Spatiotemporal features of β-γ phase-amplitude coupling in Parkinson’s disease derived from scalp EEG

Abstract

Abnormal phase-amplitude coupling between β and broadband-γ activities has been identified in recordings from the cortex or scalp of patients with Parkinson’s disease. While enhanced phase-amplitude coupling has been proposed as a biomarker of Parkinson’s disease, the neuronal mechanisms underlying the abnormal coupling and its relationship to motor impairments in Parkinson’s disease remain unclear. To address these issues, we performed an in-depth analysis of high-density EEG recordings at rest in 19 patients with Parkinson’s disease and 20 age- and sex-matched healthy control subjects. EEG signals were projected onto the individual cortical surfaces using source reconstruction techniques and separated into spatiotemporal components using independent component analysis. Compared to healthy controls, phase-amplitude coupling of Parkinson’s disease patients was enhanced in dorsolateral prefrontal cortex, premotor cortex, primary motor cortex and somatosensory cortex, the difference being statistically significant in the hemisphere contralateral to the clinically more affected side. β and γ signals involved in generating abnormal phase-amplitude coupling were not strictly phase-phase coupled, ruling out that phase-amplitude coupling merely reflects the abnormal activity of a single oscillator in a recurrent network. We found important differences for couplings between the β and γ signals from identical components as opposed to those from different components (originating from distinct spatial locations). While both couplings were abnormally enhanced in patients, only the latter were correlated with clinical motor severity as indexed by part III of the Movement Disorder Society Unified Parkinson’s Disease Rating Scale. Correlations with parkinsonian motor symptoms of such inter-component couplings were found in premotor, primary motor and somatosensory cortex, but not in dorsolateral prefrontal cortex, suggesting motor domain specificity. The topography of phase-amplitude coupling demonstrated profound differences in patients compared to controls. These findings suggest, first, that enhanced phase-amplitude coupling in Parkinson’s disease patients originates from the coupling between distinct neural networks in several brain regions involved in motor control. Because these regions included the somatosensory cortex, abnormal phase-amplitude coupling is not exclusively tied to the hyperdirect tract connecting cortical regions monosynaptically with the subthalamic nucleus. Second, only the coupling between β and γ signals from different components appears to have pathophysiological significance, suggesting that therapeutic approaches breaking the abnormal lateral coupling between neuronal circuits may be more promising than targeting phase-amplitude coupling per se.

A ventromedial prefrontal dysrhythmia in obsessive-compulsive disorder is attenuated by nucleus accumbens deep brain stimulation

“…This could point to a primarily cortical pathology underlying aberrant PAC in OCD. Relevant to this proposal is the recent suggestion that scalp EEG recorded PAC in PD could be a manifestation of the activity of two physiologically distinct oscillators from two spatially distinct cortical substrates [46]. The interpretation of our intracranial analysis is, however, clearly limited by the small sample size and further recordings are required to systematically compare the cortical pattern of PAC to oscillations within the accumbens.…”

“…A recent meta-analysis identified OCD as a possible risk factor for subsequently developing PD [45]. While most studies of PAC in PD patients have exclusively focused on motor cortex oscillations, a recent scalp EEG study with whole-brain source localization demonstrated beta-gamma coupling in dorsolateral prefrontal, premotor cortex, primary motor and somatosensory cortices, greater in the hemisphere contralateral to the clinically more affected side [46]. Aberrant mediofrontal synchronization was not observed in PD [46], pointing to a potential neuroanatomical difference between OCD and PD for a shared underlying neurophysiological abnormality.…”

On the role of arkypallidal and prototypical neurons for phase transitions in the external pallidum

“…Then, the KL-MI of the distribution of the average amplitude across phase bins was calculated as described in (Tort et al, 2010), which measures the difference to a uniform distribution. Furthermore, we evaluated PPC for the GPe-p firing rates filtered around f p and f a using the waveform analysis described in (Gong et al, 2020). In short, this method calculates the average waveform of the high-frequency signal, time-locked to the zero-crossing of the low-frequency signal.…”

“…In Parkinson's disease (PD), synchronized oscillations have been reported throughout all major BG nuclei (Wichmann, 2019) including the GPe (Wichmann and Soares, 2006;Mallet et al, 2008). These oscillations are characterized by transient power increases in the beta frequency band (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) and an increased phase-amplitude coupling between the phase of a beta signal and the amplitude of a high-frequency gamma signal (50-250 Hz) (Jenkinson et al, 2013;Lofredi et al, 2019;Gong et al, 2020). Computational models of BG phase transitions in PD suggest that the GPe is involved in the oscillation generation, either via its recurrent coupling with the subthalamic nucleus (STN) or via its processing of inputs from striatum (STR) (Pavlides et al, 2015;Schroll and Hamker, 2016;Rubin, 2017).…”

Cross-frequency phase-amplitude coupling in repetitive movements in patients with Parkinson’s disease

“…Cross-frequency coupling between the phase of β oscillations and the amplitude of γ oscillations is widely considered as a pathophysiological biomarker for Parkinson's disease. 1 Recordings via subdural electrocorticography (ECoG), local field potentials (LFP), and even non-invasive EEG revealed enhanced β-γ phase-amplitude coupling (PAC) during the resting state of patients with Parkinson's disease in both cortex [1][2][3] and subthalamic nucleus (STN) 4 , as compared with either healthy controls or patients with non-movement disorders. Exaggerated β-γ PAC at rest in patients with Parkinson's disease has been associated with motor impairment 1,[3][4][5] and can be attenuated by deep brain stimulation of the STN or by dopamine replacement therapy.…”