Publications by authors named "Claude Lepage"

31 Publications

Association between Quantitative MR Markers of Cortical Evolving Organization and Gene Expression during Human Prenatal Brain Development.

Cereb Cortex 2021 Apr 9. Epub 2021 Apr 9.

The Fetal-Neonatal Neuroimaging and Developmental Science Center, Boston Children's Hospital, Boston, MA 02115, USA.

The relationship between structural changes of the cerebral cortex revealed by Magnetic Resonance Imaging (MRI) and gene expression in the human fetal brain has not been explored. In this study, we aimed to test the hypothesis that relative regional thickness (a measure of cortical evolving organization) of fetal cortical compartments (cortical plate [CP] and subplate [SP]) is associated with expression levels of genes with known cortical phenotype. Mean regional SP/CP thickness ratios across age measured on in utero MRI of 25 healthy fetuses (20-33 gestational weeks [GWs]) were correlated with publicly available regional gene expression levels (23-24 GW fetuses). Larger SP/CP thickness ratios (more pronounced cortical evolving organization) was found in perisylvian regions. Furthermore, we found a significant association between SP/CP thickness ratio and expression levels of the FLNA gene (mutated in periventricular heterotopia, congenital heart disease, and vascular malformations). Further work is needed to identify early MRI biomarkers of gene expression that lead to abnormal cortical development.
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http://dx.doi.org/10.1093/cercor/bhab035DOI Listing
April 2021

Robust Cortical Thickness Morphometry of Neonatal Brain and Systematic Evaluation Using Multi-Site MRI Datasets.

Front Neurosci 2021 17;15:650082. Epub 2021 Mar 17.

Department of Neurology, USC Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.

The human brain grows the most dramatically during the perinatal and early post-natal periods, during which pre-term birth or perinatal injury that may alter brain structure and lead to developmental anomalies. Thus, characterizing cortical thickness of developing brains remains an important goal. However, this task is often complicated by inaccurate cortical surface extraction due to small-size brains. Here, we propose a novel complex framework for the reconstruction of neonatal WM and pial surfaces, accounting for large partial volumes due to small-size brains. The proposed approach relies only on T1-weighted images unlike previous T2-weighted image-based approaches while only T1-weighted images are sometimes available under the different clinical/research setting. Deep neural networks are first introduced to the neonatal magnetic resonance imaging (MRI) pipeline to address the mis-segmentation of brain tissues. Furthermore, this pipeline enhances cortical boundary delineation using combined models of the cerebrospinal fluid (CSF)/GM boundary detection with edge gradient information and a new skeletonization of sulcal folding where no CSF voxels are seen due to the limited resolution. We also proposed a systematic evaluation using three independent datasets comprising 736 pre-term and 97 term neonates. Qualitative assessment for reconstructed cortical surfaces shows that 86.9% are rated as accurate across the three site datasets. In addition, our landmark-based evaluation shows that the mean displacement of the cortical surfaces from the true boundaries was less than a voxel size (0.532 ± 0.035 mm). Evaluating the proposed pipeline (namely NEOCIVET 2.0) shows the robustness and reproducibility across different sites and different age-groups. The mean cortical thickness measured positively correlated with post-menstrual age (PMA) at scan ( < 0.0001); Cingulate cortical areas grew the most rapidly whereas the inferior temporal cortex grew the least rapidly. The range of the cortical thickness measured was biologically congruent (1.3 mm at 28 weeks of PMA to 1.8 mm at term equivalent). Cortical thickness measured on T1 MRI using NEOCIVET 2.0 was compared with that on T2 using the established dHCP pipeline. It was difficult to conclude that either T1 or T2 imaging is more ideal to construct cortical surfaces. NEOCIVET 2.0 has been open to the public through CBRAIN (https://mcin-cnim.ca/technology/cbrain/), a web-based platform for processing brain imaging data.
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http://dx.doi.org/10.3389/fnins.2021.650082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010150PMC
March 2021

CIVET-Macaque: An automated pipeline for MRI-based cortical surface generation and cortical thickness in macaques.

Neuroimage 2021 02 8;227:117622. Epub 2020 Dec 8.

Laboratory of Brain and Cognition, National Institute of Mental Health, Bethesda, MD, USA. Electronic address:

The MNI CIVET pipeline for automated extraction of cortical surfaces and evaluation of cortical thickness from in-vivo human MRI has been extended for processing macaque brains. Processing is performed based on the NIMH Macaque Template (NMT), as the reference template, with the anatomical parcellation of the surface following the D99 and CHARM atlases. The modifications needed to adapt CIVET to the macaque brain are detailed. Results have been obtained using CIVET-macaque to process the anatomical scans of the 31 macaques used to generate the NMT and another 95 macaques from the PRIME-DE initiative. It is anticipated that the open usage of CIVET-macaque will promote collaborative efforts in data collection and processing, sharing, and automated analyses from which the non-human primate brain imaging field will advance.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117622DOI Listing
February 2021

A collaborative resource platform for non-human primate neuroimaging.

Neuroimage 2021 02 20;226:117519. Epub 2020 Nov 20.

Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Direction de la Recherche Fondamentale, NeuroSpin Center, Gif-sur-Yvette, France; Cognitive Neuroimaging Unit, Institut National de la Santé et de la Recherche Médicale U992, Gif-sur-Yvette, France.

Neuroimaging non-human primates (NHPs) is a growing, yet highly specialized field of neuroscience. Resources that were primarily developed for human neuroimaging often need to be significantly adapted for use with NHPs or other animals, which has led to an abundance of custom, in-house solutions. In recent years, the global NHP neuroimaging community has made significant efforts to transform the field towards more open and collaborative practices. Here we present the PRIMatE Resource Exchange (PRIME-RE), a new collaborative online platform for NHP neuroimaging. PRIME-RE is a dynamic community-driven hub for the exchange of practical knowledge, specialized analytical tools, and open data repositories, specifically related to NHP neuroimaging. PRIME-RE caters to both researchers and developers who are either new to the field, looking to stay abreast of the latest developments, or seeking to collaboratively advance the field .
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http://dx.doi.org/10.1016/j.neuroimage.2020.117519DOI Listing
February 2021

Influence of Processing Pipeline on Cortical Thickness Measurement.

Cereb Cortex 2020 Jul;30(9):5014-5027

Research Centre Jülich, Institute of Neuroscience and Medicine (INM-7: Brain and Behavior), 52425, Jülich, Germany.

In recent years, replicability of neuroscientific findings, specifically those concerning correlates of morphological properties of gray matter (GM), have been subject of major scrutiny. Use of different processing pipelines and differences in their estimates of the macroscale GM may play an important role in this context. To address this issue, here, we investigated the cortical thickness estimates of three widely used pipelines. Based on analyses in two independent large-scale cohorts, we report high levels of within-pipeline reliability of the absolute cortical thickness-estimates and comparable spatial patterns of cortical thickness-estimates across all pipelines. Within each individual, absolute regional thickness differed between pipelines, indicating that in-vivo thickness measurements are only a proxy of actual thickness of the cortex, which shall only be compared within the same software package and thickness estimation technique. However, at group level, cortical thickness-estimates correlated strongly between pipelines, in most brain regions. The smallest between-pipeline correlations were observed in para-limbic areas and insula. These regions also demonstrated the highest interindividual variability and the lowest reliability of cortical thickness-estimates within each pipeline, suggesting that structural variations within these regions should be interpreted with caution.
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http://dx.doi.org/10.1093/cercor/bhaa097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391418PMC
July 2020

BigBrain 3D atlas of cortical layers: Cortical and laminar thickness gradients diverge in sensory and motor cortices.

PLoS Biol 2020 04 3;18(4):e3000678. Epub 2020 Apr 3.

McGill Centre for Integrative Neuroscience, Montréal Neurological Institute, Montréal, Canada.

Histological atlases of the cerebral cortex, such as those made famous by Brodmann and von Economo, are invaluable for understanding human brain microstructure and its relationship with functional organization in the brain. However, these existing atlases are limited to small numbers of manually annotated samples from a single cerebral hemisphere, measured from 2D histological sections. We present the first whole-brain quantitative 3D laminar atlas of the human cerebral cortex. It was derived from a 3D histological atlas of the human brain at 20-micrometer isotropic resolution (BigBrain), using a convolutional neural network to segment, automatically, the cortical layers in both hemispheres. Our approach overcomes many of the historical challenges with measurement of histological thickness in 2D, and the resultant laminar atlas provides an unprecedented level of precision and detail. We utilized this BigBrain cortical atlas to test whether previously reported thickness gradients, as measured by MRI in sensory and motor processing cortices, were present in a histological atlas of cortical thickness and which cortical layers were contributing to these gradients. Cortical thickness increased across sensory processing hierarchies, primarily driven by layers III, V, and VI. In contrast, motor-frontal cortices showed the opposite pattern, with decreases in total and pyramidal layer thickness from motor to frontal association cortices. These findings illustrate how this laminar atlas will provide a link between single-neuron morphology, mesoscale cortical layering, macroscopic cortical thickness, and, ultimately, functional neuroanatomy.
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http://dx.doi.org/10.1371/journal.pbio.3000678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7159250PMC
April 2020

A molecular gradient along the longitudinal axis of the human hippocampus informs large-scale behavioral systems.

Nat Commun 2020 02 19;11(1):960. Epub 2020 Feb 19.

Montreal Neurological Institute, McGill University, Montréal, QC, Canada.

The functional organization of the hippocampus is distributed as a gradient along its longitudinal axis that explains its differential interaction with diverse brain systems. We show that the location of human tissue samples extracted along the longitudinal axis of the adult human hippocampus can be predicted within 2mm using the expression pattern of less than 100 genes. Futhermore, this model generalizes to an external set of tissue samples from prenatal human hippocampi. We examine variation in this specific gene expression pattern across the whole brain, finding a distinct anterioventral-posteriodorsal gradient. We find frontal and anterior temporal regions involved in social and motivational behaviors, and more functionally connected to the anterior hippocampus, to be clearly differentiated from posterior parieto-occipital regions involved in visuospatial cognition and more functionally connected to the posterior hippocampus. These findings place the human hippocampus at the interface of two major brain systems defined by a single molecular gradient.
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http://dx.doi.org/10.1038/s41467-020-14518-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031290PMC
February 2020

Intersection of verbal memory and expressivity on cortical contrast and thickness in first episode psychosis.

Psychol Med 2020 08 28;50(11):1923-1936. Epub 2019 Aug 28.

Department of Psychiatry, McGill University, Verdun, Canada.

Background: Longitudinal studies of first episode of psychosis (FEP) patients are critical to understanding the dynamic clinical factors influencing functional outcomes; negative symptoms and verbal memory (VM) deficits are two such factors that remain a therapeutic challenge. This study uses white-gray matter contrast at the inner edge of the cortex, in addition to cortical thickness, to probe changes in microstructure and their relation with negative symptoms and possible intersections with verbal memory.

Methods: T1-weighted images and clinical data were collected longitudinally for patients (N = 88) over a two-year period. Cognitive data were also collected at baseline. Relationships between baseline VM (immediate/delayed recall) and rate of change in two negative symptom dimensions, amotivation and expressivity, were assessed at the behavioral level, as well as at the level of brain structure.

Results: VM, particularly immediate recall, was significantly and positively associated with a steeper rate of expressivity symptom decline (r = 0.32, q = 0.012). Significant interaction effects between baseline delayed recall and change in expressivity were uncovered in somatomotor regions bilaterally for both white-gray matter contrast and cortical thickness. Furthermore, interaction effects between immediate recall and change in expressivity on cortical thickness rates were uncovered across higher-order regions of the language processing network.

Conclusions: This study shows common neural correlates of language-related brain areas underlying expressivity and VM in FEP, suggesting deficits in these domains may be more linked to speech production rather than general cognitive capacity. Together, white-gray matter contrast and cortical thickness may optimally inform clinical investigations aiming to capture peri-cortical microstructural changes.
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http://dx.doi.org/10.1017/S0033291719002071DOI Listing
August 2020

Amygdalar reactivity is associated with prefrontal cortical thickness in a large population-based sample of adolescents.

PLoS One 2019 2;14(5):e0216152. Epub 2019 May 2.

Department of Psychiatry and Neuroimaging Center, Technische Universität Dresden, Dresden, Germany.

In structural neuroimaging studies, reduced cerebral cortical thickness in orbital and ventromedial prefrontal regions is frequently interpreted as reflecting an impaired ability to downregulate neuronal activity in the amygdalae. Unfortunately, little research has been conducted in order to test this conjecture. We examine the extent to which amygdalar reactivity is associated with cortical thickness in a population-based sample of adolescents. Data were obtained from the IMAGEN study, which includes 2,223 adolescents. While undergoing functional neuroimaging, participants passively viewed video clips of a face that started from a neutral expression and progressively turned angry, or, instead, turned to a second neutral expression. Left and right amygdala ROIs were used to extract mean BOLD signal change for the angry minus neutral face contrast for all subjects. T1-weighted images were processed through the CIVET pipeline (version 2.1.0). In variable-centered analyses, local cortical thickness was regressed against amygdalar reactivity using first and second-order linear models. In a follow-up person-centered analysis, we defined a "high reactive" group of participants based on mean amygdalar BOLD signal change for the angry minus neutral face contrast. Between-group differences in cortical thickness were examined ("high reactive" versus all other participants). A significant association was revealed between the continuous measure of amygdalar reactivity and bilateral ventromedial prefrontal cortical thickness in a second-order linear model (p < 0.05, corrected). The "high reactive" group, in comparison to all other participants, possessed reduced cortical thickness in bilateral orbital and ventromedial prefrontal cortices, bilateral anterior temporal cortices, left caudal middle temporal gyrus, and the left inferior and middle frontal gyri (p < 0.05, corrected). Results are consistent with non-human primate studies, and provide empirical support for an association between reduced prefrontal cortical thickness and amygdalar reactivity. Future research will likely benefit from investigating the degree to which psychopathology qualifies relations between prefrontal cortical structure and amygdalar reactivity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216152PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497259PMC
February 2020

White matter microstructure is associated with hyperactive/inattentive symptomatology and polygenic risk for attention-deficit/hyperactivity disorder in a population-based sample of adolescents.

Neuropsychopharmacology 2019 08 6;44(9):1597-1603. Epub 2019 Apr 6.

Bloorview Research Institute, Holland Bloorview Kids Rehabilitation Hospital and Departments of Psychology and Psychiatry, University of Toronto, Toronto, ON, M6A 2E1, Canada.

Few studies have investigated the link between putative biomarkers of attention-deficit/hyperactivity disorder (ADHD) symptomatology and genetic risk for ADHD. To address this, we investigate the degree to which ADHD symptomatology is associated with white matter microstructure and cerebral cortical thickness in a large population-based sample of adolescents. Critically, we then test the extent to which multimodal correlates of ADHD symptomatology are related to ADHD polygenic risk score (PRS). Neuroimaging, genetic, and behavioral data were obtained from the IMAGEN study. A dimensional ADHD composite score was derived from multi-informant ratings of ADHD symptomatology. Using tract-based spatial statistics, whole brain voxel-wise regressions between fractional anisotropy (FA) and ADHD composite score were calculated. Local cortical thickness was regressed on ADHD composite score. ADHD PRS was based on a very recent genome-wide association study, and calculated using PRSice. ADHD composite score was negatively associated with FA in several white matter pathways, including bilateral superior and inferior longitudinal fasciculi (p < 0.05, corrected). ADHD composite score was negatively associated with orbitofrontal cortical thickness (p < 0.05, corrected). The ADHD composite score was correlated with ADHD PRS (p < 0.001). FA correlates of ADHD symptomatology were significantly associated with ADHD PRS, whereas cortical thickness correlates of ADHD symptomatology were unrelated to ADHD PRS. Variation in hyperactive/inattentive symptomatology was associated with white matter microstructure, which, in turn, was related to ADHD PRS. Results suggest that genetic risk for ADHD symptomatology may be tied to biological processes affecting white matter microstructure.
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http://dx.doi.org/10.1038/s41386-019-0383-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784993PMC
August 2019

Structural Associations of Cortical Contrast and Thickness in First Episode Psychosis.

Cereb Cortex 2019 12;29(12):5009-5021

McGill Centre for Integrative Neuroscience, McGill University, Montreal, Canada.

There is growing evidence that psychosis is characterized by brain network abnormalities. Analyzing morphological abnormalities with T1-weighted structural MRI may be limited in discovering the extent of deviations in cortical associations. We assess whether structural associations of either cortical white-gray contrast (WGC) or cortical thickness (CT) allow for a better understanding of brain structural relationships in first episode of psychosis (FEP) patients. Principal component and structural covariance analyses were applied to WGC and CT derived from T1-weighted MRI for 116 patients and 88 controls, to explore sets of brain regions that showed group differences, and associations with symptom severity and cognitive ability in patients. We focused on 2 principal components: one encompassed primary somatomotor regions, which showed trend-like group differences in WGC, and the second included heteromodal cortices. Patients' component scores were related to general psychopathology for WGC, but not CT. Structural covariance analyses with WGC revealed group differences in pairwise correlations across widespread brain regions, mirroring areas derived from PCA. More group differences were uncovered with WGC compared with CT. WGC holds potential as a proxy measure of myelin from commonly acquired T1-weighted MRI and may be sensitive in detecting systems-level aberrations in early psychosis, and relationships with clinical/cognitive profiles.
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http://dx.doi.org/10.1093/cercor/bhz040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918925PMC
December 2019

Mapping Cortical Laminar Structure in the 3D BigBrain.

Cereb Cortex 2018 07;28(7):2551-2562

Department of Neurology and Neurosurgery, Montreal Neurological Institute (MNI), McGill University, Montreal, Canada.

Histological sections offer high spatial resolution to examine laminar architecture of the human cerebral cortex; however, they are restricted by being 2D, hence only regions with sufficiently optimal cutting planes can be analyzed. Conversely, noninvasive neuroimaging approaches are whole brain but have relatively low resolution. Consequently, correct 3D cross-cortical patterns of laminar architecture have never been mapped in histological sections. We developed an automated technique to identify and analyze laminar structure within the high-resolution 3D histological BigBrain. We extracted white matter and pial surfaces, from which we derived histologically verified surfaces at the layer I/II boundary and within layer IV. Layer IV depth was strongly predicted by cortical curvature but varied between areas. This fully automated 3D laminar analysis is an important requirement for bridging high-resolution 2D cytoarchitecture and in vivo 3D neuroimaging. It lays the foundation for in-depth, whole-brain analyses of cortical layering.
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http://dx.doi.org/10.1093/cercor/bhy074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5998962PMC
July 2018

Assessing neuronal density in peri-infarct cortex with PET: Effects of cortical topology and partial volume correction.

Hum Brain Mapp 2017 01 10;38(1):326-338. Epub 2016 Sep 10.

Montreal Neurological Institute, McGill University, Montreal, Canada.

The peri-infarct cortex (PIC) is the site of long-term physiologic changes after ischemic stroke. Traditional methods for delineating the peri-infarct gray matter (GM) have used a volumetric Euclidean distance metric to define its extent around the infarct. This metric has limitations in the case of cortical stroke, i.e., those where ischemia leads to infarction in the cortical GM, because the vascularization of the cerebral cortex follows the complex, folded topology of the cortical surface. Instead, we used a geodesic distance metric along the cortical surface to subdivide the PIC into equidistant rings emanating from the infarct border and compared this new approach to a Euclidean distance metric definition. This was done in 11 patients with [F-18]-Flumazenil ([18-F]-FMZ) positron emission tomography (PET) scans at 2 weeks post-stroke and at 6 month follow-up. FMZ is a PET radiotracer with specific binding to the alpha subunits of the type A γ-aminobutyric acid (GABAA) receptor. Additionally, we used partial-volume correction (PVC) of the PET images to compensate for potential cortical thinning and long-term neuronal loss in follow-up images. The difference in non-displaceable binding potential (BP ) between the stroke unaffected and affected hemispheres was 35% larger in the geodesic versus the Euclidean peri-infarct models in initial PET images and 48% larger in follow-up PET images. The inter-hemispheric BP difference was approximately 17-20% larger after PVC when compared to uncorrected PET images. PET studies of peri-infarct GM in cortical strokes should use a geodesic model and include PVC as a preprocessing step. Hum Brain Mapp 38:326-338, 2017. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/hbm.23363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6866936PMC
January 2017

NEOCIVET: Towards accurate morphometry of neonatal gyrification and clinical applications in preterm newborns.

Neuroimage 2016 Sep 13;138:28-42. Epub 2016 May 13.

Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA.

Cerebral cortical folding becomes dramatically more complex in the fetal brain during the 3rd trimester of gestation; the process continues in a similar fashion in children who are born prematurely. To quantify this morphological development, it is necessary to extract the interface between gray matter and white matter, which is particularly challenging due to changing tissue contrast during brain maturation. We employed the well-established CIVET pipeline to extract this cortical surface, with point correspondence across subjects, using a surface-based spherical registration. We then developed a variant of the pipeline, called NEOCIVET, that quantified cortical folding using mean curvature and sulcal depth while addressing the well-known problems of poor and temporally-varying gray/white contrast as well as motion artifact in neonatal MRI. NEOCIVET includes: i) a tissue classification technique that analyzed multi-atlas texture patches using the nonlocal mean estimator and subsequently applied a label fusion approach based on a joint probability between templates, ii) neonatal template construction based on age-specific sub-groups, and iii) masking of non-interesting structures using label-fusion approaches. These techniques replaced modules that might be suboptimal for regional analysis of poor-contrast neonatal cortex. The proposed segmentation method showed more accurate results in subjects with various ages and with various degrees of motion compared to state-of-the-art methods. In the analysis of 158 preterm-born neonates, many with multiple scans (n=231; 26-40weeks postmenstrual age at scan), NEOCIVET identified increases in cortical folding over time in numerous cortical regions (mean curvature: +0.003/week; sulcal depth: +0.04mm/week) while folding did not change in major sulci that are known to develop early (corrected p<0.05). The proposed pipeline successfully mapped cortical structural development, supporting current models of cerebral morphogenesis, and furthermore, revealed impairment of cortical folding in extremely preterm newborns relative to relatively late preterm newborns, demonstrating its potential to provide biomarkers of prematurity-related developmental outcome.
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http://dx.doi.org/10.1016/j.neuroimage.2016.05.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4982765PMC
September 2016

Quantitative and Qualitative Analysis of Transient Fetal Compartments during Prenatal Human Brain Development.

Front Neuroanat 2016 24;10:11. Epub 2016 Feb 24.

Department of Developmental Neuroscience, Croatian Institute for Brain Research, School of Medicine, University of Zagreb Zagreb, Croatia.

The cerebral wall of the human fetal brain is composed of transient cellular compartments, which show characteristic spatiotemporal relationships with intensity of major neurogenic events (cell proliferation, migration, axonal growth, dendritic differentiation, synaptogenesis, cell death, and myelination). The aim of the present study was to obtain new quantitative data describing volume, surface area, and thickness of transient compartments in the human fetal cerebrum. Forty-four postmortem fetal brains aged 13-40 postconceptional weeks (PCW) were included in this study. High-resolution T1 weighted MR images were acquired on 19 fetal brain hemispheres. MR images were processed using in-house software (MNI-ACE toolbox). Delineation of fetal compartments was performed semi-automatically by co-registration of MRI with histological sections of the same brains, or with the age-matched brains from Zagreb Neuroembryological Collection. Growth trajectories of transient fetal compartments were reconstructed. The composition of telencephalic wall was quantitatively assessed. Between 13 and 25 PCW, when the intensity of neuronal proliferation decreases drastically, the relative volume of proliferative (ventricular and subventricular) compartments showed pronounced decline. In contrast, synapse- and extracellular matrix-rich subplate compartment continued to grow during the first two trimesters, occupying up to 45% of telencephalon and reaching its maximum volume and thickness around 30 PCW. This developmental maximum coincides with a period of intensive growth of long cortico-cortical fibers, which enter and wait in subplate before approaching the cortical plate. Although we did not find significant age related changes in mean thickness of the cortical plate, the volume, gyrification index, and surface area of the cortical plate continued to exponentially grow during the last phases of prenatal development. This cortical expansion coincides developmentally with the transformation of embryonic cortical columns, dendritic differentiation, and ingrowth of axons. These results provide a quantitative description of transient human fetal brain compartments observable with MRI. Moreover, they will improve understanding of structural-functional relationships during brain development, will enable correlation between in vitro/in vivo imaging and fine structural histological studies, and will serve as a reference for study of perinatal brain injuries.
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http://dx.doi.org/10.3389/fnana.2016.00011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764715PMC
March 2016

Gray matter responsiveness to adaptive working memory training: a surface-based morphometry study.

Brain Struct Funct 2016 12 23;221(9):4369-4382. Epub 2015 Dec 23.

Universidad Autónoma de Madrid, 28049, Madrid, Spain.

Here we analyze gray matter indices before and after completing a challenging adaptive cognitive training program based on the n-back task. The considered gray matter indices were cortical thickness (CT) and cortical surface area (CSA). Twenty-eight young women (age range 17-22 years) completed 24 training sessions over the course of 3 months (12 weeks, 24 sessions), showing expected performance improvements. CT and CSA values for the training group were compared with those of a matched control group. Statistical analyses were computed using a ROI framework defined by brain areas distinguished by their genetic underpinning. The interaction between group and time was analyzed. Middle temporal, ventral frontal, inferior parietal cortices, and pars opercularis were the regions where the training group showed conservation of gray matter with respect to the control group. These regions support working memory, resistance to interference, and inhibition. Furthermore, an interaction with baseline intelligence differences showed that the expected decreasing trend at the biological level for individuals showing relatively low intelligence levels at baseline was attenuated by the completed training.
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http://dx.doi.org/10.1007/s00429-015-1168-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919225PMC
December 2016

Reproducibility of neuroimaging analyses across operating systems.

Front Neuroinform 2015 24;9:12. Epub 2015 Apr 24.

McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University Montreal, QC, Canada.

Neuroimaging pipelines are known to generate different results depending on the computing platform where they are compiled and executed. We quantify these differences for brain tissue classification, fMRI analysis, and cortical thickness (CT) extraction, using three of the main neuroimaging packages (FSL, Freesurfer and CIVET) and different versions of GNU/Linux. We also identify some causes of these differences using library and system call interception. We find that these packages use mathematical functions based on single-precision floating-point arithmetic whose implementations in operating systems continue to evolve. While these differences have little or no impact on simple analysis pipelines such as brain extraction and cortical tissue classification, their accumulation creates important differences in longer pipelines such as subcortical tissue classification, fMRI analysis, and cortical thickness extraction. With FSL, most Dice coefficients between subcortical classifications obtained on different operating systems remain above 0.9, but values as low as 0.59 are observed. Independent component analyses (ICA) of fMRI data differ between operating systems in one third of the tested subjects, due to differences in motion correction. With Freesurfer and CIVET, in some brain regions we find an effect of build or operating system on cortical thickness. A first step to correct these reproducibility issues would be to use more precise representations of floating-point numbers in the critical sections of the pipelines. The numerical stability of pipelines should also be reviewed.
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http://dx.doi.org/10.3389/fninf.2015.00012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408913PMC
May 2015

Cortical thickness, cortico-amygdalar networks, and externalizing behaviors in healthy children.

Biol Psychiatry 2014 Jan 25;75(1):65-72. Epub 2013 Jul 25.

Department of Psychiatry, The Hospital for Sick Children, University of Toronto, Toronto.

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.
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http://dx.doi.org/10.1016/j.biopsych.2013.06.008DOI Listing
January 2014

BigBrain: an ultrahigh-resolution 3D human brain model.

Science 2013 Jun;340(6139):1472-5

Institute of Neuroscience and Medicine (INM-1, INM-4), Research Centre Jülich, Jülich, Germany.

Reference brains are indispensable tools in human brain mapping, enabling integration of multimodal data into an anatomically realistic standard space. Available reference brains, however, are restricted to the macroscopic scale and do not provide information on the functionally important microscopic dimension. We created an ultrahigh-resolution three-dimensional (3D) model of a human brain at nearly cellular resolution of 20 micrometers, based on the reconstruction of 7404 histological sections. "BigBrain" is a free, publicly available tool that provides considerable neuroanatomical insight into the human brain, thereby allowing the extraction of microscopic data for modeling and simulation. BigBrain enables testing of hypotheses on optimal path lengths between interconnected cortical regions or on spatial organization of genetic patterning, redefining the traditional neuroanatomy maps such as those of Brodmann and von Economo.
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http://dx.doi.org/10.1126/science.1235381DOI Listing
June 2013

Symptom attribution in first episode psychosis: a cortical thickness study.

Psychiatry Res 2012 Jul 20;203(1):6-13. Epub 2012 Aug 20.

Brain Imaging Group, Douglas Mental Health University Institute, Verdun, Canada.

One dimension of insight in psychosis is the ability to attribute correctly one's symptoms to a mental disorder. Recent work suggests that gray matter volumes of the orbitofrontal cortex (OFC) are correlated with aggregate symptom attribution scores in first-episode schizophrenia. Whether regions beyond the OFC are important for symptom attribution remains to be established. Further, whether common or separable neural systems underlie attribution of specific symptoms (e.g., delusions, asociality) has not been studied. In the current magnetic resonance imaging study, 52 people with a first-episode psychosis (FEP) were rated with the Scale for Assessment of Unawareness of Mental Disorder on attribution of hallucinations, delusions, flat affect and asociality. Attribution ratings were regressed on cortical thickness at 81,924 vertices. Mapping statistics revealed that delusion misattribution was associated with thickness in the OFC [Brodmann's area (BA) 11/47]. Delusion, flat affect and asociality misattribution were associated with cortical thinness in the dorsolateral prefrontal cortex (BA 9/46). Differential associations emerged between each attribution item and cortical thickness/thinness in a variety of frontal, temporal, parietal and occipital areas. The results imply a selective role for the OFC in delusion misattribution in FEP. Evidence for cortical thickness covariation in a variety of regions suggests partial independence in the neural architecture underlying attribution for different symptoms in FEP.
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http://dx.doi.org/10.1016/j.pscychresns.2011.09.009DOI Listing
July 2012

Overlapping and segregating structural brain abnormalities in twins with schizophrenia or bipolar disorder.

Arch Gen Psychiatry 2012 Apr;69(4):349-59

Department of Psychiatry, Rudolf Magnus Institute for Neuroscience, University Medical Center Utrecht, the Netherlands.

Context: The nosologic dichotomy between schizophrenia and bipolar disorder (BD) as formulated by Kraepelin is currently being questioned, stimulated by the finding that schizophrenia and BD partly share a common genetic origin. Although both disorders are characterized by changes in brain structure, family studies suggest more segregating than overlapping neuroanatomical abnormalities in both disorders.

Objectives: To investigate whether patients with schizophrenia and patients with BD display overlapping abnormalities in brain volumes and cortical thickness and whether these are caused by shared genetic or environmental influences.

Design: Magnetic resonance imaging findings of monozygotic (MZ) and dizygotic (DZ) twin pairs discordant for schizophrenia, twin pairs concordant and discordant for BD, and healthy twin pairs were compared using structural equation modeling.

Setting: The Netherlands Twin Register and University Medical Center Utrecht.

Participants: A total of 310 individuals from 158 (152 complete and 6 incomplete) twin pairs were included: 26 pairs discordant for schizophrenia (13 MZ and 13 DZ), 49 pairs with BD (9 MZ and 4 DZ concordant; 14 MZ and 22 DZ discordant), and 83 healthy twin pairs (44 MZ and 39 DZ).

Main Outcome Measures: Estimates of additive genetic and unique environmental associations between schizophrenia and BD with overlapping and nonoverlapping volumes and cortical thickness.

Results: Higher genetic liabilities for schizophrenia and BD were associated with smaller white matter volume, thinner right (and left) parahippocampus, thinner right orbitofrontal cortex, and thicker temporoparietal and left superior motor cortices; higher environmental liabilities were associated with thinner right medial occipital cortex. Genetic liability for schizophrenia was associated with thicker right parietal cortex; for BD, with larger intracranial volume.

Conclusions: Brain structures reflect overlapping and segregating genetic liabilities for schizophrenia and BD. The overlapping smaller white matter volume and common areas of thinner cortex suggest that both disorders share genetic (neurodevelopmental) roots.
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http://dx.doi.org/10.1001/archgenpsychiatry.2011.1615DOI Listing
April 2012

Changes in cortical thickness during the course of illness in schizophrenia.

Arch Gen Psychiatry 2011 Sep;68(9):871-80

Rudolf Magnus Institute of Neuroscience, Department of Psychiatry, University Medical Center Utrecht, Heidelberglaan, the Netherlands.

Context: Whether cortical thickness changes in schizophrenia over time are more pronounced relative to the changes that can be attributed to normal aging has not been studied.

Objective: To compare patients with schizophrenia and healthy control participants on cortical thickness change.

Design: A 5-year longitudinal study comparing schizophrenic patients and healthy controls using 2 magnetic resonance images of the brain.

Setting: Patients were recruited from the Department of Psychiatry at the University Medical Centre Utrecht and from other psychiatric hospitals in the Netherlands. Healthy controls were recruited via advertisement in newspapers and notice boards.

Participants: Ninety-six schizophrenic patients and 113 healthy controls aged 16 to 56 years.

Main Outcome Measures: Cortical thickness and change in cortical thickness on a vertex-by-vertex basis across the cortical mantle, measures of functional and symptomatic outcome, and cumulative intake of antipsychotics during the scan interval.

Results: At baseline, the schizophrenic patients had thinner left orbitofrontal and right parahippocampal and superior temporal cortices and a thicker superior parietal lobule and occipital pole compared with the controls. Mean cortical thickness did not differ between the groups. Over time, excessive cortical thinning was found in widespread areas on the cortical mantle, most pronounced bilaterally in the temporal cortex and in the left frontal area. Poor outcome in patients was associated with more pronounced cortical thinning. Higher cumulative intake of typical antipsychotics during the scan interval was associated with more pronounced cortical thinning, whereas higher cumulative intake of atypical antipsychotic medication was associated with less pronounced cortical thinning.

Conclusions: In schizophrenia, the cortex shows excessive thinning over time in widespread areas of the brain, most pronounced in the frontal and temporal areas, and progresses across the entire course of the illness. The excessive thinning of the cortex appears related to outcome and medication intake.
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http://dx.doi.org/10.1001/archgenpsychiatry.2011.88DOI Listing
September 2011

Developmental cortical thinning in fetal alcohol spectrum disorders.

Neuroimage 2011 Sep 17;58(1):16-25. Epub 2011 Jun 17.

Department of Biomedical Engineering, University of Alberta, Edmonton, Alberta, Canada.

Regional cortical thickness was evaluated using CIVET processing of 3D T1-weighted images (i) to compare the variation in cortical thickness between 33 participants with fetal alcohol spectrum disorders (FASD) aged 6-30 years (mean age 12.3 years) versus 33 age/sex/hand-matched controls, and (ii) to examine developmental changes in cortical thickness with age from children to young adults in both groups. Significant cortical thinning was found in the participants with FASD in large areas of the bilateral middle frontal lobe, pre- and post- central areas, lateral and inferior temporal and occipital lobes compared to controls. No significant cortical thickness increases were observed for the FASD group. Cortical thinning with age in a linear model was observed in both groups, but the locations were different for each group. FASD participants showed thinning with age in the left middle frontal, bilateral precentral, bilateral precuneus and paracingulate, left inferior occipital and bilateral fusiform gyri; while controls showed decreases with age in the bilateral middle frontal gyrus, right inferior frontal gyrus, bilateral precuneus gyrus, and bilateral occipital gyrus. A battery of cognitive assessments of memory, attention, motor, and verbal abilities was conducted with many of the FASD participants, but no significant correlations were found between these cognitive scores and regional cortical thickness. Non-invasive measurements of cortical thickness in children to young adults with FASD have identified both key regions of cortex that may be more deleteriously affected by prenatal alcohol exposure as well as cortical changes with age that differ from normal developmental thinning.
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http://dx.doi.org/10.1016/j.neuroimage.2011.06.026DOI Listing
September 2011

Right anterior cingulate cortical thickness and bilateral striatal volume correlate with child behavior checklist aggressive behavior scores in healthy children.

Biol Psychiatry 2011 Aug 30;70(3):283-90. Epub 2011 Apr 30.

McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, Quebec, Canada.

Background: The anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and basal ganglia have been implicated in pathological aggression. This study aimed at identifying neuroanatomical correlates of impulsive aggression in healthy children.

Methods: Data from 193 representative 6- to 18-year-old healthy children were obtained from the National Institutes of Health Magnetic Resonance Imaging Study of Normal Brain Development after a blinded quality control. Cortical thickness and subcortical volumes were obtained with automated software. Aggression levels were measured with the Aggressive Behavior scale (AGG) of the Child Behavior Checklist. AGG scores were regressed against cortical thickness and basal ganglia volumes using first- and second-order linear models while controlling for age, gender, scanner site, and total brain volume. Gender by AGG interactions were analyzed.

Results: There were positive associations between bilateral striatal volumes and AGG scores (right: r = .238, p = .001; left: r = .188, p = .01). A significant association was found with right ACC and subgenual ACC cortical thickness in a second-order linear model (p < .05, corrected). High AGG scores were associated with a relatively thin right ACC cortex. An AGG by gender interaction trend was found in bilateral OFC and ACC associations with AGG scores.

Conclusions: This study shows the existence of relationships between impulsive aggression in healthy children and the structure of the striatum and right ACC. It also suggests the existence of gender-specific patterns of association in OFC/ACC gray matter. These results may guide research on oppositional-defiant and conduct disorders.
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http://dx.doi.org/10.1016/j.biopsych.2011.03.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3134605PMC
August 2011

Cortical thickness correlates of specific cognitive performance accounted for by the general factor of intelligence in healthy children aged 6 to 18.

Neuroimage 2011 Apr 15;55(4):1443-53. Epub 2011 Jan 15.

McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.

Prevailing psychometric theories of intelligence posit that individual differences in cognitive performance are attributable to three main sources of variance: the general factor of intelligence (g), cognitive ability domains, and specific test requirements and idiosyncrasies. Cortical thickness has been previously associated with g. In the present study, we systematically analyzed associations between cortical thickness and cognitive performance with and without adjusting for the effects of g in a representative sample of children and adolescents (N=207, Mean age=11.8; SD=3.5; Range=6 to 18.3 years). Seven cognitive tests were included in a measurement model that identified three first-order factors (representing cognitive ability domains) and one second-order factor representing g. Residuals of the cognitive ability domain scores were computed to represent g-independent variance for the three domains and seven tests. Cognitive domain and individual test scores as well as residualized scores were regressed against cortical thickness, adjusting for age, gender and a proxy measure of brain volume. g and cognitive domain scores were positively correlated with cortical thickness in very similar areas across the brain. Adjusting for the effects of g eliminated associations of domain and test scores with cortical thickness. Within a psychometric framework, cortical thickness correlates of cognitive performance on complex tasks are well captured by g in this demographically representative sample.
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http://dx.doi.org/10.1016/j.neuroimage.2011.01.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3070152PMC
April 2011

Cortical thickness is associated with poor insight in first-episode psychosis.

J Psychiatr Res 2011 Jun 19;45(6):781-7. Epub 2010 Nov 19.

Brain Imaging Group, Douglas Mental Health University Institute, 6875 LaSalle Blvd., Verdun, Quebec, Canada H4H 1R3.

Through conceptualizing poor insight in psychotic disorders as a form of anosognosia (neurological deficit), frontal lobe dysfunction is often ascribed a vital role in its pathogenesis. Whether non-frontal brain regions are important for insight remains to be investigated. We used a multi-method approach to examine the neural morphometry of all cortical regions for insight in first-episode psychosis. Insight was rated in 79 people with a first-episode psychosis with the awareness of illness and awareness of treatment need and efficacy items of the Scale for assessment of Unawareness of Mental Disorder. Participants were assessed with magnetic resonance imaging. Cortical thickness analysis and voxel-based morphometry were utilized to identify the possible neuroanatomical basis of insight. Cortical thickness technique revealed that poorer awareness of illness was associated with regional thinning in left middle frontal and inferior temporal gyri. Poorer awareness of treatment need and efficacy was associated with cortical thinning in left medial frontal gyrus, precuneus and temporal gyri. No significant associations emerged between any insight measure and gray matter density using voxel-based morphometry. The results confirm predictions derived from the anosognosia/neuropsychology account and assert that regional thickness in frontal cortex is associated with awareness of illness in the early phase of psychosis. The fact that prominent thickness reductions emerged in non-frontal regions of the brain in parietal and temporal cortices for both awareness of illness and awareness of treatment need and efficacy suggests that the neural signature of insight involves a network of brain structures, and not only the frontal lobes as previously suggested.
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http://dx.doi.org/10.1016/j.jpsychires.2010.10.016DOI Listing
June 2011

Mapping reliability in multicenter MRI: voxel-based morphometry and cortical thickness.

Hum Brain Mapp 2010 Dec 16;31(12):1967-82. Epub 2010 Apr 16.

Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.

Multicenter structural MRI studies can have greater statistical power than single-center studies. However, across-center differences in contrast sensitivity, spatial uniformity, etc., may lead to tissue classification or image registration differences that could reduce or wholly offset the enhanced statistical power of multicenter data. Prior work has validated volumetric multicenter MRI, but robust methods for assessing reliability and power of multisite analyses with voxel-based morphometry (VBM) and cortical thickness measurement (CORT) are not yet available. We developed quantitative methods to investigate the reproducibility of VBM and CORT to detect group differences and estimate heritability when MRI scans from different scanners running different acquisition protocols in a multicenter setup are included. The method produces brain maps displaying information such as lowest detectable effect size (or heritability) and effective number of subjects in the multicenter study. We applied the method to a five-site multicenter calibration study using scanners from four different manufacturers, running different acquisition protocols. The reliability maps showed an overall good comparability between the sites, providing a reasonable gain in sensitivity in most parts of the brain. In large parts of the cerebrum and cortex scan pooling improved heritability estimates, with "effective-N" values upto the theoretical maximum. For some areas, "optimal-pool" maps indicated that leaving out a site would give better results. The reliability maps also reveal which brain regions are in any case difficult to measure reliably (e.g., around the thalamus). These tools will facilitate the design and analysis of multisite VBM and CORT studies for detecting group differences and estimating heritability.
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http://dx.doi.org/10.1002/hbm.20991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6870904PMC
December 2010

Cannabis use and progressive cortical thickness loss in areas rich in CB1 receptors during the first five years of schizophrenia.

Eur Neuropsychopharmacol 2010 Dec 22;20(12):855-65. Epub 2010 Sep 22.

Rudolf Magnus Institute of Neuroscience, Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands.

Cerebral grey matter volume reductions are progressive in schizophrenia, with larger grey matter volume decreases associated with cannabis use. It is unknown whether this grey matter loss is globally distributed over the entire brain or more pronounced in specific cortical brain regions. Fifty-one patients with recent-onset schizophrenia and 31 matched healthy subjects were included. For all subjects, magnetic resonance imaging scans were obtained at inclusion and at 5-year follow-up. Nineteen patients (ab-)used cannabis but no other illicit drugs; 32 patients and the healthy comparison subjects did not use any drugs during the 5-year follow-up. At follow-up, clinical outcome was measured. To evaluate the local differences in cortical thickness change over five years between the two groups regression analysis was carried out over the cortical surface. At inclusion cortical thickness did not differ between patients and controls and between cannabis-using and non-using patients. Over the follow-up period we found excessive thinning of the right supplementary motor cortex, inferior frontal cortex, superior temporal gyrus, angular gyrus, occipital and parietal lobe in patients relative to controls after controlling for cannabis use. Patients who used cannabis showed additional thinning in the left dorsolateral prefrontal cortex (DLPFC), left anterior cingulate cortex (ACC) and left occipital lobe as compared to those patients that did not use cannabis during the scan interval. First-episode schizophrenia patients who use cannabis show a more pronounced cortical thinning than non-using patients in areas known for their high density of CB1 receptors, such as the ACC and the DLPFC.
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http://dx.doi.org/10.1016/j.euroneuro.2010.08.008DOI Listing
December 2010

Brain plasticity and intellectual ability are influenced by shared genes.

J Neurosci 2010 Apr;30(16):5519-24

Rudolf Magnus Institute for Neuroscience, Department of Psychiatry, University Medical Centre Utrecht, 3584 CX Utrecht, The Netherlands.

Although the adult brain is considered to be fully developed and stable until senescence when its size steadily decreases, such stability seems at odds with continued human (intellectual) development throughout life. Moreover, although variation in human brain size is highly heritable, we do not know the extent to which genes contribute to individual differences in brain plasticity. In this longitudinal magnetic resonance imaging study in twins, we report considerable thinning of the frontal cortex and thickening of the medial temporal cortex with increasing age and find this change to be heritable and partly related to cognitive ability. Specifically, adults with higher intelligence show attenuated cortical thinning and more pronounced cortical thickening over time than do subjects with average or below average IQ. Genes influencing variability in both intelligence and brain plasticity partly drive these associations. Thus, not only does the brain continue to change well into adulthood, these changes are functionally relevant because they are related to intelligence.
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http://dx.doi.org/10.1523/JNEUROSCI.5841-09.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6632359PMC
April 2010

Development of cortical asymmetry in typically developing children and its disruption in attention-deficit/hyperactivity disorder.

Arch Gen Psychiatry 2009 Aug;66(8):888-96

Child Psychiatry Branch, National Institute of Mental Health, Bethesda, MD 20892, USA.

Context: Just as typical development of anatomical asymmetries in the human brain has been linked with normal lateralization of motor and cognitive functions, disruption of asymmetry has been implicated in the pathogenesis of neurodevelopmental disorders such as attention-deficit/hyperactivity disorder (ADHD). No study has examined the development of cortical asymmetry using longitudinal neuroanatomical data.

Objective: To delineate the development of cortical asymmetry in children with and without ADHD.

Design: Longitudinal study.

Setting: Government Clinical Research Institute.

Participants: A total of 218 children with ADHD and 358 typically developing children, from whom 1133 neuroanatomical magnetic resonance images were acquired prospectively.

Main Outcome Measures: Cortical thickness was estimated at 40 962 homologous points in the left and right hemispheres, and the trajectory of change in asymmetry was defined using mixed-model regression.

Results: In right-handed typically developing individuals, a mean (SE) increase in the relative thickness of the right orbitofrontal and inferior frontal cortex with age of 0.011 (0.0018) mm per year (t(337) = 6.2, P < .001) was balanced against a relative left-hemispheric increase in the occipital cortical regions of 0.013 (0.0015) mm per year (t(337) = 8.1, P < .001). Age-related change in asymmetry in non-right-handed typically developing individuals was less extensive and was localized to different cortical regions. In ADHD, the posterior component of this evolving asymmetry was intact, but the prefrontal component was lost.

Conclusions: These findings explain the way that, in typical development, the increased dimensions of the right frontal and left occipital cortical regions emerge in adulthood from the reversed pattern of childhood cortical asymmetries. Loss of the prefrontal component of this evolving asymmetry in ADHD is compatible with disruption of prefrontal function in the disorder and demonstrates the way that disruption of typical processes of asymmetry can inform our understanding of neurodevelopmental disorders.
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http://dx.doi.org/10.1001/archgenpsychiatry.2009.103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948210PMC
August 2009