Phase-dependent modulation as a novel approach for therapeutic brain stimulation

Abstract

Closed-loop paradigms provide us with the opportunity to optimize stimulation protocols for perturbation of pathological oscillatory activity in brain-related disorders. In this vein, spiking activity of motor cortex neurons and beta activity of local field potentials in the subthalamic nucleus have both been used independently of each other as neuronal signals to trigger deep brain stimulation for alleviating Parkinsonism. These approaches were superior to the standard continuous high-frequency stimulation protocols used in daily practice. However, they achieved their effects by bursts of stimulation that were applied at high-frequency as well, i.e., independent of the phase information in the stimulated region. In this context, we propose that, by timing stimulation pulses relative to the ongoing oscillation, an alternative approach, namely the targeted perturbation of pathological rhythms, could be obtained. In this modeling study, we first captured the underlying dynamics of neuronal oscillations in the human subthalamic nucleus by phased coupled neuronal oscillators. We then quantified the nature of the interaction between these coupled oscillators by obtaining a physiologically informed phase response curve from local field potentials. Reconstruction of the phase response curve predicted the sensitivity of the phase oscillator to external stimuli, revealing phase intervals that optimally maximized the degree of perturbation. We conclude that our specifically timed intervention based on the coupled oscillator concept will enable us to identify personalized ways of delivering stimulation pulses in closed-loop paradigms triggered by the phase of pathological oscillations. This will pave the way for novel physiological insights and substantial clinical benefits. In addition, this precisely phased modulation may be capable of modifying the effective interactions between oscillators in an entirely new manner.

Augmented Phase Reduction of (Not So) Weakly Perturbed Coupled Oscillators

“…to an initial state of (3) in \gamma , then the isochron associated with \bfita (0) is the set of all initial conditions \bfitb (0) for which (4) lim t\rightar\infty | | \bfita (t) -\bfitb (t)| | = 0, where | | \cdot | | can be any norm. Using this definition, the isochron of an initial condition gives a sense of its asymptotic convergence to the periodic orbit.…”

Parkinson’s disease uncovers an underlying sensitivity of subthalamic nucleus neurons to beta-frequency cortical input

“…For other approaches, it could be possible to utilise the lower amplitude information. Several authors have postulated that phase-dependent stimulation could be an effective therapeutic strategy for treating motor symptoms (Rosin B et al 2011;Azodi-Avval R and A Gharabaghi 2015;Holt AB et al 2016;Meidahl AC et al 2017) and we have recently demonstrated the potential efficacy of this approach (Holt AB et al 2018). Together, these studies show that it may be possible to utilise phase-dependent stimulation at low amplitudes, disrupting the most synchronised population of neurons before pathologically sustained beta bursts arise.…”

An update on adaptive deep brain stimulation in Parkinson's disease

“…Increased clinical benefit is suggested by targeting specific pathological neurophysiological phases in PD . Also, phase‐dependent aDBS might induce long‐lasting beneficial effects attributed to possible long‐term potentiation/depotentiation in the STN . Moreover, phase‐dependent aDBS reduced tremor severity and prevented breakthrough tremor while consuming less energy compared to cDBS .…”

“…6,32,34 Also, phase-dependent aDBS might induce long-lasting beneficial effects attributed to possible long-term potentiation/depotentiation in the STN. 81 Moreover, phase-dependent aDBS reduced tremor severity and prevented breakthrough tremor while consuming less energy compared to cDBS. 82 Studies assessing these suggested advantages of phase dependency in aDBS are required.…”