Distinct Regionalization Patterns of Cortical Morphology are Associated with Cognitive Performance Across Different Domains.

Cognitive performance in children is predictive of academic and social outcomes; therefore, understanding neurobiological mechanisms underlying individual differences in cognition during development may be important for improving quality of life. The belief that a single, psychological construct underlies many cognitive processes is pervasive throughout society. However, it is unclear if there is a consistent neural substrate underlying many cognitive processes. Here, we show that a distributed configuration of cortical surface area and apparent thickness, when controlling for global imaging measures, is differentially associated with cognitive performance on different types of tasks in a large sample (N = 10 145) of 9-11-year-old children from the Adolescent Brain and Cognitive DevelopmentSM (ABCD) study. The minimal overlap in these regionalization patterns of association has implications for competing theories about developing intellectual functions. Surprisingly, not controlling for sociodemographic factors increased the similarity between these regionalization patterns. This highlights the importance of understanding the shared variance between sociodemographic factors, cognition and brain structure, particularly with a population-based sample such as ABCD.

Heritable influences on amygdala and orbitofrontal cortex contribute to genetic variation in core dimensions of personality.

While many studies have reported that individual differences in personality traits are genetically influenced, the neurobiological bases mediating these influences have not yet been well characterized. To advance understanding concerning the pathway from genetic variation to personality, here we examined whether measures of heritable variation in neuroanatomical size in candidate regions (amygdala and medial orbitofrontal cortex) were associated with heritable effects on personality. A sample of 486 middle-aged (mean=55 years) male twins (complete MZ pairs=120; complete DZ pairs=84) underwent structural brain scans and also completed measures of two core domains of personality: positive and negative emotionality. After adjusting for estimated intracranial volume, significant phenotypic (r(p)) and genetic (r(g)) correlations were observed between left amygdala volume and positive emotionality (r(p)=.16, p<.01; r(g)=.23, p<.05, respectively). In addition, after adjusting for mean cortical thickness, genetic and nonshared-environmental correlations (r(e)) between left medial orbitofrontal cortex thickness and negative emotionality were also observed (r(g)=.34, p<.01; r(e)=-.19, p<.05, respectively). These findings support a model positing that heritable bases of personality are, at least in part, mediated through individual differences in the size of brain structures, although further work is still required to confirm this causal interpretation.

Brain morphometric correlates of metabolic variables in HIV: the CHARTER study.

Obesity and other metabolic variables are associated with abnormal brain structural volumes and cognitive dysfunction in HIV-uninfected populations. Since individuals with HIV infection on combined antiretroviral therapy (CART) often have systemic metabolic abnormalities and changes in brain morphology and function, we examined associations among brain volumes and metabolic factors in the multisite CNS HIV AntiRetroviral Therapy Effects Research (CHARTER) cohort, cross-sectional study of 222 HIV-infected individuals. Metabolic variables included body mass index (BMI), total blood cholesterol (C), low- and high-density lipoprotein C (LDL-C and HDL-C), blood pressure, random blood glucose, and diabetes. MRI measured volumes of cerebral white matter, abnormal white matter, cortical and subcortical gray matter, and ventricular and sulcal CSF. Multiple linear regression models allowed us to examine metabolic variables separately and in combination to predict each regional volume. Greater BMI was associated with smaller cortical gray and larger white matter volumes. Higher total cholesterol (C) levels were associated with smaller cortex volumes; higher LDL-C was associated with larger cerebral white matter volumes, while higher HDL-C levels were associated with larger sulci. Higher blood glucose levels and diabetes were associated with more abnormal white matter. Multiple atherogenic metabolic factors contribute to regional brain volumes in HIV-infected, CART-treated patients, reflecting associations similar to those found in HIV-uninfected individuals. These risk factors may accelerate cerebral atherosclerosis and consequent brain alterations and cognitive dysfunction.

Reduction of edge-localized mode intensity using high-repetition-rate pellet injection in tokamak H-mode plasmas.

High repetition rate injection of deuterium pellets from the low-field side (LFS) of the DIII-D tokamak is shown to trigger high-frequency edge-localized modes (ELMs) at up to 12× the low natural ELM frequency in H-mode deuterium plasmas designed to match the ITER baseline configuration in shape, normalized beta, and input power just above the H-mode threshold. The pellet size, velocity, and injection location were chosen to limit penetration to the outer 10% of the plasma. The resulting perturbations to the plasma density and energy confinement time are thus minimal (<10%). The triggered ELMs occur at much lower normalized pedestal pressure than the natural ELMs, suggesting that the pellet injection excites a localized high-n instability. Triggered ELMs produce up to 12× lower energy and particle fluxes to the divertor, and result in a strong decrease in plasma core impurity density. These results show for the first time that shallow, LFS pellet injection can dramatically accelerate the ELM cycle and reduce ELM energy fluxes on plasma facing components, and is a viable technique for real-time control of ELMs in ITER.

Cerebral serotonin transporter binding is inversely related to body mass index.

Overweight and obesity is a health threat of increasing concern and understanding the neurobiology behind obesity is instrumental to the development of effective treatment regimes. Serotonergic neurotransmission is critically involved in eating behaviour; cerebral level of serotonin (5-HT) in animal models is inversely related to food intake and body weight and some effective anti-obesity agents involve blockade of the serotonin transporter (SERT). We investigated in 60 healthy volunteers body mass index (BMI) and regional cerebral SERT binding as measured with [(11)C]DASB PET. In a linear regression model with adjustment for relevant covariates, we found that cortical and subcortical SERT binding was negatively correlated to BMI (-0.003 to -0.012 BP(ND) unit per kg/m(2)). Tobacco smoking and alcohol consumption did not affect cerebral SERT binding. Several effective anti-obesity drugs encompass blockade of the SERT; yet, our study is the first to demonstrate an abnormally decreased cerebral SERT binding in obese individuals. Whether the SERT has a direct role in the regulation of appetite and eating behaviour or whether the finding is due to a compensatory downregulation of SERT secondary to other dysfunction(s) in the serotonergic transmitter system, such as low baseline serotonin levels, remains to be established.

Polygenic risk for psychiatric disorders correlates with executive function in typical development.

Executive functions are a diverse and critical suite of cognitive abilities that are often disrupted in individuals with psychiatric disorders. Despite their moderate to high heritability, little is known about the molecular genetic factors that contribute to variability in executive functions and how these factors may be related to those that predispose to psychiatric disorders. We examined the relationship between polygenic risk scores built from large genome-wide association studies of psychiatric disorders and executive functioning in typically developing children. In our discovery sample (N = 417), consistent with previous reports on general cognitive abilities, polygenic risk for autism spectrum disorder was associated with better performance on the Dimensional Change Card Sort test from the NIH Cognition Toolbox, with the largest effect in the youngest children. Polygenic risk for major depressive disorder was associated with poorer performance on the Flanker test in the same sample. This second association replicated for performance on the Penn Conditional Exclusion Test in an independent cohort (N = 3681). Our results suggest that the molecular genetic factors contributing to variability in executive function during typical development are at least partially overlapping with those associated with psychiatric disorders, although larger studies and further replication are needed.

Recruiting the ABCD sample: Design considerations and procedures.

The ABCD study is a new and ongoing project of very substantial size and scale involving 21 data acquisition sites. It aims to recruit 11,500 children and follow them for ten years with extensive assessments at multiple timepoints. To deliver on its potential to adequately describe adolescent development, it is essential that it adopt recruitment procedures that are efficient and effective and will yield a sample that reflects the nation's diversity in an epidemiologically informed manner. Here, we describe the sampling plans and recruitment procedures of this study. Participants are largely recruited through the school systems with school selection informed by gender, race and ethnicity, socioeconomic status, and urbanicity. Procedures for school selection designed to mitigate selection biases, dynamic monitoring of the accumulating sample to correct deviations from recruitment targets, and a description of the recruitment procedures designed to foster a collaborative attitude between the researchers, the schools and the local communities, are provided.

Computed tomographic evidence for generalized sulcal and ventricular enlargement in schizophrenia.

Quantification of ventricular and sulcal volumes from the computed tomographic (CT) scans of 45 schizophrenic patients and 57 normal controls was carried out using a semi-automated computerized approach. The sizes of all cerebrospinal fluid spaces measured were significantly related to age in the control population. An age regression model was used to compare patients and controls. Schizophrenics had slightly larger ventricles and considerably larger sulci than controls. Enlargement of the ventricles and sulci was not correlated with measures of negative symptoms or neuropsychological impairment. The CT scans of eight very ill chronically institutionalized schizophrenics were also analyzed. Their CT findings did not differ significantly from the larger group of schizophrenics studied. Our results show that the cerebral atrophy found in schizophrenia is diffuse in nature and does not relate clearly to measures of disease severity or chronicity.

Magnetic resonance imaging abnormalities in lenticular nuclei and cerebral cortex in schizophrenia.

Neuropathologic and brain imaging studies have produced evidence of brain abnormalities in schizophrenic patients, often within the cerebrum's limbic lobe, and, less frequently, within basal ganglia. In the present study we used magnetic resonance imaging morphometric techniques to estimate volumes of specific cerebral structures in schizophrenic patients and age- and sex-matched normal controls. Estimates of the volume of mesial temporal lobe structures were reduced and estimates of the volume of the lenticular nucleus were increased in the schizophrenic patients. There was also evidence of reduced cranial volume in some schizophrenics. The magnitude of the lenticular abnormality, but not the temporal lobe abnormality, was associated with age at first psychiatric contact; earlier onset was associated with larger lenticular nuclei. The possible relevance of these results to neurodevelopmental hypotheses about the pathogenesis of schizophrenia is discussed.

Computed tomography in schizophrenics and normal volunteers. II. Cranial asymmetry.

We studied cranial asymmetry in 31 schizophrenics and 32 normal volunteers, all of whom were male and right-handed. Automated measures of computed tomographic (CT) scans were used to estimate global hemicranial and hemispheric ventricular volume differences. A manual method was used to measure hemicranial asymmetries between the widths of the frontal and occipital areas on CT images. The observers making the measurements were unaware of the group membership of the subjects. High reliability was established for the manual method. In contrast to findings by other investigators, no group differences were observed. Methodologic flaws in earlier studies may account for this discrepancy.

Computed tomography in schizophrenics and normal volunteers. I. Fluid volume.

Recent findings of enlarged ventricles and sulcal widening in the computed tomographic (CT) scans of schizophrenic subjects have raised questions about the etiology and treatment of this disorder. Measures obtained from computerized analyses of CT scans of 30 schizophrenic and 33 normal subjects showed no significant difference between the groups in ventricular or sulcal fluid volumes. The discrepancy between our findings and those of other investigators may have been due to different measurement techniques or to differences in the samples. A second study was undertaken to examine the first possibility. Its results suggest that our findings and those based on measurements of planimetric ventricle-brain ratios (VBRs) are highly correlated, but that VBRs from one study may not be compared with those in another to establish population differences. Differences in patient samples appear to constitute an important source of discrepancy in CT findings.

Magnetic resonance imaging and mood disorders. Localization of white matter and other subcortical abnormalities.

BACKGROUND: Recent reports in the literature document an association between focal white matter abnormalities in bipolar as well as unipolar mood disorder. The importance of this finding and other associated anatomic differences is uncertain. METHODS: We examined the volume of abnormal white matter and other brain volumes using quantitative magnetic resonance imaging analysis. We explored the relationship of these variables with diagnosis, cognitive function, and clinical variables in 36 patients with bipolar disorder, 30 patients with unipolar disorder, and 26 control subjects who were free from significant medical and neurologic illness. RESULTS: Younger patients with bipolar disorder (but not similarly aged patients with unipolar disorder or controls) have an increased volume of abnormal white matter. Data also indicate that the total volume of abnormal white matter may be associated with increased cognitive impairment, increased rate of psychiatric illness in the family, and onset after adolescence. CONCLUSION: Patients with bipolar disorder demonstrate a pattern of subcortical brain morphologic abnormalities and cognitive impairment.

Subcortical abnormalities detected in bipolar affective disorder using magnetic resonance imaging. Clinical and neuropsychological significance.

Magnetic resonance imaging was utilized to determine the nature and rate of subcortical abnormalities in bipolar affective disorder. Nine of 19 bipolar patients and no controls demonstrated subcortical signal hyperintensities on blind evaluation of the images. There was no apparent change in the appearance of the hyperintensities in 7 of 7 subjects with abnormal magnetic resonance images who underwent repeated imaging at 1 year. Bipolar patients with abnormalities had a history of more hospitalizations and appeared more impaired on tests of fluency and recall when compared with bipolar patients without abnormalities or with controls. The possible etiology and significance of signal hyperintensities in bipolar affective disorder is discussed.

Cerebral structure on MRI, Part II: Specific changes in Alzheimer's and Huntington's diseases.

Using magnetic resonance (MR) imaging and morphometric techniques, groups of patients with Alzheimer's disease (AD) and Huntington's disease (HD) were compared with a large group of normal control subjects. Measures of volume loss in specific subcortical nuclei and eight cortical regions as well as an index of white matter abnormality were obtained. Results indicated expected widespread cortical volume reductions in AD, which were especially severe in mesial cortices; but comparable reductions were present in subcortical structures, particularly the thalamus. In HD, the greatest reductions were in striatal structures, but significant abnormalities were also detected in the thalamus and inferior cortical areas, especially in mesial temporal lobe structures. Significant degeneration in white matter was present in both groups, but was more dramatic in the HD patients. The significant diencephalic reduction in AD may make an important contribution to early memory deficits in the disorder, which are usually attributed to hippocampal damage. Similarly, damage to both the thalamus and mesial temporal lobe structures may play a role in the memory deficits of HD.

Cerebral structure on MRI, Part I: Localization of age-related changes.

In this report, earlier findings of age-related changes in brain morphology on magnetic resonance (MR) images are extended to include measurements of individual cerebral grey matter structures and an index of white matter degeneration. Volumes of caudate, lenticular, and diencephalic structures are estimated, as are grey matter volumes in eight separate cortical regions. Results suggest that between 30 and 79 years significant decreases occur in the volume of the caudate nucleus, in anterior diencephalic structures, and in the grey matter of most cortical regions. The data suggest that the volumes of the thalamus and the anterior cingulate cortex may be unchanged. Among those cortical regions found to be affected in aging, some evidence is present for greater change in association cortices and mesial temporal lobe structures. There are also dramatic age-related changes in the white matter, manifest as lengthened T2 values on MR images.

Effects of age on tissues and regions of the cerebrum and cerebellum.

Normal volunteers, aged 30 to 99 years, were studied with MRI. Age was related to estimated volumes of: gray matter, white matter, and CSF of the cerebrum and cerebellum; gray matter, white matter, white matter abnormality, and CSF within each cerebral lobe; and gray matter of eight subcortical structures. The results were: 1) Age-related losses in the hippocampus were significantly accelerated relative to gray matter losses elsewhere in the brain. 2) Among the cerebral lobes, the frontal lobes were disproportionately affected by cortical volume loss and increased white matter abnormality. 3) Loss of cerebral and cerebellar white matter occurred later than, but was ultimately greater than, loss of gray matter. It is estimated that between the ages of 30 and 90 volume loss averages 14% in the cerebral cortex, 35% in the hippocampus, and 26% in the cerebral white matter. Separate analyses were conducted in which genetic risk associated with the Apolipoprotein E epsilon4 allele was either overrepresented or underrepresented among elderly participants. Accelerated loss of hippocampal volume was observed with both analyses and thus does not appear to be due to the presence of at-risk subjects. MR signal alterations in the tissues of older individuals pose challenges to the validity of current methods of tissue segmentation, and should be considered in the interpretation of the results.

Quantitative magnetic resonance imaging of the brain in late-life schizophrenia.

OBJECTIVE: This study compared morphometric analyses of brain regions in elderly subjects with early- or late-onset schizophrenia to identify structural abnormalities responsible for schizophrenia. METHOD: Quantitative analyses of magnetic resonance images of the brain were performed in 16 patients with DSM-III-R-diagnosed late-onset schizophrenia (i.e., onset after age 45), 14 patients with early-onset schizophrenia, and 28 normal comparison subjects, all of whom were over the age of 45. The three groups were similar in age, sex, education, and handedness. RESULTS: The groups differed significantly in ventricular and thalamic volumes. The patients with late-onset schizophrenia had significantly larger ventricles than the normal comparison subjects and significantly larger thalamic volumes than the patients with early-onset schizophrenia. There were no significant linear correlations between thalamic volume and age at onset, duration of illness, or mean current neuroleptic dose. CONCLUSIONS: Differences in thalamic volume may account for the putative disruption in thalamofrontal ciruitry in schizophrenia.

Past substance abuse and clinical course of schizophrenia.

To evaluate the effects of previous alcohol and drug use on the course and symptoms of schizophrenia, the authors compared 34 patients with schizophrenia who had histories of substance abuse with 17 patients with schizophrenia who were lifelong abstainers. Surprisingly, they did not find that individuals with past histories of abuse were more impaired or had more symptoms.

Anomalous brain morphology on magnetic resonance images in Williams syndrome and Down syndrome.

Quantitative studies of brain morphology in a group of subjects with Williams syndrome revealed a distinctive pattern of dysmorphology unlike that observed in another form of mental retardation. Down syndrome. Reduced cerebral size but normal cerebellar size was observed in Williams syndrome, in contrast to reductions in both brain components in Down syndrome. Examination of cerebellar vermal morphology suggested significantly increased area of neocerebellar vermal lobules in Williams syndrome, with low-normal size in the paleocerebellar vermal lobules. Thus, a highly selective effect on brain development appears to accompany Williams syndrome, with some brain subsystems, possibly later-developing ones, relatively spared.

Abnormal neuroanatomy in a nonretarded person with autism. Unusual findings with magnetic resonance imaging.

Recent studies of infantile autism using computed tomographic scanning emphasized the importance of studying cases of classic autism (Kanner's syndrome) without complicating conditions such as mental retardation. Computed tomographic scan studies of such patients reported no evidence of anatomical abnormalities of cerebral hemispheres or of subcortical structures, which are defined by landmarks such as the lateral ventricles and lentiform nuclei. Examination of the cerebellum was not mentioned. The most recent postmortem neuropathologic study reported significant cerebellar abnormality, but the study was of a severely retarded autistic individual. Using magnetic resonance imaging, we have found in vivo evidence of a significant and unusual cerebellar malformation in a person with the classic form of autism uncomplicated by mental retardation (current nonverbal IQ = 112), epilepsy, history of drug use, postnatal trauma, or disease. The finding showed hypoplasia of the declive, folium, and tuber in posterior vermis, but not of the anterior vermis, and hypoplasia of only the medial aspect of each cerebellar hemisphere. The right posterior cerebral hemisphere also showed pathologic findings.