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Non-technical summary  Deep brain stimulation (DBS) refers to a neurosurgical technique where chronically implanted electrodes serve to deliver electrical impulses to highly defined brain regions in neuropsychiatric disorders including Parkinson's disease (PD), depression and obsessive–compulsive disorders. Despite its broad acceptance as a safe and effective treatment for advanced PD, DBS has remained enigmatic with respect to its underlying mechanism(s). In general terms, DBS is capable of reinstating regular electrical activity in the complex neuronal networks that exhibit aberrant firing properties in PD, but how this effect is achieved at the network and cellular level is still highly debated. Our study focuses on a crucial, but hitherto neglected, issue in this controversy, namely the propagation of impulses within and away from the site of electrical stimulation. We propose that DBS overburdens the capacity of axons to transmit signals, thereby filtering and abating the pathological activity in the brain motor loops of PD patients.

Abstract  Deep brain stimulation (DBS) has been established as an effective surgical therapy for advanced Parkinson's disease (PD) and gains increasing acceptance for otherwise intractable neuropsychiatric diseases such as major depression or obsessive–compulsive disorders. In PD, DBS targets predominantly the subthalamic nucleus (STN) and relieves motor deficits only at high frequency (>100 Hz). In contrast to the well-documented clinical efficacy of DBS, its underlying principle remains enigmatic spawning a broad and, in part, contradictory spectrum of suggested synaptic and non-synaptic mechanisms within and outside STN. Here we focused on a crucial, but largely neglected issue in this controversy, namely the axonal propagation of DBS within and away from STN. In rat brain slices preserving STN projections to substantia nigra (SN) and entopeduncular nucleus (EP, the rodent equivalent of internal globus pallidus), STN-DBS disrupted synaptic excitation onto target neurons through an unexpected failure of axonal signalling. The rapid onset and, upon termination of DBS, recovery of this effect was highly reminiscent of the time course of DBS in the clinical setting. We propose that DBS-induced suppression of axonal projections from and to STN serves to shield basal ganglia circuitry from pathological activity arising in or amplified by this nucleus.