Search

Background Although aspects of brain morphology have been associated with chronic posttraumatic stress disorder (PTSD), limited work has investigated multimodal patterns in brain morphology that are linked to acute posttraumatic stress severity. In the present study, we utilized multimodal magnetic resonance imaging to investigate if structural covariance networks (SCNs) assessed acutely following trauma were linked to acute posttraumatic stress severity. Methods Structural magnetic resonance imaging data were collected around 1 month after civilian trauma exposure in 78 participants. Multimodal magnetic resonance imaging data fusion was completed to identify combinations of SCNs, termed structural covariance profiles (SCPs), related to acute posttraumatic stress severity collected at 1 month. Analyses assessed the relationship between participant SCP loadings, acute posttraumatic stress severity, the change in posttraumatic stress severity from 1 to 12 months, and depressive symptoms. Results We identified an SCP that reflected greater gray matter properties of the anterior temporal lobe, fusiform face area, and visual cortex (i.e., the ventral visual stream) that varied curvilinearly with acute posttraumatic stress severity and the change in PTSD symptom severity from 1 to 12 months. The SCP was not associated with depressive symptoms. Conclusions We identified combinations of multimodal SCNs that are related to variability in PTSD symptoms in the early aftermath of trauma. The identified SCNs may reflect patterns of neuroanatomical organization that provide unique insight into acute posttraumatic stress. Furthermore, these multimodal SCNs may be potential candidates for neural markers of susceptibility to both acute posttraumatic stress and the future development of PTSD.

This study was supported by the Spanish Ministry of Economy and Competitiveness (DEP2013-47540, DEP2016-79512-R, and DEP2017-91544-EXP), the European Regional Development Fund, the European Commission (No 667302) and the Alicia Koplowitz Foundation. This study was partially funded by the UGR Research and Knowledge Transfer Fund (PPIT) 2016, Excellence Actions Programme. Units of Scientific Excellence; Scientific Unit of Excellence on Exercise and Health (UCEES) and by the Regional Government of Andalusia, Regional Ministry of Economy, Knowledge, Entreprises and University and European Regional Development Fund (ERDF), ref. SOMM17/6107/UGR. In addition, this study was further supported by the SAMID III network, RETICS, funded by the PN IthornDthornI 2017-2021 (Spain). Additional funding was obtained from the Andalusian Operational Programme supported with European Regional Development Funds (ERDF in English, FEDER in Spanish, project ref: B-CTS-355-UGR18). PS-U is supported by a grant from ANID/BECAS Chile/72180543. IE-C is supported by the Spanish Ministries of Economy and Competitiveness (RTI2018-095284-J-100), and Science and Innovation (RYC2019-027287-I). JV-R is supported by a grant from the Spanish Ministry of Science, Innovation and Universities (FJCI-2017-33396). Funding for open access charge: Universidad de Granada/CBUA. We would like to thank all the families participating in the ActiveBrains. We are grateful to Ms. Ana Yara Postigo-Fuentes for her assistance with the English language. We also acknowledge everyone who helped with the data collection and all of the members involved in the fieldwork for their effort, enthusiasm, and support. This work is part of Ph.D. Thesis conducted in the Biomedicine Doctoral Studies of the University of Granada, Spain., Background & aims: Exposure to a suboptimal environment during the fetal and early infancy period's results in long-term consequences for brain morphology and function. We investigated the associations of early life factors such as anthropometric neonatal data (i.e., birth length, birth weight and birth head circumference) and breastfeeding practices (i.e., exclusive and any breastfeeding) with white matter (WM) microstructure, and ii) we tested whether WM tracts related to early life factors are associated with academic performance in children with overweight/obesity. Methods: 96 overweight/obese children (10.03 +/- 1.16 years; 38.7% girls) were included from the ActiveBrains Project. WM microstructure indicators used were fractional anisotropy (FA) and mean diffusivity (MD), derived from Diffusion Tensor Imaging. Academic performance was evaluated with the Battery III Woodcock-Munoz Tests of Achievement. Regression models were used to examine the associations of the early life factors with tract-specific FA and MD, as well as its association with academic performance. Results: Head circumference at birth was positively associated with FA of the inferior fronto-occipital fasciculus tract (0.441; p = 0.005), as well as negatively associated with MD of the cingulate gyrus part of cingulum (-0.470; p = 0.006), corticospinal (-0.457; p = 0.005) and superior thalamic radiation tract (-0.476; p = 0.001). Association of birth weight, birth length and exclusive breastfeeding with WM microstructure did not remain significant after false discovery rate correction. None tract related to birth head circumference was associated with academic performance (all p > 0.05). Conclusions: Our results highlighted the importance of the perinatal growth in WM microstructure later in life, although its possible academic implications remain inconclusive., Spanish Government DEP2013-47540 DEP2016-79512-R DEP2017-91544-EXP, European Commission European Commission European Commission Joint Research Centre 667302, Alicia Koplowitz Foundation, UGR Research and Knowledge Transfer Fund (PPIT) 2016, Excellence Actions Programme, European Commission SOMM17/6107/UGR, SAMID III network, RETICS - PN I+D+I 2017-2021 (Spain), Andalusian Operational Programme - European Regional Development Funds B-CTS-355-UGR18, ANID/BECAS Chile 72180543, Spanish Government RTI2018-095284-J-100 FJCI-2017-33396 RYC2019-027287-I

Background Childhood trauma confers risk for psychosis and is associated with increased ‘schizotypy’ (a multi-dimensional construct reflecting risk for psychosis in the general population). Structural brain alterations are associated with both childhood trauma and schizotypy, but the potential role of trauma exposure in moderating associations between schizotypy and brain morphology has yet to be determined. Methods Participants were 160 healthy individuals (mean age: 40.08 years, SD = 13.64, range 18–64; 52.5% female). Childhood trauma exposure was assessed using the Childhood Adversity Questionnaire, and schizotypy was assessed using the Schizotypal Personality Questionnaire. Univariate voxel-based morphometry and multivariate analyses of grey matter volume covariation (GMC; derived from independent component analysis) were performed to determine the main effects of schizotypy, trauma exposure and their interaction on these indices of grey matter volume. Moderation analyses were performed following significant interaction. Results Levels of schizotypy, in particular the Cognitive-Perceptual and Interpersonal dimensions, were negatively associated with GMC in the striatum, the hippocampus/parahippocampal gyrus, thalamus and insulae. Trauma exposure was negatively associated with GMC of the middle frontal gyrus and parietal lobule, while negatively associated with GMC in the cerebellum. Levels of schizotypy (total scores, and the cognitive-perceptual dimension) were negatively associated with striatal GMC in individuals not exposed to trauma, but not in those exposed to trauma. Conclusions Schizotypy and childhood trauma were independently associated with changes of grey matter in brain regions critical for cognition and social cognition. In individuals not exposed to trauma, increased schizotypy was associated with decreased striatal and limbic grey matter.

Background Alterations in the immune system, particularly C4A, have been implicated in the pathophysiology of schizophrenia. C4A promotes synapse elimination by microglia in preclinical models; however, it is unknown whether this process is also present in living humans and how it affects brain morphology. Methods Participants (N = 111; 33 patients with psychosis, 37 individuals at clinical high risk, and 41 healthy control subjects) underwent a TSPO [18F]FEPPA positron emission tomography scan and a magnetic resonance imaging scan. Brain C4A expression was genetically predicted as a function of the dosage of each of 4 structural elements (C4AL, C4BL, C4AS, C4BS). Results Higher genetically predicted brain C4A expression was associated with higher brain microglial marker (TSPO) and altered hippocampal morphology, including reduced surface area and medial displacement in the CA1 area. This study is the first to quantify genetically predicted brain C4A expression in individuals at clinical high risk, showing significantly lower C4A in individuals at clinical high risk compared with healthy control subjects. We also showed a robust effect of sex on genetically predicted brain C4A expression and effects of both sex and cannabis use on brain TSPO. Conclusions This study shows for the first time complement system (C4A) coupling with a microglial marker (TSPO) and hippocampal morphology in living human brain. These findings pave the way for future research on the interaction between C4A and glial cell function, which has the potential to inform the disease mechanism underlying psychosis and schizophrenia.

BACKGROUND: Although electroconvulsive therapy (ECT) is a safe and effective treatment for patients with severe late life depression (LLD), transient cognitive impairment can be a reason to discontinue the treatment. The aim of the current study was to evaluate the association between structural brain characteristics and general cognitive function during and after ECT. METHODS: A total of 80 patients with LLD from the prospective naturalistic follow-up Mood Disorders in Elderly treated with Electroconvulsive Therapy study were examined. Magnetic resonance imaging scans were acquired before ECT. Overall brain morphology (white and grey matter) was evaluated using visual rating scales. Cognitive functioning before, during, and after ECT was measured using the Mini Mental State Examination (MMSE). A linear mixed-model analysis was performed to analyze the association between structural brain alterations and cognitive functioning over time. RESULTS: Patients with moderate to severe white matter hyperintensities (WMH) showed significantly lower MMSE scores than patients without severe WMH (F(1,75.54) = 5.42, p = 0.02) before, during, and post-ECT, however their trajectory of cognitive functioning was similar as no time × WMH interaction effect was observed (F(4,65.85) = 1.9, p = 0.25). Transient cognitive impairment was not associated with medial temporal or global cortical atrophy (MTA, GCA). CONCLUSION: All patients showed a significant drop in cognitive functioning during ECT, which however recovered above baseline levels post-ECT and remained stable until at least 6 months post-ECT, independently of severity of WMH, GCA, or MTA. Therefore, clinicians should not be reluctant to start or continue ECT in patients with severe structural brain alterations. ispartof: American Journal Of Geriatric Psychiatry vol:29 issue:11 pages:1117-1128 ispartof: location:England status: accepted

Deficits in brain morphology are one of the most widely replicated neuropathological features in schizophrenia-spectrum disorder (SSD), although their biological underpinnings remain unclear. Despite the existence of hypotheses by which peripheral inflammation may impact brain structure, few studies have examined this relationship in SSD. This study aimed to establish the relationship between peripheral markers of inflammation and brain morphology and determine whether such relationships differed across healthy controls and individuals with first episode psychosis (FEP) and chronic schizophrenia. A panel of 13 pro- and anti-inflammatory cytokines were quantified from serum in 175 participants [n = 84 Healthy Controls (HC), n = 40 FEP, n = 51 Chronic SCZ]. We first performed a series of permutation tests to identify the cytokines most consistently associated with brain structural regions. Using moderation analysis, we then determined the extent to which individual variation in select cytokines, and their interaction with diagnostic status, predicted variation in brain structure. We found significant interactions between cytokine level and diagnosis on brain structure. Diagnostic status significantly moderated the relationship of IFNγ, IL4, IL5 and IL13 with frontal thickness, and of IFNγ and IL5 and total cortical volume. Specifically, frontal thickness was positively associated with IFNγ, IL4, IL5 and IL13 cytokine levels in the healthy control group, whereas pro-inflammatory cytokines IFNγ and IL5 were associated with lower total cortical volume in the FEP group. Our findings suggest that while there were no relationships detected in chronic schizophrenia, the relationship between peripheral inflammatory markers and select brain regions are differentially impacted in FEP and healthy controls. Longitudinal investigations are required to determine whether the relationship between brain structure and peripheral inflammation changes over time.

Advanced Alzheimer's disease (AD) is characterized by higher noradrenaline metabolite levels that may be associated with AD pathology. The locus coeruleus (LC) is the main site for cerebral noradrenaline synthesis and LC volume loss occurs as early as Braak stage 1. This study investigates the association between noradrenergic turnover and brain morphology, and the modifying effect of AD pathology. The study sample included 77 memory clinic patients (37 cognitively unimpaired and 40 cognitively impaired (mild cognitive impairment or AD dementia)). Cortical thickness and volumetric analyses were performed using FreeSurfer. Cerebrospinal fluid was analyzed for noradrenergic metabolite 3-methoxy-4hydroxyphenylethyleneglycol (MHPG), A beta 42 and phosphorylated tau. Higher MHPG was associated with lower cortical thickness and hippocampal volume at lower, but subthreshold, levels of A beta 42 and at higher p-tau levels. These associations remained significant after adding APOE-E4 or cognitive status as covariates. Our results suggest that greater MHPG together with worse AD pathology contributes to neurodegeneration, possibly before significant amyloidosis. The noradrenergic system may play an important role in early detection of AD-related processes. (C) 2021 The Authors. Published by Elsevier Inc.

The association between cerebrospinal fluid (CSF) amyloid beta (Aβ) Aβ38 or Aβ40 and brain grey- and white matter integrity is poorly understood. We studied this in 213 cognitively normal 70-year-olds, and in subgroups defined by presence/absence of the APOE ε4 allele and Aβ pathology: Aβ-/APOE-, Aβ+/APOE-, Aβ-/APOE+ and Aβ+/APOE+. CSF Aβ was quantified using ELISA and genotyping for APOE was performed. Low CSF Aβ42 defined Aβ plaque pathology. Brain volumes were assessed using Freesurfer-5.3, and white matter integrity using tract-based statistics in FSL. Aβ38 and Aβ40 were positively correlated with cortical thickness, some subcortical volumes and white matter integrity in the total sample, and in 3 of the subgroups: Aβ-/APOE-, Aβ+/APOE- and Aβ-/APOE+. In Aβ+/APOE+ subjects, higher Aβ38 and Aβ40 were linked to reduced cortical thickness and subcortical volumes. We hypothesize that production of all Aβ species decrease in brain regions with atrophy. In Aβ+/APOE+, Aβ-dysregulation may be linked to cortical atrophy in which high Aβ levels is causing pathological changes in the gray matter of the brain.

Objective Obsessive-compulsive (OC) symptoms are common in the general population, but it is unclear whether subclinical OC symptoms and obsessive-compulsive disorder (OCD) are part of a neuroanatomical continuum. The goal of this study was to investigate the relation between OC symptoms and subcortical and cortical morphology in a population-based sample of children. Method The study included 2,551 participants, aged 9–12 years, from the population-based Generation R Study. OC symptoms were measured using the 7-item caregiver-rated Short Obsessive-Compulsive Disorder Screener (SOCS). Structural (3T) magnetic resonance imaging scans were processed using FreeSurfer to study the thalamus and other subcortical volumes, intracranial volume, vertexwise cortical thickness, and surface area. We used linear regression models to investigate the association between OC symptoms and brain morphology. Emulating case-control studies from the literature, we compared children scoring above the clinical cutoff of the SOCS (probable OCD cases, n = 164) with matched children without symptoms. Results Children with probable OCD had larger thalami compared with the control group (d 0.16, p = .044). Vertexwise analysis showed a positive association between OC symptoms and thickness of the right inferior parietal cortex, which disappeared after adjusting for total behavioral problems. SOCS scores correlated negatively with intracranial volume (B = −2444, p = .038). Conclusion Children with probable OCD showed thalamus alterations similar to those previously reported in unmedicated children with OCD. OC symptoms showed a stronger association with total intracranial volume than regional brain measures. Longitudinal studies are needed to further elucidate similarities and distinctions between neural correlates of subclinical and clinical OC symptoms.

Background Characterisation of brain morphological features common to cognitively similar individuals with bipolar disorder (BD) and schizophrenia spectrum disorders (SSD) may be key to understanding their shared neurobiological deficits. In the current study we examined whether three previously characterised cross-diagnostic cognitive subgroups differed among themselves and in comparison to healthy controls across measures of brain morphology. Method T1-weighted structural magnetic resonance imaging scans were obtained for 143 individuals; 65 healthy controls and 78 patients (SSD, n = 40; BD I, n = 38) classified into three cross-diagnostic cognitive subgroups: Globally Impaired (n = 24), Selectively Impaired (n = 32), and Superior/Near-Normal (n = 22). Cognitive subgroups were compared to each other and healthy controls on three separate analyses investigating (1) global, (2) regional, and (3) vertex-wise comparisons of brain volume, thickness, and surface area. Results No significant subgroup differences were evident in global measures of brain morphology. In region of interest analyses, the Selectively Impaired subgroup had greater right accumbens volume than those Superior/Near-Normal subgroup and healthy controls, and the Superior/Near-Normal subgroup had reduced volume of the left entorhinal region compared to all other groups. In vertex-wise comparisons, the Globally Impaired subgroup had greater right precentral volume than the Selectively Impaired subgroup, and thicker cortex in the postcentral region relative to the Superior/Near-Normal subgroup. Limitations Exploration of medication effects was limited in our data. Conclusions Although some differences were evident in this sample, generally cross-diagnostic cognitive subgroups of individuals with SSD and BD did not appear to be clearly distinguished by patterns in brain morphology.

Highlights • First study of both serum and DNAm CRP associations with depression/neuroimaging. • Serum CRP is associated with somatic symptoms and reduced entorhinal cortex thickness. • DNAm CRP is associated with widespread reductions in white matter integrity. • Evidence for central effects of peripheral inflammation from serum and DNAm markers., Inflammatory processes are implicated in the aetiology of Major Depressive Disorder (MDD); however, the relationship between peripheral inflammation, brain structure and depression remains unclear, partly due to complexities around the use of acute/phasic inflammatory biomarkers. Here, we report the first large-scale study of both serological and methylomic signatures of CRP (considered to represent acute and chronic measures of inflammation respectively) and their associations with depression status/symptoms, and structural neuroimaging phenotypes (T1 and diffusion MRI) in a large community-based sample (Generation Scotland; NMDD cases = 271, Ncontrols = 609). Serum CRP was associated with overall MDD severity, and specifically with current somatic symptoms- general interest (β = 0.145, PFDR = 6 × 10−4) and energy levels (β = 0.101, PFDR = 0.027), along with reduced entorhinal cortex thickness (β = −0.095, PFDR = 0.037). DNAm CRP was significantly associated with reduced global grey matter/cortical volume and widespread reductions in integrity of 16/24 white matter tracts (with greatest regional effects in the external and internal capsules, βFA= −0.12 to −0.14). In general, the methylation-based measures showed stronger associations with imaging metrics than serum-based CRP measures (βaverage = −0.15 versus βaverage = 0.01 respectively). These findings provide evidence for central effects of peripheral inflammation from both serological and epigenetic markers of inflammation, including in brain regions previously implicated in depression. This suggests that these imaging measures may be involved in the relationship between peripheral inflammation and somatic/depressive symptoms. Notably, greater effects on brain morphology were seen for methylation-based rather than serum-based measures of inflammation, indicating the importance of such measures for future studies.

Background Childhood trauma (CT) is a major yet elusive psychiatric risk factor, whose multidimensional conceptualization and heterogeneous effects on brain morphology might demand advanced mathematical modeling. Therefore, we present an unsupervised machine learning approach to characterize the clinical and neuroanatomical complexity of CT in a larger, transdiagnostic context. Methods We used a multicenter European cohort of 1076 female and male individuals (discovery: n = 649; replication: n = 427) comprising young, minimally medicated patients with clinical high-risk states for psychosis; patients with recent-onset depression or psychosis; and healthy volunteers. We employed multivariate sparse partial least squares analysis to detect parsimonious associations between combinations of items from the Childhood Trauma Questionnaire and gray matter volume and tested their generalizability via nested cross-validation as well as via external validation. We investigated the associations of these CT signatures with state (functioning, depressivity, quality of life), trait (personality), and sociodemographic levels. Results We discovered signatures of age-dependent sexual abuse and sex-dependent physical and sexual abuse, as well as emotional trauma, which projected onto gray matter volume patterns in prefronto-cerebellar, limbic, and sensory networks. These signatures were associated with predominantly impaired clinical state- and trait-level phenotypes, while pointing toward an interaction between sexual abuse, age, urbanicity, and education. We validated the clinical profiles for all three CT signatures in the replication sample. Conclusions Our results suggest distinct multilayered associations between partially age- and sex-dependent patterns of CT, distributed neuroanatomical networks, and clinical profiles. Hence, our study highlights how machine learning approaches can shape future, more fine-grained CT research.

Objective Despite the clinical effectiveness of Spinal Cord Stimulation (SCS), potential structural brain modifications have not been explored. Our aim was to identify structural volumetric changes during subsensory SCS, in patients with Failed Back Surgery Syndrome (FBSS). Methods In this cohort study, twenty-two FBSS patients underwent a magnetic resonance imaging protocol before SCS and 3 months after SCS. Clinical parameters were correlated with volumetric changes, calculated with voxel-based morphometry. Results After 3 months, a significant volume decrease was found in the inferior frontal gyrus, precuneus, cerebellar posterior lobe and middle temporal gyrus. Significant increases were found in the inferior temporal gyrus, precentral gyrus and the middle frontal gyrus after SCS. Additionally, significant increases in volume of superior frontal and parietal white matter and a significant decrease in volume of white matter underlying the premotor/middle frontal gyrus were revealed after SCS. A significant correlation was highlighted between white matter volume underlying premotor/middle frontal gyrus and leg pain relief. Conclusions This study revealed for the first time that SCS is able to induce volumetric changes in gray and white matter, suggesting the reversibility of brain alterations after chronic pain treatment. Significance Volumetric brain alterations are observable after 3 months of subsensory SCS in FBSS patients.

Fractal geometry provides a method of analyzing natural and especially biological morphologies. To investigate the relationship between the complexity measure, which is indexed as fractal dimensionality (FD), and the traditional Euclidean metrics, such as the volume and thickness, of the brain in older age, we analyzed 483 MRI scans of 161 community-dwelling, nondemented individuals aged 70–90 years at the baseline and their 2-year and 6-year follow-ups. We quantified changes in neuroimaging metrics in cortical lobes and subcortical structures and investigated the effects of age, sex, hemisphere, and education on FD. We also analyzed the mediating effects of these metrics for further investigation. FD showed significant age-related decline in all structures, and its trajectory was best modeled quadratically in the bilateral frontal, parietal, and occipital lobes, as well as in the bilateral caudate, putamen, hippocampus, amygdala, and accumbens. FD showed specific mediating effects on aging and cognitive decline in some regions. Our findings suggest that FD is reliable yet shows a different pattern of decline compared with volumetric measures.

Background Studies in adult depressed patients have indicated that altered DNA methylation patterns at genes related to serotonin and HPA axis functioning (e.g., SLC6A4, FKBP5) are associated with changes in frontolimbic functional connectivity and structure. Here, we examined whether these associations can be generalized to adolescents. Methods 25 adolescents with depression (Mean age = 15.72 ± 0.94 SD; 20 girls) and 20 healthy controls (Mean age = 16.05 ± 1.5 SD; 16 girls) underwent a functional and structural magnetic resonance imaging protocol, which included a resting-state assessment and measures of brain morphometry. DNA was obtained from saliva. Levels of SLC6A4 and FKBP5 methylation were determined using pyrosequencing. Results SLC6A4 methylation was linked to amygdala-frontal operculum resting-state functional connectivity (rs-FC), regardless of diagnosis, and was differentially associated with inferior orbitofrontal gyrus (IFOG) gray matter (GM) volume in adolescents with depression and controls. Replicating and extending previous findings in adults, FKBP5 methylation was associated with IFOG GM volume in depressed and healthy adolescents, as well as orbitofrontal cortex (OFC)-rostral prefrontal cortex (RPFC) connectivity in healthy adolescents only. Limitations Effects of medication use or genotype cannot be ruled out. Further, the relatively small sample size and predominately female sample may limit generalizability. Conclusions These findings suggest that previously observed associations between SLC6A4 and FKBP5 methylation and frontolimbic processes in adult depressed patients can be in part generalized to adolescent patients. Further, findings suggest that measuring peripheral methylation at these genes deserves further attention as potential markers of typical and atypical development.

Highlights • Longitudinal magnetic resonance imaging identified increased total brain volume in older mdx mice. • Decreases in grey matter volume of mdx mouse hippocampus were noticeable from 12 months. • Mdx mice demonstrated deficits in hippocampal long-term spatial learning and memory. • Increased levels of anxiety-related behaviour shown by older mdx mice., Duchenne muscular dystrophy (DMD) is an X-linked recessive muscle wasting disease caused by mutations in the DMD gene, which encodes the large cytoskeletal protein dystrophin. Approximately one-third of DMD patient's exhibit cognitive problems yet it is unknown if cognitive impairments worsen with age. The mdx mouse model is deficient in dystrophin demonstrates cognitive abnormalities, but no studies have investigated this longitudinally. We assessed the consequences of dystrophin deficiency on brain morphology and cognition in male mdx mice. We utilised non-invasive methods to monitor CNS pathology with an aim to identify changes longitudinally (between 4 and 18 months old) which could be used as outcome measures. MRI identified a total brain volume (TBV) increase in control mice with ageing (p

Neurodevelopment represents a period of increased opportunity and vulnerability, during which a complex confluence of genetic and environmental factors influences brain growth trajectories, cognitive and mental health outcomes. Recently, magnetic resonance imaging (MRI) studies on twins have increased our knowledge of the extent to which genes, the environment and their interactions shape inter-individual brain variability. The present review draws from highly salient MRI studies in young twin samples to provide a robust assessment of the heritability of structural and functional brain changes during development. The available studies suggest that (as with many other traits), global brain morphology and network organization are highly heritable from early childhood to young adulthood. Conversely, genetic correlations among brain regions exhibit heterogeneous trajectories, and this heterogeneity reflects the progressive, experience-related increase in brain network complexity. Studies also support the key role of environment in mediating brain network differentiation via changes of genetic expression and hormonal levels. Thus, rest- and task-related functional brain circuits seem to result from a contextual and dynamic expression of heritability.

Visual fields are of particular interest to comparative biologists studying the complex interplay between anatomy, physiology, ecology, and optics. Visual fields have been measured in nearly 100 bird species, and investigators have uncovered associations between quantitative aspects of visual fields and foraging behavior, skull dimensions, and even brain morphology. However, limiting factors including time, access to living subjects, and experimental constraints complicate study of the visual apparatus of rare, endangered, or extinct species. We introduce a modeling technique called virtual ophthalmoscopy (VO) for estimating visual fields of vertebrates. We compare this in-silico technique, which draws on geometrical optics, morphometrics of eyes, and 3D visualization, against experimental data from 12 bird species from behavioral literature. Known values of optical properties, including axial length, lens curvatures, and refractive index, are used to construct and test virtual, schematic eyes in ray-tracing software. Resulting visual fields are measured in 3D-visualization software. These measurements are compared qualitatively and quantitatively with visual fields from the literature. Schematic eyeballs and in-silico visual fields, after iterative improvements using anatomical information from cadaveric specimens, approximate experimental data to the extent of falling within the range of intraspecific variation, suggesting VO is a viable technique for modeling visual fields. Virtual ophthalmoscopy creates an opportunity to expand the sample of species for which visual fields can be quantified and allows new hypotheses regarding the evolution of visual systems to be tested.

Background In the United States, the average duration of untreated psychosis (DUP) is 21 months, and it remains unknown how longer DUP may affect brain functioning in antipsychotic-naive patients with first-episode psychosis. The objective was to determine the effects of DUP on functional connectivity and brain morphology measured with resting-state functional and structural magnetic resonance imaging. Methods Medication-naive patients with first-episode psychosis were referred from various clinical settings. After accounting for exclusion criteria, attrition, and data quality, final analyses included 55 patients (35 male and 20 female; mean age, 24.18 years). Patients with first-episode psychosis were subjected to a 16-week trial of risperidone, a commonly used antipsychotic drug. Treatment response was calculated as change in the psychosis subscale of the Brief Psychiatric Rating Scale between baseline and 16 weeks. Resting-state functional connectivity magnetic resonance imaging and brain morphology (surface area and cortical thickness) were assessed. Results Longer DUP was associated with worse treatment response and reduced functional connectivity—more specifically in the default, salience, and executive networks. Moreover, longer DUP was associated with reduced surface area in the salience and executive networks and with increased cortical thickness in the default mode and salience networks. When the functional connectivity of the default mode network was added as a mediator, the relationship between DUP and treatment response was no longer significant. Conclusions These data suggest that several neurobiological alterations in the form of reduced functional connectivity and surface area and increased cortical thickness underpin the effect of prolonged DUP.

Purpose Only a few studies have investigated the brain morphology abnormalities in structural MRI in patients with drug-naive idiopathic generalized epilepsy (IGE) and mainly focused on brain volume changes. In the present study, we aimed to investigate the changes in three morphologic measurement differences including cortical thickness, cortical volume, and surface area using FreeSurfer in a pediatric cohort of recent-onset, drug-naive IGE. Methods Forty-five recent-onset, drug-naive patients diagnosed with IGE and 32 demographically matched healthy controls were recruited. All participants underwent structural MRI scans with a 3.0 T MR system. FreeSurfer, an automated cortical surface reconstruction toolbox, was applied to compare the cortical morphology between patients and controls. The brain regions with significant group differences after multiple comparison correction were extracted in common space for each patient, and then correlated with their clinical characteristics (including onset age, duration of epilepsy, and mini-mental state examination (MMSE)) using partial correlation analysis with age, sex and intracranial volume as covariates. Results Compared with controls, IGE patients showed decreased cortical thickness in the left rostral middle frontal gyrus, decreased cortical volume in the right cuneus and left superior frontal gyrus that extended to the precentral gyrus, and decreased surface area in the right cuneus and right inferior parietal gyrus. None of these regions showed significant relationships with clinical measurements in the patient group. Conclusion Our findings suggest that cortical thickness, cortical volume, and surface area changes occurred in the early stage of IGE. These findings provide structural neuroimaging evidence underlying the pathology of IGE.

Subjective well-being (SWB) is closely related to our physical and mental health. Existing studies show that neural or genetic basis underpins individual difference in SWB. Moreover, researchers have found high enrichment of SWB-related mutations in the central nervous system, but the relationship between the genetic architecture of SWB and brain morphology has not been explored. Considering the polygenic nature of SWB, in this study, we aim to establish a measure of additive genetic effect on SWB and explore its relationship to the brain anatomical structure. Based on the results of genome-wide association study (GWAS) on SWB, the polygenic scores (PGSs) of SWB at eight different thresholds were calculated in a large Chinese sample (N = 585). Then, we analyzed the associations between the PGSs of SWB and cortical thickness (CT) or gray matter volume (GMV) measured from 3.0-T structural imaging data. In whole-brain analyses, we found that a higher PGS was significantly associated with increased CT in the right superior temporal gyrus (STG) and GMV in the right insula, both of which are involved in social cognition and emotional processing. More importantly, these findings were repeatable at some different thresholds. The results may suggest that the brain morphology of right STG and insula is partly regulated by SWB-related genetic factors.

Antipsychotic treatment may affect brain morphology, and enlargement of the basal ganglia (BG) is a replicated finding. Here we investigated associations between antipsychotic treatment and BG volumes in patients with psychotic and bipolar disorders. We hypothesized that current treatment and, among those medicated, higher dosage, estimated D2R occupancy and being in remission would predict larger BG volumes. Structural covariance analysis was performed to examine if correlations between BG volumes and cortical thickness differed by treatment status. 224 patients treated with antipsychotics; 26 previously treated, 29 never treated and 301 healthy controls (HC) were included from the TOP study cohort (NORMENT, Norway). T1-weighted MR images were processed using FreeSurfer. D2R occupancy was estimated based on serum concentration measurements for patients receiving stable monotherapy. Statistical analyses were adjusted for age, gender and estimated intracranial volume (ICV). We found larger right (p 0.003) and left putamen (p 0.02) and right globus pallidus (GP) (p 0.03) in currently medicated patients compared to HC. Bilateral regional cortical thinning was also observed in currently and previously medicated patients compared to HC. In medicated patients, higher chlorpromazine equivalent dose (CPZ) was associated with larger left GP (p 0.04). There was no association with estimated D2R occupancy (n = 47) or remission status. Lower positive correlation between left putamen volume and cortical thickness of the left lateral occipital cortex was found in medicated patients compared to HC. We replicated the BG enlargement in medicated patients, but found no association with estimated D2R occupancy. Further studies are needed to clarify the underlying mechanisms.

Abnormal fine motor function is a frequent finding in schizophrenia and has been linked to structural and functional brain alterations. However, whether fine motor function is related to functional alterations within the motor system remains unclear. The aim of this study was to assess whether abnormalities in resting-state functional connectivity are present in schizophrenia patients and to investigate how these abnormalities may be related to fine motor function. We examined 19 schizophrenia patients and 16 healthy controls using resting-state functional connectivity for 11 bilateral regions of interest. Fine motor function was assessed on a set of copying tasks and the Symbol-Digit-Substitution Test. We found significantly reduced functional connectivity between the left caudate nucleus and bilateral dorsolateral prefrontal cortex (DLPFC) and between the left putamen and bilateral supplementary motor area (SMA) proper in patients compared to controls. Altered connectivity from DLPFC to caudate nucleus was related to fine motor tasks, which are sensitive to psychomotor speed, whereas aberrant connectivity between the SMA proper and putamen was associated to both, fine motor task, which are sensitive to psychomotor speed and to speed of information processing. Our findings emphasize the role of fronto-striatal connections in the pathogenesis of fine motor impairments in schizophrenia.

Striatal medium spiny neurons (MSNs) control motor function. Hyper- or hypo-activity of MSNs coincides with basal ganglia-related movement disorders. Based on the assumption that lasting alterations in neuronal activity lead to structural changes in the brain, understanding these structural alterations may be used to infer MSN functional abnormalities. To infer MSN function from structural data, understanding how long-lasting alterations in MSN activity affect brain morphology is essential. To address this, we utilized a simplified model of functional induction by stimulating MSNs expressing channelrhodopsin 2 (ChR2). Subsequent structural alterations which induced long-term activity changes in these MSNs were investigated in the striatal pathway and its associated regions by diffusion tensor imaging (DTI) and histological assessment with super-resolution microscopy. DTI detected changes in the striatum, substantia nigra, and motor cortex. Histological assessment found a reduction in the diameter of myelinated cortical axons as well as MSN dendrites and axons. The structural changes showed a high correlation between DTI parameters and histological data. These results demonstrated that long-term neural activation in the MSNs alters the diameter of MSN and cortical neurons fibers. This study provides a tool for understanding the causal relationship between functional and structural alterations.

Exploring sexual dimorphisms in the brain morphology is important for their impact and therapeutic implications for several neurological diseases. The hypothesis that sex could influence the transcriptome of brain cells could be the basis regarding the different response to cognitive decline identified in men and women. In this paper, we analyzed several prefrontal cortices (PFC) microarrays datasets of young/middle-aged healthy subjects and then Alzheimer's disease (AD) patients, according to the sex. The significant transcriptomes were overlapped with the main genes characterizing cells of the central nervous system (CNS) in order to determine the respective weighted percentages of significantly expression gene modulation (WPSEG). We identified differences in brain transcriptional activity between young and middle-aged. In middle-aged women, the WPSEG were higher for the Astrocytes, the Endotheliocytes, and the Microglia. In addition, the sex-matched analysis of transcriptome identified a convergent molecular signature in men and women AD patients. Furthermore, the WPSEG belonging to CNS cells in PFC of healthy middle-aged subjects was correlated to AD profiles according to the sex. Since our results, it is possible to conclude that during the aging the PFC' cells adopt transcriptional strategies sex-dependent that could potentially control the development of neurodegenerative diseases.

The etiology of depression is characterized by the interplay of genetic and environmental factors and brain structural alteration. Childhood adversity is a major contributing factor in the development of depression. Interactions between childhood adversity and candidate genes for depression could affect brain morphology via the modulation of neurotrophic factors, serotonergic neurotransmission, or the hypothalamus-pituitary-adrenal (HPA) axis, and this pathway may explain the subsequent onset of depression. Childhood adversity is associated with structural changes in the hippocampus, amygdala, anterior cingulate cortex (ACC), and prefrontal cortex (PFC), as well as white matter tracts such as the corpus callosum, cingulum, and uncinate fasciculus. Childhood adversity showed an interaction with the brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism, serotonin transporter-linked promoter region (5-HTTLPR), and FK506 binding protein 51 (FKBP5) gene rs1360780 in brain morphologic changes in patients with depression and in a non-clinical population. Individuals with the Met allele of BDNF Val66Met and a history of childhood adversity had reduced volume in the hippocampus and its subfields, amygdala, and PFC and thinner rostral ACC in a study of depressed patients and healthy controls. The S allele of 5-HTTLPR combined with exposure to childhood adversity or a poorer parenting environment was associated with a smaller hippocampal volume and subsequent onset of depression. The FKBP5 gene rs160780 had a significant interaction with childhood adversity in the white matter integrity of brain regions involved in emotion processing. This review identified that imaging genetic studies on childhood adversity may deepen our understanding on the neurobiological background of depression by scrutinizing complicated pathways of genetic factors, early psychosocial environments, and the accompanying morphologic changes in emotion-processing neural circuitry.

Recent studies have revealed that several psychotic symptom changes observed in the 'at risk mental state' (ARMS) are associated with changes in the striatum. We investigated if structural changes in the striatum are associated with recovery of sub-threshold psychotic symptoms in subjects with an ARMS who did not develop psychosis (ARMS-N). Sixteen healthy controls and 42 subjects with an ARMS participated in this study. Striatal volumes (caudate, putamen, and nucleus accumbens) were analyzed using MRI. The sub-threshold psychotic symptoms of the subjects with an ARMS were measured using the SOPS. Imaging and symptoms were reevaluated after 52 weeks. Significant right putamen volume reduction was observed at the follow-up in ARMS-N subjects. Improvement in sub-threshold positive symptoms significantly correlated with an increase in volume in the right accumbens at follow up. No relationship was found for negative symptoms. From these findings, the association between improvement in sub-threshold positive symptoms and an increase in the volume of the right accumbens may suggest that changes in the accumbens, which is a major site for dopamine innervation, are associated with symptom recovery. These findings may point to neurobiological resilience that may be associated with lower transition to psychosis.

Background While several research methods were developed to estimate individual-based representations of brain connectional wiring (i.e., a connectome), traditionally captured using multimodal MRI data (e.g., functional and diffusion MRI), very limited works aimed to estimate brain network atlas for a population of connectomes. Estimating well-representative brain templates is a key step for group comparison studies. However, estimating a network atlas for a population of multi-source brain connectomes lying on different manifolds is absent. New method To fill this gap, we propose a cluster-based multi-view brain connectivity fusion framework to estimate a brain network atlas for a population of multi-view brain networks, where each view captures a specific facet of the brain construct. Specifically, given a population of subjects, each with multi-view networks, we first non-linearly fuse multi-view networks into a single fused network for each subject. Then, we cluster the fused networks to identify individuals sharing similar connectional traits in an unsupervised way, which are next averaged within each cluster to generate a representative network atlas. Finally, we construct the final multi-view network atlas by averaging the obtained templates of all clusters. Results We evaluated our method on both healthy and disordered populations (with autism and dementia) and spotted differences between network atlases for healthy and autistic groups. Comparison with existing methods and conclusions Compared to other baseline methods, our fusion strategy achieved the best results in terms of template centeredness and population representativeness.

Sensory input for hearing plays a significant role in the development of human brain. Absence of an early auditory input leads to the alteration of important neural regions, which in turn results in a complex process known as cross-modal neuroplasticity. Previous studies related to the structural brain alteration of adult deaf individuals have shown inconsistent results. To address this issue, we investigated the brain morphology in 50 prelingual adult deaf individuals and compared it with the same number of individuals with normal hearing, using structural magnetic resonance imaging and three inter-related but completely distinct analysis methods namely univariate approach (voxel based morphometry), multivariate approach (source based morphometry), and projection based cortical thickness. The findings from all these inter-related analyses suggest alterations in important neural regions such as bilateral superior temporal gyrus, bilateral inferior temporal, bilateral fusiform gyrus, and bilateral middle frontal. These findings also justify a strong ventral visual pathway in the deaf group. We suggest that these morphological alterations in important brain regions are due to the compensatory cross-modal reorganization.

The topographic organization of the cerebral cortex has been proposed to provide hierarchical axes, as gradients, which revealed systematic variations of brain structure and function. However, the hierarchical organization of macroscopic brain morphology and how it constrains cortical function along the organizing axis is still unclear. We mapped systematic axes (gradients) of cortical morphometric similarity connectome, which combined multiple morphometric features conceptualized as a “fingerprint” of an individual’s brain. We observed that the principal gradient was anchored by motor and sensory cortices at two extreme ends, which were stable across numbers of feature combinations and reproducible across independent samples. Importantly, in contrast to canonical functional gradient, the morphometric gradient diverged in motor and sensory hierarchies, and that was consistent to laminar histological thickness gradient. Furthermore, the morphometric and functional gradients dissociated in the higher-order association cortices, like the fronto-parietal and default mode networks. Finally, the spatial pattern of morphometric gradients was closely associated with fundamental properties of cortical organization, including cyto- and myeloarchitectural profiles, as well as evolutionary expansion. These findings help understand the hierarchical organization of morphological markers of cortical structure.

Background Childhood trauma, particularly sexual abuse, has been associated with transition to psychosis in individuals at “ultra-high risk” (UHR). This study investigated whether the effects of various forms of childhood trauma on transition to psychosis are mediated by cortical thickness and surface area abnormalities. Methods This prospective study used data from 62 UHR individuals from a previous (PACE 400) cohort study. At follow-up, 24 individuals had transitioned to psychosis (UHR-T) and 38 individuals had not transitioned (UHR-NT). Student-t/Mann-Whitney-U tests were performed to assess morphological differences in childhood trauma (low/high) and transition. Mediation analyses were conducted using regression and bootstrapping techniques. Results UHR individuals with high sexual trauma histories presented with decreased cortical thickness in bilateral middle temporal gyri and the left superior frontal gyrus compared to those with low sexual trauma. Participants with high physical abuse had increased cortical thickness in the right middle frontal gyrus compared to those with low physical abuse. No differences were found for emotional abuse or physical/emotional neglect. Reduced cortical thickness in the right middle temporal gyrus and increased surface area in the right cingulate were found in UHR-T compared to UHR-NT individuals. Sexual abuse had an indirect effect on transition to psychosis, where decreased cortical thickness in the right middle temporal gyrus was a mediator. Conclusions Results suggest that childhood sexual abuse negatively impacted on cortical development of the right temporal gyrus, and this heightened the risk of transition to psychosis in our sample. Further longitudinal studies are needed to precisely understand this link.

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 18kDa 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 [(18)F]FEPPA positron emission tomography (PET) targeting TSPO. A significant [(18)F]FEPPA binding-by-group interaction was observed in morphological measures across the left hippocampus. In first-episode psychosis, we observed associations between [(18)F]FEPPA V(T) (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 [(18)F]FEPPA V(T) and other structural brain characteristics. Our findings suggest a link between TSPO expression and alterations in hippocampal morphology in first-episode psychosis.

Genetic and environmental etiologies may contribute to schizophrenia and its associated neurobiological profile. We examined the interaction between dopaminergic polymorphisms, childhood adversity and diagnosis (schizophrenia/schizoaffective disorder) on dopamine-related brain structures. Childhood adversity histories and structural MRI data were obtained from 249 (153 schizophrenia/schizoaffective, 96 controls) participants registered in the Australian Schizophrenia Research Bank. Polymorphisms in DRD2 and COMT were genotyped and a dopaminergic risk allelic load (RAL) was calculated. Regression analysis was used to test the main and interaction effects of RAL, childhood adversity and diagnosis on volumes of dopamine-related brain structures (caudate, putamen, nucleus accumbens, dorsolateral prefrontal cortex and hippocampus). A schizophrenia/schizoaffective diagnosis showed significant main effects on bilateral hippocampus, left dorsolateral prefrontal cortex and bilateral putamen volumes. RAL showed a significant main effect on left putamen volumes. Furthermore, across the whole sample, a significant two-way interaction between dopaminergic RAL and childhood adversity was found for left putamen volumes. No brain structure volumes were predicted by a three-way interaction that included diagnosis. Our finding suggests the left putamen may be particularly sensitive to dopaminergic gene-environment interactions regardless of diagnosis. However, larger studies are needed to assess whether these interactions are more or less pronounced in those with schizophrenia/schizoaffective disorders.

BACKGROUND: The age of a person’s brain can be estimated from structural brain images using an aggregate measure of variation in morphology across the whole brain. The brain age gap estimation (BrainAGE) score is computed as the difference between kernel-estimated brain age and chronological age. In this exploratory study, we investigated the application of the BrainAGE measure to identify potential novel effects of pharmacological agents on brain morphology. METHODS: Twenty healthy participants (23–47 years of age) completed three structural magnetic resonance imaging scans 45 minutes after administration of placebo or 200 or 600 mg of ibuprofen in a double-blind, crossover study. An externally derived BrainAGE model from a sample of 480 healthy participants was used to examine the acute effect of ibuprofen on temporary neuroanatomical changes in healthy individuals. RESULTS: The BrainAGE model produced age prediction for each participant with a mean absolute error of 6.7 years between the estimated and chronological age. The intraclass correlation coefficient for BrainAGE was 0.96. Relative to placebo, 200 and 600 mg of ibuprofen significantly decreased BrainAGE by 1.18 and 1.15 years, respectively (p < .05). The trained BrainAGE model identified the medial prefrontal cortex to be the strongest age predictor. CONCLUSIONS: BrainAGE is a potentially useful construct to examine neurological effects of therapeutic drugs. Ibuprofen temporarily reduces BrainAGE by approximately 1 year, which is likely due to its acute anti-inflammatory effects.

Although neonatal exposure to estrogen or estrogenic compounds results in irreversible changes in the brain function and reproductive abnormalities during adulthood but the underlying mechanisms are still largely unknown. The present study has attempted to compare the protein profiles of sexually dimorphic brain regions of adult female rats which were exposed to estradiol- 17 beta during neonatal period. The total proteins extracted from pre-optic area (POA), hypothalamus, hippocampus and pituitary of control and neonatally E2 treated female rats was subjected to 2D-SDS-PAGE and differentially expressed proteins were identified by MALDI TOF/TOF-MS. Our results revealed that a total of 21 protein spots which were identified as differentially expressed in all the four regions analyzed; the differential expression was further validated by RT-PCR and western blotting. The differentially expressed proteins such as 14-3-3 zeta/delta (POA), LMNA (hippocampus), Axin2 (hypothalamus), Syntaxin-7 (hippocampus), prolactin and somatotropin (pituitary) which have very important functions in the process of neuronal differentiation, migration, axon outgrowth, formation of dendritic spine density and synaptic plasticity and memory have not been previously reported in association with neonatal estrogen exposure. The affected brain functions are very important for the establishment of sex specific brain morphology and behavior. Our results suggest that the differentially expressed proteins may play an important role in irreversible changes in the brain function as well as reproductive abnormalities observed in the female rats during adulthood.

Background Post-stroke cognitive impairment is a clinically heterogeneous condition and its types have a different course and prognosis. The aim of the present study is to address the roles of inflammation, white matter pathology, and brain atrophy in different neuropsychological types of cognitive impairment in the acute period of ischemic stroke. Methods In 92 patients, we performed an assessment of the cognitive status and measured concentrations of cytokines (interleukin [IL]-1β, IL-6, tumor necrosis factor-alpha, IL-10) in liquor and serum, as well as a number of magnetic resonance imaging (MRI) morphometric parameters and fractional anisotropy. The control group consisted of 14 individuals without cerebrovascular disease. Results All patients had a higher level of IL-10 in serum than the control group. Patients with dysexecutive cognitive impairment had a higher concentration of IL-1β and IL-10 in liquor, IL-6 level in serum, and a lower fractional anisotropy of the ipsilateral thalamus than patients with normal cognition. Patients with mixed cognitive impairment were characterized by a lower fractional anisotropy of contralateral fronto-occipital fasciculus, compared with patients with dysexecutive cognitive impairment. Patients with both dysexecutive and mixed cognitive deficit had a wide area of leukoaraiosis and a reduced fractional anisotropy of the contralateral cingulum, compared with patients without cognitive impairment. Also, we found numerous correlations between cognitive status and levels of cytokines, MRI morphometric parameters, and fractional anisotropy of certain regions of the brain. Conclusions The concentrations of cytokines in serum and cerebrospinal fluid studied in combination with MRI morphometric parameters and fractional anisotropy appear to be informative biomarkers of clinical types of post-stroke cognitive impairment.

Background The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (rs6265) has been associated with several neuropsychiatric disorders and regional structural brain changes in adults, but little is known about Val66Met's effect on brain morphology during typical or atypical neurodevelopment. Windows of vulnerability to psychopathology may be associated with the different alleles of the Val66Met polymorphism during childhood and adolescence. Methodology We investigated the effect of Val66Met on cortical thickness in MRI scans of 718 children and adolescents (6–12 years old) with typical development, and in those meeting DSM criteria for a psychiatric disorder. Results Val66Met had a significant effect on cortical thickness. Considering the typically developing group, Met-carriers presented thicker parietal and occipital lobes and prefrontal cortices compared to Val homozygotes. Met-carriers with psychiatric disorders presented thicker medial and lateral temporal cortices than Val homozygotes. Furthermore, a significant genotype × psychiatric diagnosis interaction was found: Met-carriers with a psychiatric diagnosis presented thinner bilateral prefrontal cortices than Val homozygotes. Conclusion This study provides evidence that Val66Met is associated with cortical maturation in children and adolescents with and without psychiatric disorders.

Background Observational studies of the Mediterranean diet suggest cognitive benefits, potentially reducing dementia risk. Objective We performed the first published review to our knowledge of randomized controlled trials (RCTs) investigating Mediterranean diet effects on cognition or brain morphology and function, with an additional focus on intervention diet quality and its relation to "traditional" Mediterranean dietary patterns. Design We searched 9 databases from inception (final update December 2017) for RCTs testing a Mediterranean compared with alternate diet for cognitive or brain morphology and function outcomes. Results Analyses were based on 66 cognitive tests and 1 brain function outcome from 5 included studies (n = 1888 participants). The prescribed Mediterranean diets varied considerably between studies, particularly with regards to quantitative food advice. Only 8/66 (12.1%) of individual cognitive outcomes at trial level significantly favored a Mediterranean diet for cognitive performance, with effect sizes (ESs) ranging from small (0.32) to large (1.66), whereas 2 outcomes favored controls. Data limitations precluded a meta-analysis. Of 8 domain composite cognitive scores from 2 studies, the 3 (Memory, Frontal, and Global function) from PREDIMED (PREvencion con DIeta MEDiterranea) were significant, with ESs ranging from 0.39 to 1.29. A posttest comparison at a second PREDIMED site found that the Mediterranean diet modulates the effect of several genotypes associated with dementia risk for some cognitive outcomes, with mixed results. Finally, the risk of low-plasma brain-derived neurotrophic factor was reduced by 78% (OR = 0.22; 95% CI: 0.05, 0.90) in those who consumed a Mediterranean diet compared to control diet at 3 y in this trial. There was no benefit of the Mediterranean diet for incident cognitive impairment or dementia. Conclusions Five RCTs of the Mediterranean diet and cognition have been published to date. The data are mostly nonsignificant, with small ESs. However, the significant improvements in cognitive domain composites in the most robustly designed study warrant additional research.

Objective/Background Massive changes in brain morphology and function in the first years of life reveal a postero-anterior trajectory of cortical maturation accompanied by regional modifications of NREM sleep. One of the most sensible marker of this maturation process is represented by electroencephalographic (EEG) activity within the frequency range of sleep spindles. However, direct evidence that these changes actually reflect maturational modifications of fast and slow spindles still lacks. Our study aimed at answering the following questions: 1. Do cortical changes at 11.50 Hz frequency correspond to slow spindles? 2. Do fast and slow spindles show different age trajectories and different topographical distributions? 3. Do changes in peak frequency explain age changes of slow and fast spindles? Patients/Methods We measured the antero-posterior changes of slow and fast spindles in the first 60 min of nightly sleep of 39 infants and children (0–48 mo.). Results We found that (A) changes of slow spindles from birth to childhood mostly affect frontal areas (B) variations of fast and slow spindles across age groups go in opposite direction, the latter progressively increasing across ages; (C) this process is not merely reducible to changes of spindle frequency. Conclusions As a main finding, our cross-sectional study shows that the first form of mature spindle (i.e., corresponding to the adult phasic event of NREM sleep) is marked by the emergence of slow spindles on anterior regions around the age of 12 months.

Purpose The purpose of this study was to examine cortical thickness and subcortical volumes in professional rugby players with an extensive history of concussions compared to control subjects. Method Participants included 24 active and former professional rugby league players [Age M(SD) = 33.3(6.3); Range = 21–44] with an extensive history of concussion and 18 age- and education-matched controls with no history of neurotrauma or participation in contact sports. Participants underwent T1-weighted imaging and completed a neuropsychological battery, including two tests of memory. Whole brain cortical thickness analysis and structural volume analysis was performed using FreeSurfer version 6.0. Results Professional rugby league players reported greater alcohol consumption (p, Highlights • No differences in cortical thickness were observed in rugby players compared to controls. • Smaller hippocampal and amygdala volumes were observed in rugby players. • Greater alcohol use was associated with smaller bilateral hippocampi and left amygdala volumes in rugby players.

The ongoing Chinese Color Nest Project (CCNP) was established to create normative charts for brain structure and function across the human lifespan, and link age-related changes in brain imaging measures to psychological assessments of behavior, cognition, and emotion using an accelerated longitudinal design. In the initial stage, CCNP aims to recruit 1520 healthy individuals (6–90 years), which comprises three phases: developing (devCCNP: 6–18 years, N = 480), maturing (matCCNP: 20–60 years, N = 560) and aging (ageCCNP: 60–84 years, N = 480). In this paper, we present an overview of the devCCNP, including study design, participants, data collection and preliminary findings. The devCCNP has acquired data with three repeated measurements from 2013 to 2017 in Southwest University, Chongqing, China (CCNP-SWU, N = 201). It has been accumulating baseline data since July 2018 and the second wave data since September 2020 in Chinese Academy of Sciences, Beijing, China (CCNP-CAS, N = 168). Each participant in devCCNP was followed up for 2.5 years at 1.25-year intervals. The devCCNP obtained longitudinal neuroimaging, biophysical, social, behavioral and cognitive data via MRI, parent- and self-reported questionnaires, behavioral assessments, and computer tasks. Additionally, data were collected on children’s learning, daily life and emotional states during the COVID-19 pandemic in 2020. We address data harmonization across the two sites and demonstrated its promise of characterizing the growth curves for the overall brain morphometry using multi-center longitudinal data. CCNP data will be shared via the National Science Data Bank and requests for further information on collaboration and data sharing are encouraged.

Diminished physical growth is a common marker of malnutrition and it affects approximately 200 million children worldwide. Despite its importance and prevalence, it is not clear whether diminished growth relates to brain development and general cognitive ability. Further, diminished growth is more common in areas of extreme poverty, raising the possibility that it may mediate previously shown links between socioeconomic status (SES) and brain structure. To address these gaps, 79 children growing up in an extremely poor, urban area of Bangladesh underwent MRI at age six years. Structural brain images were submitted to Mindboggle software, a Docker-compliant and high-reproducibility tool for tissue segmentation and regional estimations of volume, surface area, cortical thickness, sulcal depth, and mean curvature. Diminished growth predicted brain morphometry and mediated the link between SES and brain morphometry most consistently for subcortical and white matter subcortical volumes. Meanwhile, brain volume in left pallidum and right ventral diencephalon mediated the relationship between diminished growth and full-scale IQ. These findings offer malnutrition as one possible pathway through which SES affects brain development and general cognitive ability in areas of extreme poverty.

Epilepsy with myoclonic atonic seizure (EMAS) occurs in young children with previously normal to subnormal development. The outcome ranges from seizure freedom with preserved cognitive abilities to refractory epilepsy with intellectual disability (ID). Routine brain imaging typically shows no abnormalities. We aimed to compare the brain morphometry of EMAS patients with healthy subjects several years after epilepsy onset, and to correlate it to epilepsy severity and cognitive findings.Fourteen EMAS patients (4 females, 5-14 years) and 14 matched healthy controls were included. Patients were classified into three outcome groups (good, intermediate, poor) according to seizure control and cognitive and behavioral functioning. Individual anatomical data (T1-weighted sequence) were processed using the FreeSurfer pipeline. Cortical volume (CV), cortical thickness (CT), local gyrification index (LGI), and subcortical volumes were used for group-comparison and linear regression analyses.Morphometric comparison between EMAS patients and healthy controls revealed that patients have 1) reduced CV in frontal, temporal and parietal lobes (p = .001; 0.009 and 0.024 respectively); 2) reduced CT and LGI in frontal lobes (p = 0.036 and 0.032 respectively); and 3) a neat cerebellar volume reduction (p = 0.011). Neither the number of anti-seizure medication nor the duration of epilepsy was related to cerebellar volume (both p 0.62). Poor outcome group was associated with lower LGI. Patients in good and intermediate outcome groups had a comparable LGI to their matched healthy controls (p 0.27 for all lobes).Structural brain differences were detectable in our sample of children with EMAS, mainly located in the frontal lobes and cerebellum. These findings are similar to those found in patients with genetic/idiopathic generalized epilepsies. Outcome groups correlated best with LGI. Whether these anatomical changes reflect genetically determined abnormal neuronal networks or a consequence of sustained epilepsy remains to be solved with prospective longitudinal studies.

SUMMARY Tissue-clearing methods allow every cell in the mouse brain to be imaged without physical sectioning. However, the computational tools currently available for cell quantification in cleared tissue images have been limited to counting sparse cell populations in stereotypical mice. Here, we introduce NuMorph, a group of analysis tools to quantify all nuclei and nuclear markers within the mouse cortex after clearing and imaging by light-sheet microscopy. We apply NuMorph to investigate two distinct mouse models: a Topoisomerase 1 (Top1) model with severe neurodegenerative deficits and a Neurofibromin 1 (Nf1) model with a more subtle brain overgrowth phenotype. In each case, we identify differential effects of gene deletion on individual cell-type counts and distribution across cortical regions that manifest as alterations of gross brain morphology. These results underline the value of whole-brain imaging approaches, and the tools are widely applicable for studying brain structure phenotypes at cellular resolution., Graphical abstract, In brief Krupa et al. develop an image analysis toolbox called NuMorph that accurately quantifies all nuclei within the mouse cortex after tissue clearing and light-sheet imaging. They implement NuMorph to characterize region- and cell-type-specific deficits present in two distinct mouse models, demonstrating the advantages of a whole-brain imaging approach.

Highlights • Associations between neighborhood disadvantage and trajectories of the difference between brain-predicted age and chronological age (brainAGE), and moderating factors, were investigated during adolescence. • Neighborhood disadvantage was positively associated with brainAGE during early adolescence and a deceleration (decreasing brainAGE) thereafter • Temperamental effortful control moderated this association. In adolescents exposed to high neighborhood disadvantage, low effortful control was associated with delayed development during late adolescence • Temperamental effortful control and positive parenting were independently associated with brainAGE trajectory, Neighborhood disadvantage has consistently been linked to alterations in brain structure; however, positive environmental (e.g., positive parenting) and psychological factors (e.g., temperament) may buffer these effects. We aimed to investigate associations between neighborhood disadvantage and deviations from typical neurodevelopmental trajectories during adolescence, and examine the moderating role of positive parenting and temperamental effortful control (EC). Using a large dataset (n = 1313), a normative model of brain morphology was established, which was then used to predict the age of youth from a longitudinal dataset (n = 166, three time-points at age 12, 16, and 19). Using linear mixed models, we investigated whether trajectories of the difference between brain-predicted-age and chronological age (brainAGE) were associated with neighborhood disadvantage, and whether positive parenting (positive behavior during a problem-solving task) and EC moderated these associations. We found that neighborhood disadvantage was associated with positive brainAGE during early adolescence and a deceleration (decreasing brainAGE) thereafter. EC moderated this association such that in disadvantaged adolescents, low EC was associated with delayed development (negative brainAGE) during late adolescence. Findings provide evidence for complex associations between environmental and psychological factors, and brain maturation. They suggest that neighborhood disadvantage may have long-term effects on neurodevelopment during adolescence, but high EC could buffer these effects.

Introduction Sarcoidosis is a chronic inflammatory disease often associated with chronic fatigue. Prevalence of fatigue can be measured via neuropsychological testing. Its pathophysiology is insufficiently understood. Structural analysis might help with the development of novel treatment methods. Methods We recruited 30 sarcoidosis patients whose fatigue severity and depressive symptom presence was measured through validated neuropsychological self-assessment. T1-weighted structural images were acquired and VBM preprocessing was conducted. Total scores of these tests and subscales were correlated through multiple regression analysis to the brain morphometry. Results Fatigue severity positively correlated with gray matter volumes in the striatum, the cingulate cortex and the cerebellum and negatively in the parietal and temporal lobe and posterior insula. Subscale analysis indicated a correlation between cognitive fatigue and striatum involvement as well as between physical and psychosocial fatigue and cerebellar alterations. Discussion Structural analysis delineated two structural patterns associated with the presence of fatigue. One such pattern mainly seemed to involve structures with a focus on decision-making processes while the other indicated alterations in regions vital for perception. Fatigue seems to be a heterogeneous disease, where varying dimensions of reported symptoms correlate with different patterns of structural changes.