Replicability of structural brain alterations associated with general psychopathology: evidence from a population-representative birth cohort.

Transdiagnostic research has identified a general psychopathology factor-often called the 'p' factor-that accounts for shared variation across internalizing, externalizing, and thought disorders in diverse samples. It has been argued that the p factor may reflect dysfunctional thinking present in serious mental illness. In support of this, we previously used a theory-free, data-driven multimodal neuroimaging approach to find that higher p factor scores are associated with structural alterations within a cerebello-thalamo-cortical circuit (CTCC) and visual association cortex, both of which are important for monitoring and coordinating information processing in the service of executive control. Here we attempt to replicate these associations by conducting region-of-interest analyses using data from 875 members of the Dunedin Longitudinal Study, a five-decade study of a population-representative birth cohort, collected when they were 45 years old. We further sought to replicate a more recent report that p factor scores can be predicted by patterns of distributed cerebellar morphology as estimated through independent component analysis. We successfully replicated associations between higher p factor scores and both reduced gray matter volume of the visual association cortex and fractional anisotropy of pontine white matter pathways within the CTCC. In contrast, we failed to replicate prior associations between cerebellar structure and p factor scores. Collectively, our findings encourage further focus on the CTCC and visual association cortex as core neural substrates and potential biomarkers of general psychopathology.

Schizophrenia polygenic risk score predicts mnemonic hippocampal activity.

The use of polygenic risk scores has become a practical translational approach to investigating the complex genetic architecture of schizophrenia, but the link between polygenic risk scores and pathophysiological components of this disorder has been the subject of limited research. We investigated in healthy volunteers whether schizophrenia polygenic risk score predicts hippocampal activity during simple memory encoding, which has been proposed as a risk-associated intermediate phenotype of schizophrenia. We analysed the relationship between polygenic risk scores and hippocampal activity in a discovery sample of 191 unrelated healthy volunteers from the USA and in two independent replication samples of 76 and 137 healthy unrelated participants from Europe and the USA, respectively. Polygenic risk scores for each individual were calculated as the sum of the imputation probability of reference alleles weighted by the natural log of odds ratio from the recent schizophrenia genome-wide association study. We examined hippocampal activity during simple memory encoding of novel visual stimuli assessed using blood oxygen level-dependent functional MRI. Polygenic risk scores were significantly associated with hippocampal activity in the discovery sample [P = 0.016, family-wise error (FWE) corrected within Anatomical Automatic Labeling (AAL) bilateral hippocampal-parahippocampal mask] and in both replication samples (P = 0.033, FWE corrected within AAL right posterior hippocampal-parahippocampal mask in Bari sample, and P = 0.002 uncorrected in the Duke Neurogenetics Study sample). The relationship between polygenic risk scores and hippocampal activity was consistently negative, i.e. lower hippocampal activity in individuals with higher polygenic risk scores, consistent with previous studies reporting decreased hippocampal-parahippocampal activity during declarative memory tasks in patients with schizophrenia and in their healthy siblings. Polygenic risk scores accounted for more than 8% of variance in hippocampal activity during memory encoding in discovery sample. We conclude that polygenic risk scores derived from the most recent schizophrenia genome-wide association study predict significant variability in hippocampal activity during memory encoding in healthy participants. Our findings validate mnemonic hippocampal activity as a genetic risk associated intermediate phenotype of schizophrenia, indicating that the aggregate neurobiological effect of schizophrenia risk alleles converges on this pattern of neural activity.awy004media15749593779001.

The central role of disgust in disorders of food avoidance.

BACKGROUND: Individuals with extreme food avoidance such as Avoidant Restrictive Food Intake Disorder (ARFID) experience impairing physical and mental health consequences from nutrition of insufficient variety or/and quantity. Identifying mechanisms contributing to food avoidance is essential to develop effective interventions. Anxiety figures prominently in theoretical models of food avoidance; however, there is limited evidence that repeated exposures to foods increases approach behavior in ARFID. Studying disgust, and relationships between disgust and anxiety, may offer novel insights, as disgust is functionally associated with avoidance of contamination from pathogens (as may occur via ingestion) and is largely resistant to extinction. METHOD: This exploratory, cross-sectional study included data from 1,644 adults who completed an online questionnaire. Participant responses were used to measure ARFID classification, picky eating, sensory sensitivity, disgust, and anxiety. Structural equation modeling tested a measurement model of latent disgust and anxiety factors as measured by self-reported frequency of disgust and anxiety reactions. Mediational models were used to explore causal ordering. RESULTS: A latent disgust factor was more strongly related to severity of picky eating (B ≈ 0.4) and ARFID classification (B ≈ 0.6) than the latent anxiety factor (B ≈ 0.1). Disgust partially mediated the association between anxiety and picky eating and fully mediated the association between anxiety and ARFID. Models testing the reverse causal ordering demonstrated poorer fit. Findings suggest anxiety may be associated with food avoidance in part due to increased disgust. CONCLUSIONS: Disgust may play a prominent role in food avoidance. Findings may inform novel approaches to treatment.

Dopamine genetic risk is related to food addiction and body mass through reduced reward-related ventral striatum activity.

The prevalence rate of obesity continues to rise in the U.S., but effective treatment options remain elusive resulting in increased emphasis on prevention. One such area of prevention research capitalizes on the relatively novel behavioral construct of food addiction, which has been implicated in obesity. Food addiction reflects an individual's propensity for compulsive eating despite negative consequences, and shares not only symptoms with both eating and substance use disorders but also genetic and neural correlates within neural reward-circuitry modulated by dopamine. Here, we examined associations between food addiction scores, body mass index (BMI), reward-related ventral striatum activity, and a polygenic score approximating dopamine signaling in 115 non-Hispanic Caucasian young adult university students. As predicted, polygenic dopamine scores were related to ventral striatum activity, which in turn was associated with higher food addiction scores. In addition, food addiction was related to BMI. An exploratory post-hoc path analysis further indicated that polygenic scores were indirectly related to both food addiction and BMI, in part, through ventral striatum activity. Collectively, our results provide evidence supporting the utility of food addiction in weight gain prevention research by establishing links with known risk-related neural and genetic biomarkers.

Are rash impulsive and reward sensitive traits distinguishable? A test in young adults.

Adolescents and young adults are characterized as prone to risky behavior with a wide range of traits identified as predictors of individual differences in this behavior. Here we test a crucial difference between traits that reflect rash impulsivity, the tendency to engage in risky behavior without consideration of consequences, versus reward sensitivity, the tendency to be attracted to novel and rewarding experience. To test the validity of this distinction, we examined the factorial structure of eight risk-related traits in a sample of 899 18 to 22 year-olds. We predicted that rash impulsive traits would be separable in structure from reward sensitive traits and would uniquely predict relatively maladaptive risk-taking (e.g., drug use). In addition, we predicted that reward sensitive traits would be related to both adaptive (e.g., entering competitions) and maladaptive risk behaviors. Results revealed a factorial structure that distinguished these traits, with rash impulsive and reward sensitive traits uniquely predictive of different forms of risk-taking. The results suggest that it is possible to distinguish traits that reflect these two forms of risk-taking with implications for the measurement and interpretation of risk propensities in youth.

Neural activation during anticipated peer evaluation and laboratory meal intake in overweight girls with and without loss of control eating.

The interpersonal model of loss of control (LOC) eating proposes that socially distressing situations lead to anxious states that trigger excessive food consumption. Self-reports support these links, but the neurobiological underpinnings of these relationships remain unclear. We therefore examined brain regions associated with anxiety in relation to LOC eating and energy intake in the laboratory. Twenty-two overweight and obese (BMIz: 1.9±0.4) adolescent (15.8±1.6y) girls with LOC eating (LOC+, n=10) and without LOC eating (LOC-, n=12) underwent functional magnetic resonance imaging (fMRI) during a simulated peer interaction chatroom paradigm. Immediately after the fMRI scan, girls consumed lunch ad libitum from a 10,934-kcal laboratory buffet meal with the instruction to "let yourself go and eat as much as you want." Pre-specified hypotheses regarding activation of five regions of interest were tested. Analysis of fMRI data revealed a significant group by peer feedback interaction in the ventromedial prefrontal cortex (vmPFC), such that LOC+ had less activity following peer rejection (vs. acceptance), while LOC- had increased activity (p<.005). Moreover, functional coupling between vmPFC and striatum for peer rejection (vs. acceptance) interacted with LOC status: coupling was positive for LOC+, but negative in LOC- (p<.005). Activity of fusiform face area (FFA) during negative peer feedback from high-value peers also interacted with LOC status (p<.005). A positive association between FFA activation and intake during the meal was observed among only those with LOC eating. In conclusion, overweight and obese girls with LOC eating may be distinguished by a failure to engage regions of prefrontal cortex implicated in emotion regulation in response to social distress. The relationship between FFA activation and food intake supports the notion that heightened sensitivity to incoming interpersonal cues and perturbations in socio-emotional neural circuits may lead to overeating in order to cope with negative affect elicited by social discomfort in susceptible youth.

Brain Structure Relations With Psychopathology Trajectories in the ABCD Study.

OBJECTIVE: A general psychopathology (p) factor captures shared variation across mental disorders. Structural neural alterations have been associated with the p factor concurrently, but less is known about whether these alterations relate to within-person change in the p factor over time, especially during preadolescence, a period of neurodevelopmental changes. METHOD: This study examined whether baseline brain structure was prospectively related to the trajectory of the p factor and specific forms of psychopathology over 2 years in 9,220 preadolescents (aged 9-10 at baseline) from the Adolescent Brain Cognitive Development Study (ABCD). Longitudinal multilevel models were conducted to determine whether baseline brain structure (volume, surface area, thickness) was associated with between-person differences and within-person change in the p factor (from a higher-order confirmatory factor model) and internalizing, externalizing, neurodevelopmental, somatization, and detachment factor scores (from a correlated factors model) over 3 study waves. RESULTS: Smaller global volume and surface area, but not thickness, were associated with higher between-person levels of the p factor scores, which persisted over time. None of the brain structure measures were related to within-person change in the p factor scores. Lower baseline cortical thickness was associated with steeper decreases in internalizing psychopathology, which was driven by lower thickness within sensorimotor and temporal regions. CONCLUSION: These novel results identify specific brain structure features that might contribute to transdiagnostic psychopathology development in preadolescence. Children with smaller total brain volume and surface area may be vulnerable to persistent general psychopathology during preadolescence. Cortical thinning reflective of pruning and myelination in sensorimotor and temporal brain regions specifically may protect against increases in internalizing, but not general psychopathology, during preadolescence.

Associations between Brain Structural Alterations, Executive Dysfunction, and General Psychopathology in a Healthy and Cross-Diagnostic Adult Patient Sample.

BACKGROUND: A general psychopathology 'p' factor captures shared variance across mental disorders in diverse samples and may partly reflect executive dysfunction. Higher p factor scores have been related to structural alterations within the visual association cortex (VAC) and a cerebello-thalamo-cerebrocortical circuit (CTCC), both of which are important for executive control. Here, we tested replicability of these direct associations as well as the indirect role of executive functioning in a sample of healthy and cross-diagnostic adult patients. METHODS: We conducted hypothesis-driven (i.e., region-of-interest) and exploratory whole-brain structural neuroimaging analyses using data from the Consortium for Neuropsychiatric Phenomics study of 272 adults who met diagnostic criteria for schizophrenia, bipolar disorder, or attention deficit-hyperactivity disorder or were healthy controls. Using structural equation modeling, we examined direct and indirect relations between structural neural alterations (within regions-of-interest and regions identified from exploratory analyses) and p and executive function factors. RESULTS: Higher levels of p were associated with decreased executive functioning and VAC grey matter volume, replicating previous research. In contrast, we failed to replicate prior negative relations between the p factor and CTCC structure. A significant indirect relation between VAC grey matter volume and p via executive function also emerged. Whole-brain analyses identified additional structural alterations in supplementary motor area/cingulate cortex, anterior corona radiata, and corpus callosum genu related to the p factor. CONCLUSIONS: Executive dysfunction may be one mechanism underlying relations between brain structure and general psychopathology. Replication of VAC structural alterations related to p encourages further focus on this brain structure.

Child executive function and future externalizing and internalizing problems: A meta-analysis of prospective longitudinal studies.

To determine the association between executive function and later externalizing and internalizing problems, we conducted a meta-analysis of 167 studies (1098 effect sizes, total N = 66,119) that explored the longitudinal associations between executive functions in children and subsequent externalizing and internalizing problems. The results indicated that greater child executive function was prospectively associated with fewer attention-deficit/hyperactivity disorder (ADHD) symptoms, fewer conduct problems, fewer oppositional defiant disorder symptoms, less substance use, fewer broad externalizing problems, fewer depression symptoms, and fewer broad internalizing problems, but not with subsequent anxiety symptoms. Moderator analyses revealed that the sample type moderated the associations of executive function with both ADHD symptoms and conduct problems. Age of assessment moderated the association with broad externalizing problems, and executive function context moderated associations with both substance use and broad internalizing problems. These findings suggest that executive function in children prospectively predicts numerous externalizing and internalizing behaviors, suggesting that executive function may be an important target for psychopathology prevention programs and interventions.

Is executive dysfunction a risk marker or consequence of psychopathology? A test of executive function as a prospective predictor and outcome of general psychopathology in the adolescent brain cognitive development study®.

A general psychopathology ('p') factor captures shared variation across mental disorders. One hypothesis is that poor executive function (EF) contributes to p. Although EF is related to p concurrently, it is unclear whether EF predicts or is a consequence of p. For the first time, we examined prospective relations between EF and p in 9845 preadolescents (aged 9-12) from the Adolescent Brain Cognitive Development Study® longitudinally over two years. We identified higher-order factor models of psychopathology at baseline and one- and two-year follow-up waves. Consistent with previous research, a cross-sectional inverse relationship between EF and p emerged. Using residualized-change models, baseline EF prospectively predicted p factor scores two years later, controlling for prior p, sex, age, race/ethnicity, parental education, and family income. Baseline p factor scores also prospectively predicted change in EF two years later. Tests of specificity revealed that bi-directional prospective relations between EF and p were largely generalizable across externalizing, internalizing, neurodevelopmental, somatization, and detachment symptoms. EF consistently predicted change in externalizing and neurodevelopmental symptoms. These novel results suggest that executive dysfunction is both a risk marker and consequence of general psychopathology. EF may be a promising transdiagnostic intervention target to prevent the onset and maintenance of psychopathology.

Regulatory focus and the p factor: Evidence for self-regulatory dysfunction as a transdiagnostic feature of general psychopathology.

A general psychopathology ('p') factor captures transdiagnostic features of mental illness; however, the meaning of the p factor remains unclear. Regulatory focus theory postulates that individuals regulate goal pursuit either by maximizing gains (promotion) or minimizing losses (prevention). As maladaptive goal pursuit has been associated with multiple categorical disorders, we examined whether individual differences in promotion and prevention goal pursuit are associated with p as well as internalizing- and externalizing-specific factors using structural equation modeling of data from 1330 volunteers aged 18-22. Unsuccessful attainment of promotion and prevention goals was related to increased levels of p. Over and above relations with the p factor, unsuccessful attainment of promotion goals was associated with higher internalizing-specific psychopathology, whereas unsuccessful attainment of prevention goals was related to higher externalizing-specific psychopathology. These associations also were separable from related personality traits. After controlling for sex differences in the composition of the psychopathology factors, there were no sex differences in the relations between promotion and prevention goal pursuit and p and specific internalizing and externalizing factors. These findings suggest higher general psychopathology reflects poorer overall self-regulation of goal pursuit and that maladaptive promotion and prevention orientations also are associated with internalizing- and externalizing-specific psychopathology, respectively.

Pervasively Thinner Neocortex as a Transdiagnostic Feature of General Psychopathology.

OBJECTIVE: Neuroimaging research has revealed that structural brain alterations are common across broad diagnostic families of disorders rather than specific to a single psychiatric disorder. Such overlap in the structural brain correlates of mental disorders mirrors already well-documented phenotypic comorbidity of psychiatric symptoms and diagnoses, which can be indexed by a general psychopathology or p factor. The authors hypothesized that if general psychopathology drives the convergence of structural alterations common across disorders, then 1) there should be few associations unique to any one diagnostic family of disorders, and 2) associations with the p factor should overlap with those for the broader diagnostic families. METHODS: Analyses were conducted on structural MRI and psychopathology data collected from 861 members of the population-representative Dunedin Multidisciplinary Health and Development Study at age 45. RESULTS: Study members with high scores across three broad diagnostic families of disorders (externalizing, internalizing, thought disorder) exhibited highly overlapping patterns of reduced global and widely distributed parcel-wise neocortical thickness. Study members with high p factor scores exhibited patterns of reduced global and parcel-wise neocortical thickness nearly identical to those associated with the three broad diagnostic families. CONCLUSIONS: A pattern of pervasively reduced neocortical thickness appears to be common across all forms of mental disorders and may represent a transdiagnostic feature of general psychopathology. As has been documented with regard to symptoms and diagnoses, the underlying brain structural correlates of mental disorders may not exhibit specificity, and the continued pursuit of such specific correlates may limit progress toward more effective strategies for etiological understanding, prevention, and intervention.

Vitamin D polygenic score is associated with neuroticism and the general psychopathology factor.

Vitamin D, used here to refer to both 25-hydroxyvitamin D, the main circulating form of the vitamin, and 1,25-hydroxyvitamin D, the biologically active form, has been shown to influence brain development and function. Consistent with these findings, low levels of vitamin D have been implicated in various mental disorders, including depression, schizophrenia, and autism. Recently, a shared variance across multiple categories of mental health disorders has been identified and shown to be genetically influenced. This shared variance, thought to represent a general risk for psychopathology, has been termed the p factor. Individuals with high p factor scores are characterized by high neuroticism and low agreeableness and conscientiousness. Here, we investigated the links between vitamin D polygenic scores - derived from the latest genome-wide association study of circulating vitamin D (25-hydroxyvitamin D) levels - the Big Five personality traits (neuroticism, agreeableness, conscientiousness, openness-to-experience, and extraversion), and the p factor, in a sample of 522 (278 women, mean age 20 ± 1 years) non-Hispanic Caucasians. Vitamin D polygenic scores were significantly and negatively associated with neuroticism and the p factor, even after correcting for multiple comparisons, and controlling for sex, age, ancestry, socioeconomic status, and body mass index. Based on previous research implicating neuroticism as a risk factor for psychopathology, mediation was tested. Results showed a significant indirect effect from the vitamin D polygenic score to the p factor via neuroticism. Our findings support a genetic link between vitamin D levels, neuroticism, and the p factor, but due to the cross-sectional nature of our data, future studies are needed to clarify the causal associations between these phenotypes.

Paradoxical associations between familial affective responsiveness, stress, and amygdala reactivity.

Studies of early life extremes such as trauma, abuse, and neglect highlight the critical importance of quality caregiving in the development of brain circuits supporting emotional behavior and mental health. The impact of normative variability in caregiving on such biobehavioral processes, however, is poorly understood. Here, we provide initial evidence that even subtle variability in normative caregiving maps onto individual differences in threat-related brain function and, potentially, associated psychopathology in adolescence. Specifically, we report that greater familial affective responsiveness is associated with heightened amygdala reactivity to interpersonal threat, particularly in adolescents having experienced relatively low recent stress. These findings extend the literature on the effects of caregiving extremes on brain function to subtle, normative variability but suggest that presumably protective factors may be associated with increased risk-related amygdala reactivity. We consider these paradoxical associations with regard to studies of basic associative threat learning and further consider their relevance for understanding potential effects of caregiving on psychological development. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Forgetting the best when predicting the worst: Preliminary observations on neural circuit function in adolescent social anxiety.

Social anxiety disorder typically begins in adolescence, a sensitive period for brain development, when increased complexity and salience of peer relationships requires novel forms of social learning. Disordered social learning in adolescence may explain how brain dysfunction promotes social anxiety. Socially anxious adolescents (n = 15) and adults (n = 19) and non-anxious adolescents (n = 24) and adults (n = 32) predicted, then received, social feedback from high and low-value peers while undergoing functional magnetic resonance imaging (fMRI). A surprise recall task assessed memory biases for feedback. Neural correlates of social evaluation prediction errors (PEs) were assessed by comparing engagement to expected and unexpected positive and negative feedback. For socially anxious adolescents, but not adults or healthy participants of either age group, PEs elicited heightened striatal activity and negative fronto-striatal functional connectivity. This occurred selectively to unexpected positive feedback from high-value peers and corresponded with impaired memory for social feedback. While impaired memory also occurred in socially-anxious adults, this impairment was unrelated to brain-based PE activity. Thus, social anxiety in adolescence may relate to altered neural correlates of PEs that contribute to impaired learning about social feedback. Small samples necessitate replication. Nevertheless, results suggest that the relationship between learning and fronto-striatal function may attenuate as development progresses.