Developmental changes in the endorsement of psychotic-like experiences from middle childhood through young adulthood.

BACKGROUND: Children tend to endorse psychotic-like experiences (PLEs) at higher rates than adults, although little is known about how specific symptom endorsement changes across the span of development. Here we take an observational approach to examine trends in PLE endorsement by age in two non-clinical samples: one of school-aged children and another of late adolescents and early adults. METHODS: Prodromal Questionnaire-Brief (child and adult versions) responses were investigated in individuals ages 9-13 (n = 11865) and 16-24 (n = 3209) from the Adolescent Brain and Cognitive Development Study (ABCD) and the Multisite Assessment of Psychosis-risk Study (MAP), respectively. Item-level endorsement and distressing item frequencies were examined by age throughout both cohorts. RESULTS: Unusual perceptual experiences were generally endorsed more heavily in childhood, while other PLEs were endorsed in adolescents and adults up to 4.8 times more frequently than in children. Additionally, certain experiences were endorsed by as many as 73 percent of the older sample. CONCLUSIONS: Considerations for the measurement of PLEs in childhood and adolescence are underscored. Findings from these two samples provide a window into the course of these PLEs and may serve as a scaffold for future research investigating normative versus risk-related experiences during development.

Childhood trauma, perceived stress and anhedonia in individuals at clinical high risk for psychosis: multigroup mediation analysis.

BACKGROUND: Evidence suggests that both childhood trauma and perceived stress are risk factors for the development of psychosis, as well as negative symptoms such as anhedonia. Previous findings link increases in perceived stress to anhedonia in individuals at clinical high risk for psychosis (CHR) and depression; however, the role of childhood trauma in this relationship has not yet been explored, despite consistent evidence that it is associated with sensitisation to later stress. AIMS: To examine whether perceived stress mediates the relationship between childhood trauma and anhedonia in a group of youth at CHR as well as in controls (groups with depression and with no diagnosed mental health concerns). METHOD: The study used multigroup mediation to examine the indirect effects of childhood trauma on anhedonia via perceived stress in CHR (n = 117) and depression groups (n = 284) and non-psychiatric controls (n = 124). RESULTS: Perceived stress mediated the relationship between childhood trauma and consummatory anhedonia regardless of group status. Perceived stress mediated the relationship between childhood trauma and anticipatory anhedonia for the CHR and depression groups, but not for non-psychiatric controls. Further, groups differed in the magnitude of this relationship, with the effects trending towards stronger for those in the CHR group. CONCLUSIONS: Our findings suggest a potential transdiagnostic pathway through which childhood trauma contributes to anhedonia across severe mental illness.

Eveningness chronotype preference among individuals at clinical high risk for psychosis.

BACKGROUND: Circadian rhythm disturbances are frequently implicated in psychosis. Indeed, research has suggested several avenues by which circadian rhythms may play a mechanistic role as well as contribute to clinical outcomes. Despite its potential role as a risk factor, little is known about circadian rhythm disruption among individuals at clinical high risk (CHR) for psychosis, clinical correlates, or specificity to the psychosis risk syndrome. METHODS: Eighty-four CHR, 74 individuals with depressive disorders (DD), and 101 non-psychiatric controls (NPC) participated in structured clinical interviews and provided self-reports of chronotype preference. Clinical (positive, negative, anxious, and depressive symptoms) and social functioning outcomes were self-reported and/or clinician-rated. Analyses of covariance controlling for demographics examined group differences in chronotype preference, and partial Pearson correlations evaluated associations with clinical/functional outcomes. RESULTS: Group differences were observed (F(11, 246) = 8.05, p < .001) with CHR and DD individuals indicating greater eveningness preference compared to NPC. A follow-up sensitivity analysis examining CHR participants with (n = 25) and without (n = 59) depressive disorders indicated no difference in chronotype preference (F(10,72) = 0.00, p = .99). Greater eveningness preference was related to greater negative symptoms (i.e., avolition; r = -0.25) and anxiety (r = -0.34) among CHR individuals. CONCLUSIONS: CHR and DD display greater preference for eveningness chronotype compared to NPC indicating the disruption is associated with a range of mental health concerns, and not specific to the psychosis-risk syndrome. However, comorbidity with DD did not appear to be driving the finding in the CHR group. Further research may examine shared versus non-shared underlying mechanisms contributing to chronotype preference across psychiatric presentations.

Examining self-reported social functioning, sleep quality, and psychotic-like experiences in college students.

Impairments in social and role functioning have been associated with the prodromal phase of psychosis. Additionally, sleep disturbances impacting daily functioning have been detected across the schizophrenia spectrum. Relationships between social functioning, sleep quality, and psychotic-like experiences (PLEs) in undergraduate-level student populations are less understood. The current project aimed to investigate whether self-reported measures of sleep quality would moderate the relationship between social functioning and PLE endorsement in a community sample of 3042 undergraduate student participants between the ages of 18-35. Participants completed the Social Functioning Scale, the Pittsburgh Sleep Quality Index, and the Prodromal Questionnaire, which indexed PLEs. Bivariate correlations revealed significant associations between social functioning, sleep, and PLEs. As expected, poor sleep and poor social functioning were associated with increased endorsement of PLEs. Contrary to expectation, poor sleep quality was associated with better social functioning. In hierarchical multiple regression models, the interaction between social functioning and sleep was not associated with PLE endorsement. Results indicated that both poor sleep and poor social functioning were significantly associated with PLEs when included in the same model. These findings suggest that poor social functioning and disrupted sleep may act additively to influence PLEs, and that they are both important contributors to psychotic symptoms. Due to deleterious effects of poor sleep on physical and emotional health, these findings provide impetus to further investigate relationships between sleep quality, social functioning, and PLEs using such high-resolution methods as actigraphy, mobile sensing, ecological momentary assessment, and neuroimaging.

Metabolite Alterations in Adults With Schizophrenia, First Degree Relatives, and Healthy Controls: A Multi-Region 7T MRS Study.

Proton magnetic resonance spectroscopy (MRS) studies in schizophrenia have shown altered GABAergic, glutamatergic, and bioenergetic pathways, but if these abnormalities are brain region or illness-stage specific is largely unknown. MRS at 7T MR enables reliable quantification of multiple metabolites, including GABA, glutamate (Glu) and glutamine (Gln), from multiple brain regions within the time constraints of a clinical examination. In this study, GABA, Glu, Gln, the ratio Gln/Glu, and lactate (Lac) were quantified using 7T MRS in five brain regions in adults with schizophrenia (N = 40), first-degree relatives (N = 11), and healthy controls (N = 38). Metabolites were analyzed for differences between groups, as well as between subjects with schizophrenia with either short (<5 years, N = 19 or long (>5 years, N = 21) illness duration. For analyses between the three groups, there were significant glutamatergic and GABAergic differences observed in the anterior cingulate, centrum semiovale, and dorsolateral prefrontal cortex. There were also significant relationships between anterior cingulate cortex, centrum semiovale, and dorsolateral prefrontal cortex and cognitive measures. There were also significant glutamatergic, GABAergic, and lactate differences between subjects with long and short illness duration in the anterior cingulate, centrum semiovale, dorsolateral prefrontal cortex, and hippocampus. Finally, negative symptom severity ratings were significantly correlated with both anterior cingulate and centrum semiovale metabolite levels. In summary, 7T MRS shows multi-region differences in GABAergic and glutamatergic metabolites between subjects with schizophrenia, first-degree relatives and healthy controls, suggesting relatively diffuse involvement that evolves with illness duration. Unmedicated first-degree relatives share some of the same metabolic characteristics as patients with a diagnosis of schizophrenia, suggesting that these differences may reflect a genetic vulnerability and are not solely due to the effects of antipsychotic interventions.

Multimodal Neuroimaging Study of Visual Plasticity in Schizophrenia.

Schizophrenia is a severe mental illness with visual learning and memory deficits, and reduced long term potentiation (LTP) may underlie these impairments. Recent human fMRI and EEG studies have assessed visual plasticity that was induced with high frequency visual stimulation, which is thought to mimic an LTP-like phenomenon. This study investigated the differences in visual plasticity in participants with schizophrenia and healthy controls. An fMRI visual plasticity paradigm was implemented, and proton magnetic resonance spectroscopy data were acquired to determine whether baseline resting levels of glutamatergic and GABA metabolites were related to visual plasticity response. Adults with schizophrenia did not demonstrate visual plasticity after family-wise error correction; whereas, the healthy control group did. There was a significant regional difference in visual plasticity in the left visual cortical area V2 when assessing group differences, and baseline GABA levels were associated with this specific ROI in the SZ group only. Overall, this study suggests that visual plasticity is altered in schizophrenia and related to basal GABA levels.

Sex Differences in Subjective Sleep Quality Patterns in Schizophrenia.

OBJECTIVE/BACKGROUND: 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. PARTICIPANTS: Study sample consisted of 75 patients with schizophrenia and 82 healthy controls (HC). METHODS: Participants completed the Pittsburgh Sleep Quality Index (PSQI). RESULTS: 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. CONCLUSIONS: 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.

Sleep quality is related to brain glutamate and symptom severity in schizophrenia.

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.

Brain insulin resistance and altered brain glucose are related to memory impairments in schizophrenia.

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.

Comparing the reproducibility of commonly used magnetic resonance spectroscopy techniques to quantify cerebral glutathione.

BACKGROUND: Cerebral glutathione (GSH), a marker of oxidative stress, has been quantified in neurodegenerative diseases and psychiatric disorders using proton magnetic resonance spectroscopy (MRS). Using a reproducible MRS technique is important, as it minimizes the impact of measurement technique variability on the study results and ensures that other studies can replicate the results. HYPOTHESIS: We hypothesized that very short echo time (TE) acquisitions would have comparable reproducibility to a long TE MEGA-PRESS acquisition, and that the short TE PRESS acquisition would have the poorest reproducibility. STUDY TYPE: Prospective. SUBJECTS/PHANTOMS: Ten healthy adults were scanned during two visits, and six metabolite phantoms containing varying concentrations of GSH and metabolites with resonances that overlap with GSH were scanned once. FIELD STRENGTH/SEQUENCE: At 3T we acquired MRS data using four different sequences: PRESS, SPECIAL, PR-STEAM, and MEGA-PRESS. ASSESSMENT: Reproducibility of each MRS sequence across two visits was assessed. STATISTICAL TESTS: Mean coefficients of variation (CV) and mean absolute difference (AD) were used to assess reproducibility. Linear regressions were performed on data collected from phantoms to examine the agreement between known and quantified levels of GSH. RESULTS: Of the four techniques, PR-STEAM had the lowest mean CV and AD (5.4% and 7.5%, respectively), implying excellent reproducibility, followed closely by PRESS (5.8% and 8.2%) and SPECIAL (8.0 and 10.1%), and finally by MEGA-PRESS (13.5% and 17.1%). Phantom data revealed excellent fits (R2 ≥ 0.98 or higher) using all methods. DATA CONCLUSION: Our data suggest that GSH can be quantified reproducibly without the use of spectral editing. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:176-183.

Glutamatergic metabolites are associated with visual plasticity in humans.

Long-term potentiation (LTP) is a basic cellular mechanism underlying learning and memory. LTP-like plasticity in the visual cortex can be induced by high frequency visual stimulation in rodents and humans. Since glutamate plays a fundamental role in LTP, this study investigated if visual cortical glutamate and glutamine levels, measured by proton magnetic resonance spectroscopy (MRS), relate to visual plasticity in humans. Since plasticity requires a delicate excitation and inhibition balance, GABA was also explored. Eighteen healthy participants completed MRS and a visual fMRI paradigm. Results revealed enhanced fMRI activations after high frequency visual stimulation, suggesting visual plasticity occurred. Higher activations were associated with higher resting glutamine levels after family wise error-correction. Exploratory analyses revealed that higher resting glutamate and GABA levels were associated with visual plasticity, suggesting there may be a critical excitation-inhibition balance necessary for experience dependent plasticity. This is the first empirical evidence that resting glutamine levels and potentially glutamate and GABA levels are associated with visual plasticity in humans.

Altered Glutamate and Regional Cerebral Blood Flow Levels in Schizophrenia: A 1H-MRS and pCASL study.

The neurobiology of schizophrenia (SZ) may be altered in older versus younger adults with SZ, as less frequent episodes of symptom exacerbation and increased sensitivity to medications are observed in older age. The goal of this study was to examine the effect of age and diagnosis on glutamate and cerebral blood flow (rCBF) in adults with SZ and healthy controls. Young and older adults with SZ and healthy controls were recruited to participate in this study. Participants completed a neuropsychological battery and neuroimaging that included optimized magnetic resonance spectroscopy to measure anterior cingulate (AC) glutamate (Glu) and glutamine (Gln) and arterial spin labeling evaluation for rCBF. Regression analyses revealed significant effects of age with Glu, Gln, Gln/Glu, and AC white matter (WM) rCBF. Glu and WM rCBF decreased linearly with age while Gln and Gln/Glu increased linearly with age. Glu was lower in adults with SZ compared with healthy controls and in older adults versus younger adults but there was no interaction. Glu and WM rCBF were correlated with the UCSD Performance-Based Skills Assessment (UPSA) and processing speed, and the correlations were stronger in the SZ group. In the largest sample to date, lower Glu and elevated Gln/Glu levels were observed in adults with SZ and in older subjects. Contrary to expectation, these results do not show evidence of accelerated Glu aging in the anterior cingulate region in SZ compared with healthy controls.

Effectiveness of fast mapping to promote learning in schizophrenia.

Fast mapping (FM), a process that promotes the expeditious incidental learning of information, is thought to support rapid vocabulary acquisition in young children through extra-medial temporal lobe (MTL) regions. A recent study suggested that patients with MTL damage resulting in profound amnesia were able to learn novel word-image associations using an FM paradigm. The present study investigated whether FM would be an effective strategy to promote learning for individuals with schizophrenia, a severe mental illness associated with compromised MTL functionality. Twenty-five patients with schizophrenia and 27 healthy control subjects completed trials of incidental FM encoding (experimental condition) and explicit encoding (EE, control condition) over the course of three visits spaced one week (± 2 days) apart. All participants were evaluated for recognition 10 minutes after each encoding condition was presented, and again one week (± 2 days) later. Results indicate that both groups performed better on the EE recognition trials when compared to FM (p's < 0.05). For the FM recognition trials, both groups performed similarly. However, participants with schizophrenia performed significantly worse on the EE recognition trials than healthy control participants (p's < 0.05). While participants with schizophrenia did not perform significantly worse when assessed for FM recognition, these results do not provide enough evidence to suggest that FM facilitates learning to a greater extent in schizophrenia when compared to EE. Whether FM may benefit a subgroup of patients with schizophrenia remains a focus of further investigation.

Reproducibility of phase rotation STEAM at 3T: focus on glutathione.

PURPOSE: The purpose of this study was to determine the reproducibility of a very short echo time (TE) phase rotation stimulated echo acquisition mode (STEAM) sequence at 3T with a focus on the detection of glutathione. METHODS: Ten healthy subjects were scanned on two separate visits. Spectra were acquired from voxels placed in the anterior and posterior cingulates. Reproducibility was assessed using mean coefficients of variation (CVs) and mean absolute differences (ADs), and reliability was assessed using standard error of measurement (SEM) and intraclass correlations (ICCs). Phantoms containing glutathione and metabolites with overlapping resonances were scanned to test the validity of glutathione quantification. RESULTS: Excellent reproducibility as illustrated by CVs ≤8.3% and ADs ≤11.6% for both regions was obtained for glutathione and other commonly reported metabolites. Reproducibility measures for γ-aminobutyric acid and glutamine were good overall with CVs ranging from 6.4%-10.5% and ADs ranging from 8.6%-15.5% for both regions. Glutathione absolute and relative reliability were very good (SEMs ≤9.9%) and fair (ICCs = 0.42-0.51), respectively. Phantom studies demonstrated the ability to accurately detect glutathione from other metabolites with overlapping resonances with great precision (R(2) = 0.99). CONCLUSION: A very short TE phase rotation STEAM sequence proved reproducible for metabolites difficult to quantify but important for the study of psychiatric and neurological illness.