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Reduced cerebrovascular reserve is regionally associated with cortical thickness reductions in children with sickle cell disease.
Sickle cell disease (SCD) is a genetic disorder which adversely affects cerebrovascular health. Previous studies have demonstrated regional cortical thinning in SCD. However, the reason behind regional reductions in cortical thickness remains unclear. Therefore, we aimed to explore the possible link between the state of cerebrovascular health and cortical thickness. In this study, we obtained magnetic resonance (MR) based measures of cerebrovascular reactivity (CVR), a measure of vascular health, and cortical thickness in SCD patients (N=60) and controls of similar age and similar gender ratio (N=27). The group comparison analysis revealed significant regionally specific reductions in CVR and cortical thickness in the SCD group compared to the controls. In addition, a regional association analysis was performed between CVR and cortical thickness in the SCD group which revealed a significant regional association in several brain regions with the highest strength of association observed in the left cuneus, right post central gyrus and the right temporal pole. The regional association analysis revealed that significant associations were found in brain regions with high metabolic activity (anterior cingulate, posterior cingulate, occipital gyrus, precuneus) thus demonstrating that these regions could be most vulnerable to structural damage under hypoxic conditions.
Mapping anatomical correlations across cerebral cortex (MACACC) using cortical thickness from MRI.
We introduce MACACC-Mapping Anatomical Correlations Across Cerebral Cortex-to study correlated changes within and across different cortical networks. The principal topic of investigation is whether the thickness of one area of the cortex changes in a statistically correlated fashion with changes in thickness of other cortical regions. We further extend these methods by introducing techniques to test whether different population groupings exhibit significantly varying MACACC patterns. The methods are described in detail and applied to a normal childhood development population (n = 292), and show that association cortices have the highest correlation strengths. Taking Brodmann Area (BA) 44 as a seed region revealed MACACC patterns strikingly similar to tractography maps obtained from diffusion tensor imaging. Furthermore, the MACACC map of BA 44 changed with age, older subjects featuring tighter correlations with BA 44 in the anterior portions of the superior temporal gyri. Lastly, IQ-dependent MACACC differences were investigated, revealing steeper correlations between BA 44 and multiple frontal and parietal regions for the higher IQ group, most significantly (t = 4.0) in the anterior cingulate.
Altered Neocortical Gene Expression, Brain Overgrowth and Functional Over-Connectivity in Chd8 Haploinsufficient Mice.
Truncating CHD8 mutations are amongst the highest confidence risk factors for autism spectrum disorder (ASD) identified to date. Here, we report that Chd8 heterozygous mice display increased brain size, motor delay, hypertelorism, pronounced hypoactivity, and anomalous responses to social stimuli. Whereas gene expression in the neocortex is only mildly affected at midgestation, over 600 genes are differentially expressed in the early postnatal neocortex. Genes involved in cell adhesion and axon guidance are particularly prominent amongst the downregulated transcripts. Resting-state functional MRI identified increased synchronized activity in cortico-hippocampal and auditory-parietal networks in Chd8 heterozygous mutant mice, implicating altered connectivity as a potential mechanism underlying the behavioral phenotypes. Together, these data suggest that altered brain growth and diminished expression of important neurodevelopmental genes that regulate long-range brain wiring are followed by distinctive anomalies in functional brain connectivity in Chd8+/- mice. Human imaging studies have reported altered functional connectivity in ASD patients, with long-range under-connectivity seemingly more frequent. Our data suggest that CHD8 haploinsufficiency represents a specific subtype of ASD where neuropsychiatric symptoms are underpinned by long-range over-connectivity.
Errratum to: The developing human brain: age-related changes in cortical, subcortical, and cerebellar anatomy (Brain and Behavior, (2016), 10.1002/brb3.515)
© 2016 The Authors. Brain and Behavior published by Wiley Periodicals, Inc. In Sussman. D. 2016, “The” was inserted in the article title, so it reads as “The developing human brain: Age-related changes in cortical, subcortical and cerebellar anatomy.”. The online version of the article has been corrected.
BDNF-Dependent Effects on Amygdala-Cortical Circuitry and Depression Risk in Children and Youth.
The brain-derived neurotrophic factor (BDNF) is critical for brain development, and the functional BDNF Val66Met polymorphism is implicated in risk for mood disorders. The objective of this study was to determine how the Val66Met polymorphism influences amygdala-cortical connectivity during neurodevelopment and assess the relevance for mood disorders. Age- and sex-specific effects of the BDNF Val66Met polymorphism on amygdala-cortical connectivity were assessed by examining covariance of amygdala volumes with thickness throughout the cortex in a sample of Caucasian youths ages 8-22 that were part of the Philadelphia Neurodevelopmental Cohort (n = 339). Follow-up analyses assessed corresponding BDNF genotype effects on resting-state functional connectivity (n = 186) and the association between BDNF genotype and major depressive disorder (MDD) (n = 2749). In adolescents, amygdala-cortical covariance was significantly stronger in Met allele carriers compared with Val/Val homozygotes in amygdala-cortical networks implicated in depression; these differences were driven by females. In follow-up analyses, the Met allele was also associated with stronger resting-state functional connectivity in adolescents and increased likelihood of MDD in adolescent females. The BDNF Val66Met polymorphism may confer risk for mood disorders in females through effects on amygdala-cortical connectivity during adolescence, coinciding with a period in the lifespan when onset of depression often occurs, more commonly in females.
Sexual dimorphism revealed in the structure of the mouse brain using three-dimensional magnetic resonance imaging.
A large variety of sexual dimorphisms have been described in the brains of many vertebrate species, including humans. Naturally occurring sexual dimorphism has been implicated in the risk, progression and recovery from numerous neurological disorders, including head injury, multiple sclerosis and stroke. Genetically altered mice are a key tool in the study of structure-function relationships in the mammalian central nervous system and serve as models for human neuropsychiatric and neurological disorders. However, there are a limited number of quantitative three-dimensional analyses of the adult mouse brain structures. In order to address limitations in our knowledge of anatomical differences, a comprehensive study was undertaken using full 3D magnetic resonance imaging (MRI) to examine sexual dimorphisms in the C57BL/6J whole mouse brain. An expected difference in overall brain size between the sexes was found, where male brains were 2.5% larger in volume than female brains. Beyond the overall brain size differences in the sexes, the following significantly different regions were found: males were larger in the thalamus, primary motor cortex and posterior hippocampus, while females were larger in posterior hypothalamic area, entorhinal cortex and anterior hippocampus. Using high-definition 3D MRI on a normal inbred mouse strain, we have mapped in detail many sex-associated statistically significant differences in brain structures.
Cortical and Subcortical Brain Morphometry Differences Between Patients With Autism Spectrum Disorder and Healthy Individuals Across the Lifespan: Results From the ENIGMA ASD Working Group.
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.
Environmental enrichment is associated with rapid volumetric brain changes in adult mice.
Environmental enrichment is a model of increased structural brain plasticity. Previous histological observations have shown molecular and cellular changes in a few pre-determined areas of the rodent brain. However, little is known about the time course of enrichment-induced brain changes and how they distribute across the whole brain. Here we expose adult mice to three weeks of environmental enrichment using a novel re-configurable maze design. In-vivo MRI shows volumetric brain changes in brain areas related to spatial memory, navigation, and sensorimotor experience, such as the hippocampal formation and the sensorimotor cortex. Evidence from a second cohort of mice indicates that these plastic changes might occur as early as 24h after exposure. This suggests that novel experiences are powerful modulators of plasticity even in the adult brain. Understanding and harnessing the underlying molecular mechanisms could advance future treatments of neurological disease.
Cerebral asymmetries in 12-week-old C57Bl/6J mice measured by magnetic resonance imaging.
Asymmetries of multiple components of the rodent cerebrum have been described at various levels of organization. Yet, despite its ubiquitous nature, many confusing and sometimes contradictory reports regarding structural asymmetries in the rodent brain have been published. There is a need, therefore, for a whole-brain imaging analysis technique for asymmetry studies that is both accurate, reproducible and robust. To this end, a comprehensive three-dimensional examination of differences in brain structure in an inbred mouse strain was undertaken. The goal of this study was thus to use high-resolution magnetic resonance imaging to assess structural asymmetries in the adult C57Bl/6J mouse brain. Fixed brain T2-weighted images of 20 male C57Bl/6J mice were acquired on a 7T scanner at 32 microm isotropic resolution. We used voxel-based analyses to examine structural asymmetries throughout the whole mouse brain. The striatum, medial-posterior regions of the thalamus, and motor, sensorimotor, and visual cortex were found to be asymmetrical. The most significant asymmetry was found in the hippocampus and, specifically, the dentate gyrus. In each case, the left region was larger than the right. No other regions of the mouse brain showed structural asymmetry. The results in the dentate gyrus were confirmed using stereology, revealing a correlation of r=0.61 between magnetic resonance and stereological measures. Hippocampal, along with cortical asymmetry, has been discussed repeatedly in the literature, yet a clear pattern of directionality, until this point, has not been described. The findings of asymmetry in the striatum and absence of asymmetry in the rest of the brain are novel and show the advantage of using the whole-brain three-dimensional techniques developed herein for assessing asymmetry.
Language Ability Predicts Cortical Structure and Covariance in Boys with Autism Spectrum Disorder.
There is significant clinical heterogeneity in language and communication abilities of individuals with Autism Spectrum Disorders (ASD). However, no consistent pathology regarding the relationship of these abilities to brain structure has emerged. Recent developments in anatomical correlation-based approaches to map structural covariance networks (SCNs), combined with detailed behavioral characterization, offer an alternative for studying these relationships. In this study, such an approach was used to study the integrity of SCNs of cortical thickness and surface area associated with language and communication, in 46 high-functioning, school-age children with ASD compared with 50 matched, typically developing controls (all males) with IQ > 75. Findings showed that there was alteration of cortical structure and disruption of fronto-temporal cortical covariance in ASD compared with controls. Furthermore, in an analysis of a subset of ASD participants, alterations in both cortical structure and covariance were modulated by structural language ability of the participants, but not communicative function. These findings indicate that structural language abilities are related to altered fronto-temporal cortical covariance in ASD, much more than symptom severity or cognitive ability. They also support the importance of better characterizing ASD samples while studying brain structure and for better understanding individual differences in language and communication abilities in ASD.
Maze training in mice induces MRI-detectable brain shape changes specific to the type of learning.
Multiple recent human imaging studies have suggested that the structure of the brain can change with learning. To investigate the mechanism behind such structural plasticity, we sought to determine whether maze learning in mice induces brain shape changes that are detectable by MRI and whether such changes are specific to the type of learning. Here we trained inbred mice for 5 days on one of three different versions of the Morris water maze and, using high-resolution MRI, revealed specific growth in the hippocampus of mice trained on a spatial variant of the maze, whereas mice trained on the cued version were found to have growth in the striatum. The structure-specific growth found furthermore correlated with GAP-43 staining, a marker of neuronal process remodelling, but not with neurogenesis nor neuron or astrocyte numbers or sizes. Our findings provide evidence that brain morphology changes rapidly at a scale detectable by MRI and furthermore demonstrate that specific brain regions grow or shrink in response to the changing environmental demands. The data presented herein have implications for both human imaging as well as rodent structural plasticity research, in that it provides a tool to screen for neuronal plasticity across the whole brain in the mouse while also providing a direct link between human and mouse studies.
Cortical thickness
© 2018, Springer Science+Business Media, LLC. Multiple studies have measured cortical thickness from MRI since the advent of high contrast and 1 mm3 resolution anatomical acquisitions and the development of advanced image processing algorithms. In this chapter we provide an overview of the methods for extracting cortical thickness, focusing on the two dominant packages in the field, FreeSurfer and CIVET. In addition, we review the confounds and artifacts that can bedevil cortical thickness studies. Lastly, we describe the potential of inferring microstructural changes based on the mesoscopic measurements acquired from standard structural acquisitions.
Improved method for automatic cerebrovascular labelling using stochastic tunnelling
The complexity and high morphological variation of cerebral vasculature make comparison and analysis of the vessel patterning difficult and laborious. A framework for automatic labelling of the cerebral vessels in high resolution 3D images has been introduced in the literature that addresses this need. The segmented vasculature is represented as an attributed relational graph. Each vessel segment is an edge in the graph with local attributes such as diameter and length, as well as relational features representing the connectivity of the vessel segments. Each edge in the graph is automatically labelled with an anatomical name through a stochastic relaxation algorithm. In this paper, we compare the performance of four different optimization schemes, including stochastic tunnelling, for automatic labelling. We validated our method on 7 micro-CT images of C57Bl/6J mice with a leave-one-out test. The mean recognition rate of complete cerebrovasculature using stochastic tunnelling is 80% and shows a 2% (>60 vessel segments) improvement compared to simulated annealing optimization. © 2014 IEEE.
Cortical thickness, cortico-amygdalar networks, and externalizing behaviors in healthy children.
BACKGROUND: Fronto-amygdalar networks are implicated in childhood psychiatric disorders characterized by high rates of externalizing (aggressive, noncompliant, oppositional) behavior. Although externalizing behaviors are distributed continuously across clinical and nonclinical samples, little is known about how brain variations may confer risk for problematic behavior. Here, we studied cortical thickness, amygdala volume, and cortico-amygdalar network correlates of externalizing behavior in a large sample of healthy children. METHODS: Two hundred ninety-seven healthy children (6-18 years; mean = 12 ± 3 years), with 517 magnetic resonance imaging scans, from the National Institutes of Health Magnetic Resonance Imaging Study of Normal Brain Development, were studied. Relationships between externalizing behaviors (measured with the Child Behavior Checklist) and cortical thickness, amygdala volume, and cortico-amygdalar structural networks were examined using first-order linear mixed-effects models, after controlling for age, sex, scanner, and total brain volume. Results significant at p ≤ .05, following multiple comparison correction, are reported. RESULTS: Left orbitofrontal, right retrosplenial cingulate, and medial temporal cortex thickness were negatively correlated with externalizing behaviors. Although amygdala volume alone was not correlated with externalizing behaviors, an orbitofrontal cortex-amygdala network predicted rates of externalizing behavior. Children with lower levels of externalizing behaviors exhibited positive correlations between orbitofrontal cortex and amygdala structure, while these regions were not correlated in children with higher levels of externalizing behavior. CONCLUSIONS: Our findings identify key cortical nodes in frontal, cingulate, and temporal cortex associated with externalizing behaviors in children; and indicate that orbitofrontal-amygdala network properties may influence externalizing behaviors, along a continuum and across healthy and clinical samples.
Neuroimaging evidence for the deficit subtype of schizophrenia
Importance: A major obstacle to the identification of the neurobiological correlates of schizophrenia is the substantial clinical heterogeneity present in this disorder. Dividing schizophrenia into "deficit" and "nondeficit" subtypes may reduce heterogeneity and facilitate identification of neurobiological markers of disease. Objective: To determine whether patients with deficit schizophrenia differ from patients with nondeficit schizophrenia and healthy controls in neuroimaging-based measures of white matter tracts and gray matter morphology. Design: A cross-sectional neuroimaging study of patients with the deficit or nondeficit subtype of schizophrenia and healthy controls. Setting: University hospital. Participants: Seventy-seven patients with schizophrenia and 79 healthy controls. Interventions: All participants were administered the Structured Clinical Interview for DSM-IV-TR Axis I Disorders and the Positive and Negative Syndrome Scale; IQ was measured using the Wechsler Test for Adult Reading; global cognitive impairment was grossly assessed using the Mini-Mental State Examination; comorbid physical illness burden was measured by administration of the Clinical Information Rating Scale-Geriatrics; high-resolution magnetic resonance imaging was performed as part of a multimodal imaging protocol; and deficit status was determined using the proxy scale for the deficit syndrome. Main Outcome Measures : Diffusion-based measures of white matter tracts, cortical thickness, cortical surface area, and volumes of subcortical structures. Results: In both an individually matched approach (18 patients with deficit schizophrenia, 18 patients with non-deficit schizophrenia, and 18 healthy controls) and an unmatched population-based approach (18 patients with deficit schizophrenia, 59 patients with nondeficit schizophrenia, and 79 health controls), the patients with deficit schizophrenia demonstrated disruption of white matter tracts compared with patients with nondeficit schizophrenia and healthy controls at the right inferior longitudinal fasciculus, the right arcuate fasciculus, and the left uncinate fasciculus. These findings were supported in patients with first-episode schizophrenia (n=20) who had a deficit score that was strongly correlated with disruption at these same tracts. In contrast, patients with schizophrenia of either subtype exhibited cortical thickness reductions compared with healthy controls, in nearidentical neuroanatomic patterns. Surface areas and subcortical volumes did not differ significantly among the 3 groups. Conclusions and Relevance: The convergence of findings in our individually matched sample, our unmatched overall sample, and our first-episode schizophrenia sample demonstrate (1) white matter tract disruption as a neurobiological feature of the deficit syndrome and (2) reductions in cortical thickness as a common feature of patients with a diagnosis of schizophrenia. When taken with previous results in gray matter, our findings in white matter tracts point to neural circuitry important for socioemotional function as a core neurobiological feature of the deficit subtype of schizophrenia. ©2013 American Medical Association. All rights reserved.
Identification of a Functional Connectome for Long-Term Fear Memory in Mice
Long-term memories are thought to depend upon the coordinated activation of a broad network of cortical and subcortical brain regions. However, the distributed nature of this representation has made it challenging to define the neural elements of the memory trace, and lesion and electrophysiological approaches provide only a narrow window into what is appreciated a much more global network. Here we used a global mapping approach to identify networks of brain regions activated following recall of long-term fear memories in mice. Analysis of Fos expression across 84 brain regions allowed us to identify regions that were co-active following memory recall. These analyses revealed that the functional organization of long-term fear memories depends on memory age and is altered in mutant mice that exhibit premature forgetting. Most importantly, these analyses indicate that long-term memory recall engages a network that has a distinct thalamic-hippocampal-cortical signature. This network is concurrently integrated and segregated and therefore has small-world properties, and contains hub-like regions in the prefrontal cortex and thalamus that may play privileged roles in memory expression. © 2013 Wheeler et al.
Effects of age and symptomatology on cortical thickness in autism spectrum disorders
Several brain regions show structural and functional abnormalities in individuals with autism spectrum disorders (ASD), but the developmental trajectory of abnormalities in these structures and how they may relate to social and communicative impairments are still unclear. We assessed the effects of age on cortical thickness in individuals with ASD, between the ages of 7 and 39 years in comparison to typically developing controls. Additionally, we examined differences in cortical thickness in relation to symptomatology in the ASD group, and their association with age. Analyses were conducted using a general linear model, controlling for sex. Social and communication scores from the Autism Diagnostic Interview-Revised (ADI-R) were correlated with the thickness of regions implicated in those functions. Controls showed widespread cortical thinning relative to the ASD group. Within regions-of-interest, increased thickness in the rostral anterior cingulate cortex was associated with poorer social scores. Additionally, a significant interaction between age and social impairment was found in the orbitofrontal cortex, with more impaired younger children having decreased thickness in this region. These results suggest that differential neurodevelopmental trajectories are present in individuals with ASD and some differences are associated with diagnostic behaviours. © 2012 Elsevier Ltd. All rights reserved.
The effects of musical training on structural brain development: A longitudinal study
Long-term instrumental music training is an intense, multisensory and motor experience that offers an ideal opportunity to study structural brain plasticity in the developing brain in correlation with behavioral changes induced by training. Here, for the first time, we demonstrate structural brain changes after only 15 months of musical training in early childhood, which were correlated with improvements in musically relevant motor and auditory skills. These findings shed light on brain plasticity, and suggest that structural brain differences in adult experts (whether musicians or experts in other areas) are likely due to training-induced brain plasticity. © 2009 New York Academy of Sciences.
Automated deformation analysis in the YAC128 Huntington disease mouse model.
The YAC128 mouse recapitulates many of the clinical features of Huntington disease (HD), including selective neuropathology with neuronal loss. Here we investigate whether differences in neuroanatomy could be detected using high-resolution magnetic resonance (MR) imaging earlier than the previously defined 9-month age of onset of striatal neuropathology. The striatum is significantly decreased in volume (3.4%, p<0.02) at 8 months of age. A subset of the brains was also analyzed using stereology, and the MR measures were found to be more robust at separating the two groups of mice. Striatal degeneration was found to be asymmetric, with the dorsal and lateral aspects of the striatum being most affected. Non-striatal changes in neuroanatomy were also investigated, revealing regions of expansion as well as atrophy. Our findings suggest that MR imaging can be used to detect and monitor subtle anatomical differences throughout the whole brain and at early time points in the YAC128 mouse-model of HD.