Abstract Background and Hypotheses Impaired executive control is a potential prognostic and endophenotypic marker of schizophrenia (SZ) and bipolar disorder (BP). Assessing children with familial high-risk (FHR) of SZ or BP enables characterization of early risk markers and we hypothesize that they express impaired executive control as well as aberrant brain activation compared to population-based control (PBC) children. Study Design Using a flanker task, we examined executive control together with functional magnetic resonance imaging (fMRI) in 11- to 12-year-old children with FHR of SZ (FHR-SZ) or FHR of BP (FHR-BP) and PBC children as part of a register-based, prospective cohort-study; The Danish High Risk and Resilience study—VIA 11. Study Results We included 85 (44% female) FHR-SZ, 63 (52% female) FHR-BP and 98 (50% female) PBC in the analyses. Executive control effects, caused by the spatial visuomotor conflict, showed no differences between groups. Bayesian ANOVA of reaction time (RT) variability, quantified by the coefficient of variation (CVRT), revealed a group effect with similarly higher CVRT in FHR-BP and FHR-SZ compared to PBC (BF10 = 6.82). The fMRI analyses revealed no evidence for between-group differences in task-related brain activation. Post hoc analyses excluding children with psychiatric illness yielded same results. Conclusion FHR-SZ and FHR-BP at age 11–12 show intact ability to resolve a spatial visuomotor conflict and neural efficacy. The increased variability in RT may reflect difficulties in maintaining sustained attention. Since variability in RT was independent of existing psychiatric illness, it may reflect a potential endophenotypic marker of risk.
Abstract The diagnostic criteria for schizophrenia comprise a diverse range of heterogeneous symptoms. As a result, individuals each present a distinct set of symptoms despite having the same overall diagnosis. Whilst previous machine learning studies have primarily focused on dichotomous patient‐control classification, we predict the severity of each individual symptom on a continuum. We applied machine learning regression within a multi‐modal fusion framework to fMRI and behavioural data acquired during an auditory oddball task in 80 schizophrenia patients. Brain activity was highly predictive of some, but not all symptoms, namely hallucinations, avolition, anhedonia and attention. Critically, each of these symptoms was associated with specific functional alterations across different brain regions. We also found that modelling symptoms as an ensemble of subscales was more accurate, specific and informative than models which predict compound scores directly. In principle, this approach is transferrable to any psychiatric condition or multi‐dimensional diagnosis.
Schizophrenia and bipolar disorder are characterized by social cognitive impairments and recent research has identified alterations of the social brain. However, it is unknown whether familial high-risk of these disorders is associated with neurobiological alterations already present in childhood. As part of The Danish High Risk and Resilience Study – VIA 11, we examined children at familial high-risk of schizophrenia (FHR-SZ, n = 121, 50% females) or bipolar disorder (FHR-BP, n = 75, 47% females) and population-based controls (PBC, n = 128, 48% females). Using functional magnetic resonance imaging and dynamic causal modeling, we investigated brain activation and effective connectivity during the social cognition paradigm from the Human Connectome Project. We found similar activation of the mentalizing network across groups, including visual area V5, dorsomedial prefrontal cortex (dmPFC), and posterior superior temporal sulcus (pSTS). Nonetheless, both familial high-risk groups showed aberrant brain connectivity in the form of increased feedforward connectivity from left V5 to pSTS compared with PBC. Children at FHR-SZ had reduced intrinsic connectivity in bilateral V5 relative to PBC, whereas children at FHR-BP showed increased reciprocal connectivity between left dmPFC and pSTS, increased intrinsic connectivity in right pSTS, and reduced feedforward connectivity from right pSTS to dmPFC compared with PBC. Our results provide first-time evidence of aberrant brain connectivity in the mentalizing network of children at FHR-SZ or FHR-BP. Longitudinal research is warranted to clarify whether aberrant brain connectivity during mentalizing constitutes an endophenotype associated with the development of a mental disorder later in life.
Children, adolescents, and young adults with at least one first-degree relative [familial high-risk (FHR)] with either schizophrenia (SZ) or bipolar disorder (BD) have a one-in-two risk of developing a psychiatric disorder. Here, we review functional magnetic resonance imaging (fMRI) studies which examined task-related brain activity in young individuals with FHR-SZ and FHR-BD. A systematic search identified all published task-related fMRI studies in children, adolescents, and young adults below an age of 27 years with a first-degree relative with SZ or BD, but without manifest psychotic or affective spectrum disorder themselves. The search identified 19 cross-sectional fMRI studies covering four main cognitive domains: 1) working memory (n = 3), 2) cognitive control (n = 4), 3) reward processing (n = 3), and 4) emotion processing (n = 9). Thirteen studies included FHR-BD, five studies included FHR-SZ, and one study included a pooled FHR group. In general, task performance did not differ between the respective FHR groups and healthy controls, but 18 out of the 19 fMRI studies revealed regional alterations in task-related activation. Brain regions showing group differences in peak activation were regions associated with the respective task domain and showed little overlap between FHR-SZ and FHR-BD. The low number of studies, together with the low number of subjects, and the substantial heterogeneity of employed methodological approaches within the domain of working memory, cognitive control, and reward processing impedes finite conclusions. Emotion processing was the most investigated task domain in FHR-BD. Four studies reported differences in activation of the amygdala, and two studies reported differences in activation of inferior frontal/middle gyrus. Together, these studies provide evidence for altered brain processing of emotions in children, adolescents, and young adults at FHR-BD. More studies of higher homogeneity, larger sample sizes and with a longitudinal study design are warranted to prove a shared or specific FHR-related endophenotypic brain activation in young first-degree relatives of individuals with SZ or BD, as well as to pinpoint specific alterations in brain activation during cognitive-, emotional-, and reward-related tasks.
Abstract Previous studies applying machine learning methods to psychosis have primarily been concerned with the binary classification of chronic schizophrenia patients and healthy controls. The aim of this study was to use electroencephalographic (EEG) data and pattern recognition to predict subclinical psychotic-like experiences on a continuum between these two extremes in otherwise healthy people. We applied two different approaches to an auditory oddball regularity learning task obtained from N = 73 participants: A feature extraction and selection routine incorporating behavioural measures, event-related potential components and effective connectivity parameters; Regularisation of spatiotemporal maps of event-related potentials. Using the latter approach, optimal performance was achieved using the response to frequent, predictable sounds. Features within the P50 and P200 time windows had the greatest contribution toward lower Prodromal Questionnaire (PQ) scores and the N100 time window contributed most to higher PQ scores. As a proof-of-concept, these findings demonstrate that EEG data alone are predictive of individual psychotic-like experiences in healthy people. Our findings are in keeping with the mounting evidence for altered sensory responses in schizophrenia, as well as the notion that psychosis may exist on a continuum expanding into the non-clinical population.
Children born to parents with severe mental illness have gained more attention during the last decades because of increasing evidence documenting that these children constitute a population with an increased risk of developing mental illness and other negative life outcomes. Because of high-quality research with cohorts of offspring with familial risk and increased knowledge about gene-environment interactions, early interventions and preventive strategies are now being developed all over the world. Adolescence is a period characterized by massive changes, both in terms of physical, neurologic, psychological, social, and behavioral aspects. It is also the period of life with the highest risk of experiencing onset of a mental disorder. Therefore, investigating the impact of various risk and resilience factors in adolescence is important.The Danish High-Risk and Resilience Study started data collection in 2012, where 522 7-year-old children were enrolled in the first wave of the study, the VIA 7 study. The cohort was identified through Danish registers based on diagnoses of the parents. A total of 202 children had a parent diagnosed with schizophrenia, 120 children had a parent diagnosed with bipolar disorder, and 200 children had parents without these diagnoses. At age 11 years, all children were assessed for the second time in the VIA 11 study, with a follow-up retention rate of 89%. A comprehensive assessment battery covering domains of psychopathology, neurocognition, social cognition and behavior, motor development and physical health, genetic analyses, attachment, stress, parental functioning, and home environment was carried out at each wave. Magnetic resonance imaging scans of the brain and electroencephalograms were included from age 11 years. This study protocol describes the third wave of assessment, the VIA 15 study, participants being 15 years of age and the full, 3-day-long assessment battery this time including also risk behavior, magnetoencephalography, sleep, and a white noise paradigm. Data collection started on May 1, 2021.We will discuss the importance of longitudinal studies and cross-sectional data collection and how studies like this may inform us about unmet needs and windows of opportunity for future preventive interventions, early illness identification, and treatment in the future.
