Kelly M. J. Diederen

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 Brocas area, bilateral insula, bilateral supramarginal gyri and right superior temporal gyrus. Brocas area and left superior temporal gyrus were not activated. Group analysis for word generation in these patients yielded activation in Brocas and Wernickes 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.

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.

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.

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.

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.

Childhood trauma and auditory verbal hallucinations.

BACKGROUND Hallucinations have consistently been associated with traumatic experiences during childhood. This association appears strongest between physical and sexual abuse and auditory verbal hallucinations (AVH). It remains unclear whether traumatic experiences mainly colour the content of AVH or whether childhood trauma triggers the vulnerability to experience hallucinations in general. In order to investigate the association between hallucinations, childhood trauma and the emotional content of hallucinations, experienced trauma and phenomenology of AVH were investigated in non-psychotic individuals and in patients with a psychotic disorder who hear voices. METHOD A total of 127 non-psychotic individuals with frequent AVH, 124 healthy controls and 100 psychotic patients with AVH were assessed for childhood trauma. Prevalence of childhood trauma was compared between groups and the relation between characteristics of voices, especially emotional valence of content, and childhood trauma was investigated. RESULTS Both non-psychotic individuals with AVH and patients with a psychotic disorder and AVH experienced more sexual and emotional abuse compared with the healthy controls. No difference in the prevalence of traumatic experiences could be observed between the two groups experiencing AVH. In addition, no type of childhood trauma could distinguish between positive or negative emotional valence of the voices and associated distress. No correlations were found between sexual abuse and emotional abuse and other AVH characteristics. CONCLUSIONS These results suggest that sexual and emotional trauma during childhood render a person more vulnerable to experience AVH in general, which can be either positive voices without associated distress or negative voices as part of a psychotic disorder.

Resting State Functional Connectivity in Patients with Chronic Hallucinations

Auditory verbal hallucinations (AVH) are not only among the most common but also one of the most distressing symptoms of schizophrenia. Despite elaborate research, the underlying brain mechanisms are as yet elusive. Functional MRI studies have associated the experience of AVH with activation of bilateral language-related areas, in particular the right inferior frontal gyrus (rIFG) and the left superior temporal gyrus (lSTG). While these findings helped to understand the neural underpinnings of hearing voices, they provide little information about possible brain mechanisms that predispose a person to experience AVH, i.e. the traits to hallucinate. In this study, we compared resting state connectivity between 49 psychotic patients with chronic AVH and 49 matched controls using the rIFG and the lSTG as seed regions, to identify functional brain systems underlying the predisposition to hallucinate. The right parahippocampal gyrus showed increased connectivity with the rIFG in patients as compared to controls. Reduced connectivity with the rIFG in patients was found for the right dorsolateral prefrontal cortex. Reduced connectivity with the lSTG in patients was identified in the left frontal operculum as well as the parietal opercular area. Connectivity between the lSTG and the left hippocampus was also reduced in patients and showed a negative correlation with the severity of hallucinations. Concluding, we found aberrant connectivity between the seed regions and medial temporal lobe structures which have a prominent role in memory retrieval. Moreover, we found decreased connectivity between language-related areas, indicating aberrant integration in this system potentially including corollary discharge mechanisms.

Microstructural alterations of the arcuate fasciculus in schizophrenia patients with frequent auditory verbal hallucinations

Auditory verbal hallucinations (AVH) is a common and stressful symptom of schizophrenia. Disrupted connectivity between frontal and temporo-parietal language areas, giving rise to the misattribution of inner speech, is speculated to underlie this phenomenon. Disrupted connectivity should be reflected in the microstructure of the arcuate fasciculi (AF); the main connection between frontal and temporo-parietal language areas. In this study we compared microstructural properties of the AF and three other fiber tracts (cortical spinal tract, cingulum and uncinate fasciculus), between 44 schizophrenia patients with chronic severe hallucinations and 42 control subjects using diffusion tensor imaging (DTI) and magnetic transfer imaging (MTI). The DTI scans were used to compute fractional anisotropy (FA) and to reconstruct the fiber bundles of interest, while the MTI scans were used to compute magnetic transfer ratio (MTR) values. The patient group showed a general decrease in FA for all bundles. In the arcuate fasciculus this decreased FA was coupled to a significant increase in MTR values. A correlation was found between mean MTR values in both arcuate fasciculi and the severity of positive symptoms. The combination of decreased FA and increased MTR values observed in the arcuate fasciculi in patients suggests increased free water concentrations, probably caused by degraded integrity of the axons or the supportive glia cells. This suggests that disintegrated fiber integrity in the connection between frontal and temporo-parietal language areas in the schizophrenia patients is associated with their liability for auditory verbal hallucinations.

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.

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.