Deep brain stimulation in the subthalamic nucleus for Parkinson's disease can restore dynamics of striatal networks

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is highly effective in alleviating movement disability in patients with Parkinsons disease (PD). However, its therapeutic mechanism of action is unknown. The healthy striatum exhibits rich dynamics resulting from an interaction of beta, gamma and theta oscillations. These rhythms are at the heart of selection, initiation and execution of motor programs, and their loss or exaggeration due to dopamine (DA) depletion in PD is a major source of the behavioral deficits observed in PD patients. Interrupting abnormal rhythms and restoring the interaction of rhythms as observed in the healthy striatum may then be instrumental in the therapeutic action of DBS. We develop a biophysical networked model of a BG pathway to study how abnormal beta oscillations can emerge throughout the BG in PD, and how DBS can restore normal beta, gamma and theta striatal rhythms. Our model incorporates STN projections to the striatum, long known but understudied, that were recently shown to preferentially target fast spiking interneurons (FSI) in the striatum. We find that DBS in STN is able to normalize striatal medium spiny neuron (MSN) activity by recruiting FSI dynamics, and restoring the inhibitory potency of FSIs observed in normal condition. We also find that DBS allows the re-expression of gamma and theta rhythms, thought to be dependent on high DA levels and thus lost in PD, through cortical noise control. Our study shows how BG connectivity can amplify beta oscillations, and delineates the role of DBS in disrupting beta oscillations and providing corrective input to STN efferents to restore healthy striatal dynamics. It also suggests how gamma oscillations can be leveraged to enhance or supplement DBS treatment and improve its effectiveness.