Morphological Brain Abnormalities Research Articles

Structural and functional brain abnormalities in children with schizotypal disorder: a pilot study

Schizotypal disorder lies in the schizophrenia spectrum and is widely studied in adult populations. Schizotypal disorder in children (SDc) is less well described. This study examined brain morphological and functional connectivity abnormalities in SDc (12 SDc and 9 typically developing children), focusing on the default mode and executive control brain networks. Results indicated that SDc is associated with reduced grey matter volume (GMV) in superior and medial frontal gyri, and increased resting-state functional connectivity between the superior frontal gyrus and inferior parietal lobule, compared to typically developing children (cluster-level FWE-corrected p < 0.05). The brain structure abnormality (GMV in left superior frontal gyrus) was correlated with clinical symptoms in SDc (r = −0.66, p = 0.026) and functional connectivity abnormality was correlated with extra-dimensional shifting impairments in all participants (r = 0.62, p = 0.011), suggesting their contribution to the underlying mechanisms of clinical presentation. These preliminary results motivate further work to characterize the neural basis of SDc and its significance as a risk factor for later psychosis.

C2H2-Type Zinc Finger Proteins in Brain Development, Neurodevelopmental, and Other Neuropsychiatric Disorders: Systematic Literature-Based Analysis.

Neurodevelopmental disorders (NDDs) are multifaceted pathologic conditions manifested with intellectual disability, autistic features, psychiatric problems, motor dysfunction, and/or genetic/chromosomal abnormalities. They are associated with skewed neurogenesis and brain development, in part through dysfunction of the neural stem cells (NSCs) where abnormal transcriptional regulation on key genes play significant roles. Recent accumulated evidence highlights C2H2-type zinc finger proteins (C2H2-ZNFs), the largest transcription factor family in humans, as important targets for the pathologic processes associated with NDDs. In this review, we identified their significant accumulation (74 C2H2-ZNFs: ~10% of all human member proteins) in brain physiology and pathology. Specifically, we discuss their physiologic contribution to brain development, particularly focusing on their actions in NSCs. We then explain their pathologic implications in various forms of NDDs, such as morphological brain abnormalities, intellectual disabilities, and psychiatric disorders. We found an important tendency that poly-ZNFs and KRAB-ZNFs tend to be involved in the diseases that compromise gross brain structure and human-specific higher-order functions, respectively. This may be consistent with their characteristic appearance in the course of species evolution and corresponding contribution to these brain activities.

Neuroimmunological effects of early life experiences.

Exposure to adverse experiences during development increases the risk of psychiatric illness later in life. Growing evidence suggests a role for the neuroimmune system in this relationship. There is now substantial evidence that the immune system is critical for normal brain development and behaviour, and responds to environmental perturbations experienced early in life. Severe or chronic stress results in dysregulated neuroimmune function, concomitant with abnormal brain morphology and function. Positive experiences including environmental enrichment and exercise exert the opposite effect, promoting normal brain and immune function even in the face of early life stress. The neuroimmune system may therefore provide a viable target for prevention and treatment of psychiatric illness. This review will briefly summarise the neuroimmune system in brain development and function, and review the effects of stress and positive environmental experiences during development on neuroimmune function. There are also significant sex differences in how the neuroimmune system responds to environmental experiences early in life, which we will briefly review.

Magnetic Resonance Imaging and Micro-Computed Tomography reveal brain morphological abnormalities in a mouse model of early moderate prenatal ethanol exposure

BackgroundThis study investigated the effects of early moderate prenatal ethanol exposure (PEE) on the brain in a mouse model that mimics a scenario in humans, whereby moderate daily drinking ceases after a woman becomes aware of her pregnancy. MethodsC57BL/6J pregnant mice were given 10% v/v ethanol from gestational day 0–8 in the drinking water. The male offspring were used for imaging. Anatomical and diffusion Magnetic Resonance Imaging were performed in vivo at postnatal day 28 (P28, adolescence) and P80 (adulthood). Micro-Computed Tomography was performed on fixed whole heads at P80. Tensor-based morphometry (TBM) was applied to detect alterations in brain structure and voxel-based morphometry (VBM) for skull morphology. Diffusion tensor and neurite orientation dispersion and density imaging models were used to detect microstructural changes. Neurofilament (NF) immunohistochemistry was used to validate findings by in vivo diffusion MRI. ResultsTBM showed that PEE mice exhibited a significantly smaller third ventricle at P28 (family-wise error rate (FWE), p < 0.05). All other macro-structural alterations did not survive FWE corrections but when displayed with an uncorrected p < 0.005 showed multiple regional volume reductions and expansions, more prominently in the right hemisphere. PEE-induced gross volume changes included a bigger thalamus, hypothalamus and ventricles at P28, and bigger total brain volumes at both P28 and P80 (2-sample t-tests). Disproportionately smaller olfactory bulbs following PEE were revealed at both time-points. No alterations in diffusion parameters were detected, but PEE animals exhibited reduced NF positive staining in the thalamus and striatum and greater bone density in various skull regions. ConclusionOur results show that early moderate PEE can cause alterations in the brain that are detectable during development and adulthood.

Missense variants in TAF1 and developmental phenotypes: challenges of determining pathogenicity.

We recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability syndrome) (MIM# 300966) caused by pathogenic variants involving the X-linked gene TAF1, which participates in RNA polymerase II transcription. The initial study reported eleven families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into intellectual disability (ID) and/or autism spectrum disorder (ASD). We have now identified an additional 27 families through a genotype-first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity, and molecular modelling was performed for those variants falling within structurally characterized domains of TAF1. A novel phenotypic clustering approach was also applied, in which the phenotypes of affected individuals were classified using 51 standardized Human Phenotype Ontology (HPO) terms. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability, but prominent among previously unreported effects were brain morphological abnormalities, seizures, hearing loss, and heart malformations. Our allelic series broadens the phenotypic spectrum of TAF1/MRXS33 intellectual disability syndrome and the range of TAF1 molecular defects in humans. It also illustrates the challenges for determining the pathogenicity of inherited missense variants, particularly for genes mapping to chromosome X. This article is protected by copyright. All rights reserved.

Brain developmental diseases and pathogenic mechanisms

Development of the human brain is a strictly complex and precisely regulated process. Brain development includes the proliferation and differentiation of neural progenitor cells, migration and maturation of neurons, myelination of neuronal axons, synaptogenesis and organization of the neural circuits. Abnormalities of these developmental processes can lead to severe malformation and dysfunction of the brain, which may result in brain developmental diseases which have a high medical burden and have attracted global attention. Brain developmental diseases are typically divided into two categories according to abnormal brain morphology and dysfunction: malformation of cortical development (MCD) and neuropsychopathy. Microcephaly and autism spectrum disorder (ASD) are representative disorders of MCD and neuropsychopathy respectively. In this review, we summarize the progresses of these two typical and relevant brain developmental diseases including the mechanism and etiology of their development, gene expression, symptoms, and related to provide theoretical guidance for basic research and management and treatment.

Brain morphological abnormalities in genetic generalized epilepsies: The starting point?

Brain morphological abnormalities in genetic generalized epilepsies: The starting point?

Abnormal spontaneous neural activity of brain regions in patients with primary blepharospasm at rest

BackgroundPrimary blepharospasm (BSP) is characterized by excessive involuntary eyelid spasms without significant morphological brain abnormalities. Its neural bases remain unclear. Resting-state functional magnetic resonance imaging (rs-fMRI) is a powerful tool for exploring cerebral function mechanisms in BSP. MethodsTwo subject groups (24 patients with BSP and 24 healthy controls) underwent rs-fMRI scans. The rs-fMRI images were analyzed using the regional homogeneity (ReHo) method to assess the local features of spontaneous brain activity. Correlation analysis was carried out to explore the relationship between the ReHo values of abnormal brain areas and clinical variables including illness duration, symptom severity, and depression/anxiety symptoms. ResultsRelative to healthy controls, patients with BSP showed significantly decreased ReHo in the left superior temporal pole/left insula, left calcarine cortex, and bilateral superior medial frontal gyrus (mSFG), and increased ReHo in the bilateral supplementary motor area (SMA). There were no significant correlations between ReHo values in these brain regions and clinical variables in the patients. ConclusionsOur results suggest that abnormal spontaneous brain activity in multiple brain regions not limited to the basal ganglia may be trait alterations in the patients, which provides more insights into the pathogenesis of BSP.

ADHD pathogenesis in the immune, endocrine and nervous systems of juvenile and maturating SHR and WKY rats

RationaleAttention-deficit/hyperactivity disorder (ADHD) is one of the most common neurobehavioural disorders with morphological and functional brain abnormalities. However, there is a growing body of evidence that abnormalities in the immune and endocrine systems may also account for the ADHD pathogenesis.ObjectivesTo test ADHD pathogenesis in neurological, immune and endocrine systems, this study examined the concentrations of cytokines, chemokines, oxidative stress markers, metabolic parameters, steroid hormones and steroidogenic enzymes in the serum and/or tissues of spontaneously hypertensive rats (SHRs, animal model of ADHD) and Wistar Kyoto rats (WKYs, control animals). Moreover, the volume of the medial prefrontal cortex (mPFC) as well as the density of dopamine 2 (D2) receptor-expressing cells and tyrosine hydroxylase (TH)-positive nerve fibres in it was also elucidated.MethodsPeripheral blood, spleen and adrenal gland samples, as well as brain sections collected on day 35 (juvenile) and day 70 (maturating) from SHRs and WKYs, were processed by ELISA and immunohistochemistry, respectively.ResultsThe results show significant increases of serum and/or tissue concentrations of cytokines, chemokines and oxidative stress markers in juvenile SHRs when compared to the age-matched WKYs. These increases were accompanied by a lowered volume of the mPFC and up-regulation of D2 in this brain region. In maturating SHRs, the levels of inflammatory and oxidative stress markers were normalised and accompanied by elevated contents of steroid hormones.ConclusionsSignificant elevations of serum and/or tissue contents of cytokines, chemokines and oxidative stress markers as well as volumetric and neurochemical alterations in the mPFC of juvenile SHRs may suggest the cooperation of neurological and immune systems in the ADHD pathogenesis. Elevated levels of steroid hormones in maturating SHRs may be a compensatory effect involved in reducing inflammation and ADHD symptoms.

RNN-based longitudinal analysis for diagnosis of Alzheimer’s disease

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder with progressive impairment of memory and other mental functions. Magnetic resonance images (MRI) have been widely used as an important imaging modality of brain for AD diagnosis and monitoring the disease progression. The longitudinal analysis of sequential MRIs is important to model and measure the progression of the disease along the time axis for more accurate diagnosis. Most existing methods extracted the features capturing the morphological abnormalities of brain and their longitudinal changes using MRIs and then designed a classifier to discriminate different groups. However, these methods have several limitations. First, since the feature extraction and classifier model are independent, the extracted features may not capture the full characteristics of brain abnormalities related to AD. Second, longitudinal MR images may be missing at some time points for some subjects, which results in difficulties for extraction of consistent features for longitudinal analysis. In this paper, we present a classification framework based on combination of convolutional and recurrent neural networks for longitudinal analysis of structural MR images in AD diagnosis. First, Convolutional Neural Networks (CNN) is constructed to learn the spatial features of MR images for the classification task. After that, recurrent Neural Networks (RNN) with cascaded three bidirectional gated recurrent units (BGRU) layers is constructed on the outputs of CNN at multiple time points for extracting the longitudinal features for AD classification. Instead of independently performing feature extraction and classifier training, the proposed method jointly learns the spatial and longitudinal features and disease classifier, which can achieve optimal performance. In addition, the proposed method can model the longitudinal analysis using RNN from the imaging data at various time points. Our method is evaluated with the longitudinal T1-weighted MR images of 830 participants including 198 AD, 403 mild cognitive impairment (MCI), and 229 normal controls (NC) subjects from Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Experimental results show that the proposed method achieves classification accuracy of 91.33% for AD vs. NC and 71.71% for pMCI vs. sMCI, demonstrating the promising performance for longitudinal MR image analysis.

Brain Morphology in Patients with Genetic Generalized Epilepsy: Its Heterogeneity among Subsyndromes

Background: We aimed to evaluate the brain morphology of patients with genetic generalized epilepsy (GGE) compared to healthy subjects. In addition, we investigated whether there are differences in brain morphology among different GGE syndromes. Methods: We enrolled 100 patients with a clinical diagnosis of GGE. The patients were classified into different syndrome groups according to their predominant seizure type, age of seizure onset, and electroencephalography characteristics (12 childhood absence epilepsy [AE], 13 juvenile AE, 56 juvenile myoclonic epilepsy, and 19 epilepsy with generalized tonic-clonic alone). We used surface-based morphometry of brain magnetic resonance imaging to evaluate brain morphology. Results: We found significantly widespread alterations of brain morphology, including cortical thickness and volumes in several regions in the patients with GGE compared to healthy controls. In addition, we observed significant differences in alterations of cortical thickness and volumes among the different GGE syndromes. However, there were no differences in cortical surface areas between the patients with GGE and healthy controls. There was a significantly negative correlation between the duration of epilepsy and most of the each measures of abnormal brain morphology. Conclusions: The main finding of this study is that brain morphology in patients with GGE is significantly different from that in healthy controls. In addition, we found that the different GGE syndromes show distinct structural brain morphology, especially cortical thickness, which can help us understand the pathogenesis of GGE syndromes.

Telomere length as a predictor of emotional processing in the brain.

Shorter telomere length (TL) has been associated with the development of mood disorders as well as abnormalities in brain morphology. However, so far, no studies have considered the role TL may have on brain function during tasks relevant to mood disorders. In this study, we examine the relationship between TL and functional brain activation and connectivity, while participants (n = 112) perform a functional magnetic resonance imaging (fMRI) facial affect recognition task. Additionally, because variation in TL has a substantial genetic component we calculated polygenic risk scores for TL to test if they predict face‐related functional brain activation. First, our results showed that TL was positively associated with increased activation in the amygdala and cuneus, as well as increased connectivity from posterior regions of the face network to the ventral prefrontal cortex. Second, polygenic risk scores for TL show a positive association with medial prefrontal cortex activation. The data support the view that TL and genetic loading for shorter telomeres, influence the function of brain regions known to be involved in emotional processing.

Counter-Balance Between Gli3 and miR-7 Is Required for Proper Morphogenesis and Size Control of the Mouse Brain.

Brain morphogenesis requires precise regulation of multiple genes to control specification of distinct neural progenitors (NPs) and neuronal production. Dysregulation of these genes results in severe brain malformation such as macrocephaly and microcephaly. Despite studies of the effect of individual pathogenic genes, the counter-balance between multiple factors in controlling brain size remains unclear. Here we show that cortical deletion of Gli3 results in enlarged brain and folding structures in the cortical midline at the postnatal stage, which is mainly caused by the increased percentage of intermediate progenitors (IPs) and newborn neurons. In addition, dysregulation of neuronal migration also contributes to the folding defects in the cortical midline region. Knockdown of microRNA (miRNA) miR-7 can rescue abnormal brain morphology in Gli3 knockout mice by recovering progenitor specification, neuronal production and migration through a counter-balance of the Gli3 activity. Moreover, miR-7 likely exerts its function through silencing target gene Pax6. Our results indicate that proper brain morphogenesis is an outcome of interactive regulations of multiple molecules such as Gli3 and miR-7. Because miRNAs are easy to synthesize and deliver, miR-7 could be a potential therapeutic means to macrocephaly caused by Gli3-deficiency.

Bullying at Workplace and Brain-Imaging Correlates

The relationship between psychosocial stress at work and mental health outcome is well-known. Brain-imaging studies hypothesize morphological brain modifications connected to work-related stress. To our knowledge this is the first study describing the link between work characteristics and brain imaging in a sample of work-related psychiatric patients assessed according to standardized clinical and diagnostic criteria. The aims of the study are: (1) to evaluate hippocampal and whole brain volumes in work-related psychiatric disturbances; (2) to verify the relationship between brain changes and the anxious and/or depressive symptoms; (3) to observe the relationship between the brain changes and the degree of the bullying at workplace. The hippocampus and whole brain volumes of 23 patients with work-related adjustment-disorders were compared with 15 controls by means of MRI. MR images highlight a smaller hippocampal volume in patients compared with controls. Significant reduction in the patients’ gray matter was found in three brain areas: right inferior temporal gyrus, left cuneus, left inferior occipital gyrus. The reduction of the hippocampi volumes was related to work distress and, above all, to bullying at workplace. The results confirm that the morphological brain abnormalities could be involved in work-related psychiatric disturbances.

TSPO expression and brain structure in the psychosis spectrum

Psychosis is associated with abnormal structural changes in the brain including decreased regional brain volumes and abnormal brain morphology. However, the underlying causes of these structural abnormalities are less understood. The immune system, including microglial activation, has been implicated in the pathophysiology of psychosis. Although previous studies have suggested a connection between peripheral proinflammatory cytokines and structural brain abnormalities in schizophrenia, no in-vivo studies have investigated whether microglial activation is also linked to brain structure alterations previously observed in schizophrenia and its putative prodrome. In this study, we investigated the link between mitochondrial 18 kDa translocator protein (TSPO) and structural brain characteristics (i.e. regional brain volume, cortical thickness, and hippocampal shape) in key brain regions such as dorsolateral prefrontal cortex and hippocampus of a large group of participants (N = 90) including individuals at clinical high risk (CHR) for psychosis, first-episode psychosis (mostly antipsychotic-naïve) patients, and healthy volunteers. The participants underwent structural brain MRI scan and [18F]FEPPA positron emission tomography (PET) targeting TSPO. A significant [18F]FEPPA binding-by-group interaction was observed in morphological measures across the left hippocampus. In first-episode psychosis, we observed associations between [18F]FEPPA VT (total volume of distribution) and outward and inward morphological alterations, respectively, in the dorsal and ventro-medial portions of the left hippocampus. These associations were not significant in CHR or healthy volunteers. There was no association between [18F]FEPPA VT and other structural brain characteristics. Our findings suggest a link between TSPO expression and alterations in hippocampal morphology in first-episode psychosis.

Disruption in Thyroid Signaling Pathway: A Mechanism for the Effect of Endocrine-Disrupting Chemicals on Child Neurodevelopment.

Thyroid hormones are crucial in normal brain development. Transient and mild thyroid hormone insufficiency in pregnancy is also associated with impaired neurodevelopment in the offspring (e.g., 3–4 IQ score loss in association with maternal free thyroxine in the lowest fifth percentile). While inadequate iodine intake remains the most common underlying cause of mild thyroid hormone insufficiency in vulnerable populations including pregnant women, other factors such as exposure to environmental contaminants have recently attracted increasing attention, in particular in interaction with iodine deficiency. Endocrine-disrupting chemicals (EDCs) are natural and synthetic substances with ubiquitous exposure in children and adults including pregnant women. EDCs interfere, temporarily or permanently, with hormonal signaling pathways in the endocrine system by binding to hormone receptors and modifying gene expression. Other mechanisms involve alterations in production, metabolism, and transfer of hormones. Experimental studies have shown that exposures to EDCs affect various brain processes such as neurogenesis, neural differentiation and migration, as well as neural connectivity. Neuroimaging studies confirm brain morphological abnormalities (e.g., cortical thinning) consistent with neurodevelopmental impairments as a result of EDC exposures at standard use levels. In this review, we provide an overview of present findings from toxicological and human studies on the anti-thyroid effect of EDCs with a specific attention to fetal and early childhood exposure. This brief overview highlights the need for additional multidisciplinary studies with a focus on thyroid disruption as an underlying mechanism for developmental neurotoxicity of EDC, which can provide insight into modifiable risk factors of developmental delays in children.

Gaussian process uncertainty in age estimation as a measure of brain abnormality

Multivariate regression models for age estimation are a powerful tool for assessing abnormal brain morphology associated to neuropathology. Age prediction models are built on cohorts of healthy subjects and are built to reflect normal aging patterns. The application of these multivariate models to diseased subjects usually results in high prediction errors, under the hypothesis that neuropathology presents a similar degenerative pattern as that of accelerated aging. In this work, we propose an alternative to the idea that pathology follows a similar trajectory than normal aging. Instead, we propose the use of metrics which measure deviations from the mean aging trajectory. We propose to measure these deviations using two different metrics: uncertainty in a Gaussian process regression model and a newly proposed age weighted uncertainty measure. Consequently, our approach assumes that pathologic brain patterns are different to those of normal aging. We present results for subjects with autism, mild cognitive impairment and Alzheimer’s disease to highlight the versatility of the approach to different diseases and age ranges. We evaluate volume, thickness, and VBM features for quantifying brain morphology. Our evaluations are performed on a large number of images obtained from a variety of publicly available neuroimaging databases. Across all features, our uncertainty based measurements yield a better separation between diseased subjects and healthy individuals than the prediction error. Finally, we illustrate differences in the disease pattern to normal aging, supporting the application of uncertainty as a measure of neuropathology.

O6.1. HIPPOCAMPAL VOLUME IN ADOLESCENTS WITH PERSISTENT PSYCHOTIC EXPERIENCES: A LONGITUDINAL POPULATION-BASED MRI STUDY

BackgroundIndividuals with schizophrenia show significant brain morphological abnormalities. The ENIGMA consortium identified that patients with schizophrenia had smaller hippocampus, amygdala, thalamus, accumbens and intracranial volumes.1 Reduced hippocampal volume is one of the most consistent findings in schizophrenia research.2–4 Also, Previous research has reported differences in hippocampal volume and white matter integrity in young adolescents who report psychotic experiences.5,6 However there has been little longitudinal research to investigate the developmental trajectory of these regions in adolescence with an increased susceptibility to psychotic disorders.Aimsto investigate two-year longitudinal changes in hippocampal volume in a sample of adolescents who reported psychotic experiences relative to their peers. To investigate the role of presence of co-morbid DSM IV mental disorders and stressful life events in influencing hippocampal volume and study the differences in hippocampus volume between adolescents who were having persistent symptoms versus adolescents with remitting symptoms.MethodsA longitudinal case-control study of 50 community-based adolescents aged 13–16 years (25 with psychotic experiences and a matched sample of 25 without psychotic experiences), compared hippocampal volume. All participants were assessed at baseline and two years follow up. T1 weighted anatomical high-resolution imaging and high angular resolution diffusion imaging data were used to conduct quantitative anatomical volumetric evaluations of global hippocampal volume. Clinical interviews also provided information on psychotic experiences, co-morbid disorders and adverse life events.ResultsThere were significant differences in the Right and Left Whole hippocampus between PE and Control group at baseline and 2-year follow up (p≤ 0.05). There were significant differences between PE persist and Control group in the left and right whole hippocampus (p≤ 0.05).DiscussionThe differences identified in our study suggest that early hippocampal reductions, may play a role in increasing vulnerability to psychosis.

Women with Borderline Personality Disorder Have Morphological Brain Abnormalities

Studies that have identified brain abnormalities in patients with borderline personality disorder (BPD), particularly low amygdala and hippocampal

Volumetric Associations Between Amygdala, Nucleus Accumbens, and Socially Anxious Tendencies in Healthy Women

Socially anxious individuals report higher social fears and feelings of distress in interpersonal interactions. Structural neuroimaging studies indicate brain morphological abnormalities in patients with social anxiety disorder (SAD), but findings are heterogeneous and partially discrepant. Studies on structural correlates of socially anxious tendencies in participants without clinical diagnoses are scarce. Using structural magnetic resonance imaging, the present study examined the relationship between social interaction anxiety and gray matter (GM) volume in 38 healthy women. The amygdala and nucleus accumbens (NAcc) were defined as a priori regions of interest. Moreover, exploratory whole-brain analyses were conducted. Higher levels of social anxiety significantly predicted increased GM volume in the right amygdala [k = 262 voxels, voxel-level threshold at p < .05 (uncorrected), with a cluster-corrected significance level of p = 0.05 calculated by Monte Carlo Simulations] and bilateral NAcc [left: k = 52 voxels, right: k = 49 voxels; at p < .05 (corrected for search volume)]. These relationships remained significant when controlling for a potential influence of trait anxiety. Additionally, socially anxious tendencies were associated with an enlarged striatum [i.e., putamen and caudate; left: k = 567 voxels, right: k = 539 voxels; at p < .001 (uncorrected)]. Our findings indicate that higher social interaction anxiety in healthy individuals is related to amygdalar and striatal volumetric increases. These brain regions are known to be involved in social perception, anxiety, and the avoidance of harm. Future studies may clarify whether the observed morphological alterations constitute a structural vulnerability factor for SAD.