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 described in extensive detail in Eisenberg and Berman (1), critical disturbances in cognitive control 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. We have recently extended this work even further, reporting on the specificity of this finding (2). By comparing prefrontal and limbic (including parahippocampal cortex) activation patterns during the N-back task in schizophrenia subjects and a working-memory performance-matched comparison group of aging, healthy adults, we show that relative to a young, healthy control group, both patients and aging groups show abnormal prefrontal-limbic function abnormalities. However, patients demonstrated prefrontal hypoactivations whereas aging individuals showed prefrontal hyperactivation. Both aging and schizophrenia groups showed diminished medial temporal lobe deactivation. These findings confirm this type of hypofrontality as an important phenotype in schizophrenia, reflecting not simply performance correlates, but rather an important aspect of the neurophysiological signature of schizophrenia. Delving then into molecular mechanisms contributing to prefrontal-limbic axis pathology in schizophrenia, 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 (3). 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. This study therefore elucidates a mechanistic explanation for variation in characteristic resting-state neural abnormalities previously identified in schizophrenia. Adopting a similar strategy, we are currently broadening our neuroimaging genetic 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. Already, we have embarked on experiments featuring brain-derived neurotrophic factor (BDNF), a key molecule regulating hippocampal development and function, which has also been implicated in aspects of schizophrenic neuropathophysiology. By taking advantage of known BDNF genetic variation at the Val66Met locus, which we have recently shown to play an important predictive role in hippocampal basal physiology, we now are able to examine important BDNF genotype-by-diagnosis interactions impacting hippocampal activity in schizophrenia. These interactions, which occur under diverse cognitive conditions, promise to refine current theories of hippocampal dysfunction in schizophrenia and its molecular underpinnings. Alongside these investigations in schizophrenia, we have completed a series of experiments exploring the impact of risk genetics on another dopamine-related illness, Parkinsons disease. In this illness, mutations in the glucocerebrosidase gene, GBA, dramatically impacts Parkinsons risk and the degree of associated cognitive impairment. In two groups of patients with Parkinsons disease (with and without GBA mutations) and two additional groups with GBA mutations (with and without a family history of Parkinsons disease), we compared presynaptic dopamine and regional cerebral blood flow with four matched control groups (4). Notably, while dopamine measurements indicated that among Parkinsons disease patients, GBA mutations do not alter the pattern of nigro-striatal dopamine deficiencies, GBA mutations did predict lateral parieto-occipital association cortex and precuneus hypoperfusion in Parkinsons individuals, a pattern reminiscent of that found in dementia with Lewy bodies. These findings provide insight into the pathophysiology of GBA-associated parkinsonism and moreover, offer an important parallel perspective with which to understand approaches to dopaminergic and cortical dysfunction in schizophrenia.

Project Start
Project End
Budget Start
Budget End
Support Year
20
Fiscal Year
2012
Total Cost
$539,338
Indirect Cost
Name
U.S. National Institute of Mental Health
Department
Type
DUNS #
City
State
Country
Zip Code
Marenco, Stefano; Meyer, Christian; Kuo, Susan et al. (2016) Prefrontal GABA Levels Measured With Magnetic Resonance Spectroscopy in Patients With Psychosis and Unaffected Siblings. Am J Psychiatry 173:527-34
Eisenberg, Daniel P; Kohn, Philip D; Hegarty, Catherine E et al. (2016) Common Variation in the DOPA Decarboxylase (DDC) Gene and Human Striatal DDC Activity In Vivo. Neuropsychopharmacology 41:2303-8
Masdeu, Joseph C; Dalmau, Josep; Berman, Karen F (2016) NMDA Receptor Internalization by Autoantibodies: A Reversible Mechanism Underlying Psychosis? Trends Neurosci :
Wei, Shau-Ming; Eisenberg, Daniel P; Nabel, Katherine G et al. (2016) Brain-Derived Neurotrophic Factor Val66Met Polymorphism Affects the Relationship Between an Anxiety-Related Personality Trait and Resting Regional Cerebral Blood Flow. Cereb Cortex :
Rasetti, Roberta; Mattay, Venkata S; White, Michael G et al. (2014) Altered hippocampal-parahippocampal function during stimulus encoding: a potential indicator of genetic liability for schizophrenia. JAMA Psychiatry 71:236-47
Dickinson, Dwight; Straub, Richard E; Trampush, Joey W et al. (2014) Differential effects of common variants in SCN2A on general cognitive ability, brain physiology, and messenger RNA expression in schizophrenia cases and control individuals. JAMA Psychiatry 71:647-56
Eisenberg, Daniel Paul; Berman, Karen F (2014) Catechol-O-methyltransferase and genetic variation under hemizygosity. Biol Psychiatry 75:346-7
Eisenberg, Daniel Paul; Kleinman, Joel; Berman, Karen F (2013) Epistasis and complex neuropsychiatric phenotypes. Psychiatry 76:295-7
Eisenberg, D P; Ianni, A M; Wei, S-M et al. (2013) Brain-derived neurotrophic factor (BDNF) Val(66)Met polymorphism differentially predicts hippocampal function in medication-free patients with schizophrenia. Mol Psychiatry 18:713-20
Eisenberg, D P; Ianni, A M; Wei, S-M et al. (2013) Hippocampal dysfunction in schizophrenia: association with brain-derived neurotrophic factor genotype. Mol Psychiatry 18:631

Showing the most recent 10 out of 15 publications