Major depressive disorder emerges from the complex interactions of biological systems that span genes and molecules through cells, networks, and behavior. Establishing how neurobiological processes coalesce to contribute to depression requires a multiscale approach, encompassing measures of brain structure and function as well as genetic and cell-specific transcriptional data. Here, we examine anatomical (cortical thickness) and functional (functional variability, global brain connectivity) correlates of depression and negative affect across three population-imaging datasets: UK Biobank, Brain Genomics Superstruct Project, and Enhancing NeuroImaging through Meta Analysis (ENIGMA; combined n ≥ 23,723). Integrative analyses incorporate measures of cortical gene expression, postmortem patient transcriptional data, depression genome-wide association study (GWAS), and single-cell gene transcription. Neuroimaging correlates of depression and negative affect were consistent across three independent datasets. Linking ex vivo gene down-regulation with in vivo neuroimaging, we find that transcriptional correlates of depression imaging phenotypes track gene down-regulation in postmortem cortical samples of patients with depression. Integrated analysis of single-cell and Allen Human Brain Atlas expression data reveal somatostatin interneurons and astrocytes to be consistent cell associates of depression, through both in vivo imaging and ex vivo cortical gene dysregulation. Providing converging evidence for these observations, GWAS-derived polygenic risk for depression was enriched for genes expressed in interneurons, but not glia. Underscoring the translational potential of multiscale approaches, the transcriptional correlates of depression-linked brain function and structure were enriched for disorder-relevant molecular pathways. These findings bridge levels to connect specific genes, cell classes, and biological pathways to in vivo imaging correlates of depression.

Inhibitory interneurons orchestrate information flow across the cortex and are implicated in psychiatric illness. Although interneuron classes have unique functional properties and spatial distributions, the influence of interneuron subtypes on brain function, cortical specialization, and illness risk remains elusive. Here, we demonstrate stereotyped negative correlation of somatostatin and parvalbumin transcripts within human and non-human primates. Cortical distributions of somatostatin and parvalbumin cell gene markers are strongly coupled to regional differences in functional MRI variability. In the general population (n = 9,713), parvalbumin-linked genes account for an enriched proportion of heritable variance in in-vivo functional MRI signal amplitude. Single-marker and polygenic cell deconvolution establish that this relationship is spatially dependent, following the topography of parvalbumin expression in post-mortem brain tissue. Finally, schizophrenia genetic risk is enriched among interneuron-linked genes and predicts cortical signal amplitude in parvalbumin-biased regions. These data indicate that the molecular-genetic basis of brain function is shaped by interneuron-related transcripts and may capture individual differences in schizophrenia risk.

Progressive grey matter loss has been demonstrated among clinical high-risk (CHR) individuals who convert to psychosis, but it is unknown whether these changes occur prior to psychosis onset. Identifying illness-related neurobiological mechanisms that occur prior to conversion is essential for targeted early intervention. Among participants in the third wave of the North American Prodrome Longitudinal Study (NAPLS3), this report investigated if steeper cortical thinning was observable prior to psychosis onset among CHR individuals who ultimately converted (CHR-C) and assessed the shortest possible time interval in which rates of cortical thinning differ between CHR-C, CHR non-converters (CHR-NC), and health controls (HC). 338 CHR-NC, 42 CHR-C, and 62 HC participants (age 19.3±4.2, 44.8% female, 52.5% racial/ethnic minority) completed up to 5 MRI scans across 8 months. Accelerated thinning among CHR-C compared to CHR-NC and HC was observed in multiple prefrontal, temporal, and parietal cortical regions. CHR-NC also exhibited accelerated cortical thinning compared to HC in several of these areas. Greater percent decrease in cortical thickness was observed among CHR-C compared to other groups across 2.9±1.8 months, on average, in several cortical areas. ROC analyses discriminating CHR-C from CHR-NC by percent thickness change in a left hemisphere region of interest, scanner, age, age2, and sex had an AUC of 0.74, with model predictive power driven primarily by percent thickness change. Findings indicate that accelerated cortical thinning precedes psychosis onset and differentiates CHR-C from CHR-NC and HC across short time intervals. Mechanisms underlying cortical thinning may provide novel treatment targets prior to psychosis onset.

Selective or ‘picky’ eating habits are common among those with autism spectrum disorder (ASD). These behaviors are often related to aberrant sensory experience in individuals with ASD, including heightened reactivity to food taste and texture. However, very little is known about the neural mechanisms that underlie taste reactivity in ASD. In the present study, food-related neural responses were evaluated in 21 young adult and adolescent males diagnosed with ASD without intellectual disability, and 21 typically-developing (TD) controls. Taste reactivity was assessed using the Adolescent/Adult Sensory Profile, a clinical self-report measure. Functional magnetic resonance imaging was used to evaluate hemodynamic responses to sweet (vs. neutral) tastants and food pictures. Subjects also underwent resting-state functional connectivity scans.The ASD and TD individuals did not differ in their hemodynamic response to gustatory stimuli. However, the ASD subjects, but not the controls, exhibited a positive association between self-reported taste reactivity and the response to sweet tastants within the insular cortex and multiple brain regions associated with gustatory perception and reward. There was a strong interaction between diagnostic group and taste reactivity on tastant response in brain regions associated with ASD pathophysiology, including the bilateral anterior superior temporal sulcus (STS). This interaction of diagnosis and taste reactivity was also observed in the resting state functional connectivity between the anterior STS and dorsal mid-insula (i.e., gustatory cortex).These results suggest that self-reported heightened taste reactivity in ASD is associated with heightened brain responses to food-related stimuli and atypical functional connectivity of primary gustatory cortex, which may predispose these individuals to maladaptive and unhealthy patterns of selective eating behavior.Trial registration(clinicaltrials.gov identifier) NCT01031407. Registered: December 14, 2009.

38Inhibitory interneurons orchestrate information flow across cortex and are implicated in psychiatric 39 illness. Although classes of interneurons have unique functional properties and spatial distributions 40 throughout the brain, the relative influence of interneuron subtypes on brain function, cortical 41 specialization, and illness risk remains elusive. Here, we demonstrate stereotyped organizational 42 properties of somatostatin and parvalbumin related transcripts within human and non-human primates. 43Interneuron spatial distributions recapitulate cortico-striato-thalamic functional networks and track regional 44 differences in functional MRI signal amplitude. In the general population (n=9,627), parvalbumin-linked 45 genes account for an enriched proportion of genome-wide heritable variance in in-vivo functional MRI 46 signal amplitude. This relationship is spatially dependent, following the topographic organization of 47 parvalbumin expression in independent post-mortem brain tissue. Finally, genetic risk for schizophrenia is 48 enriched among interneuron-linked genes and predictive of cortical signal amplitude in parvalbumin-49 biased regions. These data indicate that the molecular genetic basis of resting-state brain function across 50 cortex is shaped by the spatial distribution of interneuron-related transcripts and underlies individual 51 differences in risk for schizophrenia. 523 Key Findings 53 1.Spatial distributions of somatostatin (SST) and parvalbumin (PVALB) are negatively correlated in 67Ramón y Cajal theorized that the functional diversity of the human brain arises, in part, from the 68 vast assortment of neurons that pattern cortex 1 . Inhibitory interneurons are the most varied neuronal 69 class 2 , exhibiting divergent morphological and physiological properties and coordinating information flow 70 across the brain's collective set of functional connections (functional connectome) 3,4 . Foundational cross-71 species animal and human work provides converging evidence for the role of interneurons in healthy 72 brain functions as well as their dysregulation in psychiatric illnesses, including schizophrenia 5,6 and major 73 depressive disorder 7 . The development of densely sampled gene transcriptional atlases now enables the 74 study of cellular and molecular correlates of functional brain network architecture [8][9][10][11] . Despite these 75 methodological advances and a clear role for interneurons in the modulation of excitatory neuron activity, 76relatively little is known about how the spatial distribution of interneuron subtypes shape human brain 77 activity and associated risk for psychiatric illness. 78The topographic distribution of interneuron subtypes is theorized to contribute to regional and 79 functional network specialization, partly by altering the relative excitatory/inhibitory balance within a given 80 patch of cortex 9,12,13 . Interneurons comprise approximately 20-30% of cortical neurons 14 and form 81 stereotyped microcircuits with excitatory projection neurons 15 . Whi...