No abstract

Brain stimulation interventions are used for the treatment of neurological disorders such as Parkinson's and depression. Despite some success, the effects of stimulation are poorly understood, as evidenced by unknown mechanisms governing therapeutic outcomes, widespread side-effects, and inconsistent results in clinical translation. This incomplete understanding may originate from incomplete treatment of the effects of stimulation, as most studies limit their scale and subject of analysis to local effects of various stimulation protocols. Indeed, in a recent paper we demonstrated that neural stimulation impacts the brain at the network scale; here, we leverage advances in neural interfaces and interpretable machine learning to reveal that the cortical network is the primary controlling factor of the response to stimulation. Using optogenetic stimulation and micro-electrocorticography (μECoG) recording in two awake rhesus macaques, we induce and record widespread functional connectivity changes over large-scale sensorimotor cortical networks. We then use a novel nonparametric modeling framework to predict these changes from the stimulation protocol and from characteristics of the underlying cortical network. We observe that the stimulation protocol only explains a small portion of the network response to stimulation while the network structure characteristics explain much more of the response, implicating the underlying network as the primary mediator of the response to stimulation. We extract the relationships linking the stimulation and network characteristics to the functional connectivity changes and observe that the mappings diverge over frequency bands and successive stimulations. Finally, we uncover shared processes governing real-time and longer-term effects of stimulation, demonstrating that all neural stimulation interventions must consider both timescales for their effects to be fully understood. The insights and developments generated in this work represent a paradigm shift for the field of neural stimulation.