Biomarker-guided Brain Stimulation for the Treatment of Memory Loss

Introduction: Memory disorders represent a huge societal unmet need, with limited therapeutic options for the estimated 27 million Americans suffering from memory loss.  Traumatic Brain Injury (TBI) accounts for a large share of the total burden of memory loss.  Among the 4.3 million Americans who have survived a moderate to severe TBI, the majority will report memory loss as a primary concern.  Patients with TBI exhibit marked impairment on a variety of verbal memory tasks, and the degree to which these patients recover their verbal memory function following an injury predicts their ability to return to work, their on-the-job performance, and their degree of functional recovery.  Neurostimulation has shown promise as a therapeutic modality for treatment of memory loss, but no FDA-approved devices exist for the treatment of memory disorders.  The present study provides proof of concept for using closed-loop neurostimulation to improve human memory function, and demonstrates the performance of a prototype device in a large animal model intended for clinical translation to patients with TBI.

Methods: Patients undergoing invasive monitoring for epilepsy surgery took part in memory experiments, and we trained machine-learning classifiers to predict momentary lapses in memory performance.  Using these classifiers to control brain stimulation in subsequent closed-loop sessions, we evaluated stimulation’s acute mnemonic effects in a sham-controlled, double-blind design.  As a first step towards evaluating this therapy in a chronic setting we prototyped a 60-channel implantable system and report preliminary data in an ovine model.

Results: In acute studies involving 47 patients with implanted electrodes, we demonstrated reliable mnemonic benefits of closed-loop stimulation near white matter tracts of the lateral temporal cortex.  Stimulation also improved biomarkers of memory encoding.  In a preclinical ovine study, we demonstrated the capabilities of an implantable system developed to deliver this therapy in clinical trials for patients with memory loss.  We classified sheep movement using neural data and defined how electrical stimulation with varying parameters changed neural signals.  In a closed-loop paradigm, we monitored and modulated low frequency activity to exhibit the device’s capacity to record, decode, and modulate neural features in real-time.

Conclusion: Closed-loop brain stimulation can improve memory performance by selectively modulating networks when they shift into less functional states.  This approach shows promise in both epilepsy and TBI populations, with future clinical applications supported by novel, AI-driven neuromodulation technologies.  The present study demonstrates proof of concept for using biomarker-guided closed-loop neurostimulation to treat memory loss due to TBI.