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The putamen has been implicated in depressive disorders, but how its structure and function increase depression risk is not clearly understood. Here, we examined how putamen volume, neuronal density, and mood-modulated functional activity relate to family history and prospective course of depression. The study includes 115 second- and third-generation offspring at high or low risk for depression based on the presence or absence of major depressive disorder in the first generation. Offspring were followed longitudinally using semistructured clinical interviews blinded to their familial risk; putamen structure, neuronal integrity, and functional activation were indexed by structural magnetic resonance imaging (MRI), proton magnetic resonance spectroscopy (N -acetylaspartate/creatine ratio), and functional MRI activity modulated by valence and arousal components of a mood induction task, respectively. After adjusting for covariates, the high-risk individuals had lower putamen volume (standardized betas, β- left = −0.17, β- right = −0.15, p s =.002), N -acetylaspartate/creatine ratio (β- left = −0.40, β- right = −0.37, p s <.0001), and activation modulated by valence (β- left = −0.22, β- right = −0.27, p s <.05) than low-risk individuals. Volume differences were greater at younger ages, and N -acetylaspartate/creatine ratio differences were greater at older ages. Lower putamen volume also predicted major depressive disorder episodes up to 8 years after the scan (β- left = −0.72, p =.013; β- right = −0.83, p =.037). Magnetic resonance spectroscopy and task functional MRI measures were modestly correlated (0.27 ≤ r ≤ 0.33). Findings demonstrate abnormalities in putamen structure and function in individuals at high risk for major depressive disorder. Future studies should focus on this region as a potential biomarker for depressive illness, noting meanwhile that differences attributable to family history may peak at different ages based on which MRI modality is being used to assay them. [ABSTRACT FROM AUTHOR]

BackgroundStudies of biomarkers of hypothalamic-pituitary-adrenal activity indicate that psychotic disorders are associated with elevated cortisol. This study examined cortisol levels in healthy control subjects and individuals who met clinical high-risk (CHR) criteria for psychosis. It was hypothesized that cortisol levels would be 1) elevated in the CHR group relative to control subjects, 2) positively correlated with symptom severity, and 3) most elevated in CHR patients who transition to psychotic level severity.MethodsBaseline assessments were conducted at eight centers in the North American Prodrome Longitudinal Study. The present CHR sample included 256 individuals meeting the Scale for Prodromal Symptoms criteria and 141 control subjects, all of whom underwent baseline assessment and measurement of salivary cortisol.ResultsConsistent with previous reports, there was an effect of age on cortisol, with increases through the adolescent/early adult years. Analysis of covariance showed a main effect of diagnostic group, with the CHR group showing higher cortisol. There were modest, positive correlations of cortisol with baseline symptom severity, and analysis of covariance revealed higher baseline cortisol in those who transitioned to psychotic level symptoms when compared with healthy control subjects and CHR subjects who remitted.ConclusionsThe present findings add to accumulating evidence of heightened cortisol secretion in CHR individuals. The findings also indicate nonspecific associations between cortisol levels and symptom severity, as well as symptom progression. The role of hypothalamic-pituitary-adrenal activity in prediction of conversion to psychosis and its relation with other biomarkers of risk should receive attention in future research.

Background Schizophrenia is associated with structural brain abnormalities that may be present before disease onset. It remains unclear whether these represent general vulnerability indicators or are associated with the clinical state itself. Methods To investigate this, structural brain scans were acquired at two time points (mean scan interval 1.87 years) in a cohort of individuals at high familial risk of schizophrenia ( n = 142) and control subjects ( n = 36). Cortical reconstructions were generated using FreeSurfer. The high-risk cohort was subdivided into individuals that remained well during the study, individuals that had transient psychotic symptoms, and individuals that subsequently became ill. Baseline measures and longitudinal change in global estimates of thickness and surface area and lobar values were compared, focusing on overall differences between high-risk individuals and control subjects and then on group differences within the high-risk cohort. Results Longitudinally, control subjects showed a significantly greater reduction in cortical surface area compared with the high-risk group. Within the high-risk group, differences in surface area at baseline predicted clinical course, with individuals that subsequently became ill having significantly larger surface area than individuals that remained well during the study. For thickness, longitudinal reductions were most prominent in the frontal, cingulate, and occipital lobes in all high-risk individuals compared with control subjects. Conclusions Our results suggest that larger surface areas at baseline may be associated with mechanisms that go above and beyond a general familial disposition. A relative preservation over time of surface area, coupled with a thinning of the cortex compared with control subjects, may serve as vulnerability markers of schizophrenia. [ABSTRACT FROM AUTHOR]

Background Prefrontal cortex (PFC) function contributes to schizophrenia onset and progression. However, little is known about neural mechanisms behind PFC functional alterations along illness stages. Recent pharmacologic studies indicate that glutamate dysfunction may produce increased functional connectivity. However, pharmacologic models of schizophrenia overlook effects of illness progression on PFC function. This study compared N -methyl-D-aspartate glutamate receptor (NMDAR) antagonist effects in healthy volunteers with stages of schizophrenia with respect to PFC functional connectivity. Methods First, we tested ketamine effects on PFC functional connectivity in healthy volunteers in a data-driven way ( n = 19). Next, we compared healthy subjects ( n = 96) with three clinical groups: individuals at high risk for schizophrenia ( n = 21), people early in their course of schizophrenia (EC-SCZ) ( n = 28), and patients with chronic illness ( n = 20). Across independent analyses, we used data-driven global brain connectivity techniques restricted to PFC to identify functional dysconnectivity. Results Results revealed robust PFC hyperconnectivity in healthy volunteers administered ketamine (Cohen’s d = 1.46), resembling individuals at high risk for schizophrenia and EC-SCZ. Hyperconnectivity was not found in patients with chronic illness relative to EC-SCZ patients. Results provide the first evidence that ketamine effects on PFC functional connectivity resemble early course but not chronic schizophrenia. Conclusions Results suggest an illness phase-specific relevance of NMDAR antagonist administration for prefrontal dysconnectivity associated with schizophrenia. This finding has implications for the neurobiology of illness progression and for the widespread use of NMDAR antagonists in the development of therapeutics for schizophrenia. [ABSTRACT FROM AUTHOR]

Background: Structural differences between the brains of people with schizophrenia and control subjects are highly replicated but the timing and clinical correlates are unclear. In the Edinburgh High Risk Study, we have followed up 162 individuals at high genetic risk of schizophrenia and 36 healthy control subjects over 10 years. Methods: Participants received detailed clinical and up to five structural magnetic resonance imaging (MRI) assessments at 2-year intervals. All 436 MRI scans acquired were parcellated and adjusted for between-scanner differences. The trajectory of any structural MRI changes was then investigated using mixed effects analysis of variance. Results: Seventeen of the 146 high-risk subjects who were scanned developed schizophrenia over the 8 years of the study. People at high genetic risk of schizophrenia had significantly greater reductions over time than the control group for whole brain volume and left and right prefrontal and temporal lobes. Greater prefrontal reductions were shown in high-risk subjects who subsequently became unwell compared with those who did not. These changes were significantly associated with increasing severity of psychotic symptoms. Conclusions: Individuals at high genetic risk of schizophrenia exhibited reductions in cerebral volume that were not found in control subjects. Changes in brain structure were also associated with increasing psychotic symptom severity as people developed schizophrenia. The progressive reductions found in those who went on to develop schizophrenia suggest an additional brain insult near to the time of onset. [Copyright &y& Elsevier]

Background: Patients with depression show abnormalities in the neural circuitry supporting working memory. These abnormalities apparently persist into clinical remission, raising the possibility that they might be trait markers indicating vulnerability to depression. Methods: We studied 17 young people who had a depressed parent but no personal history of depressive illness (FH) and 15 healthy control subjects with no family history of depression. Participants performed a verbal working memory task of varying cognitive load (n-back) while undergoing functional magnetic resonance imaging scanning. We used multiple regression analyses to assess overall capacity (1-, 2-, 3-back vs. 0-back) as well as linear and quadratic modulation of cognitive demand. Results: Performance accuracy and response latency did not differ between groups, and overall capacity was similar. However, for both linear and quadratic load response activity, FH participants showed greater activation in lateral occipital cortex, superior temporal cortex, and superior parietal cortex. Conclusions: Our data suggest that, as in depressed patients, maintenance of task performance in FH participants is associated with a significant increase in the load-response activity of the cortical regions involved in working memory. This neural abnormality could form part of the predisposition to develop depressive disorders. [Copyright &y& Elsevier]

Background: Smaller hippocampal volume has been reported in some adult and pediatric studies of unipolar major depressive disorder. It is not clear whether the smaller hippocampal volume precedes or is a consequence of the illness. Early-life adversity is associated with both smaller hippocampal volume and increased vulnerability to depressive disorder. Hippocampal changes may mediate the relationship between early-life adversity and depressive illness in a subset of patients. However, there are no reports of longitudinal clinical studies that have examined this issue. Methods: Thirty adolescents with unipolar major depressive disorder, 22 adolescent volunteers with no personal history of a psychiatric illness including depression but who were at high risk for developing depression by virtue of parental depression (high-risk group), and 35 adolescent volunteers with no personal or family history of a psychiatric disorder (control subjects) underwent volumetric magnetic resonance imaging studies. Information was also gathered on early and recent adverse experiences with standard interviews. The participants were followed for up to 5 years to assess the onset and clinical course of depression. Results: Depressed and high-risk groups had significantly smaller left and right hippocampal volumes than control subjects. Higher levels of early-life adversity were associated with smaller hippocampal volumes. Smaller hippocampal volume partially mediated the effect of early-life adversity on depression during longitudinal follow-up. Conclusions: Smaller hippocampal volume in adolescents at high risk for depression suggests that it may be a vulnerability marker for the illness. Early-life adversity may interact with genetic vulnerability to induce hippocampal changes, potentially increasing the risk for depressive disorder. [Copyright &y& Elsevier]

Background: Intervention aimed at preventing schizophrenia may be most effective if targeted at specific, but modifiable, functional impairments that present during childhood. We have developed a novel method of screening community samples aged 9 to 12 years to identify children who present a triad of putative antecedents of schizophrenia (ASz), defined as 1) speech and/or motor development lags/problems; 2) internalizing, externalizing, and/or peer-relationship problems in the clinical range; and 3) psychotic-like experiences. This study examined whether ASz children display brain function abnormalities during error processing that are similar to those exhibited by adults with schizophrenia. Methods: Twenty-two ASz children and 26 typically developing (TD) children with no antecedents of schizophrenia completed an error-inducing Go/NoGo task during event-related potential recording. Group differences were examined in the amplitude and latency of four event-related potential components: the initial error-related negativity (ERN) and later error-positivity (Pe) elicited on false-alarm responses to NoGo trials, and the corresponding initial correct response negativity (CRN) and later correct response positivity (Pc) elicited during processing of correct responses to Go trials. Results: Relative to TD children, ASz children were characterized by reduced ERN amplitude but unaffected CRN, Pe, and Pc amplitudes. No group differences were observed in the latency of any component. Conclusions: Children presenting a triad of putative antecedents of schizophrenia show error-processing dysfunction mimicking that observed in adults with schizophrenia using the same Go/NoGo paradigm. The ASz children displayed specific early error-processing deficits rather than a generalized deficit in self-monitoring. [Copyright &y& Elsevier]

Background: Age of onset to begin drinking is a known risk factor for alcohol dependence. Factors have been identified that contribute to age of onset to begin regular drinking. These include reduced P300, increased postural sway, and personality variation. A longitudinal study spanning childhood to young adulthood provided the opportunity to determine if these same factors would predict the presence and onset of substance use disorders (SUD). Methods: Multiplex families were identified through two or more alcohol-dependent brothers. Offspring from these multiplex or control families (n = 133) were followed annually during childhood. Using childhood predictors previously identified as risk factors for age of onset to begin drinking, SUD outcome by young adulthood was modeled. Results: Familial risk status was a significant predictor of young adult SUD outcome as a main effect and as an interaction with P300 amplitude recorded before the age of 13. In adolescence (age 15), increased postural sway and familial risk predicted the SUD outcome by age 22. Analysis comparing the presence of one or both risk factors showed that those above the median for sway and below the median for P300 amplitude had substantially increased odds of developing SUD (odds ratio = 8.08 [confidence interval = 1.52–42.83]). Conclusions: Our findings indicate that among the factors predicting age of onset to begin regular drinking, P300 predicts SUD outcome across an 11-year span. The present findings provide the longest follow-up to date demonstrating that neurobiological factors in childhood are among the most salient predictors of young adult SUD outcome. [Copyright &y& Elsevier]

Background: Identifying trait markers specific to schizophrenia might uncover mechanisms underlying illness susceptibility. Previous research shows the N2 and P3 event-related potentials are abnormal in schizophrenia; specificity of these potential trait markers has not been well established. Methods: Electroencephalogram data were recorded from four adolescent groups: early-onset schizophrenia patients (SZ; n = 30); non-psychotic siblings of schizophrenia patients (SZ-SIB; n = 36); healthy control subjects (HC; n = 36); a neurodevelopmental attention-deficit/hyperactivity disorder (ADHD) comparison group (n = 27), during auditory oddball and visual go/no-go tasks. The P3 was measured to targets in the oddball task. The N2 and P3 were measured to go and no-go stimuli in the go/no-go task. Results: Compared with the HC group, the SZ and SZ-SIB groups showed significantly reduced auditory oddball P3 amplitude. Visual P3 amplitude was significantly reduced in the SZ group for no-go stimuli and the SZ-SIB group for go and no-go stimuli. The P3 amplitude in the ADHD group was not significantly reduced for either paradigm. The SZ and ADHD groups showed significantly reduced N2 amplitude in the go/no-go task; the SZ-SIB group was not significantly different from the HC group. Conclusions: Results revealed reduced P3 amplitude in schizophrenia patients and adolescent non-psychotic siblings in an auditory oddball and a visual go/no-go task. The SZ-SIB and ADHD groups showed a different ERP profile when each was compared with the HC group: siblings showed reduced P3 amplitude in both tasks and normal N2 in the go/no-go task; the opposite pattern was observed in the ADHD group. [Copyright &y& Elsevier]

Background: We examined pituitary volume before the onset of psychosis in subjects who were at ultra-high risk (UHR) for developing psychosis. Methods: Pituitary volume was measured on 1.5-mm, coronal, 1.5-T magnetic resonance images in 94 UHR subjects recruited from admissions to the Personal Assessment and Crisis Evaluation Clinic in Melbourne, Australia and in 49 healthy control subjects. The UHR subjects were scanned at baseline and were followed clinically for a minimum of 1 year to detect transition to psychosis. Results: Within the UHR group, a larger baseline pituitary volume was a significant predictor of future transition to psychosis. The UHR subjects who later went on to develop psychosis (UHR-P, n = 31) had a significantly larger (+12%; p = .001) baseline pituitary volume compared with UHR subjects who did not go on to develop psychosis (UHR-NP, n = 63). The survival analysis conducted by Cox regression showed that the risk of developing psychosis during the follow-up increased by 20% for every 10% increase in baseline pituitary volume (p = .002). Baseline pituitary volume of the UHR-NP subjects was smaller not only compared with UHR-P (as described above) but also compared with control subjects (−6%; p = .032). Conclusions: The phase before the onset of psychosis is associated with a larger pituitary volume, suggesting activation of the HPA axis. [Copyright &y& Elsevier]

Background: Trait functional abnormalities in BD patients have only been reported in the ventral prefrontal cortex (VPFC). We examined whether deficits in VPFC-related inhibitory processes, but not dorsal prefrontal (DPFC) based executive functions, represent an endophenotypic marker for bipolar disorder I (BDI). Methods: We used the Wisconsin Card Sorting Test (WCST), commonly associated with DPFC function, and the Hayling Sentence Completion Task (HSCT) which engages the VPFC. Performance on these tests of 43 healthy participants was compared to that of 10 remitted BDI patients and 15 of their unaffected offspring. Results: Compared to healthy participants, patients and their offspring made more errors in the HSCT but offspring achieved more categories and made fewer perseverative errors in the WCST. Conclusions: Impaired response inhibition, predominantly a VPFC related function, may reflect familial predisposition to BDI while deficits in rule attainment, a DPFC based function, may be associated only with the clinical phenotype. [Copyright &y& Elsevier]