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, which have focused on dopamine systems, cognition and genetic effects relevant to schizophrenia pathogenesis, as well as collaborative stem cell studies. Under this project, we have forwarded comprehensive, multimodal positron emission tomography (PET)-, magnetic resonance imaging-, and magnetoencephalography-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). This work is necessarily challenging to conduct but continues to yield critical data, 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. We have now completed important new work in this vein employing magnetoencephalography 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. These novel results provide important clues as to the specific cognitive subprocesses driving functional deficits in schizophrenia, critical prerequisite knowledge for principled therapeutic targeting in this domain. Furthermore, by carefully addressing the confound of antipsychotic medication on a within-subjects basis, this study identified that sluggish prefrontal cortical recruitment during task engagement was most pronounced in the unmedicated state and was ameliorated (or masked) by antipsychotic treatment. This finding suggests that the implicated neural systems are, in fact, likely targeted by antipsychotic medication, opening the door to more incisive cognitive, molecular, and neurochemical work (Rubinstein et al., 2023). We have recently shown, in fact, that there exists variability in individual cognitive treatment response, potentially guided by cognition-linked genetics, highlighting the importance of parsing the substantial heterogeneity in this illness (Blackman et al., 2022). We have devoted substantial work aimed at understanding this heterogeneity. A prime example is our work identifying key cognitive developmental phenotypes in schizophrenia. In one such investigation in a large schizophrenia sample, we characterized subgroups with different inferred trajectories of early cognitive development: pre-adolescent impairment, adolescent decline, and cognitively stable. This work revealed remarkably robust differences between subgroups on illness progression and clinical outcomes, with distinctive subgroup-specific profiles across polygenic score dimensions. Those who remained cognitively 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. Understanding molecular pathways to schizophrenia is another important focus for this project. In studies incorporating cortical interneurons generated from induced pluripotent stem cells (iPSCs) 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. Recently, this collaborative work has resulted in identifying schizophrenia associated alterations in sodium channel gating characteristics of these cells and the finding that within the patient group, some cellular electrophysiological properties may actually correspond to executive function performance (Page et al, 2022). This exciting work points to novel developmental mechanisms in schizophrenia pathogenesis and merits further investigation. From a neurochemical perspective, 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 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 now have reported that less presynaptic dopamine synthesis capacity in the striatum is associated with greater negative symptom burden, a finding we were able to replicate in a second, independently studied cohort (Eisenberg et al., 2022). 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 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. Additionally, we now have identified an important relationship between ultrasound-measured substantia nigra echogenicity and PET-measured striatal presynaptic dopamine synthesis capacity specifically among GBA1 mutation carriers who have clinical parkinsonism but not those at-risk carriers with normal motor function. This work suggests that both nigral sonography and striatal 18F-FDOPA specific uptake may track convergent facets of parkinsonian neurobiology but leaves open questions about the use of these measures as predictive tools for GBA1-associated parkinsonism, an important insight that may also have relevance for use of 18F-FDOPA PET imaging in schizophrenia. 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