Tremor is a core feature of Parkinson's disease and the most easily recognized parkinsonian sign. Nonetheless, its pathophysiology remains poorly understood. Here, we show that multispectral spiking activity in the posterior-dorso-lateral oscillatory (motor) region of the subthalamic nucleus distinguishes resting tremor from the other Parkinsonian motor signs and strongly correlates with its severity. We evaluated microelectrode-spiking activity from the subthalamic dorsolateral oscillatory region of 70 Parkinson’s disease patients who underwent deep brain stimulation surgery (114 subthalamic nuclei, 166 electrode trajectories). We then investigated the relationship between patients’ clinical Unified Parkinson’s Disease Rating Scale score and their peak theta (4-7Hz) and beta (13-30Hz) powers. We found a positive correlation between resting tremor and theta activity (r = 0.41, p < 0.01) and a non-significant negative correlation with beta activity (r=-0.2, p = 0.5). Hypothesizing that the two neuronal frequencies mask each other’s relationship with resting tremor, we created a non-linear model of their proportional spectral powers and investigated its relationship with resting tremor. As hypothesized, patients' proportional scores correlated better than either theta or beta alone (r = 0.54, p < 0.001). However, theta and beta oscillations were frequently temporally correlated (38/70 patients manifested significant positive temporal correlations and 1/70 exhibited significant negative correlation between the two frequency bands). When comparing theta and beta temporal relationship (rθβ) to patients' resting tremor scores, we found a significant negative correlation between the two (r=-0.38, p < 0.01). Patients manifesting a positive correlation between the two bands (i.e., theta and beta were likely to appear simultaneously) were found to have lower resting tremor scores than those with near zero correlation values (i.e., theta and beta were likely to appear separately). We therefore created a new model incorporating patients' proportional theta-beta power and rθβ scores to obtain an improved neural correlate of resting tremor (r = 0.62, p < 0.001). We then used the Akaike and Bayesian information criteria for model selection and found the multispectral model, incorporating theta-beta proportional power and their correlation, to be the best fitting model, with 0.96 and 0.89 probabilities respectively. Here we found that as theta increases, beta decreases and the two appear separately – resting tremor is worsened. Our results therefore show that theta and beta convey information about resting tremor in opposite ways. Furthermore, the finding that theta and beta coactivity is negatively correlated with resting tremor suggests that theta-beta non-linear scale may be a valuable biomarker for Parkinson's resting tremor in future adaptive deep brain stimulation techniques.

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AbstractEvent Related Potentials (ERPs) are widely used to study category-selective EEG responses to visual stimuli, such as the face-selective N170 component. Typically, this is done by flashing stimuli abruptly at the point of static gaze fixation. While allowing for good experimental control, these paradigms ignore the dynamic role of eye-movements in natural vision. Fixation-related potentials (FRPs) obtained using simultaneous EEG and eye-tracking, overcome this limitation. Various studies have used FRPs to study processes such as lexical processing, target detection and attention allocation. The goal of this study was to compare face-sensitive activity evoked by stimulus abrupt appearance with that evoked by self-controlled gaze fixations on a stimulus. Twelve participants were studied in three experimental conditions: Free-viewing (FRPs), Cued-viewing (FRPs) and Control (ERPs). We used a multiple regression approach to disentangle overlapping activity components. Our results show that the N170 face effect (face vs. non-face) is evident for the first fixation on a stimulus, whether it follows a self-generated saccade or stimulus appearance at fixation point. Furthermore, the N170 exhibits category-specific adaptation in free viewing. The N170 face effect had similar topography across viewing conditions, but there were major differences within each stimulus category. We ascribe these differences to an overlap of the fixation-related Lambda response and the N170. We tested the plausibility of this account using dipole simulations. This study establishes the use of the N170 face effect as a signature of face detection in free-viewing experiments while highlighting the importance of accounting for eye-movement related effects.