Behavioral changes preceded by subthalamic nucleus activity alterations in a progressive macaque model of Parkinson’s disease

Hyperdirect projections from the supplementary motor area mediate subthalamic stimulation effects on movement initiation and inhibition in Parkinson’s disease

Improved movement initiation and increased impulsivity under stimulation of the subthalamic nucleus are linked to a shared anatomical and functional substrate, namely the subthalamic nucleus-supplementary motor cortex loop supporting automatic response inhibition.

Subthalamic stimulation modulates working memory-related cortical dynamics in Parkinson’s disease

Abstract The dynamic modulation of large-scale network activity, which is inherent to cognitive processes, is disrupted in Parkinson’s disease. Subthalamic deep brain stimulation can either improve or deteriorate cognition, particularly executive function, with these effects often going unnoticed during acute parameter optimization. This highlights the need for longer stimulation periods and more focused research on the underlying cortical mechanisms, which remain underexplored. This study was a prospective clinical trial involving nineteen people with Parkinson’s disease, who were evaluated off their medication at preoperative baseline and 6 months after deep brain stimulation implantation. Brain activity related to verbal and visuospatial working memory tasks was recorded using electroencephalography at both baseline and during follow-up evaluations conducted under stimulation. The follow-up assessments were carried out following 3-week periods of either omnidirectional or directional stimulation, applied in a randomized, double-blind, crossover design. Average postoperative working memory performance remained stable at the group level regardless of the stimulation condition for both verbal and visuospatial working memory tasks. However, at the individual level, higher alpha and beta power at baseline was associated with slower visuospatial working memory reaction time at follow-up. Additionally, reductions in theta and beta power during stimulation at follow-up correlated with better verbal working memory accuracy during the task and compared with baseline, respectively. These findings suggest that task-related electroencephalography may provide candidate physiological markers of individual working memory trajectories after subthalamic deep brain stimulation. Oscillatory brain activity may help to characterize stimulation-related cognitive variability beyond motor outcomes, but these exploratory findings require validation in larger cohorts before they can inform stimulation programming or closed-loop treatment strategies. Registration: ClinicalTrials.gov: NCT03548506

Neurophysiological activity patterns associated with excessive motor behaviors during long-term dopaminergic pharmacotherapy in a primate model of Parkinson’s disease

Vestibular nucleus stimulation for ameliorating locomotor dynamics in a Parkinsonian mouse model

It is shown that the mouse VNC feeds extensive Vglut2-defined projections into striato-thalamo-subthalamic and caudal medulla motor hubs and receives substantial input from the sensorimotor cortex and receives substantial input from the sensorimotor cortex.

Time Course and Microcircuit Mechanisms of Primary Motor Cortex Dysfunction in Progressive Parkinsonism

The optogenetic, electrophysiological, pharmacological, and CRISPR-mediated genetic studies demonstrated that impaired α5-GABAA receptor-mediated inhibition and excessive activation of NMDA receptors of M1 pyramidal neurons are key microcircu it mechanisms underlying cortical circuit remodeling during progressive striatal dopamine loss.

Movement dependent neural substates within levodopa-induced dyskinesia in Parkinson's disease.

Parkinson patients suffer from levodopa-induced dyskinesia, which occur adversely to chronic dopaminergic treatment. These abnormal involuntary movements can only partly be actively suppressed and affect quality of life. A lowered motor inhibition during hyperdopaminergic states, associated with structural and plasticity changes in the cortico-basal-ganglia motor network, is hypothesized to enable dyskinesia. Multiple oscillatory cortico-subthalamic patterns associated with dyskinesia have been described but their dependence on behavioral states such as movement presence remains unknown, which is crucial for its use in real-life application of adaptive neuromodulation. We studied invasive cortico-subthalamic oscillations in 22 patients with Parkinson's disease during dyskinesia-evoking protocols. Clinical assessments differentiated between non-dyskinetic and dyskinetic periods, and kinematic monitoring detected movement presence, leading to four behavioral states containing rest, voluntary movements, movement suppression during dyskinesia, and dyskinetic movements. Data-driven methods reduced data dimensionalities and optimized frequency-specific signal-to-noise ratios in the neural recordings and allowed feature extraction of spectral magnitudes, variances, and inter-subthalamic and cortico-subthalamic coherences. Subthalamic theta-activity and attenuated beta-activity were elevated during both dyskinetic movement suppression and execution, while cortico-subthalamic gamma-activity was only increased during dyskinetic movement execution. The subthalamic oscillations predicted dyskinesia presence, but varying behavioral states containing fluctuating movement presence affected the predictive performance. Movement-aware classifications improved dyskinesia detection based on cortical and on gamma oscillations. Introducing a movement-aware classification which considered the current behavioral state improved the neural detection of therapeutic states. We propose movement execution during dyskinesia should be considered as a distinct behavioral and neural microstate within a dopamine-depending hyperdopaminergic macrostate. Integrating this state concept may inform future adaptive neuromodulation and enhance its naturalistic robustness during every-day life.