Phase- targeted stimulation modulates phase-amplitude coupling in the motor cortex of the human brain

Background: Phase-amplitude coupling (PAC) in which the amplitude of a faster field potential oscillation is coupled to the phase of a slower rhythm, is one of the most well-studied interactions between oscillations at different frequency bands. In a healthy brain, PAC accompanies cognitive functions such as learning and memory, and changes in PAC have been associated with neurological diseases including Parkinson's disease (PD), schizophrenia, obsessive-compulsive disorder, Alzheimer's disease, and epilepsy. Objective: /Hypothesis: In PD, normalization of PAC in the motor cortex has been reported in the context of effective treatments such as dopamine replacement therapy and deep brain stimulation (DBS), but the possibility of normalizing PAC through intervention at the cortex has not been shown in humans. Phase-targeted stimulation (PDS) has a strong potential to modulate PAC levels and potentially normalize it. Methods: We applied stimulation pulses triggered by specific phases of the beta oscillations, the low frequency oscillations that define phase of gamma amplitude in beta-gamma PAC, to the motor cortex of seven PD patients at rest during DBS lead placement surgery We measured the effect on PAC modulation in the motor cortex relative to stimulation-free periods. Results: We describe a system for phase-targeted stimulation locked to specific phases of a continuously updated slow local field potential oscillation (in this case, beta band oscillations) prediction. Stimulation locked to the phase of the peak of beta oscillations increased beta-gamma coupling both during and after stimulation in the motor cortex, and the opposite phase (trough) stimulation reduced the magnitude of coupling after stimulation. Conclusion: These results demonstrate the capacity of cortical phase-targeted stimulation to modulate PAC without evoking motor activation, which could allow applications in the treatment of neurological disorders associated with abnormal PAC, such as PD.