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Schizophrenia, a devastating psychiatric illness with onset in the late teens to early 20s, is thought to involve disrupted brain connectivity. Functional and structural disconnections of cortical networks may underlie various cognitive deficits, including a substantial reduction in the speed of information processing in schizophrenia patients compared with controls. Myelinated white matter supports the speed of electrical signal transmission in the brain. To examine possible neuroanatomical sources of cognitive deficits, we used a comprehensive diffusion-weighted imaging (DWI) protocol and characterized the white matter diffusion signals using diffusion kurtosis imaging (DKI) and permeability-diffusivity imaging (PDI) in patients (n = 74), their nonill siblings (n = 41), and healthy controls (n = 113). Diffusion parameters that showed significant patient-control differences also explained the patient-control differences in processing speed. This associationwas also found for the nonill siblings of the patients. The association was specific to processing-speed abnormality but not specific to working memory abnormality or psychiatric symptoms. Our findings show that advanced diffusion MRI in white matter may capture microstructural connectivity patterns and mechanisms that govern the association between a core neurocognitive measure-- processing speed--and neurobiological deficits in schizophrenia that are detectablewith in vivo brain scans. These non-Gaussian diffusion white matter metrics are promising surrogate imaging markers for modeling cognitive deficits and perhaps, guiding treatment development in schizophrenia. [ABSTRACT FROM AUTHOR]

Background: Childhood abuse has been implicated as an environmental factor that increases the risk for developing schizophrenia. A recent large population-based case-control study found that abuse may be a risk factor for schizophrenia in women, but not men. Given the sex differences in onset and clinical course of schizophrenia, we hypothesized that childhood abuse may cause phenotypic differences in the disorder between men and women. Methods: We examined the prevalence of childhood physical abuse in a cohort of men and women with schizophrenia and schizoaffective disorder. Specifically, we examined differences in positive, negative, cognitive and depressive symptoms in men and women who reported a history of childhood physical abuse. We recruited 100 subjects for a single visit and assessed a history of childhood physical abuse using the childhood trauma questionnaire (CTQ) and clinical symptoms and cognition using the brief psychiatric rating scale (BPRS), the calgary depression scale (CDS) and the repeatable battery of the assessment of neuropsychological status (RBANS) for cognition. Results: Ninety-two subjects completed the full CTQ with abuse classified as definitely present, definitely absent or borderline. Twelve subjects who reported borderline abuse scores were excluded. Of the 80 subjects whose data was analyzed, 10 of 24 (41.6%) women and 11 of 56 (19.6%) men reported a history of childhood physical abuse (² = 4.21, df = 1, p = 0.04). Women who reported such trauma had significantly more psychotic (sex by abuse interaction; F = 4.03, df = 1.76, p = 0.048) and depressive (F = 4.23, df = 1.76, p = 0.04) symptoms compared to women who did not have a trauma history and men, regardless of trauma history. There were no differences in negative or cognitive symptoms. Conclusions: Women with schizophrenia and schizoaffective disorder may represent a distinct phenotype or subgroup with distinct etiologies and may require different, individually tailored treatments. [ABSTRACT FROM AUTHOR]

Depression is highly prevalent in patients with schizophrenia and is associated with significant clinical consequences, but there is no known biomarker for depression in schizophrenia. One of the putative neurochemical biomarkers for depression in major depressive disorder (MDD) is reduced cerebral concentration of myo-Inositol. We examined whether myo-Inositol levels provide a potential marker for depressive symptoms in schizophrenia similar to that in MDD and are informative regarding causal biological pathways underlying both depression and schizophrenia. We used proton magnetic resonance spectroscopy to examine myo-Inositol levels in the anterior cingulate cortex (ACC) in 59 schizophrenia spectrum disorder (SSD) patients and 69 matched community comparison participants. Participants completed the Maryland Trait and State Depression (MTSD) scale to measure symptoms of depression experienced around time of assessment ('State' subscale) and longitudinally ('Trait' subscale). Myo-Inositol in the ACC was negatively correlated with MTSD-Trait scores in both patients (ρ=−0.336, p=0.009) and community comparison samples (ρ=−0.328, p=0.006). Furthermore, patients with a diagnosis of schizoaffective disorder or a history of at least one major depressive episode had lower levels of myo-Inositol compared with schizophrenia patients without a current or past affective diagnosis (p=0.012). Since reduced brain myo-Inositol is associated with MDD, myo-Inositol may be a biochemical marker of depressive mood symptoms across diagnostic boundaries. If confirmed, this finding may aid investigation of the pathophysiology and therapeutics of depression common between depression, schizophrenia and other psychiatric diagnoses. [ABSTRACT FROM AUTHOR]

Summary Background The etiopathophysiology of schizophrenia has long been linked to stress and the influence of stress is important in all stages of the illness. Previous examinations of perceived stress and acute stress responses may not capture this longitudinal stress pathophysiology. We hypothesized that the cumulative negative effects of stress, indexed by allostatic load (AL), would be elevated in schizophrenia, and that the AL paradigm would be relevant to our understanding of pathophysiology in schizophrenia. Methods We assessed allostatic load in 30 patients with schizophrenia (SZ; mean age = 33; 17 males) and 20 healthy controls (HC; mean age = 35; 12 males) using 13 cardiovascular, metabolic, neuroendocrine and immune biomarkers. Participants’ perceived stress over the past month, functional capacity and psychiatric symptoms were also measured. Results Controlling for age, SZ had significantly higher AL as compared to HC ( p = 0.007). Greater AL was present in both early course and chronic SZ, and was associated with reduced functional capacity ( p = 0.006) and more psychotic symptoms ( p = 0.048) in SZ. Current level of perceived stress was not significantly elevated in SZ or associated with AL in either group. Conclusions The higher AL found in SZ may reflect increased bodily “wear and tear”, possibly caused by more chronic stress exposure or maladaptive responses to stress over time, although additional research is required to differentiate these causes. The higher AL is similarly present in early and chronic SZ, suggesting primary maladaptive stress physiology rather than secondary effects from medications or chronic illness. [ABSTRACT FROM AUTHOR]

Impaired tolerance to distress may help explain part of the cognitive and functional impairments in schizophrenia (SZ). This project investigated distress intolerance in SZ patients as compared to controls, and whether distress intolerance represented an independent domain in relationship to symptoms, cognition, and functional capacity. Healthy controls ( n =43) and SZ ( n =65) completed a psychological distress challenge experiment and their levels of intolerance to distress were estimated. SZ showed increased distress intolerance such that they were significantly more likely to terminate the distress challenge session early compared to controls. Greater distress intolerance was associated with reduced functional capacity and worse cognitive performance in SZ. Mediation analyses suggested that distress intolerance had an independent effect on functional capacity, while some of this effect was mediated by cognitive performance. Our results suggest that distress intolerance is a promising domain for treatment research, and functional capacity may be improved by targeting treatments towards SZ patient׳s ability to tolerate distress. [ABSTRACT FROM AUTHOR]

Sleep dysfunction is prevalent among patients with schizophrenia. Although sex differences have been identified in schizophrenia, sex differences in sleep patterns among patients with schizophrenia are not established. Therefore, the current study examined sex differences in subjective sleep quality patterns in people with schizophrenia utilizing a standardized inventory. Study sample consisted of 75 patients with schizophrenia and 82 healthy controls (HC). Participants completed the Pittsburgh Sleep Quality Index (PSQI). Compared to HC, patients with schizophrenia were more likely to report being poor sleepers (PSQI global score > 5), longer sleep duration, more sleep disturbances, longer sleep onset latency, increased daytime dysfunction due to poor sleep, and more frequent use of sleep medications. Regarding sex differences, female patients were more likely to report being poor sleepers and endorsed more sleep disturbances than female HC, while male patients reported longer sleep duration, more daytime dysfunction, and poorer overall sleep quality relative to male HC. Additionally, higher level of sleep dysfunction was linked to higher symptom severity in male patients only. Patients with schizophrenia endorsed a range of sleep difficulties, and male and female patients with schizophrenia differ compared to their HC counterparts. Implications for treatment of sleep complaints among patients with schizophrenia are discussed. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Up to 80% of patients with schizophrenia experience sleep disturbances, which negatively impact daytime functioning. Given that the glutamatergic system is involved in the pathophysiology of schizophrenia as well as normal sleep-wake neurobiology, the current project aimed to determine whether sleep quality was related to brain glutamate levels in schizophrenia. The Pittsburgh Sleep Quality Index (PSQI) was used to assess subjective sleep quality and proton magnetic resonance spectroscopy (MRS) was used to quantify glutamate in the bilateral anterior cingulate, left parietal cortex, and left hippocampus. Results indicate that global PSQI scores were negatively correlated with the anterior cingulate and parietal glutamate levels. In patients with schizophrenia, poorer sleep quality correlated with greater positive symptom severity. Our findings suggest that poor sleep quality is related to greater positive symptom severity and lower levels of anterior cingulate glutamate in individuals with schizophrenia. Interventions to enhance sleep quality may prove beneficial for patients. Future studies will examine whether glutamate relates to objective measures of sleep quality, and whether glutamate may mediate the relationship between sleep quality and symptom severity across the schizophrenia-spectrum. [ABSTRACT FROM AUTHOR]

Cognitive deficits contribute to functional disability in patients with schizophrenia and may be related to altered functional networks that serve cognition. We evaluated the integrity of major functional networks and assessed their role in supporting two cognitive functions affected in schizophrenia: processing speed (PS) and working memory (WM). Resting‐state functional magnetic resonance imaging (rsfMRI) data, N = 261 patients and 327 controls, were aggregated from three independent cohorts and evaluated using Enhancing NeuroImaging Genetics through Meta Analysis rsfMRI analysis pipeline. Meta‐ and mega‐analyses were used to evaluate patient‐control differences in functional connectivity (FC) measures. Canonical correlation analysis was used to study the association between cognitive deficits and FC measures. Patients showed consistent patterns of cognitive and resting‐state FC (rsFC) deficits across three cohorts. Patient‐control differences in rsFC calculated using seed‐based and dual‐regression approaches were consistent (Cohen's d: 0.31 ± 0.09 and 0.29 ± 0.08, p < 10−4). RsFC measures explained 12–17% of the individual variations in PS and WM in the full sample and in patients and controls separately, with the strongest correlations found in salience, auditory, somatosensory, and default‐mode networks. The pattern of association between rsFC (within‐network) and PS (r =.45, p =.07) and WM (r =.36, p =.16), and rsFC (between‐network) and PS (r =.52, p = 8.4 × 10−3) and WM (r =.47, p =.02), derived from multiple networks was related to effect size of patient‐control differences in the functional networks. No association was detected between rsFC and current medication dose or psychosis ratings. Patients demonstrated significant reduction in several FC networks that may partially underlie some of the core neurocognitive deficits in schizophrenia. The strength of connectivity‐cognition relationships in different networks was strongly associated with network's vulnerability to schizophrenia. [ABSTRACT FROM AUTHOR]

Objective: 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.Methods: 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.Results: 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.Conclusions: 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. [ABSTRACT FROM AUTHOR]

Cognitive mechanisms underlying auditory hallucinations (AH) in schizophrenia have been related to working memory (WM), although the formative mechanism is unknown. The phonological loop refers to subvocal rehearsals of information held online for supporting WM. As WM deficiency is frequent in schizophrenia, we hypothesized that AH and WM deficit share a common dysfunction in phonological loop operation, especially when it is taxed by ambiguous auditory and verbal associations. We developed an active phonological priming (APP) paradigm in which participants generated arbitrary verbal associations to pseudowords with ambiguous meaning. They were later asked to rate their familiarity to each pseudoword, a task that required subvocal evaluation of ambiguous auditory-verbal information. Factor and mediation analyses were used to test the hypothesis that WM, AH, and APP induced phonological bias toward perceiving ambiguous contents as familiar may share a common underlying mechanism. In 32 patients with schizophrenia (SZ) and 20 healthy controls (HC), SZ rated ambiguous pseudowords as significantly more familiar compared with HC (p = .006), indicating a proneness to APP-induced bias. This increased subjective bias to perceive ambiguous contents as familiar after APP significantly correlated with AH severity (p = .001) and mediated the relationship between WM and AH. Factor analysis demonstrated a common latent factor among WM, AH, and the bias induced by active priming to ambiguous contents. A heightened phonological loop priming to ambiguous contents appears to be mechanistically linked to WM deficits and AH in schizophrenia. These findings emphasize the importance of jointly addressing WM deficits and AH in clinical practice and research. (PsycINFO Database Record (c) 2019 APA, all rights reserved). [ABSTRACT FROM AUTHOR]

Memory is robustly impaired in schizophrenia (SZ) and related to functional outcome. Memory dysfunction has been shown to be related to altered brain glucose metabolism and brain insulin resistance in animal models and human studies of Alzheimer's disease. In this study, differences in brain glucose using magnetic resonance spectroscopy (MRS) and blood Extracellular Vesicle (EV) biomarkers of neuronal insulin resistance (i.e. Akt and signaling effectors) between SZ and controls were investigated, as well as whether these measures were related to memory impairments. Neuronal insulin resistance biomarkers showed a trend for being lower in SZ compared to controls, and memory measures were lower in SZ compared to controls. Occipital cortex glucose was higher in SZ compared to controls indicating lower brain glucose utilization. Linear regression analyses revealed significant relationships between neuronal insulin resistance biomarkers, memory measures, and brain glucose. More specifically, p70S6K, an insulin signaling effector, was related to verbal learning and brain MRS glucose in the SZ group. For the first time, we show that memory impairments in SZ may be related to brain glucose and brain insulin resistance. These data suggest that brain insulin resistance may play a role in the pathophysiology of learning and memory dysfunction in SZ. [ABSTRACT FROM AUTHOR]

Abstract Background Inhibitory deficits in motor cortex in schizophrenia have been well demonstrated using short-interval intracortical inhibition (SICI) by transcranial magnetic stimulation. However, it remains unknown whether these deficits originate from dysfunction of motor cortex itself or reflect abnormal modulations of motor cortex by other schizophrenia-related brain areas. Methods The study was completed by 24 patients with schizophrenia spectrum disorders and 30 healthy control subjects. SICI was obtained by delivering transcranial magnetic stimulation over the left motor cortex. Resting-state functional magnetic resonance imaging and diffusion tensor imaging fractional anisotropy were used to measure functional connectivity (FC) and white matter microstructures, respectively. Stimulation sites for SICI at motor cortex were used as the seeds to obtain whole-brain FC maps. Clinical symptoms were assessed with the Brief Psychiatric Rating Scale. Results In schizophrenia, left prefrontal cortex–motor cortex FC was inversely associated with SICI but positively associated with the underlying white matter microstructure at the left corona radiata and also associated with overall symptoms (all corrected p <.05). Mediation analysis showed that the prefrontal-motor cortex FC significantly mediated the corona radiata white matter effects on SICI (p =.007). Conclusions Higher resting-state left prefrontal-motor cortex FC, accompanied by a higher fractional anisotropy of left corona radiata, predicted fewer inhibitory deficits, suggesting that the inhibitory deficits in motor cortex in schizophrenia may in part be mediated by a top-down prefrontal influence. SICI may serve as a robust biomarker indexing inhibitory dysfunction at anatomic as well as circuitry levels in schizophrenia. [ABSTRACT FROM AUTHOR]

Structural imaging studies have consistently found reduced gray matter thickness of the cerebral cortex in schizophrenia, a finding that is evident in first episode psychosis and may be progressive in some cases. Although genetic predisposition and medication effects may contribute to cortical thinning, we hypothesize that the cumulative effects of stress may represent an environmental factor impacting brain morphology in schizophrenia. We examined the relationship between allostatic load, an index of peripheral biomarkers representing the cumulative effects of stress, and cortical thickness. Allostatic load was calculated for 44 patients with schizophrenia spectrum disorders (SSD) and 33 normal controls (NC) based on 13 cardiovascular, neuroendocrine, immune, and metabolic measurements. Controlling for age, SSD had significantly elevated allostatic load as compared with NC (p = 0.008). Controlling for age, whole brain average cortical thickness was lower in SSD patients compared to NC (p = 0.008). However, once allostatic load was accounted for, the group difference in cortical thickness became marginal (p = 0.058). Exploratory analyses on subcomponents of allostatic load suggested that elevated immune marker C-reactive protein, stress hormones, and cardiovascular indices within allostatic load were more strongly associated with reduced cortical thickness in SSD. In NC, only the association between immune marker C-reactive protein and cortical thickness was replicated. These results support the hypothesis that allostatic load may account for some of the gray matter deficits observed in schizophrenia. Among the allostatic indices, the inflammatory mechanism appears particularly relevant to cortical thickness in both schizophrenia patients and normal controls. [ABSTRACT FROM AUTHOR]

Glucocorticoid and immune pathways typically interact dynamically to optimize adaptation to stressful environmental challenges. We tested the hypothesis that a dysfunctional glucocorticoid–immune relationship contributes to abnormal stress response in schizophrenia. Saliva samples from 34 individuals with schizophrenia (20 male, 14 female) and 40 healthy controls (20 male, 20 female) were collected prior to and at 3 time points following completion of a computerized psychological challenge meant to be frustrating. Salivary concentrations of cortisol and interleukin-6 (IL-6) and their response to the challenge were examined. Both cortisol and IL-6 significantly increased in response to stress in the combined sample (both p < .05). In controls, the rise in cortisol following the challenge was negatively correlated to the subsequent changes in IL-6 ( r = −.461, p = .003), such that rise of cortisol immediately after stress predicts subsequently lower IL-6 levels. In contrast, this relationship was positive in schizophrenia patients ( r = .379, p = .027). The trends were significantly different ( Z = 3.7, p = .0002). This stress paradigm induces a rise in both cortisol and IL-6. In healthy controls, a more robust acute cortisol response was associated with a steeper decline of IL-6 levels following stress, corresponding to the expected anti-inflammatory effects of cortisol. Patients exhibited the opposite relationship, suggesting an inability to down-regulate inflammatory responses to psychological stress in schizophrenia; or even a paradoxical increase of IL-6 response. This finding may partially underlie abnormalities in inflammatory and stress pathways previously found in the illness, implicating dysregulated stress response in the chronic inflammatory state in schizophrenia. [ABSTRACT FROM AUTHOR]

In vivo measurement of neurotransmitters and modulators is now feasible with advanced proton magnetic resonance spectroscopy ( 1 H MRS) techniques. This review provides a basic tutorial of MRS, describes the methods available to measure brain glutamate, glutamine, γ-aminobutyric acid, glutathione, N -acetylaspartylglutamate, glycine, and serine at magnetic field strengths of 3 T or higher, and summarizes the neurochemical findings in schizophrenia. Overall, 1 H MRS holds great promise for producing biomarkers that can serve as treatment targets, prediction of disease onset, or illness exacerbation in schizophrenia and other brain diseases. [ABSTRACT FROM AUTHOR]

Introduction Diffusion tensor imaging (DTI) studies in patients with schizophrenia have shown abnormalities in the microstructure of white matter tracts. Specifically, reduced fractional anisotropy (FA) has been described across multiple white matter tracts, in studies that have mainly included patients treated with antipsychotic medications. Objective To compare FA in antipsychotic-naïve patients experiencing a first episode of psychosis (FEP) to FA in healthy controls to demonstrate that the variance of FA can be grouped, in a coincidental manner, in four predetermined factors in accordance with a theoretical partition of the white matter tracts, using a principal components analysis (PCA). Methods Thirty-five antipsychotic-naïve FEP patients and 35 age- and gender-matched healthy controls underwent DTI at 3 T. Analysis was performed using a tract-based spatial statistics (TBSS) method and exploratory PCA. Results DTI analysis showed extensive FA reduction in white matter tracts in FEP patients compared with the control group. The PCA grouped the white matter tracts into four factors explaining 66% of the total variance. Comparison of the FA values within each factor highlighted the differences between FEP patients and controls. Discussion Our study confirms extensive white matter tracts anomalies in patients with schizophrenia, more specifically, in drug-naïve FEP patients. The results also indicate that a small number of white matter tracts share common FA anomalies that relate to deficit symptoms in FEP patients. Our study adds to a growing body of literature emphasizing the need for treatments targeting white matter function and structure in FEP patients. [ABSTRACT FROM AUTHOR]

Elevated rate of age-related decline in white matter integrity, indexed by fractional anisotropy (FA) from diffusion tensor imaging, was reported in patients with schizophrenia. Its etiology is unknown. We hypothesized that a decline of blood perfusion to the white matter may underlie the accelerated age-related reduction in FA in schizophrenia. Resting white matter perfusion and FA were collected using pseudo-continuous arterial spin labeling and high-angular-resolution diffusion tensor imaging, respectively, in 50 schizophrenia patients and 70 controls (age = 18-63 years). Main outcome measures were the diagnosis-by-age interaction on whole-brain white matter perfusion, and FA. Significant age-related decline in brain white matter perfusion and FA were present in both groups. Age-by-diagnosis interaction was significant for FA (p < 0.001) but not white matter perfusion. Age-by-diagnosis interaction for FA values remained significant even after accounting for age-related decline in perfusion. Therefore, we replicated the finding of an increased rate of age-related white matter FA decline in schizophrenia and observed a significant age-related decline in white matter blood perfusion, although the latter did not contribute to the accelerated age-related decline in FA. The results suggest that factors other than reduced perfusion account for the accelerated age-related decline in white matter integrity in schizophrenia. [ABSTRACT FROM AUTHOR]

We hypothesized that reduced fractional anisotropy (FA) of water diffusion and its elevated aging-related decline in schizophrenia patients may be caused by elevated hyperintensive white matter (HWM) lesions, by reduced permeability-diffusivity index (PDI), or both. We tested this hypothesis in 40/30 control/patient participants. FA values for the corpus callosum were calculated from high angular resolution diffusion tensor imaging (DTI). Whole-brain volume of HWM lesions was quantified by 3D-T2w-fluid-attenuated inversion recovery (FLAIR) imaging. PDI for corpus callosum was ascertained using multi b-value diffusion imaging (15 b-shells with 30 directions per shell). Patients had significantly lower corpus callosum FA values, and there was a significant age-by-diagnosis interaction. Patients also had significantly reduced PDI but no difference in HWM volume. PDI and HWM volume were significant predictors of FA and captured the diagnosis-related variance. Separately, PDI robustly explained FA variance in schizophrenia patients, but not in controls. Conversely, HWM volume made equally significant contributions to variability in FA in both groups. The diagnosis-by-age effect of FA was explained by a PDI-by-diagnosis interaction. Post hoc testing showed a similar trend for PDI of gray mater. Our study demonstrated that reduced FA and its accelerated decline with age in schizophrenia were explained by pathophysiology indexed by PDI, rather than HWM volume. [ABSTRACT FROM AUTHOR]

• Deficits in all domains of cognition and hippocampal volume in patients with treatment-resistant schizophrenia as compared to healthy control group. • Only poorer performances in working memory and smaller total hippocampal volume in patients with treatment-resistant schizophrenia by comparisons with matched treatment-responsive patients. • Working memory deficits and smaller hippocampal volume contribute to higher risk of treatment resistance, but not their interactions. Some patients with schizophrenia do not respond to pharmacotherapy. More severe cognitive dysfunctions have been associated with treatment-resistant schizophrenia (TRS). This study examines cognitive functions and hippocampal volumes in 43 patients with TRS and compared them to 43 treatment-responsive patients (NTRS), matched on age, sex and education, as well as 53 healthy controls (HC). The results showed that there were significant deficits in all domains of cognition and hippocampal volumes in TRS as compared to HC group. However, TRS specific deficits, as indicated by comparisons with matched NTRS, were limited to poorer performance in working memory (p = 0.003) and smaller total hippocampal volume (p = 0.01). Logistic regression analysis showed that working memory deficits [ OR 0.94 (95% CI 0.89–0.98), p = 0.005] and smaller hippocampal volume [ OR 0.89 (95% CI 0.81–0.97), p = 0.01], but not their interactions (p = 0.68), contributed to higher risk of treatment resistance. The findings suggest that treatment-resistance to currently available antipsychotic medications may not be due to global cognitive deficits in these patients, but be associated with specific deficits in working memory and hippocampus deficits in the subgroup of schizophrenia. [ABSTRACT FROM AUTHOR]