Levodopa-induced dyskinesias are abnormal involuntary movements that limit the effectiveness of treatments for Parkinson’s disease. Although dyskinesias involve the striatum, it is unclear how striatal neurons are involved in dyskinetic movements. Here we record from striatal neurons in mice during levodopa-induced axial dyskinesias. We developed an automated 3-dimensional motion tracking system to capture the development of axial dyskinesias at ~10 ms resolution, and correlated these movements with neuronal activity of striatal medium spiny neurons and fast spiking interneurons. The average firing rate of medium spiny neurons increased as axial dyskinesias developed, and both medium spiny neurons and fast spiking interneurons were modulated around axial dyskinesias. We also found that delta field potential power increased in the striatum with dyskinesia, and that this increased delta power coupled with striatal neurons. Our findings provide insight into how striatal networks change as levodopa-induced dyskinesias develop, and suggest that increased medium spiny neuron firing, increased delta field potential power, and abnormal delta-coupling may be neurophysiological signatures of dyskinesias. These data could be helpful in understanding the role of the striatum in the pathogenesis of dyskinesias in Parkinson’s disease.

Brain rhythms are strongly linked with behavior, and abnormal rhythms can signify pathophysiology. For instance, the basal ganglia exhibit a wide range of low-frequency oscillations during movement, but pathological “beta” rhythms at ~ 20 Hz have been observed in Parkinson’s disease (PD) and in PD animal models. All brain rhythms have a frequency, which describes how often they oscillate, and a phase, which describes the precise time that peaks and troughs of brain rhythms occur. Although frequency has been extensively studied, the relevance of phase is unknown, in part because it is difficult to causally manipulate the instantaneous phase of ongoing brain rhythms. Here, we developed a phase-adaptive, real-time, closed-loop algorithm to deliver optogenetic stimulation at a specific phase with millisecond latency. We combined this Phase-Adaptive Brain STimulation (PABST) approach with cell-type-specific optogenetic methods to stimulate basal ganglia networks in dopamine-depleted mice that model motor aspects of human PD. We focused on striatal medium spiny neurons expressing D1-type dopamine receptors because these neurons can facilitate movement. We report three main results. First, we found that our approach delivered PABST within system latencies of 13 ms. Second, we report that closed-loop stimulation powerfully influenced the spike-field coherence of local brain rhythms within the dorsal striatum. Finally, we found that both 4 Hz PABST and 20 Hz PABST improved movement speed, but we found differences between phase only with 4 Hz PABST. These data provide causal evidence that phase is relevant for brain stimulation, which will allow for more precise, targeted, and individualized brain stimulation. Our findings are applicable to a broad range of preclinical brain stimulation approaches and could also inform circuit-specific neuromodulation treatments for human brain disease.

Brain rhythms are strongly linked with behavior, and abnormal rhythms can signify pathophysiology. For instance, the basal ganglia exhibit a wide range of low-frequency oscillations during movement, but pathological “beta” rhythms at ~ 20 Hz have been observed in Parkinson’s disease (PD) and in PD animal models. All brain rhythms have a frequency, which describes how often they oscillate, and a phase, which describes the precise time that peaks and troughs of brain rhythms occur. Although frequency has been extensively studied, the relevance of phase is unknown, in part because it is difficult to causally manipulate the instantaneous phase of ongoing brain rhythms. Here, we developed a phase-adaptive, real-time, closed-loop algorithm to deliver optogenetic stimulation at a specific phase with millisecond latency. We combined this Phase-Adaptive Brain STimulation (PABST) approach with cell-type-specific optogenetic methods to stimulate basal ganglia networks in dopamine-depleted mice that model motor aspects of human PD. We focused on striatal medium spiny neurons expressing D1-type dopamine receptors because these neurons can facilitate movement. We report three main results. First, we found that our approach delivered PABST within system latencies of 13 milliseconds. Second, we report that closed-loop stimulation powerfully influenced the spike-field coherence of local brain rhythms within the dorsal striatum. Finally, we found that 4-Hz, but not 20-Hz, PABST improved movement speed by 41%. These data provide causal evidence that phase is relevant for brain stimulation, which will allow for more precise, targeted, and individualized brain stimulation. Our findings are applicable to a broad range of preclinical brain stimulation approaches and could also inform circuit-specific neuromodulation treatments for human brain disease.