Sleep theta burst stimulation for improved prefrontal neuromodulation in depression

/ABSTRACT Depression affects millions of individuals worldwide, yet the treatments including transcranial magnetic stimulation (TMS), achieve only moderate success. While the exact mechanisms underlying the therapeutic effects of TMS remain unclear, they are in part attributed to the induction of neural plasticity. Notably, plasticity is most pronounced during non-rapid eye movement (NREM) sleep, particularly in slow-wave sleep (SWS), when synchronized oscillations between the cortex and thalamus may optimize neuroplastic changes. However, currently, TMS is administered in wake-state only. This research gap suggests a new frontier for TMS in depression - stimulating the brain during sleep rather than while awake. By timing TMS to coincide with critical neural events that promote plasticity and systems-level consolidation in NREM sleep, such as thalamocortical sleep spindles, we may enhance TMS efficacy to induce prefrontal plasticity for treating depression. I have developed an approach to deliver TMS during sleep, using automated systems for real-time detection of sleep stages, slow oscillations, and sleep spindles. My preliminary work has shown that intermittent theta burst stimulation (iTBS) of the primary motor cortex (M1) during NREM sleep produces more robust cortical changes than when applied during wakefulness and that spindle-guided iTBS further amplifies these plasticity effects. Building on this, I hypothesize that targeting the dorsolateral prefrontal cortex (dlPFC) with iTBS during NREM sleep will result in superior prefrontal plasticity, improving both brain function and behavior in depression. I will first test the effects of intracranial electrical iTBS of dlPFC during NREM sleep on brain activity in neurosurgical patients, using intracranial EEG (iEEG) to measure evoked responses and index plasticity (Aim 1). Next, I will focus on TMS-delivered dlPFC iTBS in depressed patients, using simultaneous TMS-EEG to measure noninvasive brain responses during NREM sleep and pre-sleep wakefulness conditions (Aim 2). Finally, I will investigate real-time sleep-spindle guided dlPFC iTBS in healthy individuals, hypothesizing that targeting events of spindles during SWS will induce even superior prefrontal plasticity and improvements in working memory (Aim 3). For training and professional development while pursuing these aims, I will rely on a mentoring team of world-class experts in invasive and noninvasive brain stimulation, depression, sleep and neural oscillations: Drs. Corey Keller, Josef Parvizi, and Andrea Goldstein-Piekarski, with Drs. György Buzsáki, and Manish Saggar as advisors. This work will deepen our understanding of the neural effects of TMS in the prefrontal cortex and its potential to enhance treatment outcomes in depression. Through this project, I will gain critical expertise in intracranial EEG, direct brain stimulation, pathophysiology of depression and learn how to design, recruit, and execute an independent clinical trial, all of which will prepare me to lead a future independent academic career in sleep-augmented brain stimulation therapies for psychiatric disorders. Project Number: 1K99MH141192-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Umair Hassan | Institution: STANFORD UNIVERSITY, STANFORD, CA | Award Amount: $116,837 | Activity Code: K99 | Study Section: Special Emphasis Panel[ZMH1 ERB-P (04)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11211442