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

Movement-responsive deep brain stimulation reinforces motor circuits in Parkinson's disease

Deep brain stimulation is an established treatment for Parkinson's disease but does not adapt to dynamic changes in brain state. Here, in four patients with sensing-enabled DBS systems, we evaluated a movement-responsive DBS (mDBS) paradigm that modulated subthalamic stimulation based on volitional motion decoded from cortical activity. During structured motor tasks, mDBS improved average forearm speed and mitigated the progressive bradykinetic slowing observed under constant-amplitude DBS (cDBS), accompanied by a cumulative increase in sensorimotor cortical beta activity and connectivity. In unconstrained, daily activities, mDBS lowered average bradykinesia severity and demonstrated progressive symptom reduction over hours of therapy, which gradually reversed upon switching to cDBS. These findings highlight the enhanced therapeutic benefit of mDBS and its potential to reinforce functional motor circuits in disorders of movement.

Impact of the brainstem in normal and impaired human movement control

The corticospinal tract represents a highly developed neural system that dominates motor control in humans. This allows the performance of skilled finger movements, such as playing the piano. In contrast, according to preclinical studies, automatically performed complex movements, such as locomotion or cooperative forelimb movements, appear to be controlled mainly by brainstem motor centres. Only in recent years, with the advancement of new methodologies, has evidence emerged that limb coordination in humans is also based on neural limb coupling mediated by brainstem motor centres. This neural limb coupling is reflected in the observation that, during a movement, unilateral electrical nerve stimulation elicits muscle responses not only in the stimulated but also in the contralateral limb(s), involved in the respective motor task. The finding that activation of the reticulospinal system by loud acoustic stimuli evokes muscle responses that closely resemble the configuration of ‘coupling responses’ induced by electrical nerve stimulation suggests a contribution of the brainstem to the neural coupling mechanism. In addition to its role in interlimb coordination during stepping or cooperative hand movements, the reticulospinal system seems to be involved in the control of other motor tasks, including posture, reaching and force development. Furthermore, recent evidence indicates that brainstem motor centres contribute to functional recovery after stroke and spinal cord injury. These observations suggest that the brainstem plays a major role in motor control not only in animals but also in humans.

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

A temporal relationship between STN dysfunction and symptom onset is revealed and site- and frequency-specific stimulation strategies to address motor and non-motor symptoms in PD are supported.

From thalamic pathology to suppression stimulation of the subthalamic nucleus in Parkinson's disease: effects of variation in stimulation parameters

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.

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.