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1.
Cereb Cortex ; 2020 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-32420595

RESUMO

22q11.2 deletion syndrome (22q11.2DS) is a genetic condition accompanied by a range of psychiatric manifestations, including autism spectrum disorder (ASD). It remains unknown, however, whether these symptoms are mediated by the same or distinct neural mechanisms as in idiopathic ASD. Here, we examined differences in lGI associated with ASD in 50 individuals with 22q11.2DS (n = 25 with ASD, n = 25 without ASD) and 81 individuals without 22q11.2DS (n = 40 with ASD, n = 41 typically developing controls). We initially utilized a factorial design to identify the set of brain regions where lGI is associated with the main effect of 22q11.2DS, ASD, and with the 22q11.2DS-by-ASD interaction term. Subsequently, we employed canonical correlation analysis (CCA) to compare the multivariate association between variability in lGI and the complex clinical phenotype of ASD between 22q11.2DS carriers and noncarriers. Across approaches, we established that even though there is a high degree of clinical similarity across groups, the associated patterns of lGI significantly differed between carriers and noncarriers of the 22q11.2 microdeletion. Our results suggest that ASD symptomatology recruits different neuroanatomical underpinnings across disorders and that 22q11.2DS individuals with ASD represent a neuroanatomically distinct subgroup that differs from 22q11.2DS individuals without ASD and from individuals with idiopathic ASD.

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.
Mol Psychiatry ; 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31925327

RESUMO

The 22q11.2 deletion syndrome (22q11.2DS) is a neurodevelopmental disorder associated with a number of volumetric brain abnormalities. The syndrome is also associated with an increased risk for neuropsychiatric disorders including schizophrenia and autism spectrum disorder. An earlier meta-analysis showed reduced grey and white matter volumes in individuals with 22q11.2DS. Since this analysis was conducted, the number of studies has increased markedly, permitting more precise estimates of effects and more regions to be examined. Although 22q11.2DS is clinically heterogeneous, it is not known to what extent this heterogeneity is mirrored in neuroanatomy. The aim of this study was thus to investigate differences in mean brain volume and structural variability within regions, between 22q11.2DS and typically developing controls. We examined studies that reported measures of brain volume using MRI in PubMed, Web of Science, Scopus and PsycINFO from inception to 1 May 2019. Data were extracted from studies in order to calculate effect sizes representing case-control difference in mean volume, and in the variability of volume (as measured using the log variability ratio (lnVR) and coefficient of variation ratio (CVR)). We found significant overall decreases in mean volume in 22q11.2DS compared with control for: total brain (g = -0.96; p < 0.001); total grey matter (g = -0.81, p < 0.001); and total white matter (g = -0.81; p < 0.001). There was also a significant overall reduction of mean volume in 22q11.2DS subjects compared with controls in frontal lobe (g = -0.47; p < 0.001), temporal lobe (g = -0.84; p < 0.001), parietal lobe (g = -0.73; p = 0.053), cerebellum (g = -1.25; p < 0.001) and hippocampus (g = -0.90; p < 0.001). Significantly increased variability in 22q11.2DS individuals compared with controls was found only for the hippocampus (VR, 1.14; p = 0.036; CVR, 1.30; p < 0.001), and lateral ventricles (VR, 1.56; p = 0.004). The results support the notion that structural abnormalities in 22q11.2DS and schizophrenia are convergent, and also to some degree with findings in autism spectrum disorder. Finally, the increased variability seen in the hippocampus in 22q11.2DS may underlie some of the heterogeneity observed in the neuropsychiatric phenotype.

4.
Dev Cogn Neurosci ; 40: 100721, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31704653

RESUMO

Fathers play a crucial role in their children's socio-emotional and cognitive development. A plausible intermediate phenotype underlying this association is father's impact on infant brain. However, research on the association between paternal caregiving and child brain biology is scarce, particularly during infancy. Thus, we used magnetic resonance imaging (MRI) to investigate the relationship between observed father-infant interactions, specifically paternal sensitivity, and regional brain volumes in a community sample of 3-to-6-month-old infants (N = 28). We controlled for maternal sensitivity and examined the moderating role of infant communication on this relationship. T2-weighted MR images were acquired from infants during natural sleep. Higher levels of paternal sensitivity were associated with smaller cerebellar volumes in infants with high communication levels. In contrast, paternal sensitivity was not associated with subcortical grey matter volumes in the whole sample, and this was similar in infants with both high and low communication levels. This preliminary study provides the first evidence for an association between father-child interactions and variation in infant brain anatomy.

5.
Eur Neuropsychopharmacol ; 29(12): 1333-1342, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31648854

RESUMO

Glutamatergic dysregulation is one of the leading theories regarding the pathoaetiolopy of schizophrenia. Meta-analysis of magnetic resonance spectroscopy studies in schizophrenia shows increased levels of glutamate and glutamine (Glx) in the medial frontal cortex and basal ganglia in clinical high-risk groups for psychosis and increased glutamine levels in the thalamus, but it is unclear if this is also the case in people at genetic high risk for psychosis. The aim of this study was to investigate glutamatergic function in the anterior cingulate cortex, striatum and thalamus in carriers of a genetic variant (22q11.2 deletion) associated with a high risk for psychosis. 53 volunteers (23 22q11.2 deletion carriers and 30 controls) underwent proton magnetic resonance spectroscopy imaging and neuropsychological assessments for prodromal psychotic symptoms, schizotypy, anxiety, depression and FSIQ. We did not find any difference between groups in Glx in the anterior cingulate cortex, striatum or thalamus (Glx: t(50)=-1.26, p = 0.21; U = 251, z = -0.7, p = 0.49; U = 316, z= -0.26, p = 0.79, respectively). No correlation was detected between Glx levels in any region and symptomatology or FSIQ. Our findings indicate that glutamatergic function is not altered in people at genetic high risk of psychosis due to the 22q11.2 deletion, which could suggest that this is not the mechanism underlying psychosis risk in 22q11.2 deletion carriers.

6.
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.

7.
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.

8.
Cereb Cortex ; 27(2): 877-887, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28057721

RESUMO

Atypical cortical organization and reduced integrity of the gray-white matter boundary have been reported by postmortem studies in individuals with autism spectrum disorder (ASD). However, there are no in vivo studies that examine these particular features of cortical organization in ASD. Hence, we used structural magnetic resonance imaging to examine differences in tissue contrast between gray and white matter in 98 adults with ASD and 98 typically developing controls, to test the hypothesis that individuals with ASD have significantly reduced tissue contrast. More specifically, we examined contrast as a percentage between gray and white matter tissue signal intensities (GWPC) sampled at the gray-white matter boundary, and across different cortical layers. We found that individuals with ASD had significantly reduced GWPC in several clusters throughout the cortex (cluster, P < 0.05). As expected, these reductions were greatest when tissue intensities were sampled close to gray-white matter interface, which indicates a less distinct gray-white matter boundary in ASD. Our in vivo findings of reduced GWPC in ASD are therefore consistent with prior postmortem findings of a less well-defined gray-white matter boundary in ASD. Taken together, these results indicate that GWPC might be utilized as an in vivo proxy measure of atypical cortical microstructural organization in future studies.


Assuntos
Transtorno do Espectro Autista/diagnóstico por imagem , Transtorno do Espectro Autista/patologia , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Adolescente , Adulto , Algoritmos , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Feminino , Lateralidade Funcional , Humanos , Processamento de Imagem Assistida por Computador , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Caracteres Sexuais , Adulto Jovem
9.
Brain Struct Funct ; 222(5): 2379-2388, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27915378

RESUMO

It is generally agreed that the human brain is responsive to environmental influences, and that the male brain may be particularly sensitive to early adversity. However, this is largely based on retrospective studies of older children and adolescents exposed to extreme environments in childhood. Less is understood about how normative variations in parent-child interactions are associated with the development of the infant brain in typical settings. To address this, we used magnetic resonance imaging to investigate the relationship between observational measures of mother-infant interactions and regional brain volumes in a community sample of 3- to 6-month-old infants (N = 39). In addition, we examined whether this relationship differed in male and female infants. We found that lower maternal sensitivity was correlated with smaller subcortical grey matter volumes in the whole sample, and that this was similar in both sexes. However, male infants who showed greater levels of positive communication and engagement during early interactions had smaller cerebellar volumes. These preliminary findings suggest that variations in mother-infant interaction dimensions are associated with differences in infant brain development. Although the study is cross-sectional and causation cannot be inferred, the findings reveal a dynamic interaction between brain and environment that may be important when considering interventions to optimize infant outcomes.


Assuntos
Encéfalo/crescimento & desenvolvimento , Desenvolvimento Infantil/fisiologia , Imagem por Ressonância Magnética , Criança , Estudos Transversais , Feminino , Humanos , Lactente , Imagem por Ressonância Magnética/métodos , Masculino , Relações Mãe-Filho , Estudos Retrospectivos , Caracteres Sexuais
10.
J Psychopharmacol ; 29(8): 933-42, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26040903

RESUMO

BACKGROUND: This study aimed to develop a clinically acceptable method of therapeutic drug monitoring (TDM) for olanzapine and risperidone and to evaluate the feasibility of its implementation. METHOD: A non-randomised study of inpatients from five Mental Health Trusts was conducted, with a clinical interview at the time of TDM and a subsequent 6-week follow-up review of clinical notes. The TDM intervention comprised: (a) a venous blood sample taken 12 hours post-dose, 7-10 days after drug initiation, and (b) rapid results feedback, with interpretation algorithm guidance. RESULTS: Thirty-two participants provided samples (19 prescribed olanzapine, 13 risperidone). Twenty-six participants remained on the target drug at study end, with seven experiencing a dose change, for whom only four of the TDM results were confirmed as having been checked. Mean dose increased for olanzapine (0.9 mg/day, range 0-10) and decreased for risperidone (-0.3 mg/day, range -4-3). CONCLUSION: TDM can be implemented as part of routine clinical practice for both drugs. However, the lack of robust supporting evidence for or against antipsychotic TDM has probably led to a lack of enthusiasm for and interest in the results. Nevertheless, the advent of less invasive measures and the targeting of patients who might be more likely to benefit may facilitate uptake.


Assuntos
Antipsicóticos/sangue , Benzodiazepinas/sangue , Monitoramento de Medicamentos/métodos , Risperidona/sangue , Esquizofrenia/tratamento farmacológico , Adulto , Antipsicóticos/administração & dosagem , Benzodiazepinas/administração & dosagem , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Olanzapina , Risperidona/administração & dosagem , Adulto Jovem
11.
Brain ; 137(Pt 9): 2600-10, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25070512

RESUMO

It has been suggested that the restricted, stereotyped and repetitive behaviours typically found in autism are underpinned by deficits of inhibitory control. The biological basis of this is unknown but may include differences in the modulatory role of neurotransmitters, such as serotonin, which are implicated in the condition. However, this has never been tested directly. We therefore assessed the modifying role of serotonin on inhibitory brain function during a Go/No-Go task in 14 adults with autism and normal intelligence and 14 control subjects that did not differ in gender, age and intelligence. We undertook a double-blind, placebo-controlled, crossover trial of acute tryptophan depletion using functional magnetic resonance imaging. Following sham, adults with autism relative to controls had reduced activation in key inhibitory regions of inferior frontal cortex and thalamus, but increased activation of caudate and cerebellum. However, brain activation was modulated in opposite ways by depletion in each group. Within autistic individuals depletion upregulated fronto-thalamic activations and downregulated striato-cerebellar activations toward control sham levels, completely 'normalizing' the fronto-cerebellar dysfunctions. The opposite pattern occurred in controls. Moreover, the severity of autism was related to the degree of differential modulation by depletion within frontal, striatal and thalamic regions. Our findings demonstrate that individuals with autism have abnormal inhibitory networks, and that serotonin has a differential, opposite, effect on them in adults with and without autism. Together these factors may partially explain the severity of autistic behaviours and/or provide a novel (tractable) treatment target.


Assuntos
Transtorno Autístico/metabolismo , Encéfalo/metabolismo , Imagem por Ressonância Magnética , Tempo de Reação/fisiologia , Serotonina/metabolismo , Triptofano/metabolismo , Adolescente , Adulto , Transtorno Autístico/diagnóstico , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Inibição Neural/fisiologia , Estimulação Luminosa/métodos , Adulto Jovem
12.
Ther Drug Monit ; 36(4): 486-93, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24384695

RESUMO

BACKGROUND: Why psychiatrists choose a particular dose of antipsychotic for an individual patient with schizophrenia is unknown. This study aimed to investigate consultant psychiatrists' perspectives on the dose titration and their attitudes towards therapeutic drug monitoring (TDM) for antipsychotics. METHOD: A cross-sectional quantitative questionnaire study of consultant psychiatrists based in London was conducted. A new questionnaire was developed, in part, based on the findings from focus groups. Themes included dose choice, titration, switching, and the pros and cons of TDM use. RESULTS: For 105 consultant psychiatrists, choice of antipsychotic was most influenced by perceived side-effects/tolerance (63.8%). When choosing an optimum dose, most based this on their past clinical experience of patients presenting in a similar way (80.0%), perspectives on the equivalent doses of 2 antipsychotics (69.5%), or the individual patient's stated dose preference (61.9%). Factors thought to warrant a lower dose (eg, first episode psychosis) were consistent with a former study, and 59.0% of the clinicians believed it acceptable to switch antipsychotics ≥4 per year. The majority of clinicians currently routinely use TDM for clozapine (82.9%), and previous use of TDM for clozapine was found to predict likely future use of TDM with antipsychotics (χ = 5.51, P = 0.019). Furthermore, clinicians agreed that TDM could assist in minimizing the risk of dose-related side effects (77.1%). However, 32.4% did not agree that TDM would improve clinical outcomes. Overall, there was a positive attitude towards TDM for antipsychotics, and almost all clinicians (84.8%, 95% confidence interval, 77.9-91.7) would use it if widely available. CONCLUSIONS: Current prescribing decisions regarding antipsychotic dose are mainly influenced by clinician intuition, previous experience, and patient preference. Although some expressed concerns regarding the evidence base, most clinicians reported that they would use TDM for antipsychotics if readily available.


Assuntos
Antipsicóticos/uso terapêutico , Transtornos Psicóticos/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Adulto , Estudos Transversais , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Londres , Masculino , Pessoa de Meia-Idade , Padrões de Prática Médica , Psiquiatria/métodos , Inquéritos e Questionários
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