The Cascade of Care for Early Psychosis Detection in a College Counseling Center.

OBJECTIVE: Programs for early detection of psychosis help identify individuals experiencing emerging psychosis and link them with appropriate services, thereby reducing the duration of untreated psychosis (DUP). The authors used the cascade-of-care framework to identify various care stages between screening and enrollment in coordinated specialty care (CSC) and to determine attrition at each stage, with the goal of identifying points in the referral process that may affect DUP. METHODS: Project partners included a college counseling center and CSC program. All college students seeking mental health services at a counseling center between 2020 and 2022 (N=1,945) completed the Prodromal Questionnaire-Brief (PQ-B) at intake. Students who met the distress cutoff score were referred for a phone screening. Those who met criteria on the basis of this screening were referred for assessment and possible enrollment into CSC. RESULTS: Six stages in the cascade of care for early detection were identified. Of the students who completed the PQ-B as part of intake (stage 1), 547 (28%) met the PQ-B cutoff score (stage 2). Counselors referred 428 (78%) students who met the PQ-B cutoff score (stage 3), and 212 (50%) of these students completed the phone screening (stage 4). Seventy-two (34%) students completed a CSC eligibility assessment (stage 5), 21 (29%) of whom were enrolled in CSC (stage 6). CONCLUSIONS: The cascade-of-care framework helped conceptualize the flow within a program for early psychosis detection in order to identify stages that may contribute to lengthier DUP. Future research is warranted to better understand the factors that contribute to DUP at these stages.

Trauma exposure and disclosure in Hispanic youth at clinical high risk for psychosis: A retrospective review study.

AIM: This exploratory study aimed to examine differences in rates of self and clinician-reports of trauma in youth at clinical high risk for psychosis (CHR) and whether rates of reporting differed by ethnicity. METHODS: Self-reported history of trauma was collected at intake amongst youth at CHR enrolled in Coordinated Specialty Care (CSC) services (N = 52). A structured chart review was conducted for the same sample to identify clinician-reported history of trauma throughout treatment in CSC. RESULTS: For all patients, frequency of self-reported trauma at intake to CSC (56%) was lower compared to clinician-reports of trauma throughout treatment (85%). Hispanic patients self-reported trauma at intake (35%) less frequently than non-Hispanics (69%) (p = .02). No differences were found in clinician reported exposure to trauma by ethnicity throughout treatment. CONCLUSION: Whilst further research is needed, these findings suggest the need for formalised, repeated, and culturally appropriate assessments of trauma within CSC.

Toll-Like Receptor mRNA Levels in Schizophrenia: Association With Complement Factors and Cingulate Gyrus Cortical Thinning.

BACKGROUND AND HYPOTHESES: Previous studies revealed innate immune system activation in people with schizophrenia (SZ), potentially mediated by endogenous pathogen recognition receptors, notably Toll-like receptors (TLR). TLRs are activated by pathogenic molecules like bacterial lipopolysaccharides (TLR1 and TLR4), viral RNA (TLR3), or both (TLR8). Furthermore, the complement system, another key component of innate immunity, has previously been linked to SZ. STUDY DESIGN: Peripheral mRNA levels of TLR1, TLR3, TLR4, and TLR8 were compared between SZ and healthy controls (HC). We investigated their relationship with immune activation through complement expression and cortical thickness of the cingulate gyrus, a region susceptible to immunological hits. TLR mRNA levels and peripheral complement receptor mRNA were extracted from 86 SZ and 77 HC white blood cells; structural MRI scans were conducted on a subset. STUDY RESULTS: We found significantly higher TLR4 and TLR8 mRNA levels and lower TLR3 mRNA levels in SZ compared to HC. TLRs and complemental factors were significantly associated in SZ and HC, with the strongest deviations of TLR mRNA levels in the SZ subgroup having elevated complement expression. Cortical thickness of the cingulate gyrus was inversely associated with TLR8 mRNA levels in SZ, and with TLR4 and TLR8 levels in HC. CONCLUSIONS: The study underscores the role of innate immune activation in schizophrenia, indicating a coordinated immune response of TLRs and the complement system. Our results suggest there could be more bacterial influence (based on TLR 4 levels) as opposed to viral influence (based on TLR3 levels) in schizophrenia. Specific TLRs were associated with brain cortical thickness reductions of limbic brain structures.

Adjunctive canakinumab reduces peripheral inflammation markers and improves positive symptoms in people with schizophrenia and inflammation: A randomized control trial.

BACKGROUND: Clinical trials of anti-inflammatories in schizophrenia do not show clear and replicable benefits, possibly because patients were not recruited based on elevated inflammation status. Interleukin 1-beta (IL-1ß) mRNA and protein levels are increased in serum, plasma, cerebrospinal fluid, and brain of some chronically ill patients with schizophrenia, first episode psychosis, and clinical high-risk individuals. Canakinumab, an approved anti-IL-1ß monoclonal antibody, interferes with the bioactivity of IL-1ß and interrupts downstream signaling. However, the extent to which canakinumab reduces peripheral inflammation markers, such as, high sensitivity C-reactive protein (hsCRP) and symptom severity in schizophrenia patients with inflammation is unknown. TRIAL DESIGN: We conducted a randomized, placebo-controlled, double-blind, parallel groups, 8-week trial of canakinumab in chronically ill patients with schizophrenia who had elevated peripheral inflammation. METHODS: Twenty-seven patients with schizophrenia or schizoaffective disorder and elevated peripheral inflammation markers (IL-1ß, IL-6, hsCRP and/or neutrophil to lymphocyte ratio: NLR) were randomized to a one-time, subcutaneous injection of canakinumab (150 mg) or placebo (normal saline) as an adjunctive antipsychotic treatment. Peripheral blood hsCRP, NLR, IL-1ß, IL-6, IL-8 levels were measured at baseline (pre injection) and at 1-, 4- and 8-weeks post injection. Symptom severity was assessed at baseline and 4- and 8-weeks post injection. RESULTS: Canakinumab significantly reduced peripheral hsCRP over time, F(3, 75) = 5.16, p = 0.003. Significant hsCRP reductions relative to baseline were detected only in the canakinumab group at weeks 1, 4 and 8 (p's = 0.0003, 0.000002, and 0.004, respectively). There were no significant hsCRP changes in the placebo group. Positive symptom severity scores were significantly reduced at week 8 (p = 0.02) in the canakinumab group and week 4 (p = 0.02) in the placebo group. The change in CRP between week 8 and baseline (b = 1.9, p = 0.0002) and between week 4 and baseline (b = 6.0, p = 0.001) were highly significant predictors of week 8 change in PANSS Positive Symptom severity scores. There were no significant changes in negative symptoms, general psychopathology or cognition in either group. Canakinumab was well tolerated and only 7 % discontinued. CONCLUSIONS: Canakinumab quickly reduces peripheral hsCRP serum levels in patients with schizophrenia and inflammation; after 8 weeks of canakinumab treatment, the reductions in hsCRP are related to reduced positive symptom severity. Future studies should consider increased doses or longer-term treatment to confirm the potential benefits of adjunctive canakinumab in schizophrenia. Australian and New Zealand Clinical Trials Registry number: ACTRN12615000635561.

Characterizing Subcortical Structural Heterogeneity in Autism.

Autism presents with significant phenotypic and neuroanatomical heterogeneity, and neuroimaging studies of the thalamus, globus pallidus and striatum in autism have produced inconsistent and contradictory results. These structures are critical mediators of functions known to be atypical in autism, including sensory gating and motor function. We examined both volumetric and fine-grained localized shape differences in autism using a large (n=3145, 1045-1318 after strict quality control), cross-sectional dataset of T1-weighted structural MRI scans from 32 sites, including both males and females (assigned-at-birth). We investigated three potentially important sources of neuroanatomical heterogeneity: sex, age, and intelligence quotient (IQ), using a meta-analytic technique after strict quality control to minimize non-biological sources of variation. We observed no volumetric differences in the thalamus, globus pallidus, or striatum in autism. Rather, we identified a variety of localized shape differences in all three structures. Including age, but not sex or IQ, in the statistical model improved the fit for both the pallidum and striatum, but not for the thalamus. Age-centered shape analysis indicated a variety of age-dependent regional differences. Overall, our findings help confirm that the neurodevelopment of the striatum, globus pallidus and thalamus are atypical in autism, in a subtle location-dependent manner that is not reflected in overall structure volumes, and that is highly non-uniform across the lifespan.

Longitudinal Changes in Structural Connectivity in Young People at High Genetic Risk for Bipolar Disorder.

OBJECTIVE: Recent studies of patients with bipolar disorder or at high genetic risk reveal structural dysconnections among key brain networks supporting cognitive and affective processes. Understanding the longitudinal trajectories of these networks across the peak age range of bipolar disorder onset could inform mechanisms of illness onset or resilience. METHODS: Longitudinal diffusion-weighted MRI and phenotypic data were acquired at baseline and after 2 years in 183 individuals ages 12-30 years in two cohorts: 97 unaffected individuals with a first-degree relative with bipolar disorder (the high-risk group) and 86 individuals with no family history of mental illness (the control group). Whole-brain structural networks were derived using tractography, and longitudinal changes in these networks were studied using network-based statistics and mixed linear models. RESULTS: Both groups showed widespread longitudinal changes, comprising both increases and decreases in structural connectivity, consistent with a shared neurodevelopmental process. On top of these shared changes, high-risk participants showed weakening of connectivity in a network encompassing the left inferior and middle frontal areas, left striatal and thalamic structures, the left fusiform, and right parietal and occipital regions. Connections among these regions strengthened in the control group, whereas they weakened in the high-risk group, shifting toward a cohort with established bipolar disorder. There was marginal evidence for even greater network weakening in those who had their first manic or hypomanic episode before follow-up. CONCLUSIONS: Neurodevelopment from adolescence into early adulthood is associated with a substantial reorganization of structural brain networks. Differences in these maturational processes occur in a multisystem network in individuals at high genetic risk of bipolar disorder. This may represent a novel candidate to understand resilience and predict conversion to bipolar disorder.

Feasibility of a virtual reality-based exercise intervention and low-cost motion tracking method for estimation of motor proficiency in youth with autism spectrum disorder.

BACKGROUND: Motor impairment is widely acknowledged as a core feature in children with autism spectrum disorder (ASD), which can affect adaptive behavior and increase severity of symptoms. Low-cost motion capture and virtual reality (VR) game technologies hold a great deal of promise for providing personalized approaches to motor intervention in ASD. The present study explored the feasibility, acceptability and potential efficacy of a custom-designed VR game-based intervention (GaitWayXR™) for improving gross motor skills in youth with ASD. METHODS: Ten children and adolescents (10-17 years) completed six, 20-min VR-based motor training sessions over 2 weeks while whole-body movement was tracked with a low-cost motion capture system. We developed a methodology for using motion tracking data to quantify whole-body movement in terms of efficiency, synchrony and symmetry. We then studied the relationships of the above quantities with standardized measures of motor skill and cognitive flexibility. RESULTS: Our results supported our presumption that the VR intervention is safe, with no adverse events and very few minor to moderate side-effects, while a large proportion of parents said they would use the VR game at home, the most prohibitive reasons for adopting the system for home therapy were cost and space. Although there was little evidence of any benefits of the GaitWayXR™ intervention in improving gross motor skills, we showed several positive correlations between the standardized measures of gross motor skills in ASD and our measures of efficiency, symmetry and synchrony from low-cost motion capture. CONCLUSIONS: These findings, though preliminary and limited by small sample size, suggest that low-cost motion capture of children with ASD is feasible with movement exercises in a VR-based game environment. Based on these preliminary findings, we recommend conducting larger-scale studies with methods for improving adherence to VR gaming interventions over longer periods.

In vivo hippocampal subfield volumes in bipolar disorder-A mega-analysis from The Enhancing Neuro Imaging Genetics through Meta-Analysis Bipolar Disorder Working Group.

The hippocampus consists of anatomically and functionally distinct subfields that may be differentially involved in the pathophysiology of bipolar disorder (BD). Here we, the Enhancing NeuroImaging Genetics through Meta-Analysis Bipolar Disorder workinggroup, study hippocampal subfield volumetry in BD. T1-weighted magnetic resonance imaging scans from 4,698 individuals (BD = 1,472, healthy controls [HC] = 3,226) from 23 sites worldwide were processed with FreeSurfer. We used linear mixed-effects models and mega-analysis to investigate differences in hippocampal subfield volumes between BD and HC, followed by analyses of clinical characteristics and medication use. BD showed significantly smaller volumes of the whole hippocampus (Cohen's d = -0.20), cornu ammonis (CA)1 (d = -0.18), CA2/3 (d = -0.11), CA4 (d = -0.19), molecular layer (d = -0.21), granule cell layer of dentate gyrus (d = -0.21), hippocampal tail (d = -0.10), subiculum (d = -0.15), presubiculum (d = -0.18), and hippocampal amygdala transition area (d = -0.17) compared to HC. Lithium users did not show volume differences compared to HC, while non-users did. Antipsychotics or antiepileptic use was associated with smaller volumes. In this largest study of hippocampal subfields in BD to date, we show widespread reductions in nine of 12 subfields studied. The associations were modulated by medication use and specifically the lack of differences between lithium users and HC supports a possible protective role of lithium in BD.

Peripheral complement is increased in schizophrenia and inversely related to cortical thickness.

BACKGROUND: There is growing evidence for complement system involvement in the pathophysiology of schizophrenia, although the extent and magnitude of complement factor disturbances has not been fully reported. It also remains unclear whether complement abnormalities are characteristic of all patients with schizophrenia or whether they are representative of a subgroup of patients who show signs of heightened inflammation. The aim of the present study was to quantify and compare the levels of a range of complement factors, receptors and regulators in healthy controls and people with schizophrenia and to determine the extent to which the levels of these peripheral molecules relate to measures of brain structure, particularly cortical thickness. METHOD: Seventy-five healthy controls and 90 patients with schizophrenia or schizoaffective disorder were included in the study. Peripheral blood samples were collected from all participants and mRNA expression was quantified in 20 complement related genes, four complement proteins, as well as for four cytokines. T1-weighted structural MRI scans were acquired and analysed to determine cortical thickness measures. RESULTS: There were significant increases in peripheral mRNA encoding receptors (C5ar1, CR1, CR3a), regulators (CD55, C59) and protein concentrations (C3, C3b, C4) in people with schizophrenia relative to healthy controls. C4a expression was significantly increased in a subgroup of patients displaying elevated peripheral cytokine levels. A higher inflammation index score derived from mRNA expression patterns predicted reductions in cortical thickness in the temporal lobe (superior temporal gyrus, transverse temporal gyrus, fusiform gyrus, insula) in patients with schizophrenia and healthy controls. CONCLUSIONS: Analysis of all three major complement pathways supports increased complement activity in schizophrenia and also shows that peripheral C4a up-regulation is related to increased peripheral pro-inflammatory cytokines in healthy controls. Our region-specific, neuroimaging findings linked to an increased peripheral complement mRNA expression pattern suggests a role for complement in cortical thinning. Further studies are required to further clarify clinical and neurobiological consequences of aberrant complement levels in schizophrenia and related psychoses.

Longitudinal Structural Brain Changes in Bipolar Disorder: A Multicenter Neuroimaging Study of 1232 Individuals by the ENIGMA Bipolar Disorder Working Group.

BACKGROUND: Bipolar disorder (BD) is associated with cortical and subcortical structural brain abnormalities. It is unclear whether such alterations progressively change over time, and how this is related to the number of mood episodes. To address this question, we analyzed a large and diverse international sample with longitudinal magnetic resonance imaging (MRI) and clinical data to examine structural brain changes over time in BD. METHODS: Longitudinal structural MRI and clinical data from the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) BD Working Group, including 307 patients with BD and 925 healthy control subjects, were collected from 14 sites worldwide. Male and female participants, aged 40 ± 17 years, underwent MRI at 2 time points. Cortical thickness, surface area, and subcortical volumes were estimated using FreeSurfer. Annualized change rates for each imaging phenotype were compared between patients with BD and healthy control subjects. Within patients, we related brain change rates to the number of mood episodes between time points and tested for effects of demographic and clinical variables. RESULTS: Compared with healthy control subjects, patients with BD showed faster enlargement of ventricular volumes and slower thinning of the fusiform and parahippocampal cortex (0.18

Increased Glutamate Plus Glutamine in the Right Middle Cingulate in Early Schizophrenia but Not in Bipolar Psychosis: A Whole Brain 1H-MRS Study.

Proton magnetic resonance spectroscopy (1H-MRS) studies have examined glutamatergic abnormalities in schizophrenia and bipolar-I disorders, mostly in single voxels. Though the critical nodes remain unknown, schizophrenia and bipolar-I involve brain networks with broad abnormalities. To provide insight on the biochemical differences that may underlie these networks, the combined glutamine and glutamate signal (Glx) and other metabolites were examined in patients in early psychosis with whole brain 1H-MRS imaging (1H-MRSI). Data were acquired in young schizophrenia subjects (N = 48), bipolar-I subjects (N = 21) and healthy controls (N = 51). Group contrasts for Glx, as well as for N-acetyl aspartate, choline, myo-inositol and creatine, from all voxels that met spectral quality criteria were analyzed in standardized brain space, followed by cluster-corrected level alpha-value (CCLAV ≤ 0.05) analysis. Schizophrenia subjects had higher Glx in the right middle cingulate gyrus (19 voxels, CCLAV = 0.05) than bipolar-I subjects. Healthy controls had intermediate Glx values, though not significant. Schizophrenia subjects also had higher N-acetyl aspartate (three clusters, left occipital, left frontal, right frontal), choline (two clusters, left and right frontal) and myo-inositol (one cluster, left frontal) than bipolar-I, with healthy controls having intermediate values. These increases were likely accounted for by antipsychotic medication effects in the schizophrenia subgroup for N-acetyl aspartate and choline. Likewise, creatine was increased in two clusters in treated vs. antipsychotic-naïve schizophrenia, supporting a medication effect. Conversely, the increments in Glx in right cingulate were not driven by antipsychotic medication exposure. We conclude that increments in Glx in the cingulate may be critical to the pathophysiology of schizophrenia and are consistent with the NMDA hypo-function model. This model however may be more specific to schizophrenia than to psychosis in general. Postmortem and neuromodulation schizophrenia studies focusing on right cingulate, may provide critical mechanistic and therapeutic advancements, respectively.

Characteristics of Hispanics Referred to Coordinated Specialty Care for First-Episode Psychosis and Factors Associated With Enrollment.

OBJECTIVE: The primary objectives of this study were to examine referral sources and demographic, clinical, and socioenvironmental characteristics of Hispanics referred to and enrolled in a program of coordinated specialty care (Early CSC program) for first-episode psychosis, to compare them with characteristics of other referred and enrolled racial-ethnic groups, and to identify factors associated with enrollment in the program. METHODS: A retrospective review was conducted for all individuals referred to and enrolled in the Early CSC program over a 2-year period. Extracted data included referral sources and demographic and clinical characteristics. Zip code-level data from publicly available sources were cross-referenced with individual records. Nonparametric tests and appropriate secondary analysis were used to determine significant differences across racial-ethnic groups referred to (N=180) or enrolled in (N=75) the Early CSC program. A random forest model was used to determine which factors or interacting factors were associated with enrollment among the eligible referrals (N=114). RESULTS: Hispanic individuals were more likely to be referred from inpatient or outpatient mental health providers and not from other community sources. Among eligible Hispanic referrals, those who lived in areas with a lower percentage of Spanish speaking in the home were more likely to enroll in services, compared with those who lived in areas with a higher percentage of Spanish speaking. CONCLUSIONS: Continued exploration of factors associated with referral and enrollment in CSC programs for the growing Hispanic ethnic group in the United States can help determine best steps for developing these programs.

Increased peripheral inflammation in schizophrenia is associated with worse cognitive performance and related cortical thickness reductions.

While the biological substrates of brain and behavioural changes in persons with schizophrenia remain unclear, increasing evidence implicates that inflammation is involved. In schizophrenia, including first-episode psychosis and anti-psychotic naïve patients, there are numerous reports of increased peripheral inflammation, cognitive deficits and neuropathologies such as cortical thinning. Research defining the relationship between inflammation and schizophrenia symptomatology and neuropathology is needed. Therefore, we analysed the level of C-reactive protein (CRP), a peripheral inflammation marker, and its relationship with cognitive functioning in a cohort of 644 controls and 499 schizophrenia patients. In a subset of individuals who underwent MRI scanning (99 controls and 194 schizophrenia cases), we tested if serum CRP was associated with cortical thickness. CRP was significantly increased in schizophrenia patients compared to controls, co-varying for age, sex, overweight/obesity and diabetes (p < 0.006E-10). In schizophrenia, increased CRP was mildly associated with worse performance in attention, controlling for age, sex and education (R =- 0.15, p = 0.001). Further, increased CRP was associated with reduced cortical thickness in three regions related to attention: the caudal middle frontal, the pars opercularis and the posterior cingulate cortices, which remained significant after controlling for multiple comparisons (all p < 0.05). Together, these findings indicate that increased peripheral inflammation is associated with deficits in cognitive function and brain structure in schizophrenia, especially reduced attention and reduced cortical thickness in associated brain regions. Using CRP as a biomarker of peripheral inflammation in persons with schizophrenia may help to identify vulnerable patients and those that may benefit from adjunctive anti-inflammatory treatments.

Examining the Boundary Sharpness Coefficient as an Index of Cortical Microstructure in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is associated with atypical brain development. However, the phenotype of regionally specific increased cortical thickness observed in ASD may be driven by several independent biological processes that influence the gray/white matter boundary, such as synaptic pruning, myelination, or atypical migration. Here, we propose to use the boundary sharpness coefficient (BSC), a proxy for alterations in microstructure at the cortical gray/white matter boundary, to investigate brain differences in individuals with ASD, including factors that may influence ASD-related heterogeneity (age, sex, and intelligence quotient). Using a vertex-based meta-analysis and a large multicenter structural magnetic resonance imaging (MRI) dataset, with a total of 1136 individuals, 415 with ASD (112 female; 303 male), and 721 controls (283 female; 438 male), we observed that individuals with ASD had significantly greater BSC in the bilateral superior temporal gyrus and left inferior frontal gyrus indicating an abrupt transition (high contrast) between white matter and cortical intensities. Individuals with ASD under 18 had significantly greater BSC in the bilateral superior temporal gyrus and right postcentral gyrus; individuals with ASD over 18 had significantly increased BSC in the bilateral precuneus and superior temporal gyrus. Increases were observed in different brain regions in males and females, with larger effect sizes in females. BSC correlated with ADOS-2 Calibrated Severity Score in individuals with ASD in the right medial temporal pole. Importantly, there was a significant spatial overlap between maps of the effect of diagnosis on BSC when compared with cortical thickness. These results invite studies to use BSC as a possible new measure of cortical development in ASD and to further examine the microstructural underpinnings of BSC-related differences and their impact on measures of cortical morphology.

Cortical mediation of relationships between dopamine receptor D2 and cognition is absent in youth at risk of bipolar disorder.

Bipolar disorder is associated with cognitive deficits and cortical changes for which the developmental dynamics are not well understood. The dopamine D2 receptor (DRD2) gene has been associated with both psychiatric disorders and cognitive variability. Here we examined the mediating role of brain structure in the relationship between DRD2 genomic variation and cognitive performance, with target cortical regions selected based on evidence of association with DRD2, bipolar disorder and/or cognition from prior literature. Participants (n = 143) were aged 12-30 years and comprised 62 first-degree relatives of bipolar patients (deemed 'at-risk'), 55 controls, and 26 patients with established bipolar disorder; all were unrelated Caucasian individuals with complete data across the three required modalities (structural magnetic resonance imaging, neuropsychological and genetic data). A DRD2 haplotype was derived from three functional polymorphisms (rs1800497, rs1076560, rs2283265) associated with alternative splicing (i.e., D2-short/-long isoforms). Moderated mediation analyses explored group differences in relationships between this DRD2 haplotype, three structural brain networks which subsume the identified cortical regions of interest (frontoparietal, dorsal-attention, and ventral-attention), and three cognitive indices (intelligence, attention, and immediate memory). Controls who were homozygous for the DRD2 major haplotype demonstrated greater cognitive performance as a result of dorsal-attention network mediation. However, this association was absent in the 'at-risk' group. This study provides the first evidence of a functional DRD2-brain-cognition pathway. The absence of typical brain-cognition relationships in young 'at-risk' individuals may reflect biological differences that precede illness onset. Further insight into early pathogenic processes may facilitate targeted early interventions.

Impact of gonadectomy on maturational changes in brain volume in adolescent macaques.

Adolescence is a transitional period between childhood and adulthood characterized by significant changes in global and regional brain tissue volumes. It is also a period of increasing vulnerability to psychiatric illness. The relationship between these patterns and increased levels of circulating sex steroids during adolescence remains unclear. The objective of the current study was to determine whether gonadectomy, prior to puberty, alters adolescent brain development in male rhesus macaques. Ninety-six structural MRI scans were acquired from 12 male rhesus macaques (8 time points per animal over a two-year period). Six animals underwent gonadectomy and 6 animals underwent a sham operation at 29 months of age. Mixed-effects models were used to determine whether gonadectomy altered developmental trajectories of global and regional brain tissue volumes. We observed a significant effect of gonadectomy on the developmental trajectory of prefrontal gray matter (GM), with intact males showing peak volumes around 3.5 years of age with a subsequent decline. In contrast, prefrontal GM volumes continued to increase in gonadectomized males until the end of the study. We did not observe a significant effect of gonadectomy on prefrontal white matter or on any other global or regional brain tissue volumes, though we cannot rule out that effects might be detected in a larger sample. Results suggest that the prefrontal cortex is more vulnerable to gonadectomy than other brain regions.

Cortisol-dehydroepiandrosterone ratios are inversely associated with hippocampal and prefrontal brain volume in schizophrenia.

While high levels of glucocorticoids are generally neuro-damaging, a related adrenal steroid, dehydroepiandrosterone (DHEA), has anti-glucocorticoid and neuroprotective properties. Previous work has shown increased circulating levels of DHEA and abnormal cortisol/DHEA ratios in people with schizophrenia, however reports are limited and their relationship to neuropathology is unclear. We performed the largest study to date to compare levels of serum DHEA and cortisol/DHEA ratios in people with schizophrenia and healthy controls, and investigated the extent to which cortisol/DHEA ratios predict brain volume. Serum cortisol and DHEA were assayed in 94 people with schizophrenia and 81 healthy controls. T1-weighted high-resolution anatomical scans were obtained using a 3 T Achieva scanner on a subset of 59 people with schizophrenia and 60 healthy controls. Imaging data were preprocessed and analyzed using SPM12. People with schizophrenia had significantly increased serum DHEA levels (p = 0.002), decreased cortisol/DHEA ratios (p = 0.02) and no difference in cortisol levels compared to healthy controls. Cortisol/DHEA ratios were inversely correlated with hippocampal (r = -0.33 p = 0.01) and dorsolateral prefrontal cortex (r = -0.30, p = 0.02) volumes in patients. Our findings suggest that the cortisol/DHEA ratio may be a molecular blood signature of hippocampal and cortical damage. These results further implicate the role of DHEA and hypothalamic-pituitary-adrenal axis dysfunction in the pathophysiology of schizophrenia.

Glutamatergic hypo-function in the left superior and middle temporal gyri in early schizophrenia: a data-driven three-dimensional proton spectroscopic imaging study.

Proton magnetic resonance spectroscopy (1H-MRS) studies have examined glutamatergic abnormalities in schizophrenia, mostly in single voxels. Though the critical brain nodes remain unknown, schizophrenia involves networks with broad abnormalities. Hence, glutamine plus glutamate (Glx) and other metabolites were examined with whole-brain 1H-MRS, in early schizophrenia. Three dimensional 1H-MRS was acquired in young schizophrenia subjects (N = 36, 19 antipsychotic-naïve and 17 antipsychotic-treated) and healthy controls (HC, N = 29). Glx (as well as N-acetylaspartate, choline, myo-inositol and creatine) group contrasts from all individual voxels that met spectral quality, were analyzed in common brain space, followed by cluster-corrected level alpha-value (CCLAV ≤ 0.05). Schizophrenia subjects had lower Glx in the left superior (STG) and middle temporal gyri (16 voxels, CCLAV = 0.04) and increased creatine in two clusters involving left temporal, parietal and occipital regions (32, and 18 voxels, CCLAV = 0.02 and 0.04, respectively). Antipsychotic-treated and naïve patients (vs HC) had similar Glx reductions (8/16 vs 10/16 voxels respectively, but CCLAV's > 0.05). However, creatine was higher in antipsychotic-treated vs HC's in a larger left hemisphere cluster (100 voxels, CCLAV = 0.01). Also in treated patients, choline was increased in left middle frontal gyrus (18 voxels, CCLAV = 0.04). Finally in antipsychotic-naive patients, NAA was reduced in right frontal gyri (19 voxels, CCLAV = 0.05) and myo-inositol was reduced in the left cerebellum (34 voxels, CCLAV = 0.02). We conclude that data-driven spectroscopic brain examination supports that reductions in Glx in the left STG may be critical to the pathophysiology of schizophrenia. Postmortem and neuromodulation schizophrenia studies focusing on left STG, may provide critical mechanistic and therapeutic advancements, respectively.