Cholinergic input from the pedunculopontine nucleus to the cerebellum: implications for deep brain stimulation in Parkinson's disease.

Abstract

Deep brain stimulation (DBS) is a well established electrophysiological treatment initially applied to treat medication-refractory motor symptoms in Parkinson's disease (PD), and is now being explored for several neurological and psychiatric disorders. The specific physiological mechanisms underlying the effectiveness of DBS are not fully understood, although some hypothesized general mechanisms may be acceptable (Wichmann and DeLong, 2016). Early hypotheses suggested that stimulation of the subthalamic nucleus (STN) in PD produced the same clinical effect as a lesion. In other words, DBS was initially considered to suppress or modulate the abnormal bursting discharge patterns that occur in STN neurons in parkinsonian patients. Several mechanisms have been proposed to explain this effect, invoking what would happen at the site of stimulation and/or in the neuronal circuitry to which the targeted region for stimulation is functionally connected. These mechanisms include depolarization block caused by increase of potassium currents, inactivation of sodium channels, presynaptic depression of excitatory afferents, and stimulation-induced activation of inhibitory afferents. However, evidence in favor of activation of STN neurons was also provided, possibly mediated by stimulation-induced activation of excitatory projections from the motor cortex, or by a direct effect of stimulation directly on STN neurons. Moreover, neuronal activity may be phase locked to the pulse train, with following frequencies dictated by the stimulus interval.