Katie L. Nugent

Multimodal white matter imaging to investigate reduced fractional anisotropy and its age-related decline in schizophrenia.

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.

Stress-Induced Increase in Kynurenic Acid as a Potential Biomarker for Patients With Schizophrenia and Distress Intolerance

IMPORTANCE Several lines of evidence have linked the endogenous neuromodulator kynurenic acid (KYNA) to schizophrenia. The pathophysiology of schizophrenia is commonly associated with stress, and stress plays a key regulatory role in the first, rate-limiting step of the kynurenine pathway, which produces KYNA. OBJECTIVE To determine whether the level of KYNA changes following psychological stress and whether this change is associated with stress-related behavior. DESIGN, SETTING, AND PARTICIPANTS The KYNA level was measured in saliva samples taken at baseline and at 2 times following a laboratory-based psychological stress challenge in 128 participants (64 patients with schizophrenia from outpatient clinics and 64 healthy controls from the community). EXPOSURE Laboratory-based psychological stress challenge. MAIN OUTCOMES AND MEASURES Quitting the stressful task early was used as a behavioral marker of distress intolerance. RESULTS Patients with schizophrenia showed a significantly higher rate of distress intolerance compared with healthy controls (P = .003). Salivary KYNA levels increased significantly between baseline and 20 minutes following the stress task in both patients and controls (mean [SEM], 6.72nM [0.65nM] vs 8.43nM [1.05nM], respectively; P = .007). Patients who were unable to tolerate the stressful tasks and quit early showed significantly higher levels of KYNA than patients who tolerated the psychological stressor (P = .02) or healthy controls (P = .02). In patients with distress intolerance, KYNA elevation significantly correlated with the severity of clinical symptoms (ρ = 0.64; P = .008). CONCLUSIONS AND RELEVANCE Distress intolerance is more common in patients with schizophrenia. Patients with this behavioral phenotype have elevated salivary KYNA levels. This stress response behavior-linked biomarker may aid heterogeneity reduction in schizophrenia and other stress-related psychiatric conditions.

Schizotypy, psychotic-like experiences and distress: an interaction model.

Psychotic-like experiences (PLEs) have been found to exist on a continuum in both general and clinical populations. Such experiences may characterize normal and abnormal variations in personality, as well as prodromal or high risk states for the development of psychotic disorders. High risk paradigms tend to emphasize distress and impairment associated with PLEs, yet the extent to which individuals find PLEs to be distressing likely depends on moderating factors. In particular, individuals high in trait schizotypy may differ in their appraisal and reaction to PLEs. The current study examines the relationship between schizotypy, PLEs, and distress associated with PLEs in a college sample. Participants (N=355) completed the Schizotypal Personality Questionnaire - Brief Version (SPQ-B), which assesses schizotypal traits, and the Prodromal Questionnaire - Brief Version (PQ-B), which assesses both PLEs and associated distress. Schizotypy was found to significantly moderate the association between PLEs and subjective distress. Individuals high in trait schizotypy reported more PLEs, yet less distress associated with PLEs, relative to individuals low in trait schizotypy. Implications for high-risk state assessment are discussed.

Perfusion shift from white to gray matter may account for processing speed deficits in schizophrenia

Reduced speed of cerebral information processing is a cognitive deficit associated with schizophrenia. Normal information processing speed (PS) requires intact white matter (WM) physiology to support information transfer. In a cohort of 107 subjects (47/60 patients/controls), we demonstrate that PS deficits in schizophrenia patients are explained by reduced WM integrity, which is measured using diffusion tensor imaging, mediated by the mismatch in WM/gray matter blood perfusion, and measured using arterial spin labeling. Our findings are specific to PS, and testing this hypothesis for patient‐control differences in working memory produces no explanation. We demonstrate that PS deficits in schizophrenia can be explained by neurophysiological alterations in cerebral WM. Whether the disproportionately low WM integrity in schizophrenia is due to illness or secondary due to this disorder deserves further examination. Hum Brain Mapp 36:3793–3804, 2015.

Perceived Trauma During Hospitalization and Treatment Participation Among Individuals With Psychotic Disorders

UNLABELLED OBJECTIVE; This study assessed the association of perceptions of traumatic experiences during psychiatric hospitalizations and treatment participation. METHODS Participants (N=395) in the Suffolk County Mental Health Project, who had been admitted for the first time for a psychotic disorder ten years earlier, were interviewed. The authors examined associations of perceived trauma and distressing or coercive experiences during hospitalizations in the past ten years with patient characteristics and treatment participation. RESULTS Sixty-nine percent of participants reported perceived trauma. Perceived trauma was more common among females versus males and homemakers versus full-time workers. It was not associated with treatment seeking or time in treatment. However, reporting forced medication was associated with reduced time in treatment, especially for persons with schizophrenia spectrum disorders. CONCLUSIONS Although perceptions of trauma during psychiatric hospitalization were common, they may be unrelated to treatment participation. However, there was modest evidence of a link between coercive experiences and reduced treatment time.

Distress intolerance and clinical functioning in persons with schizophrenia

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.

Cortisol Reactivity to Stress and Its Association With White Matter Integrity in Adults With Schizophrenia.

Objectives Although acute hypothalamic-pituitary-adrenal axis response to stress is often adaptive, prolonged responses may have detrimental effects. Many components of white matter structures are sensitive to prolonged cortisol exposure. We aimed to identify a behavioral laboratory assay for cortisol response related to brain pathophysiology in schizophrenia. We hypothesized that an abnormally prolonged cortisol response to stress may be linked to abnormal white matter integrity in patients with schizophrenia. Methods Acute and prolonged salivary cortisol response was measured outside the scanner at pretest and then at 0, 20, and 40 minutes after a psychological stress task in patients with schizophrenia (n = 45) and controls (n = 53). Tract-averaged white matter was measured by 64-direction diffusion tensor imaging in a subset of patients (n = 30) and controls (n = 33). Results Patients who did not tolerate the psychological stress task and quit had greater acute (t = 2.52 [p = .016] and t = 3.51 [p = .001] at 0 and 20 minutes) and prolonged (t = 3.62 [p = .001] at 40 minutes) cortisol reactivity compared with patients who finished the task. Abnormally prolonged cortisol reactivity in patients was significantly associated with reduced white matter integrity (r = −0.468, p = .009). Regardless of task completion status, acute cortisol response was not related to the white matter measures in patients or controls. Conclusions This paradigm was successful at identifying a subset of patients whose cortisol response was associated with brain pathophysiology. Abnormal cortisol response may adversely affect white matter integrity, partly explaining this pathology observed in schizophrenia. Prolonged stress responses may be targeted for intervention to test for protective effects against white matter damages.

Association of tardive dyskinesia with variation in CYP2D6: Is there a role for active metabolites?:

Background: The aim of this study was to examine whether there was an association between tardive dyskinesia (TD) and number of functional CYP2D6 genes. Methods: A Caucasian sample of 70 patients was recruited in 1996–1997 from South London and Maudsley National Health Service (NHS) Foundation Trust, UK. Subjects had a DSM-IIIR diagnosis of schizophrenia and were treated with typical antipsychotics at doses equivalent to at least 100 mg chlorpromazine daily for at least 12 months prior to assessment. All patients were genotyped for CYP2D6 alleles*3–5, *41, and for amplifications of the gene. Results: There were 13 patients with TD. The mean (standard deviation (SD)) years of duration of antipsychotic treatment in TD-positive was 15.8 (7.9) vs TD-negative 11.1 (7.4) (p=0.04). Increased odds of experiencing TD were associated with increased ability to metabolize CYP2D6, as measured by genotypic category (odds ratio (OR)=4.2), increasing duration in treatment (OR=1.0), and having drug-induced Parkinsonism (OR=9.7). Discussion: We found a significant association between CYP2D6 genotypic category and TD with the direction of effect being an increase in the number of functional CYP2D6 genes being associated with an increased risk of TD. This is the first study to examine the association between TD and CYP2D6 in Caucasians with this number of genotypic categories. In the future, metabolomics may be utilized in the discovery of biomarkers and novel drug targets.

Assessing Psychotic-Like Symptoms using the BASC-2: Adolescent, Parent, and Teacher Agreement

The aim of the current study was to investigate the psychometric properties of the BASC‐2 (Behavior Assessment System for Children, Second Edition) Atypicality subscale in a sample of adolescents receiving mental health services.

Heritability of complex white matter diffusion traits assessed in a population isolate.

Diffusion weighted imaging (DWI) methods can noninvasively ascertain cerebral microstructure by examining pattern and directions of water diffusion in the brain. We calculated heritability for DWI parameters in cerebral white (WM) and gray matter (GM) to study the genetic contribution to the diffusion signals across tissue boundaries.