Theta burst modulation of hippocampal-cortical rhythms in schizophrenia

Stanford University, Stanford CA

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Schizophrenia affects 0.5-1% of people worldwide and features a loss of properly-structured relational knowledge, manifested as dramatic disorganization of thought, delusions, hallucinations, and profound deficits in core cognitive functions. The hippocampus – the seat of relational information processing – plays a key role in the pathogenesis of schizophrenia, with evidence suggesting a loss of normal inhibitory tone, disrupted neural oscillations, and reduced connectivity with a distributed network of neocortical regions. A breakdown in the or- ganization of hippocampal oscillations and hippocampal-cortical interactions may therefore underlie schizophre- nia symptoms, but we do not know whether these signatures are responsive to neuromodulation. Intriguingly, theta burst-stimulation (TBS) mimics the endogenous hippocampal 3-8 Hz theta rhythm and has been used to alter hippocampal function in healthy humans by targeting the posterior parietal node of the hippocampal-cortical network. The overarching goal of this research and training plan is to ask whether connectivity-guided TBS to this parietal node can affect hippocampal neural activity and cognitive function in the context of schizophrenia. I propose a combination of invasive and non-invasive brain stimulation experiments that will bridge core hippo- campal electrophysiology with approaches that can be readily deployed in the schizophrenia population. I will first ask how direct electrical TBS influences hippocampal oscillations via intracranial recordings from neurosur- gical patients (Aim 1), and then use non-invasive TBS delivered via transcranial magnetic stimulation (TMS) to explore effects in schizophrenia patients via scalp electroencephalography (EEG; Aim 2). Finally, I will ask whether TMS-delivered TBS can enhance hippocampal cognitive function in schizophrenia, by stimulating pa- tients between sessions of an associative inference task (Aim 3). This research will advance our understanding of how the hippocampus responds to theta burst stimulation, and whether we can use this form of stimulation to alter hippocampal physiology and cognitive function in patients with schizophrenia. My extensive background in human intracranial electrophysiology and hippocampal memory function – as well as my clinical training – makes me uniquely qualified to pursue this clinically-relevant research that stays grounded in basic neuroscience. I will rely on a mentoring team of world-class experts in invasive and non-invasive brain stimulation and schizophrenia: Drs. Corey Keller, Josef Parvizi, and Jacob Ballon, with Drs. Karl Deisseroth and Fabio Ferrarelli as advisors. In completing this work, I will deepen my understanding of connectivity-guided intracranial stimulation, develop expertise in the use of combined TMS and scalp EEG, and learn how to design, recruit, and execute a study in a unique clinical population. Stanford University and Medical Center provide the ideal multidisciplinary environ- ment to carry out this deeply translational work. When complete, this proposal will address a major gap in our understanding of hippocampal pathophysiology while preparing me to launch an independent research career that leverages invasive and non-invasive neuromodulation in psychiatric populations.