Imaging of Neuropsychiatric Disorders with Developmental and Genetic Mechanisms

National Institute Of Mental Health

Investigators

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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 within the Clinical and Translational Neuroscience Branch have been manifold, including studies examining pathophysiology and phenotypic heterogeneity in our patient volunteers, collaborative stem cell studies, and studies focused on genetic and gene-by-environment interactions relevant to schizophrenia pathogenesis. Under this project, we have forwarded comprehensive, multimodal positron emission tomography- and magnetic resonance imaging-based studies of a unique and steadily growing cohort of individuals with schizophrenia who have agreed to be studied under placebo conditions (i.e., free of psychiatric medication). Though this work is necessarily challenging to conduct, we continue to make progress in data collection, which includes characterization of dopamine-dependent neurocognitive functions and brain activity, striatal presynaptic dopamine synthetic capacity, and both D1 and D2/3 dopamine receptor availability, and cognition. 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. For instance, in multimodal, longitudinal PET studies of subcortical neurochemistry and neurophysiology in schizophrenia, we have shown that medication-related changes in both striatal basal blood flow and clinical ratings were predicted by the degree of ventral striatal presynaptic dopaminergic tone present. We have now 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 (Eisenberg et al., 2021). These efforts pave new avenues for delineating the neurochemical mechanisms underlying heterogeneity in symptoms and in therapeutic response and form the basis of a number of studies currently underway. This body of work is informed by collaborative efforts to understand dopaminergic regulatory processes in a separate neuropsychiatric context: that of idiopathic and GBA-mutation-linked Parkinsons disease. In this vein, we have recently completed an unprecedented series of studies in which we were able to characterize years-long trajectories of striatal presynaptic dopamine synthesis capacity in GBA mutation carriers with and without Parkinsonism (Lopez et al., 2020). Recognizing both the multifaceted nature of and the interindividual variation in clinical and cognitive disruptions in schizophrenia, we have embarked on a series of experiments aimed at parsing variability in both symptoms and neuropsychological performance measurements in order to generate biologically meaningful patient subgroups that might ultimately have implications for personalized treatment in this illness. For example, in cluster analyses of clinical ratings from a large cohort of individuals with schizophrenia, we have identified three reliable clinical subgroups based on symptom profile: low-symptom, deficit, and distress groups; these groups demonstrated distinct patterns of clinical illness severity, cognitive functioning, and personality ratings, and were consistent with an independent sample of individuals with childhood-onset schizophrenia. Furthermore, in the adult sample, these subgroups were distinguished by differential frontoparietal neural recruitment during working memory performance, suggesting that clinical distinctions between these groups extend to neurobiology. Having established over many years that frontoparietal network, working memory-related deficits are an important phenotype in schizophrenia, we continue to build on this work in search of more detailed understanding of this complex phenomenon. For instance, we and collaborators have used dynamic causal modeling in conjunction with fMRI techniques to suggest a predominance of deficits in certain working memory subprocesses (i.e., updating/manipulating information) that appear particularly prominent in individuals with greater delusion symptom severity (Greenman et al., 2021). In healthy volunteers, this same signature is found in those with greater polygenic risk for schizophrenia. We have also engaged in work aimed at understanding key cognitive developmental phenotypes in schizophrenia. In one recent investigation in a large schizophrenia sample, we sought to identify and characterize subgroups with different trajectories of early cognitive development, and then to profile the subgroups across four polygenic score dimensions. Premorbid and current IQ were used as inputs in cluster analyses and three cognitive trajectory subgroups were derived pre-adolescent impairment, adolescent decline, and cognitively stable with very different cognitive, clinical and functional characteristics. Separate polygenic scores were derived in our sample representing schizophrenia genetics, cognition genetics, education genetics, and ADHD genetics, and profiles of these four genetic scores were likewise quite different across trajectory subgroups. There was a striking convergence of subgroup differences in illness progression and clinical outcomes with subgroup profiles across polygenic score dimensions. Those who remained cognitive stable through adolescence only differed from controls on schizophrenia genetics. Those with an adolescent decline in cognition and more severe adult symptoms had the highest schizophrenia genetics and disadvantageous cognitive genetics. The subgroup whose members showed pre-adolescent impairment in cognitive and academic performance, and poor adult outcome, also had the most generalized, disadvantageous genetic profile relative to controls (Dickinson et al., 2020). Furthermore, in collaborative meta-analytic studies, we have helped find that individuals with metabolic syndrome, diabetes or hypertension are in fact at greater risk for cognitive impairment (Hagi et al., 2021). Understanding molecular, genetic and environmental pathways to schizophrenia is another important focus for this project. In light of epidemiological findings of association between obstetric/perinatal complications and schizophrenia risk, we have previously shown that such complications interact with hypoxia-responsive schizophrenia risk genes to affect illness risk. Along with collaborators, we have greatly advanced this work to show that the cumulative effect of the most strongly associated schizophrenia genetic risk loci is greatly amplified in patients with a history of obstetric/perinatal complications. In studies incorporating cortical interneurons generated from induced pluripotent stem cells derived from our patient cohorts, we have worked with a team of scientists to identify that such cells show synaptic density and arborization aberrancies in line with concurrent dysregulated expression of protocadherin genes and improved with PKC an enzyme in the protocadherin pathway inhibition. This exciting work points to novel developmental mechanisms in schizophrenia pathogenesis and merits further investigation. Ongoing 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