Cerebello-Midbrain Contributions to Negative Symptoms in Psychosis

PROJECTSUMMARY/ABSTRACT Individuals with schizophrenia spectrum disorders experience a range of symptoms that cause high levels of functional impairment, thus representing a large personal and public health burden. Therefore, studies evaluating early psychosis can help to uncover how symptoms of schizophrenia first arise and elucidate more effective avenues for early intervention. Of particular importance is the examination of negative symptoms (NS), such as avolition, anhedonia, asociality, and expressive deficits, as they tend to present prior to the onset of positive symptoms, are more resistant to treatment, and are more strongly predictive of functional outcomes. Mounting evidence suggests that the cerebellum (Cb) is involved in diseases of disordered socio-affective and volitional functioning. Further, preliminary findings from stimulation of the Cb midline have shown promise for mitigating NS in schizophrenia. Despite these converging lines of research, no one, to date, has examined Cb-VTA connectivity as being a critical substrate in the pathophysiology of specific NS in psychosis. Therefore, the proposed study will examine the association between structural and functional Cb-VTA connectivity and aberrant goal-directed, hedonic, social, and expressive functioning. The proposed study will use data from the Human Connectome Project for Early Psychosis to study first early 16-35-year-olds who represent both affective and non-affective psychosis manifestation. Via clinical interviews, resting state functional magnetic resonance imaging (rsfMRI), and diffusion-weighted imaging scans, I will take a multi-modal, computational approach to understanding Cb contributions to NS in psychosis. Specifically, I will reconstruct the Cb-VTA tract across sagittal segments of the Cb cortex, and probe for dissociable contributions to distinct NS based on hierarchical Cb seed regions and examine differences in tract micro- and macrostructure between early psychosis patients and healthy controls. Next, I will assess for physio-physiological interactions and effective connectivity profiles between the Cb, VTA and higher-order structures such as the dorsolateral, orbitofrontal, and premotor cortices, plus the ventral striatum, and amygdala to assess how the Cb-VTA substrate may contribute to perturbations upstream in the context of distinct NS. Findings from the proposed study have the capacity to provide additional insight into previously established frontal and reward-related alterations associated with NS, thus providing a novel framework for understanding the relations between the Cb, frontal lobe, reward mechanisms and NS. Further, we will explore potential differences in the association between various structural segments of the Cb- VTA white matter tract and NS across first-episode and control individuals to assess specificity. To complete this study, a training plan has been developed that consists of formal coursework, workshops, technical development, and mentorship. This fellowship would allow me to obtain additional training opportunities that would not otherwise be available to me, so that I may cultivate expertise on functional neuroimaging, reward, Cb functional anatomy, and psychosis necessary to become an independent cognitive neuroscientist.