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Patients with schizophrenia have patterns of brain deficits including reduced cortical thickness, subcortical gray matter volumes, and cerebral white matter integrity. We proposed the regional vulnerability index (RVI) to translate the results of Enhancing Neuro Imaging Genetics Meta‐Analysis studies to the individual level. We calculated RVIs for cortical, subcortical, and white matter measurements and a multimodality RVI. We evaluated RVI as a measure sensitive to schizophrenia‐specific neuroanatomical deficits and symptoms and studied the timeline of deficit formations in: early (≤5 years since diagnosis, N = 45, age = 28.8 ± 8.5); intermediate (6–20 years, N = 30, age 43.3 ± 8.6); and chronic (21+ years, N = 44, age = 52.5 ± 5.2) patients and healthy controls (N = 76, age = 38.6 ± 12.4). All RVIs were significantly elevated in patients compared to controls, with the multimodal RVI showing the largest effect size, followed by cortical, white matter and subcortical RVIs (d = 1.57, 1.23, 1.09, and 0.61, all p, We developed the regional vulnerability index (RVI) to quantify individual similarity to the expected schizophrenia deficits patterns derived from large‐scale meta‐analyses performed by Enhancing Neuro Imaging Genetics Meta‐Analysis (ENIGMA) consortium. RVIs for cortical, subcortical, and white matter measurements and a cross‐modality RVI showed significant association with illness duration, cognitive deficits and symptoms. The similarity to expected disorder patterns captured by RVI may be useful for early diagnosis and as quantitative targets for more effective treatment strategies aiming to alter the formation of neuroanatomical deficits.

The ENIGMA‐DTI (diffusion tensor imaging) workgroup supports analyses that examine the effects of psychiatric, neurological, and developmental disorders on the white matter pathways of the human brain, as well as the effects of normal variation and its genetic associations. The seven ENIGMA disorder‐oriented working groups used the ENIGMA‐DTI workflow to derive patterns of deficits using coherent and coordinated analyses that model the disease effects across cohorts worldwide. This yielded the largest studies detailing patterns of white matter deficits in schizophrenia spectrum disorder (SSD), bipolar disorder (BD), major depressive disorder (MDD), obsessive–compulsive disorder (OCD), posttraumatic stress disorder (PTSD), traumatic brain injury (TBI), and 22q11 deletion syndrome. These deficit patterns are informative of the underlying neurobiology and reproducible in independent cohorts. We reviewed these findings, demonstrated their reproducibility in independent cohorts, and compared the deficit patterns across illnesses. We discussed translating ENIGMA‐defined deficit patterns on the level of individual subjects using a metric called the regional vulnerability index (RVI), a correlation of an individual's brain metrics with the expected pattern for a disorder. We discussed the similarity in white matter deficit patterns among SSD, BD, MDD, and OCD and provided a rationale for using this index in cross‐diagnostic neuropsychiatric research. We also discussed the difference in deficit patterns between idiopathic schizophrenia and 22q11 deletion syndrome, which is used as a developmental and genetic model of schizophrenia. Together, these findings highlight the importance of collaborative large‐scale research to provide robust and reproducible effects that offer insights into individual vulnerability and cross‐diagnosis features.

Cardiovascular risk factors such as dyslipidemia and hypertension increase the risk for white matter pathology and cognitive decline. We hypothesize that white matter levels of N-acetylaspartate (NAA), a chemical involved in the metabolic pathway for myelin lipid synthesis, could serve as a biomarker that tracks the influence of cardiovascular risk factors on white matter prior to emergence of clinical changes. To test this, we measured levels of NAA across white matter and gray matter in the brain using echo planar spectroscopic imaging (EPSI) in 163 individuals and examined the relationship of regional NAA levels and cardiovascular risk factors as indexed by the Framingham Cardiovascular Risk Score (FCVRS). NAA was strongly and negatively correlated with FCVRS across the brain, but, after accounting for age and sex, the association was found primarily in white matter regions, with additional effects found in the thalamus, hippocampus, and cingulate gyrus. FCVRS was also negatively correlated with creatine levels, again primarily in white matter. The results suggest that cardiovascular risks are related to neurochemistry with a predominantly white matter pattern and some subcortical and cortical gray matter involvement. NAA mapping of the brain may provide early surveillance for the potential subclinical impact of cardiovascular and metabolic risk factors on the brain.

Although schizophrenia is a brain disorder, increasing evidence suggests that there may be body-wide involvement in this illness. However, direct evidence of brain structures involved in the presumed peripheral-central interaction in schizophrenia is still unclear. Seventy-nine previously treatment-naïve first-episode schizophrenia patients who were within 2-week antipsychotics initial stabilization, and 41 age- and sex-matched healthy controls were enrolled in the study. Group differences in subcortical brain regional structures measured by MRI and the subclinical cardiovascular, metabolic, immune, and neuroendocrine biomarkers as indexed by allostatic load, and their associations were explored. Compared with controls, patients with schizophrenia had significantly higher allostatic load (P = .001). Lateral ventricle (P < .001), choroid plexus (P < .001), and thalamus volumes (P < .001) were significantly larger, whereas amygdala volume (P = .001) was significantly smaller in patients. The choroid plexus alone was significantly correlated with higher allostatic load after age, sex, education level, and the total intracranial volume were taken into account (t = 3.60, P < .001). Allostatic load was also significantly correlated with PANSS positive (r = 0.28, P = .016) and negative (r = −0.31, P = .008) symptoms, but in opposite directions. The peripheral multisystemic and central nervous system abnormalities in schizophrenia may interact through the choroid plexus during the early stage of the illness. The choroid plexus might provide a sensitive structural biomarker to study the treatment and prevention of brain-periphery interaction abnormalities in schizophrenia.

Failure of antipsychotic medications to resolve symptoms in patients with schizophrenia creates a clinical challenge that is known as treatment resistance. The causes of treatment resistance are unknown, but it is associated with earlier age at onset and more severe cognitive deficits. The authors tested the hypothesis that white matter deficits that are involved in both neurodevelopment and severity of cognitive deficits in schizophrenia are associated with a higher risk of treatment resistance.The study sample (N=122; mean age, 38.2 years) included schizophrenia patients at treatment initiation (N=45), patients whose symptoms were treatment responsive (N=40), and patients whose symptoms were treatment resistant (N=37), as well as healthy control subjects (N=78; mean age, 39.2 years). White matter regional vulnerability index (RVI) was tested as a predictor of treatment resistance and cognitive deficits. Higher RVI is indicative of better agreement between diffusion tensor imaging fractional anisotropy across the brain in an individual and the pattern identified by the largest-to-date meta-analysis of white matter deficits in schizophrenia.Patients with treatment-resistant symptoms showed the highest white matter RVI (mean=0.38 [SD=0.2]), which was significantly higher than the RVI among patients with treatment-responsive symptoms (mean=0.30 [SD=0.02]). At the onset of treatment, schizophrenia patients showed significantly higher RVI than healthy control subjects (mean=0.18 [SD=0.03] and mean=0.13 [SD=0.02], respectively). RVIs were significantly correlated with performance on processing speed and negative symptoms.Schizophrenia affects white matter microstructure in specific regional patterns. Susceptibility to white matter regional deficits is associated with an increased likelihood of treatment resistance. Developments to overcome schizophrenia treatment resistance should consider white matter as an important target.

Occupational exposure to hypobaria (low atmospheric pressure) is a risk factor for reduced white matter integrity, increased white matter hyperintensive burden, and decline in cognitive function. We tested the hypothesis that a discrete hypobaric exposure will have a transient impact on cerebral physiology. Cerebral blood flow, fractional anisotropy of water diffusion in cerebral white matter, white matter hyperintensity volume, and concentrations of neurochemicals were measured at baseline and 24 hr and 72 hr postexposure in N = 64 healthy aircrew undergoing standard US Air Force altitude chamber training and compared to N = 60 controls not exposed to hypobaria. We observed that hypobaric exposure led to a significant rise in white matter cerebral blood flow (CBF) 24 hr postexposure that remained elevated, albeit not significantly, at 72 hr. No significant changes were observed in structural measurements or gray matter CBF. Subjects with higher baseline concentrations of neurochemicals associated with neuroprotection and maintenance of normal white matter physiology (glutathione, N‐acetylaspartate, glutamate/glutamine) showed proportionally less white matter CBF changes. Our findings suggest that discrete hypobaric exposure may provide a model to study white matter injury associated with occupational hypobaric exposure.

Reduced cortical gray matter integrity and cognitive abilities are among core deficits in schizophrenia. We hypothesized that higher allostatic load (AL) that accounts for exposure to chronic stress is a contributor to structural and cognitive deficits in schizophrenia. One hundred and sixty-seven schizophrenia patients who were on average with normal weight, normal systolic, and diastolic blood pressure and 72 healthy controls were enrolled in the study. Group differences in subclinical cardiovascular, metabolic, immune, and neuroendocrine biological markers as indexed by AL and contribution of AL components to the structural and cognitive deficits in schizophrenia were explored. Compared with controls, schizophrenia patients who were normotensive, normoweight, and had low total cholesterol levels still had significantly higher AL mainly due to lower high-density lipoprotein cholesterol and higher heart rate, waist-hip ratio, hemoglobinA1c, hypersensitive C-reactive protein, and overnight-urine cortisol levels. Patients also had decreased whole-brain mean cortical thickness, and lower cognition assessed by the MATRICS consensus cognitive battery. AL was inversely correlated with mean cortical thickness and cognition in schizophrenia, while none of these relationships existed in controls. Mediation analyses showed the effect of AL on cognitive deficits in schizophrenia was significantly mediated by cortical thinning, and the most significant mediating cortical area was the left superior frontal gyrus. Cortical thickness may act as a mediator between AL and cognitive deficits in schizophrenia. Early intervention strategies to reduce cortical thinning and cognitive dysfunction in schizophrenia should target specific aspects of their high AL in addition to weight gain, hypertension and high cholesterol levels.

Highlights • RVI for MDD and AD was derived based on large meta-analytical findings. • RVI-MDD and AD were significantly elevated in UKBB subjects with respective illnesses. • There was no elevation of RVI-MDD in subjects with AD or RVI-AD in subjects with MDD. • RVI captures neuroanatomic deviation patterns. • RVI is a useful biomarker for assessing similarity to neuropsychiatric illnesses., Neurological and psychiatric illnesses are associated with regional brain deficit patterns that bear unique signatures and capture illness-specific characteristics. The Regional Vulnerability Index (RVI) was developed to quantify brain similarity by comparing individual white matter microstructure, cortical gray matter thickness and subcortical gray matter structural volume measures with neuroanatomical deficit patterns derived from large-scale meta-analytic studies. We tested the specificity of the RVI approach for major depressive disorder (MDD) and Alzheimer’s disease (AD) in a large epidemiological sample of UK Biobank (UKBB) participants (N = 19,393; 9138 M/10,255F; age = 64.8 ± 7.4 years). Compared to controls free of neuropsychiatric disorders, participants with MDD (N = 2,248; 805 M/1443F; age = 63.4 ± 7.4) had significantly higher RVI-MDD values (t = 5.6, p = 1·10−8), but showed no detectable difference in RVI-AD (t = 2.0, p = 0.10). Subjects with dementia (N = 7; 4 M/3F; age = 68.6 ± 8.6 years) showed significant elevation in RVI-AD (t = 4.2, p = 3·10−5) but not RVI-MDD (t = 2.1, p = 0.10) compared to controls. Even within affective illnesses, participants with bipolar disorder (N = 54) and anxiety disorder (N = 773) showed no significant elevation in whole-brain RVI-MDD. Participants with Parkinson’s disease (N = 37) showed elevation in RVI-AD (t = 2.4, p = 0.01) while subjects with stroke (N = 247) showed no such elevation (t = 1.1, p = 0.3). In summary, we demonstrated elevation in RVI-MDD and RVI-AD measures in the respective illnesses with strong replicability that is relatively specific to the respective diagnoses. These neuroanatomic deviation patterns offer a useful biomarker for population-wide assessments of similarity to neuropsychiatric illnesses.

We hypothesized that cerebral white matter deficits in schizophrenia (SZ) are driven in part by accelerated white matter aging and are associated with cognitive deficits. We used machine learning model to predict individual age from diffusion tensor imaging features and calculated the delta age (Δage) as the difference between predicted and chronological age. Through this approach, we translated multivariate white matter imaging features into an age-scaled metric and used it to test the temporal trends of accelerated aging-related white matter deficit in SZ and its association with the cognition. Followed feature selection, a machine learning model was trained with fractional anisotropy values in 34 of 43 tracts on a training set consisted of 107 healthy controls (HC). The brain age of 166 SZs and 107 HCs in the testing set were calculated using this model. Then, we examined the SZ-HC group effect on Δage and whether this effect was moderated by chronological age using the regression spline model. The results showed that Δage was significantly elevated in the age >30 group in patients (p < 0.001) but not in age ⩽ 30 group (p = 0.364). Δage in patients was significantly and negatively associated with both working memory (β = −0.176, p = 0.007) and processing speed (β = −0.519, p = 0.035) while adjusting sex and chronological age. Overall, these findings indicate that the Δage is elevated in SZs and become significantly from middle life stage; the increase of Δage in SZs is associated with the decline neurocognitive performance.

Schizophrenia (SZ) is a severe psychiatric illness associated with an elevated risk for developing Alzheimer’s disease (AD). Both SZ and AD have white matter abnormalities and cognitive deficits as core disease features. We hypothesized that aging in SZ patients may be associated with the development of cerebral white matter deficit patterns similar to those observed in AD. We identified and replicated aging-related increases in the similarity between white matter deficit patterns in patients with SZ and AD. The white matter “regional vulnerability index” (RVI) for AD was significantly higher in SZ patients compared with healthy controls in both the independent discovery (Cohen’s d = 0.44, P = 1·10–5, N = 173 patients/230 control) and replication (Cohen’s d = 0.78, P = 9·10–7, N = 122 patients/64 controls) samples. The degree of overlap with the AD deficit pattern was significantly correlated with age in patients (r = .21 and .29, P < .01 in discovery and replication cohorts, respectively) but not in controls. Elevated RVI-AD was significantly associated with cognitive measures in both SZ and AD. Disease and cognitive specificities were also tested in patients with mild cognitive impairment and showed intermediate overlap. SZ and AD have diverse etiologies and clinical courses; our findings suggest that white matter deficits may represent a key intersecting point for these 2 otherwise distinct diseases. Identifying mechanisms underlying this white matter deficit pattern may yield preventative and treatment targets for cognitive deficits in both SZ and AD patients.

Background We are developing the miniature pig (Sus scrofa domestica), an in-vivo translational, gyrencephalic model for brain development, as an alternative to laboratory rodents/non-human primates. We analyzed longitudinal changes in adolescent pigs using proton magnetic resonance spectroscopy (1H-MRS) and examined the relationship with white matter (WM) integrity derived from diffusion weighted imaging (DWI). New method Twelve female Sinclair™ pigs underwent three imaging/spectroscopy sessions every 23.95 ± 3.73 days beginning at three months of age using a clinical 3 T scanner. 1H-MRS data were collected using 1.2 × 1.0 × 3.0 cm voxels placed in left and right hemisphere WM using a Point Resolved Spectroscopy sequence (TR = 2000 ms, TE = 30 ms). Concentrations of N-acetylaspartate, myo-inositol (MI), glutamate + glutamine, choline, creatine, and macromolecules (MM) 09 and 14 were averaged from both hemispheres. DWI data were collected using 15 shells of b-values (b = 0–3500 s/mm2) with 32 directions/shell and fit using the WM Tract Integrity model to calculate fractional anisotropy (FA), kurtosis anisotropy (KA) and permeability-diffusivity index. Results MI and MM09 significantly declined with age. Increased FA and KA significantly correlated with decline in MI and MM09. Correlations lost significance once corrected for age. Comparison with existing methods MRI scanners/protocols can be used to collect 1H-MRS and DWI data in pigs. Pigs have a larger, more complex, gyrencephalic brain than laboratory rodents but are less complex than non-human primates, thus satisfying the “replacement” principle of animal research. Conclusions Longitudinal effects in MRS measurements were similar to those reported in adolescent humans. MRS changes correlated with diffusion measurements indicating ongoing WM myelination/maturation.

BACKGROUND Neuroscience research in brain development and disorders can benefit from an in vivo animal model that portrays normal white matter (WM) development trajectories and has a sufficiently large cerebrum for imaging with human MRI scanners and protocols. NEW METHOD Twelve three-month-old Sinclair™ miniature pigs (Sus scrofa domestica) were longitudinally evaluated during adolescent development using advanced diffusion weighted imaging (DWI) focused on cerebral WM. Animals had three MRI scans every 23.95 ± 3.73 days using a 3-T scanner. The DWI imaging protocol closely modeled advanced human structural protocols and consisted of fifteen b-shells (b = 0-3500 s/mm2) with 32-directions/shell. DWI data were analyzed using diffusion kurtosis and bi-exponential modeling that provided measurements that included fractional anisotropy (FA), radial kurtosis, kurtosis anisotropy (KA), axial kurtosis, tortuosity, and permeability-diffusivity index (PDI). RESULTS Significant longitudinal effects of brain development were observed for whole-brain average FA, KA, and PDI (all p

A novel mega-analytical approach that reduced methodological variance was evaluated using a multisite diffusion tensor imaging (DTI) fractional anisotropy (FA) data by comparing white matter integrity in people with schizophrenia to controls. Methodological variance was reduced through regression of variance captured from quality assurance (QA) and by using Marchenko-Pastur Principal Component Analysis (MP-PCA) denoising. N = 192 (119 patients/73 controls) data sets were collected at three sites equipped with 3T MRI systems: GE MR750, GE HDx, and Siemens Trio. DTI protocol included five b = 0 and 60 diffusion-sensitized gradient directions (b = 1,000 s/mm2 ). In-house DTI QA protocol data was acquired weekly using a uniform phantom; factor analysis was used to distil into two orthogonal QA factors related to: SNR and FA. They were used as site-specific covariates to perform mega-analytic data aggregation. The effect size of patient-control differences was compared to these reported by the enhancing neuro imaging genetics meta-analysis (ENIGMA) consortium before and after regressing QA variance. Impact of MP-PCA filtering was evaluated likewise. QA-factors explained ∼3-4% variance in the whole-brain average FA values per site. Regression of QA factors improved the effect size of schizophrenia on whole brain average FA values-from Cohen's d = .53 to .57-and improved the agreement between the regional pattern of FA differences observed in this study versus ENIGMA from r = .54 to .70. Application of MP-PCA-denoising further improved the agreement to r = .81. Regression of methodological variances captured by routine QA and advanced denoising that led to a better agreement with a large mega-analytic study.

Objective To assess the association between peripheral lipid/fat profiles and cerebral gray matter (GM) and white matter (WM) in healthy Old Order Amish (OOA). Methods Blood lipids, abdominal adiposity, liver lipid contents, and cerebral microstructure were assessed in OOA (N = 64, 31 males/33 females, ages 18-77). Orthogonal factors were extracted from lipid and imaging adiposity measures. GM assessment used the Human Connectome Project protocol to measure whole-brain average cortical thickness. Diffusion-weighted imaging was used to derive WM fractional anisotropy and kurtosis anisotropy measurements. Results Lipid/fat measures were captured by three orthogonal factors explaining 80% of the variance. Factor one loaded on cholesterol and/or low-density lipoprotein cholesterol measurements; factor two loaded on triglyceride/liver measurements; and factor three loaded on abdominal fat measurements. A two-stage regression including age/sex (first stage) and the three factors (second stage) examined the peripheral lipid/fat effects. Factors two and three significantly contributed to WM measures after Bonferroni corrections (P

Subanesthetic administration of ketamine is a pharmacological model to elicit positive and negative symptoms of psychosis in healthy volunteers. We used resting‐state pharmacological functional MRI (rsPhfMRI) to identify cerebral networks affected by ketamine and compared them to the functional connectivity (FC) in schizophrenia. Ketamine can produce sedation and we contrasted its effects with the effects of the anxiolytic drug midazolam. Thirty healthy male volunteers (age = 19–37 years) underwent a randomized, three‐way, cross‐over study consisting of three imaging sessions, with 48 hr between sessions. A session consisted of a control period followed by infusion of placebo or ketamine or midazolam. The ENIGMA rsfMRI pipeline was used to derive two long‐distance (seed‐based and dual‐regression) and one local (regional homogeneity, ReHo) FC measures. Ketamine induced significant reductions in the connectivity of the salience network (Cohen's d: 1.13 ± 0.28, p = 4.0 × 10−3), auditory network (d: 0.67 ± 0.26, p = .04) and default mode network (DMN, d: 0.63 ± 0.26, p = .05). Midazolam significantly reduced connectivity in the DMN (d: 0.77 ± 0.27, p = .03). The effect sizes for ketamine for resting networks showed a positive correlation (r = .59, p = .07) with the effect sizes for schizophrenia‐related deficits derived from ENIGMA's study of 261 patients and 327 controls. Effect sizes for midazolam were not correlated with the schizophrenia pattern (r = −.17, p = .65). The subtraction of ketamine and midazolam patterns showed a significant positive correlation with the pattern of schizophrenia deficits (r = .68, p = .03). RsPhfMRI reliably detected the shared and divergent pharmacological actions of ketamine and midazolam on cerebral networks. The pattern of disconnectivity produced by ketamine was positively correlated with the pattern of connectivity deficits observed in schizophrenia, suggesting a brain functional basis for previously poorly understood effects of the drug.

BACKGROUND: Abnormal cerebral levels of myo-inositol, a molecule involved in membrane phospholipid synthesis and regulation of intracellular processes, may be a biomarker for depression, including experience of depression within schizophrenia spectrum disorders. However, studies to date have resulted in mixed findings, in part due to limitations in comprehensive assessment of myo-inositol levels in different regions of the brain. METHODS: We aimed to determine the regional pattern of myo-inositol changes in cortical gray matter in depression by using echo-planar spectroscopic imaging (EPSI) at 3T in a sample of 193 individuals from the Amish and Mennonite communities, of whom 59 had a current or past history of unipolar depression. The relationship of myo-inositol levels to depression was examined from a categorical approach (using diagnosis of unipolar depressive disorder) as well as a dimensional approach (measuring symptoms of depression using the Maryland Trait and State Depression scales). Regression models covarying for age, sex, and accounting for the high correlation of brain metabolites between regions were used to examine these relationships, with false discovery rate used to control for multiple comparisons. RESULTS: Myo-inositol levels were lower in individuals with a history of depression compared to controls in 4 regions of the frontal and parietal cortex. Using a dimensional approach, myo-inositol levels were inversely correlated with trait depression (frequency of symptoms experienced over course of life) in 19 regions, primarily in frontal, limbic, and subcortical regions; however, myo-inositol was not strongly related to state depressive symptoms. Furthermore, lower myo-inositol was related to greater experience of stressful life events in 14 regions, largely overlapping with the regions associated with trait depression. DISCUSSION: These results indicate that decreased myo-inositol levels specifically in frontal regions may be a biomarker for depression. The finding of a relationship between stressful life events and myo-inositol levels may have implications for further study of the trans-diagnostic mechanisms of stress related psychopathology.

Introduction Quantitative longitudinal magnetic resonance imaging and spectroscopy (MRI/S) is used to assess progress of brain disorders and treatment effects. Understanding the significance of MRI/S changes requires knowledge of the inherent technical and physiological consistency of these measurements. This longitudinal study examined the variance and reproducibility of commonly used quantitative MRI/S measurements in healthy subjects while controlling physiological and technical parameters. Methods Twenty-five subjects were imaged three times over 5 days on a Siemens 3T Verio scanner equipped with a 32-channel phase array coil. Structural (T1, T2-weighted, and diffusion-weighted imaging) and physiological (pseudocontinuous arterial spin labeling, proton magnetic resonance spectroscopy) data were collected. Consistency of repeated images was evaluated with mean relative difference, mean coefficient of variation, and intraclass correlation (ICC). Finally, a “reproducibility rating” was calculated based on the number of subjects needed for a 3% and 10% difference. Results Structural measurements generally demonstrated excellent reproducibility (ICCs 0.872–0.998) with a few exceptions. Moderate-to-low reproducibility was observed for fractional anisotropy measurements in fornix and corticospinal tracts, for cortical gray matter thickness in the entorhinal, insula, and medial orbitofrontal regions, and for the count of the periependymal hyperintensive white matter regions. The reproducibility of physiological measurements ranged from excellent for most of the magnetic resonance spectroscopy measurements to moderate for permeability-diffusivity coefficients in cingulate gray matter to low for regional blood flow in gray and white matter. Discussion This study demonstrates a high degree of longitudinal consistency across structural and physiological measurements in healthy subjects, defining the inherent variability in these commonly used sequences. Additionally, this study identifies those areas where caution should be exercised in interpretation. Understanding this variability can serve as the basis for interpretation of MRI/S data in the assessment of neurological disorders and treatment effects.