Fetal Gene Regulatory Gene Deletions are Associated with Poor Cognition and Altered Cortical Morphology in Schizophrenia and Community-Based Samples.

Schizophrenia spectrum disorders (SSDs) are characterized by substantial clinical and genetic heterogeneity. Multiple recurrent copy number variants (CNVs) increase risk for SSDs; however, how known risk CNVs and broader genome-wide CNVs influence clinical variability is unclear. The current study examined associations between borderline intellectual functioning or childhood-onset psychosis, known risk CNVs, and burden of deletions affecting genes in 18 previously validated neurodevelopmental gene-sets in 618 SSD individuals. CNV associations were assessed for replication in 235 SSD relatives and 583 controls, and 9,930 youth from the Adolescent Brain Cognitive Development (ABCD) Study. Known SSD- and neurodevelopmental disorder (NDD)-risk CNVs were associated with borderline intellectual functioning in SSD cases (odds ratios (OR) = 7.09 and 4.57, respectively); NDD-risk deletions were nominally associated with childhood-onset psychosis (OR = 4.34). Furthermore, deletion of genes involved in regulating gene expression during fetal brain development was associated with borderline intellectual functioning across SSD cases and non-cases (OR = 2.58), with partial replication in the ABCD cohort. Exploratory analyses of cortical morphology showed associations between fetal gene regulatory gene deletions and altered gray matter volume and cortical thickness across cohorts. Results highlight contributions of known risk CNVs to phenotypic variability in SSD and the utility of a neurodevelopmental framework for identifying mechanisms that influence phenotypic variability in SSDs, as well as the broader population, with implications for personalized medicine approaches to care.

Intrinsic Infant Hippocampal Function Supports Inhibitory Processing.

Impaired cerebral inhibition is commonly observed in neurodevelopmental disorders and may represent a vulnerability factor for their development. The hippocampus plays a key role in inhibition among adults and undergoes significant and rapid changes during early brain development. Therefore, the structure represents an important candidate region for early identification of pathology that is relevant to inhibitory dysfunction. To determine whether hippocampal function corresponds to inhibition in the early postnatal period, the present study evaluated relationships between hippocampal activity and sensory gating in infants 4-20 weeks of age (N = 18). Resting-state functional magnetic resonance imaging was used to measure hippocampal activity, including the amplitude of low-frequency fluctuations (ALFFs) and fractional ALFF. Electroencephalography during a paired-stimulus paradigm was used to measure sensory gating (P50). Higher activity of the right hippocampus was associated with better sensory gating (P50 ratio), driven by a reduction in response to the second stimulus. These findings suggest that meaningful effects of hippocampal function can be detected early in infancy. Specifically, higher intrinsic hippocampal activity in the early postnatal period may support effective inhibitory processing. Future work will benefit from longitudinal analysis to clarify the trajectory of hippocampal function, alterations of which may contribute to the risk of neurodevelopmental disorders and represent an intervention target.

Task-based default mode network connectivity predicts cognitive impairment and negative symptoms in first-episode schizophrenia.

Individuals diagnosed with schizophrenia (SZ) demonstrate difficulty distinguishing between internally and externally generated stimuli. These aberrations in "source monitoring" have been theorized as contributing to symptoms of the disorder, including hallucinations and delusions. Altered connectivity within the default mode network (DMN) of the brain has been proposed as a mechanism through which discrimination between self-generated and externally generated events is disrupted. Source monitoring abnormalities in SZ have additionally been linked to impairments in selective attention and inhibitory processing, which are reliably observed via the N100 component of the event-related brain potential elicited during an auditory paired-stimulus paradigm. Given overlapping constructs associated with DMN connectivity and N100 in SZ, the present investigation evaluated relationships between these measures of disorder-related dysfunction and sought to clarify the nature of task-based DMN function in SZ. DMN connectivity and N100 measures were assessed using EEG recorded from SZ during their first episode of illness (N = 52) and demographically matched healthy comparison participants (N = 25). SZ demonstrated less evoked theta-band connectivity within DMN following presentation of pairs of identical auditory stimuli than HC. Greater DMN connectivity among SZ was associated with better performance on measures of sustained attention (p = .03) and working memory (p = .09), as well as lower severity of negative symptoms, though it was not predictive of N100 measures. Together, present findings provide EEG evidence of lower task-based connectivity among first-episode SZ, reflecting disruptions of DMN functions that support cognitive processes. Attentional processes captured by N100 appear to be supported by different neural mechanisms.

Oscillatory Coupling Between Neural and Cardiac Rhythms.

Oscillations serve a critical role in organizing biological systems. In the brain, oscillatory coupling is a fundamental mechanism of communication. The possibility that neural oscillations interact directly with slower physiological rhythms (e.g., heart rate, respiration) is largely unexplored and may have important implications for psychological functioning. Oscillations in heart rate, an aspect of heart rate variability (HRV), show remarkably robust associations with psychological health. Mather and Thayer proposed coupling between high-frequency HRV (HF-HRV) and neural oscillations as a mechanism that partially accounts for such relationships. We tested this hypothesis by measuring phase-amplitude coupling between HF-HRV and neural oscillations in 37 healthy adults at rest. Robust coupling was detected in all frequency bands. Granger causality analyses indicated stronger heart-to-brain than brain-to-heart effects in all frequency bands except gamma. These findings suggest that cardiac rhythms play a causal role in modulating neural oscillations, which may have important implications for mental health.

Connectome-based predictive modeling of empathy in adolescents with and without the low-prosocial emotion specifier.

Empathy impairments are an important part of a broader affective impairments defining the youth antisocial phenotype callous-unemotional (CU) traits and the DSM-5 low prosocial emotion (LPE) specifier. While functional connectivity underlying empathy and CU traits have been well studied, less is known about what functional connections underly differences in empathy amongst adolescents qualifying for the LPE specifier. Such information can provide mechanistic distinctions for this clinically relevant specifier. The present study uses connectome-based predictive modeling that uses whole-brain resting-state functional connectivity data to predict cognitive and affective empathy for those meeting the LPE specifier (n = 29) and those that do not (n = 57). Additionally, we tested if models of empathy generalized between groups as well as density differences for each model of empathy between groups. Results indicate the LPE group had lower cognitive and affective empathy as well as higher CU traits and conduct problems. Negative and positive models were identified for affective empathy for both groups, but only the negative model for the LPE and positive model for the normative group reliably predicted cognitive empathy. Models predicting empathy did not generalize between groups. Density differences within the default mode, salience, executive control, limbic, and cerebellar networks were found as well as between the executive control, salience, and default mode networks. And, importantly, connections between the executive control and default mode networks characterized empathy differences the LPE group such that more positive connections characterized cognitive differences and less negative connections characterized affective differences. These findings indicate neural differences in empathy for those meeting LPE criteria that may explain decrements in empathy amongst these youth. These findings support theoretical accounts of empathy decrements in the LPE clinical specifier and extend them to identify specific circuits accounting for variation in empathy impairments. The identified negative models help understand what connections inhibit empathy whereas the positive models reveal what brain patterns are being used to support empathy in those with the LPE specifier. LPE differences from the normative group and could be an appropriate biomarker for predicting CU trait severity. Replication and validation using other large datasets are important next steps.

Alterations in the default mode-salience network circuit provide a potential mechanism supporting negativity bias in depression.

Aberrant effective connectivity between default mode (DMN) and salience (SAL) networks may support the tendency of depressed individuals to find it difficult to disengage from self-focused, negatively-biased thinking and may contribute to the onset and maintenance of depression. Assessment of effective connectivity, which can statistically characterize the direction of influence between regions within neural circuits, may provide new insights into the nature of DMN-SAL connectivity disruptions in depression. Functional magnetic resonance imaging (fMRI) was collected from 38 individuals with a history of major depression and 50 healthy comparison participants during completion of an emotion-word Stroop task. Activation within DMN and SAL networks and effective connectivity between DMN and SAL, assessed via Granger causality, were examined. Individuals with a history of depression exhibited greater overall network activation, greater directed connectivity from DMN to SAL, and less directed connectivity from SAL to DMN than healthy comparison participants during negative-word trials. Among individuals with a history of depression, greater DMN-to-SAL connectivity was associated with lower overall network activation and worse task performance during positive-word trials; this pattern was not observed among healthy participants. Present findings indicate that greater network activation and, specifically, influence of DMN on SAL, support negativity bias among previously depressed individuals.

Effective connectivity between Broca's area and amygdala as a mechanism of top-down control in worry.

Individuals higher in trait worry exhibit increased activation in Broca's area during inhibitory processing tasks. To identify whether such activity represents an adaptive mechanism supporting top-down control, functional and effective connectivity of Broca's area were investigated during a task of inhibitory control. fMRI data obtained from 106 participants performing an emotion-word Stroop task were examined using psychophysiological interaction and Granger Causality (GC) analyses. Findings revealed greater directed connectivity from Broca's to amygdala in the presence of emotional distraction. Furthermore, a predictive relationship was observed between worry and the asymmetry in effective connectivity, with worriers exhibiting greater directed connectivity from Broca's to amygdala. When performing the task, worriers with greater GC directional asymmetry were more accurate than worriers with less asymmetry. Present findings indicate that individuals with elevated trait worry employ a mechanism of top-down control in which communication from Broca's to amygdala fosters successful compensation for interference effects.

Magnetoencephalography for Schizophrenia.

Schizophrenia (Sz) is a chronic mental disorder characterized by disturbances in thought (such as delusions and confused thinking), perception (hearing voices), and behavior (lack of motivation). The lifetime prevalence of Sz is between 0.3% and 0.7%, with late adolescence and early adulthood, the peak period for the onset of psychotic symptoms. Causal factors in Sz include environmental and genetic factors and especially their interaction. About 50% of individuals with a diagnosis of Sz have lifelong impairment.

Extreme-groups designs in studies of dimensional phenomena: Advantages, caveats, and recommendations.

Extreme-groups designs (EGDs) are common in psychopathology research, often using diagnostic category as an independent variable. Continuous-variable analysis strategies drawing from a general linear model framework can be applied to such designs. The growing emphasis on dimensional examinations of psychological constructs, encouraged by the National Institute of Mental Health Research Domain Criteria framework, encourages continuous-variable analytic strategies. However, the interpretative implications of applying these strategies to various types of populations and sample score distributions, including those used in EGDs, are not always recognized. Appropriateness and utility of EGDs depend in part on whether the goal is to determine whether a relationship exists between 2 variables or to determine its strength. Whereas the literature investigating EGDs has emphasized symmetrical thresholds for defining extreme groups (e.g., bottom 10% vs. top 10%), psychopathologists often employ asymmetric thresholds (e.g., above a diagnostic threshold vs. a broader range of scores in a healthy comparison group). The present article selectively reviews literature on EGDs and extends it with simulations of symmetric and asymmetric selection criteria. Results indicate that including a wide range of scores in EGDs substantially mitigates problems (e.g., inflation of effect size) that arise when using statistical methods classically employed for continuous variables. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Human behavioural discrimination of human, chimpanzee and macaque affective vocalisations is reflected by the neural response in the superior temporal sulcus.

Accurate perception of the emotional content of vocalisations is essential for successful social communication and interaction. However, it is not clear whether our ability to perceive emotional cues from vocal signals is specific to human signals, or can be applied to other species' vocalisations. Here, we address this issue by evaluating the perception and neural response to affective vocalisations from different primate species (humans, chimpanzees and macaques). We found that the ability of human participants to discriminate emotional valence varied as a function of phylogenetic distance between species. Participants were most accurate at discriminating the emotional valence of human vocalisations, followed by chimpanzee vocalisations. They were, however, unable to accurately discriminate the valence of macaque vocalisations. Next, we used fMRI to compare human brain responses to human, chimpanzee and macaque vocalisations. We found that regions in the superior temporal lobe that are closely associated with the perception of complex auditory signals, showed a graded response to affective vocalisations from different species with the largest response to human vocalisations, an intermediate response to chimpanzees, and the smallest response to macaques. Together, these results suggest that neural correlates of differences in the perception of different primate affective vocalisations are found in auditory regions of the human brain and correspond to the phylogenetic distances between the species.