Neuroanatomical Abnormalities Research Articles

Bridging the Brain‐Age Gap: Quantifying regional contributions using Shapley‐Owen values

AbstractBackgroundThe concept of brain age gap (BAG) is increasingly being used to express the deviation of brain from the normative trajectory. However, each brain region is subject to independent aging transformations due to differences in neurobiological processes. So, reducing high‐dimensional imaging features down to a single number for simultaneously evaluating brain health, capacity, and residual lifespan is an error‐prone task. Furthermore, brain age is observed to be correlated with chronological age. Therefore, there is need for a systematic empirical evaluation of BAG to understand contributions of different regions when considering BAG as a potential aging biomarker for age‐related neuroanatomical abnormalities. Although methods such as saliency maps have been proposed, there is need for a model‐agnostic technique that quantifies consistent feature contributions across various predictive models.MethodWe used morphological features estimated by Freesurfer from T1w (OASIS3 dataset) to train predictive models for BAG. The bias‐correction was performed using two strategies (i.e., scale‐down and scale up) on each of linear regression and XGBoost models as shown in Figure 1. We present feature importance for top‐10 features (based on median feature importance scores) across 100 bootstrap runs (Figures 2 and 3 respectively), along with correlations with chronological age. We use Shapley‐Owen feature attribution technique as a way of assigning importance to features.ResultAs shown in Figures 2 and 3, we found sub‐cortical, anterior cingulate, and ventricle volumes among the most relevant features. We also observe that SHAP determines an almost identical set of most relevant features for predicting corrected BAG irrespective of the predictive model (linear regression or XGboost) or the bias‐correction approach. Furthermore, we found the results to be consistent with prior literature e.g., subcortical brain volumes esp. gray matter. We also empirically observe that bias‐correction mitigates dependence on chronological age.ConclusionWe present a systematic empirical evaluation to identify the most relevant morphological features for predicting corrected BAG using SHAP. A consistent overlap of most relevant features irrespective of predictive model and the bias‐correction approach provides evidence for the robustness of using Shapley‐Owen values in explaining the contribution of morphological features for predicting corrected BAG.

Mapping the neuroanatomical abnormalities in a phenotype of male compulsive rats

Compulsivity is considered a transdiagnostic dimension in obsessive–compulsive and related disorders, characterized by heterogeneous cognitive and behavioral phenotypes associated with abnormalities in cortico-striatal-thalamic-cortical circuitry. The present study investigated the structural morphology of white and gray matter in rats selected for low- (LD) and high- (HD) compulsive drinking behavior on a schedule-induced polydipsia (SIP) task. Regional brain morphology was assessed using ex-vivo high-resolution magnetic resonance imaging (MRI). Voxel-based morphometry of segmented MRI images revealed larger white matter volumes in anterior commissure and corpus callosum of HD rats compared with LD rats. HD rats also showed significantly larger regional volumes of dorsolateral orbitofrontal cortex, striatum, amygdala, hippocampus, midbrain, sub-thalamic nucleus, and cerebellum. By contrast, the medial prefrontal cortex was significantly smaller in HD rats compared with LD rats with no significant group differences in whole brain, ventricular, or cerebrospinal fluid volumes. These findings show that limbic cortico-basal ganglia structures implicated in impulse control disorders are distinct in rats that are vulnerable to develop compulsive behavior. Such abnormalities may be relevant to the etiology of compulsive disorders in humans.

Reduced Cortical Complexity in Children with Developmental Delay in Saudi Arabia.

Developmental delay (DD) is a neurodevelopmental disorder characterized by delays in multiple domains. The investigation of brain structure in DD has been enhanced by advanced neuroimaging techniques that can identify regional surface deformities. Neuroimaging studies have identified structural brain abnormalities in individuals with DD, but research specific to the Saudi Arabian population is limited. In this study, we examine the neuroanatomical abnormalities in the cortical and subcortical regions of Saudi Arabian children with DD. A T1-weighted, 1-mm-thick MRI was used to acquire structural brain images of 29 children with DD and age-matched healthy controls. Analysis of the MRI data revealed significant differences in several cortical and subcortical structures of gray matter (GM) and white matter (WM) in several brain regions of the DD group. Specifically, significant deformities were observed in the caudate nucleus, globus pallidus, frontal gyrus, pars opercularis, pars orbitalis, cingulate gyrus, and subcallosal gyrus. These findings suggest disrupted neurodevelopment in these regions, which may contribute to the cognitive, motor, and behavioral impairments commonly observed in individuals with DD. The present study provides valuable insights into the neuroanatomical differences in Saudi Arabian children with DD. Our results provide evidence for cortical and subcortical abnormalities in DD. Deformities in the observed regions may contribute to cognitive impairment, emotional dysregulation, mood disorders, and language deficits commonly observed in DD. The structural analysis may enable the identification of neuroanatomical biomarkers to facilitate the early diagnosis or progression of DD. These results suggest that lower cortical complexity in DD children due to alterations in networks may play a critical role in early brain development.

Causal Associations of Genetically Determined Tinnitus With Neuroimaging Traits: Evidence From a Mendelian Randomization Study.

Potential reverse causality and unmeasured confounding factors are common biases in most neuroimaging studies on tinnitus and central correlates. The causal association of tinnitus with neuroimaging features also remains unclear. This study aimed to investigate the causal relationship of tinnitus with neuroplastic alterations using Mendelian randomization. Summary-level data from a genome-wide association study of tinnitus were derived from UK Biobank (n = 117,882). The genome-wide association study summary statistics for 4 global-brain tissue and 14 sub-brain gray matter volumetric traits were also obtained (n = up to 33,224). A bidirectional Mendelian randomization analysis was conducted to explore the causal relationship between tinnitus and neuroanatomical features at global-brain and sub-brain levels. Genetic susceptibility to tinnitus was causally associated with increased white matter volume (odds ratio [OR] = 2.361, 95% confidence interval [CI], 1.033 to 5.393) and total brain volume (OR = 2.391, 95% CI, 1.047 to 5.463) but inversely associated with cerebrospinal fluid volume (OR = 0.362, 95% CI, 0.158 to 0.826). A smaller gray matter volume in the left Heschl's gyrus and right insular cortex and larger gray matter volume in the posterior division of the left parahippocampal gyrus may lead to an increased risk for tinnitus (OR = 0.978, 95% CI, 0.961 to 0.996; OR = 0.987, 95% CI, 0.976 to 0.998; and OR = 1.015, 95% CI, 1.001 to 1.028, respectively). Genetic susceptibility to tinnitus was causally associated with increased white matter volume and total brain volume. Volume alteration in several cortical regions may indicate a higher tinnitus risk, and further research is recommended for causality inference at the level of sub-brain regions. Our findings provide genetic evidence for elucidating the underlying pathophysiological mechanisms of tinnitus-related neuroanatomical abnormalities.

Effect of lithium in pyramidal neurons of Cornu Ammonis in an animal model

Bipolar disorder has been associated with a decrease in hippocampal size, and lithium appears to reverse this neuroanatomical abnormality. The objective of this work was to evaluate, at a cellular level, the size of both cell body and nucleus of pyramidal neurons located throughout the Cornu Ammonis (CA1 to CA4 regions). To perform this duty, we used 16 rats that were randomized into two groups: control and dietary lithium-treated. After one month, they were sacrificed and their brains removed for histopathological analysis. Serial photos of the entire Cornu Ammonis were taken and, after dividing them into 4 regions of interest, we measured the cell body and nucleus on each pyramidal neuron belonging to the first 5 photos of each region of interest. As a result of this histological analysis, cell body area and nuclear area were significantly larger in the experimental group in a specific area of the Cornu Ammonis that could correspond to CA2 or the transition between CA1 and CA2. These results suggest that the effect of lithium is not homogeneous throughout the hippocampus and allows directing future studies to a specific area of this structure.

Attention Deficit-Hyperactivity Disorder (ADHD): From Abnormal Behavior to Impairment in Synaptic Plasticity.

Attention deficit-hyperactivity disorder (ADHD) is a neurodevelopmental disorder with high incidence in children and adolescents characterized by motor hyperactivity, impulsivity, and inattention. Magnetic resonance imaging (MRI) has revealed that neuroanatomical abnormalities such as the volume reduction in the neocortex and hippocampus are shared by several neuropsychiatric diseases such as schizophrenia, autism spectrum disorder and ADHD. Furthermore, the abnormal development and postnatal pruning of dendritic spines of neocortical neurons in schizophrenia, autism spectrum disorder and intellectual disability are well documented. Dendritic spines are dynamic structures exhibiting Hebbian and homeostatic plasticity that triggers intracellular cascades involving glutamate receptors, calcium influx and remodeling of the F-actin network. The long-term potentiation (LTP)-induced insertion of postsynaptic glutamate receptors is associated with the enlargement of spine heads and long-term depression (LTD) with spine shrinkage. Using a murine model of ADHD, a delay in dendritic spines' maturation in CA1 hippocampal neurons correlated with impaired working memory and hippocampal LTP has recently reported. The aim of this review is to summarize recent evidence that has emerged from studies focused on the neuroanatomical and genetic features found in ADHD patients as well as reports from animal models describing the molecular structure and remodeling of dendritic spines.

Craniofacial Encephalocele: Updates on Management.

Craniofacial encephaloceles are rare, yet highly debilitating neuroanatomical abnormalities that result from herniation of neural tissue through a bony defect and can lead to death, cognitive delay, seizures, and issues integrating socially. The etiology of encephaloceles is still being investigated, with evidence pointing towards the Sonic Hedgehog pathway, Wnt signaling, glioma-associated oncogene (GLI) transcription factors, and G protein-coupled receptors within primary cilia as some of the major genetic regulators that can contribute to improper mesenchymal migration and neural tube closure. Consensus on the proper approach to treating craniofacial encephaloceles is confounded by the abundance of surgical techniques and parameters to consider when determining the optimal timing and course of intervention. Minimally invasive approaches to encephalocele and temporal seizure treatment have increasingly shown evidence of successful intervention. Recent evidence suggests that a single, two-stage operation utilizing neurosurgeons to remove the encephalocele and plastic surgeons to reconstruct the surrounding tissue can be successful in many patients. The HULA procedure (H = hard-tissue sealant, U = undermine and excise encephalocele, L = lower supraorbital bar, A = augment nasal dorsum) and endoscopic endonasal surgery using vascularized nasoseptal flaps have surfaced as less invasive and equally successful approaches to surgical correction, compared to traditional craniotomies. Temporal encephaloceles can be a causative factor in drug-resistant temporal seizures and there has been success in curing patients of these seizures by temporal lobectomy and amygdalohippocampectomy, but magnetic resonance-guided laser interstitial thermal therapy has been introduced as a minimally invasive method that has shown success as well. Some of the major concerns postoperatively include infection, cerebrospinal fluid (CSF) leakage, infringement of craniofacial development, elevated intracranial pressure, wound dehiscence, and developmental delay. Depending on the severity of encephalocele prior to surgery, the surgical approach taken, any postoperative complications, and the age of the patient, rehabilitation approaches may vary.

Historical postmortem studies on catatonia: Close reading and analysis of Kahlbaum's cases and scientific texts between 1800 and 1900

In the 19th century, postmortem brain examination played a central role in the search for the neurobiological origin of psychiatric and neurological disorders. During that time, psychiatrists, neurologists, and neuropathologists examined autopsied brains from catatonic patients and postulated that catatonia is an organic brain disease. In line with this development, human postmortem studies of the 19th century became increasingly important in the conception of catatonia and might be seen as precursors of modern neuroscience. In this report, we closely examined autopsy reports of eleven catatonia patients of Karl Ludwig Kahlbaum. Further, we performed a close reading and analysis of previously (systematically) identified historical German and English texts between 1800 and 1900 for autopsy reports of catatonia patients. Two main findings emerged: (i) Kahlbaum's most important finding in catatonia patients was the opacity of the arachnoid; (ii) historical human postmortem studies of catatonia patients postulated a number of neuroanatomical abnormalities such as cerebral enlargement or atrophy, anemia, inflammation, suppuration, serous effusion, or dropsy as well as alterations of brain blood vessels such as rupture, distension or ossification in the pathogenesis of catatonia. However, the exact localization has often been missing or inaccurate, probably due to the lack of standardized subdivision/nomenclature of the respective brain areas. Nevertheless, Kahlbaum's 11 autopsy reports and the identified neuropathological studies between 1800 and 1900 made important discoveries, which still have the potential to inform and bolster modern neuroscientific research in catatonia.

Data-driven Approach to Identify Subtypes and Progression of Parkinson’s disease using Multimodal Imaging Data (P6-11.006)

<h3>Objective:</h3> To identify neuroanatomical subtypes of patients with Parkinson’s disease (PD) and to define how they differ in motor symptoms. To investigate how the neuroanatomy and motor symptoms of these subtypes change over time. <h3>Background:</h3> Novel approaches to parse the heterogeneity in PD based on neurobiological mechanisms are needed to improve the efforts in precision medicine. Here, we used multimodal imaging data to identify PD subtypes and their progression. <h3>Design/Methods:</h3> T1-weighted, diffusion tensor imaging data and clinical motor scores were obtained from the Parkinson’s Progression Markers Initiative database (www.ppmi-info.org/data) for 61 PD patients at both baseline and 48-month follow-up, and 70 healthy controls (HC) at baseline only. We extracted mean cortical thickness (CTh, reflecting cortical morphometry) from 68 cortical regions, and mean quantitative anisotropy (QA, reflecting the axonal integrity) from 45 white matter tracts. Using Mahalanobis distance, multivariate summary scores of CTh (M_CTh) and QA (M_QA) were derived and selected as features for heterogeneity through discriminative analysis. Group differences in neuroanatomical variables (M_CTh, M_QA), and motor symptoms between HC and PD subtypes were tested using ANOVA. To assess the longitudinal changes, a linear mixed-effect model was used. <h3>Results:</h3> Three PD subtypes were identified. Subtype 1 showed no detectable neuroanatomical abnormalities and mild motor symptoms at baseline. However, over time, these patients demonstrated substantial axonal degeneration with worsened motor symptoms. Subtype 2 showed cortical atrophy and severe motor symptoms at baseline, but with significant axonal degeneration and absence of changes in motor symptoms over time. Subtype 3 characterized by axonal damage and severe motor symptoms at baseline, displays no neuroanatomical or motor symptom deterioration over time. <h3>Conclusions:</h3> We parsed the heterogeneity of PD using CTh and QA data and identified three distinct PD subtypes with different severity levels of motor symptoms and different patterns of neuroanatomical and symptom progression. <b>Disclosure:</b> Dr. Ambili Vijayakumari has nothing to disclose. Dr. Fernandez has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbvie. Dr. Fernandez has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cerevel. Dr. Fernandez has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amneal. Dr. Fernandez has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. The institution of Dr. Fernandez has received research support from Biogen. The institution of Dr. Fernandez has received research support from Michael J Fox Founda. The institution of Dr. Fernandez has received research support from Roche. The institution of Dr. Fernandez has received research support from Parkinson Foundation. The institution of Dr. Fernandez has received research support from UCB. Dr. Fernandez has received publishing royalties from a publication relating to health care. Dr. Fernandez has received personal compensation in the range of $10,000-$49,999 for serving as a Steering Committee/Advisory Committee Member with Parkinson Study Group. Dr. Walter has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Acorda. Dr. Walter has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Lundbeck. Dr. Walter has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Medtronic. Dr. Walter has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Teva. Dr. Walter has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Abbott.

The Use of Stem Cell Therapy in the Treatment of Autism Spectrum Disorder

Research on the use of stem cell therapy in regenerative medicine has shown great potential in the treatment of neurological disorders. Specifically, mesenchymal stem cells, adult stem cells from the umbilical cord and embryonic stem cells have been used in both animal models and clinical trials to treat autism spectrum disorder. Autism Spectrum Disorder (ASD) is an incurable neurological disorder characterized by behavioral and neuroanatomical abnormalities, commonly co-occurring with other neurological disorders including anxiety, depression and obsessive-compulsive disorder. Stem cell therapies are currently being researched to alleviate the behavioral tendencies typically seen in individuals with ASD.

Brain vitamin D3-auto/paracrine system in relation to structural, neurophysiological, and behavioral disturbances associated with glucocorticoid-induced neurotoxicity.

Vitamin D3 (VD3) is a potent para/autocrine regulator and neurosteroid that can strongly influence nerve cell function and counteract the negative effects of glucocorticoid (GC) therapy. The aim of the study was to reveal the relationship between VD3 status and behavioral, structural-functional and molecular changes associated with GC-induced neurotoxicity. Female Wistar rats received synthetic GC prednisolone (5 mg/kg b.w.) with or without VD3 (1000 IU/kg b.w.) for 30 days. Behavioral, histological, physiological, biochemical, molecular biological (RT-PCR, Western blotting) methods, and ELISA were used. There was no difference in open field test (OFT), while forced swim test (FST) showed an increase in immobility time and a decrease in active behavior in prednisolone-treated rats, indicative of depressive changes. GC increased the perikaryon area, enlarged the size of the nuclei, and caused a slight reduction of cell density in CA1-CA3 hippocampal sections. We established a GC-induced decrease in the long-term potentiation (LTP) in CA1-CA3 hippocampal synapses, the amplitude of high K+-stimulated exocytosis, and the rate of Ca2+-dependent fusion of synaptic vesicles with synaptic plasma membranes. These changes were accompanied by an increase in nitration and poly(ADP)-ribosylation of cerebral proteins, suggesting the development of oxidative-nitrosative stress. Prednisolone upregulated the expression and phosphorylation of NF-κB p65 subunit at Ser311, whereas downregulating IκB. GC loading depleted the circulating pool of 25OHD3 in serum and CSF, elevated VDR mRNA and protein levels but had an inhibitory effect on CYP24A1 and VDBP expression. Vitamin D3 supplementation had an antidepressant-like effect, decreasing the immobility time and stimulating active behavior. VD3 caused a decrease in the size of the perikaryon and nucleus in CA1 hippocampal area. We found a recovery in depolarization-induced fusion of synaptic vesicles and long-term synaptic plasticity after VD3 treatment. VD3 diminished the intensity of oxidative-nitrosative stress, and suppressed the NF-κB activation. Its ameliorative effect on GC-induced neuroanatomical and behavioral abnormalities was accompanied by the 25OHD3 repletion and partial restoration of the VD3-auto/paracrine system. GC-induced neurotoxicity and behavioral disturbances are associated with increased oxidative-nitrosative stress and impairments of VD3 metabolism. Thus, VD3 can be effective in preventing structural and functional abnormalities in the brain and behavior changes caused by long-term GC administration.

A comprehensive longitudinal study of magnetic resonance imaging identifies novel features of the Mecp2 deficient mouse brain

Rett syndrome (RTT) is a X-linked neurodevelopmental disorder which represents the leading cause of severe incurable intellectual disability in females worldwide. The vast majority of RTT cases are caused by mutations in the X-linked MECP2 gene, and preclinical studies on RTT largely benefit from the use of mouse models of Mecp2, which present a broad spectrum of symptoms phenocopying those manifested by RTT patients.Neurons represent the core targets of the pathology; however, neuroanatomical abnormalities that regionally characterize the Mecp2 deficient mammalian brain remain ill-defined.Neuroimaging techniques, such as MRI and MRS, represent a key approach for assessing in vivo anatomic and metabolic changes in brain. Being non-invasive, these analyses also permit to investigate how the disease progresses over time through longitudinal studies.To foster the biological comprehension of RTT and identify useful biomarkers, we have performed a thorough in vivo longitudinal study of MRI and MRS in Mecp2 deficient mouse brains. Analyses were performed on both genders of two different mouse models of RTT, using an automatic atlas-based segmentation tool that permitted to obtain a detailed and unbiased description of the whole RTT mouse brain. We found that the most robust alteration of the RTT brain consists in an overall reduction of the brain volume. Accordingly, Mecp2 deficiency generally delays brain growth, eventually leading, in heterozygous older animals, to stagnation and/or contraction. Most but not all brain regions participate in the observed deficiency in brain size; similarly, the volumetric defect progresses diversely in different brain areas also depending on the specific Mecp2 genetic lesion and gender. Interestingly, in some regions volumetric defects anticipate overt symptoms, possibly revealing where the pathology originates and providing a useful biomarker for assessing drug efficacy in pre-clinical studies.

Exploration of the relationships between clinical traits and functional connectivity based on surface morphology abnormalities in bulimia nervosa

Bulimia nervosa is a recurrent eating disorder with uncertain pathogenesis. Recently, there has been growing interest in using neuroimaging techniques to explore brain structural and functional alterations in bulimia nervosa, but the findings of previous studies have a great number of inconsistencies. Here, we collected anatomical and resting-state functional magnetic resonance imaging data from 43 bulimia nervosa patients and 34 matched healthy controls (HCs). We applied a surface-based morphology analysis to explore brain cortical morphology differences and a novel surface-based functional connectivity (FC) analysis to investigate functional abnormalities. Principal component analysis was performed to analyze the behavioral data of the participants. We further analyzed the relationships between abnormalities in cortical characteristics or FC and clinical features. We observed increased greater sulcal depth in the right superior temporal gyrus (STG) and the right medial orbitofrontal cortex (mOFC) in bulimia nervosa patients than in the HCs. Additionally, the patients exhibited increased FC between the right STG and right ventral tegmental area but decreased function between the right mOFC and right putamen, which was significantly negatively correlated with the first principal component reflecting the severity of bulimia nervosa symptom. Our findings provide evidence of neuroanatomical and functional abnormalities in bulimia nervosa patients. Moreover, the FC between the right mOFC and right putamen was associated with symptom severity of bulimia nervosa, which may be a neural marker and involved in the neuropathological mechanism of bulimia nervosa.

Analysis of structural variation among inbred mouse strains

Background‘Long read’ sequencing methods have been used to identify previously uncharacterized structural variants that cause human genetic diseases. Therefore, we investigated whether long read sequencing could facilitate genetic analysis of murine models for human diseases.ResultsThe genomes of six inbred strains (BTBR T + Itpr3tf/J, 129Sv1/J, C57BL/6/J, Balb/c/J, A/J, SJL/J) were analyzed using long read sequencing. Our results revealed that (i) Structural variants are very abundant within the genome of inbred strains (4.8 per gene) and (ii) that we cannot accurately infer whether structural variants are present using conventional short read genomic sequence data, even when nearby SNP alleles are known. The advantage of having a more complete map was demonstrated by analyzing the genomic sequence of BTBR mice. Based upon this analysis, knockin mice were generated and used to characterize a BTBR-unique 8-bp deletion within Draxin that contributes to the BTBR neuroanatomic abnormalities, which resemble human autism spectrum disorder.ConclusionA more complete map of the pattern of genetic variation among inbred strains, which is produced by long read genomic sequencing of the genomes of additional inbred strains, could facilitate genetic discovery when murine models of human diseases are analyzed.

Relevance of neuroanatomical abnormalities for cognition and daily functioning in patients with mood disorders

Relevance of neuroanatomical abnormalities for cognition and daily functioning in patients with mood disorders

Comprehensive quantitative analyses of fetal magnetic resonance imaging in isolated cerebral ventriculomegaly

Isolated cerebral ventriculomegaly (IVM) is the most common prenatally diagnosed brain anomaly occurs in 0.2–1 % of pregnancies. However, knowledge of fetal brain development in IVM is limited. There is no prenatal predictor for IVM to estimate individual risk of neurodevelopmental disability occurs in 10 % of children. To characterize brain development in fetuses with IVM and delineate their individual neuroanatomical variances, we performed comprehensive post-acquisition quantitative analysis of fetal magnetic resonance imaging (MRI). In volumetric analysis, brain MRI of fetuses with IVM (n = 20, 27.0 ± 4.6 weeks of gestation, mean ± SD) had revealed significantly increased volume in the whole brain, cortical plate, subcortical parenchyma, and cerebrum compared to the typically developing fetuses (controls, n = 28, 26.3 ± 5.0). In the cerebral sulcal developmental pattern analysis, fetuses with IVM had altered sulcal positional (both hemispheres) development and combined features of sulcal positional, depth, basin area, in both hemispheres compared to the controls. When comparing distribution of similarity index of individual fetuses, IVM group had shifted toward to lower values compared to the control. About 30 % of fetuses with IVM had no overlap with the distribution of control fetuses. This proof-of-concept study shows that quantitative analysis of fetal MRI can detect emerging subtle neuroanatomical abnormalities in fetuses with IVM and their individual variations.

The BBSome regulates mitochondria dynamics and function

ObjectiveThe essential role of mitochondria in regulation of metabolic function and other physiological processes has garnered enormous interest in understanding the mechanisms controlling the function of this organelle. We assessed the role of the BBSome, a protein complex composed of eight Bardet-Biedl syndrome (BBS) proteins, in the control of mitochondria dynamic and function. MethodsWe used a multidisciplinary approach that include CRISPR/Cas9 technology-mediated generation of a stable Bbs1 gene knockout hypothalamic N39 neuronal cell line. We also analyzed the phenotype of BBSome deficient mice in presence or absence of the gene encoding A-kinase anchoring protein 1 (AKAP1). ResultsOur data show that the BBSome play an important role in the regulation of mitochondria dynamics and function. Disruption of the BBSome cause mitochondria hyperfusion in cell lines, fibroblasts derived from patients as well as in hypothalamic neurons and brown adipocytes of mice. The morphological changes in mitochondria translate into functional abnormalities as indicated by the reduced oxygen consumption rate and altered mitochondrial distribution and calcium handling. Mechanistically, we demonstrate that the BBSome modulates the activity of dynamin-like protein 1 (DRP1), a key regulator of mitochondrial fission, by regulating its phosphorylation and translocation to the mitochondria. Notably, rescuing the decrease in DRP1 activity through deletion of one copy of the gene encoding AKAP1 was effective to normalize the defects in mitochondrial morphology and activity induced by BBSome deficiency. Importantly, this was associated with improvement in several of the phenotypes caused by loss of the BBSome such as the neuroanatomical abnormalities, metabolic alterations and obesity highlighting the importance of mitochondria defects in the pathophysiology of BBS. ConclusionsThese findings demonstrate a critical role of the BBSome in the modulation of mitochondria function and point to mitochondrial defects as a key disease mechanism in BBS.

Linking neuroanatomical abnormalities in autism spectrum disorder with gene expression of candidate ASD genes: A meta-analytic and network-oriented approach.

Autism spectrum disorder (ASD) is a set of developmental conditions with widespread neuroanatomical abnormalities and a strong genetic basis. Although neuroimaging studies have indicated anatomical changes in grey matter (GM) morphometry, their associations with gene expression remain elusive. Here, we aim to understand how gene expression correlates with neuroanatomical atypicalities in ASD. To do so, we performed a coordinate-based meta-analysis to determine the common GM variation pattern in the autistic brain. From the Allen Human Brain Atlas, we selected eight genes from the SHANK, NRXN, NLGN family and MECP2, which have been implicated with ASD, particularly in regards to altered synaptic transmission and plasticity. The gene expression maps for each gene were built. We then assessed the correlation between the gene expression maps and the GM alteration maps. Lastly, we projected the obtained clusters of GM alteration-gene correlations on top of the canonical resting state networks, in order to provide a functional characterization of the structural evidence. We found that gene expression of most genes correlated with GM alteration (both increase and decrease) in regions located in the default mode network. Decreased GM was also correlated with gene expression of some ASD genes in areas associated with the dorsal attention and cerebellar network. Lastly, single genes were found to be significantly correlated with increased GM in areas located in the somatomotor, limbic and ganglia/thalamus networks. This approach allowed us to combine the well beaten path of genetic and brain imaging in a novel way, to specifically investigate the relation between gene expression and brain with structural damage, and individuate genes of potential interest for further investigation in the functional domain.

Pathological fear, anxiety and negative affect exhibit distinct neurostructural signatures: evidence from psychiatric neuroimaging meta-analysis

Internalizing disorders encompass anxiety, fear and depressive disorders, which exhibit overlap at both conceptual and symptom levels. Given that a neurobiological evaluation is lacking, we conducted a Seed-based D-Mapping comparative meta-analysis including coordinates as well as original statistical maps to determine common and disorder-specific gray matter volume alterations in generalized anxiety disorder (GAD), fear-related anxiety disorders (FAD, i.e., social anxiety disorder, specific phobias, panic disorder) and major depressive disorder (MDD). Results showed that GAD exhibited disorder-specific altered volumes relative to FAD including decreased volumes in left insula and lateral/medial prefrontal cortex as well as increased right putamen volume. Both GAD and MDD showed decreased prefrontal volumes compared to controls and FAD. While FAD showed less robust alterations in lingual gyrus compared to controls, this group presented intact frontal integrity. No shared structural abnormalities were found. Our study is the first to provide meta-analytic evidence for distinct neuroanatomical abnormalities underlying the pathophysiology of anxiety-, fear-related and depressive disorders. These findings may have implications for determining promising target regions for disorder-specific neuromodulation interventions (e.g. transcranial magnetic stimulation or neurofeedback).

Combining neuroanatomical features to support diagnosis of fetal alcohol spectrum disorders.

To identify easily accessible neuroanatomical abnormalities useful for diagnosing fetal alcohol spectrum disorders (FASD) in fetal alcohol syndrome (FAS) but more importantly for the probabilistic diagnosis of non-syndromic forms (NS-FASD). We retrospectively collected monocentric data from 52 individuals with FAS, 37 with NS-FASD, and 94 paired typically developing individuals (6-20 years, 99 males, 84 females). On brain T1-weighted magnetic resonance imaging, we measured brain size, corpus callosum length and thicknesses, vermis height, then evaluated vermis foliation (Likert scale). For each parameter, we established variations with age and brain size in comparison individuals (growth and scaling charts), then identified participants with abnormal measurements (<10th centile). According to growth charts, there was an excess of FAS with abnormally small brain, isthmus, splenium, and vermis. According to scaling charts, this excess remained only for isthmus thickness and vermis height. The vermis foliation was pathological in 18% of those with FASD but in no comparison individual. Overall, 39% of those with FAS, 27% with NS-FASD, but only 2% of comparison individuals presented with two FAS-recurrent abnormalities, and 19% of those with FAS had all three. Considering the number of anomalies, there was a higher likelihood of a causal link with alcohol in 14% of those with NS-FASD. Our results suggest that adding an explicit composite neuroanatomical-radiological criterion for FASD diagnosis may improve its specificity, especially in NS-FASD. Neuroanatomical anomalies independent of microcephaly can be measured with clinical-imaging tools. Small-for-age brain, small-for-brain-size callosal isthmus or vermian height, and disrupted vermis foliation are fetal alcohol syndrome (FAS)-recurrent anomalies. Associations of these anomalies are frequent in fetal alcohol spectrum disorder (FASD) even without FAS, while exceptional in typically developing individuals. These associations support higher likelihood of causal link with alcohol in some individuals with non-syndromic FASD. A new explicit and composite neuroanatomical-radiological criterion can improve the specificity of FASD diagnosis.