.e., hypersexuality). We assessed the impact of sexual cues on response inhibition using a novel erotic stop signal task inside an fMRI. A total of 50 participants were included divided in 16 hypersexual and 17 non-hypersexual Parkinson’s disease patients and 17 healthy controls. Task-related activations, functional and anatomical connectivity models were performed. Additionally, a separate sample of 20 hypersexual Parkinson’s disease patients received excitatory neuromodulation (sham-controlled) over the pre-supplementary motor area (based on fMRI group-based results) aiming to improve response inhibition when exposed to sexual cues. Compared with their non-hypersexual peers, medication perturbed response inhibition upon presentation of sexual cues in patients with hypersexuality, recruiting a network involving caudate, pre-supplementary motor area, ventral tegmental area, and anterior cingulate cortex. Dynamic causal modelling revealed distinct best models to account for cortico-subcortical interactions with reduced task-related inputs in pre-supplementary motor area and descending connectivity to caudate in hypersexual compared to non- hypersexual Parkinson’s disease patients (while medicated). This was sustained by enhanced fractional anisotropy and reduced mean diffusivity in the pre-supplementary motor area-caudate pathway. Importantly, stimulation over the pre-supplementary motor area improved response inhibition when exposed to sexual cues in hypersexual Parkinson’s disease. We identified a specific fronto-striatal and mesolimbic circuitry underlying uncontrolled sexual behaviours in Parkinson’s disease induced by medication, with recovery options by applying neuromodulation.

Transcranial direct-current stimulation (tDCS) is a non-invasive brain stimulation technique consisting in the application of weak electric currents on the scalp. Although previous studies have demonstrated the clinical value of tDCS for modulating sensory, motor, and cognitive functions, there are still huge gaps in the knowledge of the underlying physiological mechanisms. To define the immediate impact as well as the after-effects of tDCS on sensory processing, we first performed electrophysiological recordings in primary somatosensory cortex (S1) of alert mice during and after administration of S1-tDCS, and followed up with immunohistochemical analysis of the stimulated brain regions. During the application of cathodal and anodal transcranial currents we observed polarity-specific bidirectional changes in the N1 component of the sensory-evoked potentials (SEPs) and associated gamma oscillations. Regarding the long-term effects observed after 20 min of tDCS, cathodal stimulation produced significant after-effects including a decreased SEP amplitude for up to 30 min, a power reduction in the 20-80 Hz range and a decrease in gamma event related synchronization (ERS). In contrast, no significant long-term changes in SEP amplitude or power analysis were observed after anodal stimulation except for a significant increase in gamma ERS after tDCS cessation. The polarity-specific differences of these long-term effects were corroborated by immunohistochemical analysis, which revealed an unbalance of GAD 65-67 immunoreactivity between the stimulated vs. non-stimulated S1 region only after cathodal tDCS. These results highlight the differences between immediate and long-term effects of tDCS, as well as the asymmetric long-term changes induced by anodal and cathodal stimulation. Significance Statement: Here we provide a first glimpse at the immediate and long-term impact of tDCS on neural processing in alert animals. The obtained results highlight the complexity of tDCS-associated effects, which include both bidirectional as well as asymmetrical modulation depending on the polarity of the stimulation. This asymmetry suggests the implication of different mechanisms underlying the long-term effects induced by anodal and cathodal transcranial currents. Identifying and defining these effects and its associated mechanisms is crucial to help design effective protocols for clinical applications.