Structural Brain Abnormalities in Youth With Psychosis Spectrum Symptoms.

Structural brain abnormalities are prominent in psychotic disorders, including schizophrenia. However, it is unclear when aberrations emerge in the disease process and if such deficits are present in association with less severe psychosis spectrum (PS) symptoms in youth.



To investigate the presence of structural brain abnormalities in youth with PS symptoms.



The Philadelphia Neurodevelopmental Cohort is a prospectively accrued, community-based sample of 9498 youth who received a structured psychiatric evaluation. A subsample of 1601 individuals underwent neuroimaging, including structural magnetic resonance imaging, at an academic and children's hospital health care network between November 1, 2009, and November 30, 2011.



Measures of brain volume derived from T1-weighted structural neuroimaging at 3 T. Analyses were conducted at global, regional, and voxelwise levels. Regional volumes were estimated with an advanced multiatlas regional segmentation procedure, and voxelwise volumetric analyses were conducted as well. Nonlinear developmental patterns were examined using penalized splines within a general additive model. Psychosis spectrum (PS) symptom severity was summarized using factor analysis and evaluated dimensionally.



Following exclusions due to comorbidity and image quality assurance, the final sample included 791 participants aged youth 8 to 22 years. Fifty percent (n = 393) were female. After structured interviews, 391 participants were identified as having PS features (PS group) and 400 participants were identified as typically developing comparison individuals without significant psychopathology (TD group). Compared with the TD group, the PS group had diminished whole-brain gray matter volume (P = 1.8 × 10-10) and expanded white matter volume (P = 2.8 × 10-11). Voxelwise analyses revealed significantly lower gray matter volume in the medial temporal lobe (maximum z score = 5.2 and cluster size of 1225 for the right and maximum z score = 4.5 and cluster size of 310 for the left) as well as in frontal, temporal, and parietal cortex. Volumetric reduction in the medial temporal lobe was correlated with PS symptom severity.



Structural brain abnormalities that have been commonly reported in adults with psychosis are present early in life in youth with PS symptoms and are not due to medication effects. Future longitudinal studies could use the presence of such abnormalities in conjunction with clinical presentation, cognitive profile, and genomics to predict risk and aid in stratification to guide early interventions.

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title: A follow-up magnetic resonance imaging study of schizophrenia. Relationship of neuroanatomical changes to clinical and neurobehavioral measures.
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Magnetic resonance brain imaging and neurobehavioral studies were conducted at baseline and after 30.63 +/- 12.92 months (mean +/- SD) in 40 patients with schizophrenia (23 men and 17 women) and 17 healthy controls (13 men and 4 women). The schizophrenia group included 20 first-episode and 20 previously treated subjects. Volumes of whole-brain, cerebrospinal fluid, and frontal and temporal lobes were measured. The severity of negative and positive symptoms was assessed, medications were monitored, and neurobehavioral functioning in 8 domains was evaluated.



Both first-episode and previously treated patients had smaller brains and frontal and temporal lobes than controls at intake. Longitudinally, reduction in frontal lobe volume was found only in patients, whereas temporal lobe reduction was also seen in controls. The association between volume reduction and symptom changes differed between patient groups, but volume reduction was associated with decline in some neurobehavioral functions in both groups. Exploratory analysis suggested that neuroleptic dose is correlated with changes in all 3 domains.



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title: Temporolimbic volume reductions in schizophrenia.
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Magnetic resonance imaging was performed in 100 patients with schizophrenia (58 men, 42 women; 39 neuroleptic naive, 61 previously treated) and 110 healthy controls (51 men, 59 women). Gray and white matter volumes of temporolimbic (hippocampus and amygdala) and neocortical regions (superior temporal gyrus and temporal pole) were examined. Symptoms, functioning, and neurocognition were assessed concurrently.



Hippocampal gray matter volume was reduced in men (7%) and women (8.5%) with schizophrenia. In the amygdala, however, decreased volume was evident for men (8%) whereas women (10.5%) had increased volume. Magnetic resonance imaging of the temporal pole showed decreased gray matter in men (10%) and women (8.5%). For the superior temporal gyrus, the decrease exceeded that of whole-brain only in men (11.5%). Volumes were largely uncorrelated with clinical measures, but higher hippocampal volumes were associated with better memory performance for all groups. Cortical volumes were associated with better memory performance in healthy women.



Schizophrenia is associated with reduced gray matter volume in temporolimbic structures. In men, reduction was manifested in all regions, whereas women showed decreased hippocampal volumes but increased amygdala volumes. The abnormalities are evident in patients with first-episode schizophrenia and correlate more strongly with cognitive performance than with symptom severity.

title: The ENIGMA Consortium: large-scale collaborative analyses of neuroimaging and genetic data
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abstract: Regional cerebral blood flow (rCBF) data from two PET‐15O water schizophrenia studies were analyzed using individually placed, magnetic resonance (MR)‐guided hippocampal volumes of interest (VOI). In one study, normal (N = 10) and schizophrenic (N = 18) volunteers performed an overlearned auditory discrimination task in rest, control, and decision conditions. In the other study, schizophrenic and normal volunteers received the noncompetitive NMDA receptor antagonist ketamine and placebo and had sequential rCBF evaluations. Moreover, the schizophrenic volunteers were off drug in one study and on antipsychotic drug in the second study, allowing an additional comparison of medication status. VOIs were placed on anterior, middle, and posterior hippocampal areas in each PET image from both studies, redirected from an MR scan, and individually adjusted. While no hippocampal activation was apparent in either the normal or schizophrenic group in the task vs. condition comparison, rCBF was higher in the schizophrenic than in the normal hippocampus in both task and control conditions, independently. In addition, at rest rCBF was significantly higher in the unmedicated group of schizophrenics than in the group of medicated patient volunteers and higher than in the normal comparison group. This suggests that schizophrenia is associated with elevated rCBF in the hippocampus, which “normalizes” with antipsychotic drug treatment. Ketamine, the noncompetitive NMDA receptor antagonist, was more potent in reducing rCBF in the schizophrenic group compared to the normal volunteer group. These data are consistent with a previous report from our laboratory of reduced NMDA receptor NR1 subunit expression and possible abnormal NMDA receptor composition in schizophrenia. These data show an abnormality of hippocampal function in schizophrenia and suggest that this abnormality may be associated with the pathophysiology of the illness. Hippocampus 2001;11:543–550.

title: Molecular abnormalities of the hippocampus in severe psychiatric illness: postmortem findings from the Stanley Neuropathology Consortium
abstract: Between 1997 and 2002, 48 data sets from the hippocampus were produced on samples from the Stanley Neuropathology Consortium. From these data sets, 224 total measures were available from the various subdivisions of the hippocampus. An integrative analysis of these measures was performed using a multivariate, nonparametric analysis of variance (ANOVA). ANOVA with correction for multiple comparisons indicated that parvalbumin-containing cells in CA2 were reduced in schizophrenia and bipolar disorder. In addition, reelin protein in the molecular layer of the dentate gyrus was decreased in schizophrenia, bipolar disorder, and depression at the trend level of statistical significance (P=0.065). These results strongly suggest a dysfunction of inhibitory GABA-ergic interneurons in severe mental illness. Without correction for multiple comparisons, 31 measures were abnormal in at least one disease, whereas 11 measures would be expected to appear abnormal by chance. Abnormal molecules included measures of synaptic density or neuronal plasticity (reelin, SNAP-25, BDNF, Complexin I and II), as well as parvalbumin, tyrosine receptor kinase A, glucocorticoid receptors, glutamate NR1 receptor subunits, serotonin 5HT2A and 5HT1B receptors, and dopamine D5 receptors.

title: Impaired recruitment of the hippocampus during conscious recollection in schizophrenia
abstract: Poor attention and impaired memory are enduring and core features of schizophrenia. These impairments have been attributed either to global cortical dysfunction or to perturbations of specific components associated with the dorsolateral prefrontal cortex (DLPFC), hippocampus and cerebellum. Here, we used positron emission tomography (PET) to dissociate activations in DLPFC and hippocampus during verbal episodic memory retrieval. We found reduced hippocampal activation during conscious recollection of studied words, but robust activation of the DLPFC during the effort to retrieve poorly encoded material in schizophrenic patients. This finding provides the first evidence of hippocampal dysfunction during episodic memory retrieval in schizophrenia.

title: Neuroimaging studies of the hippocampus in schizophrenia
abstract: Three neuroimaging techniques, morphometric neuroimaging, magnetic resonance spectroscopy, and functional neuroimaging, have provided evidence for abnormal hippocampal structure and function in schizophrenia. Hippocampal volume reduction is now one of the most consistent structural abnormalities found in schizophrenia: it is present at the onset of the illness and, to a lesser degree, in first‐degree relatives of schizophrenic probands. Decreased levels of N‐acetyl‐aspartate point towards a cellular basis of such volume changes. Functional neuroimaging studies have demonstrated abnormal levels of hippocampal activity at rest, during the experience of auditory hallucinations, and during the performance of memory retrieval tasks. These results of neuroimaging studies complement evidence from post‐mortem and behavioral studies, which have found regionally specific abnormalities of the hippocampus and of memory function in schizophrenia. Hippocampus 2001;11:520–528.

title: Ionotropic glutamate receptors and expression of N-methyl-D-aspartate receptor subunits in subregions of human hippocampus: effects of schizophrenia.
abstract: Multiple quantifiable biologic abnormalities have been localized to the hippocampus in schizophrenia. Alterations in glutamate-mediated transmission at N-methyl-D-aspartic acid (NMDA)-sensitive receptors in hippocampus have been implicated in the pathophysiology of the illness. The authors tested the hypothesis that glutamatergic transmission within and efferent from hippocampus is altered in schizophrenia.



The authors analyzed postmortem hippocampal tissue from individuals with schizophrenia and from healthy individuals. The tissue samples had been collected by two brain tissue banks, one in Maryland and the other in Melbourne, Australia. lonotropic receptor binding for the NMDA, kainate, and (3)H-amino-3-hydroxy-5-methylisoxazol-4-propionate (AMPA) receptors was quantified by using usual radioligand techniques. In situ hybridization autoradiography was used to quantify mRNA for the NMDA receptor subunits NR1, NR2A, and NR2B.



Ligand binding to the ionotropic glutamate receptors (NMDA, kainate, and AMPA) did not differ significantly overall or in any subregion between the schizophrenia tissue and the healthy comparison tissue. The only exception was AMPA receptor binding in hippocampal subregion CA2, which was slightly but significantly less in schizophrenia. However, the level of mRNA for the NMDA receptor subunits NR1 and NR2B was significantly different between groups; in several hippocampal subregions, the level of NR1 mRNA was lower and the level of NR2B mRNA higher in schizophrenia.



Because the NR1 subunit of the NMDA receptor is critical to full receptor activity, a reduction of NR1 in hippocampus in schizophrenia suggests a functional impairment in glutamatergic transmission at the NMDA receptor, resulting in reduced glutamatergic transmission within and possibly efferent from the hippocampus in schizophrenia. This defect could underlie a hypoglutamatergic state in regions of limbic cortex, consistent with published results from other lines of research in schizophrenia.

title: Hippocampus and amygdala volumes in children and young adults at high-risk of schizophrenia: Research synthesis
abstract: Studies have reported hippocampal and amygdala volume abnormalities in schizophrenic patients. It is necessary to explore the potential for these structures as early disease markers in subjects at high risk (HR) of schizophrenia.



We performed a review of 29 magnetic resonance imaging (MRI) studies measuring hippocampal and amygdala volumes in subjects at HR for schizophrenia. We reclassified subjects in 3 new HR categories: presence of only risk symptoms (psychotic moderate symptoms), presence of only risk factors (genetic, developmental or environmental), and presence of combined risk symptoms/factors.



Hippocampal volume reductions were detected in subjects with first episode (FE) of psychosis, in all young adults and in adolescents at HR of schizophrenia. The loss of tissue was mainly located in the posterior part of hippocampus and the right side seems more vulnerable in young adults with only risk symptoms. Instead, the anterior sector seems more involved in HR subjects with genetic risks. Abnormal amygdala volumes were found in FE subjects, in children with combined risk symptoms/factors and in older subjects using different inclusion criteria, but not in young adults.



Hippocampal and amygdala abnormalities may be present before schizophrenia onset. Further studies should be conducted to clarify whether these abnormalities are causally or effectually related to neurodevelopment. Shape analysis could clarify the impact of environmental, genetic, and developmental factors on the medial temporal structures during the evolution of this disease.

title: Hippocampal Shape Abnormalities Predict Symptom Progression in Neuroleptic-Free Youth at Ultrahigh Risk for Psychosis.
abstract: Hippocampal abnormalities have been widely studied in schizophrenia spectrum populations including those at ultrahigh risk (UHR) for psychosis. There have been inconsistent findings concerning hippocampal morphology prior to and during the transition to psychosis, and little is known about how specific subregions are related to the symptom progression.



A total of 80 participants (38 UHR and 42 healthy controls) underwent a 3T MRI scan, as well as structured clinical interviews. Shape analysis of hippocampi was conducted with FSL/FIRST vertex analysis to yield a localized measure of shape differences between groups. A subgroup of the sample (24 UHR and 24 controls) also returned for a 12-month clinical follow-up assessment.



The UHR group exhibited smaller hippocampal volumes bilaterally, and shape analysis revealed significant inversion in the left ventral posterior hippocampus in the UHR group. Greater inversion in this subregion was related to elevated symptomatology at baseline and increased positive symptoms, negative symptoms, and impaired tolerance to normal stress 12 months later. These results did not hold when left hippocampal volume was used as a predictor instead.



This represents the first study to use vertex analysis in a UHR sample and results suggest that abnormalities in hippocampal shape appear to reflect underlying pathogenic processes driving the progression of illness. These findings suggest that examining shape and volume may provide an important new perspective for our conception of brain alterations in the UHR period.

title: Brain volumes in relatives of patients with schizophrenia: a meta-analysis.
abstract: Smaller brain volumes have consistently been found in patients with schizophrenia, particularly in gray matter and medial temporal lobe structures. Although several studies have investigated brain volumes in nonpsychotic relatives of patients with schizophrenia, results have been inconsistent.



To determine the magnitude and extent of brain volume differences in first-degree relatives of schizophrenic patients.



A systematic search was conducted to identify relevant studies. Computer searches of the MEDLINE database were performed for English-language articles published before July 2005. Relevant abstracts published in 2005 were also selected.



Magnetic resonance imaging studies that examined differences in brain volumes between first-degree relatives of patients with schizophrenia and healthy control subjects were obtained through computerized databases, including MEDLINE. Studies had to report sufficient data for computation of effect sizes.



For each study, the Cohen d was calculated. Data extraction and calculation of the effect size were performed by 2 authors (H.B.M.B. and A.A.) who reached a consensus in cases of uncertainty and discrepancies. All analyses were performed using the random-effects model.



Twenty-five studies were identified as suitable for analysis and included 1065 independent first-degree relatives of patients, 679 patients with schizophrenia, and 1100 healthy control subjects. The largest difference between relatives and healthy control subjects was found in hippocampal volume, with relatives having smaller volumes than controls (d = 0.31; 95% confidence interval [CI], 0.13-0.49; 9 effect sizes). Gray matter was smaller (d = 0.18; 95% CI, 0.02-0.33; 7 effect sizes) and third-ventricle volume was larger (d = 0.21; 95% CI, 0.03-0.40; 7 effect sizes) in relatives compared with healthy control subjects.



Brain abnormalities are present in nonpsychotic first-degree relatives of patients with schizophrenia and are most pronounced in the hippocampus.

title: Meta-analysis of brain volumes in unaffected first-degree relatives of patients with schizophrenia overemphasizes hippocampal deficits.
abstract: W e read with interest the important metaanalysis of brain volumes in unaffected firstdegree relatives of patients with schizophrenia by Boos and colleagues. Given the highly influential status of meta-analysis in the hierarchy of evidence, methodological rigor in carrying out a meta-analysis is paramount. However, we note several apparent errors and question the authors’ conclusion that brain abnormalities in such relatives are “most pronounced in the hippocampus.” The number of subjects contributing data for the total hippocampal volume meta-analysis is overestimated as reported in the forest plot of effect sizes in relatives compared with controls . First, the authors include as relatives all the “ultra highrisk” subjects from Wood et al. However, most of these subjects were not relatives of a patient with psychotic illness at all but rather had an “at-risk mental state.” Second, 2 of the studies included in Figure 1 report overlapping samples, thus contravening the key methodological principle that subjects should be used only once in a given meta-analysis. As outlined in the subject recruitment sections of each original article, both Schulze et al and van Haren et al include unaffected relatives and controls who had been first described in McDonald et al. van Haren et al include new data on hippocampal volume from a twin sample. Third, the study referred to as Toulopoulou et al is misplaced as it reports no data on hippocampal volume in relatives and indeed was not included in Table 1 in the Boos et al article, which lists the studies contributing to the meta-analysis. Table 1 contains other errors in the “Included Brain Volumes” column that serve to obscure the authors’ data sources. For example, hippocampal volume is not listed as an included region in Baaré et al, O’Driscoll et al are reported as providing hippocampal data rather than amygdala-hippocampal data, and Narr et al are reported as providing hippocampal data but are not included in Figure 1 in the Boos et al article, nor should this study have been included in the meta-analysis of hippocampal volume since it was based on a subject sample superseded by van Erp et al. In Table 2 of the Boos et al article, the authors misleadingly report that the amygdala-hippocampus was assessed in 12 studies. From the subject numbers stated, the authors have combined 3 studies measuring the amygdala-hippocampal complex with those 9 studies from which total hippocampal volume was derived. In fact, the amygdala-hippocampus was specifically measured in only 4 studies. Boos et al erroneously state in their discussion that 2 of 3 studies excluded from the meta-analysis found reduced hippocampal volume in relatives compared with controls. In fact, neither of these studies reported data to support this assertion. Waldo et al reported that unaffected siblings with P50 sensory gating defects had larger hippocampal volumes than patients with schizophrenia. Job et al reported a trend toward reduced left parahippocampal gyrus in high-risk subjects and specifically did not identify hippocampal differences. Indeed, the whole-brain exploratory computational neuroanatomy studies published to date that included relatives of patients with schizophrenia have failed to identify hippocampal deficits as markers of genetic liability and instead implicate various prefrontal cortical or thalamic deficits as most endophenotypic for the syndrome. Boos and colleagues correctly point out the vulnerability of the hippocampus to volumetric deficit in the presence of environmental factors such as perinatal hypoxia and stress-induced glucocorticoid excess. Additional evidence that hippocampal volume is more susceptible than other brain regions to environmental factors is the lower heritability of this structure estimated from normal twin studies when compared with global or frontal regions. Furthermore, there is evidence that hippocampal volume is not state-independent but decreases with the onset of psychotic illness. Boos et al also rightly point out that other regional brain structures are less commonly chosen for analysis. The popularity of the hippocampus for measurement in such studies is highlighted by the fact that it was the only brain tissue region that met inclusion criteria for their metaanalysis; other volumes included were global tissue or cerebrospinal fluid. We suggest that this popularity is unwarranted given the higher heritability of other volumetric brain regions, the stronger evidence for prefrontal endophenotypic involvement from nonhypothesis-based computational neuroanatomy studies, and the apparent susceptibility of the hippocampus to environmental risk factors and illness progression. Accordingly, we suggest that researchers should more thoroughly evaluate alternative brain regions to the hippocampus in region of interest imaging studies of unaffected relatives of patients with schizophrenia in the search for more powerful neuroanatomical endophenotypes for the syndrome.

title: Heritability of Subcortical and Limbic Brain Volume and Shape in Multiplex-Multigenerational Families with Schizophrenia
abstract: Brain abnormalities of subcortical and limbic nuclei are common in patients with schizophrenia, and variation in these structures is considered a putative endophenotype for the disorder. Multiplex-multigenerational families with schizophrenia provide an opportunity to investigate the impact of shared genetic ancestry, but these families have not been previously examined to study structural brain abnormalities. We estimate the heritability of subcortical and hippocampal brain volumes in multiplex-multigenerational families and the heritability of subregions using advanced shape analysis.



The study comprised 439 participants from two sites who underwent 3T structural magnetic resonance imaging. The participants included 190 European-Americans from 32 multiplex-multigenerational families with schizophrenia and 249 healthy comparison subjects. Subcortical and hippocampal volume and shape were measured in 14 brain structures. Heritability was estimated for volume and shape.



Volume and shape were heritable in families. Estimates of heritability in subcortical and limbic volumes ranged from .45 in the right hippocampus to .84 in the left putamen. The shape of these structures was heritable (range, .40-.49), and specific subregional shape estimates of heritability tended to exceed heritability estimates of volume alone.



These results demonstrate that volume and shape of subcortical and limbic brain structures are potential endophenotypic markers in schizophrenia. The specificity obtained using shape analysis may improve selection of imaging phenotypes that better reflect the underlying neurobiology. Our findings can aid in the identification of specific genetic targets that affect brain structure and function in schizophrenia.

title: Voxel-based morphometry for separation of schizophrenia from other types of psychosis in first episode psychosis.
abstract: Schizophrenia is a psychiatric disorder which involves distortions in thought and perception, blunted affect, and behavioural disturbances. The longer psychosis goes unnoticed and untreated, the more severe the repercussions for relapse and recovery. There is some evidence that early intervention services can help, and diagnostic techniques that could contribute to early intervention may offer clinical utility in these situations. The index test being evaluated in this review is the structural magnetic resonance imaging (MRI) analysis technique known as voxel-based morphometry (VBM) that estimates the distribution of grey matter tissue volume across several brain regions. This review is an exploratory examination of the diagnostic 'potential' of VBM for use as an additional tool in the clinical examination of patients with first episode psychosis to establish whether an individual will progress on to developing schizophrenia as opposed to other types of psychosis.



To determine whether VBM applied to the brain can be used to differentiate schizophrenia from other types of psychosis in participants who have received a clinical diagnosis of first episode psychosis.



In December 2013, we updated a previous search (May 2012) of MEDLINE, EMBASE, and PsycInfo using OvidSP.



We included retrospective and prospective studies that consecutively or randomly selected adolescent and adult participants (< 45 years) with a first episode of psychosis; and that evaluated the diagnostic accuracy of VBM for differentiating schizophrenia from other psychoses compared with a clinical diagnosis made by a qualified mental health professional, with or without the use of standard operational criteria or symptom checklists. We excluded studies in children, and in adult participants with organic brain disorders or who were at high risk for schizophrenia, such as people with a genetic predisposition.



Two review authors screened all references for inclusion. We assessed the quality of studies using the QUADAS-2 instrument. Due to a lack of data, we were not able to extract 2 x 2 data tables for each study nor undertake any meta-analysis.



We included four studies with a total of 275 participants with first episode psychosis. VBM was not used to diagnose schizophrenia in any of the studies, instead VBM was used to quantify the magnitude of differences in grey matter volume. Therefore, none of the included studies reported data that could be used in the analysis, and we summarised the findings narratively for each study.



There is no evidence to currently support diagnosing schizophrenia (as opposed to other psychotic disorders) using the pattern of brain changes seen in VBM studies in patients with first episode psychosis. VBM has the potential to discriminate between diagnostic categories but the methods to do this reliably are currently in evolution. In addition, the lack of applicability of the use of VBM to clinical practice in the studies to date limits the usefulness of VBM as a diagnostic aid to differentiate schizophrenia from other types of psychotic presentations in people with first episode of psychosis.

title: Brain structure in people at ultra-high risk of psychosis, patients with first-episode schizophrenia, and healthy controls: a VBM study
abstract: Early intervention research in schizophrenia has suggested that brain structural alterations might be present in subjects at high risk of developing psychosis. The heterogeneity of regional effects of these changes, which is established in schizophrenia, however, has not been explored in prodromal or high-risk populations. We used high-resolution MRI and voxel-based morphometry (VBM8) to analyze grey matter differences in 43 ultra high-risk subjects for psychosis (meeting ARMS criteria, identified through CAARMS interviews), 24 antipsychotic-naïve first-episode schizophrenia patients and 49 healthy controls (groups matched for age and gender). Compared to healthy controls, resp., first-episode schizophrenia patients had reduced regional grey matter in left prefrontal, insula, right parietal and left temporal cortices, while the high-risk group showed reductions in right middle temporal and left anterior frontal cortices. When dividing the ultra-high-risk group in those with a genetic risk vs. those with attenuated psychotic symptoms, the former showed left anterior frontal, right caudate, as well as a smaller right hippocampus, and amygdala reduction, while the latter subgroup showed right middle temporal cortical reductions (each compared to healthy controls). Our findings in a clinical psychosis high-risk cohort demonstrate variability of brain structural changes according to subgroup and background of elevated risk, suggesting frontal and possibly also hippocampal/amygdala changes in individuals with genetic susceptibility. Heterogeneity of structural brain changes (as seen in schizophrenia) appears evident even at high-risk stage, prior to potential onset of psychosis.

title: Hippocampal, amygdala and nucleus accumbens volume in first-episode schizophrenia patients and individuals at high familial risk: A cross-sectional comparison
abstract: It is unknown whether brain changes occur prior to onset of schizophrenia or after it develops. Prospective familial high risk studies provide a good method to investigate this. In the Edinburgh High Risk Study, structural MRI scans of 150 young individuals at familial high risk of schizophrenia, 34 patients with first-episode schizophrenia and 36 matched controls were obtained. Of the high risk participants with scans suitable for analysis, 17 developed schizophrenia after the scans were taken, whilst 57 experienced isolated or sub-clinical psychotic symptoms, and 70 remained well. We used Freesurfer to extract volumetric measurements of the hippocampus, amygdala and nucleus accumbens with the aim of assessing whether any alterations found were present in all those at high risk, or selectively in the high risk cohort based on future clinical outcome, or only in those experiencing their first-episode of psychosis. We found no significant differences in any examined regions between controls and those at high risk, or between those at high risk who later developed schizophrenia and those who remained well. However, patients with first-episode schizophrenia demonstrated significant volumetric reductions in the bilateral hippocampus, left amygdala, and right nucleus accumbens compared to high risk individuals and healthy controls, which were not significantly associated with the intake of anti-psychotic medication or duration of illness. We found that patients had significantly smaller left amygdalae and bilateral hippocampus compared to HR[ill]. Our findings suggest that volumetric reductions of the hippocampus, amygdala and nucleus accumbens occur early in the first-episode of psychosis. The apparent absence of high risk versus control differences we found using Freesurfer is at odds with our previous studies conducted on the same sample, and possible methodological reasons for these apparent discrepancies are discussed.

title: Progressive Reduction in Cortical Thickness as Psychosis Develops: A Multisite Longitudinal Neuroimaging Study of Youth at Elevated Clinical Risk
abstract: Individuals at clinical high risk (CHR) who progress to fully psychotic symptoms have been observed to show a steeper rate of cortical gray matter reduction compared with individuals without symptomatic progression and with healthy control subjects. Whether such changes reflect processes associated with the pathophysiology of schizophrenia or exposure to antipsychotic drugs is unknown.



In this multisite study, 274 CHR cases, including 35 individuals who converted to psychosis, and 135 healthy comparison subjects were scanned with magnetic resonance imaging at baseline, 12-month follow-up, or the point of conversion for the subjects who developed fully psychotic symptoms.



In a traveling subjects substudy, excellent reliability was observed for measures of cortical thickness and subcortical volumes. Controlling for multiple comparisons throughout the brain, CHR subjects who converted to psychosis showed a steeper rate of gray matter loss in the right superior frontal, middle frontal, and medial orbitofrontal cortical regions as well as a greater rate of expansion of the third ventricle compared with CHR subjects who did not convert to psychosis and healthy control subjects. Differential tissue loss was present in subjects who had not received antipsychotic medications during the interscan interval and was predicted by baseline levels of an aggregate measure of proinflammatory cytokines in plasma.



These findings demonstrate that the brain changes are not explained by exposure to antipsychotic drugs but likely play a role in psychosis pathophysiology. Given that the cortical changes were more pronounced in subjects with briefer durations of prodromal symptoms, contributing factors may predominantly play a role in acute-onset forms of psychosis.

title: The psychosis spectrum in a young U.S. community sample: findings from the Philadelphia Neurodevelopmental Cohort
abstract: Little is known about the occurrence and predictors of the psychosis spectrum in large non‐clinical community samples of U.S. youths. We aimed to bridge this gap through assessment of psychosis spectrum symptoms in the Philadelphia Neurodevelopmental Cohort, a collaborative investigation of clinical and neurobehavioral phenotypes in a prospectively accrued cohort of youths, funded by the National Institute of Mental Health. Youths (age 11‐21; N=7,054) and collateral informants (caregiver/legal guardian) were recruited through the Children's Hospital of Philadelphia and administered structured screens of psychosis spectrum symptoms, other major psychopathology domains, and substance use. Youths were also administered a computerized neurocognitive battery assessing five neurobehavioral domains. Predictors of psychosis spectrum status in physically healthy participants (N=4,848) were examined using logistic regression. Among medically healthy youths, 3.7% reported threshold psychotic symptoms (delusions and/or hallucinations). An additional 12.3% reported significant sub‐psychotic positive symptoms, with odd/unusual thoughts and auditory perceptions, followed by reality confusion, being the most discriminating and widely endorsed attenuated symptoms. A minority of youths (2.3%) endorsed subclinical negative/disorganized symptoms in the absence of positive symptoms. Caregivers reported lower symptom levels than their children. Male gender, younger age, and non‐European American ethnicity were significant predictors of spectrum status. Youths with spectrum symptoms had reduced accuracy across neurocognitive domains, reduced global functioning, and increased odds of depression, anxiety, behavioral disorders, substance use and suicidal ideation. These findings have public health relevance for prevention and early intervention.

title: The Philadelphia Neurodevelopmental Cohort: constructing a deep phenotyping collaborative.
abstract: An integrative multidisciplinary approach is required to elucidate the multiple factors that shape neurodevelopmental trajectories of mental disorders. The Philadelphia Neurodevelopmental Cohort (PNC), funded by the National Institute of Mental Health Grand Opportunity (GO) mechanism of the American Recovery and Reinvestment Act, was designed to characterize clinical and neurobehavioral phenotypes of genotyped youths. Data generated, which are recently available through the NIMH Database of Genotypes and Phenotypes (dbGaP), have garnered considerable interest. We provide an overview of PNC recruitment and clinical assessment methods to allow informed use and interpretation of the PNC resource by the scientific community. We also evaluate the structure of the assessment tools and their criterion validity.



Participants were recruited from a large pool of youths (n = 13,958) previously identified and genotyped at The Children's Hospital of Philadelphia. A comprehensive computerized tool for structured evaluation of psychopathology domains (GOASSESS) was constructed. We administered GOASSESS to all participants and used factor analysis to evaluate its structure.



A total of 9,498 youths (aged 8-21; mean age = 14.2; European American = 55.8%; African American = 32.9%; Other = 11.4%) were enrolled. Factor analysis revealed a strong general psychopathology factor, and specific 'anxious-misery', 'fear', and 'behavior' factors. The 'behavior' factor had a small negative correlation (-0.21) with overall accuracy of neurocognitive performance, particularly in tests of executive and complex reasoning. Being female had a high association with the 'anxious-misery' and low association with the 'behavior' factors. The psychosis spectrum was also best characterized by a general factor and three specific factors: ideas about 'special abilities/persecution,' 'unusual thoughts/perceptions', and 'negative/disorganized' symptoms.



The PNC assessment mechanism yielded psychopathology data with strong factorial validity in a large diverse community cohort of genotyped youths. Factor scores should be useful for dimensional integration with other modalities (neuroimaging, genomics). Thus, PNC public domain resources can advance understanding of complex inter-relationships among genes, cognition, brain, and behavior involved in neurodevelopment of common mental disorders.

title: Pre-onset detection and intervention research in schizophrenia psychoses: current estimates of benefit and risk.
abstract: Early detection and intervention is offering a compelling new perspective on the diagnosis and treatment of schizophrenia spectrum disorders. Relevant investigations include efforts to reduce the post-onset duration of untreated psychosis and efforts to identify and treat prodromally symptomatic high-risk patients in the pre-onset phase of the disorder. There appears to be consensus that the benefits outweigh the risks in studies aiming to treat first episode psychotic patients as soon as possible. In contrast, there is less consensus about pre-onset detection and intervention studies, the major concerns being the false positive rate of case identification, the evidence of benefit, the side effects of treatment, the potential harm from being informed that one is at risk for psychosis, the false negative rate of case identification, and the inclusion of adolescents. In this article, each of these issues is elaborated upon and discussed in terms of the existing evidence informing risk and benefit and in light of our own clinical experience conducting this research. It is concluded that we do not have enough data yet to justify pre-onset detection and intervention as standard practice, but we do have enough data concerning risk and benefit to justify pre-onset detection and intervention research.

title: Connectome-Wide Network Analysis of Youth with Psychosis Spectrum Symptoms
abstract: Adults with psychotic disorders have dysconnectivity in critical brain networks, including the default mode (DM) and the cingulo-opercular (CO) networks. However, it is unknown whether such deficits are present in youth with less severe symptoms. We conducted a multivariate connectome-wide association study examining dysconnectivity with resting state functional magnetic resonance imaging in a population-based cohort of 188 youths aged 8–22 years with psychosis-spectrum (PS) symptoms and 204 typically developing (TD) comparators. We found evidence for multi-focal dysconnectivity in PS youths, implicating the bilateral anterior cingulate, frontal pole, medial temporal lobe, opercular cortex and right orbitofrontal cortex. Follow-up seed-based and network-level analyses demonstrated that these results were driven by hyper-connectivity among DM regions and diminished connectivity among CO regions, as well as diminished coupling between frontal and DM regions. Collectively, these results provide novel evidence for functional dysconnectivity in PS youths, which show marked correspondence to abnormalities reported in adults with established psychotic disorders.

title: Functional neuroimaging abnormalities in youth with psychosis spectrum symptoms.
abstract: The continuum view of the psychosis spectrum (PS) implies that, in population-based samples, PS symptoms should be associated with neural abnormalities similar to those found in help-seeking clinical risk individuals and in schizophrenia. To our knowledge, functional neuroimaging has not previously been applied in large population-based PS samples and can help us understand the neural architecture of psychosis more broadly and identify brain phenotypes beyond symptoms that are associated with the extended psychosis phenotype.



To examine the categorical and dimensional relationships of PS symptoms to prefrontal hypoactivation during working memory and to amygdala hyperactivation during threat emotion processing.



The Philadelphia Neurodevelopmental Cohort is a genotyped, prospectively accrued, population-based sample of almost 10,000 youths who received a structured psychiatric evaluation and a computerized neurocognitive battery. The study was conducted at an academic and children's hospital health care network, between November 1, 2009 to November 30, 2011. A subsample of 1445 youths underwent neuroimaging, including functional magnetic resonance imaging tasks examined herein. Participants were youth aged 11 to 22 years old identified through structured interview as having PS features (PS group) (n = 260) and typically developing (TD) comparison youth without significant psychopathology (TD group) (n = 220).



Two functional magnetic resonance imaging paradigms were used: a fractal n-back working memory task probing executive system function and an emotion identification task probing amygdala responses to threatening faces.



In the n-back task, working memory evoked lower activation in the PS group than the TD group throughout the executive control circuitry, including dorsolateral prefrontal cortex (cluster-corrected P < .05). Within the PS group, dorsolateral prefrontal cortex activation correlated with cognitive deficits (r = .32, P < .001), but no correlation was found with positive symptom severity. During emotion identification, PS demonstrated elevated responses to threatening facial expressions in amygdala, as well as left fusiform cortex and right middle frontal gyrus (cluster-corrected P < .05). The response in the amygdala correlated with positive symptom severity (r = .16, P = .01) but not with cognitive deficits.



The pattern of functional abnormalities observed in the PS group is similar to that previously found in schizophrenia and help-seeking risk samples. Specific circuit dysfunction during cognitive and emotion-processing tasks is present early in the development of psychopathology and herein could not be attributed to chronic illness or medication confounds. Hypoactivation in executive circuitry and limbic hyperactivation to threat could reflect partly independent risk factors for PS symptoms, with the former relating to cognitive deficits that increase the risk for developing psychotic symptoms and the latter contributing directly to positive psychotic symptoms.

title: White Matter Differences Among Adolescents Reporting Psychotic Experiences: A Population-Based Diffusion Magnetic Resonance Imaging Study.
abstract: Abnormal brain connectivity is thought to have a key role in the pathophysiology of schizophrenia and other psychotic disorders. White matter (WM) abnormalities have been reported in patients with schizophrenia and patients with prodromal syndromes. To our knowledge, no studies have yet reported on WM differences among adolescents who report psychotic experiences, a known vulnerability group for later severe psychopathology, including psychotic illness.



To study WM differences using diffusion-weighted imaging (whole-brain and tractography analyses) in adolescents who report psychotic experiences.



A population-based case-control study of 28 adolescents 13 to 16 years old who reported psychotic experiences and a matched sample of 28 adolescents who did not report psychotic experiences drawn from a sample of 212 young people recruited from primary schools in North Dublin and Kildare, Ireland. The study dates were 2008 to 2011.



High-angular resolution diffusion-weighted imaging data were used to conduct whole-brain WM analysis using tract-based spatial statistics. Based on this exploratory analysis, a tractography-based approach with constrained spherical deconvolution was performed.



Compared with control group participants, adolescents who reported psychotic experiences showed WM differences bilaterally in striatal regions in proximity to the putamen (increased fractional anisotropy, P = .01, false discovery rate corrected), and tractography identified significant WM differences bilaterally in the uncinate fasciculus (increased fractional anisotropy in the right [P = .001] and axial diffusivity in the left [P = .01] uncinate fasciculus, respectively). Similar patterns of WM differences between groups survived adjustment for other psychopathology, indicating some specificity for psychotic experiences. Exploratory along-tract analyses showed WM differences between groups in the frontal projections of the right inferior fronto-occipital fasciculus (reduced radial diffusivity in approximately 32% of the tract segment [P ≤ .0001] and increased fractional anisotropy in approximately 16% of the tract segment [P ≤ .0009]).



In a population-based study of adolescents reporting psychotic experiences, we found a number of WM differences in the region of the putamen located between the inferior fronto-occipital fasciculus and the uncinate fasciculus and in the left parietal regions that include the fiber bundle of the superior longitudinal fasciculus. These findings suggest that subtle structural changes to WM microstructure are not merely a consequence of disorder but may index vulnerability to psychosis even at a very early age.

title: Structural and functional brain correlates of subclinical psychotic symptoms in 11–13 year old schoolchildren
abstract: Studying children experiencing psychotic symptoms provides a unique opportunity to examine the vulnerability to psychosis within the context of development. Using neuroimaging techniques this study investigated cognitive control functions, brain volumetrics and white matter integrity in an at-risk cohort of children. Between-subjects assessment of brain function and structure among 11 school-going, non-treatment seeking children aged 11-13 who were at symptomatic risk for psychosis (AR) and 14 healthy control children aged 11-12 without subclinical psychotic symptoms (CON). MRI assessments included functional measures of response inhibition and error-related processes, whole brain voxel-based morphometry (VBM) of gray matter (GM) and diffusion tensor imaging (DTI) utilizing fractional anisotropy to probe white matter (WM) integrity. fMRI results showed reduced activity in the AR group within right frontal and bilateral temporal cortex for response inhibition and reduced activity within the anterior cingulate, insula and middle frontal gyrus for error-related processing (p<.05, corrected). VBM analysis revealed GM increases in the AR group within middle and superior temporal gyri, angular gyrus, orbitofrontal gyrus and GM decrease within the inferior temporal gyrus (p<.05, corrected). DTI analysis identified WM decreases in the AR group along the inferior fronto-occipital fasciculus, cingulum and inferior longitudinal fasciculus (p<.05, corrected). This multimodal investigation revealed aberrant prefrontal-temporal dysfunction in addition to cingulate and insular dysfunctions which provide potential early neurocognitive risk markers related to the susceptibility for developing psychosis and subsequently the neurodevelopmental trajectory leading to schizophrenia.

title: Neuroimaging of the Philadelphia Neurodevelopmental Cohort
abstract: The Philadelphia Neurodevelopmental Cohort (PNC) is a large-scale, NIMH funded initiative to understand how brain maturation mediates cognitive development and vulnerability to psychiatric illness, and understand how genetics impacts this process. As part of this study, 1445 adolescents ages 8-21 at enrollment underwent multimodal neuroimaging. Here, we highlight the conceptual basis for the effort, the study design, and the measures available in the dataset. We focus on neuroimaging measures obtained, including T1-weighted structural neuroimaging, diffusion tensor imaging, perfusion neuroimaging using arterial spin labeling, functional imaging tasks of working memory and emotion identification, and resting state imaging of functional connectivity. Furthermore, we provide characteristics regarding the final sample acquired. Finally, we describe mechanisms in place for data sharing that will allow the PNC to become a freely available public resource to advance our understanding of normal and pathological brain development.

title: Psychotic-like experiences in the general population: characterizing a high-risk group for psychosis
abstract: Recent research shows that psychotic symptoms, or psychotic-like experiences (PLEs), are reported not only by psychosis patients but also by healthy members of the general population. Healthy individuals who report these symptoms are considered to represent a non-clinical psychosis phenotype, and have been demonstrated to be at increased risk of schizophrenia-spectrum disorder. Converging research now shows that this non-clinical psychosis phenotype is familial, heritable and covaries with familial schizophrenia-spectrum disorder. A review of the research also shows that the non-clinical phenotype is associated extensively with schizophrenia-related risk factors, including social, environmental, substance use, obstetric, developmental, anatomical, motor, cognitive, linguistic, intellectual and psychopathological risk factors. The criterion and construct validity of the non-clinical psychosis phenotype with schizophrenia demonstrates that it is a valid population in which to study the aetiology of psychosis. Furthermore, it suggests shared genetic variation between the clinical and non-clinical phenotypes. Much remains to be learned about psychosis by broadening the scope of research to include the non-clinical psychosis phenotype.

title: Prevalence of psychotic symptoms in childhood and adolescence: a systematic review and meta-analysis of population-based studies
abstract: Psychotic symptoms occur more frequently in the general population than psychotic disorder and index risk for psychopathology. Multiple studies have reported on the prevalence of these symptoms using self-report questionnaires or clinical interviews but there is a lack of consensus about the prevalence of psychotic symptoms among children and adolescents.  We conducted a systematic review of all published literature on psychotic symptom prevalence in two age groups, children aged 9–12 years and adolescents aged 13–18 years, searching through electronic databases PubMed, Ovid Medline, PsycINFO and EMBASE up to June 2011, and extracted prevalence rates.  We identified 19 population studies that reported on psychotic symptom prevalence among children and adolescents. The median prevalence of psychotic symptoms was 17% among children aged 9–12 years and 7.5% among adolescents aged 13–18 years.  Psychotic symptoms are relatively common in young people, especially in childhood. Prevalence is higher in younger (9–12 years) compared to older (13–18 years) children.

title: Identification and characterization of prodromal risk syndromes in young adolescents in the community: a population-based clinical interview study.
abstract: While a great deal of research has been conducted on prodromal risk syndromes in relation to help-seeking individuals who present to the clinic, there is a lack of research on prodromal risk syndromes in the general population. The current study aimed first to establish whether prodromal risk syndromes could be detected in non-help-seeking community-based adolescents and secondly to characterize this group in terms of Axis-1 psychopathology and general functioning. We conducted in-depth clinical interviews with a population sample of 212 school-going adolescents in order to assess for prodromal risk syndromes, Axis-1 psychopathology, and global (social/occupational) functioning. Between 0.9% and 8% of the community sample met criteria for a risk syndrome, depending on varying disability criteria. The risk syndrome group had a higher prevalence of co-occurring nonpsychotic Axis-1 psychiatric disorders (OR = 4.77, 95% CI = 1.81-12.52; P < .01) and poorer global functioning (F = 24.5, df = 1, P < .0001) compared with controls. Individuals in the community who fulfill criteria for prodromal risk syndromes demonstrate strong similarities with clinically presenting risk syndrome patients not just in terms of psychotic symptom criteria but also in terms of co-occurring psychopathology and global functioning.

title: Psychotic symptoms and population risk for suicide attempt: a prospective cohort study.
abstract: Up to 1 million persons die by suicide annually. However, a lack of risk markers makes suicide risk assessment one of the most difficult areas of clinical practice.



To assess psychotic symptoms (attenuated or frank) as a clinical marker of risk for suicide attempt.



Prospective cohort study of 1112 school-based adolescents (aged 13-16 years), assessed at baseline and at 3 and 12 months for self-reported psychopathology, psychotic symptoms, and suicide attempts.



Suicide attempts at the 3- and 12-month follow-up and acute suicide attempts (defined as those occurring in the 2 weeks before an assessment).



Of the total sample, 7% reported psychotic symptoms at baseline. Of that subsample, 7% reported a suicide attempt by the 3-month follow-up compared with 1% of the rest of the sample (odds ratio [OR], 10.01; 95% CI, 2.24-45.49), and 20% reported a suicide attempt by the 12-month follow-up compared with 2.5% of the rest of the sample (OR, 11.27; 95% CI, 4.44-28.62). Among adolescents with baseline psychopathology who reported psychotic symptoms, 14% reported a suicide attempt by 3 months (OR, 17.91; 95% CI, 3.61-88.82) and 34% reported a suicide attempt by 12 months (OR, 32.67; 95% CI, 10.42-102.41). Adolescents with psychopathology who reported psychotic symptoms had a nearly 70-fold increased odds of acute suicide attempts (OR, 67.50; 95% CI, 11.41-399.21). Differences were not explained by nonpsychotic psychiatric symptom burden, multimorbidity, or substance use. In a causative model, the population-attributable fraction of suicide attempts would be 56% to 75% for psychotic symptoms.



Adolescents with psychopathology who report psychotic symptoms are at clinical high risk for suicide attempts. More careful clinical assessment of psychotic symptoms (attenuated or frank) in mental health services and better understanding of their pathological significance are urgently needed.

title: The RDoC framework: facilitating transition from ICD/DSM to dimensional approaches that integrate neuroscience and psychopathology
abstract: In 2008, the National Institute of Mental Health (NIMH) included in its new Strategic Plan the following aim: “Develop, for research purposes, new ways of classifying mental disorders based on dimensions of observable behavior and neurobiological measures”. The implementation of this aim was named the Research Domain Criteria project, or RDoC. RDoC is a programmatic initiative that will fund grants, contracts, early‐phase trials, and similar activities for the purpose of generating studies to build a research literature that can inform future versions of psychiatric nosologies based upon neuroscience and behavioral science rather than descriptive phenomenology. RDoC departs markedly from the DSM and ICD processes, in which extensive workgroup meetings generate final and finely‐honed sets of diagnoses that are modified in field tests only if problems with clinical utility arise. Rather, in keeping with its provenance as an experimental system, the RDoC provides a framework for conducting research in terms of fundamental circuit‐based behavioral dimensions that cut across traditional diagnostic categories. While an important aim of the project is to validate particular dimensions as useful for eventual clinical work, an equally important goal is to provide information and experience about how to conceive and implement such an alternative approach to future diagnostic practices that can harness genetics and neuroscience in the service of more effective treatment and prevention. This paper summarizes the rationale for the RDoC project, its essential features, and potential methods of transitioning from DSM/ICD categories to dimensionally‐oriented designs in research studies.

title: Incidental Findings in Youths Volunteering for Brain MRI Research
abstract: Incidental abnormalities seen in research MRI brain studies of 1400 “normal” volunteer individuals aged 8-23 years were assessed. Ten percent showed incidental findings and 12 of these required further follow-up. Findings were not related to age but whites had higher numbers of pineal cysts and males had a higher incidence of cavum septum pellucidum, which was associated with psychosis-related symptoms.  MRIs are obtained in research in healthy and clinical populations, and incidental findings have been reported. Most studies have examined adults with variability in parameters of image acquisition and clinical measures available. We conducted a prospective study of youths and documented the frequency and concomitants of incidental findings.  Youths (n = 1400) with an age range from 8–23 years were imaged on the same 3T scanner, with a standard acquisition protocol providing 1.0 mm3 isotropic resolution of anatomic scans. All scans were reviewed by an experienced board-certified neuroradiologist and were categorized into 3 groups: 1) normal: no incidental findings; 2) coincidental: incidental finding(s) were noted, further reviewed with an experienced pediatric neuroradiologist, but were of no clinical significance; 3) incidental findings that on further review were considered to have potential clinical significance and participants were referred for appropriate clinical follow-up.  Overall, 148 incidental findings (10.6% of sample) were noted, and of these, 12 required clinical follow-up. Incidental findings were not related to age. However, whites had a higher incidence of pineal cysts, and males had a higher incidence of cavum septum pellucidum, which was associated with psychosis-related symptoms.  Incidental findings, moderated by race and sex, occur in approximately one-tenth of participants volunteering for pediatric research, with few requiring follow-up. The incidence supports a 2-tiered approach of neuroradiologic reading and clinical input to determine the potential significance of incidental findings detected on research MR imaging scans.

title: Neurocognitive growth charting in psychosis spectrum youths.
abstract: Psychosis-risk studies have examined help-seeking adolescents and young adults. Population-based studies evaluating psychotic symptoms and neurocognitive performance across childhood are needed for "growth charting" cognitive development. We hypothesized that psychosis spectrum youths have delayed neurocognitive age relative to chronological age. We expected larger lags with increased symptom severity and in late adolescence and early adulthood.



To examine neurocognitive age and compare typically developing participants with psychosis spectrum participants.



The Philadelphia Neurodevelopmental Cohort is a genotyped sample, with electronic medical records, enrolled in the study of brain behavior. In an academic and children's hospital health care network, a structured psychiatric evaluation was performed and a computerized neurocognitive battery administered to evaluate performance in several domains. From 18,344 youths in the recruitment pool who were aged 8 to 21 years, physically and cognitively capable of participating, and proficient in English, participants were randomly selected with stratification for age, sex, and ethnicity. A total of 9138 participants were enrolled in the study between November 1, 2009, and November 30, 2011, and 2321 endorsed psychotic symptoms: 1423 significant (psychosis spectrum) and 898 limited (psychosis limited). They had no comorbid medical conditions. They were compared with 981 participants endorsing significant other psychiatric symptoms and with 1963 typically developing children with no psychiatric or medical disorders.



The computerized neurocognitive battery provides accuracy and speed measures on 12 tests and speed measures alone on 2, yielding 26 measures used in a regression analysis to predict chronological age. Prediction was performed on the entire set and separately for each domain (executive, episodic memory, complex cognition, social cognition, and sensorimotor speed).



Throughout childhood and adolescence, the psychosis spectrum group had lower predicted age compared with the typically developing group and the group with other psychiatric symptoms. The psychosis spectrum group had a greater developmental lag than the psychosis limited group. The lags were most pronounced for complex cognition and social cognition and were smallest for sensorimotor speed.



Individuals who endorse psychotic symptoms are neurocognitively delayed across the age range; this delay relates to symptom severity and is not prominent in other psychiatric disorders. Combined clinical and neurocognitive assessment can facilitate early detection and targeted intervention to delay or ameliorate disease progression.

title: A self-reported instrument for prodromal symptoms of psychosis: Testing the clinical validity of the PRIME Screen—Revised (PS-R) in a Japanese population
abstract: Early intervention for psychosis requires an easy, useful assessment instrument to identify subjects with prodromal symptoms at an early stage. The aim of this study was to test the clinical validity of the PRIME Screen-Revised (PS-R), a 12-item self-reported instrument for prodromal symptoms of psychosis, by comparing the results for a non-clinical population with those for a clinical population.



The PS-R was administered to 1,024 subjects (496 students and 528 outpatients). Of the 528 patients, 115 were randomly recruited and tested using the Structured Interview for Prodromal Syndromes (SIPS) to determine the concordant validity of the PS-R. The predictive validity of the PS-R was measured by determining the transition rate to psychosis during a 6-month follow-up period.



The specificity and sensitivity of the PS-R, using the SIPS as a gold standard, were 0.74 and 1.00. The concordant validity of the PS-R against the SIPS was 0.43. The predictive validity of the PS-R and the SIPS, defined as the transition rate to psychosis, were 0.11 and 0.25, respectively. None of the patients with negative PS-R results developed psychosis.



Our findings showed that the PS-R was highly valid and that its usage is feasible in both general practice and clinical settings. This self-reported instrument represents a useful screening tool for alerting clinicians to subjects with psychotic prodromal symptoms.

title: Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): initial reliability and validity data.
abstract: To describe the psychometric properties of the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version (K-SADS-PL) interview, which surveys additional disorders not assessed in prior K-SADS, contains improved probes and anchor points, includes diagnosis-specific impairment ratings, generates DSM-III-R and DSM-IV diagnoses, and divides symptoms surveyed into a screening interview and five diagnostic supplements.



Subjects were 55 psychiatric outpatients and 11 normal controls (aged 7 through 17 years). Both parents and children were used as informants. Concurrent validity of the screen criteria and the K-SADS-PL diagnoses was assessed against standard self-report scales. Interrater (n = 15) and test-retest (n = 20) reliability data were also collected (mean retest interval: 18 days; range: 2 to 36 days).



Rating scale data support the concurrent validity of screens and K-SADS-PL diagnoses. Interrater agreement in scoring screens and diagnoses was high (range: 93% to 100%). Test-retest reliability kappa coefficients were in the excellent range for present and/or lifetime diagnoses of major depression, any bipolar, generalized anxiety, conduct, and oppositional defiant disorder (.77 to 1.00) and in the good range for present diagnoses of posttraumatic stress disorder and attention-deficit hyperactivity disorder (.63 to .67).



Results suggest the K-SADS-PL generates reliable and valid child psychiatric diagnoses.

title: The Philadelphia Neurodevelopmental Cohort: A publicly available resource for the study of normal and abnormal brain development in youth
abstract: The Philadelphia Neurodevelopmental Cohort (PNC) is a large-scale study of child development that combines neuroimaging, diverse clinical and cognitive phenotypes, and genomics. Data from this rich resource is now publicly available through the Database of Genotypes and Phenotypes (dbGaP). Here we focus on the data from the PNC that is available through dbGaP and describe how users can access this data, which is evolving to be a significant resource for the broader neuroscience community for studies of normal and abnormal neurodevelopment.

title: Multi-atlas skull-stripping.
abstract: We present a new method for automatic brain extraction on structural magnetic resonance images, based on a multi-atlas registration framework.



Our method addresses fundamental challenges of multi-atlas approaches. To overcome the difficulties arising from the variability of imaging characteristics between studies, we propose a study-specific template selection strategy, by which we select a set of templates that best represent the anatomical variations within the data set. Against the difficulties of registering brain images with skull, we use a particularly adapted registration algorithm that is more robust to large variations between images, as it adaptively aligns different regions of the two images based not only on their similarity but also on the reliability of the matching between images. Finally, a spatially adaptive weighted voting strategy, which uses the ranking of Jacobian determinant values to measure the local similarity between the template and the target images, is applied for combining coregistered template masks.



The method is validated on three different public data sets and obtained a higher accuracy than recent state-of-the-art brain extraction methods. Also, the proposed method is successfully applied on several recent imaging studies, each containing thousands of magnetic resonance images, thus reducing the manual correction time significantly.



The new method, available as a stand-alone software package for public use, provides a robust and accurate brain extraction tool applicable for both clinical use and large population studies.

title: Multiplicative intrinsic component optimization (MICO) for MRI bias field estimation and tissue segmentation.
abstract: This paper proposes a new energy minimization method called multiplicative intrinsic component optimization (MICO) for joint bias field estimation and segmentation of magnetic resonance (MR) images. The proposed method takes full advantage of the decomposition of MR images into two multiplicative components, namely, the true image that characterizes a physical property of the tissues and the bias field that accounts for the intensity inhomogeneity, and their respective spatial properties. Bias field estimation and tissue segmentation are simultaneously achieved by an energy minimization process aimed to optimize the estimates of the two multiplicative components of an MR image. The bias field is iteratively optimized by using efficient matrix computations, which are verified to be numerically stable by matrix analysis. More importantly, the energy in our formulation is convex in each of its variables, which leads to the robustness of the proposed energy minimization algorithm. The MICO formulation can be naturally extended to 3D/4D tissue segmentation with spatial/sptatiotemporal regularization. Quantitative evaluations and comparisons with some popular softwares have demonstrated superior performance of MICO in terms of robustness and accuracy.

title: Ensemble-based medical image labelling via sampling morphological appearance manifolds
abstract: Atlas-based image labeling is a fundamental tool in medical image segmentation. Recent years have seen extension of single-atlas warping to multi-atlas warping and fusion, which has clearly demonstrated the advantage of consensus-based segmentation. Herein, we further extend this concept, by leveraging upon morphological appearance manifolds (MAMs), which have been previously used to represent a single anatomy with a multitude of equivalent representations derived by varying the atlas or the deformation parameters. We sample the MAM by using different atlases, deformation algorithms, and regularization parameters, thereby generating an ensemble of transformations and residuals. The former are used to generate tentative labels for the individual image, and the latter are used to locally rank/weight each member of the ensemble according to its similarity with the individual. The method obtained a high accuracy both on training and testing datasets of the MICCAI’13 mid-brain segmentation challenge (average Dice score d = 0.8686).

title: Voxel-Based Morphometry Using the RAVENS Maps: Methods and Validation Using Simulated Longitudinal Atrophy
abstract: Statistical analysis of anatomical maps in a stereotaxic space has been shown to be a useful tool in population-based studies for quantifying local anatomical differences or changes, without a priori assumptions about the location and extent of the regions of interest. This paper presents an extension and validation of a previously published methodology, referred to as RAVENS, for characterizing regional atrophy in the brain. A new method for elastic, volume-preserving spatial normalization, which allows for accurate quantification of very localized atrophy, is used. The RAVENS methodology was tested on images with simulated atrophy within two gyri: precentral and superior temporal. It was found to accurately determine the regions of atrophy, despite their localized nature and the interindividual variability of cortical structures. Moreover, it was found to perform substantially better than the voxel-based morphology method of SPM'99. Improved sensitivity was achieved at the expense of human effort involved in defining a number of sulcal curves that serve as constraints on the 3D elastic warping.

title: DRAMMS: Deformable registration via attribute matching and mutual-saliency weighting.
abstract: A general-purpose deformable registration algorithm referred to as "DRAMMS" is presented in this paper. DRAMMS bridges the gap between the traditional voxel-wise methods and landmark/feature-based methods with primarily two contributions. First, DRAMMS renders each voxel relatively distinctively identifiable by a rich set of attributes, therefore largely reducing matching ambiguities. In particular, a set of multi-scale and multi-orientation Gabor attributes are extracted and the optimal components are selected, so that they form a highly distinctive morphological signature reflecting the anatomical and geometric context around each voxel. Moreover, the way in which the optimal Gabor attributes are constructed is independent of the underlying image modalities or contents, which renders DRAMMS generally applicable to diverse registration tasks. A second contribution of DRAMMS is that it modulates the registration by assigning higher weights to those voxels having higher ability to establish unique (hence reliable) correspondences across images, therefore reducing the negative impact of those regions that are less capable of finding correspondences (such as outlier regions). A continuously-valued weighting function named "mutual-saliency" is developed to reflect the matching uniqueness between a pair of voxels implied by the tentative transformation. As a result, voxels do not contribute equally as in most voxel-wise methods, nor in isolation as in landmark/feature-based methods. Instead, they contribute according to the continuously-valued mutual-saliency map, which dynamically evolves during the registration process. Experiments in simulated images, inter-subject images, single-/multi-modality images, from brain, heart, and prostate have demonstrated the general applicability and the accuracy of DRAMMS.

title: Imaging patterns of brain development and their relationship to cognition.
abstract: We present a brain development index (BDI) that concisely summarizes complex imaging patterns of structural brain maturation along a single dimension using a machine learning methodology. The brain was found to follow a remarkably consistent developmental trajectory in a sample of 621 subjects of ages 8-22 participating in the Philadelphia Neurodevelopmental Cohort, reflected by a cross-validated correlation coefficient between chronologic age and the BDI of r = 0.89. Critically, deviations from this trajectory related to cognitive performance. Specifically, subjects whose BDI was higher than their chronological age displayed significantly superior cognitive processing speed compared with subjects whose BDI was lower than their actual age. These results indicate that the multiparametric imaging patterns summarized by the BDI can accurately delineate trajectories of brain development and identify individuals with cognitive precocity or delay.

title: Sexual dimorphism of brain developmental trajectories during childhood and adolescence
abstract: Human total brain size is consistently reported to be approximately 8-10% larger in males, although consensus on regionally specific differences is weak. Here, in the largest longitudinal pediatric neuroimaging study reported to date (829 scans from 387 subjects, ages 3 to 27 years), we demonstrate the importance of examining size-by-age trajectories of brain development rather than group averages across broad age ranges when assessing sexual dimorphism. Using magnetic resonance imaging (MRI) we found robust male/female differences in the shapes of trajectories with total cerebral volume peaking at age 10.5 in females and 14.5 in males. White matter increases throughout this 24-year period with males having a steeper rate of increase during adolescence. Both cortical and subcortical gray matter trajectories follow an inverted U shaped path with peak sizes 1 to 2 years earlier in females. These sexually dimorphic trajectories confirm the importance of longitudinal data in studies of brain development and underline the need to consider sex matching in studies of brain development.

title: Brain development during childhood and adolescence: a longitudinal MRI study
abstract: Pediatric neuroimaging studies, up to now exclusively cross sectional, identify linear decreases in cortical gray matter and increases in white matter across ages 4 to 20. In this large-scale longitudinal pediatric neuroimaging study, we confirmed linear increases in white matter, but demonstrated nonlinear changes in cortical gray matter, with a preadolescent increase followed by a postadolescent decrease. These changes in cortical gray matter were regionally specific, with developmental curves for the frontal and parietal lobe peaking at about age 12 and for the temporal lobe at about age 16, whereas cortical gray matter continued to increase in the occipital lobe through age 20.

title: Topologically Dissociable Patterns of Development of the Human Cerebral Cortex
abstract: Over 90 years ago, anatomists noted the cortex is thinner in sulci than gyri, suggesting that development may occur on a fine scale driven by local topology. However, studies of brain development in youth have focused on describing how cortical thickness varies over large-scale functional and anatomic regions. How the relationship between thickness and local sulcal topology arises in development is still not well understood. Here, we investigated the spatial relationships between cortical thickness, folding, and underlying white matter organization to elucidate the influence of local topology on human brain development. Our approach included using both T1-weighted imaging and diffusion tensor imaging (DTI) in a cross-sectional sample of 932 youths ages 8–21 studied as part of the Philadelphia Neurodevelopmental Cohort. Principal components analysis revealed separable development-related processes of regionally specific nonlinear cortical thickening (from ages 8–14) and widespread linear cortical thinning that have dissociable relationships with cortical topology. Whereas cortical thinning was most prominent in the depths of the sulci, early cortical thickening was present on the gyri. Furthermore, decline in mean diffusivity calculated from DTI in underlying white matter was correlated with cortical thinning, suggesting that cortical thinning is spatially associated with white matter development. Spatial permutation tests were used to assess the significance of these relationships. Together, these data demonstrate that cortical remodeling during youth occurs on a local topological scale and is associated with changes in white matter beneath the cortical surface.

title: Stable and Efficient Multiple Smoothing Parameter Estimation for Generalized Additive Models
abstract: Representation of generalized additive models (GAM's) using penalized regression splines allows GAM's to be employed in a straightforward manner using penalized regression methods. Not only is inference facilitated by this approach, but it is also possible to integrate model selection in the form of smoothing parameter selection into model fitting in a computationally efficient manner using well founded criteria such as generalized cross-validation. The current fitting and smoothing parameter selection methods for such models are usually effective, but do not provide the level of numerical stability to which users of linear regression packages, for example, are accustomed. In particular the existing methods cannot deal adequately with numerical rank deficiency of the GAM fitting problem, and it is not straightforward to produce methods that can do so, given that the degree of rank deficiency can be smoothing parameter dependent. In addition, models with the potential flexibility of GAM's can also present practical fitting difficulties as a result of indeterminacy in the model likelihood: Data with many zeros fitted by a model with a log link are a good example. In this article it is proposed that GAM's with a ridge penalty provide a practical solution in such circumstances, and a multiple smoothing parameter selection method suitable for use in the presence of such a penalty is developed. The method is based on the pivoted QR decomposition and the singular value decomposition, so that with or without a ridge penalty it has good error propagation properties and is capable of detecting and coping elegantly with numerical rank deficiency. The method also allows mixtures of user specified and estimated smoothing parameters and the setting of lower bounds on smoothing parameters. In terms of computational efficiency, the method compares well with existing methods. A simulation study compares the method to existing methods, including treating GAM's as mixed models.

title: Fast stable restricted maximum likelihood and marginal likelihood estimation of semiparametric generalized linear models
abstract: Recent work by Reiss and Ogden provides a theoretical basis for sometimes preferring restricted maximum likelihood (REML) to generalized cross-validation (GCV) for smoothing parameter selection in semiparametric regression. However, existing REML or marginal likelihood (ML) based methods for semiparametric generalized linear models (GLMs) use iterative REML or ML estimation of the smoothing parameters of working linear approximations to the GLM. Such indirect schemes need not converge and fail to do so in a non-negligible proportion of practical analyses. By contrast, very reliable prediction error criteria smoothing parameter selection methods are available, based on direct optimization of GCV, or related criteria, for the GLM itself. Since such methods directly optimize properly defined functions of the smoothing parameters, they have much more reliable convergence properties. The paper develops the first such method for REML or ML estimation of smoothing parameters. A Laplace approximation is used to obtain an approximate REML or ML for any GLM, which is suitable for efficient direct optimization. This REML or ML criterion requires that Newton–Raphson iteration, rather than Fisher scoring, be used for GLM fitting, and a computationally stable approach to this is proposed. The REML or ML criterion itself is optimized by a Newton method, with the derivatives required obtained by a mixture of implicit differentiation and direct methods. The method will cope with numerical rank deficiency in the fitted model and in fact provides a slight improvement in numerical robustness on the earlier method of Wood for prediction error criteria based smoothness selection. Simulation results suggest that the new REML and ML methods offer some improvement in mean-square error performance relative to GCV or Akaike's information criterion in most cases, without the small number of severe undersmoothing failures to which Akaike's information criterion and GCV are prone. This is achieved at the same computational cost as GCV or Akaike's information criterion. The new approach also eliminates the convergence failures of previous REML- or ML-based approaches for penalized GLMs and usually has lower computational cost than these alternatives. Example applications are presented in adaptive smoothing, scalar on function regression and generalized additive model selection.

title: Impact of puberty on the evolution of cerebral perfusion during adolescence
abstract: Blood perfusion is a fundamental property of brain physiology and is known to be higher in adult females than in males. However, it is unknown when such a sex difference emerges during the lifespan, or what biological processes may cause it. In the largest study of brain perfusion yet reported, we establish for the first time to our knowledge that patterns of development of cerebral perfusion during adolescence are markedly different in males and females, and such differences are attributable in part to the effects of puberty. These results may have important implications for neuropsychiatric disorders with adolescent onset and strong gender disparities, such as mood disorders, anxiety disorders, and schizophrenia. Puberty is the defining biological process of adolescent development, yet its effects on fundamental properties of brain physiology such as cerebral blood flow (CBF) have never been investigated. Capitalizing on a sample of 922 youths ages 8–22 y imaged using arterial spin labeled MRI as part of the Philadelphia Neurodevelopmental Cohort, we studied normative developmental differences in cerebral perfusion in males and females, as well as specific associations between puberty and CBF. Males and females had conspicuously divergent nonlinear trajectories in CBF evolution with development as modeled by penalized splines. Seventeen brain regions, including hubs of the executive and default mode networks, showed a robust nonlinear age-by-sex interaction that surpassed Bonferroni correction. Notably, within these regions the decline in CBF was similar between males and females in early puberty and only diverged in midpuberty, with CBF actually increasing in females. Taken together, these results delineate sex-specific growth curves for CBF during youth and for the first time to our knowledge link such differential patterns of development to the effects of puberty.

title: Application of Information Technology: An Integrated Software Suite for Surface-based Analyses of Cerebral Cortex
abstract: The authors describe and illustrate an integrated trio of software programs for carrying out surface-based analyses of cerebral cortex. The first component of this trio, SureFit (Surface Reconstruction by Filtering and Intensity Transformations), is used primarily for cortical segmentation, volume visualization, surface generation, and the mapping of functional neuroimaging data onto surfaces. The second component, Caret (Computerized Anatomical Reconstruction and Editing Tool Kit), provides a wide range of surface visualization and analysis options as well as capabilities for surface flattening, surface-based deformation, and other surface manipulations. The third component, SuMS (Surface Management System), is a database and associated user interface for surface-related data. It provides for efficient insertion, searching, and extraction of surface and volume data from the database.

title: The Brain's Default Network
abstract: Thirty years of brain imaging research has converged to define the brain's default network—a novel and only recently appreciated brain system that participates in internal modes of cognition. Here we synthesize past observations to provide strong evidence that the default network is a specific, anatomically defined brain system preferentially active when individuals are not focused on the external environment. Analysis of connectional anatomy in the monkey supports the presence of an interconnected brain system. Providing insight into function, the default network is active when individuals are engaged in internally focused tasks including autobiographical memory retrieval, envisioning the future, and conceiving the perspectives of others. Probing the functional anatomy of the network in detail reveals that it is best understood as multiple interacting subsystems. The medial temporal lobe subsystem provides information from prior experiences in the form of memories and associations that are the building blocks of mental simulation. The medial prefrontal subsystem facilitates the flexible use of this information during the construction of self‐relevant mental simulations. These two subsystems converge on important nodes of integration including the posterior cingulate cortex. The implications of these functional and anatomical observations are discussed in relation to possible adaptive roles of the default network for using past experiences to plan for the future, navigate social interactions, and maximize the utility of moments when we are not otherwise engaged by the external world. We conclude by discussing the relevance of the default network for understanding mental disorders including autism, schizophrenia, and Alzheimer's disease.

title: Aberrant "default mode" functional connectivity in schizophrenia.
abstract: The "default mode" has been defined as a baseline condition of brain function and is of interest because its component brain regions are believed to be abnormal in schizophrenia. It was hypothesized that the default mode network would show abnormal activation and connectivity in patients with schizophrenia.



Patients with schizophrenia (N=21) and healthy comparison subjects (N=22) performed an auditory oddball task during functional magnetic resonance imaging (fMRI). Independent component analysis was used to identify the default mode component. Differences in the spatial and temporal aspects of the default mode network were examined in patients versus comparison subjects.



Healthy comparison subjects and patients had significant spatial differences in the default mode network, most notably in the frontal, anterior cingulate, and parahippocampal gyri. In addition, activity in patients in the medial frontal, temporal, and cingulate gyri correlated with severity of positive symptoms. The patients also showed significantly higher frequency fluctuations in the temporal evolution of the default mode.



Schizophrenia is associated with altered temporal frequency and spatial location of the default mode network. The authors hypothesized that this network may be under- or overmodulated by key regions, including the anterior and posterior cingulate cortex. In addition, the altered temporal fluctuations in patients may result from a change in the connectivity of these regions with other brain networks.

title: Hyperactivity and hyperconnectivity of the default network in schizophrenia and in first-degree relatives of persons with schizophrenia
abstract: We examined the status of the neural network mediating the default mode of brain function, which typically exhibits greater activation during rest than during task, in patients in the early phase of schizophrenia and in young first-degree relatives of persons with schizophrenia. During functional MRI, patients, relatives, and controls alternated between rest and performance of working memory (WM) tasks. As expected, controls exhibited task-related suppression of activation in the default network, including medial prefrontal cortex (MPFC) and posterior cingulate cortex/precuneus. Patients and relatives exhibited significantly reduced task-related suppression in MPFC, and these reductions remained after controlling for performance. Increased task-related MPFC suppression correlated with better WM performance in patients and relatives and with less psychopathology in all 3 groups. For WM task performance, patients and relatives had greater activation in right dorsolateral prefrontal cortex (DLPFC) than controls. During rest and task, patients and relatives exhibited abnormally high functional connectivity within the default network. The magnitudes of default network connectivity during rest and task correlated with psychopathology in the patients. Further, during both rest and task, patients exhibited reduced anticorrelations between MPFC and DLPFC, a region that was hyperactivated by patients and relatives during WM performance. Among patients, the magnitude of MPFC task suppression negatively correlated with default connectivity, suggesting an association between the hyperactivation and hyperconnectivity in schizophrenia. Hyperactivation (reduced task-related suppression) of default regions and hyperconnectivity of the default network may contribute to disturbances of thought in schizophrenia and risk for the illness.

title: Default mode network abnormalities in bipolar disorder and schizophrenia
abstract: The default-mode network (DMN) consists of a set of brain areas preferentially activated during internally focused tasks. We used functional magnetic resonance imaging (fMRI) to study the DMN in bipolar mania and acute schizophrenia. Participants comprised 17 patients with bipolar disorder (BD), 14 patients with schizophrenia (SZ) and 15 normal controls (NC), who underwent 10-min resting fMRI scans. The DMN was extracted using independent component analysis and template-matching; spatial extent and timecourse were examined. Both patient groups showed reduced DMN connectivity in the medial prefrontal cortex (mPFC) (BD: x=-2, y=54, z=-12; SZ: x=-2, y=22, z=18). BD subjects showed abnormal recruitment of parietal cortex (correlated with mania severity) while SZ subjects showed greater recruitment of the frontopolar cortex/basal ganglia. Both groups had significantly higher frequency fluctuations than controls. We found ventral mPFC abnormalities in BD and dorsal mPFC abnormalities in SZ. The higher frequency of BOLD signal oscillations observed in patients suggests abnormal functional organization of circuits in both disorders. Further studies are needed to determine how these abnormalities are related to specific symptoms of each condition.

title: Correlated structural and functional brain abnormalities in the default mode network in schizophrenia patients
abstract: There is increasing evidence of default mode network (DMN) dysfunction in schizophrenia. It has also been suggested that brain structural changes are maximal in a medial frontal area which overlaps with the anterior midline node of this network.



Brain deactivations were examined in 14 schizophrenic patients and 14 controls during performance of two tasks requiring identification or labelling of facial emotions. Grey matter and white matter volumes were compared using voxel-based morphometry.



Relative to the controls, the schizophrenic patients showed failure to deactivate in the anterior and posterior midline nodes of the default mode network, as well as other areas considered to be part of the network. Grey matter volume reductions in the patients were found in medial cortical regions which overlapped with the same parts of the network. The functional and structural changes showed significant correlations in a number of medial cortical areas.



Failure of deactivation in the default mode network is seen in schizophrenic patients when they perform facial emotion tasks. This failure is more extensive than that seen during performance of working memory tasks. The study also supports recent findings of brain structural changes in schizophrenia in the territory of the default mode network.

title: Childhood-onset schizophrenia: progressive brain changes during adolescence
abstract: Previous NIMH childhood onset schizophrenia (COS) anatomic brain MRI studies found progression of ventricular volume and other structural brain anomalies at 2-year follow up across mean ages 14 to 16 years. However, studies in adult patients generally do not show progression of ventricular volume or correlation of ventricular volume with duration of illness. To address issues of progression of brain anomalies in schizophrenia, this report extends previous studies to include a third longitudinal scan, uses a larger sample size, and includes measures of the amygdala and hippocampus.



Volumes of the total cerebrum, lateral ventricles, hippocampus, and amygdala were quantified on 208 brain magnetic resonance imaging scans from 42 adolescents with COS (23 with one or more repeat scan) and 74 age- and gender-matched controls (36 with one or more repeat scan). A statistical technique permitting combined use of cross-sectional and longitudinal data was used to assess age-related changes, linearity, and diagnostic group differences.



Differential nonlinear progression of brain anomalies was seen during adolescence with the total cerebrum and hippocampus decreasing and lateral ventricles increasing in the COS group. The developmental curves for these structures reached an asymptote by early adulthood for the COS group and did not significantly change with age in the control group.



These findings reconcile less striking progression of anatomic brain images usually seen for adult schizophrenia and complement other data consistent with time-limited, diagnostic-specific decreases in brain tissue. Adolescence appears to be a unique period of differential brain development in schizophrenia.

title: Childhood onset schizophrenia: support for a progressive neurodevelopmental disorder
abstract: Structural brain abnormalities have become an established feature of schizophrenia and increasing evidence points towards the progressive nature of these abnormalities. The brain abnormalities are most profound in early onset cases, which have a severe, treatment refractory phenotype and more salient genetic features. Unique insights could thus be gained in schizophrenia pathology from studying the earliest manifestations of the illness. This paper reviews and updates the findings on anatomic brain development in patients with very early onset schizophrenia while showing preliminary data from ongoing studies. Collectively, our studies demonstrate that childhood‐onset schizophrenia (COS) subjects show progressive loss of gray matter, delayed/disrupted white matter (WM) growth, and a progressive decline in cerebellar volume, some of which are shared by their healthy siblings. The developmental patterns or the ‘trajectories’ of brain development are often more striking than anatomic brain differences at any one point in time; highlighting the importance of longitudinal studies. The sibling findings of partially shared gray matter (GM) deficits which appear to normalize with age, along with other genetic analyses, provide evidence that the brain developmental ‘patterns/trajectories’ for several regions at particular ages could be useful endophenotypes (trait markers).

title: Accelerated brain aging in schizophrenia and beyond: a neuroanatomical marker of psychiatric disorders.
abstract: Structural brain abnormalities are central to schizophrenia (SZ), but it remains unknown whether they are linked to dysmaturational processes crossing diagnostic boundaries, aggravating across disease stages, and driving the neurodiagnostic signature of the illness. Therefore, we investigated whether patients with SZ (N = 141), major depression (MD; N = 104), borderline personality disorder (BPD; N = 57), and individuals in at-risk mental states for psychosis (ARMS; N = 89) deviated from the trajectory of normal brain maturation. This deviation was measured as difference between chronological and the neuroanatomical age (brain age gap estimation [BrainAGE]). Neuroanatomical age was determined by a machine learning system trained to individually estimate age from the structural magnetic resonance imagings of 800 healthy controls. Group-level analyses showed that BrainAGE was highest in SZ (+5.5 y) group, followed by MD (+4.0), BPD (+3.1), and the ARMS (+1.7) groups. Earlier disease onset in MD and BPD groups correlated with more pronounced BrainAGE, reaching effect sizes of the SZ group. Second, BrainAGE increased across at-risk, recent onset, and recurrent states of SZ. Finally, BrainAGE predicted both patient status as well as negative and disorganized symptoms. These findings suggest that an individually quantifiable "accelerated aging" effect may particularly impact on the neuroanatomical signature of SZ but may extend also to other mental disorders.

title: Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia
abstract: Neurodevelopmental models for the pathology of schizophrenia propose both polygenetic and environmental risks, as well as early (pre/perinatal) and late (usually adolescent) developmental brain abnormalities. With the use of brain mapping algorithms, we detected striking anatomical profiles of accelerated gray matter loss in very early-onset schizophrenia; surprisingly, deficits moved in a dynamic pattern, enveloping increasing amounts of cortex throughout adolescence. Early-onset patients were rescanned prospectively with MRI, at 2-year intervals at three time points, to uncover the dynamics and timing of disease progression during adolescence. The earliest deficits were found in parietal brain regions, supporting visuospatial and associative thinking, where adult deficits are known to be mediated by environmental (nongenetic) factors. Over 5 years, these deficits progressed anteriorly into temporal lobes, engulfing sensorimotor and dorsolateral prefrontal cortices, and frontal eye fields. These emerging patterns correlated with psychotic symptom severity and mirrored the neuromotor, auditory, visual search, and frontal executive impairments in the disease. In temporal regions, gray matter loss was completely absent early in the disease but became pervasive later. Only the latest changes included dorsolateral prefrontal cortex and superior temporal gyri, deficit regions found consistently in adult studies. These emerging dynamic patterns were (i) controlled for medication and IQ effects, (ii) replicated in independent groups of males and females, and (iii) charted in individuals and groups. The resulting mapping strategy reveals a shifting pattern of tissue loss in schizophrenia. Aspects of the anatomy and dynamics of disease are uncovered, in a changing profile that implicates genetic and nongenetic patterns of deficits.

title: Brain surface contraction mapped in first-episode schizophrenia: a longitudinal magnetic resonance imaging study
abstract: Schizophrenia is associated with structural brain abnormalities, but the timing of onset and course of these changes remains unclear. Longitudinal magnetic resonance imaging (MRI) studies have demonstrated progressive brain volume decreases in patients around and after the onset of illness, although considerable discrepancies exist regarding which brain regions are affected. The anatomical pattern of these progressive changes in schizophrenia is largely unknown. In this study, MRI scans were acquired repeatedly from 16 schizophrenia patients approximately 2 years apart following their first episode of illness, and also from 14 age-matched healthy subjects. Cortical Pattern Matching, in combination with Structural Image Evaluation, using Normalisation, of Atrophy, was applied to compare the rates of cortical surface contraction between patients and controls. Surface contraction in the dorsal surfaces of the frontal lobe was significantly greater in patients with first-episode schizophrenia (FESZ) compared with healthy controls. Overall, brain surface contraction in patients and healthy controls showed similar anatomical patterns, with that of the former group exaggerated in magnitude across the entire brain surface. That the pattern of structural change in the early course of schizophrenia corresponds so closely to that associated with normal development is consistent with the hypothesis that a schizophrenia-related factor interacts with normal adolescent brain developmental processes in the pathophysiology of schizophrenia. The exaggerated progressive changes seen in patients with schizophrenia may reflect an increased rate of synaptic pruning, resulting in excessive loss of neuronal connectivity, as predicted by the late neurodevelopmental hypothesis of the illness.

title: Volumetric MRI assessment of temporal lobe structures in schizophrenia
abstract: This magnetic resonance imaging (MRI) study was designed to investigate whether patients with schizophrenia have focal or lateralized deficits in the volumes of temporal lobe structures. Estimated volumes of the temporal lobes, hippocampi, superior temporal gyri, lateral ventricles, third ventricle, temporal horns of the lateral ventricles, and a frontal-parietal reference area (FPRA) were quantified for each hemisphere. The schizophrenic group had less gray matter (GM) in the temporal lobes and the FPRA relative to controls. Ventricular volumes were significantly larger in the schizophrenic group, as was cerebrospinal fluid (CSF) volume for temporal lobe sulci. No significant differences in hippocampal volumes emerged between groups. The magnitude of GM deficit was not greater in the temporal lobes relative to the FPRA. These results confirm the presence of bilateral GM volume deficits of the temporal lobes in schizophrenia but do not support the hypothesis that structural changes preferentially affect the temporal lobes or the left cerebral hemisphere.

title: Structural magnetic resonance imaging abnormalities in men with severe chronic schizophrenia and an early age at clinical onset.
abstract: Early age at onset of schizophrenia often signifies a more severe form of the illness. However, the relationship between age at onset and brain abnormalities has not been established. We assessed temporal-limbic morphometry in severely ill men with chronic schizophrenia who had a relatively early onset of illness and examined the relationships among regional brain volumes, clinical symptoms, and age at illness onset.



Temporal lobe, superior temporal gyrus, hippocampus, temporal horn, lateral ventricles, third ventricle, and frontoparietal volumes were measured on magnetic resonance imaging data from 56 schizophrenic men (mean [SD] age at illness onset, 16.6 [4.2] years) recruited from a state hospital and 52 age- and range-matched healthy control men.



Patients had significantly smaller gray matter volumes in the temporal lobe, superior temporal gyrus, and frontoparietal regions; smaller temporal lobe white matter volumes; and larger cerebrospinal fluid volumes for temporal lobe sulci and the 3 ventricular measures. There were no group differences in hippocampal volumes. Psychotic symptom subscores from the Brief Psychiatric Rating Scale were selectively correlated with smaller left posterior superior temporal gyrus gray matter volumes. None of the brain measurements were significantly correlated with age at illness onset.



Data from this unique sample of severely ill schizophrenic men emphasize a pattern of structural abnormalities involving the cortex, but not the hippocampus, in schizophrenia. Furthermore, these data support theories suggesting that superior temporal gyrus abnormalities contribute selectively to psychotic symptoms and that the extent of structural abnormalities is unrelated to age of clinical symptom onset.

title: An MRI study of temporal lobe structures in men with bipolar disorder or schizophrenia
abstract: Hippocampal atrophy has been described in postmortem and magnetic resonance imaging studies of schizophrenia. The specificity of this finding to schizophrenia remains to be determined. The neuropathology of bipolar disorder is understudied, and temporal lobe structures have only recently been evaluated.



Twenty-four bipolar, 20 schizophrenic, and 18 normal comparison subjects were evaluated using magnetic resonance brain imaging. Image data were acquired using a three-dimensional spoiled GRASS sequence, and brain images were reformatted in three planes. Temporal lobe structures including the amygdala, hippocampus, parahippocampus, and total temporal lobe were measured to obtain volumes for each structure in the three subject groups. Severity of symptoms in both patient groups was assessed at the time the magnetic resonance images were obtained.



Hippocampal volumes were significantly smaller in the schizophrenic group than in both bipolar and normal comparison subjects. Further, amygdala volumes were significantly larger in the bipolar group than in both schizophrenic and normal comparison subjects.



The results suggest differences in affected limbic structures in patients with schizophrenia and bipolar disorder. These specific neuroanatomic abnormalities may shed light on the underlying pathophysiology and presentation of the two disorders.

title: The anatomy of first-episode and chronic schizophrenia: an anatomical likelihood estimation meta-analysis.
abstract: The authors sought to map gray matter changes in first-episode schizophrenia and to compare these with the changes in chronic schizophrenia. They postulated that the data would show a progression of changes from hippocampal deficits in first-episode schizophrenia to include volume reductions in the amygdala and cortical gray matter in chronic schizophrenia.



A systematic search was conducted for voxel-based structural MRI studies of patients with first-episode schizophrenia and chronic schizophrenia in relation to comparison groups. Meta-analyses of the coordinates of gray matter differences were carried out using anatomical likelihood estimation. Maps of gray matter changes were constructed, and subtraction meta-analysis was used to compare them.



A total of 27 articles were identified for inclusion in the meta-analyses. A marked correspondence was observed in regions affected by both first-episode schizophrenia and chronic schizophrenia, including gray matter decreases in the thalamus, the left uncus/amygdala region, the insula bilaterally, and the anterior cingulate. In the comparison of first-episode schizophrenia and chronic schizophrenia, decreases in gray matter volume were detected in first-episode schizophrenia but not in chronic schizophrenia in the caudate head bilaterally; decreases were more widespread in cortical regions in chronic schizophrenia.



Anatomical changes in first-episode schizophrenia broadly coincide with a basal ganglia-thalamocortical circuit. These changes include bilateral reductions in caudate head gray matter, which are absent in chronic schizophrenia. Comparing first-episode schizophrenia and chronic schizophrenia, the authors did not find evidence for the temporolimbic progression of pathology from hippocampus to amygdala, but there was evidence for progression of cortical changes.

title: Structural brain alterations at different stages of schizophrenia: A voxel-based morphometric study
abstract: Structural alterations in schizophrenia have mainly been regarded as the result of neurodevelopmental processes. However, it remains unresolved whether the pattern of morphological brain changes differs between different stages of disease. We examined structural brain changes in 93 first-episode (FES) and 72 recurrently ill (REZ) patients with schizophrenia (SZ) and 175 matched healthy control subjects (HC) using cross-sectional and conjunctional voxel-based morphometry (VBM) of whole-brain MRI data in a three-step approach. We found significant grey matter density (GMD) reductions in FES compared to HC bilaterally in the temporal and prefrontal areas, including the anterior cingulate gyrus, as well as in both thalami. Hippocampus and amygdala were affected on the left side (P<0.05, corrected). In REZ patients this pattern was spatially extended. The basal ganglia were exclusively reduced in the recurrently ill group compared to controls. Common to both disease groups were reductions in the bilateral perisylvian regions, the opercular region, the insula, prefrontal cortex, left inferior temporal gyrus, limbic system including hippocampus and amygdala, and the thalami. In FES patients there were no regions affected that were not also affected in REZ patients. In contrast, REZ patients showed extended alterations within the frontal and temporal regions, the hippocampus, amygdala and exclusively in the basal ganglia relative to the FES patients. Our findings suggest a system-specific involvement of neuronal networks in schizophrenia. Furthermore, our data suggest that in the advanced stages of schizophrenia additional cortical and subcortical brain areas become involved in the disease process. Longitudinal data will be required to further test this hypothesis.

title: Differences in hippocampal volume between major depression and schizophrenia: a comparative neuroimaging study
abstract: Several studies have demonstrated that structural brain change is detectable in the hippocampus in both patients, with schizophrenia and major depression. Only few studies, however, compared both clinical disease entities directly and no larger study has tried to take different disease stages into account. The objectives of this study are to investigate whether hippocampal volumes are reduced in patients with schizophrenia and those with major depression with the same duration of illness compared to healthy controls and to assess further changes at different disease stages. A total of 319 inpatients and healthy controls were enrolled and investigated with magnetic resonance imaging (MRI). Hippocampal volumes were measured using the segmentation software BRAINS. Bilateral hippocampal volume reductions were detected in both schizophrenic and depressed patients compared to healthy control (HC) subjects. Although younger, schizophrenic (SZ) patients showed in their MRI scans significant bilaterally reduced hippocampal volumes compared to patients with major depression. Although the hippocampal reductions were similar at the onset of symptomatic manifestation of both diseases, there was a further significant reduction of the left hippocampus in the recurrently ill SZ subgroup. The data suggest rather dynamic structural brain alterations in schizophrenia compared to major depression. Here, the presented application of the comparative neuroscience approach, by the use of large neuroimaging MRI databases, seems highly valuable. In the field of psychiatry, with its still controversial operationalized descriptive diagnostic entities, the cross-nosological approach provides a helpful tool to better elucidate the still unknown brain pathologies and their underlying molecular mechanisms beyond a single nosological entity.

title: A review of structural neuroimaging in schizophrenia: from connectivity to connectomics
abstract: In patients with schizophrenia neuroimaging studies have revealed global differences with some brain regions showing focal abnormalities. Examining neurocircuitry, diffusion-weighted imaging studies have identified altered structural integrity of white matter in frontal and temporal brain regions and tracts such as the cingulum bundles, uncinate fasciculi, internal capsules and corpus callosum associated with the illness. Furthermore, structural co-variance analyses have revealed altered structural relationships among regional morphology in the thalamus, frontal, temporal and parietal cortices in schizophrenia patients. The distributed nature of these abnormalities in schizophrenia suggests that multiple brain circuits are impaired, a neural feature that may be better addressed with network level analyses. However, even with the advent of these newer analyses, a large amount of variability in findings remains, likely partially due to the considerable heterogeneity present in this disorder.

title: Structural brain alterations in subjects at high-risk of psychosis: A voxel-based morphometric study
abstract: Forty Untreated high-risk (HR) individuals for psychosis and 75 healthy control subjects (HC) matched for age, gender, handedness and educational level were investigated by structural MRI. HR subjects were recruited at the Early Detection and Intervention Centre for Mental Crises (FETZ) of the Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Germany. Measurements of gray matter volumes were performed by voxel-based morphometry using SPM5. The sample of HR subjects showed GM volume reductions in frontal, lateral temporal and medial temporal regions compared to the healthy control group. These regions are compatible with structural findings in the clinically apparent disease of schizophrenia.

title: Imaging Patients with Psychosis and a Mouse Model Establishes a Spreading Pattern of Hippocampal Dysfunction and Implicates Glutamate as a Driver
abstract: VIDEO 
The hippocampus in schizophrenia is characterized by both hypermetabolism and reduced size. It remains unknown whether these abnormalities are mechanistically linked. Here we addressed this question by using MRI tools that can map hippocampal metabolism and structure in patients and mouse models. In at-risk patients, hypermetabolism was found to begin in CA1 and spread to the subiculum after psychosis onset. CA1 hypermetabolism at baseline predicted hippocampal atrophy, which occurred during progression to psychosis, most prominently in similar regions. Next, we used ketamine to model conditions of acute psychosis in mice. Acute ketamine reproduced a similar regional pattern of hypermetabolism, while repeated exposure shifted the hippocampus to a hypermetabolic basal state with concurrent atrophy and pathology in parvalbumin-expressing interneurons. Parallel in vivo experiments using the glutamate-reducing drug LY379268 and direct measurements of extracellular glutamate showed that glutamate drives both neuroimaging abnormalities. These findings show that hippocampal hypermetabolism leads to atrophy in psychotic disorder and suggest glutamate as a pathogenic driver.

title: GABAergic mechanisms of hippocampal hyperactivity in schizophrenia
abstract: Schizophrenia is associated with abnormalities of hippocampal structure and function. Neuroimaging studies have shown that the hippocampus is hyperactive in schizophrenia. Here we explore GABAergic mechanisms of this hippocampal hyperactivity. The initial evidence for GABAergic abnormalities of the hippocampus in schizophrenia came from post-mortem studies of interneuron number, protein expression, and gene expression. These studies revealed marked decreases in gene and protein expression of somatostatin-positive and parvalbumin-positive interneurons, and indicated reduced interneuron numbers. Animal studies of decreased parvalbumin and NMDA-receptor function have shown that selective abnormalities of hippocampal interneurons mimic some of the cognitive deficits and clinical features of schizophrenia. The post-mortem and animal studies are consistent with the neuroimaging finding of increased hippocampal activity in schizophrenia, which can explain some of the psychotic symptoms and cognitive deficits. Taken together, these findings may guide the development of biomarkers and the development of new treatments for psychosis.

title: Toward Illness Phase–Specific Pharmacotherapy for Schizophrenia
abstract: All antipsychotics approved by the U.S. Food and Drug Administration for the treatment of schizophrenia act primarily to reduce the stimulation of dopamine D2 receptors. This finding would seem to imply that all patients, or perhaps just patients who are responsive to pharmacotherapy, manifest overstimulation of D2 receptors by dopamine (1). It also reflects a failure of medication development efforts to address adequately the heterogeneous pathophysiologies associated with schizophrenia. Given recent prominence of the hypothesis that early intervention may lead to better long-term outcomes, it may be timely to draw attention to one potential source of heterogeneity within and across patients—the dynamic time-dependent neurobiological evolution of schizophrenia across its course of illness. This interest is further fueled by an article in this issue of Biological Psychiatry, which suggests that patients early in their course of illness respond favorably to monotherapy with pomaglumetad methionil, a drug that is metabolized into an agonist of metabotropic glutamate 2/3 (mGluR2/3) receptor. The article also reports the provocative finding that the same drug is not only ineffective but also may worsen clinical outcomes for patients with long-standing illness (2). Although the article presents results supporting alternative hypotheses, the focus of this commentary is on the possible implications for illness phase– specific pharmacotherapies. The notion of illness phase–specific pharmacotherapy is predicated on the hypothesis of a dynamic schizophrenia neurobiology that evolves over the course of illness. This commentary has very limited room to review this hypothesis critically; also, nearly all clinical data on patients with chronic illness are confounded by the effects of antipsychotic treatment. Nonetheless, one might build on a published schema (3) that describes schizophrenia as progressing through four phases: 1) predrome—before the onset of obvious symptoms; 2) prodrome—symptoms and cognitive impairments are present but in an attenuated form; 3) syndrome—patients fully express the disorder; and 4) chronic illness—symptoms, cognitive dysfunction, and functional impairments persist at fluctuating levels and may progress despite treatment. Although this progression in symptom profiles suggests a changing neurobiology, these phases have yet to be linked to particular neurobiological features that would indicate the need for phase-specific pharmacotherapies. Perhaps it is time to characterize explicitly the developmental neurobiology of schizophrenia so that this knowledge might inform the pharmacotherapy of this disorder. This approach would first need to be rooted in the genetics and epigenetics of schizophrenia that implicate disturbances in glutamate synaptic signaling, calcium signaling, and

title: Mapping grey matter reductions in schizophrenia: An anatomical likelihood estimation analysis of voxel-based morphometry studies
abstract: Voxel-based morphometry (VBM) is a popular tool for mapping neuroanatomical changes in schizophrenia patients. Several recent meta-analyses have identified the brain regions in which patients most consistently show grey matter reductions, although they have not examined whether such changes reflect differences in grey matter concentration (GMC) or grey matter volume (GMV). These measures assess different aspects of grey matter integrity, and may therefore reflect different pathological processes. In this study, we used the Anatomical Likelihood Estimation procedure to analyse significant differences reported in 37 VBM studies of schizophrenia patients, incorporating data from 1646 patients and 1690 controls, and compared the findings of studies using either GMC or GMV to index grey matter differences. Analysis of all studies combined indicated that grey matter reductions in a network of frontal, temporal, thalamic and striatal regions are among the most frequently reported in literature. GMC reductions were generally larger and more consistent than GMV reductions, and were more frequent in the insula, medial prefrontal, medial temporal and striatal regions. GMV reductions were more frequent in dorso-medial frontal cortex, and lateral and orbital frontal areas. These findings support the primacy of frontal, limbic, and subcortical dysfunction in the pathophysiology of schizophrenia, and suggest that the grey matter changes observed with MRI may not necessarily result from a unitary pathological process.

title: Hippocampal atrophy in recurrent major depression.
abstract: Hippocampal volumes of subjects with a history of major depressive episodes but currently in remission and with no known medical comorbidity were compared to matched normal controls by using volumetric magnetic resonance images. Subjects with a history of major depression had significantly smaller left and right hippocampal volumes with no differences in total cerebral volumes. The degree of hippocampal volume reduction correlated with total duration of major depression. In addition, large (diameter > or = 4.5 mm)-hippocampal low signal foci (LSF) were found within the hippocampus, and their number also correlated with the total number of days depressed. These results suggest that depression is associated with hippocampal atrophy, perhaps due to a progressive process mediated by glucocorticoid neurotoxicity.

title: Medial temporal lobe structures and hippocampal subfields in psychotic disorders: findings from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study.
abstract: Structural alterations in the hippocampus and other medial temporal lobe regions have been observed in schizophrenia. How these alterations and hippocampal subfields might differ across the psychosis spectrum remains unclear.



To characterize medial temporal lobe structures, including hippocampal subfields, using magnetic resonance imaging and to examine their relation to psychosis and cognitive function across the psychosis spectrum.



Case-control, cross-sectional neuroimaging study in a large series of probands with psychotic disorders and healthy volunteers as part of the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP). Patients with psychotic disorders (schizophrenia, n = 219; schizoaffective disorder, n = 142; and psychotic bipolar disorder, n = 188) and healthy controls (n = 337) were recruited across ambulatory clinics at university health centers in the B-SNIP consortium.



Medial temporal lobe and hippocampal subfields were quantified with an automated parcellation approach using FreeSurfer software. Memory and other cognitive parameters were assessed using standardized neuropsychological tests.



Hippocampal volume reductions were seen in all 3 diagnostic groups when compared with healthy controls; alterations in the entorhinal cortex and parahippocampal regions were limited to schizophrenia and schizoaffective disorders (P < .001). Smaller volumes across the hippocampal subfields were seen in all 3 psychotic disorders, with the most prominent differences being in cornu ammonis 2/3 (P < .001). Hippocampal volumes were positively correlated with psychosis severity, declarative memory, and overall cognitive performance (P < .05).



Alterations in the hippocampus were evident across psychotic disorders. Hippocampal subfields that participate in memory-related processes supporting pattern separation and pattern completion might be abnormal and may underlie the pathophysiology of psychosis.

title: Finding the Elusive Psychiatric "Lesion" With 21st-Century Neuroanatomy: A Note of Caution.
abstract: The widespread use of MRI has led to a wealth of structural and functional anatomical findings in patients with diverse psychiatric disorders that may represent insights into pathobiology. However, recent technical reports indicate that data from popular MRI research-particularly structural MRI, resting--state functional MRI, and diffusion tensor imaging--are highly sensitive to common artifacts (e.g., head motion and breathing effects) that may dominate the results. Because these and other important confounders of MRI data (e.g., smoking, body weight, metabolic variations, medical comorbidities, psychoactive drugs, alcohol use, mental state) tend to vary systematically between patient and control groups, the evidence that findings are neurobiologically meaningful is inconclusive and may represent artifacts or epiphenomena of uncertain value. The authors caution that uncritically accepting from study to study findings that may represent fallacies of all sorts carries the risk of misinforming practitioners and patients about biological abnormalities underlying psychiatric illness.

title: Early-Course Unmedicated Schizophrenia Patients Exhibit Elevated Prefrontal Connectivity Associated with Longitudinal Change
abstract: Strong evidence implicates prefrontal cortex (PFC) as a major source of functional impairment in severe mental illness such as schizophrenia. Numerous schizophrenia studies report deficits in PFC structure, activation, and functional connectivity in patients with chronic illness, suggesting that deficient PFC functional connectivity occurs in this disorder. However, the PFC functional connectivity patterns during illness onset and its longitudinal progression remain uncharacterized. Emerging evidence suggests that early-course schizophrenia involves increased PFC glutamate, which might elevate PFC functional connectivity. To test this hypothesis, we examined 129 non-medicated, human subjects diagnosed with early-course schizophrenia and 106 matched healthy human subjects using both whole-brain data-driven and hypothesis-driven PFC analyses of resting-state fMRI. We identified increased PFC connectivity in early-course patients, predictive of symptoms and diagnostic classification, but less evidence for “hypoconnectivity.” At the whole-brain level, we observed “hyperconnectivity” around areas centered on the default system, with modest overlap with PFC-specific effects. The PFC hyperconnectivity normalized for a subset of the sample followed longitudinally (n = 25), which also predicted immediate symptom improvement. Biologically informed computational modeling implicates altered overall connection strength in schizophrenia. The initial hyperconnectivity, which may decrease longitudinally, could have prognostic and therapeutic implications.

title: Amygdala connectivity differs among chronic, early course, and individuals at risk for developing schizophrenia.
abstract: Alterations in circuits involving the amygdala have been repeatedly implicated in schizophrenia neuropathology, given their role in stress, affective salience processing, and psychosis onset. Disturbances in amygdala whole-brain functional connectivity associated with schizophrenia have yet to be fully characterized despite their importance in psychosis. Moreover, it remains unknown if there are functional alterations in amygdala circuits across illness phases. To evaluate this possibility, we compared whole-brain amygdala connectivity in healthy comparison subjects (HCS), individuals at high risk (HR) for schizophrenia, individuals in the early course of schizophrenia (EC-SCZ), and patients with chronic schizophrenia (C-SCZ). We computed whole-brain resting-state connectivity using functional magnetic resonance imaging at 3T via anatomically defined individual-specific amygdala seeds. We identified significant alterations in amygdala connectivity with orbitofrontal cortex (OFC), driven by reductions in EC-SCZ and C-SCZ (effect sizes of 1.0 and 0.97, respectively), but not in HR for schizophrenia, relative to HCS. Reduced amygdala-OFC coupling was associated with schizophrenia symptom severity (r = .32, P < .015). Conversely, we identified a robust increase in amygdala connectivity with a brainstem region around noradrenergic arousal nuclei, particularly for HR individuals relative to HCS (effect size = 1.54), but not as prominently for other clinical groups. These results suggest that deficits in amygdala-OFC coupling could emerge during the initial episode of schizophrenia (EC-SCZ) and may present as an enduring feature of the illness (C-SCZ) in association with symptom severity but are not present in individuals with elevated risk for developing schizophrenia. Instead, in HR individuals, there appears to be increased connectivity in a circuit implicated in stress response.

title: Brain Imaging During the Transition from Psychosis Prodrome to Schizophrenia
abstract: Neuroimaging studies have identified patterns of brain abnormalities in various stages of schizophrenia, but whether these abnormalities reflect primary factors associated with the causes of illness or secondary phenomena such as medications has been unclear. Recent work conducted within the prodromal risk paradigm suggests that progressive change in brain structure and function occurs around the time when clinically high-risk individuals transition into full-blown psychosis, effects that cannot be explained by exposure to medications or illness chronicity. This article reviews recent work bearing on the question of the timing of onset and course of brain changes, focusing on structural MRI, diffusion tensor imaging, and resting state connectivity MRI, in association with the onset and course of psychosis. We conclude with a consideration of potential mechanisms underlying progressive tissue changes during the prodromal phase of schizophrenia and implications for prevention.

title: Reliability of neuroanatomical measurements in a multisite longitudinal study of youth at risk for psychosis
abstract: Multisite longitudinal neuroimaging designs are used to identify differential brain structural change associated with onset or progression of disease. The reliability of neuroanatomical measurements over time and across sites is a crucial aspect of power in such studies. Prior work has found that while within‐site reliabilities of neuroanatomical measurements are excellent, between‐site reliability is generally more modest. Factors that may increase between‐site reliability include standardization of scanner platform and sequence parameters and correction for between‐scanner variations in gradient nonlinearities. Factors that may improve both between‐ and within‐site reliability include use of registration algorithms that account for individual differences in cortical patterning and shape. In this study 8 healthy volunteers were scanned twice on successive days at 8 sites participating in the North American Prodrome Longitudinal Study (NAPLS). All sites employed 3 Tesla scanners and standardized acquisition parameters. Site accounted for 2 to 30% of the total variance in neuroanatomical measurements. However, site‐related variations were trivial (<1%) among sites using the same scanner model and 12‐channel coil or when correcting for between‐scanner differences in gradient nonlinearity and scaling. Adjusting for individual differences in sulcal‐gyral geometries yielded measurements with greater reliabilities than those obtained using an automated approach. Neuroimaging can be performed across multiple sites at the same level of reliability as at a single site, achieving within‐ and between‐site reliabilities of 0.95 or greater for gray matter density in the majority of voxels in the prefrontal and temporal cortical surfaces as well as for the volumes of most subcortical structures. Hum Brain Mapp 35:2424–2434, 2014.

title: Identification of common variants associated with human hippocampal and intracranial volumes
abstract: Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10−16) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10−12). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10−7).

title: Common genetic variants influence human subcortical brain structures
abstract: The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10−33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

title: Biological Insights From 108 Schizophrenia-Associated Genetic Loci
abstract: Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.

title: Heterogeneity of structural brain changes in subtypes of schizophrenia revealed using magnetic resonance imaging pattern analysis.
abstract: Schizophrenia is a multifaceted mental disorder characterized by cognitive, perceptual, and affective symptom dimensions. This heterogeneity at the phenomenological level may be subserved by complex and heterogeneous patterns of structural abnormalities. Thus, delineating such patterns may improve the insight into the variability of disease and facilitate future magnetic resonance imaging-based diagnosis.



We aimed to identify structurally complex signatures that directly differentiate patients with predominantly negative (pNEG), positive (pPOS), and disorganized (pDIS) symptoms using Optimally-Discriminative Voxel-Based Analysis (ODVBA). ODVBA is a new analytical framework for group analysis, which showed to have superior sensitivity and specificity over conventional voxel-based morphometric approaches, thus facilitating the identification of subtle neuroanatomical signatures delineating different subgroups.



pPOS were characterized by pronounced gray matter (GM) volume reductions in the ventromedial prefrontal cortex (vmPFC), which herein is defined to include the orbitofrontal cortex, and in occipitotemporal GM and parts of the lingual gyrus. pNEG was found to have vmPFC reduction but to a lesser degree than pPOS and with a relative sparing of the more medial vmPFC regions, compared to pDIS; it also had significantly less cerebellar GM. pDIS showed relatively highest GM volume preservation among three subtypes.



Although a common prefronto-perisylvian GM reduction pattern was present at the whole-group level, marked morphometric differences emerged between the three subgroups, including reduced cerebellar GM in pNEG and reduced vmPFC and occipitotemporal GM in pPOS. Besides deepening our insight into the neurobiological underpinnings of clinical heterogeneity, these results also identify important imaging biomarkers that may aid patient stratification.