OBJECTIVE:Few studies have focused on brain structure in atypical anorexia nervosa (atypical AN). This study investigates differences in gray matter volume (GMV) between females with anorexia nervosa (AN) and atypical AN, and healthy controls (HC). METHOD:Structural magnetic resonance imaging data were acquired for 37 AN, 23 atypical AN, and 41 HC female participants. Freesurfer was used to extract GMV, cortical thickness, and surface area for six brain lobes and associated cortical regions of interest (ROI). Primary analyses employed linear mixed-effects models to compare group differences in lobar GMV, followed by secondary analyses on ROIs within significant lobes. We also explored relationships between cortical gray matter and both body mass index (BMI) and symptom severity. RESULTS:Our primary analyses revealed significant lower GMV in frontal, temporal and parietal areas (FDR < .05) in AN and atypical AN when compared to HC. Lobar GMV comparisons were non-significant between atypical AN and AN. The parietal lobe exhibited the greatest proportion of affected cortical ROIs in both AN versus HC and atypical AN versus HC. BMI, but not symptom severity, was found to be associated with cortical GMV in the parietal, frontal, temporal, and cingulate lobes. No significant differences were observed in cortical thickness or surface area. DISCUSSION:We observed lower GMV in frontal, temporal, and parietal areas, when compared to HC, but no differences between AN and atypical AN. This indicates potentially overlapping structural phenotypes between these disorders and evidence of brain changes among those who are not below the clinical underweight threshold. PUBLIC SIGNIFICANCE:Despite individuals with atypical anorexia nervosa presenting above the clinical weight threshold, lower cortical gray matter volume was observed in partial, temporal, and frontal cortices, compared to healthy individuals. No significant differences were found in cortical gray matter volume between anorexia nervosa and atypical anorexia nervosa. This underscores the importance of continuing to assess and target weight gain in clinical care, even for those who are presenting above the low-weight clinical criteria.

Pregnancy is a risk factor for increased severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other respiratory infections, but the mechanisms underlying this risk are poorly understood. To gain insight into the role of pregnancy in modulating immune responses at baseline and upon SARS-CoV-2 infection, we collected peripheral blood mononuclear cells and plasma from 226 women, including 152 pregnant individuals and 74 non-pregnant women. We find that SARS-CoV-2 infection is associated with altered T cell responses in pregnant women, including a clonal expansion of CD4-expressing CD8+ T cells, diminished interferon responses, and profound suppression of monocyte function. We also identify shifts in cytokine and chemokine levels in the sera of pregnant individuals, including a robust increase of interleukin-27, known to drive T cell exhaustion. Our findings reveal nuanced pregnancy-associated immune responses, which may contribute to the increased susceptibility of pregnant individuals to viral respiratory infection.

On average, healthy older adults prefer positive over neutral or negative stimuli. This positivity bias is related to memory and attention processes and is linked to the function and structure of several interconnected brain areas. However, the relationship between the positivity bias and white matter integrity remains elusive. The present study examines how white matter organization relates to the degree of the positivity bias among older adults. We collected imaging and behavioral data from 25 individuals (12 females, 13 males, and a mean age of 77.32). Based on a functional memory task, we calculated a Pos-Neg score , reflecting the memory for positively valenced information over negative information, and a Pos-Neu score , reflecting the memory for positively valenced information over neutral information. Diffusion-weighted magnetic resonance imaging data were processed using Tract-Based Spatial Statistics. We performed two non-parametric permutation tests to correlate whole brain white matter integrity and the Pos-Neg and Pos-Neu scores while controlling for age, sex, and years of education. We observed a statistically significant positive association between the Pos-Neu score and white matter integrity in multiple brain connections, mostly frontal. The results did not remain significant when including verbal episodic memory as an additional covariate. Our study indicates that the positivity bias in memory in older adults is associated with more organized white matter in the connections of the frontal brain. While these frontal areas are critical for memory and executive processes and have been related to pathological aging, more extensive studies are needed to fully understand their role in the positivity bias and the potential for therapeutic interventions.

BACKGROUND:Anorexia nervosa (AN) is a potentially fatal psychiatric condition, associated with structural brain changes such as gray matter volume loss. The pathophysiological mechanisms for these changes are not yet fully understood. Iron is a crucial element in the development and function of the brain. Considering the systemic alterations in iron homeostasis in AN, we hypothesized that brain iron would be altered as a possible factor associated with structural brain changes in AN.METHODS:In this study, we used quantitative susceptibility mapping (QSM) magnetic resonance imaging to investigate brain iron in current AN (c-AN) and weight-restored AN compared with healthy individuals. Whole-brain voxel wise comparison was used to probe areas with possible group differences. Further, the thalamus, caudate nucleus, putamen, nucleus accumbens, hippocampus, and amygdala were selected as the regions of interest (ROIs) for ROI-based comparison of mean QSM values.RESULTS:Whole-brain voxel-wise and ROI-based comparison of QSM did not reveal any differences between groups. Exploratory analyses revealed a correlation between higher regional QSM (higher iron) and lower body mass index, higher illness severity, longer illness duration, and younger age at onset in the c-AN group.CONCLUSIONS:This study did not find evidence of altered brain iron in AN compared to healthy individuals. However, the correlations between clinical variables and QSM suggest a link between brain iron and weight status or biological processes in AN, which warrants further investigation.

Studies applying Free Water Imaging have consistently reported significant global increases in extracellular free water (FW) in populations of individuals with early psychosis. However, these published studies focused on homogenous clinical participant groups (e.g., only first episode or chronic), thereby limiting our understanding of the time course of free water elevations across illness stages. Moreover, the relationship between FW and duration of illness has yet to be directly tested. Leveraging our multi-site diffusion magnetic resonance imaging(dMRI) harmonization approach, we analyzed dMRI scans collected by 12 international sites from 441 healthy controls and 434 individuals diagnosed with schizophrenia-spectrum disorders at different illness stages and ages (15–58 years). We characterized the pattern of age-related FW changes by assessing whole brain white matter in individuals with schizophrenia and healthy controls. In individuals with schizophrenia, average whole brain FW was higher than in controls across all ages, with the greatest FW values observed from 15 to 23 years (effect size range = [0.70–0.87]). Following this peak, FW exhibited a monotonic decrease until reaching a minima at the age of 39 years. After 39 years, an attenuated monotonic increase in FW was observed, but with markedly smaller effect sizes when compared to younger patients (effect size range = [0.32–0.43]). Importantly, FW was found to be negatively associated with duration of illness in schizophrenia ( p = 0.006), independent of the effects of other clinical and demographic data. In summary, our study finds in a large, age-diverse sample that participants with schizophrenia with a shorter duration of illness showed higher FW values compared to participants with more prolonged illness. Our findings provide further evidence that elevations in the FW are present in individuals with schizophrenia, with the greatest differences in the FW being observed in those at the early stages of the disorder, which might suggest acute extracellular processes.

OBJECTIVE:To investigate how the presence/side of hippocampal sclerosis (HS) are related to the white matter structure of cingulum bundle (CB), arcuate fasciculus (AF), and inferior longitudinal fasciculus (ILF) in mesial temporal lobe epilepsy (MTLE).METHODS:We acquired diffusion-weighted magnetic resonance imaging (MRI) from 86 healthy and 71 individuals with MTLE (22 righ-HS; right-HS, 34 left-HS; left-HS, and 15 nonlesional MTLE). We utilized two-tensor tractography and fiber clustering to compare fractional anisotropy (FA) of each side/tract between groups. Additionally, we examined the association between FA and nonverbal (WMS-R) and verbal (WMS-R, RAVLT codification) memory performance for MTLE individuals.RESULTS:White matter abnormalities depended on the side and presence of HS. The left-HS demonstrated widespread abnormalities for all tracts, the right-HS showed lower FA for ipsilateral tracts and the nonlesional MTLE group did not differ from healthy individuals. Results indicate no differences in verbal/nonverbal memory performance between the groups, but trend-level associations between higher FA of visual memory and the left CB (r = 0.286, P = 0.018), verbal memory (RAVLT) and -left CB (r = 0.335, P = 0.005), -right CB (r = 0.286, P = 0.016), and -left AF (r = 0.287, P = 0.017).SIGNIFICANCE:Our results highlight that the presence and side of HS are crucial to understand the pathophysiology of MTLE. Specifically, left-sided HS seems to be related to widespread bilateral white matter abnormalities. Future longitudinal studies should focus on developing diagnostic and treatment strategies dependent on HS's presence/side.

BACKGROUND AND PURPOSE: While brain iron dysregulation has been observed in several neurodegenerative disorders, its association with the progressive neurodegeneration in Niemann-Pick type C is unknown. Systemic iron abnormalities have been reported in patients with Niemann-Pick type C and in animal models of Niemann-Pick type C. In this study, we examined brain iron using quantitative susceptibility mapping MR imaging in individuals with Niemann-Pick type C compared with healthy controls. MATERIALS AND METHODS: A cohort of 10 patients with adolescent- and adult-onset Niemann-Pick type C and 14 age- and sex-matched healthy controls underwent 7T brain MR imaging with T1 and quantitative susceptibility mapping acquisitions. A probing whole-brain voxelwise comparison of quantitative susceptibility mapping between groups was conducted. Mean quantitative susceptibility mapping in the ROIs (thalamus, hippocampus, putamen, caudate nucleus, and globus pallidus) was further compared. The correlations between regional volume, quantitative susceptibility mapping values, and clinical features, which included disease severity on the Iturriaga scale, cognitive function, and the Social and Occupational Functioning Assessment Scale, were explored as secondary analyses. RESULTS: We observed lower volume in the thalamus and voxel clusters of higher quantitative susceptibility mapping in the pulvinar nuclei bilaterally in patients with Niemann-Pick type C compared with the control group. In patients with Niemann-Pick type C, higher quantitative susceptibility mapping in the pulvinar nucleus clusters correlated with lower volume of the thalamus on both sides. Moreover, higher quantitative susceptibility mapping in the right pulvinar cluster was associated with greater disease severity. CONCLUSIONS: Our findings suggest iron deposition in the pulvinar nucleus in Niemann-Pick type C disease, which is associated with thalamic atrophy and disease severity. This preliminary evidence supports the link between iron and neurodegeneration in Niemann-Pick type C, in line with existing literature on other neurodegenerative disorders.

Background While adolescent-onset schizophrenia (ADO-SCZ) and adolescent-onset bipolar disorder with psychosis (psychotic ADO-BPD) present a more severe clinical course than their adult forms, their pathophysiology is poorly understood. Here, we study potentially state- and trait-related white matter diffusion-weighted magnetic resonance imaging (dMRI) abnormalities along the adolescent-onset psychosis continuum to address this need. Methods Forty-eight individuals with ADO-SCZ (20 female/28 male), 15 individuals with psychotic ADO-BPD (7 female/8 male), and 35 healthy controls (HCs, 18 female/17 male) underwent dMRI and clinical assessments. Maps of extracellular free-water (FW) and fractional anisotropy of cellular tissue (FA(T)) were compared between individuals with psychosis and HCs using tract-based spatial statistics and FSL's Randomise. FA(T) and FW values were extracted, averaged across all voxels that demonstrated group differences, and then utilized to test for the influence of age, medication, age of onset, duration of illness, symptom severity, and intelligence. Results Individuals with adolescent-onset psychosis exhibited pronounced FW and FA(T) abnormalities compared to HCs. FA(T) reductions were spatially more widespread in ADO-SCZ. FW increases, however, were only present in psychotic ADO-BPD. In HCs, but not in individuals with adolescent-onset psychosis, FA(T) was positively related to age. Conclusions We observe evidence for cellular (FA(T)) and extracellular (FW) white matter abnormalities in adolescent-onset psychosis. Although cellular white matter abnormalities were more prominent in ADO-SCZ, such alterations may reflect a shared trait, i.e. neurodevelopmental pathology, present across the psychosis spectrum. Extracellular abnormalities were evident in psychotic ADO-BPD, potentially indicating a more dynamic, state-dependent brain reaction to psychosis.

Research suggests electroconvulsive therapy (ECT) induces an acute neuroinflammatory response and changes in white matter (WM) structural connectivity. However, whether these processes are related, either to each other or to eventual treatment outcomes, has yet to be determined. We examined the relationship between levels of peripheral pro-inflammatory cytokines and diffusion imaging-indexed changes in WM microstructure in individuals with treatment-resistant depression (TRD) who underwent ECT. Forty-two patients were assessed at baseline, after their second ECT (T2), and after completion of ECT (T3). A Montgomery Åsberg Depression Rating Scale improvement of >50% post-ECT defined ECT-responders ( n = 19) from non-responders ( n = 23). Thirty-four controls were also examined. Tissue-specific fractional anisotropy (FAt) was estimated using diffusion imaging data and the Free-Water method in 17 WM tracts. Inflammatory panels were evaluated from peripheral blood. Cytokines were examined to characterize the association between potential ECT-induced changes in an inflammatory state and WM microstructure. Longitudinal trajectories of both measures were also examined separately for ECT-responders and non-responders. Patients exhibited elevated Interleukin-8 (IL-8) levels at baseline compared to controls. In patients, correlations between IL-8 and FAt changes from baseline to T2 were significant in the positive direction in the right superior longitudinal fasciculus (R-SLF) and right cingulum (R-CB) ( p sig = 0.003). In these tracts, linear mixed-effects models revealed that trajectories of IL-8 and FAt were significantly positively correlated across all time points in responders, but not non-responders (R-CB-p = .001; R-SLF-p = 0.008). Our results suggest that response to ECT in TRD may be mediated by IL-8 and WM microstructure.

Brain morphology differs markedly between individuals with schizophrenia, but the cellular and genetic basis of this heterogeneity is poorly understood. Here, we sought to determine whether cortical thickness (CTh) heterogeneity in schizophrenia relates to interregional variation in distinct neural cell types, as inferred from established gene expression data and person-specific genomic variation. This study comprised 1849 participants in total, including a discovery (140 cases and 1267 controls) and a validation cohort (335 cases and 185 controls). To characterize CTh heterogeneity, normative ranges were established for 34 cortical regions and the extent of deviation from these ranges was measured for each individual with schizophrenia. CTh deviations were explained by interregional gene expression levels of five out of seven neural cell types examined: (1) astrocytes; (2) endothelial cells; (3) oligodendrocyte progenitor cells (OPCs); (4) excitatory neurons; and (5) inhibitory neurons. Regional alignment between CTh alterations with cell type transcriptional maps distinguished broad patient subtypes, which were validated against genomic data drawn from the same individuals. In a predominantly neuronal/endothelial subtype (22% of patients), CTh deviations covaried with polygenic risk for schizophrenia (sczPRS) calculated specifically from genes marking neuronal and endothelial cells ( r = −0.40, p = 0.010). Whereas, in a predominantly glia/OPC subtype (43% of patients), CTh deviations covaried with sczPRS calculated from glia and OPC-linked genes ( r = −0.30, p = 0.028). This multi-scale analysis of genomic, transcriptomic, and brain phenotypic data may indicate that CTh heterogeneity in schizophrenia relates to inter-individual variation in cell-type specific functions. Decomposing heterogeneity in relation to cortical cell types enables prioritization of schizophrenia subsets for future disease modeling efforts.

Brain iron is central to dopaminergic neurotransmission, a key component in schizophrenia pathology. Iron can also generate oxidative stress, which is one proposed mechanism for gray matter volume reduction in schizophrenia. The role of brain iron in schizophrenia and its potential link to oxidative stress has not been previously examined. In this study, we used 7-Tesla MRI quantitative susceptibility mapping (QSM), magnetic resonance spectroscopy (MRS), and structural T 1 imaging in 12 individuals with chronic schizophrenia and 14 healthy age-matched controls. In schizophrenia, there were higher QSM values in bilateral putamen and higher concentrations of phosphocreatine and lactate in caudal anterior cingulate cortex (caCC). Network-based correlation analysis of QSM across corticostriatal pathways as well as the correlation between QSM, MRS, and volume, showed distinct patterns between groups. This study introduces increased iron in the putamen in schizophrenia in addition to network-wide disturbances of iron and metabolic status.

OBJECTIVES:Disrupted auditory networks play an important role in the pathophysiology of psychosis, with abnormalities already observed in individuals at clinical high-risk for psychosis (CHR). Here, we examine structural and functional connectivity of an auditory network in CHR utilising state-of-the-art electroencephalography and diffusion imaging techniques.METHODS:Twenty-six CHR subjects and 13 healthy controls (HC) underwent diffusion MRI and electroencephalography while performing an auditory task. We investigated structural connectivity, measured as fractional anisotropy in the Arcuate Fasciculus (AF), Cingulum Bundle, and Superior Longitudinal Fasciculus-II. Gamma-band lagged-phase synchronisation, a functional connectivity measure, was calculated between cortical regions connected by these tracts.RESULTS:CHR subjects showed significantly higher structural connectivity in the right AF than HC (p < .001). Although non-significant, functional connectivity between cortical areas connected by the AF was lower in CHR than HC (p = .078). Structural and functional connectivity were correlated in HC (p = .056) but not in CHR (p = .29).CONCLUSIONS:We observe significant differences in structural connectivity of the AF, without a concomitant significant change in functional connectivity in CHR subjects. This may suggest that the CHR state is characterised by a decoupling of structural and functional connectivity, possibly due to abnormal white matter maturation.

Abstract Studies applying Free Water Imaging have consistently reported significant global increases in extracellular FW in populations of individuals with early psychosis. However, these published studies focused on homogenous clinical participant groups (e.g., only first episode or chronic), thereby limiting our understanding of the time course of free water (FW) elevations across illness stages. Moreover, the relationship between FW and duration of illness has yet to be directly tested. Leveraging our multi-site diffusion magnetic resonance imaging(dMRI) harmonization approach, we analyzed dMRI scans collected by 12 international sites from 441 healthy controls and 434 individuals diagnosed with schizophrenia-spectrum disorders who represent different illness stages and ages (15–58 years). We characterized the pattern of age-related FW changes by assessing whole brain white matter in individuals with schizophrenia and healthy controls. Quadratic and non-parametric curves were used to model between-group FW differences in averaged whole brain white matter. In individuals with schizophrenia, whole brain FW was higher than in controls across all ages, with the greatest FW values observed from 15 to 23 years of age (effect size range= [0.70-0.87]). Following this peak, FW exhibited a monotonic decrease until reaching a minima at the age of 39 years. After 39 years of age, an attenuated monotonic increase in FW was observed, but with markedly lower effect sizes when compared to younger patients (effect size range = [0.32-0.43]). Importantly, FW was found to be negatively associated with duration of illness in schizophrenia (p=0.006), independent of the effects of age. In summary, our study finds in a large, age-diverse sample that participants with schizophrenia with a shorter duration of illness showed higher FW values compared to participants with more prolonged illness. Our findings indicate that FW might be a reliable imaging marker of acute, extracellular processes which appear to occur predominantly in the early stages of schizophrenia.

Cognitive deficits are among the best predictors of real-world functioning in schizophrenia. However, our understanding of how cognitive deficits relate to neuropathology and clinical presentation over the disease lifespan is limited. Here, we combine multi-site, harmonized cognitive, imaging, demographic, and clinical data from over 900 individuals to characterize a) cognitive deficits across the schizophrenia lifespan and b) the association between cognitive deficits, clinical presentation, and white matter (WM) microstructure. Multimodal harmonization was accomplished using T-scores for cognitive data, previously reported standardization methods for demographic and clinical data, and an established harmonization method for imaging data. We applied t-tests and correlation analysis to describe cognitive deficits in individuals with schizophrenia. We then calculated whole-brain WM fractional anisotropy (FA) and utilized regression-mediation analyses to model the association between diagnosis, FA, and cognitive deficits. We observed pronounced cognitive deficits in individuals with schizophrenia (p < 0.006), associated with more positive symptoms and medication dosage. Regression-mediation analyses showed that WM microstructure mediated the association between schizophrenia and language/processing speed/working memory/non-verbal memory. In addition, processing speed mediated the influence of diagnosis and WM microstructure on the other cognitive domains. Our study highlights the critical role of cognitive deficits in schizophrenia. We further show that WM is crucial when trying to understand the role of cognitive deficits, given that it explains the association between schizophrenia and cognitive deficits (directly and via processing speed).

Research examining volume in the basal ganglia (BG) (caudate, putamen, nucleus accumbens, and pallidum) in restrictive eating disorders (R-ED) has shown mixed results. However, aggregate measures of volume do not capture the complexity and location of tissue loss. High-dimensional shape descriptors can overcome these limitations but have not been applied to R-EDs. We analyzed BG subregion volume/shape in R-EDs, hypothesizing that R-EDs would show lower volume and a greater percentage of shape deformations in the putamen compared to healthy controls (HC).

BackgroundAlterations in the peripheral inflammatory profile and white matter (WM) deterioration are frequent in Major Depressive Disorder (MDD). The present study applies free-water imaging to investigate the relationship between altered peripheral inflammation and WM microstructure and their predictive value in determining response to ketamine treatment in MDD.MethodsTen individuals with MDD underwent diffusion-weighted magnetic resonance imaging and a blood-draw before and 24 h after ketamine infusion. We utilized MANCOVAs and ANCOVAs to compare tissue-specific fractional anisotropy (FAT) and free-water (FW) of the forceps and cingulum, and the ratio of pro-inflammatory interleukin(IL)-8/anti-inflammatory IL-10 between individuals with MDD and 15 healthy controls at baseline. Next, we compared all baseline measures between ketamine responders (6) and non-responders (4) and analyzed changes in imaging and blood data after ketamine infusion.ResultsThe MDD group exhibited an increased IL-8/IL-10 ratio compared to controls at baseline (p = .040), which positively correlated with average FW across regions of interest (p = .013). Ketamine responders demonstrated higher baseline FAT in the left cingulum than non-responders (p = .023). Ketamine infusion did not influence WM microstructure but decreased the IL-8/IL-10 ratio (p = .043).LimitationsThe small sample size and short follow-up period limit the conclusion regarding the longer-term effects of ketamine in MDD.ConclusionsThis pilot study provides evidence for the role of inflammation in MDD by illustrating an association between peripheral inflammation and WM microstructure. Additionally, we demonstrate that free-water diffusion-weighted imaging might be a valuable tool to determine which individuals with MDD benefit from the anti-inflammatory mediated effects of ketamine treatment.