The hippocampal system, responsible for moderating biological stress reactivity as well as integral cognitive functions, is highly implicated in schizophrenia as it may serve as an interaction point between the environment and underlying biological susceptibility. My second line of research focuses on hippocampal development (longitudinal changes in shape, structure/connective tracts, and function), interactions with psychosocial stress and related hormones such as cortisol (using paradigms involving life-events and expressed emotion/family environment, and Trier Social Stress Test) and causal factors underlying system vulnerability (e.g., obstetric complications).
During my doctoral training at Emory, the Walker lab’s primary focus was a 5-year longitudinal study designed to track high-risk adolescents and map behavioral changes and hormonal development. I came away from this training experience with expertise in the role of stress hormones, hippocampal development, and psychosocial stress in models of psychopathology. For example, in one longitudinal investigation I found that normative developmental increases in stress hormones (resting salivary cortisol levels) in UHR youth are intricately tied with several of the markers noted above, including movement abnormalities and signs of prenatal insult (Mittal et al., 2007). Subsequently, our team used these empirical findings to refine a theory that posits that because resting levels of cortisol increase throughout adolescence, cortisol augments dopamine activity (a prominent underlying factor in positive symptoms of psychosis), and the hippocampal formation is abnormal in UHR youth, normative and irregular neuro-endocrine development may interact with gene expression and preexisting vulnerability to result in psychosis onset (Walker, Mittal, & Tessner, 2008; Tessner, Mittal, & Walker, 2011). In related review I conducted with my post-doctoral mentor, we examined evidence for various models of how genetic influence and obstetric factors operate in the etiology of schizophrenia, and developed a new theory for how multiple models can operate simultaneously to affect early hippocampal vulnerability and eventually contribute to the development of psychopathology (Mittal, Ellman, & Cannon, 2008).
After arriving at CU, I continued to develop this research program (Mittal & Walker, 2011; Mittal, Orr et al., 2013, Carol et al., under review), and have worked with expert collaborators (e.g., Robert Spencer) to incorporate new paradigms (e.g., waking cortisol) to test different aspects of the model. There are several translational components to this work that I am particularly enthusiastic about. For example, we recently reported that naturalistic nicotine use, potentially compensating for a decreased number of acetylcholine receptors in the hippocampus, is associated with improved cognitive functioning in high-risk youth and am working to develop an follow-up experiment (Gupta & Mittal, 2014). Further, I have continued to develop biomarker research aimed at linking physical markers of early insult related to the hippocampus to improve prediction; UHR individuals with a history of second trimester obstetric complications or virus exposure have a 2-5 times greater odds of converting to psychosis when compared to those without a history (Mittal Dhruv et al., 2007; Mittal, Saczawa et al., 2008; Mittal, Willhite et al., 2009; Mittal, Dean, & Pelletier, 2012; Golembo-Smith et al., 2012). I am currently collecting hospital birth records from UHR participants in a study designed to determine if we can improve our understanding of the impact of prenatal insult in this area.
It is important to consider that while several of the available treatments for UHR patients (e.g., CBT, low dosage anti-psychotics) have been found to show some promise in terms of improving prognosis, these therapeutic approaches are also associated with significant expense and side effects (in the case of medications). To this end, I have been particularly interested in translating the findings from my longitudinal naturalistic studies into a viable treatment for high-risk youth. Most recently, I have begun to develop a related line of research examining how hippocampal development is effected by physical activity in at-risk youth. Because the hippocampus is a critical structure for de-escalating the stress response, has been found to develop abnormally in UHR adolescents (Mittal et al., 2013; Dean et al., under review), and is believed to contribute to memory deficits, this structure is a key treatment target. An emerging literature from animal models and research in healthy adults suggests that regular aerobic activity can stimulate hippocampal neurogenesis, and I have begun to investigate the potential for an exercise intervention for high-risk youth. In an initial study, I found that high-risk youth engaged in significantly more sedentary but less aerobic activity than controls (assessed with actigraphy over a 5-day period) and that inactivity was associated with smaller medial temporal structures in this group (Mittal et al., 2013, See attached article). Following this investigation, I collaborated with Angela Bryan (Co-PI) to propose a related intervention and the study was funded through an innovative 5-year translational award that combines an R21 (to test the underlying mechanism and fine-tune the treatment parameters) and R33 (RCT) phase. In this ongoing study (currently in Year 1), we are working to determine if prescribed exercise (monitored exercise for 3 times a week for 12 weeks) will lead to better fitness (V02 Max), hippocampal cell growth, improved episodic memory, and reduced symptoms in this critical population. To date, a number of subjects have completed the trial and I am enthusiastic about the potential for this novel treatment approach.