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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.

Aim Mega-diverse coral reef ecosystems are declining globally, necessitating conservation prioritizations to protect biodiversity and ecosystem services of sites with high functional integrity to promote persistence. In practice however, the design of marine-protected area (MPA) systems often relies on broad classifications of habitat class and size, making the tacit assumption that all reefs are of comparable condition. We explored the impact of this assumption through a novel, pragmatic approach for incorporating variability in coral cover in a large-scale regional spatial prioritization plan. Location The Coral Triangle. Methods We developed a spatially explicit predictive model of hard coral cover based on freely available macro-ecological data to generate a complete regional map of coral cover as a proxy for reef condition. We then incorporate this information in spatial conservation prioritization software Marxan to design an MPA system that meets specific conservation objectives. Results We discover prioritizations using area-based representation of reef habitat alone may overestimate the conservation benefit, defined as the amount of hard coral cover protected, by up to 64%. We find substantial differences in conservation priorities and an overall increase in habitat quality metrics when accounting for predicted coral cover. Main conclusions This study shows that including habitat condition in a large-scale marine spatial prioritization is feasible within time and resource constraints, and calls for increased implementation, and evaluation, of such ecologically relevant planning approaches to enhance potential conservation effectiveness.

In the wake of 9/11 and the assessment of Iraq's WMD, several inquiries placed the blame primarily on the Intelligence Community. Part of the reform that followed was a codification of analytic tradecraft standards into Intelligence Community Directive (ICD) 203 and the appointment of an analytic ombudsman in the newly created Office of the Director of National Intelligence charged with monitoring the quality of analytic products from across the intelligence community. In this paper we identify three assumptions behind ICD203: (1) tradecraft standards can be employed consistently; (2) tradecraft standards sufficiently capture the key elements of good reasoning; (3) good reasoning leads to more accurate judgments. We then report on two controlled experiments that uncover operational constraints in the reliable application of the ICD203 criteria for the assessment of intelligence products. Despite criticisms of the post-9/11 and post-Iraq reform, our results highlight that ICD203, properly applied, holds potential to improve precision and accountability of intelligence processes and products.

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.

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.

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.

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.

This chapter provides an overview of the literature on bottom-up and ­top-down processes that have been suggested as mechanisms in the generation and/or perpetuation of hallucinations, both in the context of disorders, and in otherwise healthy individuals. We start from the bottom-up, and first consider the case of abnormal perceptual input, as is the case when the sensory organs themselves are impaired, or in situations of sensory deprivation. We then move further down the perceptual pathway to consider the impact of attentional mechanisms on perception, and discuss these in the context models which integrate sensory and attentional deficits to explain to occurrence of hallucinations, such as the recent Perception and Attention Deficit model. Finally, we turn to theoretical frameworks that are implicitly or explicitly based on Bayesian inference theory of perception. Central to these models is the concept that top-down factors such as expectations and prior world-knowledge greatly influence our perception. We also consider experimental evidence for the hypothesis that hallucinations are caused by an imbalance between top-down influences and bottom-up processing.

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.

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.

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.