Ans Vercammen

Auditory Hallucinations in Schizophrenia and Nonschizophrenia Populations: A Review and Integrated Model of Cognitive Mechanisms

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.

Auditory Hallucinations in Schizophrenia Are Associated with Reduced Functional Connectivity of the Temporo-Parietal Area

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.

Rethinking schizophrenia in the context of normal neurodevelopment

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.

Effects of bilateral repetitive transcranial magnetic stimulation on treatment resistant auditory-verbal hallucinations in schizophrenia: a randomized controlled trial.

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.

Disambiguating ventral striatum fMRI-related BOLD signal during reward prediction in schizophrenia.

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.

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

Transcranial direct current stimulation influences probabilistic association learning in schizophrenia.

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.

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

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.

When Broca Goes Uninformed: Reduced Information Flow to Broca’s Area in Schizophrenia Patients With Auditory Hallucinations

Auditory-verbal hallucinations (AVHs) are frequently associated with activation of the left superior temporal gyrus (including Wernickes area), left inferior frontal gyrus (including Brocas 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 Wernickes to Brocas area (97% certainty) and a trend toward a reduction in connectivity from homologs of Brocas and Wernickes areas to Brocas 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 Brocas 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.

Semantic Expectations Can Induce False Perceptions in Hallucination-Prone Individuals

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.