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Background: The COVID-19 pandemic and climate change are both significant and pressing global challenges, posing threats to public health and wellbeing. Young people represent a particularly vulnerable group to the distress both crises appear to engender, but we currently lack an understanding of the varied psychological responses to both issues, and their links with mental health conditions and feelings of agency. Methods: We conducted an online survey in August - October 2020 targeting a diverse sample of young people (16–24 years, N=530) in the United Kingdom. Findings: While UK youth reported more life disruption and concern for their future due to the COVID-19 pandemic, climate change was associated with significantly greater distress overall, particularly for individuals with low levels of generalised anxiety. COVID-19 was more associated with feelings of anxiety, isolation, disconnection, and frustration; distress around loss and grief; and effects on quality of life. Climate change was more likely to evoke interest and engagement, guilt, shame, anger, and disgust; and distress associated with guilt, feeling responsible and media coverage. Agency to address climate change was associated with greater climate distress, but COVID-related distress and agency were unrelated. Interpretation: COVID-19 and climate change are affecting the wellbeing of young people in distinct ways, with implications for health service, policy and research responses. There is a need for mental health practitioners and policy makers to account for the complex relationship between climate agency, distress and mental wellbeing in young people. Funding: Institute of Global Health Innovation, Imperial College London. Declaration of Interests: We declare no conflicts of interest. Ethics Approval Statement: The study was reviewed and received approval from the Imperial College London Science, Engineering, & Technology Research Ethics Committee (SETREC; approval number 20IC6060).

Introduction: Efficacy of repetitive Transcranial Magnetic Stimulation (rTMS) targeting the temporo-parietal junction (TPJ) for the treatment of auditory verbal hallucinations (AVH) remains under debate. We assessed the influence of a 1 Hz rTMS treatment on neural networks involved in a cognitive mechanism proposed to subserve AVH.Methods: Patients with schizophrenia (N = 24) experiencing medication-resistant AVH completed a 10-day 1 Hz rTMS treatment. Participants were randomized to active stimulation of the left or bilateral TPJ, or sham stimulation. The effects of rTMS on neural networks were investigated with an inner speech task during fMRI. Changes within and between neural networks were analyzed using Independent Component Analysis.Results: rTMS of the left and bilateral TPJ areas resulted in a weaker network contribution of the left supramarginal gyro to the bilateral fronto-temporal network. Left-sided rTMS resulted in stronger network contributions of the right superior temporal gyrus to the auditory-sensorimotor network, right inferior gyrus to the left fronto-parietal network, and left middle frontal gyrus to the default mode network. Bilateral rTMS was associated with a predominant inhibitory effect on network contribution. Sham stimulation showed different patterns of change compared to active rTMS.Conclusion: rTMS of the left temporo-parietal region decreased the contribution of the left supramarginal gyros to the bilateral fronto-temporal network, which may reduce the likelihood of speech intrusions. On the other hand, left rTMS appeared to increase the contribution of functionally connected regions involved in perception, cognitive control and self-referential processing. These findings hint to potential neural mechanisms underlying rTMS for hallucinations but need corroboration in larger samples.

Improved nature provision in urban environments offers great potential for achieving both biodiversity conservation and public health objectives. Yet there are few experimental studies that address links between specific natural environments and physiological and/or psychological changes that could contribute to the health and wellbeing co-benefits of urban nature. In addition, relative to green space, the salutogenic impact of aquatic environments are understudied. Here, we present a feasibility study examining the use of low-cost wearable technology to quantify the psychophysiological effects of short-term exposure to urban wetlands. The study took place at the WWT London Wetland Centre, which is characterized by its contrasting biodiverse wetland habitat and surrounding urban setting. Thirty-six healthy participants experienced counterbalanced exposures to an indoor space, a wetland, an urban site. We continuously recorded electroencephalographic (EEG) data and real-time physiological stress responses; with additional monitoring of post-exposure self-reported mood states. We found a significant effect of site on mean resting heart rate (HR), with increased HR in the urban setting, although this was only observed in participants with pre-existing high stress. We found no significant differences in other measures of physiological stress responses (heart rate variability and electrodermal activity). The EEG data showed modulation of high beta band activity only in the wetland setting, potentially related to changes in attention. However, the EEG findings were confounded by low quality signals and artifacts caused by movement and environmental interference. Assessments of self-reported mood states demonstrated an increase in positive feelings in the wetland setting. A pronounced decrease in negative feelings in the wetland setting was observed in stressed individuals only. Our results suggest that pre-existing stress levels may be an important modulator of the salutogenic effect of blue-green space. We provide partial support for the hypothesis that exposure to blue-green space promotes stress recovery and for the use of low-cost psychophysiological measurements to quantify the potential stress-reducing effects of blue–green space exposure in urban dwellers. Further technological refinement is required for this approach to become a viable tool to support evidence-based decision-making for public health and green/blue space provision.

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.

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.

Schizophrenia is a severe mental disorder characterized by a diverse set of symptoms, including positive (hallucinations, delusions) and negative (lack of motivation, social withdrawal, blunted affect) symptoms and cognitive impairment. Cognitive deficits are recognized as forming part of the core psychopathology of schizophrenia, with impairments in learning, memory and attention being common (Weickert et al. 2000; Palmer et al. 2009). Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors that potentiates synaptic strength and plasticity underlying learning and memory (Lu & Chow, 1999; Poo, 2001; Egan et al. 2003; Hariri et al. 2003; Lu, 2003; Dempster et al. 2005). A single nucleotide polymorphism in the human BDNF gene produces a valine to methionine substitution in the protein prodomain that influences intracellular trafficking, activity-dependent release of BDNF, learning and brain activity (Egan et al. 2003; Hariri et al. 2003). Lower levels of both brain and blood BDNF have also been implicated in the majority of studies of the pathophysiology of schizophrenia (Weickert et al. 2003; Xiu et al. 2009; Rizos et al. 2010; Green et al. 2011). Peripheral blood can provide an important reservoir of BDNF, reflecting BDNF secreted from the brain and BDNF that may be available to influence brain function (Schmidt & Duman, 2010). However, the extent to which circulating BDNF correlates with human brain activity during learning has not been demonstrated and the extent to which lower circulating BDNF may be indicative of the neural correlates of cognitive impairment in schizophrenia has not been shown. Low peripheral BDNF is reported in first-episode psychosis (Buckley et al. 2007) and is associated with cognitive impairment in chronically ill people with schizophrenia (Zhang et al. 2012b). Peripheral BDNF levels are also significantly decreased in people with mild cognitive impairment (Yu et al. 2008). Thus, peripheral BDNF levels may be useful as a biomarker in health and disease. However, to more fully interpret what any change in a potential biomarker may mean for brain function, a relationship between peripheral BDNF and brain activity should be established in the healthy and diseased states. One reason that general predictions about blood–brain relationships in schizophrenia are difficult to make is that studies of peripheral BDNF levels in schizophrenia have reported inconsistent results. Although the majority of studies report decreased circulating BDNF levels (Pirildar et al. 2004; Tan et al. 2005; Grillo et al. 2007; Rizos et al. 2008), some find increased levels (Gama et al. 2007; Reis et al. 2008), and one study reports no significant difference in plasma BDNF levels in people with schizophrenia compared to healthy controls (Lee & Kim, 2009). A recent meta-analysis supports an overall reduction in peripheral BDNF levels in schizophrenia (Green et al. 2011). However, the extent to which alterations in blood BDNF levels relate to abnormal learning-related brain activity in schizophrenia, as compared to healthy individuals, remains to be demonstrated. Healthy cortical neurons innervate and supply BDNF to several brain regions, including the striatum (Alexander et al. 1986; Altar & DiStefano, 1998). As striatal neurons are trophically dependent on BDNF supplied through anterograde transport from the frontal cortex (Hofer et al. 1990; Altar et al. 1997; Rauskolb et al. 2010; Dieni et al. 2012), higher levels of BDNF would be expected to relate to stronger frontal–striatal activity in a healthy brain, and a reduction of prefrontal cortical BDNF, as found in schizophrenia (Weickert et al. 2003; Hashimoto et al. 2005), would be expected to negatively impact striatal function in schizophrenia. There is abundant evidence from neuropsychological and neuroimaging studies demonstrating significant learning impairments and frontal–striatal dysfunction in schizophrenia (Pantelis et al. 1997; Meyer-Lindenberg et al. 2002; Murray et al. 2008; Howes et al. 2009; Weickert et al. 2010; Morris et al. 2012). Probabilistic association learning (requiring gradual learning of probabilistic-based cue–outcome associations) elicits frontal–parietal–striatal activity in healthy people (Poldrack et al. 1999; Fera et al. 2005) and is related to reduced activity in a neural network that includes the dorsolateral prefrontal cortex (DLPFC), parietal cortex and caudate nucleus in schizophrenia (Weickert et al. 2009). Probabilistic association learning is impaired in people with schizophrenia (Weickert et al. 2002; Foerde et al. 2008; Horan et al. 2008), the offspring of people with schizophrenia who are at high risk of developing schizophrenia (Wagshal et al. 2012, 2013) and in unaffected siblings of people with schizophrenia (Weickert et al. 2010; Wagshal et al. 2014), with deficits in overall performance and learning rate. In the present study, we sought to define the relationship between peripheral BDNF levels and the neural processes underlying probabilistic association learning in healthy people and people with schizophrenia. First, we confirmed the reduced brain activation in people with schizophrenia versus healthy controls during a probabilistic association learning test using functional magnetic resonance imaging (fMRI). Second, we tested the extent to which plasma BDNF levels are related to brain activity in healthy people during probabilistic association learning. Third, we determined whether a similar relationship was also present in schizophrenia. We predicted a positive relationship between plasma BDNF levels and brain activity in a neural network consisting of prefrontal–parietal cortices and striatum, which has previously been shown to be relevant for probabilistic association learning in healthy adults. Based on the majority of work showing dysregulation of either BDNF levels or prefrontal cortex activity along with an increase in the truncated BDNF receptor (Weickert et al. 2003; Hashimoto et al. 2005; Wong et al. 2010, 2013; Ray et al. 2014), which is thought to block trophic effects in schizophrenia, we further predicted an abnormal relationship between plasma BDNF levels and brain activity in schizophrenia.

Most transcranial Direct Current Stimulation (tDCS) trials of schizophrenia administer few sessions and do not assess transfer effects to other cognitive domains. In a randomized, double-blind, sham-controlled, parallel groups trial, we determined the extent to which 4-weeks of 2 mA tDCS at 20 min/day totalling 20 tDCS sessions administered during a spatial working memory test, with anodal right dorsolateral prefrontal cortex (DLPFC) and cathodal left tempo-parietal junction (TPJ) placement, as an adjunct to antipsychotics reduced auditory hallucinations and improved cognition in 12 outpatients with schizophrenia. Anodal tDCS significantly improved language-based working memory after 2 weeks and verbal fluency after 2 and 4 weeks. Thus, four weeks of tDCS appears to be safe and elicits transfer benefits to other prefrontal-dependent cognitive abilities in schizophrenia.

Auditory-verbal hallucinations (AVHs) are frequently associated with activation of the left superior temporal gyrus (including Wernicke’s area), left inferior frontal gyrus (including Broca’s area), and the right hemisphere homologs of both areas. It has been hypothesized that disconnectivity of both interhemispheric transfer and frontal and temporal areas may underlie hallucinations in schizophrenia. We investigated reduced information flow in this circuit for the first time using dynamic causal modeling, which allows for directional inference. A group of healthy subjects and 2 groups of schizophrenia patients—with and without AVH—performed a task requiring inner speech processing during functional brain scanning. We employed connectivity models between left hemispheric speech-processing areas and their right hemispheric homologs. Bayesian model averaging was used to estimate the connectivity strengths and evaluate group differences. Patients with AVH showed significantly reduced connectivity from Wernicke’s to Broca’s area (97% certainty) and a trend toward a reduction in connectivity from homologs of Broca’s and Wernicke’s areas to Broca’s area (93% and 94% certainty). The connectivity magnitude in patients without hallucinations was found to be intermediate. Our results point toward a reduced input from temporal to frontal language areas in schizophrenia patients with AVH, suggesting that Broca’s activity may be less constrained by perceptual information received from the temporal cortex. In addition, a lack of synchronization between Broca and its homolog may lead to the erroneous interpretation of emotional speech activity from the right hemisphere as coming from an external source.

While the majority of cognitive studies on auditory hallucinations (AHs) have been conducted in schizophrenia (SZ), an increasing number of researchers are turning their attention to different clinical and nonclinical populations, often using SZ findings as a model for research. Recent advances derived from SZ studies can therefore be utilized to make substantial progress on AH research in other groups. The objectives of this article were to (1) present an up-to-date review regarding the cognitive mechanisms of AHs in SZ, (2) review findings from cognitive research conducted in other clinical and nonclinical groups, and (3) integrate these recent findings into a cohesive framework. First, SZ studies show that the cognitive underpinnings of AHs include self-source-monitoring deficits and executive and inhibitory control dysfunctions as well as distortions in top-down mechanisms, perceptual and linguistic processes, and emotional factors. Second, consistent with SZ studies, findings in other population groups point to the role of top-down processing, abnormalities in executive inhibition, and negative emotions. Finally, we put forward an integrated model of AHs that incorporates the above findings. We suggest that AHs arise from an interaction between abnormal neural activation patterns that produce salient auditory signals and top-down mechanisms that include signal detection errors, executive and inhibition deficits, a tapestry of expectations and memories, and state characteristics that influence how these experiences are interpreted. Emotional factors play a particular prominent role at all levels of this hierarchy. Our model is distinctively powerful in explaining a range of phenomenological characteristics of AH across a spectrum of disorders.

Reward detection, surprise detection and prediction-error signaling have all been proposed as roles for the ventral striatum (vStr). Previous neuroimaging studies of striatal function in schizophrenia have found attenuated neural responses to reward-related prediction errors; however, as prediction errors represent a discrepancy in mesolimbic neural activity between expected and actual events, it is critical to examine responses to both expected and unexpected rewards (URs) in conjunction with expected and UR omissions in order to clarify the nature of ventral striatal dysfunction in schizophrenia. In the present study, healthy adults and people with schizophrenia were tested with a reward-related prediction-error task during functional magnetic resonance imaging to determine whether schizophrenia is associated with altered neural responses in the vStr to rewards, surprise prediction errors or all three factors. In healthy adults, we found neural responses in the vStr were correlated more specifically with prediction errors than to surprising events or reward stimuli alone. People with schizophrenia did not display the normal differential activation between expected and URs, which was partially due to exaggerated ventral striatal responses to expected rewards (right vStr) but also included blunted responses to unexpected outcomes (left vStr). This finding shows that neural responses, which typically are elicited by surprise, can also occur to well-predicted events in schizophrenia and identifies aberrant activity in the vStr as a key node of dysfunction in the neural circuitry used to differentiate expected and unexpected feedback in schizophrenia.

Neuroimaging studies have shown both dorsolateral prefrontal (DLPFC) and inferior parietal cortex (iPARC) activation during probabilistic association learning. Whether these cortical brain regions are necessary for probabilistic association learning is presently unknown. Participants' ability to acquire probabilistic associations was assessed during disruptive 1 Hz repetitive transcranial magnetic stimulation (rTMS) of the left DLPFC, left iPARC, and sham using a crossover single-blind design. On subsequent sessions, performance improved relative to baseline except during DLPFC rTMS that disrupted the early acquisition beneficial effect of prior exposure. A second experiment examining rTMS effects on task-naive participants showed that neither DLPFC rTMS nor sham influenced naive acquisition of probabilistic associations. A third experiment examining consecutive administration of the probabilistic association learning test revealed early trial interference from previous exposure to different probability schedules. These experiments, showing disrupted acquisition of probabilistic associations by rTMS only during subsequent sessions with an intervening night's sleep, suggest that the DLPFC may facilitate early access to learned strategies or prior task-related memories via consolidation. Although neuroimaging studies implicate DLPFC and iPARC in probabilistic association learning, the present findings suggest that early acquisition of the probabilistic cue-outcome associations in task-naive participants is not dependent on either region.

BackgroundIt has recently been suggested that auditory hallucinations are the result of a criterion shift when deciding whether or not a meaningful signal has emerged. The approach proposes that a liberal criterion may result in increased false-positive identifications, without additional perceptual deficit. To test this hypothesis, we devised a speech discrimination task and used signal detection theory (SDT) to investigate the underlying cognitive mechanisms.MethodSchizophrenia patients with and without auditory hallucinations and a healthy control group completed a speech discrimination task. They had to decide whether a particular spoken word was identical to a previously presented speech stimulus, embedded in noise. SDT was used on the accuracy data to calculate a measure of perceptual sensitivity (Az) and a measure of response bias (β). Thresholds for the perception of simple tones were determined.ResultsCompared to healthy controls, perceptual thresholds were higher and perceptual sensitivity in the speech task was lower in both patient groups. However, hallucinating patients showed increased sensitivity to speech stimuli compared to non-hallucinating patients. In addition, we found some evidence of a positive response bias in hallucinating patients, indicating a tendency to readily accept that a certain stimulus had been presented.ConclusionsWithin the context of schizophrenia, patients with auditory hallucinations show enhanced sensitivity to speech stimuli, combined with a liberal criterion for deciding that a perceived event is an actual stimulus.

BACKGROUND: Repetitive transcranial magnetic stimulation of the left temporo-parietal junction area has been studied as a treatment option for auditory verbal hallucinations. Although the right temporo-parietal junction area has also shown involvement in the genesis of auditory verbal hallucinations, no studies have used bilateral stimulation. Moreover, little is known about durability effects. We studied the short and long term effects of 1 Hz treatment of the left temporo-parietal junction area in schizophrenia patients with persistent auditory verbal hallucinations, compared to sham stimulation, and added an extra treatment arm of bilateral TPJ area stimulation. METHODS: In this randomized controlled trial, 51 patients diagnosed with schizophrenia and persistent auditory verbal hallucinations were randomly allocated to treatment of the left or bilateral temporo-parietal junction area or sham treatment. Patients were treated for six days, twice daily for 20 minutes. Short term efficacy was measured with the Positive and Negative Syndrome Scale (PANSS), the Auditory Hallucinations Rating Scale (AHRS), and the Positive and Negative Affect Scale (PANAS). We included follow-up measures with the AHRS and PANAS at four weeks and three months. RESULTS: The interaction between time and treatment for Hallucination item P3 of the PANSS showed a trend for significance, caused by a small reduction of scores in the left group. Although self-reported hallucination scores, as measured with the AHRS and PANAS, decreased significantly during the trial period, there were no differences between the three treatment groups. CONCLUSION: We did not find convincing evidence for the efficacy of left-sided rTMS, compared to sham rTMS. Moreover, bilateral rTMS was not superior over left rTMS or sham in improving AVH. Optimizing treatment parameters may result in stronger evidence for the efficacy of rTMS treatment of AVH. Moreover, future research should consider investigating factors predicting individual response. TRIAL REGISTRATION: Dutch Trial Register NTR1813.

The authors regret an error in Fig. 2 of this manuscript. The figure shows the PANSS scores for the hallucination item (P3) for the rTMS groups, aggregating the left and the bilateral treatment group, compared to the placebo group. The X axis plots the time points at which measurements were available: before the start of the treatment and immediately following the 6-day treatment protocol. The Y axis shows the score on the P3 item. Bubble sizes represent the number of subjects with a particular score on the Y axis.

Summary Background Sex steroids such as oestrogen and testosterone are potent neurodevelopmental hormones that also play a role in neuromodulation and neuroprotection of the mature brain. Sex steroid hormones may also be involved in the pathophysiology of schizophrenia as reduced circulating sex steroid levels and changes in brain sex steroid receptors are found in people with schizophrenia compared to controls. In men with schizophrenia, recent studies have documented an inverse correlation between serum testosterone and negative symptoms. Our study sought to confirm whether men with schizophrenia had lower levels of testosterone relative to controls and to determine whether lower testosterone levels were related to higher symptom severity and impaired cognition. Method Circulating serum hormone levels (testosterone, oestrogen, and prolactin), cognitive function and symptoms were assessed in 29 chronically ill men with schizophrenia or schizoaffective disorder. Twenty healthy men were recruited as a comparison group. A series of regression analyses were performed to determine the extent to which circulating sex steroid hormone levels predict cognition and symptoms in men with schizophrenia. Results We did not find a significant difference in serum testosterone levels between groups. However, circulating testosterone levels significantly predicted performance on verbal memory, processing speed, and working memory in men with schizophrenia. With the exception of an effect of oestrogen on verbal memory, circulating sex steroid levels did not predict cognitive function in healthy men. Testosterone levels were not related to positive or negative symptom severity, but testosterone influenced excitement/hostility levels in our schizophrenia sample. Conclusions The results suggest that circulating sex steroids may modulate cognitive deficits associated with schizophrenia.

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.

Background: Schizophrenia is characterized by deficits in executive control and impairments in emotion processing. This study as sessed the nature and extent of potential alterations in the neural substrates supporting the interaction between cognitive control mech an isms and emotion attribution processes in people with schizophrenia. Methods: Functional magnetic resonance imaging was per formed during a verbal emotional go/no-go task. People with schizophrenia and healthy controls responded to word stimuli of a prespecified emotional valence (positive, negative or neutral) while inhibiting responses to stimuli of a different valence. Results: We en rolled 20 people with schizophrenia and 23 controls in the study. Healthy controls activated an extensive dorsal prefrontal‐parietal network while inhibiting responses to negative words compared to neutral words, but showed deactivation of the midcingulate cortex while inhibiting responses to positive words compared to neutral words. People with schizophrenia failed to activate this network during re sponse inhibition to negative words, whereas during response inhibition to positive words they did not deactivate the cingulate, but showed increased responsivity in the frontal cortex. Limitations: Sample heterogeneity is characteristic of studies of schizophrenia and may have contributed to more variable neural responses in the patient sample despite the care taken to control for potentially confound ing variables. Conclusion: Our results showed that schizophrenia is associated with aberrant modulation of neural responses during the interaction between cognitive control and emotion processing. Failure of the frontal circuitry to regulate goal-directed behaviour based on emotion attributions may contribute to deficits in psychosocial functioning in daily life.

Brain circuits involved in language processing have been suggested to be compromised in patients with schizophrenia. This does not only include regions subserving language production and perception, but also auditory processing and attention. We investigated resting state network connectivity of auditory, language and attention networks of patients with schizophrenia and hypothesized that patients would show reduced connectivity.Patients with schizophrenia (n=45) and healthy controls (n=30) underwent a resting state fMRI scan. Independent components analysis was used to identify networks of the auditory cortex, left inferior frontal language regions and the anterior cingulate region, associated with attention. The time courses of the components where correlated with each other, the correlations were transformed by a Fisher's Z transformation, and compared between groups. In patients with schizophrenia, we observed decreased connectivity between the auditory and language networks. Conversely, patients showed increased connectivity between the attention and language network compared to controls. There was no relationship with severity of symptoms such as auditory hallucinations.The decreased connectivity between auditory and language processing areas observed in schizophrenia patients is consistent with earlier research and may underlie language processing difficulties. Altered anterior cingulate connectivity in patients may be a correlate of habitual suppression of unintended speech, or of excessive attention to internally generated speech. This altered connectivity pattern appears to be present independent of symptom severity, and may be suggestive of a trait, rather than a state characteristic. (C) 2011 Elsevier B.V. All rights reserved.

Functional neuroimaging techniques such as PET and fMRI have been employed successfully over the past two decades to reveal brain areas involved in the mediation of hallucinations. Numerous studies converge on the involvement of bilateral secondary sensory areas. Auditory verbal hallucinations in patients diagnosed with schizophrenia (and in those with schizophrenia spectrum disorders) have been studied most extensively. These studies have shown a central role for speech-production and speech-perception areas not only in the left hemisphere but also their homotopes in the right hemisphere. The parahippocampal gyrus is also involved in such hallucinations, presumably even in their initiation. Other relevant areas are the anterior cingulate, the insula, cerebellum, and the thalamus. In conclusion, auditory verbal hallucinations would seem to depend primarily on distributed brain networks involved in perceptual attention and memory (which may well reflect top-down processing), in addition to various modality-specific sensory areas. Especially the role of monitoring systems and of the emotional connotations of hallucinations deserve further elucidation.

Schizophrenia is associated with heterogeneity in symptoms, cognition and treatment response. Probabilistic association learning, involving a gradual learning of cue–outcome associations, activates a frontal-striatal network in healthy adults. Studies of probabilistic association learning in schizophrenia have shown frontal-striatal dysfunction although considerable heterogeneity in performance has also been reported. Anodal transcranial direct current stimulation (tDCS) to the dorsolateral prefrontal cortex has been shown to improve probabilistic association learning in healthy adults. The aim of the current study was to determine the extent to which anodal tDCS to the left dorsolateral prefrontal cortex would reverse probabilistic association learning deficits in schizophrenia. Prior to tDCS, 20 people with schizophrenia performed an initial baseline assessment without stimulation. Anodal tDCS was administered continuously for 20 min at an intensity of 2.0 mA to the left dorsolateral prefrontal cortex in a single-blind, counterbalanced, sham-controlled, cross-over design while participants performed 150 trials of a probabilistic association learning test. Although anodal tDCS failed to improve probabilistic association learning based on the whole sample performance, greater variance in the active relative to the sham conditions suggested a subset of people may respond to treatment. Further correlation, regression and cluster analyses revealed differential effects of baseline performance on active tDCS and sham treatment and that there was a subset of people with schizophrenia who displayed improvement with tDCS suggesting that anodal tDCS to the dorsolateral prefrontal cortex may facilitate access to existing prefrontal cortex neural reserves in people with schizophrenia who show adequate capacity to learn at baseline.

Auditory-verbal hallucinations are a hallmark symptom of schizophrenia. In recent years, repetitive transcranial magnetic stimulation (rTMS) targeting speech perception areas has been advanced as a potential treatment of medication-resistant hallucinations. However, the underlying neural processes remain unclear.This study aimed to assess whether 1 Hz rTMS treatment would affect functional connectivity of the temporo-parietal junction (TPJ). Resting state fMRI scans were obtained from 18 patients with schizophrenia. Patients were assessed before and after a 6 day treatment with 1 Hz rTMS to the left TPJ, or placebo treatment with sham rTMS to the same location. We assessed functional connectivity between a priori defined regions-of-interest (ROIs) comprising the putative AVH network and the bilateral TPJ seed regions, targeted with rTMS.Symptom improvement following rTMS treatment was observed in the left rTMS group, whereas no change at occurred in the placebo group. Although no corresponding changes were observed in the functional connections previously found to be associated with AVH severity, an increase in connectivity between the left TPJ and the right insula was observed in group receiving rTMS to the left TPJ. The placebo group conversely showed a decrease in connectivity between the left TPJ and left anterior cingulate.We conclude that application of 1 Hz rTMS to the left TPJ region may affect functional connectivity of the targeted region. However, the relationship between these functional changes during the resting state and the rate of clinical improvement needs further clarification. (c) 2009 Elsevier Ltd. All rights reserved.

Background: Schizophrenia has been conceptualized as a disorder of integration of neural activity across distributed networks. However, the relationship between specific symptom dimensions and patterns of functional connectivity remains unclear. The current study aimed to investigate the relationship between auditory-verbal hallucinations (AVH), a particularly prevalent and clinically relevant symptom in schizophrenia, and functional connectivity of the temporo-parietal junction (TPJ).Methods: Resting state functional magnetic resonance imaging scans were obtained from 27 schizophrenia patients with AVH and 27 matched control subjects. We calculated correlations reflecting functional connectivity between a priori defined regions-of-interest and the bilateral TPJ seed regions, comprising the neural network involved in inner speech processes and AVH.Results: Compared with healthy control subjects, schizophrenia patients showed reduced functional connectivity between left TPJ and the right homotope of Broca. Within the patient group, more severe AVH were associated with reduced neural coupling between left TPJ and bilateral anterior cingulate as well as the bilateral amygdala.Conclusions: In schizophrenia patients with chronic hallucinations, the left TPJ a critical node in the speech perception/AVH network- shows reduced functional connectivity with brain areas involved in the attribution of agency, self-referent processing, and attentional control.

Recently, it has been proposed that exaggerated top-down processing may generate spontaneous perceptual output, and that this may constitute a cognitive predisposition toward hallucinations. In this experiment, we investigated whether hallucination proneness would be associated with increased auditory-verbal perceptual expectations, and at which processing level this occurs. From 351 undergraduate students screened for hallucination proneness, using the Launay-Slade Hallucination Scale (LSHS), 42 subjects were recruited for participation. Two word recognition tasks were administered, in which top-down influences on perception were manipulated through sentence context (semantic task) or auditory imagery (phonological task). Results revealed that LSHS scores were correlated with the number of semantically primed errors. Subjects with higher levels of hallucination proneness were more likely to report hearing a word that fits the sentence context, when it was not actually presented. This effect remained significant after controlling for general performance on the task. In contrast, hallucination proneness was not associated with phonologically primed errors. We conclude that aberrant top-down processing, particularly in the form of strong semantic expectations, may contribute to the experience of auditory-verbal hallucinations.

Background: Neuroimaging findings implicate bilateral superior temporal regions in the genesis of auditory-verbal hallucinations (AVH). This study aimed to investigate whether 1 Hz repetitive transcranial magnetic stimulation (rTMS) of the bilateral temporo-parietal region would lead to increased effectiveness in the management of AVH, compared to left rTMS or placebo.Methods: 38 patients with schizophrenia (DSM-IV) and medication-resistant AVH were randomly assigned to 1 Hz rTMS treatment of the left temporo-parietal region, bilateral temporo-parietal regions, or placebo. Stimulation was conducted over 6 days, twice daily for 20 min, at 90% of the motor threshold. Effect measures included the Auditory Hallucination Rating Scale (AHRS), Positive and Negative Affect Scale (PANAS), and a score for hallucination severity obtained from the Positive and Negative Syndrome Scale (PANSS).Results: All groups showed some improvement on the total AHRS. Hallucination frequency was significantly reduced in the left rTMS group only. The bilateral rTMS group demonstrated the most remarkable reduction in self-reported affective responsiveness to AVH. A modest, but significant decrease on the PANSS hallucination item was observed in the combined rTMS treatment group, whereas no change occurred in the placebo group. The left rTMS group showed a significant reduction on the general psychopathology subscale.Conclusion: Compared to bilateral or sham stimulation, rTMS of the left temporo-parietal region appears most effective in reducing auditory hallucinations, and additionally may have an effect on general psychopathology. Placebo effects should however not be ruled out, since sham stimulation also led to improvement on a number of AVH parameters. (C) 2009 Elsevier B.V. All rights reserved.

prefrontal and parietal cortex, and the caudate nucleus in schizophrenia. We predicted that brain activity would positively correlate with peripheral BDNF levels during probabilistic association learning in healthy adults and that this relationship would be altered in schizophrenia. Methods: Twenty-five healthy adults and 17 people with schizophrenia or schizoaffective disorder performed a probabilistic association learning test during functional magnetic resonance imaging (fMRI). Plasma BDNF levels were measured by ELISA. Results: We found a positive correlation between circulating plasma BDNF levels and brain activity in the right parietal cortex in healthy adults. There was no relationship between plasma BDNF levels and task-related activity in the prefrontal, parietal or caudate regions in schizophrenia. A direct comparison of these relationships between groups revealed a significant difference. Discussion: 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 brain activity in healthy humans. The lack of relationship between plasma BDNF and task related brain activity in patients demonstrates that circulating blood BDNF is not related to frontal-parietal-striatal activity during learning in schizophrenia.

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.

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.

Significant differences in fMRI related activity between healthy adults and people with schizophrenia during reward-related prediction-errors

default-mode and the salience networks in patients with schizophrenia and healthy volunteers. Methods: 20 patients with DSM-IV schizophrenia and 20 age, gender and parental socio-occupational status matched controls participated in the study after providing informed consent. The subjects performed two functional tasks (n-back memory task and auditory oddball task) and data was also acquired when the subjects were in resting state for 5 minutes, with eyes closed. Functional MR Imaging was performed on a 3 Tesla Philips MR device employing echo-planar (EPI) acquisition (TE / TR 35 / 2100 ms; 64×64 matrix, voxel size 3.25×3.25×3.25; 35 slices). Images were reoriented, realigned, coregistered, spatially normalized and smoothed using SPM5 (http://www.fil.ion.ucl.ac.uk/spm). The smoothed images from all the subjects were subjected to Independent Component Analysis (ICA) using the GIFT software (http://icatb.sourceforge.net) to decompose the data into 20 spatially independent components. The resulting components were subjected to visual inspection and correlation with apriori masks created in MRIcron. The correlation between the networks were tested using the Functional Network Connectivity software (Jafri et al., 2008). Results: Both in the two functional tasks and the resting stage, the three components correlating to the CEN, DMN and salience networks were clearly identified in the combined group ICA. Separate group ICA of the patients and controls also led to identification of the three networks in each group. The time courses of the three components showed that the CEN, and Salience components were correlated with active tasks in the functional tasks, and the DMNwas anticorrelatedwith the tasks. The functional connectivity analysis showed the complex interplay differences between patients with schizophrenia and controls. Discussion: The three networks (CEN, DMN and Salience networks) were clearly identifiable using model-free ICA analysis in both functional tasks and the resting stage for both groups, which suggests that three networks are key to information processing in both resting and active states of brain activity. The complex interplay between the three networks that is aberrant in schizophrenia may explain the 'disconnection' resulting in the diverse range of symptoms in schizophrenia.