Sepideh Sadaghiani, Ph.D. - US grants

Project Summary Since its recent outbreak in the Americas in 2015, Zika virus (ZIKV) has become a major global health threat due to its potential to affect the nervous system. An estimated 3-4 million people have been infected by the mosquito-transmitted ZIKV since 2015. While most cases show no or only mild symptoms, some adult patients exhibit severe neurological complications including symptoms of the central nervous system. To date, there are no functional neuroimaging studies to unveil where and how ZIKV affects human brain function at the systems level. Reports of structural brain changes in adults have remained largely confined to few single cases, and the relation between structural and functional brain changes remains unknown. Unless this crucial knowledge gap is closed, the understanding of disease course, outcomes and mechanisms of ZIKV neurological complications in adults will remain incomplete. Consequently, an important opportunity to inform development of treatments in adults, as well as providing insights about potential mechanisms in infants, will be missed. The objective of this proposal is to establish the course of structural and functional changes in the brain of adults with ZIKV- related neurological complications. The central hypothesis is that ZIKV patients with central nervous manifestations show changes in brain structure and function linked to CNS inflammation. This hypothesis has been formulated on the basis of our preliminary neuroimaging data acquired in the Dominican Republic, suggestive of regionally specific changes in gray matter volume and functional network connectivity. We seek to accomplish our objective by conducting a longitudinal study (in acute, subacute and recovery phases) using structural and functional Magnetic Resonance Imaging in 25 ZIKV patients with central neurological manifestations, 25 ZIKV patients with neurological complications of the peripheral nervous system only, and matched healthy controls. In Specific Aim 1, we will identify local changes in gray matter volume and white- matter integrity caused by ZIKV. Specific Aim 2 will identify changes in intrinsic functional and structural connectomes caused by ZIKV. Finally, Specific Aim 3 will determine the association of structural and functional changes with ZIKV-related neurological manifestations. This program of research responds directly to NIH?s call to study ZIKV complications (Funding Opportunity Announcement PA-17-085). The expected outcomes would establish that ZIKV can affect the adult human brain, thus explaining how neurological complications of ZIKV extend beyond the peripheral nervous system and cause central manifestations. Once the course of structural and functional changes of ZIKV neurological manifestations are identified, more targeted efforts for development of treatments will become possible, and new avenues for translational investigations, e.g. into the pathophysiology of ZIKV, will open.

Summary The functional connectome reflects the endogenous pattern of information exchange among brain regions. However, the role of this fundamental network organization in mental disorders remains elusive, in part because its function in healthy cognition is largely unknown. The urgent need and translational importance of closing this knowledge gap is reflected in the NIMH?s strategic objective 1.3 to ?map the connectomes for mental illnesses?. The functional connectome is traditionally observed using functional Magnetic Resonance Imaging (fMRI), since this method provides a means of investigating neural connections across the whole brain with high spatial resolution. As observed with fMRI, functional connectivity is not static, instead shifting between various network configurations. While this connectome flexibility is well-documented, its relation to moment-to-moment cognition is unknown. To better understand this relationship, novel experimental paradigms must be developed to characterize the contribution of connectome reconfigurations to trial-by-trial behavioral variability. Additionally, since fMRI is an indirect measure of neural activity and prone to artifacts, the fidelity of connectome dynamics should be established using a more direct measure of neural activity (Electroencephalography, EEG) concurrently with fMRI. The current project uses simultaneous fMRI and EEG to characterize intrinsic connectome states and relate them to concurrent cognitive processes. In the current study we look to address three aims: 1) to identify cognitively significant connectome states by their impact on behavior, 2) to identify such states in the resting brain and quantify their temporal flexibility, and 3) to link this connectome flexibility to cognitive flexibility, the ability to shift among tasks and mental sets. We expect to find distinct and behaviorally relevant connectome states differing in two measures: level of global integration among networks and involvement of the default mode network (DMN). Further, we posit that connectome flexibility, the spontaneous iterations among the identified connectome states, predicts individual differences in cognitive flexibility. Cognitive flexibility is a trait implicated in numerous psychopathologies. A link between this function and connectome flexibility would have a broad clinical impact, establishing which dynamic connectome features are most promising for future biomarkers and treatment targets.