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1.
JAMA Psychiatry ; 76(7): 739-748, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30969333

RESUMO

Importance: Between-individual variability in brain structure is determined by gene-environment interactions, possibly reflecting differential sensitivity to environmental and genetic perturbations. Magnetic resonance imaging (MRI) studies have revealed thinner cortices and smaller subcortical volumes in patients with schizophrenia. However, group-level comparisons may mask considerable within-group heterogeneity, which has largely remained unnoticed in the literature. Objectives: To compare brain structural variability between individuals with schizophrenia and healthy controls and to test whether respective variability reflects the polygenic risk score (PRS) for schizophrenia in an independent sample of healthy controls. Design, Setting, and Participants: This case-control and polygenic risk analysis compared MRI-derived cortical thickness and subcortical volumes between healthy controls and patients with schizophrenia across 16 cohorts and tested for associations between PRS and MRI features in a control cohort from the UK Biobank. Data were collected from October 27, 2004, through April 12, 2018, and analyzed from December 3, 2017, through August 1, 2018. Main Outcomes and Measures: Mean and dispersion parameters were estimated using double generalized linear models. Vertex-wise analysis was used to assess cortical thickness, and regions-of-interest analyses were used to assess total cortical volume, total surface area, and white matter, subcortical, and hippocampal subfield volumes. Follow-up analyses included within-sample analysis, test of robustness of the PRS threshold, population covariates, outlier removal, and control for image quality. Results: A comparison of 1151 patients with schizophrenia (mean [SD] age, 33.8 [10.6] years; 68.6% male [n = 790] and 31.4% female [n = 361]) with 2010 healthy controls (mean [SD] age, 32.6 [10.4] years; 56.0% male [n = 1126] and 44.0% female [n = 884]) revealed higher heterogeneity in schizophrenia for cortical thickness and area (t = 3.34), cortical (t = 3.24) and ventricle (t range, 3.15-5.78) volumes, and hippocampal subfields (t range, 2.32-3.55). In the UK Biobank sample of 12 490 participants (mean [SD] age, 55.9 [7.5] years; 48.2% male [n = 6025] and 51.8% female [n = 6465]), higher PRS was associated with thinner frontal and temporal cortices and smaller left CA2/3 (t = -3.00) but was not significantly associated with dispersion. Conclusions and Relevance: This study suggests that schizophrenia is associated with substantial brain structural heterogeneity beyond the mean differences. These findings may reflect higher sensitivity to environmental and genetic perturbations in patients, supporting the heterogeneous nature of schizophrenia. A higher PRS was associated with thinner frontotemporal cortices and smaller hippocampal subfield volume, but not heterogeneity. This finding suggests that brain variability in schizophrenia results from interactions between environmental and genetic factors that are not captured by the PRS. Factors contributing to heterogeneity in frontotemporal cortices and hippocampus are key to furthering our understanding of how genetic and environmental factors shape brain biology in schizophrenia.

2.
Biol Psychiatry ; 86(1): 65-75, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30850129

RESUMO

BACKGROUND: Accumulating evidence supports cerebellar involvement in mental disorders, such as schizophrenia, bipolar disorder, depression, anxiety disorders, and attention-deficit/hyperactivity disorder. However, little is known about the cerebellum in developmental stages of these disorders. In particular, whether cerebellar morphology is associated with early expression of specific symptom domains remains unclear. METHODS: We used machine learning to test whether cerebellar morphometric features could robustly predict general cognitive function and psychiatric symptoms in a large and well-characterized developmental community sample centered on adolescence (Philadelphia Neurodevelopmental Cohort, n = 1401, age 8-23 years). RESULTS: Cerebellar morphology was associated with both general cognitive function and general psychopathology (mean correlations between predicted and observed values: r = .20 and r = .13; p < .001). Analyses of specific symptom domains revealed significant associations with rates of norm-violating behavior (r = .17; p < .001) as well as psychosis (r = .12; p < .001) and anxiety (r = .09; p = .012) symptoms. In contrast, we observed no associations with attention deficits or depressive, manic, or obsessive-compulsive symptoms. Crucially, across 52 brain-wide anatomical features, cerebellar features emerged as the most important for prediction of general psychopathology, psychotic symptoms, and norm-violating behavior. Moreover, the association between cerebellar volume and psychotic symptoms and, to a lesser extent, norm-violating behavior remained significant when adjusting for several potentially confounding factors. CONCLUSIONS: The robust associations with psychiatric symptoms in the age range when these typically emerge highlight the cerebellum as a key brain structure in the development of severe mental disorders.

3.
Nat Commun ; 10(1): 668, 2019 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-30737392

RESUMO

Oxytocin is a neuropeptide involved in animal and human reproductive and social behavior. Three oxytocin signaling genes have been frequently implicated in human social behavior: OXT (structural gene for oxytocin), OXTR (oxytocin receptor), and CD38 (oxytocin secretion). Here, we characterized the distribution of OXT, OXTR, and CD38 mRNA across the human brain by creating voxel-by-voxel volumetric expression maps, and identified putative gene pathway interactions by comparing gene expression patterns across 20,737 genes. Expression of the three selected oxytocin pathway genes was enriched in subcortical and olfactory regions and there was high co-expression with several dopaminergic and muscarinic acetylcholine genes, reflecting an anatomical basis for critical gene pathway interactions. fMRI meta-analysis revealed that the oxytocin pathway gene maps correspond with the processing of anticipatory, appetitive, and aversive cognitive states. The oxytocin signaling system may interact with dopaminergic and muscarinic acetylcholine signaling to modulate cognitive state processes involved in complex human behaviors.


Assuntos
Encéfalo/metabolismo , Ocitocina/metabolismo , Receptores de Ocitocina/metabolismo , ADP-Ribosil Ciclase 1/metabolismo , Adulto , Cognição/fisiologia , Feminino , Humanos , Hipotálamo/metabolismo , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo
4.
Biol Psychiatry ; 2018 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-30447910

RESUMO

BACKGROUND: Cerebral myeloarchitecture shows substantial development across childhood and adolescence, and aberrations in these trajectories are relevant for a range of mental disorders. Differential myelination between intracortical and subjacent white matter can be approximated using signal intensities in T1-weighted magnetic resonance imaging. METHODS: To test the sensitivity of gray/white matter contrast (GWC) to age and individual differences in psychopathology and general cognitive ability in youths (8-23 years), we formed data-driven psychopathology and cognitive components using a large population-based sample, the Philadelphia Neurodevelopmental Cohort (N = 6487, 52% female). We then tested for associations with regional GWC defined by an independent component analysis in a subsample with available magnetic resonance imaging data (n = 1467, 53% female). RESULTS: The analyses revealed a global GWC component, which showed an age-related decrease from late childhood and across adolescence. In addition, we found regional anatomically meaningful components with differential age associations explaining variance beyond the global component. When accounting for age and sex, both higher symptom levels of anxiety or prodromal psychosis and lower cognitive ability were associated with higher GWC in insula and cingulate cortices and with lower GWC in pre- and postcentral cortices. We also found several additional regional associations with anxiety, prodromal psychosis, and cognitive ability. CONCLUSIONS: Independent modes of GWC variation are sensitive to global and regional brain developmental processes, possibly related to differences between intracortical and subjacent white matter myelination, and individual differences in regional GWC are associated with both mental health and general cognitive functioning.

5.
Mov Disord ; 33(9): 1472-1480, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30277603

RESUMO

BACKGROUND: Musician's dystonia critically impacts professional musicians' careers as they may lose musical skills, which have been acquired through long and intensive training. Yet the pathophysiology of musician's dystonia and its link to the neural mechanisms supporting musical skills is poorly understood. We tested if resting-state functional connectivity might reflect an aspect of musical skill linked to the pathophysiology of musician's dystonia. We also tested a second hypothesis that the region with altered resting-state functional connectivity might be correlated with a quantitative measure of musical skills. METHODS: We studied 21 patients with musician's dystonia affecting their hands and 34 healthy musicians, using resting-state functional magnetic resonance imaging and behavioral assessment. We tested between-group differences of resting-state functional connectivity throughout the whole brain using independent component analysis. RESULTS: We found abnormal basal ganglia resting-state functional connectivity in the putamina of patients with musician's dystonia compared with those of healthy musicians (P = 0.035 corrected for multiple comparisons). We also found that the temporal precision of keystrokes was correlated with basal ganglia functional connectivity in the putamina of healthy pianists (r = 0.72, P = 0.0005), but not in pianists with musician's dystonia (r = -0.11, P = 0.64). CONCLUSIONS: We show that abnormalities of the putamen exist even at rest in musician's dystonia, whereas putaminal abnormality has previously been reported during a task. Moreover, basal ganglia resting-state functional connectivity in the putamen represented training levels in healthy musicians, and its disruption was associated with musician's dystonia. This novel finding hints at the pathophysiological mechanisms by which musician's dystonia follows extensive musical training. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

6.
Mol Psychiatry ; 2018 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-30279459

RESUMO

The hippocampus is a heterogeneous structure, comprising histologically distinguishable subfields. These subfields are differentially involved in memory consolidation, spatial navigation and pattern separation, complex functions often impaired in individuals with brain disorders characterized by reduced hippocampal volume, including Alzheimer's disease (AD) and schizophrenia. Given the structural and functional heterogeneity of the hippocampal formation, we sought to characterize the subfields' genetic architecture. T1-weighted brain scans (n = 21,297, 16 cohorts) were processed with the hippocampal subfields algorithm in FreeSurfer v6.0. We ran a genome-wide association analysis on each subfield, co-varying for whole hippocampal volume. We further calculated the single-nucleotide polymorphism (SNP)-based heritability of 12 subfields, as well as their genetic correlation with each other, with other structural brain features and with AD and schizophrenia. All outcome measures were corrected for age, sex and intracranial volume. We found 15 unique genome-wide significant loci across six subfields, of which eight had not been previously linked to the hippocampus. Top SNPs were mapped to genes associated with neuronal differentiation, locomotor behaviour, schizophrenia and AD. The volumes of all the subfields were estimated to be heritable (h2 from 0.14 to 0.27, all p < 1 × 10-16) and clustered together based on their genetic correlations compared with other structural brain features. There was also evidence of genetic overlap of subicular subfield volumes with schizophrenia. We conclude that hippocampal subfields have partly distinct genetic determinants associated with specific biological processes and traits. Taking into account this specificity may increase our understanding of hippocampal neurobiology and associated pathologies.

7.
Sci Rep ; 8(1): 14129, 2018 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-30237410

RESUMO

Supported by histological and genetic evidence implicating myelin, neuroinflammation and oligodendrocyte dysfunction in schizophrenia spectrum disorders (SZ), diffusion tensor imaging (DTI) studies have consistently shown white matter (WM) abnormalities when compared to healthy controls (HC). The diagnostic specificity remains unclear, with bipolar disorders (BD) frequently conceptualized as a less severe clinical manifestation along a psychotic spectrum. Further, the age-related dynamics and possible sex differences of WM abnormalities in SZ and BD are currently understudied. Using tract-based spatial statistics (TBSS) we compared DTI-based microstructural indices between SZ (n = 128), BD (n = 61), and HC (n = 293). We tested for age-by-group and sex-by-group interactions, computed effect sizes within different age-bins and within genders. TBSS revealed global reductions in fractional anisotropy (FA) and increases in radial (RD) diffusivity in SZ compared to HC, with strongest effects in the body and splenium of the corpus callosum, and lower FA in SZ compared to BD in right inferior longitudinal fasciculus and right inferior fronto-occipital fasciculus, and no significant differences between BD and HC. The results were not strongly dependent on age or sex. Despite lack of significant group-by-age interactions, a sliding-window approach supported widespread WM involvement in SZ with most profound differences in FA from the late 20 s.

8.
Eur J Hum Genet ; 26(7): 1049-1059, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29700391

RESUMO

Cognitive and brain development are determined by dynamic interactions between genes and environment across the lifespan. Aside from marker-by-marker analyses of polymorphisms, biologically meaningful features of the whole genome (derived from the combined effect of individual markers) have been postulated to inform on human phenotypes including cognitive traits and their underlying biological substrate. Here, estimates of inbreeding and genetic susceptibility for schizophrenia calculated from genome-wide data-runs of homozygosity (ROH) and schizophrenia polygenic risk score (PGRS)-are analyzed in relation to cognitive abilities (n = 4183) and brain structure (n = 516) in a general-population sample of European-ancestry participants aged 8-22, from the Philadelphia Neurodevelopmental Cohort. The findings suggest that a higher ROH burden and higher schizophrenia PGRS are associated with higher intelligence. Cognition-ROH and cognition-PGRS associations obtained in this cohort may, respectively, evidence that assortative mating influences intelligence, and that individuals with high schizophrenia genetic risk who do not transition to disease status are cognitively resilient. Neuroanatomical data showed that the effects of schizophrenia PGRS on cognition could be modulated by brain structure, although larger imaging datasets are needed to accurately disentangle the underlying neural mechanisms linking IQ with both inbreeding and the genetic burden for schizophrenia.

9.
Front Neurosci ; 11: 656, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29249930

RESUMO

Magnetic field inhomogeneities cause geometric distortions of echo planar images used for functional magnetic resonance imaging (fMRI). To reduce this problem, distortion correction (DC) with field map is widely used for both task and resting-state fMRI (rs-fMRI). Although DC with field map has been reported to improve the quality of task fMRI, little is known about its effects on rs-fMRI. Here, we tested the influence of field-map DC on rs-fMRI results using two rs-fMRI datasets derived from 40 healthy subjects: one with DC (DC+) and the other without correction (DC-). Independent component analysis followed by the dual regression approach was used for evaluation of resting-state functional connectivity networks (RSN). We also obtained the ratio of low-frequency to high-frequency signal power (0.01-0.1 Hz and above 0.1 Hz, respectively; LFHF ratio) to assess the quality of rs-fMRI signals. For comparison of RSN between DC+ and DC- datasets, the default mode network showed more robust functional connectivity in the DC+ dataset than the DC- dataset. Basal ganglia RSN showed some decreases in functional connectivity primarily in white matter, indicating imperfect registration/normalization without DC. Supplementary seed-based and simulation analyses supported the utility of DC. Furthermore, we found a higher LFHF ratio after field map correction in the anterior cingulate cortex, posterior cingulate cortex, ventral striatum, and cerebellum. In conclusion, field map DC improved detection of functional connectivity derived from low-frequency rs-fMRI signals. We encourage researchers to include a DC step in the preprocessing pipeline of rs-fMRI analysis.

10.
Sci Rep ; 7: 45131, 2017 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-28338052

RESUMO

Recent efforts using diffusion tensor imaging (DTI) have documented white matter (WM) alterations in Alzheimer's disease (AD). The full potential of whole-brain DTI, however, has not been fully exploited as studies have focused on individual microstructural indices independently. In patients with AD (n = 79), mild (MCI, n = 55) and subjective (SCI, n = 30) cognitive impairment, we applied linked independent component analysis (LICA) to model inter-subject variability across five complementary DTI measures (fractional anisotropy (FA), axial/radial/mean diffusivity, diffusion tensor mode), two crossing fiber measures estimated using a multi-compartment crossing-fiber model reflecting the volume fraction of the dominant (f1) and non-dominant (f2) diffusion orientation, and finally, connectivity density obtained from full-brain probabilistic tractography. The LICA component explaining the largest data variance was highly sensitive to disease severity (AD < MCI < SCI) and revealed widespread coordinated decreases in FA and f1 with increases in all diffusivity measures in AD. Additionally, it reflected regional coordinated decreases and increases in f2, mode and connectivity density, implicating bidirectional alterations of crossing fibers in the fornix, uncinate fasciculi, corpus callosum and major sensorimotor pathways. LICA yielded improved diagnostic classification performance compared to univariate region-of-interest features. Our results document coordinated WM microstructural and connectivity alterations in line with disease severity across the AD continuum.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Conectoma , Substância Branca/diagnóstico por imagem , Idoso , Variação Biológica Individual , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade
11.
Front Aging Neurosci ; 7: 219, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26640437

RESUMO

Carnosine and anserine are strong antioxidants, previously demonstrated to reduce cognitive decline in animal studies. We aimed to investigate their cognitive and neurophysiological effects, using functional MRI, on humans. Thirty-one healthy participants (age 40-78, 10 male/21 female) were recruited to a double-blind placebo-controlled study. Participants were assigned to twice-daily doses of imidazole dipeptide formula (n = 14), containing 500 mg (carnosine/anserine, ratio 1/3) or an identical placebo (n = 17). Functional MRI and neuropsychological assessments were carried out at baseline and after 3 months of supplementation. We analyzed resting state functional connectivity with the FSL fMRI analysis package. There were no differences in neuropsychological scores between the groups at baseline. After 3 months of supplementation, the carnosine/anserine group had better verbal episodic memory performance and decreased connectivity in the default mode network, the posterior cingulate cortex and the right fronto parietal network, as compared with the placebo group. Furthermore, there was a correlation between the extents of cognitive and neuroimaging changes. These results suggest that daily carnosine/anserine supplementation can impact cognitive function and that network connectivity changes are associated with its effects.

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