Information processing in the cerebral cortex involves interactions among distributed areas. Anatomical connectivity suggests that certain areas form local hierarchical relations such as within the ...visual system. Other connectivity patterns, particularly among association areas, suggest the presence of large-scale circuits without clear hierarchical relations. In this study the organization of networks in the human cerebrum was explored using resting-state functional connectivity MRI. Data from 1,000 subjects were registered using surface-based alignment. A clustering approach was employed to identify and replicate networks of functionally coupled regions across the cerebral cortex. The results revealed local networks confined to sensory and motor cortices as well as distributed networks of association regions. Within the sensory and motor cortices, functional connectivity followed topographic representations across adjacent areas. In association cortex, the connectivity patterns often showed abrupt transitions between network boundaries. Focused analyses were performed to better understand properties of network connectivity. A canonical sensory-motor pathway involving primary visual area, putative middle temporal area complex (MT+), lateral intraparietal area, and frontal eye field was analyzed to explore how interactions might arise within and between networks. Results showed that adjacent regions of the MT+ complex demonstrate differential connectivity consistent with a hierarchical pathway that spans networks. The functional connectivity of parietal and prefrontal association cortices was next explored. Distinct connectivity profiles of neighboring regions suggest they participate in distributed networks that, while showing evidence for interactions, are embedded within largely parallel, interdigitated circuits. We conclude by discussing the organization of these large-scale cerebral networks in relation to monkey anatomy and their potential evolutionary expansion in humans to support cognition.
Given the difficulty of procuring human brain tissue, a key question in molecular psychiatry concerns the extent to which epigenetic signatures measured in more accessible tissues such as blood can ...serve as a surrogate marker for the brain. Here, we aimed (1) to investigate the blood-brain correspondence of DNA methylation using a within-subject design and (2) to identify changes in DNA methylation of brain-related biological pathways in schizophrenia.We obtained paired blood and temporal lobe biopsy samples simultaneously from 12 epilepsy patients during neurosurgical treatment. Using the Infinium 450K methylation array we calculated similarity of blood and brain DNA methylation for each individual separately. We applied our findings by performing gene set enrichment analyses (GSEA) of peripheral blood DNA methylation data (Infinium 27K) of 111 schizophrenia patients and 122 healthy controls and included only Cytosine-phosphate-Guanine (CpG) sites that were significantly correlated across tissues.Only 7.9% of CpG sites showed a statistically significant, large correlation between blood and brain tissue, a proportion that although small was significantly greater than predicted by chance. GSEA analysis of schizophrenia data revealed altered methylation profiles in pathways related to precursor metabolites and signaling peptides.Our findings indicate that most DNA methylation markers in peripheral blood do not reliably predict brain DNA methylation status. However, a subset of peripheral data may proxy methylation status of brain tissue. Restricting the analysis to these markers can identify meaningful epigenetic differences in schizophrenia and potentially other brain disorders.
Converging evidence indicates that groups of patients with nominally distinct psychiatric diagnoses are not separated by sharp or discontinuous neurobiological boundaries. In healthy populations, ...individual differences in behavior are reflected in variability across the collective set of functional brain connections (functional connectome). These data suggest that the spectra of transdiagnostic symptom profiles observed in psychiatric patients may map onto detectable patterns of network function. To examine the manner through which neurobiological variation might underlie clinical presentation, we obtained fMRI data from over 1,000 individuals, including 210 diagnosed with a primary psychotic disorder or affective psychosis (bipolar disorder with psychosis and schizophrenia or schizoaffective disorder), 192 presenting with a primary affective disorder without psychosis (unipolar depression, bipolar disorder without psychosis), and 608 demographically matched healthy comparison participants recruited through a large-scale study of brain imaging and genetics. Here, we examine variation in functional connectomes across psychiatric diagnoses, finding striking evidence for disease connectomic “fingerprints” that are commonly disrupted across distinct forms of pathology and appear to scale as a function of illness severity. The presence of affective and psychotic illnesses was associated with graded disruptions in frontoparietal network connectivity (encompassing aspects of dorsolateral prefrontal, dorsomedial prefrontal, lateral parietal, and posterior temporal cortices). Conversely, other properties of network connectivity, including default network integrity, were preferentially disrupted in patients with psychotic illness, but not patients without psychotic symptoms. This work allows us to establish key biological and clinical features of the functional connectomes of severe mental disease.
Individual differences in affective and social processes may arise from variability in amygdala-medial prefrontal (mPFC) circuitry and related genetic heterogeneity. To explore this possibility in ...humans, we examined the structural correlates of trait negative affect in a sample of 1050 healthy young adults with no history of psychiatric illness. Analyses revealed that heightened negative affect was associated with increased amygdala volume and reduced thickness in a left mPFC region encompassing the subgenual and rostral anterior cingulate cortex. The most extreme individuals displayed an inverse correlation between amygdala volume and mPFC thickness, suggesting that imbalance between these structures is linked to negative affect in the general population. Subgroups of participants were further evaluated on social (n = 206) and emotional (n = 533) functions. Individuals with decreased mPFC thickness exhibited the poorest social cognition and were least able to correctly identify facial emotion. Given prior links between disrupted amygdala-mPFC circuitry and the presence of major depressive disorder (MDD), we explored whether the individual differences in anatomy observed here in healthy young adults were associated with polygenic risk for MDD (n = 438) using risk scores derived from a large genome-wide association analysis (n = 18,759). Analyses revealed associations between increasing polygenic burden for MDD and reduced cortical thickness in the left mPFC. These collective findings suggest that, within the healthy population, there is significant variability in amygdala-mPFC circuitry that is associated with poor functioning across affective and social domains. Individual differences in this circuitry may arise, in part, from common genetic variability that contributes to risk for MDD.
•IL-6 and IFN-g have distinct effects on gene expression in neuronal differentiation.•IL-6 exposure during differentiation affects mitochondrial respiration in neurons.•IFN-g exposure during neuronal ...differentiation affects dendritic spine density.•Folic acid ameliorates cellular effects of IL-6 and IFN-g exposure.
Translational evidence suggests that cytokines involved in maternal immune activation (MIA), such as interleukin-6 (IL-6) and interferon-γ (IFN-γ), can cross the placenta, injure fetal brain, and predispose to neuropsychiatric disorders. To elaborate developmental neuronal sequelae of MIA, we differentiated human pluripotent stem cells to cortical neurons over a two-month period, exposing them to IL-6 or IFN-γ. IL-6 impacted expression of genes regulating extracellular matrix, actin cytoskeleton and TGF-β signaling while IFN-γ impacted genes regulating antigen processing, major histocompatibility complex and endoplasmic reticulum biology. IL-6, but not IFN-γ, altered mitochondrial respiration while IFN-γ, but not IL-6, induced reduction in dendritic spine density. Pre-treatment with folic acid, which has known neuroprotective and anti-inflammatory properties, ameliorated IL-6 effects on mitochondrial respiration and IFN-γ effects on dendritic spine density. These findings suggest distinct mechanisms for how fetal IL-6 and IFN-γ exposure influence risk for neuropsychiatric disorders, and how folic acid can mitigate such risk.
Numerous adverse prenatal exposures have been individually associated with risk for psychiatric illness in the offspring. However, such exposures frequently co-occur, raising questions about their ...cumulative impact. We evaluated effects of cumulative adverse prenatal exposure burden on psychopathology risk in school-aged children.
Using baseline surveys from the U.S.-based Adolescent Brain and Cognitive Development (ABCD) Study (7,898 non-adopted, unrelated children from 21 sites, age 9-10, and their primary caregivers), we examined 8 retrospectively-reported adverse prenatal exposures in relation to caregiver-reported total and subscale Child Behavior Checklist (CBCL) scores. We also assessed cumulative effects of these factors on CBCL total as a continuous measure, as well as on odds of clinically significant psychopathology (CBCL total ≥60), in both the initial set and a separate ABCD sample comprising an additional 696 sibling pairs. Analyses were conducted before and after adjustment for 14 demographic and environmental covariates.
In minimally and fully adjusted models, 6 exposures (unplanned pregnancy; maternal alcohol, marijuana, and tobacco use early in pregnancy; pregnancy complications; and birth complications) independently associated with significant but small increases in CBCL total score. Among these 6, none increased the odds of crossing the threshold for clinically significant symptoms by itself. However, odds of exceeding this threshold became significant with 2 exposures (OR = 1.86, 95% CI 1.47-2.36), and increased linearly with each level of exposure (OR = 1.39, 95% CI 1.31-1.47), up to 3.53-fold for ≥4 exposures versus none. Similar effects were observed in confirmatory analysis among siblings. Within sibling pairs, greater discordance for exposure load associated with greater CBCL total differences, suggesting that results were not confounded by unmeasured family-level effects.
Children exposed to multiple common, adverse prenatal events showed dose-dependent increases in broad, clinically significant psychopathology at age 9-10. Fully prospective studies are needed to confirm and elaborate upon this pattern.
Individuals vary widely in their tendency to seek stimulation and act impulsively, early developing traits with genetic origins. Failures to regulate these behaviors increase risk for maladaptive ...outcomes including substance abuse. Here, we explored the neuroanatomical correlates of sensation seeking and impulsivity in healthy young adults. Our analyses revealed links between sensation seeking and reduced cortical thickness that were preferentially localized to regions implicated in cognitive control, including anterior cingulate and middle frontal gyrus (n = 1015). These associations generalized to self-reported motor impulsivity, replicated in an independent group (n = 219), and correlated with heightened alcohol, tobacco, and caffeine use. Critically, the relations between sensation seeking and brain structure were evident in participants without a history of alcohol or tobacco use, suggesting that observed associations with anatomy are not solely a consequence of substance use. These results demonstrate that individual differences in the tendency to seek stimulation, act on impulse, and engage in substance use are correlated with the anatomical structure of cognitive control circuitry. Our findings suggest that, in healthy populations, covariation across these complex multidimensional behaviors may in part originate from a common underlying biology.
Impaired cognitive control may result in a tendency to seek stimulation impulsively and an increased risk for maladaptive outcomes, including substance abuse. Here, we examined the structural correlates of sensation seeking and impulsivity in a large cohort of healthy young adults. Our analyses revealed links between sensation seeking and reduced cortical thickness that were preferentially localized to regions implicated in cognitive control, including anterior cingulate and middle frontal gyrus. The observed associations generalized to motor impulsivity, replicated in an independent group, and predicted heightened alcohol, tobacco, and caffeine use. These data indicate that normal variability in cognitive control system anatomy predicts sensation seeking and motor impulsivity in the healthy populations, potentially increasing risk for substance use disorders.
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