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

Abstract

Parkinson's disease (PD) is associated with abnormal beta oscillations (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) in the basal ganglia and motor cortex (M1). Recent reports show that M1 beta-high gamma 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. IntroductionParkinson's disease (PD) is characterized by neuronal degeneration in multiple systems, including midbrain dopaminergic neurons. Though beta (13-30 Hz) oscillations are a normal feature of the basal ganglia-thalamocortical loop, PD is associated with excessive neuronal synchronization in the beta band (1, 2). Despite an established relationship between beta band neuronal synchronization and PD, the physiological mechanism causing motor dysfunction has been unclear. Excessive phase-amplitude coupling (PAC) between beta phase and high gamma amplitude (50-200 Hz) may offer an explanation (3)(4)(5). PAC between distant neural populations has been linked to enhanced neural information flow (6-8), long-term potentiation (9), and improved behavioral performance (10). However PAC strength is greater in M1 of PD patients compared to patients with isolated cervical dystonia or epilepsy (3), leading to the hypothesis that beyond its facilitative role, PAC may play a role in neural pathology (3,4,11).Analyses of PAC implicitly presuppose two separate, interacting physiological processes: a low-frequency component associated with an oscillation in the synaptic currents and a separate high-frequency component associated with local...

Discriminating Valid from Spurious Indices of Phase-Amplitude Coupling

“…This would produce a saw-tooth like shape (Fig. 2 e ), which indeed has been observed in the rat hippocampus (Terrazas et al, 2005; Belluscio et al, 2012; Sheremet et al, 2016) and in electrocorticography recordings in the human motor cortex (Cole et al, 2016). Another possibility is pulses of neuronal activity repeated at a fixed frequency.…”

“…However, the reliability of PAC has recently been questioned since the measure is sensitive to nonsinusoidal properties of the neuronal oscillations (Kramer et al, 2008; Aru et al, 2015). Indeed, recent articles have reported PAC, which can fully be explained by the lower-frequency oscillation, as having a saw-tooth like shape (Cole et al, 2016; Sheremet et al, 2016; Cole and Voytek, 2017). Although these concerns are valid, they do not exclude the existence of a true measure of PAC that is associated with neuronal activity in different frequency bands.…”

“…Note that, due to frequency smoothing as a result of estimating the envelope for the fast frequencies, the harmonic contributions are often “bleeding” together in the PAC plot. Therefore, great care must be taken when interpreting measures of PAC, in particular in the frequency bands of the higher harmonics, additionally taking into account the effective frequency smoothing (Kramer et al, 2008; Aru et al, 2015; Cole et al, 2016; Jones, 2016; Lozano-Soldevilla et al, 2016). In particular, Cole et al (2016) and Sheremet et al (2016) provide concrete examples from respective intracranial human and hippocampal rat recordings in which nonsinusoidal oscillations contribute to estimates of PAC.…”

Prefrontal cortex modulates posterior alpha oscillations during top-down guided visual perception

“…Behavior was probed at ≈30 Hz. Thus, we could only resolve rhythmic fluctuations of up to 15 Hz and the observed signal modulation at >10 Hz could in theory also constitute a broad-band shift (19) or be the result of sharp transients in the discretely sampled signal (40). Notably, we observed a similar peak in the intertrial coherence (ITC) spectra, which suggests a circumscribed effect in the high alpha range and previous reports have indicated that delta-to-beta coupling might underlie temporal prediction accuracy (41).…”

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“…Furthermore nonstationary processes, such as most neural signals in general, would exhibit spectral correlations missed by a stationary Fourier expansion that could be misinterpreted (Lii & Rosenblatt, 2002). Also recent studies (Cole et al, 2016;Sheremet, Burke, & Maurer, 2016) provided concrete examples of human and rat hippocampal recordings with nonsinusoidal oscillations contributing to PAC estimates. Lower frequency periodic but non sinusoidal signals can be expressed, by their Fourier decompositions, as a weighted sum of harmonics.…”