Rapid motor fluctuations reveal short-timescale neurophysiological biomarkers of Parkinson's disease

Objective.Identifying neural activity biomarkers of brain disease is essential to provide objective estimates of disease burden, obtain reliable feedback regarding therapeutic efficacy, and potentially to serve as a source of control for closed-loop neuromodulation. In Parkinson's disease (PD), microelectrode recordings (MER) are routinely performed in the basal ganglia to guide electrode implantation for deep brain stimulation (DBS). While pathologically-excessive oscillatory activity has been observed and linked to PD motor dysfunction broadly, the extent to which these signals provide quantitative information about disease expression and fluctuations, particularly at short timescales, is unknown. Furthermore, the degree to which informative signal features are similar or different across patients has not been rigorously investigated. We sought to determine the extent to which motor error in PD across patients can be decoded on a rapid timescale using spectral features of neural activity.Approach.Here, we recorded neural activity from the subthalamic nucleus (STN) of subjects with PD undergoing awake DBS surgery while they performed an objective, continuous behavioral assessment that synthesized heterogenous PD motor manifestations to generate a scalar measure of motor dysfunction at short timescales. We then leveraged natural motor performance variations as a 'ground truth' to identify corresponding neurophysiological biomarkers.Main results.Support vector machines using multi-spectral decoding of neural signals from the STN succeeded in tracking the degree of motor impairment at short timescales (as short as one second). Spectral power across a wide range of frequencies, beyond the classic 'beta' oscillations, contributed to this decoding, and multi-spectral models consistently outperformed those generated using more isolated frequency bands. While generalized decoding models derived across subjects were able to estimate motor impairment, patient-specific models typically performed better.Significance.These results demonstrate that quantitative information about short-timescale PD motor dysfunction is available in STN neural activity, distributed across various patient-specific spectral components, such that an individualized approach will be critical to fully harness this information for optimal disease tracking and closed-loop neuromodulation.