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.

Cerebellar activity in young people with familial risk for psychosis--The Oulu Brain and Mind Study.

OBJECTIVE: The cerebellum plays a critical role in cognition and behavior. Altered function of the cerebellum has been related to schizophrenia and psychosis but it is not known how this applies to spontaneous resting state activity in young people with familial risk for psychosis. METHODS: We conducted resting-state functional MRI (R-fMRI) in 72 (29 male) young adults with a history of psychosis in one or both parents (FR) but without their own psychosis, and 72 (29 male) similarly healthy control subjects without parental psychosis. Both groups in the Oulu Brain and Mind Study were drawn from the Northern Finland Birth Cohort 1986. Participants were 20-25 years old. Parental psychosis was established using the Care Register for Health Care. R-fMRI data pre-processing was conducted using independent component analysis with 30 and 70 components. A dual regression technique was used to detect between-group differences in the cerebellum with p<0.05 threshold corrected for multiple comparisons. RESULTS: FR participants demonstrated statistically significantly increased activity compared to control subjects in the anterior lobe of the right cerebellum in the analysis with 70 components. The volume of the increased activity was 73 mm(3). There was no difference between the groups in the analysis with 30 components. CONCLUSION: The finding suggests that increased activity of the anterior lobe of the right cerebellum may be associated with increased vulnerability to psychosis. The finding is novel, and needs replication to be confirmed.

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.

Association between Dopamine Receptor D2 (DRD2) Variations rs6277 and rs1800497 and Cognitive Performance According to Risk Type for Psychosis: A Nested Case Control Study in a Finnish Population Sample.

BACKGROUND: There is limited research regarding the association between genes and cognitive intermediate phenotypes in those at risk for psychotic disorders. METHODS: We measured the association between established psychosis risk variants in dopamine D2 receptor (DRD2) and cognitive performance in individuals at age 23 years and explored if associations between cognition and these variants differed according to the presence of familial or clinical risk for psychosis. The subjects of the Oulu Brain and Mind Study were drawn from the general population-based Northern Finland 1986 Birth Cohort (NFBC 1986). Using linear regression, we compared the associations between cognitive performance and two candidate DRD2 polymorphisms (rs6277 and rs1800497) between subjects having familial (n=61) and clinical (n=45) risk for psychosis and a random sample of participating NFBC 1986 controls (n=74). Cognitive performance was evaluated using a comprehensive battery of tests at follow-up. RESULTS: Principal components factor analysis supported a three-factor model for cognitive measures. The minor allele of rs6277 was associated with poorer performance on a verbal factor (p=0.003) but this did not significantly interact with familial or clinical risk for psychosis. The minor allele of rs1800497 was associated with poorer performance on a psychomotor factor (p=0.038), though only in those at familial risk for psychotic disorders (interaction p=0.049). CONCLUSION: The effect of two DRD2 SNPs on cognitive performance may differ according to risk type for psychosis, suggesting that cognitive intermediate phenotypes differ according to the type (familial or clinical) risk for psychosis.

Functional mapping of dynamic happy and fearful facial expressions in young adults with familial risk for psychosis - Oulu Brain and Mind Study.

BACKGROUND: Social interaction requires mirroring to other people's mental state. Psychotic disorders have been connected to social interaction and emotion recognition impairment. We compared the brain activity between young adults with familial risk for psychosis (FR) and matched controls during visual exposure to emotional facial expression. We also investigated the role of the amygdala, the key region for social interaction and emotion recognition. METHODS: 51 FR and 52 control subjects were drawn from the Northern Finland 1986 Birth Cohort (Oulu Brain and Mind Study). None of the included participants had developed psychosis. The FR group was defined as having a parent with psychotic disorder according to the Finnish Hospital Discharge Register. Participants underwent functional MRI (fMRI) using visual presentation of dynamic happy and fearful facial expressions. FMRI data were processed to produce maps of activation for happy and fearful facial expression, which were then compared between groups. Two spherical regions of interest (ROIs) in the amygdala were set to extract BOLD responses during happy and fearful facial expression. BOLD responses were then compared with subjects' emotion recognition, which was assessed after fMRI. Psychophysiological interaction (PPI) for the left and right amygdala during happy and fearful facial expression was conducted using the amygdala as seed regions. RESULTS: FR subjects had increased activity in the left premotor cortex and reduced deactivation of medial prefrontal cortex structures during happy facial expression. There were no between-group differences during fearful facial expression. The FR group also showed a statistically significant linear correlation between mean amygdala BOLD response and facial expression recognition. PPI showed that there was a significant negative interaction between the amygdala and the dorsolateral prefrontal cortex (dlPFC) and superior temporal gyrus in FR subjects. CONCLUSIONS: Increased activations by positive valence in FR were in brain regions crucial to emotion recognition and social interaction. Increased activation of the premotor cortex may serve as a compensatory mechanism as FR subjects may have to exert more effort on processing the stimuli, as has been found earlier in schizophrenia. Failure to deactivate PFC structures may imply error in the default mode network. Abnormal PFC function in FR was also suggested by PPI, as the dlPFC showed decreased functional connectivity with the amygdala in the FR group. This may indicate that in FR subjects the amygdala have to take a greater role in emotion recognition and social functioning. This inference was supported by our discovery of statistically significant correlations between the amygdala BOLD response and emotion recognition in the FR group but not in controls.

Central executive network in young people with familial risk for psychosis--the Oulu Brain and Mind Study.

OBJECTIVE: The central executive network controls and manages high-level cognitive functions. Abnormal activation in the central executive network has been related to psychosis and schizophrenia but it is not established how this applies to people with familial risk for psychosis (FR). METHODS: We conducted a resting-state functional MRI (R-fMRI) in 72 (29 males) young adults with a history of psychosis in one or both parents (FR) but without psychosis themselves, and 72 (29 males) similarly healthy control subjects without parental psychosis. Both groups in the Oulu Brain and Mind Study were drawn from the Northern Finland Birth Cohort 1986. Participants were 20-25years old. Parental psychosis was established using the Care Register for Health Care. R-fMRI data pre-processing was conducted using independent component analysis with 30 and 70 components. A dual regression technique was used to detect between-group differences in the central executive network with p<0.05 threshold corrected for multiple comparisons. RESULTS: FR participants demonstrated statistically significantly lower activity compared to control subjects in the right inferior frontal gyrus, a key area of central executive network corresponding to Brodmann areas 44 and 45, known as Broca's area. The volume of the lower activation area with 30 components was 896mm(3) and with 70 components was 1151mm(3). CONCLUSION: The activity of the central executive network differed in the right inferior frontal gyrus between FR and control groups. This suggests that abnormality of the right inferior frontal gyrus may be a central part of vulnerability for psychosis.

Brain structure in different psychosis risk groups in the Northern Finland 1986 birth cohort.

We tested the hypothesis that family risk for psychosis (FR) and clinical risk for psychosis (CR) are associated with structural brain abnormalities, with increased deficits in those at both family risk and clinical risk for psychosis (FRCR). The study setting was the Oulu Brain and Mind Study, with subjects drawn from the Northern Finland 1986 Birth Cohort (n=9479) using register and questionnaire based screening, and interviews using the Structured Interview for Prodromal Symptoms. After this procedure, 172 subjects were included in the study, classified as controls (n=73) and three risk groups: FR excluding CR (FR, n=60), CR without FR (CR, n=26), and individuals at both FR and CR (FRCR, n=13). T1-weighted brain scans were acquired and processed in a voxel-based analysis using permutation-based statistics. In the comparison between FRCR versus controls, we found lower grey matter volume (GMV) in a cluster (1689 voxels at -4.00, -72.00, -18.00mm) covering both cerebellar hemispheres and the vermis. This cluster was subsequently used as a mask to extract mean GMV in all four groups: FR had a volume intermediate between controls and FRCR. Within FRCR there was an association between cerebellar cluster brain volume and motor function. These findings are consistent with an evolving pattern of cerebellar deficits in psychosis risk with the most pronounced deficits in those at highest risk of psychosis.

Default mode network in young people with familial risk for psychosis--the Oulu Brain and Mind study.

OBJECTIVE: The default mode network (DMN) is active in the brain at rest and de-activated during cognitive tasks. Abnormal function in the DMN has been reported in people with schizophrenia but it is not known whether this applies also to people with a familial risk for psychosis (FR). We compared the activity of the DMN between FR participants and controls. METHODS: We conducted a resting state functional MRI (R-fMRI) in 72 young adults without psychosis and with a history of psychosis in one or both parents (FR group) and 72 age matched controls without parental psychosis, and without current psychosis or a current prodromal syndrome. Both groups were drawn from the Northern Finland Birth Cohort 1986 (Oulu Brain and Mind study). Parental psychosis was established using the Finnish hospital discharge register. We pre-processed R-fMRI data using independent component analysis followed by a dual regression approach to assess differences between the groups. The FR vs. Control group differences were assessed using non-parametric permutation tests utilizing threshold-free cluster enhancement and correcting for multiple comparisons (p<0.05). RESULTS: FR participants demonstrated significantly lower activity compared with controls in the posterior cingulate cortex, the central node of the DMN. The size of the region was 41 mm(3). CONCLUSION: The activity of the DMN differed between FR and control groups. This suggests that familial risk for psychotic disorders may be mediated through genetic effects on connectivity in the posterior cingulate cortex.

Young people at risk for psychosis: case finding and sample characteristics of the Oulu Brain and Mind Study.

AIM: Set within the general population-based Northern Finland Birth Cohort 1986, the Oulu Brain and Mind Study aims to explore the causes and pathogenesis of psychotic illness by following young people at risk for psychosis due to having a first-degree relative with psychotic illness or due to having experienced psychotic-like symptoms themselves. We report the study methods and explore the relationship between these definitions of high risk for psychosis and operational criteria for a prodromal psychosis syndrome based on interview. METHODS: Prospectively collected data from earlier follow-ups of this cohort were combined with health register data to categorize subjects as those with familial risk (n = 272), symptomatic risk (n = 117), psychosis (n = 78), attention deficit hyperactivity disorder (ADHD) (n = 103) and a sample of controls (n = 193) drawn randomly from the remaining cohort. The Structured Interview for Prodromal Syndromes (SIPS) was applied to all, 295 participants together with questionnaires measuring psychosis vulnerability and schizotypal traits. RESULTS: There were 29 (10%) current prodromal cases. Criteria for the current prodromal syndrome were fulfilled by 12% of the familial risk group and 19% of the symptomatic risk group, compared with 5% of the ADHD group and 4% of controls. CONCLUSION: We successfully detected young people with a prodromal psychosis syndrome although relatively few subjects deemed to be at high risk met the full operational criteria according to the SIPS interview. Combining methods from familial, clinical and psychometric high-risk approaches provides a tractable method for studying risk of psychosis in the general population.

Different vulnerability indicators for psychosis and their neuropsychological characteristics in the Northern Finland 1986 Birth Cohort.

This study is one of very few that has investigated the neuropsychological functioning of both familial and clinical high risk subjects for psychosis. Participants (N = 164) were members of the Northern Finland 1986 Birth Cohort in the following four groups: familial risk for psychosis (n = 62), clinical risk for psychosis (n = 20), psychosis (n = 13), and control subjects (n = 69). The neurocognitive performance of these groups was compared across 19 cognitive variables. The two risk groups did not differ significantly from controls, but differed from the psychosis group in fine motor function. Neuropsychological impairments were not evident in a non-help-seeking high-risk sample.