The Section on Integrative Neuroimaging continues to make advances toward its goals of understanding the nature, molecular underpinnings, underlying neurochemistry, and clinical correlates of neural systems-level dysfunction in schizophrenia. This year, we have made substantial progress in furthering our multimodal neuroimaging studies of a unique and growing cohort of medication-free patients with schizophrenia. In particular, new efforts to characterize not only presynaptic dopamine synthetic capacity, but also D1 and D2/3 receptor availability in this population have been successful in this years participants, and with further accrual, will allow evaluation of key hypotheses about integrated pre- and post-synaptic dopamine functioning in this disorder. In conjunction with cortical cognitive activation data collected in the same patients, these data will also provide a platform to expand work from this lab yolking characteristic schizophrenia-associated impairments in prefrontal activation during executive task performance and exaggerated striatal dopamine synthesis. Specifically, this ongoing project will allow us to directly evaluate theories that schizophrenic neuropathophysiological changes are reflected in failures of maintaining task appropriate network activity via disturbed cortical dopaminergic tone and impaired signal-to-noise ratios due to suboptimal D1 to D2/3 receptor relationships. As we have previously described, critical disturbances in cognitive control and mnemonic neural circuitry in schizophrenia not only serve as sources of marked disability in affected individuals, but also provide a valuable phenotype for testing hypotheses regarding how genes implicated in schizophrenia might contribute risk. For example, by measuring regional cerebral blood flow during the N-back continuous working memory task, we have re-confirmed an aberrant prefrontal activation pattern even in patients who perform relatively well on the task and further demonstrated profoundly aberrant connectivity in prefrontal and medial temporal lobe regions, which showed strong ability to discriminate between healthy and ill participants. This latter finding was prospectively validated in two additional data sets, suggesting that disturbances in the prefrontal-limbic functional axis may be an illness trait marker. Delving then into contributing molecular mechanisms, we have also reported on a unique gene-diagnosis interaction operating on regional cerebral blood flow involving the gene coding for catechol-O-methyltransferase, COMT, which harbors common variation that is weakly but consistently associated with schizophrenia risk and strongly implicated in both prefrontal and limbic functioning during executive and affective challenge, respectively, in healthy individuals. In particular, we have identified that even at rest there exists in patients with schizophrenia an inverse relationship between dorsolateral prefrontal cortical and medial temporal lobe blood flow, which is mediated by COMT genotype. This is an effect not seen in healthy study participants and suggests an important intersection between genetically determined cortical dopaminergic tone and fundamental biases in baseline prefrontal-limbic neural network activity in patients suffering with schizophrenia. Adopting a similar strategy, we have broadened our work in this cohort to identify gene-diagnosis interactions with other risk genes that impact neural functioning during both working-memory performance and basal resting conditions. This year, we have shown that genetic variation in brain-derived neurotrophic factor (BDNF), a key molecule regulating hippocampal development and function, which has also been implicated in aspects of schizophrenic neuropathophysiology, plays an important, independent predictive role in hippocampal physiology under multiple cognitive conditions and does so much differently in medication-withdrawn patients with schizophrenia (Eisenberg et al., 2013). Together, this series of experiments elucidates a mechanistic explanation for variation in characteristic resting-state and cognitive challenge-related neural abnormalities previously identified in schizophrenia. In addition, we have very recently extended our study of schizophrenia-associated hippocampal dysfunction by establishing that activity during mnemonic encoding is a likely indicator of genetic liability for this illness (Rasetti et al, 2013). Advancing these lines of research provides an important complement to studies of other central biomarkers (e.g., Masdeu et als report screening for autoimmunity in schizophrenia (2013)) and ultimately promises to aid treatment target discovery. (Masdeu et al., 2013) In parallel, in collaboration with the Behavioral Neuroendocrinology Section we have employed an incisive hormone manipulation, multimodal neuroimaging approach aimed at understanding the neural substrate of premenstrual dysphoric disorder (Baller et al., 2013). Measuring both fMRI and PET indices of working-memory during sex steroid hormone suppression with a GnRH agonist and individually, progesterone and estrogen add-back administration, in both healthy and PMDD patients, we found that regardless of the modality or hormone condition, PMDD patients showed exaggerated prefrontal neural response to working memory challenge, which was related to clinical symptom measurements, providing a much-needed foothold towards unraveling the neural underpinnings of this common and costly mental disorder. Finally, in collaboration with Dr. Sidransky in NHGRI, we have been able to advance insight into the pathophysiology of parkinsonism associated with genetic mutations in GBA, a gene disrupted in Gauchers disease. With our multitracer PET approach, we have characterized both dopaminergic and perfusion abnormalities related to idiopathic and GBA-linked parkinsonism (Goker-Alpan et al., 2012).