Personalized aperiodic transcranial alternating current stimulation as a treatment for antenatal depression

About This Grant

Antenatal depression affects 7–20% of pregnant females and is linked to obstetric, fetal, and infant complications1. Treatment options during pregnancy are limited, with many avoiding medication due to concerns about fetal exposure. There is an urgent need for safe, scalable, non-pharmacologic alternatives. This R61/R33 project evaluates a novel, personalized brain stimulation intervention, ‘Personalized Antenatal Depression Aperiodic transcranial alternating current stimulation (PandA-tACS)’, which uses EEG-derived waveforms to normalize neural excitation/inhibition (E/I) balance, a core mechanism of depression. The current leading tACS approach for depression, individual alpha frequency (IAF)-tACS, targets pathologically elevated alpha rhythms2,3. However, recent evidence suggests that depression involves broader shifts in E/I imbalance across multiple frequency bands (not just alpha), particularly in the pregnant brain4. Specifically, depression relates to increased cortical inhibition, indexed by a steeper aperiodic slope (1/f decay) in the EEG power spectrum, particularly in the left dorsolateral prefrontal cortex (dlPFC)5. Flattening of this slope has been linked to clinical response to antidepressants, including esketamine, suggesting it is a mechanistic target of therapeutic change6. PandA-tACS represents a paradigm shift from narrowband, rhythm-based stimulation to broadband, aperiodic modulation. It delivers naturalistic waveforms derived from each participant’s EEG, modified to flatten the left dlPFC aperiodic slope, a region implicated in depression and anhedonia 5–8. In the R61 Phase, 60 pregnant females with moderate-to-severe depression will be randomized to receive a single session of PandA-tACS, IAF-tACS, or sham. High-density EEG (HD-EEG) will measure slope flattening in the left dlPFC as the primary target engagement outcome. Safety, feasibility, and tolerability will also be assessed. These Go/No-Go criteria will determine progression to the R33 Phase. In the R33 Phase, a new cohort of 60 females with antenatal depression will receive five daily sessions of PandA-tACS or sham. EEG and clinical outcomes (e.g., HDRS-17) will be measured at baseline, post-intervention, and two-week follow-up. Primary outcomes are replicated target engagement and associated symptom improvement, alongside safety, feasibility and tolerability. This project is the first brain stimulation trial to directly target the aperiodic slope and to personalize stimulation using EEG-derived waveforms. By shifting from alpha-specific to broadband E/I-targeted modulation, it addresses the unique neurobiology of antenatal depression. This work will lay the foundation for safe, accessible brain-based treatments in pregnancy and advance transdiagnostic neuromodulation research aligned with NIMH priorities.