Rhythmic modulation of subthalamo-pallidal interactions depends on synaptic rewiring through inhibitory plasticity

Aberrant oscillatory activity is a hallmark of several brain disorders including Parkinson's disease (PD). Specifically, interactions between neurons of the subthalamic nucleus (STN) and globus pallidus externus (GPe) may contribute to the emergence and maintenance of overly synchronized beta-band (15–30 Hz) oscillations and may be associated with the motor symptoms of PD. Excessive beta synchrony can be mitigated by pharmacological intervention and deep brain stimulation (DBS). Alternatively, brain stimulation strategies that aim to selectively modulate interpopulation connections may have therapeutic potential. Here, we tested computationally whether dual targeting of STN and GPe by time-shifted stimulation can modulate pathologically strong synapses through inhibitory spike-timing-dependent plasticity. More specifically, we examined how time-shifted paired stimuli delivered to the STN and GPe can lead to interpopulation synaptic rewiring. To that end, we first theoretically analyzed the optimal range of stimulation time shift and frequency for effective synaptic rewiring. Then, as a minimal model for generating oscillations in healthy and PD conditions, we considered a STN-GPe loop with biologically inspired model parameters. Time-shifted stimulation modified STN-GPe interactions by long-lasting synaptic rewiring. This ultimately caused desynchronizing aftereffects, resulting in a reduced coupling of the STN-GPe network and restoration of healthy dynamics. Our findings demonstrate the critical role of neuroplasticity in shaping long-lasting stimulation effects and contribute to the optimization of a variety of multisite stimulation paradigms aimed at reshaping dysfunctional brain networks by targeting inhibitory plasticity.