The Danish High Risk and Resilience Study-VIA 11: Study Protocol for the First Follow-Up of the VIA 7 Cohort -522 Children Born to Parents With Schizophrenia Spectrum Disorders or Bipolar Disorder and Controls Being Re-examined for the First Time at Age 11.

Introduction: Offspring of parents with severe mental illness have an increased risk of developing mental illnesses themselves. Familial high risk cohorts give a unique opportunity for studying the development over time, both the illness that the individual is predisposed for and any other diagnoses. These studies can also increase our knowledge of etiology of severe mental illness and provide knowledge about the underlying mechanisms before illness develops. Interventions targeting this group are often proposed due to the potential possibility of prevention, but evidence about timing and content is lacking. Method: A large, representative cohort of 522 7-year old children born to parents with schizophrenia, bipolar disorder or controls was established based on Danish registers. A comprehensive baseline assessment including neurocognition, motor functioning, psychopathology, home environment, sociodemographic data, and genetic information was conducted from January 1, 2013 to January 31, 2016. This study is the first follow-up of the cohort, carried out when the children turn 11 years of age. By assessing the cohort at this age, we will evaluate the children twice before puberty. All instruments have been selected with a longitudinal perspective and most of them are identical to those used at inclusion into the study at age 7. A diagnostic interview, motor tests, and a large cognitive battery are conducted along with home visits and information from teachers. This time we examine the children's brains by magnetic resonance scans and electroencephalograms. Measures of physical activity and sleep are captured by a chip placed on the body, while we obtain biological assays by collecting blood samples from the children. Discussion: Findings from the VIA 7 study revealed large variations across domains between children born to parents with schizophrenia, bipolar and controls, respectively. This study will further determine whether the children at familial risk reveal delayed developmental courses, but catch up at age 11, or whether the discrepancies between the groups have grown even larger. We will compare subgroups within each of the familial high risk groups in order to investigate aspects of resilience. Data on brain structure and physical parameters will add a neurobiological dimension to the study

Children at Familial High risk of Schizophrenia and Bipolar Disorder Exhibit Altered Connectivity Patterns During Pre-attentive Processing of an Auditory Prediction Error.

Individuals with schizophrenia or bipolar disorder have attenuated auditory mismatch negativity (MMN) responses, indicating impaired sensory information processing. Computational models of effective connectivity between brain areas underlying MMN responses show reduced connectivity between fronto-temporal areas in individuals with schizophrenia. Here we ask whether children at familial high risk (FHR) of developing a serious mental disorder show similar alterations. We recruited 67 children at FHR for schizophrenia, 47 children at FHR for bipolar disorder as well as 59 matched population-based controls from the Danish High Risk and Resilience study. The 11-12-year-old participants engaged in a classical auditory MMN paradigm with deviations in frequency, duration, or frequency and duration, while we recorded their EEG. We used dynamic causal modeling (DCM) to infer on the effective connectivity between brain areas underlying MMN. DCM yielded strong evidence for differences in effective connectivity among groups in connections from right inferior frontal gyrus (IFG) to right superior temporal gyrus (STG), along with differences in intrinsic connectivity within primary auditory cortex (A1). Critically, the 2 high-risk groups differed in intrinsic connectivity in left STG and IFG as well as effective connectivity from right A1 to right STG. Results persisted even when controlling for past or present psychiatric diagnoses. We provide novel evidence that connectivity underlying MMN responses in children at FHR for schizophrenia and bipolar disorder is altered at the age of 11-12, echoing findings that have been found in individuals with manifest schizophrenia

Psychotic experiences in seven-year-old children with familial high risk of schizophrenia or bipolar disorder in: The Danish High Risk and Resilience Study - VIA 7; A population-based cohort study.

We aimed to examine the prevalence of psychotic experiences (PEs) in children with familial high risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) and, in exploratory analyses, to examine the possible associations between PEs and mental disorders as well as level of functioning. A cohort of seven-year-old children with FHR-SZ (N = 199), FHR-BP (N = 118) and controls (N = 196) was recruited through Danish nationwide registers. Lifetime PEs were assessed through interviews using the psychosis section of the 'Schedule for Affective Disorders and Schizophrenia for School-Age Children - Present and Lifetime Version' (K-SADS-PL). Lifetime DSM-IV diagnoses were ascertained through K-SADS-PL and the level of functioning of the children through 'Children's Global Assessment Scale'. Both children with FHR-SZ (OR = 2.9, 95% CI = 1.4-6.2, p = 0.005) and FHR-BP (OR = 2.9, 95% CI = 1.3-6.7, p = 0.011) had an increased risk of having experienced "severe" PEs compared with controls. In the overall cohort PEs were associated with any lifetime mental disorder, Attention-Deficit/Hyperactivity Disorder, anxiety disorders and a lower level of functioning. The findings of a higher proportion of high risk children reporting PEs could represent an early manifestation of later more severe psychopathology or simply an unspecific transitory symptom. Future follow-up studies of this cohort will explore the predictive value of the occurrence of PEs at age seven

Heterogeneity of social cognitive and language functions in children at familial high-risk of severe mental illness; The Danish High Risk and Resilience Study VIA 7.

Cognitive heterogeneity characterizes individuals with schizophrenia and bipolar disorder; however, little is known of cognitive heterogeneity within young children at familial high-risk of schizophrenia or bipolar disorder. This study aimed to investigate heterogeneity across social cognitive and language functions in children at familial high-risk of schizophrenia or bipolar disorder, i.e. severe mental illness (FHR-SMI). This may help designate subgroups in need of intervention initiatives. A data-driven, hierarchical cluster analysis was applied across a sample of 322 children at FHR-SMI (FHR-SZ, n = 200; FHR-BP, n = 120) on measures of Theory of Mind, facial emotion recognition, social cognitive processing speed, receptive and pragmatic language. We examined differences between subgroups as well as differences between subgroups and a control group. Exploratively, the subgroups were compared in terms of social responsiveness and global functioning. A Typical-High Functioning Subgroup with intact social cognitive and language functioning (34.5%), a Mildly Impaired Subgroup with selective impairments in explicit Theory of Mind and language functioning (58.7%), and a Significantly Impaired Subgroup with social cognitive and language functioning impairments (6.8%) were identified. The subgroups differed significantly from each other and overall compares to the controls. The Significantly and Mildly Impaired Subgroups presented with poorer social responsiveness and global functioning than the Typical-High Functioning Subgroup. In young children with FHR-SMI, three subgroups with relatively homogeneous social cognitive and language functioning profiles were observed. Only a small proportion of children at FHR-SMI displayed large social cognitive and language functioning impairments in middle childhood

Affective lability in parents with schizophrenia or bipolar disorder and their co-parents - The Danish High Risk and Resilience Study VIA 7.

In bipolar disorder, dysregulation of affect is a core feature while knowledge on affective lability in schizophrenia is sparse. Research on affective lability in partners to individuals with schizophrenia or bipolar disorder is also lacking. The objective of this study was to investigate affective lability in parents with schizophrenia or bipolar disorder, and their co-parents without these disorders. The Danish High Risk and Resilience Study - VIA 7 is a population-based cohort study. This study focuses on parents diagnosed with schizophrenia (n = 148), their co-parents (n = 157), parents with bipolar disorder (n = 98), their co-parents (n = 89) and control parents (n = 359). The Affective Lability Scale - short form (ALS-SF) was used to measure affective lability. We found significantly higher levels of affective lability in parents with schizophrenia and bipolar disorder compared with controls, but no significant differences between bipolar disorder and schizophrenia. Co-parents to parents with schizophrenia had significantly higher levels of affective lability compared to controls. Our results add to the existing knowledge concerning underlying transdiagnostic factors and nonrandom mating in schizophrenia and bipolar disorder and highlight the need for studies of parental affective lability as a potential risk factor for offspring in families with parental schizophrenia or bipolar disorder

Neurocognitive heterogeneity in 7-year-old children at familial high risk of schizophrenia or bipolar disorder: The Danish high risk and resilience study - VIA 7.

Studies of neurocognitive heterogeneity in young children at familial high-risk of bipolar disorder (FHR-BP) or schizophrenia (FHR-SZ) are important to investigate inter-individual neurocognitive differences. We aimed to identify neurocognitive subgroups, describe prevalence of FHR-BP or FHR-SZ children herein, and examine risk ratios (RR) compared with controls. In a population-based cohort of 514 7-year-old children (197 FHR-SZ, 118 FHR-BP, and 199 matched controls) we used hierarchical cluster analyses to identify subgroups across 14 neurocognitive indices. Three neurocognitive subgroups were derived: A Mildly Impaired (30%), Typical (51%), and Above Average subgroup (19%). The Mildly Impaired subgroup significantly underperformed controls (Cohen d = 0.11-1.45; Ps < 0.001) except in set-shifting (P = .84). FHR-SZ children were significantly more prevalent in the Mildly Impaired subgroup; FHR-BP children were more so in the Above Average subgroup (X <sup>2</sup> (2, N = 315) = 9.64, P < .01). 79.7% FHR-BP and 64.6% FHR-SZ children demonstrated typical or above average neurocognitive functions. Neurocognitive heterogeneity related significantly to concurrent functioning, psychopathology severity, home environment adequacy, and polygenic scores for schizophrenia (Ps <. 01). Compared with controls, FHR-SZ and FHR-BP children had a 93% (RR, 1.93; 95% CI, 1.40-2.64) and 8% (RR, 1.08; 95% CI, 0.71-1.66) increased risk of Mildly Impaired subgroup membership. Limitations include the cross-sectional design and smaller FHR-BP sample size. Identification of neurocognitive heterogeneity in preadolescent children at FHR-BP or FHR-SZ may ease stigma and enable pre-emptive interventions to enhance neurocognitive functioning and resilience to mental illness in the impaired sub-population

The Strengths and Difficulties Questionnaire Is of Clinical Significance Regarding Emotional and Behavioral Problems in 7-Year-Old Children With Familial Risk of Schizophrenia or Bipolar Disorder and Population-Based Controls the Danish High Risk and Resilience Study-VIA 7; A Population-Based Cohort Study.

Children born to parents with severe mental illness are at increased risk of mental and behavioral difficulties during childhood. We aimed to investigate the occurrence of clinically significant behavioral difficulties in 7-year-old children of parents diagnosed with schizophrenia or bipolar disorder as well as in control children by using the Strengths and Difficulties Questionnaire (SDQ). Further, we aimed to determine if the SDQ could function as a screening instrument for clinically relevant behavioral problems of children at high risk of these severe mental illnesses. By means of the Danish National Registers, we established a cohort of 522 7-year old children stratified by familial high risk for schizophrenia spectrum disorder (N = 202), bipolar disorder (N =120), and controls (N = 200). The child's primary caregiver completed the SDQ parent version and the Child Behavior Checklist (CBCL) while the schoolteacher completed the SDQ teacher version and the CBCL teacher equivalent; the Teachers Report Form (TRF). Finally, global functioning was assessed with the Children's Global Assessment Scale (CGAS). Children with familial high risk of schizophrenia spectrum disorder or bipolar disorder have a significantly increased risk (OR = 3.8 and 2.3) of suffering clinically significant behavioral difficulties at age 7-years according to SDQ parent ratings. The SDQ discriminates with moderate to high sensitivity and high specificity between familial high-risk children with and without a psychiatric diagnosis and has overall compelling discriminatory abilities in line with the more time consuming CBCL/TRF.Conclusions Familial high-risk children have more behavioral difficulties and more frequently at a level indicative of mental illness compared to control children as measured by the SDQ. The SDQ works well as a screening instrument for clinically relevant behavioral problems in high-risk children

Quality of life and self-esteem in 7-year-old children with familial high risk of schizophrenia or bipolar disorder: the Danish High Risk and Resilience Study-VIA 7-a population-based cohort study.

It is well established that children with familial high risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) have a higher risk of developing mental disorders, however, little is known of to what degree the genetic and environmental vulnerabilities affect the quality of life and self-esteem of these children. We aimed to compare the quality of life and self-esteem between children with FHR-SZ or FHR-BP and controls. We used Danish nationwide registers to retrieve a cohort of 522 7-year-old children with FHR-SZ or FHR-BP and controls. Quality of life was assessed with the 'Health-related Quality of Life Screening Instrument', KIDSCREEN-27, and the scale 'Social Acceptance (Bullying)' from the KIDSCREEN-52. Self-esteem was assessed with the self-report scale 'I think I am'. Assessors were blind to familial risk status of the children. Children with FHR-SZ displayed lower levels of the general quality of life, as well as lower scores on the 'Psychological Well-being' scale and the 'School Environment' scale of the KIDSCREEN-27 compared with controls. Both children with FHR-SZ and FHR-BP reported more bullying victimization compared with controls. Children with FHR-SZ reported lower self-esteem on the total scale of 'I think I am', as well as on the 'Skills and talents', the 'Psychological well-being', and the 'Relationships with others' subscales compared with controls. The findings of lower quality of life and self-esteem in children with FHR-SZ together with more bullying victimization in both familial high-risk groups call for studies on low risk, early intervention strategies towards this group of vulnerable children

Executive functions in 7-year-old children of parents with schizophrenia or bipolar disorder compared with controls: The Danish High Risk and Resilience Study-VIA 7, a population-based cohort study.

Cognitive impairments are strongly associated with schizophrenia (SZ) and bipolar disorder (BP) with executive functions (EF) impairments as a likely key feature. Studies of everyday behavior rated EF in young children at familial high risk of SZ (FHR-SZ) are scarce and, to our knowledge, non-existent in young children at familial high risk of BP (FHR-BP). We aimed to compare everyday behavior-rated EF of FHR-SZ, FHR-BP, and control children. A nationwide population-based cohort of 522 7-year-old children with parents diagnosed with either SZ (N = 202) or BP (N = 120) and matched controls (N = 200) were recruited using the Danish national registries. The children's EF were assessed with the Behavior Rating Inventory of Executive Functions questionnaire rated by primary caregivers and teachers. According to primary caregiver assessments, FHR-SZ children displayed widespread EF impairments and had an odds ratio of 3.7 (2.0-6.9) of having clinically significant global EF impairments compared to controls. FHR-BP children were most severely impaired regarding EF related to emotional control and had an odds ratio of 2.5 (1.2-5.1) of clinically significant global EF impairments compared to controls. Teacher assessments were overall comparable to primary caregiver assessments but teachers rated more difficulties in the FHR-SZ group than primary caregivers. Already at age 7, children with a parental history of SZ or BP displayed significant impairments of EF in everyday-life situations. FHR-SZ children displayed widespread significant impairments of EF, whereas FHR-BP children were most severely impaired on emotional control. Clinicians should be aware of potential EF impairments in FHR children

Emotion regulation in 7-year-old children with familial high risk for schizophrenia or bipolar disorder compared to controls - The Danish High Risk and Resilience Study - VIA 7, a population-based cohort study.

Emotion regulation is a predictor of overall life outcome. Problems of emotion regulation are associated with multiple psychiatric disorders and could be a potential treatment target for improving well-being and functioning. Children at familial high risk of severe mental illness have a markedly increased risk of various psychopathology and constitute a group at significant risk of emotion regulation problems. Investigations of emotion regulation in children at familial high risk of severe mental illness are sparse. We applied an instrument for assessing emotion regulation, the Tangram Emotion Coding Manual (TEC-M), to a population-based cohort of 522 7-year-old children born to parents diagnosed with either schizophrenia or bipolar disorder and matched controls. The TEC-M is an ecologically valid, clinician-rated observational test measure of spontaneous emotion regulation. We aimed to compare emotion regulation between risk groups and to investigate associations between emotion regulation and psychopathology and daily life functioning, and between emotion regulation and an acknowledged questionnaire-based dysregulation profile. In this early developmental phase, we found no between group differences in emotion regulation. We found a significant but weak negative association between emotion regulation and both child psychopathology and the presence of a dysregulation profile on the Child Behavior Checklist and a weak positive association between emotion regulation and current level of functioning. These findings contribute to the understanding of emotion regulation in familial high-risk children and further studies of emotion regulation in children at familial high risk of severe mental illness are warranted