Children with chromosome 22q11.2 deletion syndrome (22q11.2DS), Fragile X syndrome (FXS), or Turner syndrome (TS) are considered to belong to distinct genetic groups, as each disorder is caused by separate genetic alterations. Even so, they have similar cognitive and behavioral dysfunctions, particularly in visuospatial and numerical abilities. To assess evidence for common underlying neural microstructural alterations, we set out to determine whether these groups have partially overlapping white matter abnormalities, relative to typically developing controls. We scanned 101 female children between 7 and 14years old: 25 with 22q11.2DS, 18 with FXS, 17 with TS, and 41 aged-matched controls using diffusion tensor imaging (DTI). Anisotropy and diffusivity measures were calculated and all brain scans were nonlinearly aligned to population and site-specific templates. We performed voxel-based statistical comparisons of the DTI-derived metrics between each disease group and the controls, while adjusting for age. Girls with 22q11.2DS showed lower fractional anisotropy (FA) than controls in the association fibers of the superior and inferior longitudinal fasciculi, the splenium of the corpus callosum, and the corticospinal tract. FA was abnormally lower in girls with FXS in the posterior limbs of the internal capsule, posterior thalami, and precentral gyrus. Girls with TS had lower FA in the inferior longitudinal fasciculus, right internal capsule and left cerebellar peduncle. Partially overlapping neurodevelopmental anomalies were detected in all three neurogenetic disorders. Altered white matter integrity in the superior and inferior longitudinal fasciculi and thalamic to frontal tracts may contribute to the behavioral characteristics of all of these disorders.

Developmental prosopagnosia is a disorder characterized by profound and lifelong difficulties with face recognition in the absence of sensory or intellectual deficits or known brain injury. While there has been a surge in research on developmental prosopagnosia over the last decade and a half, the cognitive mechanisms behind the disorder and its neural underpinnings remain elusive. Most recently it has been proposed that developmental prosopagnosia may be a manifestation of widespread disturbance in neural migration which affects both face responsive brain regions as well as other category-sensitive visual areas. We present a combined behavioural and functional MRI study of face, object and word processing in a group of developmental prosopagnosics (N = 15). We show that developmental prosopagnosia is associated with reduced activation of core ventral face areas during perception of faces. The reductions were bilateral but tended to be more pronounced in the left hemisphere. As the first study to address category selectivity for word processing in developmental prosopagnosia, we do not, however, find evidence for reduced activation of the visual word form area during perception of orthographic material. We also find no evidence for reduced activation of the lateral occipital complex during perception of objects. These imaging findings correspond well with the behavioural performance of the developmental prosopagnosics, who show severe impairment for faces but normal reading and recognition of line drawings. Our findings suggest that a general deficit in neural migration across ventral occipito-temporal cortex is not a viable explanation for developmental prosopagnosia. The finding of left hemisphere involvement in our group of developmental prosopagnosics was at first surprising. However, a closer look at existing studies shows similar, but hitherto undiscussed, findings. These left hemisphere abnormalities seen in developmental prosopagnosia contrasts with lesion and imaging studies suggesting primarily right hemisphere involvement in acquired prosopagnosia, and this may reflect that the left hemisphere is important for the development of a normal face recognition network.

Insufficient suppression and connectivity of the default mode network (DMN) is a potential mediator of cognitive dysfunctions across various disorders, including attention deficit/hyperactivity disorder (ADHD). However, it remains unclear if alterations in sustained DMN suppression, variability and connectivity during prolonged cognitive engagement are implicated in adult ADHD pathophysiology, and to which degree methylphenidate (MPH) remediates any DMN abnormalities. This randomized, double-blinded, placebo-controlled, cross-over clinical trial of MPH (clinicaltrials.gov/ct2/show/NCT01831622) explored large-scale brain network dynamics in 20 adults with ADHD on and off MPH, compared to 27 healthy controls, while performing a reward based decision-making task. DMN task-related activation, variability, and connectivity were estimated and compared between groups and conditions using independent component analysis, dual regression, and Bayesian linear mixed models. The results show that the DMN exhibited more variable activation patterns in unmedicated patients compared to healthy controls. Group differences in functional connectivity both between and within functional networks were evident. Further, functional connectivity between and within attention and DMN networks was sensitive both to task performance and case-control status. MPH altered within-network connectivity of the DMN and visual networks, but not between-network connectivity or temporal variability. This study thus provides novel fMRI evidence of reduced sustained DMN suppression in adults with ADHD during value-based decision-making, a pattern that was not alleviated by MPH. We infer from multiple analytical approaches further support to the default mode interference hypothesis, in that higher DMN activation variability is evident in adult ADHD and associated with lower task performance.

In network analysis, the so-called "rich club" describes the core areas of the brain that are more densely interconnected among themselves than expected by chance, and has been identified as a fundamental aspect of the human brain connectome. This is the first in-depth diffusion imaging study to investigate the rich club along with other organizational changes in the brain's anatomical network in behavioral frontotemporal dementia (bvFTD), and a matched cohort with early-onset Alzheimer's disease (EOAD). Our study sheds light on how bvFTD and EOAD affect connectivity of white matter fiber pathways in the brain, revealing differences and commonalities in the connectome among the dementias. To analyze the breakdown in connectivity, we studied three groups: 20 bvFTD, 23 EOAD, and 37 healthy elderly controls. All participants were scanned with diffusion-weighted magnetic resonance imaging (MRI), and based on whole-brain probabilistic tractography and cortical parcellations, we analyzed the rich club of the brain's connectivity network. This revealed distinct patterns of disruption in both forms of dementia. In the connectome, we detected less disruption overall in EOAD than in bvFTD [false discovery rate (FDR) critical Pperm  = 5.7 × 10(-3) , 10,000 permutations], with more involvement of richly interconnected areas of the brain (chi-squared P = 1.4 × 10(-4) )-predominantly posterior cognitive alterations. In bvFTD, we found a greater spread of disruption including the rich club (FDR critical Pperm  = 6 × 10(-4) ), but especially more peripheral alterations (chi-squared P = 6.5 × 10(-3) ), particularly in medial frontal areas of the brain, in line with the known behavioral socioemotional deficits seen in these patients.

Obesity is a crucial public health issue in developed countries, with implications for cardiovascular and brain health as we age. A number of commonly-carried genetic variants are associated with obesity. Here we aim to see whether variants in obesity-associated genes--NEGR1, FTO, MTCH2, MC4R, LRRN6C, MAP2K5, FAIM2, SEC16B, ETV5, BDNF-AS, ATXN2L, ATP2A1, KCTD15, and TNN13K--are associated with white matter microstructural properties, assessed by high angular resolution diffusion imaging (HARDI) in young healthy adults between 20 and 30 years of age from the Queensland Twin Imaging study (QTIM). We began with a multi-locus approach testing how a number of common genetic risk factors for obesity at the single nucleotide polymorphism (SNP) level may jointly influence white matter integrity throughout the brain and found a wide spread genetic effect. Risk allele rs2815752 in NEGR1 was most associated with lower white matter integrity across a substantial portion of the brain. Across the area of significance in the bilateral posterior corona radiata, each additional copy of the risk allele was associated with a 2.2% lower average FA. This is the first study to find an association between an obesity risk gene and differences in white matter integrity. As our subjects were young and healthy, our results suggest that NEGR1 has effects on brain structure independent of its effect on obesity.

Individuals at Clinical High Risk for Psychosis (CHR-P) demonstrate heterogeneity in clinical profiles and outcome features. However, the extent of neuroanatomical heterogeneity in the CHR-P state is largely undetermined. We aimed to quantify the neuroanatomical heterogeneity in structural magnetic resonance imaging measures of cortical surface area (SA), cortical thickness (CT), subcortical volume (SV), and intracranial volume (ICV) in CHR-P individuals compared with healthy controls (HC), and in relation to subsequent transition to a first episode of psychosis. The ENIGMA CHR-P consortium applied a harmonised analysis to neuroimaging data across 29 international sites, including 1579 CHR-P individuals and 1243 HC, offering the largest pooled CHR-P neuroimaging dataset to date. Regional heterogeneity was indexed with the Variability Ratio (VR) and Coefficient of Variation (CV) ratio applied at the group level. Personalised estimates of heterogeneity of SA, CT and SV brain profiles were indexed with the novel Person-Based Similarity Index (PBSI), with two complementary applications. First, to assess the extent of within-diagnosis similarity or divergence of neuroanatomical profiles between individuals. Second, using a normative modelling approach, to assess the 'normativeness' of neuroanatomical profiles in individuals at CHR-P. CHR-P individuals demonstrated no greater regional heterogeneity after applying FDR corrections. However, PBSI scores indicated significantly greater neuroanatomical divergence in global SA, CT and SV profiles in CHR-P individuals compared with HC. Normative PBSI analysis identified 11 CHR-P individuals (0.70%) with marked deviation (>1.5 SD) in SA, 118 (7.47%) in CT and 161 (10.20%) in SV. Psychosis transition was not significantly associated with any measure of heterogeneity. Overall, our examination of neuroanatomical heterogeneity within the CHR-P state indicated greater divergence in neuroanatomical profiles at an individual level, irrespective of psychosis conversion. Further large-scale investigations are required of those who demonstrate marked deviation.

Characterizing brain changes in Alzheimer's disease (AD) is important for patient prognosis and for assessing brain deterioration in clinical trials. In this diffusion weighted imaging study, we used a new fiber-tract modeling method to investigate white matter integrity in 50 elderly controls (CTL), 113 people with mild cognitive impairment, and 37 AD patients. After clustering tractography using a region-of-interest atlas, we used a shortest path graph search through each bundle's fiber density map to derive maximum density paths (MDPs), which we registered across subjects. We calculated the fractional anisotropy (FA) and mean diffusivity (MD) along all MDPs and found significant MD and FA differences between AD patients and CTL subjects, as well as MD differences between CTL and late mild cognitive impairment subjects. MD and FA were also associated with widely used clinical scores. As an MDP is a compact low-dimensional representation of white matter organization, we tested the utility of diffusion tensor imaging measures along these MDPs as features for support vector machine based classification of AD.

People with HIV are living longer as combination antiretroviral therapy (cART) becomes more widely available. However, even when plasma viral load is reduced to untraceable levels, chronic HIV infection is associated with neurological deficits and brain atrophy beyond that of normal aging. HIV is often marked by cortical and subcortical atrophy, but the integrity of the brain's white matter (WM) pathways also progressively declines. Few studies focus on older cohorts where normal aging may be compounded with HIV infection to influence deficit patterns. In this relatively large diffusion tensor imaging (DTI) study, we investigated abnormalities in WM fiber integrity in 56 HIV+ adults with access to cART (mean age: 63.9 ± 3.7 years), compared to 31 matched healthy controls (65.4 ± 2.2 years). Statistical 3D maps revealed the independent effects of HIV diagnosis and age on fractional anisotropy (FA) and diffusivity, but we did not find any evidence for an age by diagnosis interaction in our current sample. Compared to healthy controls, HIV patients showed pervasive FA decreases and diffusivity increases throughout WM. We also assessed neuropsychological (NP) summary z-score associations. In both patients and controls, fiber integrity measures were associated with NP summary scores. The greatest differences were detected in the corpus callosum and in the projection fibers of the corona radiata. These deficits are consistent with published NP deficits and cortical atrophy patterns in elderly people with HIV.

Diffusion weighted magnetic resonance imaging (DW-MRI) are now widely used to assess brain integrity in clinical populations. The growing interest in mapping brain connectivity has made it vital to consider what scanning parameters affect the accuracy, stability, and signal-to-noise of diffusion measures. Trade-offs between scan parameters can only be optimized if their effects on various commonly-derived measures are better understood. To explore angular versus spatial resolution trade-offs in standard tensor-derived measures, and in measures that use the full angular information in diffusion signal, we scanned eight subjects twice, 2 weeks apart, using three protocols that took the same amount of time (7 min). Scans with 3.0, 2.7, 2.5 mm isotropic voxels were collected using 48, 41, and 37 diffusion-sensitized gradients to equalize scan times. A specially designed DTI phantom was also scanned with the same protocols, and different b-values. We assessed how several diffusion measures including fractional anisotropy (FA), mean diffusivity (MD), and the full 3D orientation distribution function (ODF) depended on the spatial/angular resolution and the SNR. We also created maps of stability over time in the FA, MD, ODF, skeleton FA of 14 TBSS-derived ROIs, and an information uncertainty index derived from the tensor distribution function, which models the signal using a continuous mixture of tensors. In scans of the same duration, higher angular resolution and larger voxels boosted SNR and improved stability over time. The increased partial voluming in large voxels also led to bias in estimating FA, but this was partially addressed by using "beyond-tensor" models of diffusion.

Multiple sclerosis (MS) is an inflammatory disorder of the central nervous system. By combining longitudinal MRI-based brain morphometry and brain age estimation using machine learning, we tested the hypothesis that MS patients have higher brain age relative to chronological age than healthy controls (HC) and that longitudinal rate of brain aging in MS patients is associated with clinical course and severity. Seventy-six MS patients [71% females, mean age 34.8 years (range 21-49) at inclusion] were examined with brain MRI at three time points with a mean total follow up period of 4.4 years (±0.4 years). We used additional cross-sectional MRI data from 235 HC for case-control comparison. We applied a machine learning model trained on an independent set of 3,208 HC to estimate individual brain age and to calculate the difference between estimated and chronological age, termed brain age gap (BAG). We also assessed the longitudinal change rate in BAG in individuals with MS. MS patients showed significantly higher BAG (4.4 ± 6.6 years) compared to HC (Cohen's D = 0.69, p = 4.0 × 10-6). Longitudinal estimates of BAG in MS patients showed high reliability and suggested an accelerated rate of brain aging corresponding to an annual increase of 0.41 (SE = 0.15) years compared to chronological aging (p = 0.008). Multiple regression analyses revealed higher rate of brain aging in patients with more brain atrophy (Cohen's D = 0.86, p = 4.3 × 10-15) and increased white matter lesion load (WMLL) (Cohen's D = 0.55, p = 0.015). On average, patients with MS had significantly higher BAG compared to HC. Progressive brain aging in patients with MS was related to brain atrophy and increased WMLL. No significant clinical associations were found in our sample, future studies are warranted on this matter. Brain age estimation is a promising method for evaluation of subtle brain changes in MS, which is important for predicting clinical outcome and guide choice of intervention.

Reduced telomere length (TL) and structural brain abnormalities have been reported in patients with schizophrenia (SZ) and bipolar disorder (BD). Childhood traumatic events are more frequent in SZ and BD than in healthy individuals (HC), and based on recent findings in healthy individuals could represent one important factor for TL and brain aberrations in patients. The study comprised 1024 individuals (SZ [n = 373]; BD [n = 249] and HC [n = 402]). TL was measured by quantitative polymerase chain reaction (qPCR), and childhood trauma was assessed using the Childhood Trauma Questionnaire (CTQ). Diagnosis was obtained by the Structured Clinical Interview (SCID) for the diagnostic and statistical manual of mental disorders-IV (DSM-IV). FreeSurfer was used to obtain regional and global brain volumes from T1-weighted magnetic resonance imaging (MRI) brain scans. All analyses were adjusted for current age and sex. Patients had on average shorter TL (F = 7.87, p = 0.005, Cohen's d = 0.17) and reported more childhood trauma experiences than HC (χ2 = 148.9, p < 0.001). Patients with a history of childhood sexual, physical or emotional abuse had shorter TL relative to HC and to patients without a history of childhood abuse (F = 6.93, p = 0.006, Cohen's d = 0.16). After adjusting for childhood abuse, no difference in TL was observed between patients and HC (p = 0.12). There was no statistically significant difference in reported childhood abuse exposure or TL between SZ and BD. Our analyses revealed no significant associations between TL and clinical characteristics or brain morphometry. We demonstrate shorter TL in SZ and BD compared with HC and showed that TL is sensitive to childhood trauma experiences. Further studies are needed to identify the biological mechanisms of this relationship.

Accurate outcome prediction models for patients with mild traumatic brain injury (MTBI) are key for prognostic assessment and clinical decision-making. Using multivariate machine learning, we tested the unique and added predictive value of (1) magnetic resonance imaging (MRI)-based brain morphometric and volumetric characterization at 4-week postinjury and (2) demographic, preinjury, injury-related, and postinjury variables on 12-month outcomes, including global functioning level, postconcussion symptoms, and mental health in patients with MTBI.

Sustained anabolic-androgenic steroid (AAS) use has adverse behavioral consequences, including aggression, violence and impulsivity. Candidate mechanisms include disruptions of brain networks with high concentrations of androgen receptors and critically involved in emotional and cognitive regulation. Here, we tested the effects of AAS on resting-state functional brain connectivity in the largest sample of AAS-users to date. We collected resting-state functional magnetic resonance imaging (fMRI) data from 151 males engaged in heavy resistance strength training. 50 users tested positive for AAS based on the testosterone to epitestosterone (T/E) ratio and doping substances in urine. 16 previous users and 59 controls tested negative. We estimated brain network nodes and their time-series using ICA and dual regression and defined connectivity matrices as the between-node partial correlations. In line with the emotional and behavioral consequences of AAS, current users exhibited reduced functional connectivity between key nodes involved in emotional and cognitive regulation, in particular reduced connectivity between the amygdala and default-mode network (DMN) and between the dorsal attention network (DAN) and a frontal node encompassing the superior and inferior frontal gyri (SFG/IFG) and the anterior cingulate cortex (ACC), with further reductions as a function of dependency, lifetime exposure, and cycle state (on/off).

Pregnancy involves maternal brain adaptations, but little is known about how parity influences women's brain aging trajectories later in life. In this study, we replicated previous findings showing less apparent brain aging in women with a history of childbirths, and identified regional brain aging patterns linked to parity in 19,787 middle- and older-aged women. Using novel applications of brain-age prediction methods, we found that a higher number of previous childbirths were linked to less apparent brain aging in striatal and limbic regions. The strongest effect was found in the accumbens-a key region in the mesolimbic reward system, which plays an important role in maternal behavior. While only prospective longitudinal studies would be conclusive, our findings indicate that subcortical brain modulations during pregnancy and postpartum may be traceable decades after childbirth.

The ratio of T1-weighted (T1w) and T2-weighted (T2w) magnetic resonance imaging (MRI) images is often used as a proxy measure of cortical myelin. However, the T1w/T2w-ratio is based on signal intensities that are inherently non-quantitative and known to be affected by extrinsic factors. To account for this a variety of processing methods have been proposed, but a systematic evaluation of their efficacy is lacking. Given the dependence of the T1w/T2w-ratio on scanner hardware and T1w and T2w protocols, it is important to ensure that processing pipelines perform well also across different sites.

Both neurodegenerative and neurodevelopmental abnormalities have been suggested to be part of the etiopathology of severe mental illness (SMI). Neuron-specific enolase (NSE), mainly located in the neuronal cytoplasm, may indicate the process as it is upregulated after neuronal injury while a switch from non-neuronal enolase to NSE occurs during neuronal maturation.

The lack of robust neuroanatomical markers of psychosis risk has been traditionally attributed to heterogeneity. A complementary hypothesis is that variation in neuroanatomical measures in the majority of individuals at psychosis risk may be nested within the range observed in healthy individuals.

The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group.

Narcolepsy type 1 (NT1) is a neurological sleep disorder. Postmortem studies have shown 75%-90% loss of the 50 000-70 000 hypocretin-producing neurons and 64%-94% increase in the 64 000-120 000 histaminergic neurons and conflicting indications of gliosis in the hypothalamus of NT1 patients. The aim of this study was to compare MRI-based volumes of the hypothalamus in patients with NT1 and controls in vivo.

It is unclear if and how exogenous oxytocin (OT) reaches the brain to improve social behavior and cognition and what is the optimal dose for OT response. To better understand the delivery routes of intranasal OT administration to the brain and the dose-response, we compared amygdala response to facial stimuli by means of functional magnetic resonance imaging (fMRI) in four treatment conditions, including two different doses of intranasal OT using a novel Breath Powered device, intravenous (IV) OT, which provided similar concentrations of blood plasma OT, and placebo. We adopted a randomized, double-blind, double-dummy, crossover design, with 16 healthy male adults administering a single-dose of these four treatments. We observed a treatment effect on right amygdala activation during the processing of angry and happy face stimuli, with pairwise comparisons revealing reduced activation after the 8IU low dose intranasal treatment compared to placebo. These data suggest the dampening of amygdala activity in response to emotional stimuli occurs via direct intranasal delivery pathways rather than across the blood-brain barrier via systemically circulating OT.