Autonomic regulation of brain function and cognition in patients with first-episode schizophrenia and healthy individuals

Schizophrenia (SZ) involves distinct changes in brain network organization, in which disrupted oscillatory communication between brain regions is thought to contribute to a breakdown in cognitive and perceptual processes. In addition to widespread changes in central nervous system (CNS) activity, SZ involves distinct alterations in the rhythmic activity of the autonomic nervous system (ANS). A growing body of evidence suggests that physiological cycles such as heart rate, respiration, and heart rate variability (HRV) interact with the rhythms of the brain and may help coordinate oscillatory communication within brain networks. Whether and how ANS dysfunction in SZ mechanistically contributes to disorganized brain activity and cognition remain to be explored. SZ is characterized by prominent changes in the parasympathetic branch of the ANS, which can be indexed by the cyclical fluctuations in heart rate associated with respiration, known as high-frequency (HF) HRV. HF-HRV is robustly associated with psychological health and cognitive functioning and is consistently found to be lower in SZ. Our group recently showed that, rather than simply reflecting shared neural systems supporting physiological and psychological regulation, the associations between HF-HRV and psychological functioning may be due in part to a causal influence of cardiac autonomic rhythms on brain activity. We observed that HF-HRV oscillations modulate EEG oscillations through phase-amplitude coupling (PAC), a well-established mechanism of oscillatory organization in the brain that appears to extend to brain- body interactions. Crucially, directions of effects were stronger from heart-to-brain than brain-to-heart. We also found that HRV-EEG coupling is lower in individuals with SZ and that this deficit is associated with impaired sustained attention. Our findings suggest that dysregulated neural activity and cognitive dysfunction are due in part to disrupted body-to-brain communication in SZ. To further probe the causal mechanisms through which autonomic rhythms influence brain activity, the proposed study will examine whether increasing HF-HRV can lead to changes in oscillatory activity and cognitive functioning in patients with first-episode SZ and healthy comparison (HC) participants. Prior research shows that simply reducing respiratory rate results in immediate and sizeable increases in HF-HRV. In the proposed study, SZ and HC participants will complete a series of tasks measuring cognitive functioning before and after completing a slow-paced breathing exercise, with EEG, EKG, and respiration measured throughout. We hypothesize that increasing HF-HRV through slow-paced breathing will lead to increased HRV-EEG coupling, increased oscillatory connectivity within relevant brain networks, and cognitive improvements. We aim to clarify how autonomic rhythms influence brain activity and cognition and to bridge largely separate literatures on ANS and CNS dysfunction in SZ. Ultimately, understanding how psychological health depends on the integrated functioning of the brain and body may introduce new treatment avenues for SZ and other mental illnesses. Project Number: 1R21MH142995-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: CINDY YEE-BRADBURY | Institution: UNIVERSITY OF CALIFORNIA LOS ANGELES, LOS ANGELES, CA | Award Amount: $408,843 | Activity Code: R21 | Study Section: Adult Lifespan Psychopathology Study Section[ALP] View on NIH RePORTER: https://reporter.nih.gov/project-details/11289183