Familial Risk for Schizophrenia vs Bipolar Disorder and Task-Based Neural Activation: A functional Magnetic Resonance Imaging Meta-Analysis.

BACKGROUND AND HYPOTHESIS: Individuals at familial risk for developing schizophrenia (FRSZ) or bipolar disorder (FRBD) have shared and unique genetic risks. Few studies have compared neural activation between these two groups. Therefore, the present meta-analysis investigated functional brain similarities and differences between FRSZ and FRBD individuals. STUDY DESIGN: A systematic literature review was conducted of articles that compared FRSZ or FRBD individuals to healthy controls (31 FRSZ and 22 FRBD). Seed-based d mapping was used to conduct the meta-analysis. Analyses included comparisons of FRSZ to controls, FRBD to controls, and both relative groups to each other. STUDY RESULTS: Using a highly conservative family-wise error rate correction, there were no significant findings. Using a less conservative threshold, FRSZ compared to controls had lower activation in the left precuneus (Puncorrected = .02) across all studies and in the left middle frontal gyrus (Puncorrected = .03) in nonsocial cognition studies. FRBD compared to controls had lower activation in the left superior parietal gyrus (Puncorrected = .03) and right angular gyrus (Puncorrected = .03) in nonsocial cognition studies, and higher activation in the left superior frontal gyrus (Puncorrected = .01) in social tasks. Differences between FRSZ and FRBD were not significant. CONCLUSIONS: There were few robust differences between FRSZ or FRBD compared to controls. This suggests only weak support for neural activation differences between individuals at genetic risk for schizophrenia or bipolar disorder and controls. The tentative findings observed were in different brain regions for FRSZ and FRBD, with no strong evidence for shared effects between schizophrenia and bipolar genetic risk on neural activation.

Age-dependent effects of schizophrenia genetic risk on cortical thickness and cortical surface area: Evaluating evidence for neurodevelopmental and neurodegenerative models of schizophrenia.

Risk for schizophrenia peaks during early adulthood, a critical period for brain development. Although several influential theoretical models have been proposed for the developmental relationship between brain pathology and clinical onset, to our knowledge, no study has directly evaluated the predictions of these models for schizophrenia developmental genetic effects on brain structure. To address this question, we introduce a framework to estimate the effects of schizophrenia genetic variation on brain structure phenotypes across the life span. Five-hundred and six participants, including 30 schizophrenia probands, 200 of their relatives (aged 12-85 years) from 32 families with at least two first-degree schizophrenia relatives, and 276 unrelated controls, underwent MRI to assess regional cortical thickness (CT) and cortical surface area (CSA). Genetic variance decomposition analyses were conducted to distinguish among schizophrenia neurogenetic effects that are most salient before schizophrenia peak age-of-risk (i.e., early neurodevelopmental effects), after peak age-of-risk (late neurodevelopmental effects), and during the later plateau of age-of-risk (neurodegenerative effects). Genetic correlations between schizophrenia and cortical traits suggested early neurodevelopmental effects for frontal and insula CSA, late neurodevelopmental effects for overall CSA and frontal, parietal, and occipital CSA, and possible neurodegenerative effects for temporal CT and parietal CSA. Importantly, these developmental neurogenetic effects were specific to schizophrenia and not found with nonpsychotic depression. Our findings highlight the potentially dynamic nature of schizophrenia genetic effects across the lifespan and emphasize the utility of integrating neuroimaging methods with developmental behavior genetic approaches to elucidate the nature and timing of risk-conferring processes in psychopathology. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Age-dependent patterns of schizophrenia genetic risk affect cognition.

Cognition shares substantial genetic overlap with schizophrenia, yet it remains unclear whether such genetic effects become significant during developmental periods of elevated risk for schizophrenia, such as the peak age of onset. We introduce an investigative framework integrating epidemiological, developmental, and genetic approaches to determine whether genetic effects shared between schizophrenia and cognition are significant across periods of differing risk for schizophrenia onset, and whether these effects are shared with depression. 771 European-American participants, including 636 (ages 15-84 years) from families with at least two first-degree relatives with schizophrenia and 135 unrelated controls, were divided into three age-risk groups based on ages relative to epidemiological age of onset patterns for schizophrenia: Pre-Peak (before peak age-of-onset: 15 to 22 years), Post-Peak (after peak age-of-onset: 23-42 years), and Plateau (during plateau of age-of-onset: over 42 years). For general cognition and 11 specific cognitive traits, we estimated genetic correlations with schizophrenia and with depression within each age-risk group. Genetic effects shared between deficits in general cognition and schizophrenia were nonsignificant before peak age of onset, yet were high and significant after peak age of onset and during the plateau of onset. These age-dependent genetic effects were largely consistent across specific cognitive traits and not transdiagnostically shared with depression. Schizophrenia genetic effects appear to influence cognitive traits in an age-dependent manner, supporting late developmental and perhaps neurodegenerative models that hypothesize increased expression of schizophrenia risk genes during and after the peak age of risk. Our findings underscore the utility of cognitive traits for tracking schizophrenia genetic effects across the lifespan.

Why does age of onset predict clinical severity in schizophrenia? A multiplex extended pedigree study.

Schizophrenia has substantial variation in symptom severity, course of illness, and overall functioning. Earlier age of onset (AOO) is consistently associated with negative outcomes and yet the causes of this association are still unknown. We used a multiplex, extended pedigree design (total N = 771; 636 relatives from 43 multigenerational families with at least 2 relatives diagnosed with schizophrenia and 135 matched controls) to examine among the schizophrenia relatives (N = 103) the relationship between AOO and negative and positive symptom severity, cognition, and community functioning. Most importantly, we assessed whether there are shared genetic effects between AOO and negative symptoms, positive symptoms, cognition, and community functioning. As expected, earlier AOO was significantly correlated with increased severity of negative and positive symptoms and poorer cognition and community functioning among schizophrenia patients. Notably, the genetic correlation between AOO of schizophrenia and negative symptoms was significant (Rg = -1.00, p = .007). Although the genetic correlations between AOO and positive symptoms, cognition, and community functioning were estimated at maximum and in the predicted direction, they were not statistically significant. AOO of schizophrenia itself was modestly heritable, although not significant and negative symptoms, positive symptoms, and cognition were all strongly and significantly heritable. In sum, we replicated prior findings indicating that earlier AOO is associated with increased symptom severity and extended the literature by detecting shared genetic effects between AOO and negative symptoms, suggestive of pleiotropy.

Alterations in white matter microstructure in individuals at persistent risk for psychosis.

Abnormalities in brain white matter (WM) are reported in youth at-risk for psychosis. Yet, the neurodevelopmental time course of these abnormalities remains unclear. Thus, longitudinal diffusion-weighted imaging (DWI) was used to investigate WM abnormalities in youth at-risk for psychosis. A subset of individuals from the Philadelphia Neurodevelopmental Cohort (PNC) completed two DWI scans approximately 20 months apart. Youths were identified through structured interview as having subthreshold persistent psychosis risk symptoms (n = 46), and were compared to healthy typically developing participants (TD; n = 98). Analyses were conducted at voxelwise and regional levels. Nonlinear developmental patterns were examined using penalized splines within a generalized additive model. Compared to TD, youth with persistent psychosis risk symptoms had lower whole-brain WM fractional anisotropy (FA) and higher radial diffusivity (RD). Voxelwise analyses revealed clusters of significant WM abnormalities within the temporal and parietal lobes. Lower FA within the cingulum bundle of hippocampus and cerebrospinal tracts were the most robust deficits in individuals with persistent psychosis symptoms. These findings were consistent over two visits. Thus, it appears that WM abnormalities are present early in youth with persistent psychosis risk symptoms, however, there is little evidence to suggest that these features emerge in late adolescence or early adulthood. Future studies should seek to characterize WM abnormalities in younger individuals and follow individuals as subthreshold psychotic symptoms emerge.

A Quantitative Meta-analysis of Olfactory Dysfunction in Epilepsy.

Olfactory dysfunction in epilepsy is well-documented in several olfactory domains. However, the clinical specificity of these deficits remains unknown. The aim of this systematic meta-analysis was to determine which domains of olfactory ability were most impaired in individuals with epilepsy, and to assess moderating factors affecting olfactory ability. Extant peer-reviewed literature on olfaction in epilepsy were identified via a computerized literature search using PubMed, MEDLINE, PsycInfo, and Google Scholar databases. Twenty-one articles met inclusion criteria. These studies included a total of 912 patients with epilepsy and 794 healthy comparison subjects. Included studies measured olfaction using tests of odor identification, discrimination, memory, and detection threshold in patients with different types of epilepsy, including temporal lobe epilepsy (TLE), mixed frontal epilepsy (M-F), and mixed epilepsy (MIX). Olfactory deficits were robust in patients with epilepsy when compared to healthy individuals, with effect sizes in the moderate to large range for several olfactory domains, including odor identification (d = -1.59), memory (d = -1.10), discrimination (d = -1.04), and detection threshold (d = -0.58). Olfactory deficits were most prominent in patients with TLE and M-F epilepsy. Amongst patients with epilepsy, sex, age, smoking status, education, handedness, and age of illness onset were significantly related to olfactory performance. Overall, these meta-analytic findings indicate that the olfactory system is compromised in epilepsy and suggest that detailed neurobiological investigations of the olfactory system may provide further insight into this disorder.

Social aversive conditioning in youth at clinical high risk for psychosis and with psychosis: An ERP study.

BACKGROUND: Social cognition and emotion processing are compromised in schizophrenia. Disruptions in these domains may also be present during the psychosis-risk state. Aversive conditioning is an established translational research paradigm to investigate affective reactivity and learning. Using an aversive conditioning ERP paradigm with social cues, we examined whether psychosis patients and at-risk youths differentially respond to aversively conditioned faces. METHODS: Participants (ages 10-30) were enrolled into three demographically-matched groups: clinical risk for psychosis (CR, n = 32), psychosis (PS, n = 26), and healthy control (HC, n = 33). EEGs were recorded during a delay aversive conditioning task in which three neutral faces were paired with an aversive tone at 100%, 50% and 0% contingencies. Analysis focused on group differences in ERP peaks representing visual processing (occipital P120), emotional valence (frontal VPP), and directed attention (parietal-occipital P300), for dimensions of aversiveness (100% vs. 0%) and unpredictability (50% vs. 100% + 0%). RESULTS: HC, but not CR or PS, showed increased P300 amplitude to aversive vs. non-aversive conditioned stimuli. CR, but not PS or HC, showed increased VPP amplitude to unpredictable vs. predictable stimuli. CONCLUSIONS: PS and CR both fail to allocate appropriate salience to social cues that are predictably aversive. CR, but not PS exhibit heightened emotional reactivity to social cues that are of uncertain salience. Clinical risk for schizophrenia may involve neural abnormalities distinct from both healthy and fully-established disease states.

Modular Segregation of Structural Brain Networks Supports the Development of Executive Function in Youth.

The human brain is organized into large-scale functional modules that have been shown to evolve in childhood and adolescence. However, it remains unknown whether the underlying white matter architecture is similarly refined during development, potentially allowing for improvements in executive function. In a sample of 882 participants (ages 8-22) who underwent diffusion imaging as part of the Philadelphia Neurodevelopmental Cohort, we demonstrate that structural network modules become more segregated with age, with weaker connections between modules and stronger connections within modules. Evolving modular topology facilitates global network efficiency and is driven by age-related strengthening of hub edges present both within and between modules. Critically, both modular segregation and network efficiency are associated with enhanced executive performance and mediate the improvement of executive functioning with age. Together, results delineate a process of structural network maturation that supports executive function in youth.