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1.
Biol Psychiatry ; 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-32143830

RESUMO

BACKGROUND: 22q11.2 deletions and duplications are copy number variations (CNVs) that predispose to developmental neuropsychiatric disorders. Both CNVs are associated with autism spectrum disorder (ASD), while the deletion confers disproportionate risk for schizophrenia. Neurobehavioral profiles associated with these reciprocal CNVs in conjunction with brain imaging measures have not been reported. METHODS: We profiled the impact of 22q11.2 CNVs on neurobehavioral measures relevant to ASD and psychosis in 106 22q11.2 deletion carriers, 38 22q11.2 duplication carriers, and 82 demographically matched healthy control subjects. To determine whether brain-behavior relationships were altered in CNV carriers, we further tested for interactions between group and regional brain structure on neurobehavioral domains. RESULTS: Cognitive deficits were observed in both CNV groups, with the lowest IQs in deletion carriers. ASD and dimensionally measured ASD traits were elevated in both CNV groups; however, duplication carriers exhibited increased stereotypies compared to deletion carriers. Moreover, discriminant analysis using ASD subdomains distinguished between CNV cases with 76% accuracy. Both psychotic disorder diagnosis and dimensionally measured positive and negative symptoms were elevated in deletion carriers. Finally, healthy control subjects showed an inverse relationship between processing speed and cortical thickness in heteromodal association areas, which was absent in both CNV groups. CONCLUSIONS: 22q11.2 CNVs differentially modulate intellectual functioning and psychosis-related symptomatology but converge on broad ASD-related symptomatology. However, subtle differences in ASD profiles distinguish CNV groups. Processing speed impairments, coupled with the lack of normative relationship between processing speed and cortical thickness in CNV carriers, implicate aberrant development of the cortical mantle in the pathology underlying impaired processing speed ability.

2.
Am J Psychiatry ; : appiajp201919060583, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32046535

RESUMO

OBJECTIVE: 22q11.2 deletion syndrome (22q11DS) is among the strongest known genetic risk factors for schizophrenia. Previous studies have reported variable alterations in subcortical brain structures in 22q11DS. To better characterize subcortical alterations in 22q11DS, including modulating effects of clinical and genetic heterogeneity, the authors studied a large multicenter neuroimaging cohort from the ENIGMA 22q11.2 Deletion Syndrome Working Group. METHODS: Subcortical structures were measured using harmonized protocols for gross volume and subcortical shape morphometry in 533 individuals with 22q11DS and 330 matched healthy control subjects (age range, 6-56 years; 49% female). RESULTS: Compared with the control group, the 22q11DS group showed lower intracranial volume (ICV) and thalamus, putamen, hippocampus, and amygdala volumes and greater lateral ventricle, caudate, and accumbens volumes (Cohen's d values, -0.90 to 0.93). Shape analysis revealed complex differences in the 22q11DS group across all structures. The larger A-D deletion was associated with more extensive shape alterations compared with the smaller A-B deletion. Participants with 22q11DS with psychosis showed lower ICV and hippocampus, amygdala, and thalamus volumes (Cohen's d values, -0.91 to 0.53) compared with participants with 22q11DS without psychosis. Shape analysis revealed lower thickness and surface area across subregions of these structures. Compared with subcortical findings from other neuropsychiatric disorders studied by the ENIGMA consortium, significant convergence was observed between participants with 22q11DS with psychosis and participants with schizophrenia, bipolar disorder, major depressive disorder, and obsessive-compulsive disorder. CONCLUSIONS: In the largest neuroimaging study of 22q11DS to date, the authors found widespread alterations to subcortical brain structures, which were affected by deletion size and psychotic illness. Findings indicate significant overlap between 22q11DS-associated psychosis, idiopathic schizophrenia, and other severe neuropsychiatric illnesses.

3.
Schizophr Bull ; 46(2): 395-407, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-31424081

RESUMO

BACKGROUND: Resting-state functional neuroimaging captures large-scale network organization; whether this organization is intact or disrupted during adolescent development across the psychosis spectrum is unresolved. We investigated the integrity of network organization in psychosis spectrum youth and those with first episode psychosis (FEP) from late childhood through adulthood. METHODS: We analyzed data from Philadelphia Neurodevelopmental Cohort (PNC; typically developing = 450, psychosis spectrum = 273, 8-22 years), a longitudinal cohort of typically developing youth (LUNA; N = 208, 1-3 visits, 10-25 years), and a sample of FEP (N = 39) and matched controls (N = 34). We extracted individual time series and calculated correlations from brain regions and averaged them for 4 age groups: late childhood, early adolescence, late adolescence, adulthood. Using multiple analytic approaches, we assessed network stability across 4 age groups, compared stability between controls and psychosis spectrum youth, and compared group-level network organization of FEP to controls. We explored whether variability in cognition or clinical symptomatology was related to network organization. RESULTS: Network organization was stable across the 4 age groups in the PNC and LUNA typically developing youth and PNC psychosis spectrum youth. Psychosis spectrum and typically developing youth had similar functional network organization during all age ranges. Network organization was intact in PNC youth who met full criteria for psychosis and in FEP. Variability in cognitive functioning or clinical symptomatology was not related to network organization in psychosis spectrum youth or FEP. DISCUSSION: These findings provide rigorous evidence supporting intact functional network organization in psychosis risk and psychosis from late childhood through adulthood.

4.
Schizophr Bull ; 46(2): 408-421, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-31219595

RESUMO

Psychosis spectrum disorders are conceptualized as neurodevelopmental disorders accompanied by disruption of large-scale functional brain networks. Dynamic functional dysconnectivity has been described in patients with schizophrenia and in help-seeking individuals at clinical high risk for psychosis. Less is known, about developmental aspects of dynamic functional network connectivity (dFNC) associated with psychotic symptoms (PS) in the general population. Here, we investigate resting state functional magnetic resonance imaging data using established dFNC methods in the Philadelphia Neurodevelopmental Cohort (ages 8-22 years), including 129 participants experiencing PS and 452 participants without PS (non-PS). Functional networks were identified using group spatial independent component analysis. A sliding window approach and k-means clustering were applied to covariance matrices of all functional networks to identify recurring whole-brain connectivity states. PS-associated dysconnectivity of default mode, salience, and executive networks occurred only in a few states, whereas dysconnectivity in the sensorimotor and visual systems in PS youth was more pervasive, observed across multiple states. This study provides new evidence that disruptions of dFNC are present even at the less severe end of the psychosis continuum in youth, complementing previous work on help-seeking and clinically diagnosed cohorts that represent the more severe end of this spectrum.

5.
Cereb Cortex ; 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31670797

RESUMO

Significant improvements in cognitive control occur from childhood through adolescence, supported by the maturation of prefrontal systems. However, less is known about the neural basis of refinements in cognitive control proceeding from adolescence to adulthood. Accumulating evidence indicates that integration between hippocampus (HPC) and prefrontal cortex (PFC) supports flexible cognition and has a protracted neural maturation. Using a longitudinal design (487 scans), we characterized developmental changes from 8 to 32 years of age in HPC-PFC functional connectivity at rest and its associations with cognitive development. Results indicated significant increases in functional connectivity between HPC and ventromedial PFC (vmPFC), but not dorsolateral PFC. Importantly, HPC-vmPFC connectivity exclusively predicted performance on the Stockings of Cambridge task, which probes problem solving and future planning. These data provide evidence that maturation of high-level cognition into adulthood is supported by increased functional integration across the HPC and vmPFC through adolescence.

6.
Nat Commun ; 10(1): 4958, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31673008

RESUMO

Altered structural brain asymmetry in autism spectrum disorder (ASD) has been reported. However, findings have been inconsistent, likely due to limited sample sizes. Here we investigated 1,774 individuals with ASD and 1,809 controls, from 54 independent data sets of the ENIGMA consortium. ASD was significantly associated with alterations of cortical thickness asymmetry in mostly medial frontal, orbitofrontal, cingulate and inferior temporal areas, and also with asymmetry of orbitofrontal surface area. These differences generally involved reduced asymmetry in individuals with ASD compared to controls. Furthermore, putamen volume asymmetry was significantly increased in ASD. The largest case-control effect size was Cohen's d = -0.13, for asymmetry of superior frontal cortical thickness. Most effects did not depend on age, sex, IQ, severity or medication use. Altered lateralized neurodevelopment may therefore be a feature of ASD, affecting widespread brain regions with diverse functions. Large-scale analysis was necessary to quantify subtle alterations of brain structural asymmetry in ASD.

7.
Mol Psychiatry ; 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31358905

RESUMO

22q11.2 deletion syndrome (22q11DS)-a neurodevelopmental condition caused by a hemizygous deletion on chromosome 22-is associated with an elevated risk of psychosis and other developmental brain disorders. Prior single-site diffusion magnetic resonance imaging (dMRI) studies have reported altered white matter (WM) microstructure in 22q11DS, but small samples and variable methods have led to contradictory results. Here we present the largest study ever conducted of dMRI-derived measures of WM microstructure in 22q11DS (334 22q11.2 deletion carriers and 260 healthy age- and sex-matched controls; age range 6-52 years). Using harmonization protocols developed by the ENIGMA-DTI working group, we identified widespread reductions in mean, axial and radial diffusivities in 22q11DS, most pronounced in regions with major cortico-cortical and cortico-thalamic fibers: the corona radiata, corpus callosum, superior longitudinal fasciculus, posterior thalamic radiations, and sagittal stratum (Cohen's d's ranging from -0.9 to -1.3). Only the posterior limb of the internal capsule (IC), comprised primarily of corticofugal fibers, showed higher axial diffusivity in 22q11DS. 22q11DS patients showed higher mean fractional anisotropy (FA) in callosal and projection fibers (IC and corona radiata) relative to controls, but lower FA than controls in regions with predominantly association fibers. Psychotic illness in 22q11DS was associated with more substantial diffusivity reductions in multiple regions. Overall, these findings indicate large effects of the 22q11.2 deletion on WM microstructure, especially in major cortico-cortical connections. Taken together with findings from animal models, this pattern of abnormalities may reflect disrupted neurogenesis of projection neurons in outer cortical layers.

8.
Artigo em Inglês | MEDLINE | ID: mdl-30852127

RESUMO

BACKGROUND: A longer duration of untreated psychosis (DUP) has been linked with poor clinical outcomes and variation in resting-state striatal connectivity with central executive regions. However, the link between DUP and task-based activation of executive neurocognition has not previously been examined. This functional magnetic resonance imaging study examined the association between DUP and both activation and frontostriatal functional connectivity during a visual working memory (WM) paradigm in patients with first-episode psychosis. METHODS: Patients with first-episode psychosis (n = 37) underwent functional magnetic resonance imaging scanning while performing a visual WM task. At the single-subject level, task conditions were modeled; at the group level, each condition was examined along with DUP. Activation was examined within the dorsolateral prefrontal cortex, a primary region supporting visual WM activation. Frontostriatal functional connectivity during the WM was examined via psychophysical interaction between the dorsal caudate and the dorsolateral prefrontal cortex. Results were compared with a reference range of connectivity values in a matched group of healthy volunteers (n = 25). Task performance was also examined in relation to neuroimaging findings. RESULTS: No significant association was observed between DUP and WM activation. Longer DUP showed less functional frontostriatal connectivity with the maintenance of increasing WM load. Results were not related to task performance measures, consistent with previous work. CONCLUSIONS: Our data suggest that DUP may affect frontostriatal circuitry that supports executive functioning. Future work is necessary to examine if these findings contribute to the mechanism underlying the relationship between DUP and worsened clinical outcomes.


Assuntos
Antipsicóticos/uso terapêutico , Memória de Curto Prazo/fisiologia , Córtex Pré-Frontal/patologia , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/patologia , Tempo para o Tratamento , Adolescente , Adulto , Criança , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Vias Neurais/diagnóstico por imagem , Vias Neurais/patologia , Córtex Pré-Frontal/diagnóstico por imagem , Transtornos Psicóticos/diagnóstico por imagem , Adulto Jovem
9.
J Am Acad Child Adolesc Psychiatry ; 58(11): 1079-1091, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30768396

RESUMO

OBJECTIVE: Adults with established diagnoses of serious mental illness (bipolar disorder and schizophrenia) exhibit structural brain abnormalities, yet less is known about how such abnormalities manifest earlier in development. METHOD: Cross-sectional data publicly available from the Philadelphia Neurodevelopmental Cohort (PNC) were analyzed. Structural magnetic resonance neuroimaging data were collected on a subset of the PNC (N = 989; 9-22 years old). Cortical thickness, surface area (SA), and subcortical volumes were calculated. Study participants were assessed for psychiatric symptomatology using a structured interview and the following groups were created: typically developing (n = 376), psychosis spectrum (PS; n = 113), bipolar spectrum (BP; n = 117), and BP + PS (n = 109). Group and developmental differences in structural magnetic resonance neuroimaging measures were examined. In addition, the extent to which any structural aberration was related to neurocognition, global functioning, and clinical symptomatology was examined. RESULTS: Compared with other groups, PS youth exhibited significantly decreased SA in the orbitofrontal, cingulate, precentral, and postcentral regions. PS youth also exhibited deceased thalamic volume compared with all other groups. The strongest effects for precentral and posterior cingulate SA decreases were seen during early adolescence (13-15 years old) in PS youth. The strongest effects for decreases in thalamic volume and orbitofrontal and postcentral SA were observed in mid-adolescence (16-18 years) in PS youth. Across groups, better overall functioning was associated with increased lateral orbitofrontal SA. Increased postcentral SA was associated with better executive cognition and less severe negative symptoms in the entire sample. CONCLUSION: In a community-based sample, decreased cortical SA and thalamic volume were present early in adolescent development in youth with PS symptoms, but not in youth with BP symptoms or with BP and PS symptoms. These findings point to potential biological distinctions between PS and BP conditions, which could suggest additional biomarkers relevant to early identification.

10.
Artigo em Inglês | MEDLINE | ID: mdl-30745004

RESUMO

BACKGROUND: Psychosis onset typically occurs in adolescence, and subclinical psychotic experiences peak in adolescence. Adolescence is also a time of critical neural and cognitive maturation. Using cross-sectional data from the Philadelphia Neurodevelopmental Cohort, we examined whether regional white matter (WM) development is disrupted in youths with psychosis spectrum (PS) features and whether WM maturation mediates the relationship between age and cognition in typically developing (TD) youths and youths with PS features. METHODS: We examined WM microstructure, as assessed via diffusion tensor imaging, in 670 individuals (age 10-22 years; 499 TD group, 171 PS group) by using tract-based spatial statistics. Multiple regressions were used to evaluate age × group interactions on regional WM indices. Mediation analyses were conducted on four cognitive domains-executive control, complex cognition, episodic memory, and social cognition-using a bootstrapping approach. RESULTS: There were age × group interactions on fractional anisotropy (FA) in the superior longitudinal fasciculus (SLF) and retrolenticular internal capsule. Follow-up analyses revealed these effects were significant in both hemispheres. Bilateral SLF FA mediated the relationship between age and complex cognition in the TD group, but not the PS group. Regional FA did not mediate the age-associated increase in any of the other cognitive domains. CONCLUSIONS: Our results showed aberrant age-related effects in SLF and retrolenticular internal capsule FA in youths with PS features. SLF development supports emergence of specific higher-order cognitive functions in TD youths, but not in youths with PS features. Future mechanistic explanations for these relationships could facilitate development of earlier and refined targets for therapeutic interventions.


Assuntos
Encéfalo/patologia , Cognição/fisiologia , Transtornos Psicóticos/patologia , Substância Branca/patologia , Adolescente , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/crescimento & desenvolvimento , Criança , Estudos Transversais , Imagem de Tensor de Difusão , Feminino , Humanos , Masculino , Transtornos Psicóticos/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Substância Branca/crescimento & desenvolvimento , Adulto Jovem
11.
Am J Psychiatry ; 176(3): 196-207, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30654642

RESUMO

OBJECTIVE: The authors created normative growth charts of amygdala functional connectivity in typically developing youths, assessed age-associated deviations of these trajectories in youths with psychosis spectrum disorders, and explored how these disruptions are related to clinical symptomatology. METHODS: Resting-state functional neuroimaging data from four samples (three cross-sectional, one longitudinal) were collected for 1,062 participants 10-25 years of age (622 typically developing control youths, 194 youths with psychosis spectrum disorders, and 246 youths with other psychopathology). The authors assessed deviations in the psychosis spectrum and other psychopathology groups in age-related changes in resting-state functional MRI amygdala-to-whole brain connectivity from a normative range derived from the control youths. The authors explored relationships between age-associated deviations in amygdala connectivity and positive symptoms in the psychosis spectrum group. RESULTS: Normative trajectories demonstrated significant age-related decreases in centromedial amygdala connectivity with distinct regions of the brain. In contrast, the psychosis spectrum group failed to exhibit any significant age-associated changes between the centromedial amygdala and the prefrontal cortices, striatum, occipital cortex, and thalamus (all q values <0.1). Age-associated deviations in centromedial amygdala-striatum and centromedial amygdala-occipital connectivity were unique to the psychosis spectrum group and were not observed in the other psychopathology group. Exploratory analyses revealed that greater age-related deviation in centromedial amygdala-thalamus connectivity was significantly associated with increased severity of positive symptoms (r=0.19; q=0.05) in the psychosis spectrum group. CONCLUSIONS: Using neurodevelopmental growth charts to identify a lack of normative development of amygdala connectivity in youths with psychosis spectrum disorders may help us better understand the neural basis of affective impairments in psychosis, informing prediction models and interventions.


Assuntos
Tonsila do Cerebelo/fisiopatologia , Vias Neurais/fisiopatologia , Transtornos Psicóticos/fisiopatologia , Adolescente , Adulto , Fatores Etários , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/crescimento & desenvolvimento , Encéfalo/diagnóstico por imagem , Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiopatologia , Estudos de Casos e Controles , Criança , Feminino , Neuroimagem Funcional , Humanos , Imagem por Ressonância Magnética , Masculino , Adulto Jovem
12.
Neuropsychopharmacology ; 43(13): 2556-2563, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30082891

RESUMO

Suicide is major public health concern; one million individuals worldwide die by suicide each year of which there are many more attempts. Thus, it is imperative that robust and reliable indicators, or biomarkers, of suicide risk be identified so that individuals at risk can be identified and provided appropriate interventions as quickly as possible. Previous work has revealed a relationship between low levels of circulating cholesterol and suicide risk, implicating cholesterol level as one such potential biomarker, but the factors underlying this relationship remain unknown. In the present study, we applied a combination of bivariate polygenic and coefficient-of-relatedness analysis, followed by mediation analysis, in a large sample of Mexican-American individuals from extended pedigrees [N = 1897; 96 pedigrees (average size = 19.17 individuals, range = 2-189) 60% female; mean age = 42.58 years, range = 18-97 years, sd = 15.75 years] with no exclusion criteria for any given psychiatric disorder. We observed that total esterified cholesterol measured at the time of psychiatric assessment shared a significant genetic overlap with risk for suicide attempt (ρg = -0.64, p = 1.24 × 10-04). We also found that total unesterified cholesterol measured around 20 years prior to assessment varied as a function of genetic proximity to an affected individual (h2 = 0.21, se = 0.10, p = 8.73 × 10-04; ßsuicide = -0.70, se = 0.25, p = 8.90 × 10-03). Finally, we found that the relationship between total unesterified cholesterol and suicide risk was significantly mediated by ABCA-1-specific cholesterol efflux capacity (ßsuicide-efflux = -0.45, p = 0.039; ßefflux-cholexterol = -0.34, p < 0.0001; ßindirect = -0.15, p = 0.044). These findings suggest that the relatively well-delineated process of cholesterol metabolism and associated molecular pathways will be informative for understanding the neurobiological underpinnings of risk for suicide attempt.


Assuntos
Colesterol/sangue , Colesterol/genética , Predisposição Genética para Doença/genética , Predisposição Genética para Doença/psicologia , Ideação Suicida , Tentativa de Suicídio/psicologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Suscetibilidade a Doenças/sangue , Suscetibilidade a Doenças/psicologia , Feminino , Humanos , Masculino , Transtornos Mentais/sangue , Transtornos Mentais/diagnóstico , Transtornos Mentais/psicologia , Pessoa de Meia-Idade , Linhagem , Fatores de Risco , Adulto Jovem
13.
Mol Psychiatry ; 2018 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-29895892

RESUMO

The 22q11.2 deletion (22q11DS) is a common chromosomal microdeletion and a potent risk factor for psychotic illness. Prior studies reported widespread cortical changes in 22q11DS, but were generally underpowered to characterize neuroanatomic abnormalities associated with psychosis in 22q11DS, and/or neuroanatomic effects of variability in deletion size. To address these issues, we developed the ENIGMA (Enhancing Neuro Imaging Genetics Through Meta-Analysis) 22q11.2 Working Group, representing the largest analysis of brain structural alterations in 22q11DS to date. The imaging data were collected from 10 centers worldwide, including 474 subjects with 22q11DS (age = 18.2 ± 8.6; 46.9% female) and 315 typically developing, matched controls (age = 18.0 ± 9.2; 45.9% female). Compared to controls, 22q11DS individuals showed thicker cortical gray matter overall (left/right hemispheres: Cohen's d = 0.61/0.65), but focal thickness reduction in temporal and cingulate cortex. Cortical surface area (SA), however, showed pervasive reductions in 22q11DS (left/right hemispheres: d = -1.01/-1.02). 22q11DS cases vs. controls were classified with 93.8% accuracy based on these neuroanatomic patterns. Comparison of 22q11DS-psychosis to idiopathic schizophrenia (ENIGMA-Schizophrenia Working Group) revealed significant convergence of affected brain regions, particularly in fronto-temporal cortex. Finally, cortical SA was significantly greater in 22q11DS cases with smaller 1.5 Mb deletions, relative to those with typical 3 Mb deletions. We found a robust neuroanatomic signature of 22q11DS, and the first evidence that deletion size impacts brain structure. Psychotic illness in this highly penetrant deletion was associated with similar neuroanatomic abnormalities to idiopathic schizophrenia. These consistent cross-site findings highlight the homogeneity of this single genetic etiology, and support the suitability of 22q11DS as a biological model of schizophrenia.

14.
NPJ Schizophr ; 4(1): 3, 2018 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-29449557

RESUMO

Contextual information is used to support and organize episodic memory. Prior research has reliably shown memory deficits in psychosis; however, little research has characterized how this population uses contextual information during memory recall. We employed an approach founded in a computational framework of free recall to quantify how individuals with first episode of psychosis (FEP, N = 97) and controls (CON, N = 55) use temporal and semantic context to organize memory recall. Free recall was characterized using the Hopkins Verbal Learning Test-Revised (HVLT-R). We compared FEP and CON on three measures of free recall: proportion recalled, temporal clustering, and semantic clustering. Measures of temporal/semantic clustering quantified how individuals use contextual information to organize memory recall. We also assessed to what extent these measures relate to antipsychotic use and differentiated between different types of psychosis. We also explored the relationship between these measures and intelligence. In comparison to CON, FEP had reduced recall and less temporal clustering during free recall (p < 0.05, Bonferroni-corrected), and showed a trend towards greater semantic clustering (p = 0.10, Bonferroni-corrected). Within FEP, antipsychotic use and diagnoses did not differentiate between free recall accuracy or contextual organization of memory. IQ was related to free recall accuracy, but not the use of contextual information during recall in either group (p < 0.05, Bonferroni-corrected). These results show that in addition to deficits in memory recall, FEP differed in how they organize memories compared to CON.

15.
Am J Psychiatry ; 175(4): 359-369, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29145754

RESUMO

OBJECTIVE: Neuroimaging studies show structural differences in both cortical and subcortical brain regions in children and adults with autism spectrum disorder (ASD) compared with healthy subjects. Findings are inconsistent, however, and it is unclear how differences develop across the lifespan. The authors investigated brain morphometry differences between individuals with ASD and healthy subjects, cross-sectionally across the lifespan, in a large multinational sample from the Enhancing Neuroimaging Genetics Through Meta-Analysis (ENIGMA) ASD working group. METHOD: The sample comprised 1,571 patients with ASD and 1,651 healthy control subjects (age range, 2-64 years) from 49 participating sites. MRI scans were preprocessed at individual sites with a harmonized protocol based on a validated automated-segmentation software program. Mega-analyses were used to test for case-control differences in subcortical volumes, cortical thickness, and surface area. Development of brain morphometry over the lifespan was modeled using a fractional polynomial approach. RESULTS: The case-control mega-analysis demonstrated that ASD was associated with smaller subcortical volumes of the pallidum, putamen, amygdala, and nucleus accumbens (effect sizes [Cohen's d], 0.13 to -0.13), as well as increased cortical thickness in the frontal cortex and decreased thickness in the temporal cortex (effect sizes, -0.21 to 0.20). Analyses of age effects indicate that the development of cortical thickness is altered in ASD, with the largest differences occurring around adolescence. No age-by-ASD interactions were observed in the subcortical partitions. CONCLUSIONS: The ENIGMA ASD working group provides the largest study of brain morphometry differences in ASD to date, using a well-established, validated, publicly available analysis pipeline. ASD patients showed altered morphometry in the cognitive and affective parts of the striatum, frontal cortex, and temporal cortex. Complex developmental trajectories were observed for the different regions, with a developmental peak around adolescence. These findings suggest an interplay in the abnormal development of the striatal, frontal, and temporal regions in ASD across the lifespan.


Assuntos
Transtorno do Espectro Autista/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Córtex Cerebral/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador , Imagem por Ressonância Magnética , Adolescente , Adulto , Fatores Etários , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valores de Referência , Adulto Jovem
16.
Schizophr Res ; 197: 357-364, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29137828

RESUMO

INTRODUCTION: We probed the neural basis of working memory in individuals with first episode of psychosis (FEP) and assessed how these neural abnormalities are associated with behavioral performance and/or core to psychosis pathophysiology. METHODS: FEP (N=35) and matched controls (N=25) performed a visuospatial working memory task during fMRI acquisition. We isolated neural activity during the maintenance period and examined neural activity within regions typically engaged during a working memory task. Functional connectivity estimates were derived using psychophysiological interaction analysis. We examined correlations between brain function and behavioral performance and clinical symptomatology. RESULTS: FEP had reduced accuracy and slower reaction times compared to controls (p<0.05, q<0.05). During the maintenance period, FEP exhibited reduced right dorsolateral prefrontal cortex (DLPFC) activation compared to controls (p=0.007, q=0.01), even when behavioral performance was matched between groups (p=0.01, q=0.03). Unlike controls, FEP failed to show increased dorsal anterior cingulate (dACC) activity with increased load level (p=0.02, q=0.06). Compared to controls, FEP showed increased negative DLPFC-dACC coupling during the maintenance period (p=0.05). Increased DLPFC activation was significantly associated with greater negative symptoms (p<0.005, q=0.02), while greater dACC activation was significantly associated with better performance in FEP (p<0.05, q<0.17). CONCLUSION: WM impairment in psychosis may be specific to abnormalities in the ability of frontal systems processing executive commands (DLPFC) and monitoring performance (dACC) during the maintenance of information. Our results add to accumulating evidence indicating that DLPFC abnormalities may be core to psychosis psychopathology. We also provide new insights regarding how DLPFC abnormalities may undermine dACC processing during the maintenance of information.


Assuntos
Disfunção Cognitiva/fisiopatologia , Função Executiva/fisiologia , Giro do Cíngulo/fisiopatologia , Memória de Curto Prazo/fisiologia , Córtex Pré-Frontal/fisiopatologia , Transtornos Psicóticos/fisiopatologia , Adolescente , Adulto , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/etiologia , Feminino , Giro do Cíngulo/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Masculino , Córtex Pré-Frontal/diagnóstico por imagem , Transtornos Psicóticos/complicações , Transtornos Psicóticos/diagnóstico por imagem , Adulto Jovem
17.
Front Hum Neurosci ; 11: 394, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28848413

RESUMO

Individuals with schizophrenia (SZ) consistently show deficits in spatial working memory (WM) and associated atypical patterns of neural activity within key WM regions, including the dorsolateral prefrontal cortex (dlPFC) and parietal cortices. However, little research has focused on adolescent psychosis (AP) and potential age-associated disruptions of WM circuitry that may occur in youth with this severe form of illness. Here we utilized each subject's individual spatial WM capacity to investigate task-based neural dysfunction in 17 patients with AP (16.58 ± 2.60 years old) as compared to 17 typically developing, demographically comparable adolescents (18.07 ± 3.26 years old). AP patients showed lower behavioral performance at higher WM loads and lower overall WM capacity compared to healthy controls. Whole-brain activation analyses revealed greater bilateral precentral and right postcentral activity in controls relative to AP patients, when controlling for individual WM capacity. Seed-based psychophysiological interaction (PPI) analyses revealed significantly greater co-activation between the left dlPFC and left frontal pole in controls relative to AP patients. Significant group-by-age interactions were observed in both whole-brain and PPI analyses, with AP patients showing atypically greater neural activity and stronger coupling between WM task activated brain regions as a function of increasing age. Additionally, AP patients demonstrated positive relationships between right dlPFC neural activity and task performance, but unlike healthy controls, failed to show associations between neural activity and out-of-scanner neurocognitive performance. Collectively, these findings are consistent with atypical WM-related functioning and disrupted developmental processes in youth with AP.

18.
J Neurosci ; 37(26): 6183-6199, 2017 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-28536274

RESUMO

Reciprocal chromosomal rearrangements at the 22q11.2 locus are associated with elevated risk of neurodevelopmental disorders. The 22q11.2 deletion confers the highest known genetic risk for schizophrenia, but a duplication in the same region is strongly associated with autism and is less common in schizophrenia cases than in the general population. Here we conducted the first study of 22q11.2 gene dosage effects on brain structure in a sample of 143 human subjects: 66 with 22q11.2 deletions (22q-del; 32 males), 21 with 22q11.2 duplications (22q-dup; 14 males), and 56 age- and sex-matched controls (31 males). 22q11.2 gene dosage varied positively with intracranial volume, gray and white matter volume, and cortical surface area (deletion < control < duplication). In contrast, gene dosage varied negatively with mean cortical thickness (deletion > control > duplication). Widespread differences were observed for cortical surface area with more localized effects on cortical thickness. These diametric patterns extended into subcortical regions: 22q-dup carriers had a significantly larger right hippocampus, on average, but lower right caudate and corpus callosum volume, relative to 22q-del carriers. Novel subcortical shape analysis revealed greater radial distance (thickness) of the right amygdala and left thalamus, and localized increases and decreases in subregions of the caudate, putamen, and hippocampus in 22q-dup relative to 22q-del carriers. This study provides the first evidence that 22q11.2 is a genomic region associated with gene-dose-dependent brain phenotypes. Pervasive effects on cortical surface area imply that this copy number variant affects brain structure early in the course of development.SIGNIFICANCE STATEMENT Probing naturally occurring reciprocal copy number variation in the genome may help us understand mechanisms underlying deviations from typical brain and cognitive development. The 22q11.2 genomic region is particularly susceptible to chromosomal rearrangements and contains many genes crucial for neuronal development and migration. Not surprisingly, reciprocal genomic imbalances at this locus confer some of the highest known genetic risks for developmental neuropsychiatric disorders. Here we provide the first evidence that brain morphology differs meaningfully as a function of reciprocal genomic variation at the 22q11.2 locus. Cortical thickness and surface area were affected in opposite directions with more widespread effects of gene dosage on cortical surface area.


Assuntos
Síndrome da Deleção 22q11/genética , Síndrome da Deleção 22q11/patologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Variações do Número de Cópias de DNA/genética , Dosagem de Genes/genética , Mapeamento Encefálico , Feminino , Rearranjo Gênico/genética , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão/genética
19.
Artigo em Inglês | MEDLINE | ID: mdl-28367513

RESUMO

BACKGROUND: 22q11.2 Microdeletion syndrome (22q11DS) is associated with elevated rates of autism spectrum disorders (ASDs), although the diagnosis is controversial. In order to determine whether there is a biological substrate of ASD in 22q11DS, we examined neurocognitive and structural neuroanatomic differences between those with 22q11DS and an ASD diagnosis (22q11DS-ASD+) and those with 22q11DS without ASD (22q11DS-ASD-); we then determined whether these differences were better characterized within a categorical or dimensional framework. METHODS: We collected multiple neurocognitive measures and high-resolution T1-weighted scans on 116 individuals (29 22q11DS-ASD+, 32 22q11DS-ASD-, 55 typically developing controls) between 6 and 26 years of age. Measures of subcortical volume, cortical thickness (CT), and surface area were extracted using the FreeSurfer image analysis suite. Group differences in neurocognitive and neuroanatomic measures were assessed; regression analyses were then performed to determine whether a categorical or dimensional measure of ASD was a better predictor of neurocognitive impairment and/or neuroanatomic abnormalities observed in 22q11DS-ASD+. RESULTS: In comparison to 22q11DS-ASD-, 22q11DS-ASD+ participants exhibited decreased bilateral hippocampal CT and decreased right amygdala volumes. Those with 22q11DS-ASD+ also showed slowed processing speed and impairments in visuospatial and facial memory. Neurocognitive impairments fit a dimensional model of ASD, whereas reductions in parahippocampal CT were best explained by a categorical measure of ASD. CONCLUSIONS: A combination of categorical and dimensional measures of ASD may provide the most comprehensive understanding of ASDs in 22q11DS.

20.
Biol Psychiatry ; 82(7): 511-521, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28274468

RESUMO

BACKGROUND: Connectivity between the amygdala and ventromedial prefrontal cortex (vmPFC) is compromised in multiple psychiatric disorders, many of which emerge during adolescence. To identify to what extent the deviations in amygdala-vmPFC maturation contribute to the onset of psychiatric disorders, it is essential to characterize amygdala-vmPFC connectivity changes during typical development. METHODS: Using an accelerated cohort longitudinal design (1-3 time points, 10-25 years old, n = 246), we characterized developmental changes of the amygdala-vmPFC subregion functional and structural connectivity using resting-state functional magnetic resonance imaging and diffusion-weighted imaging. RESULTS: Functional connectivity between the centromedial amygdala and rostral anterior cingulate cortex (rACC), anterior vmPFC, and subgenual cingulate significantly decreased from late childhood to early adulthood in male and female subjects. Age-associated decreases were also observed between the basolateral amygdala and the rACC. Importantly, these findings were replicated in a separate cohort (10-22 years old, n = 327). Similarly, structural connectivity, as measured by quantitative anisotropy, significantly decreased with age in the same regions. Functional connectivity between the centromedial amygdala and the rACC was associated with structural connectivity in these same regions during early adulthood (22-25 years old). Finally, a novel time-varying coefficient analysis showed that increased centromedial amygdala-rACC functional connectivity was associated with greater anxiety and depression symptoms during early adulthood, while increased structural connectivity in centromedial amygdala-anterior vmPFC white matter was associated with greater anxiety/depression during late childhood. CONCLUSIONS: Specific developmental periods of functional and structural connectivity between the amygdala and the prefrontal systems may contribute to the emergence of anxiety and depressive symptoms and may play a critical role in the emergence of psychiatric disorders in adolescence.


Assuntos
Tonsila do Cerebelo/diagnóstico por imagem , Ansiedade/diagnóstico por imagem , Transtorno Depressivo/diagnóstico por imagem , Vias Neurais/diagnóstico por imagem , Córtex Pré-Frontal/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Adolescente , Adulto , Tonsila do Cerebelo/crescimento & desenvolvimento , Criança , Estudos de Coortes , Estudos Transversais , Imagem de Difusão por Ressonância Magnética , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Vias Neurais/crescimento & desenvolvimento , Córtex Pré-Frontal/crescimento & desenvolvimento , Escalas de Graduação Psiquiátrica , Adulto Jovem
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