Lower region-specific gray matter volume in females with atypical anorexia nervosa and anorexia nervosa.

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.

More organized white matter is associated with positivity bias in older adults.

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.

Investigation of brain iron in anorexia nervosa, a quantitative susceptibility mapping study.

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.

Exploring the impact of hippocampal sclerosis on white matter tracts and memory in individuals with mesial temporal lobe epilepsy.

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.

Characterization of the extracellular free water signal in schizophrenia using multi-site diffusion MRI harmonization.

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.

Shared and distinct white matter abnormalities in adolescent-onset schizophrenia and adolescent-onset psychotic bipolar disorder.

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 (FAT) were compared between individuals with psychosis and HCs using tract-based spatial statistics and FSL's Randomise. FAT 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 FAT abnormalities compared to HCs. FAT 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, FAT was positively related to age. CONCLUSIONS: We observe evidence for cellular (FAT) 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.

The decoupling of structural and functional connectivity of auditory networks in individuals at clinical high-risk for psychosis.

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.

In Vivo 7-Tesla MRI Investigation of Brain Iron and Its Metabolic Correlates in Chronic Schizophrenia.

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 T1 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.

Cognitive deficits, clinical variables, and white matter microstructure in schizophrenia: a multisite harmonization study.

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).

Association between peripheral inflammation and free-water imaging in Major Depressive Disorder before and after ketamine treatment - A pilot study.

BACKGROUND: Alterations 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. METHODS: Ten 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. RESULTS: The 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). LIMITATIONS: The small sample size and short follow-up period limit the conclusion regarding the longer-term effects of ketamine in MDD. CONCLUSIONS: This 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.

Longitudinal trajectory of response to electroconvulsive therapy associated with transient immune response & white matter alteration post-stimulation.

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) (psig = 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.

Cell type-specific manifestations of cortical thickness heterogeneity in schizophrenia.

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.

Meta-analysis of structural MRI studies in anorexia nervosa and the role of recovery: a systematic review protocol.

BACKGROUND: Anorexia nervosa (AN) is associated with structural brain abnormalities. Studies have reported less cerebral tissue and more cerebrospinal fluid (CSF) in individuals with AN relative to healthy controls, although findings are variable and inconsistent due to variations in sample size, age, and disease state (e.g., active AN, weight-recovered AN). Further, it remains unclear if structural brain abnormalities observed in AN are a consequence of specific brain pathologies or malnutrition, as very few longitudinal neuroimaging studies in AN have been completed. METHODS: To overcome this issue, this comprehensive meta-analysis will combine region-of-interest (ROI) and voxel-based morphometry (VBM) approaches to understand how regional and global structural brain abnormalities differ among individuals with AN and healthy controls (HCs). Additionally, we aim to understand how clinical characteristics and physiological changes during the course of illness, including acute illness vs. weight recovery, may moderate these structural abnormalities. We will create an online database of studies that have investigated structural brain abnormalities in AN. Data will be reviewed independently by two members of our team using MEDLINE databases, Web of Science, PsycINFO, EMBASE, and CINAHL. We will conduct ROI and VBM meta-analysis using seed-based d mapping in AN and HCs. We will include all studies that include structural neuroimaging of individuals with AN (both acute and weight-recovered) and HCs between January 1997 and 2020. DISCUSSION: This systematic review will assess the effects of AN compared to HC on brain structure. Futhermore, it will explore the role of acute AN and weight-recovered AN on brain structure. Findings will help researchers and clinicians to better understand the course of illness in AN and the nature of recovery, in terms of weight, malnutrition, and the state of the brain. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020180921.

Sex-Related Differences in White Matter Asymmetry and Its Implications for Verbal Working Memory in Psychosis High-Risk State.

Objective: Sexual dimorphism has been investigated in schizophrenia, although sex-specific differences among individuals who are at clinical high-risk (CHR) for developing psychosis have been inconclusive. This study aims to characterize sexual dimorphism of language areas in the brain by investigating the asymmetry of four white matter tracts relevant to verbal working memory in CHR patients compared to healthy controls (HC). HC typically show a leftward asymmetry of these tracts. Moreover, structural abnormalities in asymmetry and verbal working memory dysfunctions have been associated with neurodevelopmental abnormalities and are considered core features of schizophrenia. Methods: Twenty-nine subjects with CHR (17 female/12 male) for developing psychosis and twenty-one HC (11 female/10 male) matched for age, sex, and education were included in the study. Two-tensor unscented Kalman filter tractography, followed by an automated, atlas-guided fiber clustering approach, were used to identify four fiber tracts related to verbal working memory: the superior longitudinal fasciculi (SLF) I, II and III, and the superior occipitofrontal fasciculus (SOFF). Using fractional anisotropy (FA) of tissue as the primary measure, we calculated the laterality index for each tract. Results: There was a significantly greater right>left asymmetry of the SLF-III in CHR females compared to HC females, but no hemispheric difference between CHR vs. HC males. Moreover, the laterality index of SLF-III for CHR females correlated negatively with Backward Digit Span performance, suggesting a greater rightward asymmetry was associated with poorer working memory functioning. Conclusion: This study suggests increased rightward asymmetry of the SLF-III in CHR females. This finding of sexual dimorphism in white matter asymmetry in a language-related area of the brain in CHR highlights the need for a deeper understanding of the role of sex in the high-risk state. Future work investigating early sex-specific pathophysiological mechanisms, may lead to the development of novel personalized treatment strategies aimed at preventing transition to a more chronic and difficult-to-treat disorder.

Improving the predictive potential of diffusion MRI in schizophrenia using normative models-Towards subject-level classification.

Diffusion MRI studies consistently report group differences in white matter between individuals diagnosed with schizophrenia and healthy controls. Nevertheless, the abnormalities found at the group-level are often not observed at the individual level. Among the different approaches aiming to study white matter abnormalities at the subject level, normative modeling analysis takes a step towards subject-level predictions by identifying affected brain locations in individual subjects based on extreme deviations from a normative range. Here, we leveraged a large harmonized diffusion MRI dataset from 512 healthy controls and 601 individuals diagnosed with schizophrenia, to study whether normative modeling can improve subject-level predictions from a binary classifier. To this aim, individual deviations from a normative model of standard (fractional anisotropy) and advanced (free-water) dMRI measures, were calculated by means of age and sex-adjusted z-scores relative to control data, in 18 white matter regions. Even though larger effect sizes are found when testing for group differences in z-scores than are found with raw values (p < .001), predictions based on summary z-score measures achieved low predictive power (AUC < 0.63). Instead, we find that combining information from the different white matter tracts, while using multiple imaging measures simultaneously, improves prediction performance (the best predictor achieved AUC = 0.726). Our findings suggest that extreme deviations from a normative model are not optimal features for prediction. However, including the complete distribution of deviations across multiple imaging measures improves prediction, and could aid in subject-level classification.

White matter changes in psychosis risk relate to development and are not impacted by the transition to psychosis.

Subtle alterations in white matter microstructure are observed in youth at clinical high risk (CHR) for psychosis. However, the timing of these changes and their relationships to the emergence of psychosis remain unclear. Here, we track the evolution of white matter abnormalities in a large, longitudinal cohort of CHR individuals comprising the North American Prodrome Longitudinal Study (NAPLS-3). Multi-shell diffusion magnetic resonance imaging data were collected across multiple timepoints (1-5 over 1 year) in 286 subjects (aged 12-32 years): 25 CHR individuals who transitioned to psychosis (CHR-P; 61 scans), 205 CHR subjects with unknown transition outcome after the 1-year follow-up period (CHR-U; 596 scans), and 56 healthy controls (195 scans). Linear mixed effects models were fitted to infer the impact of age and illness-onset on variation in the fractional anisotropy of cellular tissue (FAT) and the volume fraction of extracellular free water (FW). Baseline measures of white matter microstructure did not differentiate between HC, CHR-U and CHR-P individuals. However, age trajectories differed between the three groups in line with a developmental effect: CHR-P and CHR-U groups displayed higher FAT in adolescence, and 4% lower FAT by 30 years of age compared to controls. Furthermore, older CHR-P subjects (20+ years) displayed 4% higher FW in the forceps major (p < 0.05). Prospective analysis in CHR-P did not reveal a significant impact of illness onset on regional FAT or FW, suggesting that transition to psychosis is not marked by dramatic change in white matter microstructure. Instead, clinical high risk for psychosis-regardless of transition outcome-is characterized by subtle age-related white matter changes that occur in tandem with development.

Cellular and extracellular white matter alterations indicate conversion to psychosis among individuals at clinical high-risk for psychosis.

OBJECTIVES: It is important to find biomarkers associated with transition to illness in individuals at clinical high-risk for psychosis (CHR). Here, we use free-water imaging, an advanced diffusion MRI technique, to identify white matter alterations in the brains of CHR subjects who subsequently develop psychosis (CHR-P) compared to those who do not (CHR-NP). METHODS: Twenty-four healthy controls (HC) and 30 CHR individuals, 8 of whom converted to schizophrenia after a mean follow-up of 15.16 months, received baseline MRI scans. Maps of fractional anisotropy (FA), FA of cellular tissue (FAT), and extracellular free-water (FW) were extracted using tract-based spatial statistics after which voxel-wise non-parametric group statistics and correlations with symptom severity were performed. RESULTS: There were no significant differences between HCs and the combined CHR group. However, prior to conversion, CHR-P showed widespread lower FA compared to CHR-NP (pFWE < 0.05). FA changes in CHR-P were associated with significantly lower FAT and higher FW, compared to CHR-NP. Positive symptoms correlated significantly with diffusion parameters in similar regions as those discriminating CHR-P from CHR-NP. CONCLUSIONS: Our study suggests that cellular (FAT) and extracellular (FW) white matter alterations are associated with positive symptom severity and indicate an elevated illness risk among CHR individuals.

A 16-week randomized placebo-controlled trial investigating the effects of omega-3 polyunsaturated fatty acid treatment on white matter microstructure in recent-onset psychosis patients concurrently treated with risperidone.

We examined the impact of treatment with fish oil (FO), a rich source of omega-3 polyunsaturated fatty acids (n-3 PUFA), on white matter in 37 recent-onset psychosis patients receiving risperidone in a double-blind placebo-controlled randomized clinical trial. Patients were scanned at baseline and randomly assigned to receive 16-weeks of treatment with risperidone + FO or risperidone + placebo. Eighteen patients received follow-up MRIs (FO, n = 10/Placebo, n = 8). Erythrocyte levels of n-3 PUFAs eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and docosapentaenoic acid (DPA) were obtained at both time points. We employed Free Water Imaging metrics representing the extracellular free water fraction (FW) and fractional anisotropy of the tissue (FA-t). Analyses were conducted using Tract-Based-Spatial-Statistics and nonparametric permutation-based tests with family-wise error correction. There were significant positive correlations of FA-t with DHA and DPA among all patients at baseline. Patients treated with risperidone + placebo demonstrated reductions in FA-t and increases in FW, whereas patients treated with risperidone + FO exhibited no significant changes in FW and FA-t reductions were largely attenuated. The correlations of DPA and DHA with baseline FA-t support the hypothesis that n-3 PUFA intake or biosynthesis are associated with white matter abnormalities in psychosis. Adjuvant FO treatment may partially mitigate against white matter alterations observed in recent-onset psychosis patients following risperidone treatment.

Studying pre-treatment and ketamine-induced changes in white matter microstructure in the context of ketamine's antidepressant effects.

Ketamine is increasingly being used as a therapeutic for treatment-resistant depression (TRD), yet the effects of ketamine on the human brain remain largely unknown. This pilot study employed diffusion magnetic resonance imaging (dMRI) to examine relationships between ketamine treatment and white matter (WM) microstructure, with the aim of increasing the current understanding of ketamine's neural mechanisms of action in humans. Longitudinal dMRI data were acquired from 13 individuals with TRD two hours prior to (pre-infusion), and four hours following (post-infusion), an intravenous ketamine infusion. Free-water imaging was employed to quantify cerebrospinal fluid-corrected mean fractional anisotropy (FA) in 15 WM bundles pre- and post-infusion. Analyses revealed that higher pre-infusion FA in the left cingulum bundle and the left superior longitudinal fasciculus was associated with greater depression symptom improvement 24 h post-ketamine. Moreover, four hours after intravenous administration of ketamine, FA rapidly increased in numerous WM bundles in the brain; this increase was significantly associated with 24 h symptom improvement in select bundles. Overall, the results of this preliminary study suggest that WM properties, as measured by dMRI, may have a potential impact on clinical improvement following ketamine. Ketamine administration additionally appears to be associated with rapid WM diffusivity changes, suggestive of rapid changes in WM microstructure. This study thus points to pre-treatment WM structure as a potential factor associated with ketamine's clinical efficacy, and to post-treatment microstructural changes as a candidate neuroimaging marker of ketamine's cellular mechanisms.

Quantifying Genetic and Environmental Influence on Gray Matter Microstructure Using Diffusion MRI.

Early neuroimaging work in twin studies focused on studying genetic and environmental influence on gray matter macrostructure. However, it is also important to understand how gray matter microstructure is influenced by genes and environment to facilitate future investigations of their influence in mental disorders. Advanced diffusion MRI (dMRI) measures allow more accurate assessment of gray matter microstructure compared with conventional diffusion tensor measures. To understand genetic and environmental influence on gray matter, we used diffusion and structural MRI data from a large twin and sibling study (N = 840) and computed advanced dMRI measures including return to origin probability (RTOP), which is heavily weighted toward intracellular and intra-axonal restricted spaces, and mean squared displacement (MSD), more heavily weighted to diffusion in extracellular space and large cell bodies in gray matter. We show that while macrostructural features like brain volume are mainly genetically influenced, RTOP and MSD can together tap into both genetic and environmental influence on microstructure.