Re-emergent Tremor during stable posture in Parkinson's Disease: Evidence of Pathological Beta and Prokinetic Gamma Activity

Re-emergent tremor (RET) during stable posture in Parkinsons disease (PD) is characterized as a continuation of resting tremor (RT) and is often highly therapy refractory. The pathophysiology of both RT and RET is linked to deficits in cerebello-cortical circuits and dopaminergic depletion. However, it remains unclear how these two types of tremors differ functionally. The aim of this study is to examine the differences in brain activity between RT and RET in PD, as well as to investigate the relationship between neuronal oscillatory activity, in PD tremor phenotype patients. Forty PD patients (25 males, mean age 66.78 {+/-} 5.03 years) and 40 age- and sex-matched healthy controls were assessed. 256 channel HD-EEG and EMG signals were recorded while the participants extended their hands against gravity. Tremor was recorded in both L-dopa ON and OFF for PD patients and mimicked by healthy controls. Coherent sources of EEG-EMG were located using beamforming technique, and information flow between different sources was estimated using time-resolved partial-directed coherence. Cross-frequency coupling (CFC) was then used to analyze the association between tremor frequency and neuronal oscillatory activity. Under L-dopa administration, coherent sources referenced to the tremor frequency revealed differences in brain activity between RT and RET in the premotor cortex and cerebellum of PD patients, which were similar to those observed in healthy controls. However, PD patients exhibited an additional source location in the primary sensorimotor cortex. Withdrawal of L-dopa led to coherent sources being observed in the supplementary motor area and subthalamic nucleus. Furthermore, L-dopa was found to suppress the strength of connections between these coherent sources and modulate the tremor-associated beta and gamma frequency, leading to a decrease in beta power and an increase in gamma power. The findings of this study reveal discernible neural activity patterns during resting and re-emergent tremors. In patients with PD, the primary sensorimotor cortex plays a primordial role as the exclusive source of activity involved in the generation of RET. It shows a significant amount of co-activation within the network involving the premotor areas and cerebellum, and its activation accounts for the discrepancy in tremor phenotypes. Moreover, the oscillatory neuronal responses involve pathological beta and prokinetic gamma activity alterations that are highly specific to tremor phenotypes. These peculiarities play an essential role in our understanding of tremor phenomena and its therapeutic modulation by dopamine medication or deep brain stimulation, which could specifically target the tremor- and motor-control-related pathological beta and prokinetic gamma oscillations.