Therapeutic Deep Brain Stimulation Disrupts Subthalamic Nucleus Activity Dynamics in Parkinsonian Mice

Subthalamic nucleus deep brain stimulation (STN DBS) relieves many motor
symptoms of Parkinson’s Disease (PD), but its underlying therapeutic
mechanisms remain unclear. Since its advent, three major theories have
been proposed: (1) DBS inhibits the STN and basal ganglia output; (2) DBS
antidromically activates motor cortex; and (3) DBS disrupts firing
dynamics within the STN. Previously, stimulation-related electrical
artifacts limited mechanistic investigations using electrophysiology. We
used electrical artifact-free calcium imaging to investigate activity in
basal ganglia nuclei during STN DBS in parkinsonian mice. To test whether
the observed changes in activity were sufficient to relieve motor
symptoms, we then combined electrophysiological recording with targeted
optical DBS protocols. Our findings suggest that STN DBS exerts its
therapeutic effect through the disruption of STN dynamics, rather than
inhibition or antidromic activation. These results provide insight into
optimizing PD treatments and establish an approach for investigating DBS
in other neuropsychiatric conditions.