Stressed heart-brain communication in Veterans with schizophrenia: neurovascular and autonomic mechanisms

Veterans Affairs Med Ctr San Francisco, San Francisco CA

Investigators

Abstract

Schizophrenia is a debilitating psychiatric illness that also increases the risk of cardiovascular disease. Cardiovascular and metabolic disease is the leading cause of premature death for veterans with schizophrenia. Although cellular and genetic studies have suggested that metabolic impairments may underlie neural and cardiac dysfunction, studies in clinical neuroscience are limited. Functional magnetic resonance imaging (fMRI) is widely used as a clinical research tool and has identified aberrant activity across brain networks that may underlie psychiatric symptoms. Aberrant brain activity in schizophrenia is inefficient: excessive hemodynamic recruitment at rest and deficient hemodynamic recruitment during cognitively demanding tasks. However, fMRI does not assay neural activity directly, and instead, reflects slow changes in the regional level of blood oxygen (hemodynamics) commonly interpreted as a surrogate for neural activity. Moreover, these vascular brain signals are influenced by systemic physiology, including cardiac activity under the control of the autonomic nervous system (ANS). Therefore, brain inefficiency in schizophrenia (as measured using fMRI) might reflect cardiovascular dysfunction or inefficiency in the coupling of neural activity to vascular blood flow. In turn, brain inefficiency may underlie cognitive deficits, the leading cause of functional impairment in schizophrenia. Vascular signals from fMRI are typically modeled to reflect neurovascular coupling, the recruitment of blood and oxygen to support active neural tissue. Stress signals within the ANS delay neurovascular coupling in the brain and increase heart rate, blood pressure and cardiac output to meet behavioral demands. In schizophrenia, ANS signals are dysregulated, and neurovascular coupling is delayed, while at rest. The relationships between neural, hemodynamic, and ANS activity are unknown in schizophrenia; new approaches are needed to understand neurovascular coupling and the relationship to ANS stress physiology. Electroencephalography (EEG) can measure neural activity directly, and when used concurrently with fMRI (EEG-fMRI), is a promising research tool for examining neurovascular coupling. Continuous blood pressure monitoring (CBP) can be used to examine the ANS function, but links between CBP derived measure of ANS function and neurovascular coupling in the brain are unknown. This CDA-2 proposal hypothesizes that neurovascular coupling is inefficient in schizophrenia, can be measured using simultaneous CBP-EEG-fMRI and is mediated by dysregulated ANS activity as assayed by CBP. This CDA-2 enables a path to scientific independence by examining the role of neurovascular and autonomic function in relation to cognitive and clinical symptoms in schizophrenia. Treatments targeting underlying pathology in schizophrenia are lacking and current pharmacotherapies exacerbate metabolic disease. Measures of neurovascular coupling may serve as a biomarker to guide novel treatments, leading to new perspectives on the intersection between cardiovascular disease and mental health. This five-year CDA-2 provides training in the acquisition and analysis of ANS physiology with ongoing training in simultaneous EEG- fMRI. The career and training plan will develop the Principal Investigator’s experience in ANS physiology and multimodal neuroimaging through coursework, methodological workshops, and collaboration with established investigators. This study combines modalities (CBP, EEG and fMRI) to achieve three specific aims: 1) Examine neurovascular coupling in schizophrenia and healthy veterans at rest and during cognitive stress, 2) Assess the role of ANS function in schizophrenia and healthy veterans during cognitive stress and 3) Determine associations between autonomic dysregulation, neurovascular coupling, and psychiatric symptoms. All aims support the primary goal of mentored training in heart-brain health to develop scientific independence and expertise in the role of stress on neurovascular and cardiovascular function in psychiatric illness.