Perspective: Phase Amplitude Coupling–Based Phase–Dependent Neuromodulation in Parkinson’s Disease

Bradykinesia is a cardinal motor symptom in Parkinson's disease whose pathophysiology is incompletely understood. When signals are recorded from the cortex or scalp at rest, affected patients display enhanced phase-amplitude coupling between β (13-30Hz) and broadband γ (50-150Hz) oscillatory activities. However, it remains unclear whether and how abnormal phase-amplitude coupling is involved in slowing Parkinsonian movements during their execution. To address these questions, we analyzed high-density EEG signals recorded simultaneously with various motor activities and at rest in 19 patients with Parkinson's disease and 20 healthy controls. The motor tasks consisted of repetitive index finger pressing, and slow and fast tapping movements. Individual EEG source signals were computed for the premotor cortex, primary motor cortex, primary somatosensory cortex, and primary somatosensory complex. For the resting condition and the pressing task, phase-amplitude coupling averaged over the 4 motor regions and the entire movement period was larger in patients than in controls. In contrast, in all tapping tasks, state-related phase-amplitude coupling was similar between patients and controls. These findings were not aligned with motor performance and EMG data, which showed abnormalities in patients for tapping but not for pressing, suggesting that the strength of β-broadband γ phase-amplitude coupling during the movement period does not directly relate to Parkinsonian bradykinesia. Subsequently, we examined the dynamics of oscillatory EEG signals during motor transitions. When healthy controls performed the pressing task, dynamic phase-amplitude coupling increased shortly before pressing onset and decreased subsequently. A strikingly similar motif of coupling rise and decay was observed around the offset of pressing and around the onset of slow tapping, suggesting that such transient phase-amplitude coupling changes may be linked to transitions between different movement states - akin to preparatory states in dynamical systems theory of motor control. In patients, the modulation of phase-amplitude coupling was similar in (normally executed) pressing, but flattened in slow (abnormally executed) tapping compared to the controls. These deviations in phase-amplitude coupling around motor action transients may indicate dysfunctional evolution of neuronal population dynamics from the preparatory state to movement generation in Parkinson's disease. These findings may indicate that cross-frequency coupling is involved in the pathophysiology of bradykinesia in Parkinson's disease through its abnormal dynamic modulation.

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Synchronised spiking activity underlies phase amplitude coupling in the subthalamic nucleus of Parkinson's disease patients

Neurobiology of Disease ◽

10.1016/j.nbd.2019.02.005 ◽

2019 ◽

Vol 127 ◽

pp. 101-113 ◽

Cited By ~ 18

Author(s):

Anders Christian Meidahl ◽

Christian K.E. Moll ◽

Bernadette C.M. van Wijk ◽

Alessandro Gulberti ◽

Gerd Tinkhauser ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Subthalamic Nucleus ◽

Phase Amplitude ◽

Spiking Activity

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P58 Increased phase-amplitude coupling in Parkinson’s disease: Evidence from source localized electroencephalography

Clinical Neurophysiology ◽

10.1016/j.clinph.2019.12.169 ◽

2020 ◽

Vol 131 (4) ◽

pp. e44

Author(s):

R. Gong ◽

C. Mühlberg ◽

M. Wegscheider ◽

V. Nikulin ◽

T. Knösche ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Phase Amplitude

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

Brain ◽

10.1093/brain/awaa400 ◽

2020 ◽

Author(s):

Ruxue Gong ◽

Mirko Wegscheider ◽

Christoph Mühlberg ◽

Richard Gast ◽

Christopher Fricke ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Prefrontal Cortex ◽

Somatosensory Cortex ◽

Dorsolateral Prefrontal Cortex ◽

Primary Motor Cortex ◽

Rating Scale ◽

Depth Analysis ◽

Dorsolateral Prefrontal ◽

Phase Amplitude

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.

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Embedded Phase-Amplitude Coupling Based Closed-loop Platform for Parkinson's Disease

2018 IEEE Biomedical Circuits and Systems Conference (BioCAS) ◽

10.1109/biocas.2018.8584699 ◽

2018 ◽

Author(s):

M. Alexandre ◽

S. Luan ◽

Z. Mari ◽

W. S. Anderson ◽

Y. Salimpour ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Closed Loop ◽

Phase Amplitude

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Nonsinusoidal oscillations underlie pathological phase-amplitude coupling in the motor cortex in Parkinson’s disease

10.1101/049304 ◽

2016 ◽

Cited By ~ 6

Author(s):

Scott R. Cole ◽

Erik J. Peterson ◽

Roemer van der Meij ◽

Coralie de Hemptinne ◽

Philip A. Starr ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Basal Ganglia ◽

Motor Cortex ◽

Field Potential ◽

Synaptic Activity ◽

Motor Deficit ◽

Beta Oscillations ◽

High Gamma ◽

Phase Amplitude

AbstractParkinson’s disease (PD) is associated with abnormal beta oscillations (13-30 Hz) in the basal ganglia and motor cortex (M1). Recent reports show that M1 beta-high gamma (50-200 Hz) phase-amplitude coupling (PAC) is exaggerated in PD and is reduced following acute deep brain stimulation (DBS). Here we analyze invasive M1 electrocorticography recordings in PD patients on and off DBS, and in isolated cervical dystonia patients, and show that M1 beta oscillations are nonsinusoidal, having sharp and asymmetric features. These sharp oscillatory beta features underlie the previously reported PAC, providing an alternative to the standard interpretation of PAC as an interaction between two distinct frequency components. Specifically, the ratio between peak and trough sharpness is nearly perfectly correlated with beta-high gamma PAC (r = 0.96) and predicts PD-related motor deficit. Using a simulation of the local field potential, we demonstrate that sharp oscillatory waves can arise from synchronous synaptic activity. We propose that exaggerated beta-high gamma PAC may actually reflect such synchronous synaptic activity, manifesting as sharp beta oscillations that are “smoothed out” with DBS. These results support the “desynchronization” hypothesis of DBS wherein DBS counteracts pathological synchronization throughout the basal ganglia-thalamocortical loop. We argue that PAC can be influenced by more than one mechanism. In this case synaptic synchrony, rather than the often assumed spike-field coherence, may underlie exaggerated PAC. These often overlooked temporal features of the oscillatory waveform carry critical physiological information about neural processes and dynamics that may lead to better understanding of underlying neuropathology.

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Parkinsonism and vigilance: alteration in neural oscillatory activity and phase-amplitude coupling in the basal ganglia and motor cortex

Journal of Neurophysiology ◽

10.1152/jn.00388.2017 ◽

2017 ◽

Vol 118 (5) ◽

pp. 2654-2669 ◽

Cited By ~ 16

Author(s):

David Escobar Sanabria ◽

Luke A. Johnson ◽

Shane D. Nebeck ◽

Jianyu Zhang ◽

Matthew D. Johnson ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Basal Ganglia ◽

Neural Activity ◽

High Frequency ◽

Closed Loop ◽

Oscillatory Activity ◽

Motor Circuit ◽

Phase Amplitude ◽

Frequency Power

Oscillatory neural activity in different frequency bands and phase-amplitude coupling (PAC) are hypothesized to be biomarkers of Parkinson’s disease (PD) that could explain dysfunction in the motor circuit and be used for closed-loop deep brain stimulation (DBS). How these putative biomarkers change from the normal to the parkinsonian state across nodes in the motor circuit and within the same subject, however, remains unknown. In this study, we characterized how parkinsonism and vigilance altered oscillatory activity and PAC within the primary motor cortex (M1), subthalamic nucleus (STN), and globus pallidus (GP) in two nonhuman primates. Static and dynamic analyses of local field potential (LFP) recordings indicate that 1) after induction of parkinsonism using the neurotoxin MPTP, low-frequency power (8–30 Hz) increased in the STN and GP in both subjects, but increased in M1 in only one subject; 2) high-frequency power (~330 Hz) was present in the STN in both normal subjects but absent in the parkinsonian condition; 3) elevated PAC measurements emerged in the parkinsonian condition in both animals, but in different sites in each animal (M1 in one subject and GPe in the other); and 4) the state of vigilance significantly impacted how oscillatory activity and PAC were expressed in the motor circuit. These results support the hypothesis that changes in low- and high-frequency oscillatory activity and PAC are features of parkinsonian pathophysiology and provide evidence that closed-loop DBS systems based on these biomarkers may require subject-specific configurations as well as adaptation to changes in vigilance. NEW & NOTEWORTHY Chronically implanted electrodes were used to record neural activity across multiple nodes in the basal ganglia-thalamocortical circuit simultaneously in a nonhuman primate model of Parkinson’s disease, enabling within-subject comparisons of electrophysiological biomarkers between normal and parkinsonian conditions and different vigilance states. This study improves our understanding of the role of oscillatory activity and phase-amplitude coupling in the pathophysiology of Parkinson’s disease and supports the development of more effective DBS therapies based on pathophysiological biomarkers.

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