Cortical thickness in individuals with non-clinical and clinical psychotic symptoms.

Symptoms that are linked to psychosis are also experienced by individuals who are not in need of care. In the present study, cortical thickness was investigated in these individuals. Fifty individuals with non-clinical auditory verbal hallucinations (most of them also experienced other non-clinical psychotic symptoms), 50 patients with a psychotic disorder and auditory verbal hallucinations, and 50 healthy control subjects underwent structural magnetic resonance imaging. Data were analysed using FreeSurfer. Cortical thickness in the pars orbitalis, paracentral lobule, fusiform gyrus and inferior temporal gyrus was lowest in patients, intermediate in the non-clinical hallucinating group, and highest in control subjects. The patients also showed thinning in widespread additional areas compared to the two other groups, whereas both hallucinating groups showed similar levels of thinning in the insula. Ranking the levels of cortical thickness per brain region across groups revealed that for 88% of brain regions, cortical thickness was lowest in patients, intermediate in the non-clinical hallucinating group, and highest in controls. These findings show that individuals with non-clinical psychotic symptoms show a similar but less pronounced pattern of cortical thinning as patients with a psychotic disorder, which is suggestive of a similar, but milder underlying pathophysiology in this group compared to the psychosis group.

Initial evaluation of the effects of competitive memory training (COMET) on depression in schizophrenia-spectrum patients with persistent auditory verbal hallucinations: a randomized controlled trial.

OBJECTIVES: This study investigates whether depression can be ameliorated by weakening the associations between auditory verbal hallucinations and easily activated networks with negative self-evaluations, by strengthening the access to competing memories of positive self-esteem. Design. A randomized controlled clinical trial comparing competitive memory training (COMET) with treatment as usual (TAU) in schizophrenia patients with persistent auditory hallucinations. METHODS: Patients with schizophrenia-spectrum disorders were randomized into COMET (n = 39) versus TAU (n = 38). COMET consisted of seven sessions with four stages: (1) identification of aspects of negative self-esteem reinforced by the voice; (2) retrieval and re-living of memories associated with positive self-esteem; (3) positive self-esteem is brought in to compete with the content of the voices to weaken the association between voice content and negative self-evaluation; and (4) learning to disengage from the voices and to accept the voices as psychic phenomena. RESULTS: Compared to TAU the COMET group improved on depression but there were no significant effects on auditory hallucinations. The effect of COMET on depression was fully mediated by self-esteem and acceptance of voices, and partially mediated by social rank and attributed power to the voices. CONCLUSIONS: COMET can be helpful in reappraising the meaning and changing the emotional impact of auditory hallucinations. These findings are consistent with the results of comparable COMET protocols applied in other psychiatric diagnoses. The technique can be used within regular cognitive behavioural therapy.

Decreased language lateralization is characteristic of psychosis, not auditory hallucinations.

Decreased language lateralization is a well-replicated finding in psychotic patients. It is currently unclear, however, whether this abnormality is related to a particular symptom of psychosis or to psychosis in general. It has been argued that decreased language lateralization may be related to auditory verbal hallucinations. To elucidate this, these hallucinations should be studied in isolation. Thirty-five patients with a psychotic disorder, 35 non-psychotic subjects with relatively isolated auditory verbal hallucinations and 35 healthy control subjects participated in this study. All subjects were scanned on a 3T magnetic resonance imaging scanner, while covertly performing a paced verbal fluency task. In order to measure performance on the task, one additional task block was presented during which subjects had to generate words overtly. In addition to calculating language lateralization indices, group-wise brain activation during verbal fluency was compared between the three groups. Task performance was nearly maximal for all groups and did not differ significantly between the groups. Compared with the healthy control subjects and non-psychotic subjects with auditory verbal hallucinations, language lateralization was significantly reduced for the patient group. In addition, the patients displayed significantly greater activity in the right precentral gyrus and left insula when compared with the healthy control subjects and the non-psychotic subjects with auditory verbal hallucinations. Furthermore, the patients showed greater activity in the right superior parietal lobule when compared with the healthy control subjects. Lateralization indices did not differ significantly between the non-psychotic subjects with auditory verbal hallucinations and the healthy control subjects. Moreover, there were no significant differences in brain activation during verbal fluency between the two non-psychotic groups. As language lateralization was not significantly reduced in the non-psychotic individuals with auditory verbal hallucinations, a direct relationship between auditory verbal hallucinations and decreased language lateralization can not be established at present.

Auditory verbal hallucinations predominantly activate the right inferior frontal area.

The pathophysiology of auditory verbal hallucinations (AVH) is largely unknown. Several functional imaging studies have measured cerebral activation during these hallucinations, but sample sizes were relatively small (one to eight subjects) and findings inconsistent. In this study cerebral activation was measured using fMRI in 24 psychotic patients while they experienced AVH in the scanner and, in another session, while they silently generated words. All patients were right handed and diagnosed with schizophrenia, schizo-affective disorder or psychotic disorder not otherwise specified. Group analysis for AVH revealed activation in the right homologue of Broca's area, bilateral insula, bilateral supramarginal gyri and right superior temporal gyrus. Broca's area and left superior temporal gyrus were not activated. Group analysis for word generation in these patients yielded activation in Broca's and Wernicke's areas and to a lesser degree their right-sided homologues, bilateral insula and anterior cingulate gyri. Lateralization of activity during AVH was not correlated with language lateralization, but rather with the degree to which the content of the hallucinations had a negative emotional valence. The main difference between cerebral activity during AVH and activity during normal inner speech appears to be the lateralization. The predominant engagement of the right inferior frontal area during AVH may be related to the typical low semantic complexity and negative emotional content.

High frequency rTMS; a more effective treatment for auditory verbal hallucinations?

The great majority of studies on repetitive transcranial magnetic stimulation (rTMS) as a therapeutic tool for auditory verbal hallucinations (AVH) have used 1-Hz stimulation with inconsistent results. Recently, it has been suggested that 20-Hz rTMS has strong therapeutic effects. It is conceivable that this 20-Hz stimulation is more effective than 1-Hz stimulation. The aim of this preliminary study is to investigate the efficacy of 20-Hz rTMS compared with 1-Hz rTMS as a treatment for AVH. Eighteen schizophrenia patients with medication-resistant AVH were randomized over two treatment groups. Each group received either 20 min of 1-Hz rTMS or 13 trains of 20-Hz rTMS daily over 1 week. After week 1, patients received a follow-up treatment once a week for 3 weeks. Stimulation location was based on individual AVH-related activation patterns identified with functional magnetic resonance imaging. Severity of AVH was monitored with the Auditory Hallucination Rating Scale (AHRS). Both groups showed a decrease in AVH after week 1 of rTMS. This decrease was significant for the 20-Hz group and the 1-Hz group. When the two treatment types were compared, no treatment type was superior. Based on these results we cannot conclude whether high frequency rTMS is more effective against AVH than is traditional 1-Hz rTMS. More research is needed to optimize stimulation parameters and to investigate potential target locations for stimulation.

Symptom dimensions of the psychotic symptom rating scales in psychosis: a multisite study.

The Psychotic Symptom Rating Scales (PSYRATS) is an instrument designed to quantify the severity of delusions and hallucinations and is typically used in research studies and clinical settings focusing on people with psychosis and schizophrenia. It is comprised of the auditory hallucinations (AHS) and delusions subscales (DS), but these subscales do not necessarily reflect the psychological constructs causing intercorrelation between clusters of scale items. Identification of these constructs is important in some clinical and research contexts because item clustering may be caused by underlying etiological processes of interest. Previous attempts to identify these constructs have produced conflicting results. In this study, we compiled PSYRATS data from 12 sites in 7 countries, comprising 711 participants for AHS and 520 for DS. We compared previously proposed and novel models of underlying constructs using structural equation modeling. For the AHS, a novel 4-dimensional model provided the best fit, with latent variables labeled Distress (negative content, distress, and control), Frequency (frequency, duration, and disruption), Attribution (location and origin of voices), and Loudness (loudness item only). For the DS, a 2-dimensional solution was confirmed, with latent variables labeled Distress (amount/intensity) and Frequency (preoccupation, conviction, and disruption). The within-AHS and within-DS dimension intercorrelations were higher than those between subscales, with the exception of the AHS and DS Distress dimensions, which produced a correlation that approached the range of the within-scale correlations. Recommendations are provided for integrating these underlying constructs into research and clinical applications of the PSYRATS.

The auditory dorsal stream plays a crucial role in projecting hallucinated voices into external space.

INTRODUCTION: Verbal auditory hallucinations (VAHs) are experienced as spoken voices which seem to originate in the extracorporeal environment or inside the head. Animal and human research has identified a 'where' pathway for sound processing comprising the planum temporale, the middle frontal gyrus and the inferior parietal lobule. We hypothesize that increased activity of that 'where' pathway mediates the exteriorization of VAHs. METHODS: The fMRI scans of 52 right-handed psychotic patients experiencing frequent VAHs were compared with the reported location of hallucinations, as rated with the aid of the PSYRATS-AHRS. For each subject, a unique VAH activation model was created based on the VAH timings, and subsequently convolved with a gamma function to model the hemodynamic response. In order to examine the neurofunctional equivalents of perceived VAH location, second-level group effects of subjects experiencing either internal (n = 24) or external (n = 28) VAHs were contrasted within planum temporale, middle frontal gyrus, and inferior parietal lobule regions of interest (ROIs). RESULTS: Three ROIs were tested for increased activity in relation with the exteriorization of VAHs. The analysis revealed a left-sided medial planum temporale and a right-sided middle frontal gyrus cluster of increased activity. No significant activity was found in the inferior parietal lobule. CONCLUSIONS: Our study indicates that internal and external VAHs are mediated by a fronto-temporal pattern of neuronal activity while the exteriorization of VAHs stems from additional brain activity in the auditory 'where' pathway, comprising the planum temporale and prefrontal regions.

Dopaminergic function in the psychosis spectrum: an [18F]-DOPA imaging study in healthy individuals with auditory hallucinations.

BACKGROUND: The psychosis phenotype appears to exist in the population as a continuum, but it is not clear if subclinical psychotic symptoms and psychotic disorders share the same neurobiology. We investigated whether the dopaminergic dysfunction seen in psychotic disorders is also present in healthy, well-functioning people with hallucinations. METHODS: We compared dopamine synthesis capacity (using 6-[(18)F]fluoro-L-DOPA [[(18)F]-DOPA] positron emission tomography imaging) in 16 healthy individuals with frequent persistent auditory verbal hallucinations (hallucinating group) with that in 16 matched controls. RESULTS: There was no significant difference in dopamine synthesis capacity in the striatum, or its functional subdivisions, between groups and no relationship between subclinical psychotic symptom severity or schizotypal traits and dopamine synthesis capacity in the hallucinating group. CONCLUSIONS: Altered dopamine synthesis capacity is unlikely to underlie subclinical hallucinations, suggesting that although there may be a phenomenological psychosis continuum, there are distinctions at the neurobiological level.

The influence of semantic top-down processing in auditory verbal hallucinations.

BACKGROUND: Auditory verbal hallucinations (AVH) are one of the most prominent symptoms of schizophrenia but have also been reported in the general population. Several cognitive models have tried to elucidate the mechanism behind auditory verbal hallucinations, among which a top-down model. According to this model, perception is biased towards top-down information (e.g., expectations), reducing the influence of bottom-up information coming from the sense organs. This bias predisposes to false perceptions, i.e., hallucinations. METHODS: The current study investigated this hypothesis in non-psychotic individuals with frequent AVH, psychotic patients with AVH and healthy control subjects by applying a semantic top-down task. In this task, top-down processes are manipulated through the semantic context of a sentence. In addition, the association between hallucination proneness and semantic top-down errors was investigated. RESULTS: Non-psychotic individuals with AVH made significantly more top-down errors compared to healthy controls, while overall accuracy was similar. The number of top-down errors, corrected for overall accuracy, in the patient group was in between those of the other two groups and did not differ significantly from either the non-psychotic individuals with AVH or the healthy controls. The severity of hallucination proneness correlated with the number of top-down errors. DISCUSSION: These findings confirm that non-psychotic individuals with AVH are stronger influenced by top-down processing (i.e., perceptual expectations) than healthy controls. In contrast, our data suggest that in psychotic patients semantic expectations do not play a role in the etiology of AVH. This finding may point towards different cognitive mechanisms for pathological and nonpathological hallucinations.

Oscillatory cortical network involved in auditory verbal hallucinations in schizophrenia.

BACKGROUND: Auditory verbal hallucinations (AVH), a prominent symptom of schizophrenia, are often highly distressing for patients. Better understanding of the pathogenesis of hallucinations could increase therapeutic options. Magnetoencephalography (MEG) provides direct measures of neuronal activity and has an excellent temporal resolution, offering a unique opportunity to study AVH pathophysiology. METHODS: Twelve patients (10 paranoid schizophrenia, 2 psychosis not otherwise specified) indicated the presence of AVH by button-press while lying in a MEG scanner. As a control condition, patients performed a self-paced button-press task. AVH-state and non-AVH state were contrasted in a region-of-interest (ROI) approach. In addition, the two seconds before AVH onset were contrasted with the two seconds after AVH onset to elucidate a possible triggering mechanism. RESULTS: AVH correlated with a decrease in beta-band power in the left temporal cortex. A decrease in alpha-band power was observed in the right inferior frontal gyrus. AVH onset was related to a decrease in theta-band power in the right hippocampus. CONCLUSIONS: These results suggest that AVH are triggered by a short aberration in the theta band in a memory-related structure, followed by activity in language areas accompanying the experience of AVH itself.

Auditory hallucinations elicit similar brain activation in psychotic and nonpsychotic individuals.

While auditory verbal hallucinations (AVH) are most characteristic for schizophrenia, they also occur in nonpsychotic individuals in the absence of a psychiatric or neurological disorder and in the absence of substance abuse. At present, it is unclear if AVH in these nonpsychotic individuals constitute the same phenomenon as AVH in psychotic patients. Comparing brain activation during AVH between nonpsychotic and psychotic individuals could provide important clues regarding this question. 21 nonpsychotic subjects with AVH and 21 matched psychotic patients indicated the presence of AVH during 3T functional magnetic resonance imaging (fMRI) scanning. To identify common areas of activation during the experience of AVH in both groups, a conjunction analysis was performed. In addition, a 2-sample t-test was employed to discover possible differences in AVH-related activation between the groups. Several common areas of activation were observed for the psychotic and nonpsychotic subjects during the experience of AVH, consisting of the bilateral inferior frontal gyri, insula, superior temporal gyri, supramarginal gyri and postcentral gyri, left precentral gyrus, inferior parietal lobule, superior temporal pole, and right cerebellum. No significant differences in AVH-related brain activation were present between the groups. The presence of multiple common areas of AVH-related activation in psychotic and nonpsychotic individuals, in the absence of significant differences, implicates the involvement of the same cortical network in the experience of AVH in both groups.

Auditory verbal hallucinations and cognitive functioning in healthy individuals.

Auditory verbal hallucinations (AVH) are a characteristic symptom in schizophrenia, and also occur in the general, non-clinical population. In schizophrenia patients, several specific cognitive deficits, such as in speech processing, working memory, source memory, attention, inhibition, episodic memory and self-monitoring have been associated with auditory verbal hallucinations. Such associations are interesting, as they may identify specific cognitive traits that constitute a predisposition for AVH. However, it is difficult to disentangle a specific relation with AVH in patients with schizophrenia, as so many other factors can affect the performance on cognitive tests. Examining the cognitive profile of healthy individuals experiencing AVH may reveal a more direct association between AVH and aberrant cognitive functioning in a specific domain. For the current study, performance in executive functioning, memory (both short- and long-term), processing speed, spatial ability, lexical access, abstract reasoning, language and intelligence performance was compared between 101 healthy individuals with AVH and 101 healthy controls, matched for gender, age, handedness and education. Although performance of both groups was within the normal range, not clinically impaired, significant differences between the groups were found in the verbal domain as well as in executive functioning. Performance on all other cognitive domains was similar in both groups. The predisposition to experience AVH is associated with lower performance in executive functioning and aberrant language performance. This association might be related to difficulties in the inhibition of irrelevant verbal information.

The same or different? A phenomenological comparison of auditory verbal hallucinations in healthy and psychotic individuals.

OBJECTIVE: Whereas auditory verbal hallucinations (AVHs) are most characteristic of schizophrenia, their presence has frequently been described in a continuum, ranging from severely psychotic patients to schizotypal personality disorder patients to otherwise healthy participants. It remains unclear whether AVHs at the outer borders of this spectrum are indeed the same phenomenon. Furthermore, specific characteristics of AVHs may be important indicators of a psychotic disorder. METHOD: To investigate differences and similarities in AVHs in psychotic and nonpsychotic individuals, the phenomenology of AVHs in 118 psychotic outpatients was compared to that in 111 otherwise healthy individuals, both experiencing AVHs at least once a month. The study was performed between September 2007 and March 2010 at the University Medical Center, Utrecht, the Netherlands. Characteristics of AVHs were quantified using the Psychotic Symptoms Rating Scales Auditory Hallucinations subscale. RESULTS: The perceived location of voices (inside/outside the head), the number of voices, loudness, and personification did not differentiate between psychotic and healthy individuals. The most prominent differences between AVHs in healthy and psychotic individuals were the emotional valence of the content, the frequency of AVHs, and the control subjects had over their AVHs (all P values < .001). Age at onset of AVHs was at a significantly younger age in the healthy individuals (P < .001). In our sample, the negative emotional valence of the content of AVHs could accurately predict the presence of a psychotic disorder in 88% of the participants. CONCLUSIONS: We cannot ascertain whether AVHs at the outer borders of the spectrum should be considered the same phenomenon, as there are both similarities and differences. The much younger age at onset of AVHs in the healthy subjects compared to that in psychotic patients may suggest a different pathophysiology. The high predictive value of the emotional content of voices implies that inquiring after the emotional content of AVHs may be a crucial step in the diagnosis of psychotic disorders in individuals hearing voices.

Can low-frequency repetitive transcranial magnetic stimulation really relieve medication-resistant auditory verbal hallucinations? Negative results from a large randomized controlled trial.

BACKGROUND: Several studies have applied low-frequency repetitive transcranial magnetic stimulation (rTMS) directed at the left temporoparietal area (TP) for the treatment of auditory verbal hallucinations (AVH), but findings on efficacy are inconsistent. Furthermore, recent functional magnetic resonance imaging (fMRI) studies indicate that the left TP is not a general focus of activation during the experience of AVH. The aims of this study are twofold: to investigate the effects of rTMS on AVH in a double blind, randomized, sham-controlled study; and to investigate whether the efficacy can be improved when rTMS is guided by individual fMRI scans of hallucinatory activation. METHODS: Sixty-two patients with medication-resistant AVH were randomized over three conditions: rTMS targeted at the area of maximal hallucinatory activation calculated from individual fMRI scans during AVH, rTMS directed at the left TP, and sham treatment. Repetitive TMS was applied during 15 sessions of 20 min each, at 1 Hz and 90% of the individual motor threshold. The severity of AVH and other psychotic symptoms were monitored during treatment and 3-month follow-up, with the Auditory Hallucination Rating Scale, the Positive and Negative Syndrome Scale, and the Psychotic Symptom Rating Scales. RESULTS: The effects of fMRI-guided rTMS and left TP rTMS on the severity of AVH were comparable to those of sham treatment. No differences in severity of general psychotic symptoms were found among the three treatment conditions. CONCLUSIONS: Low-frequency rTMS administered to the left TP or to the site of maximal hallucinatory activation is not more effective for medication-resistant AVH than sham treatment.

Formal thought disorder in non-clinical individuals with auditory verbal hallucinations.

BACKGROUND: Auditory verbal hallucinations (AVH) and formal thought disorder (FTD) may originate from the same aberration in the language system. The hypothesis of a shared neurobiological basis would be strengthened by the presence of FTD in individuals who frequently experience AVH, but do not meet DSM-IV criteria for a psychotic disorder. METHODS: In this study, FTD was quantified in 40 non-clinical subjects with AVH, in 50 healthy subjects without AVH and in 40 schizophrenia patients with AVH. Recorded speech samples were analysed by one rater who was blind to the presence/absence of AVH and to diagnosis, using the Thought and Language Index. RESULTS: Negative FTD was barely present in non-clinical subjects with AVH and in healthy controls without AVH. Positive FTD, however, was significantly higher in both groups experiencing AVH than in controls without AVH. Severity of positive FTD did not differ significantly between non-clinical subjects with AVH and schizophrenia patients with AVH. CONCLUSION: Negative FTD (alogia) appears not to be associated with AVH. However, the fact that positive FTD (disorganised speech) in schizophrenia patients with AVH is equally high in non-clinical subjects with AVH indicates that these two symptoms tend to co-occur, which may be suggestive of a shared neurobiological substrate.

Healthy individuals with auditory verbal hallucinations; who are they? Psychiatric assessments of a selected sample of 103 subjects.

Epidemiological studies suggest that auditory verbal hallucinations (AVH) occur in approximately 10%-15% of the general population, of whom only a small proportion has a clinically relevant psychotic disorder. It is unclear whether these hallucinations occur as an isolated phenomenon or if AVH in nonclinical individuals are part of a more general susceptibility to schizophrenia. For this study, 103 healthy individuals with frequent AVH were compared with 60 controls matched for sex, age, and education. All participants were examined by a psychiatrist using standardized diagnostic interviews and questionnaires. The individuals with AVH did not have clinically defined delusions, disorganization, or negative or catatonic symptoms, nor did they meet criteria for cluster A personality disorder. However, their global level of functioning was lower than in the controls and there was a pronounced increase on all subclusters of the Schizotypal Personality Questionnaire (SPQ) and the Peters Delusion Inventory, indicating a general increased schizotypal and delusional tendency in the hallucinating subjects. History of childhood trauma and family history of axis I disorders were also more prevalent in these individuals. We showed that higher SPQ scores, lower education, and higher family loading for psychiatric disorders, but not presence of AVH, were associated with lower global functioning. Our data suggest that AVH in otherwise healthy individuals are not an isolated phenomenon but part of a general vulnerability for schizophrenia.

Deactivation of the parahippocampal gyrus preceding auditory hallucinations in schizophrenia.

OBJECTIVE: Activation in a network of language-related regions has been reported during auditory verbal hallucinations. It remains unclear, however, how this activation is triggered. Identifying brain regions that show significant signal changes preceding auditory hallucinations might reveal the origin of these hallucinations. METHOD: Twenty-four patients with a psychotic disorder indicated the presence of auditory verbal hallucinations during 3-Tesla functional magnetic resonance imaging by squeezing a handheld balloon. A one-sample t test was performed to reveal groupwise activation during hallucinations. To enable analysis of brain activation 6 to 0 seconds preceding hallucinations, a tailored 'selective averaging' method, without any a priori assumptions concerning the hemodynamic response profile, was performed. To control for motor-related activation, 15 healthy comparison subjects squeezed a balloon at matched time intervals. RESULTS: Groupwise analysis during auditory verbal hallucinations revealed brain activation in bilateral (right more than left) language-related regions and bilateral motor regions. Prominent deactivation preceding these hallucinations was observed in the left parahippocampal gyrus. In addition, significant deactivation preceding hallucinations was found in the left superior temporal, right inferior frontal, and left middle frontal gyri as well as in the right insula and left cerebellum. No significant signal changes were revealed prior to the matched balloon squeezing among the comparison subjects. CONCLUSION: Auditory verbal hallucinations in patients with a psychotic disorder are consistently preceded by deactivation of the parahippocampal gyrus. The parahippocampus has been hypothesized to play a central role in memory recollection, sending information from the hippocampus to the association areas. Dysfunction of this region could trigger inadequate activation of right language areas during auditory hallucinations.