Functional and anatomical connectivity predict brain stimulation's mnemonic effects

Direct electrical stimulation of the brain, when applied or optimized in a closed-loop manner, can lead to improvements in memory (Ezzyat et al., 2018) and mood (Scangos et al., 2021a). In these approaches, brain states control the timing of stimulation or the choice of parameters, which build off the notion that stimulation's neural and behavioral effects depend on brain state at the time of delivery (Ezzyat et al., 2017; Scangos et al., 2021b). Although closed-loop algorithms provide greater control over stimulation's physiological and behavioral effects, variability in outcomes remains a primary challenge for using stimulation for clinical and experimental neuromodulation. Here, we evaluate the hypothesis that stimulation's behavioral and physiological effects depend on the anatomical and functional network properties of the stimulation target. Closed-loop stimulation was delivered via intracranially-implanted electrodes as neurosurgical patients studied and recalled word lists. Multivariate classifiers, trained to predict momentary lapses in memory function, triggered stimulation of the lateral temporal cortex (LTC) during the study phase of the task. We found that stimulating LTC locations with high functional network connectivity led to greater physiological and behavioral effects of stimulation. Further, stimulation specifically improved memory performance when delivered to targets near white matter pathways. These data reveal how functional and anatomical networks mediate stimulation's physiological and behavioral effects, provide further evidence that closed-loop LTC stimulation modulates episodic memory, and suggest future strategies for stimulation targeting for effective neuromodulation.