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Cortical thickness analysis examined through power analysis and a population simulation.
We have previously developed a procedure for measuring the thickness of cerebral cortex over the whole brain using 3-D MRI data and a fully automated surface-extraction (ASP) algorithm. This paper examines the precision of this algorithm, its optimal performance parameters, and the sensitivity of the method to subtle, focal changes in cortical thickness. The precision of cortical thickness measurements was studied using a simulated population study and single subject reproducibility metrics. Cortical thickness was shown to be a reliable method, reaching a sensitivity (probability of a true-positive) of 0.93. Six different cortical thickness metrics were compared. The simplest and most precise method measures the distance between corresponding vertices from the white matter to the gray matter surface. Given two groups of 25 subjects, a 0.6-mm (15%) change in thickness can be recovered after blurring with a 3-D Gaussian kernel (full-width half max = 30 mm). Smoothing across the 2-D surface manifold also improves precision; in this experiment, the optimal kernel size was 30 mm.
A large data resource of genomic copy number variation across neurodevelopmental disorders
© 2019, The Author(s). Copy number variations (CNVs) are implicated across many neurodevelopmental disorders (NDDs) and contribute to their shared genetic etiology. Multiple studies have attempted to identify shared etiology among NDDs, but this is the first genome-wide CNV analysis across autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), and obsessive-compulsive disorder (OCD) at once. Using microarray (Affymetrix CytoScan HD), we genotyped 2,691 subjects diagnosed with an NDD (204 SCZ, 1,838 ASD, 427 ADHD and 222 OCD) and 1,769 family members, mainly parents. We identified rare CNVs, defined as those found in <0.1% of 10,851 population control samples. We found clinically relevant CNVs (broadly defined) in 284 (10.5%) of total subjects, including 22 (10.8%) among subjects with SCZ, 209 (11.4%) with ASD, 40 (9.4%) with ADHD, and 13 (5.6%) with OCD. Among all NDD subjects, we identified 17 (0.63%) with aneuploidies and 115 (4.3%) with known genomic disorder variants. We searched further for genes impacted by different CNVs in multiple disorders. Examples of NDD-associated genes linked across more than one disorder (listed in order of occurrence frequency) are NRXN1, SEH1L, LDLRAD4, GNAL, GNG13, MKRN1, DCTN2, KNDC1, PCMTD2, KIF5A, SYNM, and long non-coding RNAs: AK127244 and PTCHD1-AS. We demonstrated that CNVs impacting the same genes could potentially contribute to the etiology of multiple NDDs. The CNVs identified will serve as a useful resource for both research and diagnostic laboratories for prioritization of variants.
White matter changes caused by mild traumatic brain injury in mice evaluated using neurite orientation dispersion and density imaging.
Mild traumatic brain injury (mTBI) is common and can lead to persistent cognitive and behavioural symptoms. While diffusion tensor imaging (DTI) has demonstrated some sensitivity to changes in white matter following mTBI, recent studies have suggested that more complex geometric models of diffusion, including the Neurite Orientation Dispersion and Density Imaging (NODDI) model, may be more sensitive and specific. Here we evaluate microstructural changes in white matter following mTBI using DTI and NODDI in a mouse model and compare the time course of these changes to behavioural impairment and recovery. We also assess volumetric changes for a comprehensive picture of the structural alterations in the brain and histological staining to identify cellular changes that may contribute to the differences detected in the imaging data. Increased orientation dispersion index (ODI) was observed in the optic tracts of mTBI mice compared to shams. Changes in fractional anisotropy (FA) were not statistically significant. Volume deficits were detected in the optic tract as well as in several gray matter regions: the lateral geniculate nuclei of the thalamus, the entorhinal cortex, and the superior colliculi. GFAP and Iba1 staining was increased in the optic tracts of mTBI brains and this staining correlated with ODI values. A transient impairment in working memory was observed, which resolved by 6 weeks, while increased ODI, GFAP, and Iba1 persisted to 18 weeks post-injury. We conclude that The optic tracts are particularly vulnerable to damage from the closed-skull impact model used in this study and ODI may be a more sensitive metric to this damage than FA. Differences in ODI and in histological measures of astrogliosis, neuroinflammation and axonal degeneration persist beyond behavioural impairment in this model. Keywords: mild TBI, white matter, neurite orientation dispersion and density imaging (NODDI), diffusion tensor imaging (DTI), mice.
Pten haploinsufficiency disrupts scaling across brain areas during development in mice.
Haploinsufficiency for PTEN is a cause of autism spectrum disorder and brain overgrowth; however, it is not known if PTEN mutations disrupt scaling across brain areas during development. To address this question, we used magnetic resonance imaging to analyze brains of male Pten haploinsufficient (Pten+/-) mice and wild-type littermates during early postnatal development and adulthood. Adult Pten+/- mice display a consistent pattern of abnormal scaling across brain areas, with white matter (WM) areas being particularly affected. This regional and WM enlargement recapitulates structural abnormalities found in individuals with PTEN haploinsufficiency and autism. Early postnatal Pten+/- mice do not display the same pattern, instead exhibiting greater variability across mice and brain regions than controls. This suggests that Pten haploinsufficiency may desynchronize growth across brain regions during early development before stabilizing by maturity. Pten+/- cortical cultures display increased proliferation of glial cell populations, indicating a potential substrate of WM enlargement, and provide a platform for testing candidate therapeutics. Pten haploinsufficiency dysregulates coordinated growth across brain regions during development. This results in abnormally scaled brain areas and associated behavioral deficits, potentially explaining the relationship between PTEN mutations and neurodevelopmental disorders.
Genetic effects on cerebellar structure across mouse models of autism using a magnetic resonance imaging atlas.
Magnetic resonance imaging (MRI) of autism populations is confounded by the inherent heterogeneity in the individuals' genetics and environment, two factors difficult to control for. Imaging genetic animal models that recapitulate a mutation associated with autism quantify the impact of genetics on brain morphology and mitigate the confounding factors in human studies. Here, we used MRI to image three genetic mouse models with single mutations implicated in autism: Neuroligin-3 R451C knock-in, Methyl-CpG binding protein-2 (MECP2) 308-truncation and integrin β3 homozygous knockout. This study identified the morphological differences specific to the cerebellum, a structure repeatedly linked to autism in human neuroimaging and postmortem studies. To accomplish a comparative analysis, a segmented cerebellum template was created and used to segment each study image. This template delineated 39 different cerebellar structures. For Neuroligin-3 R451C male mutants, the gray (effect size (ES) = 1.94, FDR q = 0.03) and white (ES = 1.84, q = 0.037) matter of crus II lobule and the gray matter of the paraflocculus (ES = 1.45, q = 0.045) were larger in volume. The MECP2 mutant mice had cerebellar volume changes that increased in scope depending on the genotype: hemizygous males to homozygous females. The integrin β3 mutant mouse had a drastically smaller cerebellum than controls with 28 out of 39 cerebellar structures smaller. These imaging results are discussed in relation to repetitive behaviors, sociability, and learning in the context of autism. This work further illuminates the cerebellum's role in autism.
Development of short-range white matter in healthy children and adolescents.
Neural communication is facilitated by intricate networks of white matter (WM) comprised of both long and short range connections. The maturation of long range WM connections has been extensively characterized, with projection, commissural, and association tracts showing unique trajectories with age. There, however, remains a limited understanding of age-related changes occurring within short range WM connections, or U-fibers. These connections are important for local connectivity within lobes and facilitate regional cortical function and greater network economy. Recent studies have explored the maturation of U-fibers primarily using cross-sectional study designs. Here, we analyzed diffusion tensor imaging (DTI) data for healthy children and adolescents in both a cross-sectional (n = 78; mean age = 13.04 ± 3.27 years) and a primarily longitudinal (n = 26; mean age = 10.78 ± 2.69 years) cohort. We found significant age-related differences in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) across the frontal, parietal, and temporal lobes of participants within the cross-sectional cohort. By contrast, we report significant age-related differences in only FA for participants within the longitudinal cohort. Specifically, larger FA values were observed with age in frontal, parietal, and temporal lobes of the left hemisphere. Our results extend previous findings restricted to long range WM to demonstrate regional changes in the microstructure of short range WM during childhood and adolescence. These changes possibly reflect continued myelination and axonal organization of short range WM with increasing age in more anterior regions of the left hemisphere. Hum Brain Mapp 39:204-217, 2018. © 2017 Wiley Periodicals, Inc.
Examining overlap and homogeneity in ASD, ADHD, and OCD: a data-driven, diagnosis-agnostic approach.
The validity of diagnostic labels of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and obsessive compulsive disorder (OCD) is an open question given the mounting evidence that these categories may not correspond to conditions with distinct etiologies, biologies, or phenotypes. The objective of this study was to determine the agreement between existing diagnostic labels and groups discovered based on a data-driven, diagnosis-agnostic approach integrating cortical neuroanatomy and core-domain phenotype features. A machine learning pipeline, called bagged-multiview clustering, was designed to discover homogeneous subgroups by integrating cortical thickness data and measures of core-domain phenotypic features of ASD, ADHD, and OCD. This study was conducted using data from the Province of Ontario Neurodevelopmental Disorders (POND) Network, a multi-center study in Ontario, Canada. Participants (n = 226) included children between the ages of 6 and 18 with a diagnosis of ASD (n = 112, median [IQR] age = 11.7[4.8], 21% female), ADHD (n = 58, median [IQR] age = 10.2[3.3], 14% female), or OCD (n = 34, median [IQR] age = 12.1[4.2], 38% female), as well as typically developing controls (n = 22, median [IQR] age = 11.0[3.8], 55% female). The diagnosis-agnostic groups were significantly different than each other in phenotypic characteristics (SCQ: χ2(9) = 111.21, p < 0.0001; SWAN: χ2(9) = 142.44, p < 0.0001) as well as cortical thickness in 75 regions of the brain. The analyses revealed disagreement between existing diagnostic labels and the diagnosis-agnostic homogeneous groups (normalized mutual information < 0.20). Our results did not support the validity of existing diagnostic labels of ASD, ADHD, and OCD as distinct entities with respect to phenotype and cortical morphology.
Consortium neuroscience of attention deficit/hyperactivity disorder and autism spectrum disorder: The ENIGMA adventure.
Neuroimaging has been extensively used to study brain structure and function in individuals with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) over the past decades. Two of the main shortcomings of the neuroimaging literature of these disorders are the small sample sizes employed and the heterogeneity of methods used. In 2013 and 2014, the ENIGMA-ADHD and ENIGMA-ASD working groups were respectively, founded with a common goal to address these limitations. Here, we provide a narrative review of the thus far completed and still ongoing projects of these working groups. Due to an implicitly hierarchical psychiatric diagnostic classification system, the fields of ADHD and ASD have developed largely in isolation, despite the considerable overlap in the occurrence of the disorders. The collaboration between the ENIGMA-ADHD and -ASD working groups seeks to bring the neuroimaging efforts of the two disorders closer together. The outcomes of case-control studies of subcortical and cortical structures showed that subcortical volumes are similarly affected in ASD and ADHD, albeit with small effect sizes. Cortical analyses identified unique differences in each disorder, but also considerable overlap between the two, specifically in cortical thickness. Ongoing work is examining alternative research questions, such as brain laterality, prediction of case-control status, and anatomical heterogeneity. In brief, great strides have been made toward fulfilling the aims of the ENIGMA collaborations, while new ideas and follow-up analyses continue that include more imaging modalities (diffusion MRI and resting-state functional MRI), collaborations with other large databases, and samples with dual diagnoses.
Cyclin D2-knock-out mice with attenuated dentate gyrus neurogenesis have robust deficits in long-term memory formation.
Neurobehavioral studies have produced contradictory findings concerning the function of neurogenesis in the adult dentate gyrus. Previous studies have proved inconsistent across several behavioral endpoints thought to be dependent on dentate neurogenesis, including memory acquisition, short-term and long-term retention of memory, pattern separation, and reversal learning. We hypothesized that the main function of dentate neurogenesis is long-term memory formation because we assumed that a newly formed and integrated neuron would have a long-term impact on the local neural network. We used a cyclin D2-knock-out (cyclin D2-/-) mouse model of endogenously deficient dentate neurogenesis to test this hypothesis. We found that cyclin D2-/- mice had robust and sustained loss of long-term memory in two separate behavioral tasks, Morris water maze (MWM) and touchscreen intermediate pattern separation. Moreover, after adjusting for differences in brain volumes determined by magnetic resonance (MR) imaging, reduced dentate neurogenesis moderately correlated with deficits in memory retention after 24 hours. Importantly, cyclin D2-/- mice did not show deficits in learning acquisition in a touchscreen paradigm of intermediate pattern separation or MWM platform location, indicating intact short-term memory. Further evaluation of cyclin D2-/- mice is necessary to confirm that deficits are specifically linked to dentate gyrus neurogenesis since cyclin D2-/- mice also have a reduced size of the olfactory bulb, hippocampus, cerebellum and cortex besides reduced dentate gyrus neurogenesis.
Effects of Antipsychotic Medication on Brain Structure in Patients With Major Depressive Disorder and Psychotic Features: Neuroimaging Findings in the Context of a Randomized Placebo-Controlled Clinical Trial.
Importance: Prescriptions for antipsychotic medications continue to increase across many brain disorders, including off-label use in children and elderly individuals. Concerning animal and uncontrolled human data suggest antipsychotics are associated with change in brain structure, but to our knowledge, there are no controlled human studies that have yet addressed this question. Objective: To assess the effects of antipsychotics on brain structure in humans. Design, Setting, and Participants: Prespecified secondary analysis of a double-blind, randomized, placebo-controlled trial over a 36-week period at 5 academic centers. All participants, aged 18 to 85 years, were recruited from the multicenter Study of the Pharmacotherapy of Psychotic Depression II (STOP-PD II). All participants had major depressive disorder with psychotic features (psychotic depression) and were prescribed olanzapine and sertraline for a period of 12 to 20 weeks, which included 8 weeks of remission of psychosis and remission/near remission of depression. Participants were then were randomized to continue receiving this regimen or to be switched to placebo and sertraline for a subsequent 36-week period. Data were analyzed between October 2018 and February 2019. Interventions: Those who consented to the imaging study completed a magnetic resonance imaging (MRI) scan at the time of randomization and a second MRI scan at the end of the 36-week period or at time of relapse. Main Outcomes and Measures: The primary outcome measure was cortical thickness in gray matter and the secondary outcome measure was microstructural integrity of white matter. Results: Eighty-eight participants (age range, 18-85 years) completed a baseline scan; 75 completed a follow-up scan, of which 72 (32 men and 40 women) were useable for final analyses. There was a significant treatment-group by time interaction in cortical thickness (left, t = 3.3; P = .001; right, t = 3.6; P < .001) but not surface area. No significant interaction was found for fractional anisotropy, but one for mean diffusivity of the white matter skeleton was present (t = -2.6, P = .01). When the analysis was restricted to those who sustained remission, exposure to olanzapine compared with placebo was associated with significant decreases in cortical thickness in the left hemisphere (β [SE], 0.04 [0.009]; t34.4 = 4.7; P <.001), and the right hemisphere (β [SE], 0.03 [0.009]; t35.1 = 3.6; P <.001). Post hoc analyses showed that those who relapsed receiving placebo experienced decreases in cortical thickness compared with those who sustained remission. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, antipsychotic medication was shown to change brain structure. This information is important for prescribing in psychiatric conditions where alternatives are present. However, adverse effects of relapse on brain structure support antipsychotic treatment during active illness. Trial Registration: ClinicalTrials.gov Identifier: NCT01427608.
Altered structural brain asymmetry in autism spectrum disorder in a study of 54 datasets.
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.
Cortical thickness in children receiving intensive therapy for idiopathic apraxia of speech.
Children with idiopathic apraxia experience difficulties planning the movements necessary for intelligible speech. There is increasing evidence that targeted early interventions, such as Prompts for Restructuring Oral Muscular Phonetic Targets (PROMPT), can be effective in treating these disorders. In this study, we investigate possible cortical thickness correlates of idiopathic apraxia of speech in childhood, and changes associated with participation in an 8-week block of PROMPT therapy. We found that children with idiopathic apraxia (n = 11), aged 3-6 years, had significantly thicker left supramarginal gyri than a group of typically-developing age-matched controls (n = 11), t(20) = 2.84, p ≤ 0.05. Over the course of therapy, the children with apraxia (n = 9) experienced significant thinning of the left posterior superior temporal gyrus (canonical Wernicke's area), t(8) = 2.42, p ≤ 0.05. This is the first study to demonstrate experience-dependent structural plasticity in children receiving therapy for speech sound disorders.
Neuroanatomical consequences of very preterm birth in middle childhood.
Individuals born preterm can demonstrate reductions in brain volume, cortical surface area and thickness. However, the extent of these neuroanatomical deficits and the relation among these measures in middle childhood, a critical developmental period, have not been determined. We assessed differences in brain structure by acquiring high-resolution T(1)-weighted scans in 25 children born very preterm (<32 weeks gestational age) without significant post-natal neurological sequelae and 32 age-matched term-born children (7-10 years). Children born very preterm had decreased brain volume, surface area and cortical thickness compared to term-born children. Furthermore, children born preterm did not display the robust relation between total brain volume and basal ganglia and thalamic volume apparent in the term-born children. Cortical thickness analyses revealed that the cortex was thinner for children born preterm than term-born children in the anterior cingulate cortex/supplementary motor area, isthmus of the cingulate gyrus, right superior temporal sulcus, right anterior insula, postcentral gyrus and precuneus. Follow-up analyses revealed that right precuneus thickness was correlated with gestational age. Thus, even without significant postnatal medical sequelae, very preterm-born children showed atypical brain structure and developmental patterns in areas related to higher cognitive function. Disruptions of the typical neurodevelopmental trajectory in the third trimester of pregnancy likely underlie these differences persisting into middle childhood.