Cortical phase-amplitude coupling is key to the occurrence and treatment of freezing of gait

Abstract

Freezing of gait is a debilitating symptom in advanced Parkinson’s disease and responds heterogeneously to treatments such as deep brain stimulation. Recent studies indicated that cortical dysfunction is involved in the development of freezing, while evidence depicting the specific role of the primary motor cortex in the multi-circuit pathology of freezing is lacking. Since abnormal beta-gamma phase-amplitude coupling recorded from the primary motor cortex in patients with Parkinson’s disease indicates parkinsonian state and responses to therapeutic deep brain stimulation, we hypothesized this metric might reveal unique information on understanding and improving therapy on freezing of gait. Here we directly recorded potentials in the primary motor cortex using subdural electrocorticography and synchronously captured gait freezing using optoelectronic motion-tracking systems in 16 freely-walking patients with Parkinson’s disease who received subthalamic nucleus deep brain stimulation surgery. Overall, we recorded 451 timed up-and-go walking trials, and quantified 7,073 s of stable walking and 3,384 s of gait freezing in conditions of ON/OFF-stimulation and with/without dual-tasking. We found that (i) high beta-gamma phase-amplitude coupling in the primary motor cortex was detected in freezing trials (i.e., walking trials that contained freezing), but not nonfreezing trials, and the high coupling in freezing trials was not caused by dual-tasking or the lack of movement; (ii) nonfreezing episodes within freezing trials also demonstrated abnormally high couplings, which predicted freezing severity; (iii) deep brain stimulation of subthalamic nucleus reduced these abnormal couplings and simultaneously improved freezing; and (iv) in trials that were at similar coupling levels, stimulation trials still demonstrated lower freezing severity than no-stimulation trials. These findings suggest that elevated phase-amplitude coupling in the primary motor cortex indicates higher probabilities of freezing. Therapeutic deep brain stimulation alleviates freezing by both decoupling cortical oscillations and enhancing cortical resistance to abnormal coupling. We formalized these findings to a novel “bandwidth model,” which specifies the role of cortical dysfunction, cognitive burden, and therapeutic stimulation on the emergence of freezing. By targeting key elements in the model, we may develop next-generation deep brain stimulation approaches for freezing of gait.

Towards adaptive deep brain stimulation for freezing of gait

“…Low-frequency stimulation (generally 60 Hz or 80 Hz) may help some patients with axial symptoms. However in this study, 2 60 Hz stimulation did not reduce freezing episodes compared to 130 Hz stimulation. Stimulating the substantia nigra pars reticulata (SNr) has been shown to improve temporal parameters of gait 9 and combining low-frequency SNr stimulation and high-frequency STN stimulation may have a synergistic effect for some patients.…”

“…Yin and colleagues 2 showed that cortical PAC during walking was moderately correlated with the beta band waveform asymmetries, suggesting that the waveform asymmetry contributed to the PAC. However, this is unlikely to be the sole explanation for elevated PAC.…”

“…Cortical PAC during walking predicted freezing in Parkinson’s disease and correlated with waveform asymmetry (the ratio of the rising versus falling steepness). 2 However, cortical PAC during rest has also been shown to correlate with other parkinsonian symptoms including rigidity and bradykinesia, and was better explained by the asymmetry in extrema sharpness. 3 Further analysis of the cycle-by-cycle waveforms and preferred phase of high frequency activity may reveal differences in the temporal organisation of synaptic inputs and further help to differentiate rest, freezing and standing.…”

“… Schematic showing the key findings of Yin and colleagues. 2 ( A ) Potentials from primary motor cortex were recorded from patients with Parkinson’s disease undergoing surgery for DBS. ( B ) Beta-gamma PAC in the motor cortex was observed, which can arise from either nested oscillations, or deflected waveforms in the beta frequency bands, or both (adapted from Cole et al 3 and Vaz et al 4 ).…”

“…Achieving this goal will require identifying reliable biomarkers and understanding more completely the neural signatures underlying this phenomenon. In this issue of Brain , Yin and colleagues 2 make progress towards this goal by identifying increased beta-gamma phase-amplitude coupling (PAC) in the motor cortex during freezing episodes compared to normal walking in patients with Parkinson’s disease. In addition, they show that DBS of the subthalamic nucleus (STN) reduces this coupling along with freezing episodes.…”