Imaging of Neuropsychiatric Disorders with Developmental and Genetic Mechanisms

National Institute Of Mental Health

Investigators

Linked publications, trials & patents

Abstract

The core aim of this project is to elucidate the nature, molecular foundations, underlying neurochemistry, and clinical correlates of neural systems-level dysfunction in schizophrenia. Recent efforts toward that end have been manifold, including studies examining pathophysiology and phenotypic heterogeneity in our patient volunteers, which have focused on cognition, dopamine systems, and genetic effects relevant to schizophrenia pathogenesis. Under this project, we have forwarded comprehensive, multimodal positron emission tomography (PET)-, magnetic resonance imaging-, and magnetoencephalography-based studies of a unique cohort of individuals with schizophrenia who have agreed to be studied under placebo conditions (i.e., free of psychiatric medication). This work is necessarily challenging to conduct but yields critical data, which includes characterization of dopamine-dependent neurocognitive functions and brain activity, striatal presynaptic dopamine synthesis capacity, both D1 and D2/3 dopamine receptor availability, and cognition. Along with complementary data collection from healthy comparison cohorts, these studies provide the opportunity to better understand illness-related neurobiology in a clinically meaningful context, while accounting for medication effects, and to define contributors to the considerable illness heterogeneity observed in schizophrenia, which may ultimately lead to the development of precision, personalized clinical care. Our early work established prefrontal dysfunction during executive task performance as a hallmark cognitive neural phenotype in schizophrenia, with much now known through our and others’ neuroimaging studies about its localization, context, and heritability. We have now completed important new studies leveraging the high spatiotemporal resolution of magnetoencephalography and our inpatient protocol to not only capture spatial signatures of working memory-related cortical dysfunction in schizophrenia but to also define at the millisecond level exactly when during particular cognitive demands this dysfunction appears. This precision allowed the inference that cognitive subprocesses involving information updating and motor planning may be central in driving canonical working memory-related prefrontal abnormalities. Additionally, we found that this dysfunction normalized with antipsychotic treatment, which, along with prior findings, implicates dopamine-driven mesocorticostriatal circuitry. From a neurochemical perspective, in multimodal, longitudinal PET studies of subcortical neurochemistry and neurophysiology in schizophrenia, we have found that individuals with less ventral striatal presynaptic dopaminergic tone showed less antipsychotic medication-related physiological (i.e., blood flow) changes in the same region. We have further expanded this work to better delineate the relationships between symptom profiles and presynaptic dopaminergic tone more widely throughout the striatum in our inpatient cohorts. We have reported that less presynaptic dopamine synthesis capacity in the striatum is also associated with a greater burden of negative symptoms, a type of symptomatology that is particularly challenging to treat with modern medicines. Importantly, we were able to replicate this finding in a second, independently studied cohort. To better understand possible connections between lower striatal dopaminergic tone and insufficient antipsychotic treatment response, we conducted a neuroimaging genetics investigation utilizing polygenic metrics of liability for both schizophrenia generally and for treatment resistance specifically. We discovered that whereas greater genetic risk for schizophrenia predicted greater striatal dopaminergic tone, genetic risk that is specific for treatment-resistant schizophrenia was associated with less presynaptic dopamine synthesis in the striatum. These data are the first to support the notion that there are genetic predisposing factors (as opposed to medication exposure or other clinical effects) that may underly previous observations that have linked inadequate antipsychotic treatment response to low striatal dopaminergic tone. These efforts have reshaped understanding of the neurochemical mechanisms underlying heterogeneity in symptoms and in therapeutic response in people with schizophrenia. Alongside collaborators, we have embarked on an important series of experiments addressing the molecular contributions of dopamine dysfunction in schizophrenia, identifying a central dopaminergic subnetwork of schizophrenia risk genes and their effects on the brain. This multidimensional project involved generation of novel polygenic risk scores based on innovative analytics of two independent, large, multiregional postmortem human brain tissue collections, and ultimate translation of genetic associations in post-mortem brain tissue to functional analyses in vivo in four human [18F]-FDOPA PET and fMRI datasets. This research took advantage of an advanced data reduction (tensor decomposition) method applied to gene expression data in multi-regional human brain tissue and subsequent case-control and genetic risk association analyses to identify and characterize a gene set showing convergent patient-control differences and genetic risk association. This gene set is prominently represented in striatal medium spiny neurons and is enriched for dopamine transmission genes. It was also used to parse large-scale genome-wide association study data into a biologically functional measure of cumulative schizophrenia genetic risk. Finally, we showed that scoring individuals based on this parsed polygenic profile allowed prediction of striatal presynaptic dopamine synthesis measured with PET as well as of colocalized neural responses to reward anticipation measured with fMRI, two phenotypes known to be disordered in schizophrenia. Together, these studies have uncovered a path from aggregated schizophrenia risk genetics to gene expression, and finally, to neurochemical and neurofunctional outcomes, providing a key molecular update to the dopamine hypothesis of schizophrenia. Work in these directions will prove important for refining models of illness and antipsychotic treatment and will inform therapeutic targeting. This work involves the following studies: NCT00942981, NCT00001258, NCT00024622, NCT00004571, NCT00001247, NCT00001486, NCT00044083, NCT00057707