Psychotic disorders are characterized by distinct domains of symptoms as well as emotional, nonverbal, and cognitive deficits drawing upon a host of disparate mechanisms and structures. My first line of research tests the idea that the frontal-subcortical circuits, which are responsible for dynamic communication between the subcortical structures that govern basic functions and the frontal regions that underlie higher order cognition, are a good target for improving our understanding why such a wide variety of functions are affected in psychosis. To this end, I employ a range of methodologies to examine the biomarkers, developmental trajectories and ultimate pathogenic contribution that basal ganglia and cerebellar circuits play in the etiology of psychosis.
A body of evidence suggests that movement abnormalities are present from infancy in individuals who later develop schizophrenia. Because dopamine function in the basal ganglia circuits governs movement, and dysregulation in these same circuits is thought to underlie psychotic symptomatology, it is possible that abnormal movements are indicative of early vulnerability. In my doctoral research (at Emory University under Elaine Walker), I advanced this theory by finding evidence that early striatal circuit abnormalities later interact with maturational endocrine factors during adolescence, and that tracking subsequent elevations in movement abnormalities can be used to help identify those individuals undergoing a transition to psychosis (Mittal & Walker, 2007; Mittal, Tessner et al., 2007; Mittal, Neumann et al., 2008). During this time I developed significant expertise in formulating nonverbal coding schemes and studying a range of motor abnormalities including neurological soft signs, dyspraxia, as well as gestures (Mittal et al., 2006; Mittal, Hasenkamp et al., 2007; Millman et al., 2014; Schiffman et al., in press; Bernard et al., under review). Then, during my postdoctoral training at UCLA (under Tyrone Cannon) I was immersed in a culture employing cutting-edge imaging modalities, and consequently extended my program to utilize these methodologies to understand the neural substrates underlying abnormal motor behaviors (i.e., changes in brain structure, connectivity, chemistry, and functional networks). I also continued to develop this research program by integrating other markers of frontal subcortical dysfunction including cognitive deficits, while learning valuable strategies for conducting multi-site studies (Mittal, Walker, Walder et al., 2010; Mittal, Daley et al., 2010; Mittal, Jalbrzikowski, et al., 2011).
At the present time I am continuing this line of study as an Assistant Professor at the University of Colorado Boulder, and have established the Adolescent Development and Preventive Treatment (ADAPT) research program, specializing in the prospective evaluation and treatment of adolescents at imminent risk for developing psychotic illness. By drawing upon the noted movement and imaging training experiences and continuing to develop my ideas about frontal-subcortical circuit pathology, I was able to apply for large scale extramural funding and was awarded an R01 through the NIMH Biobehavioral Research Awards for Innovative New Scientists (BRAINS) program. This ongoing 5-year project (currently in year 4) is following 150 high-risk adolescents to determine if movement dysfunction is in fact a biomarker of abnormal grey and white matter development in the frontal subcortical circuits. This work is distinguished from previous studies, as it extends the neurodevelopmental model beyond endocrine function (central to the neural diathesis-stress model I worked with during my graduate training) by focusing on aberrant brain development as well. To this end, I have worked with collaborators (e.g., Jessica Turner, Vincent Calhoun, Marie Banich, Tor Wager) to incorporate the most innovative structural and functional imaging approaches to provide and in-depth and dynamic perspective of basal ganglia circuit dysfunction (Mittal, Dean, Bernard, Orr et al., 2013; Bernard et al., 2014, Orr et al., 2014; Bernard et al under review, Orr et al., under review). I have also collaborated with several groups (e.g., Michael Caligiuri, Bill Hetrick, Hans Leo Tuelings) in an effort to develop instrumental measures of motor dysfunction (e.g., balance/force variability tasks) which are proving to be capable of highlighting those persons who would be detected using the traditional observer-based rating scales as well as an integral subset of patients who exhibit more subtle signs of dysfunction that would not be apparent to the naked eye. This effort has lead to several breakthroughs, as we are now able to detect signs of dysfunction in populations that were not previously believed to show certain domains of movement abnormalities (Mittal, Dean, et al., 2011; Mittal, Smolen et al., 2012; Mittal, Orr, Turner et al., 2013). In a related line of work, I have also started to examine frontal-subcortical dysfunction in other spectrum populations, aiming to expand our conception of the psychosis continuum. This work involves assessing motor and related brain dysfunction in otherwise healthy individuals who occasionally experience hallucinations or unusual thoughts (e.g., 1x per year). As emerging evidence indicates that up to 7-10% of the population reports having these experiences occasionally, this is an incredibly important area with significant potential to refine the way we conceptualize psychotic disorders (Mittal, Dean et al., 2011; Mittal, Dean, & Pelletier, 2012; Mittal, Smolen et al., 2012; Pelletier et al., 2013; Mittal, Orr et al., 2013; Mittal, Dean, & Pelletier, 2013; Mittal, Orr, Turner, Pelletier et al., 2013; Orr et al., 2014; Pelletier et al., 2014).
In addition, I have expanded the study of movement function in psychosis beyond the basal ganglia/dopamine conceptions to the cerebellum- another critical structure that is affected in schizophrenia and believed to govern coordination and balance as well as synchronize cognitive functions (Dean et al., 2013a, See attached article; Bernard et al., 2014). I am particularly excited about this last point, as our newest findings suggest that the cerebellar-thalamic circuits represent a unique contribution to the etiology of psychosis, accounting for a distinct domain of negative symptoms (Mittal, Dean, Bernard, Orr et al., 2013; Bernard & Mittal, 2014). A postdoctoral student in my lab (Jessica Bernard) was awarded and NRSA to help further develop this new line of research, and together we are working to determine overlapping and distinct basal ganglia and cerebellar contributions to subtypes of symptom presentations in UHR youth in a new proposal. In addition, I am mentoring Dr. Bernard on a NARSAD young investigator award she received to conduct an fMRI project to examine longitudinal changes in cerebellar dysfunction in the UHR youth participating in my program.
There is a significant translational component to this research program that applies specifically to early identification. Currently, approximately 10-33% of UHR individuals go on to develop psychosis, but because we don’t know which of the initial cases (who exhibit similar clinical presentations) will be in this group, blanket intervention is not feasible (due to costs and side effects associated with many of the currently available treatments). My work with biomarker development has significantly helped to improve efforts to identify which individuals in this initial group are most likely to develop psychosis. For example, by combining distinct markers of basal ganglia dysfunction (including movement abnormalities as well as specific cognitive domains) I created a model that correctly classified 72.3% of the baseline cases that eventually went on to develop a psychotic disorder in a two-year period (Mittal, Walker, Walder, Trottman et al., 2010). I have also been working with researchers to develop tools that can be used to disseminate these findings to clinical settings, and be applied to improve treatment decisions. For example, I worked with a team developing a program for analyzing pen dysfluencies in handwriting (possible to be assessed on any tablet computer), and our preliminary results suggest by focusing on average normalized jerk and velocity scaling abnormalities, we can accurately detect the same movement abnormalities that previously would have required a highly specialized neurological training background (Dean, Caligiuri et al., 2013b). I am currently working with an international group of motor specialists to refine these tools for this purpose (e.g., Peter Van Harten, Michael Caligiuri, Sebastian Walther). With regard to the cerebellar circuits, I have recently reported findings that suggest that deficits determined by a brief neurological battery can significantly predict abnormalities in cerebellar-thalamic white matter tracts that are tied to progressively worse symptoms (Mittal, Dean, Bernard, Orr et al., 2013, See attached article). As a result, clinicians who do not have access to neuroimaging facilities may also be able identify patients in greatest need of intervention.