PURPOSE:Diffusion MRI is widely used to characterize tissue microstructure, but standardization remains challenging, particularly for advanced models or regions with crossing fibers. Phantoms provide controlled environments to assess measurement repeatability independent of biological variability. This study evaluated the repeatability of higher-order diffusion tensor metrics using a novel anisotropic diffusion phantom designed to mimic white matter tract geometry. METHODS:The phantom, containing linear, crossing (30°, 45°, 90°), and bifurcating synthetic fiber bundles, was scanned seven times using a GE Healthcare 3.0 T MRI system. Four acquisition protocols were evaluated: 30-direction DTI (b = 1000s/mm2), 60 and 90-direction High Angular Resolution Diffusion Imaging (HARDI; b = 1300s/mm2), and 30-direction Diffusion Kurtosis Imaging (DKI; b = 250, 500, 750, 1000, 1500, 2000, 2500, 3000 s/mm2). Repeatability was quantified using coefficient of variation (CoV) and intraclass correlation coefficient (ICC) for scalar diffusion metrics across six regions of interest. Fiber orientation distribution functions (fODFs) were analyzed to assess crossing fiber resolution accuracy. RESULTS:DTI-derived metrics demonstrated excellent repeatability, with fractional anisotropy (FA) CoV < 10% and mean, axial, and radial diffusivities < 3%. DKI-derived metrics exhibited greater variability, though kurtosis FA remained stable (CoV ∼7%). Generalized FA showed improved reliability with increased angular resolution (ICC = 0.8445 for 90-direction HARDI). fODFs accurately resolved crossing fibers at 90° (RMSE = 3.49°) and 45° (RMSE = 8.92°) but failed at 30° separation. CONCLUSION:The phantom provides reliable repeatability for standard DTI metrics and demonstrates utility for quality assurance of advanced diffusion models with high angular resolution protocols.

Impaired insight into illness occurs in up to 98% of patients with schizophrenia, depending on the stage of illness, and leads to negative clinical outcomes. Previous neuroimaging studies suggest that impaired insight in patients with schizophrenia may be related to structural and functional anomalies in frontoparietal brain regions. To date, limited studies have investigated the association between regional cerebral blood flow (CBF) and impaired insight in schizophrenia. Therefore, we sought to investigate the relationship between regional CBF, as measured by arterial spin labeling (ASL), and impaired insight in participants with schizophrenia. A total of 32 participants were included in the analysis. Impaired insight in patients with schizophrenia was measured using the VAGUS, Self-report (VAGUS-SR). Resting-state regional CBF was measured using pseudo-continuous ASL (pCASL) and extracted using SPM12 and REX toolbox. Whole brain analysis found that impaired insight was associated with higher regional CBF in the right angular gyrus, left supramarginal gyrus, and right superior frontal region when controlling for age, gender, smoking status, and illness severity. The results indicate that impaired insight in schizophrenia is related to regional CBF in frontoparietal areas. These neuroimaging findings can serve as therapeutic targets for intervention, such as with non-invasive brain stimulation.

Introduction: In epidemiological studies, people who use cannabis have a lower prevalence of obesity. Furthermore, the endocannabinoid system is recognized as a potential target for obesity treatment and partial agonism of the cannabinoid type-1 (CB1) receptor may reduce body weight. We thus hypothesized that 12 weeks of pharmacotherapy with the partial CB1 receptor agonist nabilone would reduce body weight, relative to placebo, in adults with obesity. Methods: We conducted a randomized, double-blind, placebo-controlled pilot clinical trial that investigated the feasibility, tolerability, and efficacy of 12 weeks of treatment with nabilone compared with placebo in adults with obesity. Otherwise healthy adults aged 25-45 years with obesity were randomized in a 1:1:1 ratio to one of three parallel treatment arms: high-dose nabilone (6 mg/day), low-dose nabilone (2 mg/day), or placebo. Safety and feasibility outcomes included adverse events (AEs), number of dropouts, and medication adherence per treatment arm. Efficacy outcomes included body weight, body mass index (BMI), and waist circumference. Secondary outcomes included gut microbiome changes, blood biomarkers (e.g., glucose and insulin levels), and mood. Results: Overall, 18 participants were randomized and 15 participants received at least one dose of drug (4 high-dose arm, 5 low-dose arm, 6 placebo). The trial was terminated early due to poor tolerability of the medication (e.g., all four participants allocated to high-dose nabilone withdrew due to AEs). Only eight participants completed per protocol (four in the low-dose arm and four in the placebo arm). Using data from completers only (n = 8), we saw a significant treatment effect on body weight (p < 0.001) and BMI (p < 0.001) that appeared to be driven by greater decreases in the low-dose arm (n = 4) relative to placebo (n = 4). Based on the Bray-Curtis dissimilarity, the low-dose arm showed a greater change in the overall fecal microbiome composition compared with the placebo arm (p < 0.05). Discussion: This pilot trial found poor tolerability of nabilone pharmacotherapy (especially at 6 mg/day) for adults with obesity who had not used any cannabinoid drugs for 6 months prior to enrolment. Preliminary results suggest a possible impact of nabilone on the gut microbiome.

Adolescence is a sensitive developmental period for neural sex/gender differentiation. The present study used multiparametric mapping to better characterize adolescent white matter (WM) microstructure. WM microstructure was investigated using diffusion tensor indices (fractional anisotropy; mean, radial, and axial diffusivity [AD]) and quantitative T1 relaxometry (T1) in hormone therapy naïve adolescent cisgender girls, cisgender boys, and transgender boys (i.e., assigned female at birth and diagnosed with gender dysphoria). Diffusion indices were first analyzed for group differences using tract-based spatial statistics, which revealed a group difference in AD. Thus, two multiparametric and multivariate analyses assessed AD in conjunction with T1 relaxation time, and with respect to developmental proxy variables (i.e., age, serum estradiol, pubertal development, sexual attraction) thought to be relevant to adolescent brain development. The multivariate analyses showed a shared pattern between AD and T1 such that higher AD was associated with longer T1, and AD and T1 strongly related to all five developmental variables in cisgender boys (10 significant correlations, r range: 0.21-0.73). There were fewer significant correlations between the brain and developmental variables in cisgender girls (three correlations, r range: -0.54-0.54) and transgender boys (two correlations, r range: -0.59-0.77). Specifically, AD related to direction of sexual attraction (i.e., gynephilia, androphilia) in all groups, and T1 related to estradiol inversely in cisgender boys compared with transgender boys. These brain patterns may be indicative of less myelination and tissue density in cisgender boys, which corroborates other reports of protracted WM development in cisgender boys. Further, these findings highlight the importance of considering developmental trajectory when assessing the subtleties of neural structure associated with variations in sex, gender, and sexual attraction.

In lieu of the conventional lymphatic system, the human brain possesses a glial-dependent waste drainage pathway called the glymphatic system. Notably, a compromised glymphatic system can be reflected via the accumulation of waste materials in the brain as observed in aging, neurodegeneration, and neurovascular diseases. Despite genetic, metabolic-vascular and neuroimaging evidence suggesting disrupted glymphatic system in schizophrenia, our previous proton magnetic resonance spectroscopy (1H-MRS) study did not find elevated macromolecule (MM) in patients with schizophrenia versus healthy controls. The present analysis investigates MM aggregation in schizophrenia subtypes, according to treatment response.

Regulation of biological processes according to a 24-hr rhythm is essential for the normal functioning of an organism. Temporal variation in brain MRI data has often been attributed to circadian or diurnal oscillations; however, it is not clear if such oscillations exist. We provide the first evidence that diurnal oscillations indeed govern multiple MRI metrics. We recorded cerebral blood flow, diffusion-tensor metrics, T1 relaxation, and cortical structural features every three hours over a 24-hr period in each of 16 male controls and eight male bipolar disorder patients. Diurnal oscillations were detected in numerous MRI metrics at the whole-brain level, and regionally. Rhythmicity parameters in the bipolar disorder patients were similar to the controls for most metrics, except for a larger phase variation in cerebral blood flow. The ubiquitous nature of diurnal oscillations has broad implications for neuroimaging studies and furthers our understanding of the dynamic nature of the human brain.

Impaired illness awareness (IIA) occurs in up to 98% of patients with schizophrenia and leads to negative clinical outcomes. Previous functional MRI studies suggest that IIA may be related to interhemispheric imbalance in the posterior parietal area (PPA). Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation that applies a weak current passed between anodal and cathodal electrodes placed on the scalp. Recent studies support the potential value of tDCS to improve IIA in schizophrenia. Arterial spin labeling (ASL) is a brain imaging technique that provides an absolute measure of regional cerebral blood flow (CBF). We investigated the effect of tDCS on regional CBF and changes in IIA.

Restricted access dataset used for the study "Diurnal oscillations of MRI metrics in human brains". Contains subject-level data within the following files: whole_brain_data.csv - average of each MRI metric across the relevant atlas for each time point. processed_ROI_data.csv - average of each MRI metric within each atlas ROI for each time point. whole_brain_techvar_data.csv - average of each MRI metric across the relevant atlas for each time point and back-to-back replicate. weights_kg.csv - body weight at each time point. actigraphy_3day.csv - steps registered by the FitBit device each minute for the 3 days of observation. actigraphy_sleep.csv - sleep intervals registered by the FitBit device during the 3 days of observation.

Regulation of biological processes according to a 24-hr rhythm is essential for the normal functioning of an organism. Temporal variation in brain MRI data has often been attributed to circadian or diurnal oscillations; however, it is not clear if such oscillations exist. Here, we provide evidence that diurnal oscillations indeed govern multiple MRI metrics. We recorded cerebral blood flow, diffusion-tensor metrics, T1 relaxation, and cortical structural features every three hours over a 24-hr period in each of 16 adult male controls and eight adult male participants with bipolar disorder. Diurnal oscillations are detected in numerous MRI metrics at the whole-brain level, and regionally. Rhythmicity parameters in the participants with bipolar disorder are similar to the controls for most metrics, except for a larger phase variation in cerebral blood flow. The ubiquitous nature of diurnal oscillations has broad implications for neuroimaging studies and furthers our understanding of the dynamic nature of the human brain.

IntroductionOxidative stress has been implicated in psychiatric disorders, including posttraumatic stress disorder (PTSD). Currently, the status of glutathione (GSH), the brain's most abundant antioxidant, in PTSD remains uncertain. Therefore, the current study investigated brain concentrations of GSH and peripheral concentrations of blood markers in individuals with PTSD vs. Healthy Controls (HC).MethodsGSH spectra was acquired in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) using MEGA-PRESS, a J-difference-editing acquisition method. Peripheral blood samples were analyzed for concentrations of metalloproteinase (MMP)-9, tissue inhibitors of MMP (TIMP)-1,2, and myeloperoxidase (MPO).ResultsThere was no difference in GSH between PTSD and HC in the ACC (n = 30 PTSD, n = 20 HC) or DLPFC (n = 14 PTSD, n = 18 HC). There were no group differences between peripheral blood markers (P > 0.3) except for (non-significantly) lower TIMP-2 in PTSD. Additionally, TIMP-2 and GSH in the ACC were positively related in those with PTSD. Finally, MPO and MMP-9 were negatively associated with duration of PTSD.ConclusionsWe do not report altered GSH concentrations in the ACC or DLPFC in PTSD, however, systemic MMPs and MPO might be implicated in central processes and progression of PTSD. Future research should investigate these relationships in larger sample sizes.

Introduction Preclinical data suggest methamphetamine (MA), a widely used stimulant drug, can harm the brain by causing oxidative stress and inflammation, but only limited information is available in humans. We tested the hypothesis that levels of glutathione (GSH), a major antioxidant, would be lower in the brains of chronic human MA preferring polysubstance users. We also explored if concentrations of peripheral immunoinflammatory blood biomarkers were related with brain GSH concentrations. Methods 20 healthy controls (HC) (33 years; 11 M) and 14 MA users (40 years; 9 M) completed a magnetic resonance spectroscopy (MRS) scan, with GSH spectra obtained by the interleaved J-difference editing MEGA-PRESS method in anterior cingulate cortex (ACC) and left dorsolateral prefrontal cortex (DLPFC). Peripheral blood samples were drawn for measurements of immunoinflammatory biomarkers. Independent samples t-tests evaluated MA vs. HC differences in GSH. Results GSH levels did not differ between HC and MA users (ACC p = 0.30; DLPFC p = 0.85). A total of 17 of 25 immunoinflammatory biomarkers were significantly elevated in MA users and matrix metalloproteinase (MMP)-2 (r = 0.577, p = 0.039), myeloperoxidase (MPO) (r = –0.556, p = 0.049), and MMP-9 (r = 0.660, p = 0.038) were correlated with brain levels of GSH. Conclusion Normal brain GSH in living brain of chronic MA users is consistent with our previous postmortem brain finding and suggests that any oxidative stress caused by MA, at the doses used by our participants, might not be sufficient to cause either a compensatory increase in, or substantial overutilization of, this antioxidant. Additionally, more research is required to understand how oxidative stress and inflammatory processes are related and potentially dysregulated in MA use.

Background Risk of breast cancer in adult life is influenced by body size and height in childhood, but the mechanisms responsible for these associations are currently unknown. We carried out research to determine if, at age 15-18, measures of dietary intake were associated with body size, hormones, and with variations in breast tissue composition that in adult life are associated with risk of breast cancer. Methods In a cross-sectional study of 766 healthy Caucasian women aged 15-18, we measured percent breast water (PBW), total breast water and fat by magnetic resonance (MR), and assessed dietary intake using a validated food frequency questionnaire. We also measured height, weight, skin-fold thicknesses and waist-to-hip ratio, and in fasting blood assayed glucose and insulin. Results After adjustment for age, measures of body size, and energy intake, dietary fiber (insoluble and total fiber) and insulin were associated positively and significantly with PBW. Conclusions Dietary fiber and fasting insulin were associated with breast tissue measures. These data suggest a potential approach to breast cancer prevention.

Neuromelanin (NM) is a product of monoamine metabolism including dopamine (DA). NM-sensitive MRI sequences allow in vivo quantification of NM levels in the substantia nigra (SN). NM-MRI signal is thought to serve as a biomarker for SN dopamine neuron integrity, and in turn, striatal DA functioning. Increased striatal DA synthesis has been associated with response to first-line antipsychotics (FLR) in patients with schizophrenia, while normal striatal DA synthesis has been associated with treatment-resistant schizophrenia (TRS). As such, we hypothesized that FLR patients would show increased SN-NM levels and TRS would show normal SN-NM levels.

(1) Objective: Considering that current knowledge of mechanisms involved in the molecular pathogenesis of Social Anxiety Disorder (SAD) is limited, we conducted a systematic review to evaluate cumulative data obtained by Proton Magnetic Resonance Spectroscopic (1H MRS) studies. (2) Methods: A computer-based literature search of Medline, EMBASE, PsycInfo, and ProQuest was performed. Only cross-sectional studies using 1H MRS techniques in participants with SAD and healthy controls (HCs) were selected. (3) Results: The search generated eight studies. The results indicated regional abnormalities in the ‘fear neurocircuitry’ in patients with SAD. The implicated regions included the anterior cingulate cortex (ACC), dorsomedial prefrontal cortex (dmPFC), dorsolateral prefrontal cortex (dlPFC), insula, occipital cortex (OC), as well as the subcortical regions, including the thalamus, caudate, and the putamen. (4) Conclusions: The evidence derived from eight studies suggests that possible pathophysiological mechanisms of SAD include impairments in the integrity and function of neurons and glial cells, including disturbances in energy metabolism, maintenance of phospholipid membranes, dysregulations of second messenger systems, and excitatory/inhibitory neurocircuitry. Conducting more cross-sectional studies with larger sample sizes is warranted given the limited evidence in this area of research.

Schizophrenia (SCZ) is a severe and chronic neuropsychiatric disorder that is often subcategorized into 3 treatment-response-subgroups: 1) Patients with improved positive symptom response (PSr) following conventional, non-clozapine, antipsychotic treatment (APT) (i.e., treatment responders; TR), 2) patients with improved-PSr solely to clozapine treatment (i.e., clozapine responders; ClzR+), and 3) patients with no or suboptimal improved-PSr to APTs, including clozapine treatment (i.e., clozapine resistant; ClzR-). Aberrant glutamate cycling and glial activity have long been postulated in SCZ and treatment-response-subgroups. Indeed, our group has previously reported 1) increased glutamate+glutamine (Glx) in the dorsal-anterior cingulate cortex (dACC) of ClzR-, and 2) elevated myo-Inositol (mI; glial biomarker) in the dACC of patients with SCZ compared to controls. In the present analysis, we explore the relationship between Glx and mI in the dACC of treatment-response-subgroups and controls.

Gamma-aminobutyric acid (GABA) signaling plays a crucial role in drug reward and the development of addiction. Historically, GABA neurochemistry in humans has been difficult to study due to methodological limitations. In recent years, proton magnetic resonance spectroscopy (1H-MRS, MRS) has emerged as a non-invasive imaging technique that can detect and quantify human brain metabolites in vivo. Novel sequencing and spectral editing methods have since been developed to allow for quantification of GABA. This review outlines the clinical research utilization of 1H-MRS in understanding GABA neurochemistry in addiction and summarizes current literature that reports GABA measurements by MRS in addiction. Research on alcohol, nicotine, cocaine, and cannabis addiction all suggest medications that modulate GABA signaling may be effective in reducing withdrawal, craving, and other addictive behaviors. Thus, we discuss how improvements in current MRS techniques and design can optimize GABA quantification in future studies and explore how monitoring changes to brain GABA could help identify risk factors, improve treatment efficacy, further characterize the nature of addiction, and provide crucial insights for future pharmacological development.

Dysregulation of hippocampus glutamatergic neurotransmission and reductions in hippocampal volume have been associated with psychiatric disorders. The endocannabinoid system modulates glutamate neurotransmission and brain development, including hippocampal remodeling. In humans, elevated levels of anandamide and lower activity of its catabolic enzyme fatty acid amide hydrolase (FAAH) are associated with schizophrenia diagnosis and psychotic symptom severity, respectively (Neuropsychopharmacol, 29(11), 2108–2114; Biol. Psychiatry 88 (9), 727–735). Although preclinical studies provide strong evidence linking anandamide and FAAH to hippocampus neurotransmission and structure, these relationships remain poorly understood in humans. We recruited young adults with and without psychotic disorders and measured FAAH activity, hippocampal glutamate and glutamine (Glx), and hippocampal volume using [11C]CURB positron emission tomography (PET), proton magnetic resonance spectroscopy (1H-MRS) and T1-weighted structural MRI, respectively. We hypothesized that higher FAAH activity would be associated with greater hippocampus Glx and lower hippocampus volume, and that these effects would differ in patients with psychotic disorders relative to healthy control participants. After attrition and quality control, a total of 37 participants (62% male) completed [11C]CURB PET and 1H-MRS of the left hippocampus, and 45 (69% male) completed [11C]CURB PET and hippocampal volumetry. Higher FAAH activity was associated with greater concentration of hippocampal Glx (F1,36.36 = 9.17, p = 0.0045; Cohen’s f = 0.30, medium effect size) and smaller hippocampal volume (F1,44.70 = 5.94, p = 0.019, Cohen’s f = 0.26, medium effect size). These effects did not differ between psychosis and healthy control groups (no group interaction). This multimodal imaging study provides the first in vivo evidence linking hippocampal Glx and hippocampus volume with endocannabinoid metabolism in the human brain.

Gender dysphoria (GD) is characterized by distress due to an incongruence between experienced gender and sex assigned at birth. Brain functional connectivity in adolescents who experience GD may be associated with experienced gender (vs. assigned sex) and/or brain networks implicated in own-body perception. Furthermore, sexual orientation may be related to brain functional organization given commonalities in developmental mechanisms proposed to underpin GD and same-sex attractions. Here, we applied group independent component analysis to resting-state functional magnetic resonance imaging (rs-fMRI) BOLD timeseries data to estimate inter-network (i.e., between independent components) timeseries correlations, representing functional connectivity, in 17 GD adolescents assigned female at birth (AFAB) not receiving gender-affirming hormone therapy, 17 cisgender girls, and 15 cisgender boys (ages 12-17 years). Sexual orientation was represented by degree of androphilia-gynephilia and sexual attractions strength. Multivariate partial least squares analyses found that functional connectivity differed among cisgender boys, cisgender girls, and GD AFAB, with the largest difference between cisgender boys and GD AFAB. Regarding sexual orientation and age, the brain’s intrinsic functional organization of GD AFAB was both similar to and different from cisgender girls, and both differed from cisgender boys. The pattern of group differences and the networks involved aligned with the hypothesis that brain functional organization is different among GD AFAB (vs. cisgender) adolescents, and certain aspects of this organization relate to brain areas implicated in own-body perception and self-referential thinking. Overall, brain functional organization of GD AFAB was generally more similar to that of cisgender girls than cisgender boys.

Waste clearance in the brain is mediated through the glymphatic system, which has been explored in neurodegeneration, sleep, and aging. Genetic, metabolic-vascular, and neuroimaging evidence suggest that clearance of debris via the glymphatic system is affected in schizophrenia (SCZ). We aimed to quantify the aggregation of high-molecular-weight macromolecules (MM), as a measure of compromised glymphatic system, in patients with SCZ. We hypothesised: 1) patients with SCZ would have higher MM levels than controls; 2) Age would be associated with less glymphatic system efficiency in both SCZ and controls.

Gender dysphoria (GD) is characterized by distress due to an incongruence between experienced gender and sex assigned at birth. Sex-differentiated brain regions are hypothesized to reflect the experienced gender in GD and may play a role in sexual orientation development. Magnetic resonance brain images were acquired from 16 GD adolescents assigned female at birth (AFAB) not receiving hormone therapy, 17 cisgender girls, and 14 cisgender boys (ages 12–17 years) to examine three morphological and microstructural gray matter features in 76 brain regions: surface area (SA), cortical thickness (CT), and T1 relaxation time. Sexual orientation was represented by degree of androphilia-gynephilia and sexual attraction strength. Multivariate analyses found that cisgender boys had larger SA than cisgender girls and GD AFAB. Shorter T1, reflecting denser, macromolecule-rich tissue, correlated with older age and stronger gynephilia in cisgender boys and GD AFAB, and with stronger attractions in cisgender boys. Thus, cortical morphometry (mainly SA) was related to sex assigned at birth, but not experienced gender. Effects of experienced gender were found as similarities in correlation patterns in GD AFAB and cisgender boys in age and sexual orientation (mainly T1), indicating the need to consider developmental trajectories and sexual orientation in brain studies of GD.