Neuregulin-1 genotype is associated with structural differences in the normal human brain.

The human neuregulin-1 (NRG-1) gene is highly expressed in the brain, is implicated in numerous functions associated with neuronal development, and is a leading candidate gene for schizophrenia. The T allele of SNP8NRG243177, part of a risk haplotype for schizophrenia, has been previously associated with decreases in white matter in the right anterior internal capsule and the left anterior thalamic radiation. To our knowledge no studies have described the effects of SNP8NRG243177 on grey matter volume at a voxelwise level. We assessed associations between this SNP and brain structure in 79 general population volunteers from the Northern Finland 1966 Birth Cohort (NFBC 1966). We show, for the first time, that genetic variation in SNP8NRG243177 is associated with variation in frontal brain structure in both grey and white matter. T allele carriers showed decreased grey matter volume in several frontal gyri, including inferior, middle and superior frontal gyri and the anterior cingulate gyrus, as well as decreased white matter volume in the regions of the genu and body of the corpus callosum, anterior and superior corona radiata, anterior limb of the internal capsule and external capsule regions traversed by major white matter tracts of the anterior thalamic radiation, and the inferior fronto-occipital fasciculus. These results suggest that this genetic variant may mediate risk for schizophrenia, in part, through its effect on brain structure in these regions.

Use of inverse probability weighting to adjust for non-participation in estimating brain volumes in schizophrenia patients.

Low participation is a potential source of bias in population-based studies. This article presents use of inverse probability weighting (IPW) in adjusting for non-participation in estimation of brain volumes among subjects with schizophrenia. Altogether 101 schizophrenia subjects and 187 non-psychotic comparison subjects belonging to the Northern Finland 1966 Birth Cohort were invited to participate in a field study during 1999-2001. Volumes of grey matter (GM), white matter (WM) and cerebrospinal fluid (CSF) were compared between the 54 participating schizophrenia subjects and 100 comparison subjects. IPW by illness-related auxiliary variables did not affect the estimated GM and WM mean volumes, but increased the estimated CSF mean volume in schizophrenia subjects. When adjusted for intracranial volume and family history of psychosis, IPW led to smaller estimated GM and WM mean volumes. Especially IPW by a disability pension and a higher amount of hospitalisation due to psychosis had effect on estimated mean brain volumes. The IPW method can be used to improve estimates affected by non-participation by reflecting the true differences in the target population.

The brain structural disposition to social interaction.

Social reward dependence (RD) in humans is a stable pattern of attitudes and behaviour hypothesized to represent a favourable disposition towards social relationships and attachment as a personality dimension. It has been theorized that this long-term disposition to openness is linked to the capacity to process primary reward. Using brain structure measures from magnetic resonance imaging, and a measure of RD from Cloninger's temperament and character inventory, a self-reported questionnaire, in 41 male subjects sampled from a general population birth cohort, we investigated the neuro-anatomical basis of social RD. We found that higher social RD in men was significantly associated with increased gray matter density in the orbitofrontal cortex, basal ganglia and temporal lobes, regions that have been previously shown to be involved in processing of primary rewards. These findings provide evidence for a brain structural disposition to social interaction, and that sensitivity to social reward shares a common neural basis with systems for processing primary reward information.

Volumes of brain, grey and white matter and cerebrospinal fluid in schizophrenia in the Northern Finland 1966 Birth Cohort: an epidemiological approach to analysis.

Magnetic resonance imaging (MRI) studies in schizophrenia have seldom involved a general population birth cohort or other epidemiological samples. We studied the Northern Finland 1966 Birth Cohort and identified all people with psychotic disorders. Along with an unaffected age-matched control sample (n = 100) from the cohort, 54 subjects with schizophrenia underwent MRI brain scan at age 33-35 years from which we defined volumes of whole brain, grey and white matter and intracranial cerebrospinal fluid (CSF). Whole brain, grey and white matter volumes were 2-3% smaller in the schizophrenia subjects, who showed a 7% increase in CSF volume. These volume changes were independent of the effects of gender, family history of psychosis, perinatal risks or age at onset of illness. Moreover, there was no evidence that the effects were due to particular subgroups of cases having very low or high values. Rather, there were linear trends in the associations between whole brain and grey matter volume measures and schizophrenia. Our study replicates the previous findings of brain volume differences in schizophrenia on a general population level.

Hippocampus and amygdala volumes in schizophrenia and other psychoses in the Northern Finland 1966 birth cohort.

Structural brain differences have been reported in many studies with schizophrenia, but few have involved a general population birth cohort. We investigated differences in volume, shape and laterality of hippocampus and amygdala in patients with schizophrenia, all psychoses and comparison subjects within a large general birth cohort sample, and explored effects of family history of psychosis, perinatal risk and age-at-onset of illness. All subjects with psychosis from the Northern Finland 1966 birth cohort were invited to a survey including MRI scan of the brain, conducted in 1999-2001. Comparison subjects not known to have psychosis were randomly selected from the same cohort. Volumes of hippocampus and amygdala were measured in 56 subjects with DSM-III-R schizophrenia, 26 patients with other psychoses and 104 comparison subjects. Small hippocampal volume reductions in schizophrenia (2%) and all psychoses (3%) were not significant when adjusted for total brain volume. The shape of hippocampus in schizophrenia did not differ significantly from comparison subjects. Right hippocampus and amygdala were significantly larger than the left in all groups. Mean amygdala volume in schizophrenia or all psychoses did not differ from comparison subjects. Patients with family history of psychosis had larger hippocampus than patients without. Neither perinatal risk nor age-at-onset of illness had any effect on hippocampal or amygdala volumes. Small hippocampal volume reduction in schizophrenia and all psychoses was not disproportionate to reduced whole brain volume in this population-based sample. Perinatal events that have been suggested as of etiological importance in structural pathology of psychosis had no effect.

Longitudinal changes in total brain volume in schizophrenia: relation to symptom severity, cognition and antipsychotic medication.

Studies show evidence of longitudinal brain volume decreases in schizophrenia. We studied brain volume changes and their relation to symptom severity, level of function, cognition, and antipsychotic medication in participants with schizophrenia and control participants from a general population based birth cohort sample in a relatively long follow-up period of almost a decade. All members of the Northern Finland Birth Cohort 1966 with any psychotic disorder and a random sample not having psychosis were invited for a MRI brain scan, and clinical and cognitive assessment during 1999-2001 at the age of 33-35 years. A follow-up was conducted 9 years later during 2008-2010. Brain scans at both time points were obtained from 33 participants with schizophrenia and 71 control participants. Regression models were used to examine whether brain volume changes predicted clinical and cognitive changes over time, and whether antipsychotic medication predicted brain volume changes. The mean annual whole brain volume reduction was 0.69% in schizophrenia, and 0.49% in controls (p = 0.003, adjusted for gender, educational level, alcohol use and weight gain). The brain volume reduction in schizophrenia patients was found especially in the temporal lobe and periventricular area. Symptom severity, functioning level, and decline in cognition were not associated with brain volume reduction in schizophrenia. The amount of antipsychotic medication (dose years of equivalent to 100 mg daily chlorpromazine) over the follow-up period predicted brain volume loss (p = 0.003 adjusted for symptom level, alcohol use and weight gain). In this population based sample, brain volume reduction continues in schizophrenia patients after the onset of illness, and antipsychotic medications may contribute to these reductions.

No association of COMT (Val158Met) genotype with brain structure differences between men and women.

We examined the effect of the catechol-O-methyltransferase (COMT) Val158Met polymorphism (rs4680), on brain structure in a subset (N = 82) of general population members of the Northern Finland 1966 Birth Cohort, selected through a randomization procedure, aged 33-35. Optimised voxel-based morphometry was used to produce grey matter maps from each subject's high resolution T1 weighted brain magnetic resonance images, which were subsequently entered into a general linear model with COMT genotype as defined by Met allele loading, gender and genotype by gender interaction as independent variables. Additional analyses were carried out on grey matter volumes within the dorsal lateral pre-frontal cortex (DLPFC) to examine effects on overall DLPFC volume and also using the DLPFC as a mask for voxelwise analyses, as this is an area previously reported as associated with Met allele loading. We failed to find any statistically significant association with grey matter volume and Met allele loading in the COMT gene or interaction affects between COMT and gender in either the whole brain voxel-wise analysis or in the area of the DLPFC.

Is prematurity associated with adult cognitive outcome and brain structure?

Previous studies have indicated that preterm birth and low birth weight are associated with structural brain abnormalities and neurocognitive deficits in childhood and adolescence, although very few studies have included follow-up in adulthood. Here we assessed the effect of preterm delivery (524 subjects; mean 34.6 weeks, S.D. = 1.7) or low birth weight (366 subjects; mean 2159 g, S.D. = 303) on educational and occupational outcomes at age 31 years in the Northern Finland 1966 Birth Cohort, along with 10,132 term, normal birth weight control subjects. Cognitive tests and brain morphology using magnetic resonance imaging were assessed at age 33-35 years in a subset of the cohort (9 subjects; 95 controls). The preterm or low birth weight subjects had slightly lower school ratings and lower educational levels in adulthood, and they performed worse in verbal learning. The low birth weight subjects were less likely to be employed. There were no mean differences in the magnetic resonance imaging tissue segmentation analysis of the brain. In conclusion, although there were no overall changes in brain morphology in the preterm or low birth weight group, there was evidence for slightly poorer educational and occupational careers and cognitive capacity, which may reflect functional disruption not evident in structure.

Morphometric brain abnormalities in schizophrenia in a population-based sample: relationship to duration of illness.

Biased recruitment and sample selection may cause variability in neuroimaging studies. Epidemiologically principled population-based magnetic resonance imaging (MRI) studies of schizophrenia are very rare. We gathered structural MRI data on 154 subjects from the Northern Finland 1966 Birth Cohort, aged 33-35 (100 controls, 54 schizophrenia patients). Regional differences in density of gray matter, white matter, and cerebrospinal fluid (CSF) were identified between groups using nonparametric statistical analysis, and the relationship of the regional differences to duration of illness was explored. Gray matter reductions were found bilaterally in the cerebellum, thalamus, basal ganglia, middle frontal gyrus, inferior frontal gyrus, precentral gyrus, insula, superior temporal gyrus, fusiform gyrus, parahippocampal gyrus, cuneus, and lingual gyrus; in the left posterior cingulate, superior frontal gyrus, transverse temporal gyrus, and precuneus; and in the right postcentral gyrus. Gray matter excesses were observed bilaterally in the basal ganglia, anterior cingulate, and medial orbitofrontal cortices. There were white matter deficits in an extensive network including inter- and intrahemispheric tracts bilaterally in the frontal, temporal, parietal, and occipital lobes, subcortical structures, cerebellum, and brain stem. CSF excesses were found bilaterally in the lateral ventricles, third ventricle, interhemispheric, and left Sylvian fissure. We replicated the previous findings of structural brain abnormalities in schizophrenia on a general population level. Gray and white matter deficits were associated with duration of illness suggesting either that developmental brain deficits relate to an earlier age of onset or that brain abnormalities in schizophrenia are progressive in nature.

Association between duration of untreated psychosis and brain morphology in schizophrenia within the Northern Finland 1966 Birth Cohort.

BACKGROUND: Duration of untreated psychosis (DUP) has been linked with poor prognosis and changes in the brain structure in schizophrenia at least at the beginning of the disease, but it is still unknown whether DUP relates to brain morphometry in the longer term. Our aim was to analyze the relation between DUP and the brain structure in schizophrenia in the general population, after several years of illness. METHODS: Brains of subjects with psychosis from the Northern Finland 1966 Birth Cohort (NFBC 1966) were scanned with MRI during 1999-2001 after an 11-year follow-up. DUP was assessed from medical records and regressed against global and local tissue density measurements. The brain morphometric and the DUP information were available for 46 subjects with DSM-III-R schizophrenia. RESULTS: The DUP did not correlate with volumes of the total gray or white matter or the cerebrospinal fluid. The length of DUP associated positively with reduced densities of the right limbic area and the right hippocampus. CONCLUSIONS: Long DUP was slightly associated with reductions of gray matter densities in the limbic area and especially the hippocampus after several years follow-up, supporting the hypothesis that, compared to short DUP, long DUP might be a marker of different disease trajectories including subtle morphometric changes.

Non-participation may bias the results of a psychiatric survey: an analysis from the survey including magnetic resonance imaging within the Northern Finland 1966 Birth Cohort.

OBJECTIVE: A major reason for limited validity of research is non-participation. Subjects with severe mental illness tend to cumulate in the group of non-participants, causing selection bias. We tested the hypothesis that severe psychosis is linked to non-participation in a field survey including magnetic resonance imaging (MRI) of the brain, psychiatric interviews and cognitive testing among subjects with psychosis. Furthermore, we wanted to explore other associative factors expected to affect non-participation. METHODS: Members of the Northern Finland 1966 Birth Cohort with a lifetime diagnosis of psychosis (N = 145) were invited to participate in the survey conducted in 1999-2001. Non-participation was determined by refusal or loss of contact. Data were gathered in earlier phases of the follow-up study or using register data. RESULTS: Ninety-one (63%) subjects attended the study. Compared to participants, non-participants were more often patients with schizophrenia and had more psychiatric hospitalisations, they had more positive psychosis symptoms during their illness course and they were more often on disability pension. Married subjects participated more often than those who were not married. CONCLUSION: This study suggests that among subjects with psychosis, particularly those subjects who have the most severe course of illness are less willing to participate. This may lead to biased estimates when studying subjects with severe mental disorders.

Fronto-cerebellar systems are associated with infant motor and adult executive functions in healthy adults but not in schizophrenia.

Delineating longitudinal relationships between early developmental markers, adult cognitive function, and adult brain structure could clarify the pathogenesis of neurodevelopmental disorders such as schizophrenia. We aimed to identify brain structural correlates of infant motor development (IMD) and adult executive function in nonpsychotic adults and to test for abnormal associations between these measures in people with schizophrenia. Representative samples of nonpsychotic adults (n = 93) and people with schizophrenia (n = 49) were drawn from the Northern Finland 1966 general population birth cohort. IMD was prospectively assessed at age 1 year; executive function testing and MRI were completed at age 33-35 years. We found that earlier motor development in infancy was correlated with superior executive function in nonpsychotic subjects. Earlier motor development was also normally associated with increased gray matter density in adult premotor cortex, striatum, and cerebellum and increased white matter density in frontal and parietal lobes. Adult executive function was normally associated with increased gray matter density in a fronto-cerebellar system that partially overlapped, but was not identical to, the gray matter regions normally associated with IMD. People with schizophrenia had relatively delayed IMD and impaired adult executive function in adulthood. Furthermore, they demonstrated no normative associations between fronto-cerebellar structure, IMD, or executive function. We conclude that frontal cortico-cerebellar systems correlated with adult executive function are anatomically related to systems associated with normal infant motor development. Disruption of this anatomical system may underlie both the early developmental and adult cognitive abnormalities in schizophrenia.

Predictors of schizophrenia--a review.

Schizophrenia is an aetiologically heterogeneous syndrome that usually becomes overtly manifest in adolescence and early adulthood, but in many cases subtle impairments in neurointegrative function are present from birth; hence it is considered to be a disorder with a neurodevelopmental component. The strongest risk factor that has been identified is familial risk with genetic loading. Other risk factors include pregnancy and delivery complications, infections during pregnancy, disturbances of early neuromotor and cognitive development and heavy cannabis use in adolescence. Unfortunately, to date it has not been possible to utilize the predictors of the disorder that have been identified in primary preventative interventions in a general population. However, some authors have claimed that in future it might be possible to reduce the risk for developing schizophrenia through general health policy. In clinical settings, it is helpful to map out possible early risk factors, at least familial risk for psychosis, especially in child, adolescent and young adult mental patients. Furthermore, in the future we may have predictive models combining data from genetic factors for schizophrenia, antenatal risk factors, childhood and adolescent development and clinical symptomatology, as well as brain structural and functional abnormalities.

Cardiovascular regulation and hippocampal sclerosis.

PURPOSE: Cardiovascular dysregulation has been detected in patients with temporal lobe epilepsy (TLE) by using cardiovascular reflex tests and analysis of heart rate variability (HRV). The two methods have not previously been used in the same study to compare them in the assessment of cardioregulatory function. Magnetic resonance imaging (MRI) is considered the best method to reveal structural changes such as hippocampal sclerosis associated with TLE. It is not known whether these structural changes modify cardioregulatory function in patients with TLE. METHODS: Standard cardiovascular reflex tests and analysis of spectral and dynamic measures from 24-h electrocardiogram (ECG) recordings were performed for eight patients with and 31 patients without hippocampal sclerosis and for 72 control subjects. MRI also was performed in each patient to reveal hippocampal sclerosis. RESULTS: Various measures of cardiovascular reflexes and HRV were diminished in patients with TLE compared with the control subjects. No significant differences were found in the measures obtained from the cardiovascular reflex tests or analysis of HRV between those with and without hippocampal sclerosis, although a nonsignificant trend toward reduced values was seen among those with hippocampal sclerosis. The values of cardiovascular reflexes and spectral analysis of HRV correlated with each other. CONCLUSIONS: These results suggest that functional rather than structural changes related to TLE are involved mainly as a mechanism of altered cardioregulatory function. The cardiovascular reflex test and analysis of HRV both appear to be useful in studying cardioregulation in patients with TLE.