The role of brain fronto-striato-thalamic networks in psychosis: clinical and experimental resting-state fMRI studies

© 2014 Dr. Orwa DandashPublication included in thesis:Dandash, O., Fornito, A., Lee, J., Keefe, R. S. E., Chee, M. W. L., Adcock, R. A., Pantelis, C., Wood, S. J. & Harrison, B. J. (2014). Altered striatal functional connectivity in subjects with an at-risk mental state for psychosis. Schizophrenia Bulletin, 40(4), 904-913. DOI: 10.1093/schbul/sbt093Psychosis is a severe mental illness that blurs the boundaries between reality and illusion, confining patients to a world that is considered mostly outside of normal experience. Accumulating evidence suggests that disruption of functionally integrated brain networks—i.e., neural dysconnectivity—may underlie the pathophysiology of psychosis. The evidence further points to specific involvement of the brain’s fronto-striato-thalamic networks (FSTNs), a group of anatomically and functionally connected brain regions that work in synchrony to mediate cognitive, motor and affective processes. This thesis aimed to address a number of vital questions concerning the relevance of FSTNs to the pathophysiology of psychosis, including whether dysconnectivity in these networks pre-date psychosis onset, are under genetic control, and can be linked to specific neurochemical mechanisms. I utilized resting-state functional magnetic resonance imaging (fMRI), a validated and sensitive tool for probing the functional integrity of discrete neural networks, to address these questions. Firstly, I investigated putative disturbances in the temporal coherence of fMRI signals—so-called functional connectivity—among regions comprising the FSTNs in individuals experiencing an at-risk mental state (ARMS) for psychosis. The findings of this work indicated that disruptions in the functional connectivity of both dorsal and ventral FSTNs distinguished ARMS individuals from healthy control subjects. Moreover, the magnitude of dysconnectivity in these subjects correlated significantly with positive psychotic symptoms, such as delusional ideation and hallucination, linking these aberrations to clinical expression. This analysis was followed by an investigation into the heritability of the identified disturbances in FSTNs functional connectivity. The unique variance in FSTN functional connectivity attributable to additive genetic effects was modeled in a sample of identical monozygotic (MZ) and non-identical dizygotic (DZ) twins. Studying these disturbances in twins revealed moderately strong genetic influences, particularly with the dorsal (cognitive) network where 50% of the variance in functional connectivity between the dorsal caudate and the dorsolateral prefrontal cortex (DLPFC) was explained by genetic factors. The study additionally suggested that unique environmental effects accounted for the remaining 50% of the variance, while there was no influence of common environmental effects. Finally, the mechanistic basis of FSTN dysconnectivity was assessed. In particular, the potential impact of hypofunctional N-Methyl-D-Aspartate receptors (NMDARs), one of the primary candidate molecular pathologies proposed for schizophrenia, was determined using a pharmacological challenge. I investigated whether acute NMDAR antagonism in healthy volunteers via the intravenous infusion of the psychotomimetic agent ketamine induces FSTN connectivity changes redolent of those identified in ARMS subjects. The volunteers were assessed for psychosis-like symptoms and FSTN functional connectivity following both ketamine and placebo (saline) infusion. In contrast to the general reduction in functional connectivity identified in ARMS subjects, ketamine specifically increased functional connectivity in FSTNs. Furthermore, ketamine-induced psychotic experiences correlated significantly with these drug-related changes in FSTN functional connectivity. Together, the body of work presented in this thesis provides a number of novel and unique findings that serve to advance the current state of knowledge regarding the pathophysiology of psychosis. Specifically, the findings point to the utility of resting-state fMRI to probe changes in brain function prior to the onset of psychosis and provide direct support for the role of the FSTNs, especially the dorsal (cognitive) network, as a risk biomarker for the illness that is influenced by genetic as well as unique environmental factors. In addition, the findings challenge current pharmacological models of psychosis by demonstrating that acute administration of ketamine may not recapitulate the neurobiological disturbances evident in the psychosis prodrome