Closed-Loop neuromodulation for clustering neuronal populations

Pathological synchronization of neurons is associated with symptoms of movement disorders, such as Parkinson's disease and essential tremor. High-frequency deep brain stimulation (DBS) suppresses symptoms, presumably through the desynchronization of neurons. Coordinated reset (CR) delivers trains of high-frequency stimuli to different regions in the brain through multiple electrodes and may have more persistent therapeutic effects than conventional DBS. As an alternative to CR, we present a closed-loop control setup that desynchronizes neurons in brain slices by inducing clusters using a single electrode. Our setup uses calcium fluorescence imaging to extract carbachol-induced neuronal oscillations in real time. To determine the appropriate stimulation waveform for inducing clusters in a population of neurons, we calculate the phase of the neuronal populations and then estimate the phase response curve (PRC) of those populations to electrical stimulation. The phase and PRC are then fed into a control algorithm called the input of maximal instantaneous efficiency (IMIE). By using IMIE, the synchrony across the slice is decreased by dividing the population of neurons into subpopulations without suppressing the oscillations locally. The desynchronization effect is persistent 10 s after stimulation is stopped. The IMIE control algorithm may be used as a novel closed-loop DBS approach to suppress the symptoms of Parkinson's disease and essential tremor by inducing clusters with a single electrode. Here, we present a closed-loop controller to desynchronize neurons in brain slices by inducing clusters using a single electrode using calcium imaging feedback. Phase of neurons are estimated in real time, and from the phase response curve stimulation is applied to achieve target phase differences. This method is an alternative to coordinated reset and is a novel therapy that could be used to disrupt synchronous neuronal oscillations thought to be the mechanism underlying Parkinson's disease.