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Associate Professor Tom Weickert

PUBLICATIONS

Rethinking schizophrenia in the context of normal neurodevelopment.

Catts VS, Fung SJ, Long LE, Joshi D, Vercammen A, Allen KM, Fillman SG, Rothmond DA, Sinclair D, Tiwari Y, Tsai SY, Weickert TW, Shannon Weickert C

The schizophrenia brain is differentiated from the normal brain by subtle changes, with significant overlap in measures between normal and disease states. For the past 25 years, schizophrenia has increasingly been considered a neurodevelopmental disorder. This frame of reference challenges biological researchers to consider how pathological changes identified in adult brain tissue can be accounted for by aberrant developmental processes occurring during fetal, childhood, or adolescent periods. To place schizophrenia neuropathology in a neurodevelopmental context requires solid, scrutinized evidence of changes occurring during normal development of the human brain, particularly in the cortex; however, too often data on normative developmental change are selectively referenced. This paper focuses on the development of the prefrontal cortex and charts major molecular, cellular, and behavioral events on a similar time line. We first consider the time at which human cognitive abilities such as selective attention, working memory, and inhibitory control mature, emphasizing that attainment of full adult potential is a process requiring decades. We review the timing of neurogenesis, neuronal migration, white matter changes (myelination), and synapse development. We consider how molecular changes in neurotransmitter signaling pathways are altered throughout life and how they may be concomitant with cellular and cognitive changes. We end with a consideration of how the response to drugs of abuse changes with age. We conclude that the concepts around the timing of cortical neuronal migration, interneuron maturation, and synaptic regression in humans may need revision and include greater emphasis on the protracted and dynamic changes occurring in adolescence. Updating our current understanding of post-natal neurodevelopment should aid researchers in interpreting gray matter changes and derailed neurodevelopmental processes that could underlie emergence of psychosis.

Considering the role of adolescent sex steroids in schizophrenia.

Owens SJ, Murphy CE, Purves-Tyson TD, Weickert TW, Shannon Weickert C

Schizophrenia is a disabling illness that is typically first diagnosed during late adolescence to early adulthood, has an unremitting course, and is often treatment resistance. Many clinical aspects of the illness suggest that sex steroid-nervous system interactions may contribute to the onset and course of symptoms and the cognitive impairment displayed by men and women with schizophrenia. Here, we discuss the actions of estrogen and testosterone on the brain during adolescent development and in schizophrenia from the perspective of experimental studies in animals, human post-mortem studies, magnetic resonance imaging studies in living humans, and clinical trials of sex steroid based treatments. We present evidence of potential beneficial, as well as detrimental, effects of both testosterone and estrogen. We provide a rationale for the necessity to further elucidate sex steroid mechanisms of action at different ages, genders and brain regions to more fully understand the role of testosterone and estrogen in the pathophysiology of schizophrenia. The weight of the evidence suggests that sex steroid hormones influence mammalian brain function, including both cognition and emotion and that pharmaceutical agents aimed at sex steroid receptors appear to provide a novel treatment avenue to reduce symptoms and improve cognition in men and women with schizophrenia. This article is protected by copyright. All rights reserved.

Considering the role of adolescent sex steroids in schizophrenia.

Owens SJ, Murphy CE, Purves-Tyson TD, Weickert TW, Shannon Weickert C

Schizophrenia is a disabling illness that is typically first diagnosed during late adolescence to early adulthood, has an unremitting course, and is often treatment resistance. Many clinical aspects of the illness suggest that sex steroid-nervous system interactions may contribute to the onset and course of symptoms and the cognitive impairment displayed by men and women with schizophrenia. Here, we discuss the actions of estrogen and testosterone on the brain during adolescent development and in schizophrenia from the perspective of experimental studies in animals, human post-mortem studies, magnetic resonance imaging studies in living humans, and clinical trials of sex steroid based treatments. We present evidence of potential beneficial, as well as detrimental, effects of both testosterone and estrogen. We provide a rationale for the necessity to further elucidate sex steroid mechanisms of action at different ages, genders and brain regions to more fully understand the role of testosterone and estrogen in the pathophysiology of schizophrenia. The weight of the evidence suggests that sex steroid hormones influence mammalian brain function, including both cognition and emotion and that pharmaceutical agents aimed at sex steroid receptors appear to provide a novel treatment avenue to reduce symptoms and improve cognition in men and women with schizophrenia. This article is protected by copyright. All rights reserved.

BDNF val66met genotype and schizotypal personality traits interact to influence probabilistic association learning.

Skilleter AJ, Weickert CS, Moustafa AA, Gendy R, Chan M, Arifin N, Mitchell PB, Weickert TW

The brain derived neurotrophic factor (BDNF) val66met polymorphism rs6265 influences learning and may represent a risk factor for schizophrenia. Healthy people with high schizotypal personality traits display cognitive deficits that are similar to but not as severe as those observed in schizophrenia and they can be studied without confounds of antipsychotics or chronic illness. How genetic variation in BDNF may impact learning in individuals falling along the schizophrenia spectrum is unknown. We predicted that schizotypal personality traits would influence learning and that schizotypal personality-based differences in learning would vary depending on the BDNF val66met genotype. Eighty-nine healthy adults completed the Schizotypal Personality Questionnaire (SPQ) and a probabilistic association learning test. Blood samples were genotyped for the BDNF val66met polymorphism. An ANOVA was performed with BDNF genotype (val homozygotes and met-carriers) and SPQ score (high/low) as grouping variables and probabilistic association learning as the dependent variable. Participants with low SPQ scores (fewer schizotypal personality traits) showed significantly better learning than those with high SPQ scores. BDNF met-carriers displaying few schizotypal personality traits performed best, whereas BDNF met-carriers displaying high schizotypal personality traits performed worst. Thus, the BDNF val66met polymorphism appears to influence probabilistic association learning differently depending on the extent of schizotypal personality traits displayed.

Molecular evidence of N-methyl-D-aspartate receptor hypofunction in schizophrenia.

Weickert CS, Fung SJ, Catts VS, Schofield PR, Allen KM, Moore LT, Newell KA, Pellen D, Huang XF, Catts SV, Weickert TW

Blockade of N-methyl-D-aspartate receptors (NMDARs) produces behavior in healthy people that is similar to the psychotic symptoms and cognitive deficits of schizophrenia and can exacerbate symptoms in people with schizophrenia. However, an endogenous brain disruption of NMDARs has not been clearly established in schizophrenia. We measured mRNA transcripts for five NMDAR subunit mRNAs and protein for the NR1 subunit in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia and control (n=74) brains. Five NMDAR single-nucleotide polymorphisms (SNPs) previously associated with schizophrenia were tested for association with NMDAR mRNAs in postmortem brain and for association with cognitive ability in an antemortem cohort of 101 healthy controls and 48 people with schizophrenia. The NR1 subunit (mRNA and protein) and NR2C mRNA were decreased in postmortem brain from people with schizophrenia (P=0.004, P=0.01 and P=0.01, respectively). In the antemortem cohort, the minor allele of NR2B rs1805502 (T5988C) was associated with significantly lower reasoning ability in schizophrenia. In the postmortem brain, the NR2B rs1805502 (T5988C) C allele was associated with reduced expression of NR1 mRNA and protein in schizophrenia. Reduction in NR1 and NR2C in the DLPFC of people with schizophrenia may lead to altered NMDAR stoichiometry and provides compelling evidence for an endogenous NMDAR deficit in schizophrenia. Genetic variation in the NR2B gene predicts reduced levels of the obligatory NR1 subunit, suggesting a novel mechanism by which the NR2B SNP may negatively influence other NMDAR subunit expression and reasoning ability in schizophrenia.

Serum testosterone levels are related to cognitive function in men with schizophrenia.

Moore L, Kyaw M, Vercammen A, Lenroot R, Kulkarni J, Curtis J, O'Donnell M, Carr VJ, Shannon Weickert C, Weickert TW

The results suggest that circulating sex steroids may modulate cognitive deficits associated with schizophrenia.

Testosterone is inversely related to brain activity during emotional inhibition in schizophrenia.

Vercammen A, Skilleter AJ, Lenroot R, Catts SV, Weickert CS, Weickert TW

Sex steroids affect cognitive function as well as emotion processing and regulation. They may also play a role in the pathophysiology of schizophrenia. However, the effects of sex steroids on cognition and emotion-related brain activation in schizophrenia are poorly understood. Our aim was to determine the extent to which circulating testosterone relates to brain activation in men with schizophrenia compared to healthy men during cognitive-emotional processing. We assessed brain activation in 18 men with schizophrenia and 22 age-matched healthy men during an emotional go/no-go task using fMRI and measured total serum testosterone levels on the same morning. We performed an ROI analysis to assess the relationship between serum testosterone and brain activation, focusing on cortical regions involved the emotional go/no-go task. Slower RT and reduced accuracy was observed when participants responded to neutral stimuli, while inhibiting responses to negative stimuli. Healthy men showed a robust increase in activation of the middle frontal gyrus when inhibiting responses to negative stimuli, but there was no significant association between activation and serum testosterone level in healthy men. Men with schizophrenia showed a less pronounced increase in activation when inhibiting responses to negative stimuli; however, they did show a strong inverse association between serum testosterone level and activation of the bilateral middle frontal gyrus and left insula. Additionally, increased accuracy during inhibition of response to negative words was associated with both higher serum testosterone levels and decreased activation of the middle frontal gyrus in men with schizophrenia only. We conclude that endogenous hormone levels, even within the normal range, may play an enhanced modulatory role in determining the neural and behavioural response during cognitive-emotional processing in schizophrenia.

Perceptual Category Judgment Deficits are Related to Prefrontal Decision Making Abnormalities in Schizophrenia.

Weickert TW, Terrazas A, Bigelow LB, Apud JA, Egan MF, Weinberger DR

Previous studies of perceptual category learning in patients with schizophrenia generally demonstrate impaired perceptual category learning; however, traditional cognitive studies have often failed to address the relationship of different cortical regions to perceptually based category learning and judgments in healthy participants and patients with schizophrenia. In the present study, perceptual category learning was examined in 26 patients with schizophrenia and 25 healthy participants using a dot-pattern category learning task. In the training phase, distortions of a prototypical dot pattern were presented. In the test phase, participants were shown the prototype, low and high distortions of the prototype, and random dot patterns. Participants were required to indicate whether the presented dot pattern was a member of the category of dot-patterns previously presented during the study phase. Patients with schizophrenia displayed an impaired ability to make judgments regarding marginal members of novel, perceptually based categories relative to healthy participants. Category judgment also showed opposite patterns of strong, significant correlations with behavioral measures of prefrontal cortex function in patients relative to healthy participants. These results suggest that impaired judgments regarding novel, perceptually based category membership may be due to abnormal prefrontal cortex function in patients with schizophrenia.

Common polymorphisms in dopamine-related genes combine to produce a 'schizophrenia-like' prefrontal hypoactivity.

Vercammen A, Weickert CS, Skilleter AJ, Lenroot R, Schofield PR, Weickert TW

Individual changes in dopamine-related genes influence prefrontal activity during cognitive-affective processes; however, the extent to which common genetic variations combine to influence prefrontal activity is unknown. We assessed catechol-O-methyltransferase (COMT) Val108/158Met (rs4680) and dopamine D2 receptor (DRD2) G-T (rs2283265) single nucleotide polymorphisms and functional magnetic resonance imaging during an emotional response inhibition test in 43 healthy adults and 27 people with schizophrenia to determine the extent to which COMT Val108/158Met and DRD2 G-T polymorphisms combine to influence prefrontal response to cognitive-affective challenges. We found an increased number of cognitive-deficit risk alleles in these two dopamine-regulating genes predict reduced prefrontal activation during response inhibition in healthy adults, mimicking schizophrenia-like prefrontal hypoactivity. Our study provides evidence that functionally related genes can combine to produce a disease-like endophenotype.

Peripheral BDNF: a candidate biomarker of healthy neural activity during learning is disrupted in schizophrenia.

Skilleter AJ, Weickert CS, Vercammen A, Lenroot R, Weickert TW

This is the first study to show a relationship between peripheral BDNF levels and cortical activity during learning, suggesting that plasma BDNF levels may reflect learning-related brain activity in healthy humans. The lack of relationship between plasma BDNF and task-related brain activity in patients suggests that circulating blood BDNF may not be indicative of learning-dependent brain activity in schizophrenia.

Endogenous testosterone levels are associated with neural activity in men with schizophrenia during facial emotion processing.

Ji E, Weickert CS, Lenroot R, Catts SV, Vercammen A, White C, Gur RE, Weickert TW

Growing evidence suggests that testosterone may play a role in the pathophysiology of schizophrenia given that testosterone has been linked to cognition and negative symptoms in schizophrenia. Here, we determine the extent to which serum testosterone levels are related to neural activity in affective processing circuitry in men with schizophrenia. Functional magnetic resonance imaging was used to measure blood-oxygen-level-dependent signal changes as 32 healthy controls and 26 people with schizophrenia performed a facial emotion identification task. Whole brain analyses were performed to determine regions of differential activity between groups during processing of angry versus non-threatening faces. A follow-up ROI analysis using a regression model in a subset of 16 healthy men and 16 men with schizophrenia was used to determine the extent to which serum testosterone levels were related to neural activity. Healthy controls displayed significantly greater activation than people with schizophrenia in the left inferior frontal gyrus (IFG). There was no significant difference in circulating testosterone levels between healthy men and men with schizophrenia. Regression analyses between activation in the IFG and circulating testosterone levels revealed a significant positive correlation in men with schizophrenia (r=.63, p=.01) and no significant relationship in healthy men. This study provides the first evidence that circulating serum testosterone levels are related to IFG activation during emotion face processing in men with schizophrenia but not in healthy men, which suggests that testosterone levels modulate neural processes relevant to facial emotion processing that may interfere with social functioning in men with schizophrenia.

Adjunctive raloxifene treatment improves attention and memory in men and women with schizophrenia.

Weickert TW, Weinberg D, Lenroot R, Catts SV, Wells R, Vercammen A, O'Donnell M, Galletly C, Liu D, Balzan R, Short B, Pellen D, Curtis J, Carr VJ, Kulkarni J, Schofield PR, Weickert CS

There is increasing clinical and molecular evidence for the role of hormones and specifically estrogen and its receptor in schizophrenia. A selective estrogen receptor modulator, raloxifene, stimulates estrogen-like activity in brain and can improve cognition in older adults. The present study tested the extent to which adjunctive raloxifene treatment improved cognition and reduced symptoms in young to middle-age men and women with schizophrenia. Ninety-eight patients with a diagnosis of schizophrenia or schizoaffective disorder were recruited into a dual-site, thirteen-week, randomized, double-blind, placebo-controlled, crossover trial of adjunctive raloxifene treatment in addition to their usual antipsychotic medications. Symptom severity and cognition in the domains of working memory, attention/processing speed, language and verbal memory were assessed at baseline, 6 and 13 weeks. Analyses of the initial 6-week phase of the study using a parallel groups design (with 39 patients receiving placebo and 40 receiving raloxifene) revealed that participants receiving adjunctive raloxifene treatment showed significant improvement relative to placebo in memory and attention/processing speed. There was no reduction in symptom severity with treatment compared with placebo. There were significant carryover effects, suggesting some cognitive benefits are sustained even after raloxifene withdrawal. Analysis of the 13-week crossover data revealed significant improvement with raloxifene only in attention/processing speed. This is the first study to show that daily, oral adjunctive raloxifene treatment at 120 mg per day has beneficial effects on attention/processing speed and memory for both men and women with schizophrenia. Thus, raloxifene may be useful as an adjunctive treatment for cognitive deficits associated with schizophrenia.

Elevated peripheral cytokines characterize a subgroup of people with schizophrenia displaying poor verbal fluency and reduced Broca's area volume.

Fillman SG, Weickert TW, Lenroot RK, Catts SV, Bruggemann JM, Catts VS, Weickert CS

Previous studies on schizophrenia have detected elevated cytokines in both brain and blood, suggesting neuroinflammation may contribute to the pathophysiology in some cases. We aimed to determine the extent to which elevated peripheral cytokine messenger RNA (mRNA) expression: (1) characterizes a subgroup of people with schizophrenia and (2) shows a relationship to cognition, brain volume and/or symptoms. Forty-three outpatients with schizophrenia or schizoaffective disorder and matched healthy controls were assessed for peripheral cytokine mRNAs (interleukin (IL)-1β, IL-2, IL-6, IL-8 and IL-18), intelligence quotient, memory and verbal fluency, symptom severity and cortical brain volumes integral to language (that is, Broca's and Wernicke's areas). IL-1β mRNA levels were 28% increased in schizophrenia compared with controls (t(82)=2.64, P<0.01). Using a two-step clustering procedure, we identified a subgroup of people displaying relatively elevated cytokine mRNA levels (17/43 people with schizophrenia and 9/42 controls). Individuals with schizophrenia in the elevated cytokine subgroup performed significantly worse than the low-cytokine subgroup on verbal fluency (F(1,40)=15.7, P<0.001). There was a 17% volume reduction of the left pars opercularis (POp) (Broca's area) in patients with elevated cytokines compared with patients with lower cytokines (F(1,29)=9.41, P=0.005). Negative linear relationships between IL-1β mRNA levels and both verbal fluency and left POp volume were found in schizophrenia. This study is among the first to link blood biomarkers of inflammation with both cognitive deficits and brain volume reductions in people with schizophrenia, supporting that those with elevated cytokines represent a neurobiologically meaningful subgroup. These findings raise the possibility that targeted anti-inflammatory treatments may ameliorate cognitive and brain morphological abnormalities in some people with schizophrenia.

What's Hot in Schizophrenia Research?

Weickert CS, Weickert TW

Schizophrenia is a heterogeneous psychiatric illness for which the cause or causes are presently unknown. There is increasing evidence from multiple levels of research suggesting that inflammation may play an important role in the development and persistence of psychosis and cognitive impairment in a proportion of people with schizophrenia. This overview of recent literature focuses on studies of neuroinflammation that are considered to be of increasing interest in schizophrenia research and are poised to have an impact on the cause, diagnosis, and potential treatment of at least some forms or subtypes of schizophrenia.

Adjunctive selective estrogen receptor modulator increases neural activity in the hippocampus and inferior frontal gyrus during emotional face recognition in schizophrenia.

Ji E, Weickert CS, Lenroot R, Kindler J, Skilleter AJ, Vercammen A, White C, Gur RE, Weickert TW

Estrogen has been implicated in the development and course of schizophrenia with most evidence suggesting a neuroprotective effect. Treatment with raloxifene, a selective estrogen receptor modulator, can reduce symptom severity, improve cognition and normalize brain activity during learning in schizophrenia. People with schizophrenia are especially impaired in the identification of negative facial emotions. The present study was designed to determine the extent to which adjunctive raloxifene treatment would alter abnormal neural activity during angry facial emotion recognition in schizophrenia. Twenty people with schizophrenia (12 men, 8 women) participated in a 13-week, randomized, double-blind, placebo-controlled, crossover trial of adjunctive raloxifene treatment (120 mg per day orally) and performed a facial emotion recognition task during functional magnetic resonance imaging after each treatment phase. Two-sample t-tests in regions of interest selected a priori were performed to assess activation differences between raloxifene and placebo conditions during the recognition of angry faces. Adjunctive raloxifene significantly increased activation in the right hippocampus and left inferior frontal gyrus compared with the placebo condition (family-wise error, P<0.05). There was no significant difference in performance accuracy or reaction time between active and placebo conditions. To the best of our knowledge, this study provides the first evidence suggesting that adjunctive raloxifene treatment changes neural activity in brain regions associated with facial emotion recognition in schizophrenia. These findings support the hypothesis that estrogen plays a modifying role in schizophrenia and shows that adjunctive raloxifene treatment may reverse abnormal neural activity during facial emotion recognition, which is relevant to impaired social functioning in men and women with schizophrenia.

A quantitative review of the postmortem evidence for decreased cortical N-methyl-d-aspartate receptor expression levels in schizophrenia: How can we link molecular abnormalities to mismatch negativity deficits?

Catts VS, Lai YL, Weickert CS, Weickert TW, Catts SV

Evidence suggests that anomalous mismatch negativity (MMN) in schizophrenia is related to glutamatergic abnormalities, possibly involving N-methyl-d-aspartate (NMDA) receptors. Decreased cortical expressions of NMDA receptor subunits have been observed in schizophrenia, though not consistently. To aid with integration and interpretation of previous work, we performed a meta-analysis of effect sizes of mRNA or protein levels of the obligatory NR1 subunit in prefrontal cortex from people with schizophrenia. In schizophrenia compared to unaffected controls the pooled effect size was -0.64 (95% confidence interval: -1.08 to -0.20) for NR1 mRNA reduction and -0.44 (95% confidence interval: -0.80 to -0.07) for NR1 protein reduction. These results represent the first step to a deeper understanding of the region-specific, cell-specific, and stage-specific NMDA receptor hypofunction in schizophrenia, which could be linked to mismatch negativity deficits via transgenic and pharmacological animal models.

Potential Role of Oestrogen Modulation in the Treatment of Neurocognitive Deficits in Schizophrenia.

Weickert TW, Allen KM, Weickert CS

Cognitive deficits are prevalent in schizophrenia, and these deficits represent a disabling aspect of the illness for which there are no current effective treatments. Recent work has shown that sex hormone levels correlate with brain activity and cognitive abilities differentially in patients with schizophrenia relative to healthy control groups. There is emerging evidence suggesting that oestrogen-based therapies may be useful in reversing the cognitive deficits associated with schizophrenia. To date, the results from clinical trials using oestrogen-based therapies to reverse cognitive impairment in schizophrenia have shown that the selective oestrogen receptor modulator raloxifene may be useful to improve attention, memory, learning and the associated brain activity in chronically ill men and women with schizophrenia or schizoaffective disorder. While these findings of cognitive enhancement with a selective oestrogen receptor modulator in people with schizophrenia are encouraging, additional studies will be required to replicate the initial results, assess the time frame of treatment effects, identify biomarkers in subsets of patients who may be more likely to optimally respond to treatment, and identify a more precise mechanism of action, which may include anti-inflammatory effects of oestrogen-based treatments.

Testosterone and reward prediction-errors in healthy men and men with schizophrenia.

Morris RW, Purves-Tyson TD, Weickert CS, Rothmond D, Lenroot R, Weickert TW

Sex hormones impact reward processing, which is dysfunctional in schizophrenia; however, the degree to which testosterone levels relate to reward-related brain activity in healthy men and the extent to which this relationship may be altered in men with schizophrenia has not been determined. We used functional magnetic resonance imaging (fMRI) to measure neural responses in the striatum during reward prediction-errors and hormone assays to measure testosterone and prolactin in serum. To determine if testosterone can have a direct effect on dopamine neurons, we also localized and measured androgen receptors in human midbrain with immunohistochemistry and quantitative PCR. We found correlations between testosterone and prediction-error related activity in the ventral striatum of healthy men, but not in men with schizophrenia, such that testosterone increased the size of positive and negative prediction-error related activity in a valence-specific manner. We also identified midbrain dopamine neurons that were androgen receptor immunoreactive, and found that androgen receptor (AR) mRNA was positively correlated with tyrosine hydroxylase (TH) mRNA in human male substantia nigra. The results suggest that sex steroid receptors can potentially influence midbrain dopamine biosynthesis, and higher levels of serum testosterone are linked to better discrimination of motivationally-relevant signals in the ventral striatum, putatively by modulation of the dopamine biosynthesis pathway via AR ligand binding. However, the normal relationship between serum testosterone and ventral striatum activity during reward learning appears to be disrupted in schizophrenia.

Association of serum VEGF levels with prefrontal cortex volume in schizophrenia.

Pillai A, Howell KR, Ahmed AO, Weinberg D, Allen KM, Bruggemann J, Lenroot R, Liu D, Galletly C, Weickert CS, Weickert TW

A large body of evidence indicates alterations in brain regional cellular energy metabolism and blood flow in schizophrenia. Among the different molecules regulating blood flow, vascular endothelial growth factor (VEGF) is generally accepted as the major factor involved in the process of angiogenesis. In the present study, we examined whether peripheral VEGF levels correlate with changes in the prefrontal cortex (PFC) volume in patients with schizophrenia and in healthy controls. Whole-blood samples were obtained from 96 people with schizophrenia or schizoaffective disorder and 83 healthy controls. Serum VEGF protein levels were analyzed by enzyme-linked immunosorbent assay, whereas quantitative PCR was performed to measure interleukin-6 (IL-6, a pro-inflammatory marker implicated in schizophrenia) mRNA levels in the blood samples. Structural magnetic resonance imaging scans were obtained using a 3T Achieva scanner on a subset of 59 people with schizophrenia or schizoaffective disorder and 65 healthy controls, and prefrontal volumes were obtained using FreeSurfer software. As compared with healthy controls, individuals with schizophrenia had a significant increase in log-transformed mean serum VEGF levels (t(177)=2.9, P=0.005). A significant inverse correlation (r=-0.40, P=0.002) between serum VEGF and total frontal pole volume was found in patients with schizophrenia/schizoaffective disorder. Moreover, we observed a significant positive association (r=0.24, P=0.03) between serum VEGF and IL-6 mRNA levels in patients with schizophrenia. These findings suggest an association between serum VEGF and inflammation, and that serum VEGF levels are related to structural abnormalities in the PFC of people with schizophrenia.

Selective Estrogen Receptor Modulation Increases Hippocampal Activity during Probabilistic Association Learning in Schizophrenia.

Kindler J, Weickert CS, Skilleter AJ, Catts SV, Lenroot R, Weickert TW

People with schizophrenia show probabilistic association learning impairment in conjunction with abnormal neural activity. The selective estrogen receptor modulator (SERM) raloxifene preserves neural activity during memory in healthy older men and improves memory in schizophrenia. Here, we tested the extent to which raloxifene modifies neural activity during learning in schizophrenia. Nineteen people with schizophrenia participated in a twelve-week randomized, double-blind, placebo-controlled, cross-over adjunctive treatment trial of the SERM raloxifene administered orally at 120 mg daily to assess brain activity during probabilistic association learning using functional magnetic resonance imaging (fMRI). Raloxifene improved probabilistic association learning and significantly increased fMRI BOLD activity in the hippocampus and parahippocampal gyrus relative to placebo. A separate region of interest confirmatory analysis in 21 patients vs 36 healthy controls showed a positive association between parahippocampal neural activity and learning in patients, but no such relationship in the parahippocampal gyrus of healthy controls. Thus, selective estrogen receptor modulation by raloxifene concurrently increases activity in the parahippocampal gyrus and improves probabilistic association learning in schizophrenia. These results support a role for estrogen receptor modulation of mesial temporal lobe neural activity in the remediation of learning disabilities in both men and women with schizophrenia.