The contribution of first-episode illness characteristics and cumulative antipsychotic usage to progressive structural brain changes over a long-term follow-up in schizophrenia.

Exposure to antipsychotics as well as certain first-episode illness characteristics have been associated with greater gray matter (GM) deficits in the early phase of schizophrenia. Whether the first-episode illness characteristics affect the long-term progression of the structural brain changes remain unexplored. We therefore assessed the role of first-episode illness characteristics and life-time antipsychotic use in relation to long-term structural brain GM changes in schizophrenia. Individuals with schizophrenia (SZ, n = 29) and non-psychotic controls (n = 61) from the Northern Finland Birth Cohort 1966 underwent structural MRI at the ages of 34 (baseline) and 43 (follow-up) years. At follow-up, the average duration of illness was 19.8 years. Voxel-based morphometry was used to assess the effects of predictors on longitudinal GM changes in schizophrenia-relevant brain areas. Younger age of onset (AoO), higher cumulative antipsychotic dose and severity of symptoms were associated with greater GM deficits in the SZ group at follow-up. None of the first-episode illness characteristics were associated with longitudinal GM changes during 9-year follow-up period. We conclude that a younger AoO and high life-time antipsychotic use may contribute to progression of structural brain changes in schizophrenia. Apart from AoO, other first-episode illness characteristics may not contribute to longitudinal GM changes in midlife.

Maternal Thyroid Function During Pregnancy and Offspring White Matter Microstructure in Early Adulthood: A Prospective Birth Cohort Study.

Background: The fetus is fully dependent on maternal thyroid hormones until mid-gestation and suboptimal maternal thyroid function has been associated with alterations in the neurodevelopment of the offspring. We used maternal free thyroxine (fT4) and thyrotropin (TSH) levels in early gestation to study the association of maternal thyroid function during early pregnancy and offspring brain white matter (WM) integrity in early adulthood. Methods: Our study population consisted of a total of 292 mother-child pairs. Maternal fT4 and TSH were used as predictors and offspring multimodal imaging measures of fractional anisotropy, mean diffusivity, and magnetization transfer ratio (FA, MD, and MTR) as dependent variables. First, as Global analysis, all analyzed 14 WM tracts were studied simultaneously using linear-mixed effect models. Second, if a global effect was detected, a post hoc Tract-wise analysis was carried out using linear models individually in each WM tract. Study population was stratified by sex. Results: We found a positive association between maternal fT4 and offspring Global FA in males when adjusted for all maternal and offspring covariates (n = 114; ß = 0.154; confidence interval = 0.045-0.263; p = 0.006). The finding was observed to be driven by multiple WM tracts, of which three projection fiber tracts and the forceps minor survived correcting for multiple comparisons in Tract-wise analysis. Conclusions: Maternal thyroid function in early pregnancy was observed to be associated with WM microstructure in male offspring in early adulthood. Our results suggest that maternal fT4 levels in early pregnancy may modulate axonal characteristics, with a long-term effect on offspring WM development.

Associations Between Maternal Prenatal C-Reactive Protein and Risk Factors for Psychosis in Adolescent Offspring: Findings From the Northern Finland Birth Cohort 1986.

Prenatal infection is associated with brain structural and functional abnormalities and may increase the risk for psychosis through a direct effect on neurodevelopment. Various infections may exert their effect through a proinflammatory immune response but studies of prenatal maternal inflammatory markers and offspring neurodevelopment are scarce. Using the longitudinal Northern Finland Birth Cohort 1986 study, we examined the associations of maternal prenatal C-reactive protein (CRP) levels with psychosis risk factors in adolescent offspring. CRP was measured in maternal sera collected in pregnancy. In offspring, school performance was measured at age 7 years, while school performance, psychotic experiences, and cannabis use were measured at age 16 years. We tested associations of CRP with offspring measures using regression analysis controlling for offspring sex, maternal education level, and prenatal maternal body mass index, smoking and alcohol use in pregnancy, place of birth, maternal psychiatric admission, paternal psychiatric admission, mothers age at birth, and gestational week of CRP sample. We also tested if adolescent cannabis use mediated the associations between maternal CRP and offspring outcomes. Controlling for covariates, maternal CRP was associated with academic performance at age 16 years (beta = .062, 95% CI = 0.036-0.088), but not with possible psychotic experiences at 16 years (odds ratio [OR] = 1.09, 95% CI = 0.96-1.24). Maternal CRP was also associated with adolescent cannabis use (OR = 1.24, 95% CI = 1.07-1.43). These findings suggest that prenatal inflammation may influence later mental illness risk by affecting neurodevelopment and also indirectly by increasing the risk of exposure to cannabis.

Structural and functional alterations in the brain gray matter among first-degree relatives of schizophrenia patients: A multimodal meta-analysis of fMRI and VBM studies.

OBJECTIVE: We conducted a multimodal coordinate-based meta-analysis (CBMA) to investigate structural and functional brain alterations in first-degree relatives of schizophrenia patients (FRs). METHODS: We conducted a systematic literature search from electronic databases to find studies that examined differences between FRs and healthy controls using whole-brain functional magnetic resonance imaging (fMRI) or voxel-based morphometry (VBM). A CBMA of 30 fMRI (754 FRs; 959 controls) and 11 VBM (885 FRs; 775 controls) datasets were conducted using the anisotropic effect-size version of signed differential mapping. Further, we conducted separate meta-analyses about functional alterations in different cognitive tasks: social cognition, executive functioning, working memory, and inhibitory control. RESULTS: FRs showed higher fMRI activation in the right frontal gyrus during cognitive tasks than healthy controls. In VBM studies, there were no differences in gray matter density between FRs and healthy controls. Furthermore, multi-modal meta-analysis obtained no differences between FRs and healthy controls. By utilizing the BrainMap database, we showed that the brain region which showed functional alterations in FRs (i) overlapped only slightly with the brain regions that were affected in the meta-analysis of schizophrenia patients and (ii) correlated positively with the brain regions that exhibited increased activity during cognitive tasks in healthy individuals. CONCLUSIONS: Based on this meta-analysis, FRs may exhibit only minor functional alterations in the brain during cognitive tasks, and the alterations are much more restricted and only slightly overlapping with the regions that are affected in schizophrenia patients. The familial risk did not relate to structural alterations in the gray matter.

Psychiatric research in the Northern Finland Birth Cohort 1986 - a systematic review.

The Northern Finland Birth Cohort 1986 is a large population-based birth cohort, which aims to promote health and wellbeing of the population. In this paper, we systematically review the psychiatric research performed in the cohort until today, i.e. at the age of 32 years of the cohort (2018). We conducted a systematic literature search using the databases of PubMed and Scopus and complemented it with a manual search. We found a total of 94 articles, which were classified as examining ADHD, emotional and behavioural problems, psychosis risk or other studies relating to psychiatric subjects. The articles are mainly based on two large comprehensive follow-up studies of the cohort and several substudies. The studies have often used also nationwide register data. The studies have found several early predictors for the aforementioned psychiatric outcomes, such as problems at pregnancy and birth, family factors in childhood, physical inactivity and substance use in adolescence. There are also novel findings relating to brain imaging and cognition, for instance regarding familial risk of psychosis in relation to resting state functional MRI. The Northern Finland Birth Cohort 1986 has been utilised frequently in psychiatric research and future data collections are likely to lead to new scientifically important findings. Abbreviations: attention deficit hyperactivity disorder (ADHD); magnetic resonance imaging (MRI).

Maternal prepregnancy body mass index and offspring white matter microstructure: results from three birth cohorts.

BACKGROUND AND AIMS: Prepregnancy maternal obesity is a global health problem and has been associated with offspring metabolic and mental ill-health. However, there is a knowledge gap in understanding potential neurobiological factors related to these associations. This study explored the relation between maternal prepregnancy body mass index (BMI) and offspring brain white matter microstructure at the age of 6, 10, and 26 years in three independent cohorts. SUBJECTS AND METHODS: The study used data from three European birth cohorts (n = 116 children aged 6 years, n = 2466 children aged 10 years, and n = 437 young adults aged 26 years). Information on maternal prepregnancy BMI was obtained before or during pregnancy and offspring brain white matter microstructure was measured at age 6, 10, or 26 years. We used magnetic resonance imaging-derived fractional anisotropy (FA) and mean diffusivity (MD) as measures of white matter microstructure in the brainstem, callosal, limbic, association, and projection tracts. Linear regressions were fitted to examine the association of maternal BMI and offspring white matter microstructure, adjusting for several socioeconomic and lifestyle-related confounders, including education, smoking, and alcohol use. RESULTS: Maternal BMI was associated with higher FA and lower MD in multiple brain tracts, for example, association and projection fibers, in offspring aged 10 and 26 years, but not at 6 years. In each cohort maternal BMI was related to different white matter tract and thus no common associations across the cohorts were found. CONCLUSIONS: Maternal BMI was associated with higher FA and lower MD in multiple brain tracts in offspring aged 10 and 26 years, but not at 6 years of age. Future studies should examine whether our observations can be replicated and explore the potential causal nature of the findings.

Antipsychotic and benzodiazepine use and brain morphology in schizophrenia and affective psychoses - Systematic reviews and birth cohort study.

The aim of this paper was to investigate differences in brain structure volumes between schizophrenia and affective psychoses, and whether cumulative lifetime antipsychotic or benzodiazepine doses relate to brain morphology in these groups. We conducted two systematic reviews on the topic and investigated 44 schizophrenia cases and 19 with affective psychoses from the Northern Finland Birth Cohort 1966. The association between lifetime antipsychotic and benzodiazepine dose and brain MRI scans at the age of 43 was investigated using linear regression. Intracranial volume, sex, illness severity, and antipsychotic/benzodiazepine doses were used as covariates. There were no differences between the groups in brain structure volumes. In schizophrenia, after adjusting for benzodiazepine dose and symptoms, a negative association between lifetime antipsychotic dose and the nucleus accumbens volume remained. In affective psychoses, higher lifetime benzodiazepine dose associated with larger volumes of total gray matter and hippocampal volume after controlling for antipsychotic use and symptoms. It seems that in addition to antipsychotics, the severity of symptoms and benzodiazepine dose are also associated with brain structure volumes. These results suggest, that benzodiazepine effects should also be investigated also independently and not only as a confounder.

Associations between prenatal, childhood, and adolescent stress and variations in white-matter properties in young men.

OBJECTIVE: Previous studies have shown that both pre- and post-natal adversities, the latter including exposures to stress during childhood and adolescence, explain variation in structural properties of white matter (WM) in the brain. While previous studies have examined effects of independent stress exposures within one developmental period, such as childhood, we examine effects of stress across development using data from a prospective longitudinal study. More specifically, we ask how stressful events during prenatal development, childhood, and adolescence relate to variation in WM properties in early adulthood in young men recruited from a birth cohort. METHOD: Using data from 393 mother-son pairs from a community-based birth cohort from England (Avon Longitudinal Study of Parents and Children), we examined how stressful life events relate to variation in different structural properties of WM in the corpus callosum and across the whole brain in early adulthood in men aged 18-21 years. We distinguish between stress occurring during three developmental periods: a) prenatal maternal stress, b) postnatal stress within the first four years of life, c) stress during adolescence (age 12-16 years). To obtain a comprehensive quantification of variation in WM, we assess structural properties of WM using four different measures, namely fractional anisotropy (FA), mean diffusivity (MD), magnetization transfer ratio (MTR) and myelin water fraction (MWF). RESULTS: The developmental model shows that prenatal stress is associated with lower MTR and MWF in the genu and/or splenium of the corpus callosum, and with lower MTR in global (lobar) WM. Stress during early childhood is associated with higher MTR in the splenium, and stress during adolescence is associated with higher MTR in the genu and lower MD in the splenium. We see no associations between postnatal stress and variation in global (lobar) WM. CONCLUSIONS: The current study found evidence for independent effects of stress on WM properties during distinct neurodevelopmental periods. We speculate that these independent effects are due to differences in the developmental processes unfolding at different developmental time points. We suggest that associations between prenatal stress and WM properties may relate to abnormalities in neurogenesis, affecting the number and density of axons, while postnatal stress may interfere with processes related to myelination or radial growth of axons. Potential consequences of prenatal glucocorticoid exposure should be considered in obstetric care.

Long-term antipsychotic and benzodiazepine use and brain volume changes in schizophrenia: The Northern Finland Birth Cohort 1966 study.

High doses of antipsychotics have been associated with loss in cortical and total gray matter in schizophrenia. However, previous imaging studies have not taken benzodiazepine use into account, in spite of evidence suggesting adverse effects such as cognitive impairment and increased mortality. In this Northern Finland Birth Cohort 1966 study, 69 controls and 38 individuals with schizophrenia underwent brain MRI at the ages of 34 and 43 years. At baseline, the average illness duration was over 10 years. Brain structures were delineated using an automated volumetry system, volBrain, and medication data on cumulative antipsychotic and benzodiazepine doses were collected using medical records and interviews. We used linear regression with intracranial volume and sex as covariates; illness severity was also taken into account. Though both medication doses associated to volumetric changes in subcortical structures, after adjusting for each other and the average PANSS total score, higher scan-interval antipsychotic dose associated only to volume increase in lateral ventricles and higher benzodiazepine dose associated with volume decrease in the caudate nucleus. To our knowledge, there are no previous studies reporting associations between benzodiazepine dose and brain structural changes. Further studies should focus on how these observations correspond to cognition and functioning.

Body mass index and brain white matter structure in young adults at risk for psychosis - The Oulu Brain and Mind Study.

Antipsychotic medications and psychotic illness related factors may affect both weight and brain structure in people with psychosis. Genetically high-risk individuals offer an opportunity to study the relationship between body mass index (BMI) and brain structure free from these potential confounds. We examined the effect of BMI on white matter (WM) microstructure in subjects with familial risk for psychosis (FR). We used diffusion tensor imaging and tract-based spatial statistics to explore the effect of BMI on whole brain FA in 42 (13 males) participants with FR and 46 (16 males) control participants aged 20-25 years drawn from general population-based Northern Finland Birth Cohort 1986. We also measured axial, radial and mean diffusivities. Most of the participants were normal weight rather than obese. In the FR group, decrease in fractional anisotropy and increase in radial diffusivity were associated with an increase in BMI in several brain areas. In controls the opposite pattern was seen in participants with higher BMI. There was a statistically significant interaction between group and BMI on FA and radial and mean diffusivities. Our results suggest that the effect of BMI on WM differs between individuals with FR for psychosis and controls.

White matter structure in young adults with familial risk for psychosis - The Oulu Brain and Mind Study.

According to the disconnectivity model, disruptions in neural connectivity play an essential role in the pathology of schizophrenia. The aim of this study was to determine whether these abnormalities are present in young adults with familial risk (FR) for psychosis in the general population based sample. We used diffusion tensor imaging (DTI) and tract-based spatial statistics to compare whole-brain fractional anisotropy, mean diffusivity, and axial and radial diffusion in 47 (17 males) FR subjects to 51 controls (17 males). All the participants were aged between 20 and 25 years and were members of the Northern Finland Birth Cohort 1986 (Oulu Brain and Mind Study). Region of interest analyses were conducted for 12 tracts. Separately, we analysed whole-brain FA for the subgroup with FR for schizophrenia (n=13) compared with 13 gender-matched controls. Contrary to our expectations there were no differences in any of the DTI measures between FR and control groups. This suggests that white matter abnormalities may not be a genetic feature for risk of psychosis and preceding the onset of a psychotic disorder. Our findings do not support the theory of disconnectivity as a primary sign of psychosis in young adults with FR for the illness.