[show abstract][hide abstract] ABSTRACT: 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.
Schizophrenia Research 03/2013; · 4.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: Previous studies investigated fMRI-guided repetitive Transcranial Magnetic Stimulation (rTMS) as an alternative treatment for auditory verbal hallucinations (AVH). This tailor-made treatment focuses at directing the rTMS coil to the location where hallucinatory activation is maximal, as identified with fMRI scans of individual patients. For the effective use of such treatment it is important to determine whether brain activation during AVH can be reliably detected using fMRI. Thirty-three psychotic patients indicated the presence of AVH during two subsequent scans. Reproducibility was measured by calculating 1) the distance between local maxima of significantly activated clusters and 2) percentage overlap of activation patterns over the two scans. These measurements were obtained both in single subjects and on group-level in five regions of interest (ROIs). ROIs consisted of the areas that were most frequently activated during AVH. Scans were considered reproducible if the distance between local maxima was smaller than 2cm, as rTMS-treatment may target an area of approximately 2-4cm. The median distance between local maxima was smaller than 2cm for all ROIs on single-subject level, as well as on group-level. In addition, on single-subject level median percentage overlap varied between 14 and 38% for the different ROIs. On group-level, this was substantially higher with percentages overlap varying between 34 and 98%. Based on these results, AVH-scans may be considered sufficiently reproducible to be suitable for fMRI-guided rTMS treatment.
Schizophrenia Research 02/2013; · 4.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: Auditory verbal hallucinations (AVH) are a hallmark of psychotic experience. Various mechanisms including misattribution of inner speech and imbalance between bottom-up and top-down factors in auditory perception potentially due to aberrant connectivity between frontal and temporo-parietal areas have been suggested to underlie AVH. Experimental evidence for disturbed connectivity of networks sustaining auditory-verbal processing is, however, sparse. We compared functional resting-state connectivity in 49 psychotic patients with frequent AVH and 49 matched controls. The analysis was seeded from the left middle temporal gyrus (MTG), thalamus, angular gyrus (AG) and inferior frontal gyrus (IFG) as these regions are implicated in extracting meaning from impoverished speech-like sounds. Aberrant connectivity was found for all seeds. Decreased connectivity was observed between the left MTG and its right homotope, between the left AG and the surrounding inferior parietal cortex (IPC) and the left inferior temporal gyrus, between the left thalamus and the right cerebellum, as well as between the left IFG and left IPC, and dorsolateral and ventrolateral prefrontal cortex (DLPFC/VLPFC). Increased connectivity was observed between the left IFG and the supplementary motor area (SMA) and the left insula and between the left thalamus and the left fusiform gyrus/hippocampus. The predisposition to experience AVH might result from decoupling between the speech production system (IFG, insula and SMA) and the self-monitoring system (DLPFC, VLPFC, IPC) leading to misattribution of inner speech. Furthermore, decreased connectivity between nodes involved in speech processing (AG, MTG) and other regions implicated in auditory processing might reflect aberrant top-down influences in AVH.
Brain Structure and Function 02/2013; · 7.84 Impact Factor
[show abstract][hide abstract] ABSTRACT: INTRODUCTION: Neuroimaging studies investigating auditory verbal hallucinations (AVH) have revealed involvement of several cortical structures. These findings may however be biased by brain activity related to stimulus detection and motor processes associated with the task to indicate the presence of AVH. Disentangling brain activation specifically related to AVH and to additional cognitive processes may help focus on the true neuronal substrates of AVH and strengthen the development of new focal treatment strategies. METHODS: Brain activation during AVH as indicated by button press was compared to brain activation during auditory stimulus detection indicated by button press. We performed two neuroimaging meta-analyses, assessing 10 AVH and 11 auditory stimulus detection studies. A random-effects activation likelihood estimation was performed using GingerALE to assess commonalities and differences across AVH and stimulus detection studies. RESULTS: Activity in the claustrum, pulvinar area, medial geniculum body, pyramis, culmen, putamen, insula, and parahippocampal, medial frontal, precentral, postcentral, superior temporal and right inferior frontal gyri was found to be specifically related to AVH. The pars opercularis of the left inferior frontal gyrus and the left transverse temporal gyrus were activated to a similar extent during AVH and auditory stimulus detection. DISCUSSION: Development of new focal treatment strategies for AVH may focus on the areas uniquely activated in the AVH analysis. The pars opercularis and the transverse temporal gyrus may not be directly involved in the experience of AVH itself, but rather in auditory stimulus detection.
Schizophrenia Research 01/2013; · 4.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND: Although auditory verbal hallucinations (AVH) are a core symptom of schizophrenia, they also occur in non-psychotic individuals, in the absence of other psychotic, affective, cognitive and negative symptoms. AVH have been hypothesized to result from deviant integration of inferior frontal, parahippocampal and superior temporal brain areas. However, a direct link between dysfunctional connectivity and AVH has not yet been established. To determine whether hallucinations are indeed related to aberrant connectivity, AVH should be studied in isolation, for example in non-psychotic individuals with AVH. Method Resting-state connectivity was investigated in 25 non-psychotic subjects with AVH and 25 matched control subjects using seed regression analysis with the (1) left and (2) right inferior frontal, (3) left and (4) right superior temporal and (5) left parahippocampal areas as the seed regions. To correct for cardiorespiratory (CR) pulsatility rhythms in the functional magnetic resonance imaging (fMRI) data, heartbeat and respiration were monitored during scanning and the fMRI data were corrected for these rhythms using the image-based method for retrospective correction of physiological motion effects RETROICOR. RESULTS: In comparison with the control group, non-psychotic individuals with AVH showed increased connectivity between the left and the right superior temporal regions and also between the left parahippocampal region and the left inferior frontal gyrus. Moreover, this group did not show a negative correlation between the left superior temporal region and the right inferior frontal region, as was observed in the healthy control group. CONCLUSIONS: Aberrant connectivity of frontal, parahippocampal and superior temporal brain areas can be specifically related to the predisposition to hallucinate in the auditory domain.
Psychological Medicine 11/2012; · 5.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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. Magnetoence-phalography (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. Copyright: ß 2012 van Lutterveld et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
[show abstract][hide abstract] ABSTRACT: 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.MethodA 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.
Psychological Medicine 04/2012; · 5.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
[show abstract][hide abstract] ABSTRACT: 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.
PLoS ONE 01/2012; 7(9):e43516. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Auditory verbal hallucinations (AVH) or "voices" are a characteristic symptom of schizophrenia, but can also be observed in healthy individuals in the general population. As these non-psychotic individuals experience AVH in the absence of other psychiatric symptoms and medication-use they provide an excellent model to study AVH in isolation. Indeed a number of studies used this approach and investigated brain structure and function in non-psychotic individuals with AVH. These studies showed that increased sensitivity of auditory areas to auditory stimulation and aberrant connectivity of language production and perception areas is associated with AVH. This is in concordance with investigations that observed prominent activation of these areas during the state of AVH. Moreover, while effortful attention appears not to be related to AVH, individuals prone to hallucinate seem to have an enhanced attention bias to auditory stimuli which may stem from aberrant activation of the anterior cingulated regions. Furthermore, it was observed that decreased cerebral dominance for language and dopamine dysfunction, which are consistently found in schizophrenia, are most likely not specifically related to AVH as these abnormalities were absent in healthy voice hearers. Finally, specific aspects of AVH such as voluntary control may be related to the timing of the supplementary motor area and language areas in the experience of AVH.
Frontiers in Human Neuroscience 01/2012; 6:111. · 2.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
Schizophrenia Research 06/2011; 130(1-3):68-77. · 4.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
[show abstract][hide abstract] ABSTRACT: 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.
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.
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.
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.
The Journal of Clinical Psychiatry 03/2011; 72(3):320-5. · 5.81 Impact Factor
[show abstract][hide abstract] ABSTRACT: Alice in Wonderland syndrome (AIWS) is a rare cluster of CNS symptoms characterized by visual distortions (i.e. metamorphopsias), body image distortions, time distortions, and déjà experiences. Verbal auditory hallucinations (VAHs) are the most prevalent type of hallucination in adults with or without a history of psychiatric illness. Here, we report the case of a woman with AIWS, long-lasting VAHs, and various additional perceptual and mood symptoms.
Semi-structured interviews were used to assess symptoms, and functional MRI (fMRI) was employed to localize cerebral activity during self-reported VAHs. Treatment consisted of repetitive transcranial magnetic stimulation (rTMS) at a frequency of 1 Hz at T3P3, overlying Brodmann's area 40.
Activation during VAHs was observed bilaterally in the basal ganglia, the primary auditory cortex, the association auditory cortex, the temporal poles, and the anterior cingulated gyrus. The left and right inferior frontal gyri (Broca's area and its contralateral homologue) were involved, along with the dorsolateral prefrontal cortex. Interestingly, synchronized activation was observed in the primary visual cortex (areas V1 and V2), and the bilateral dorsal visual cortex. The higher visual association cortex also showed significant, but less prominent, activation. During the second week of rTMS treatment, not only the VAHs, but also the other sensory deceptions/distortions and mood symptoms showed complete remission. The patient remained free of any symptoms during a 4-month follow-up phase. After 8 months, when many of the original symptoms had returned, a second treatment phase with rTMS was again followed by complete remission.
This case indicates that VAHs and metamorphopsias in AIWS are associated with synchronized activation in both auditory and visual cortices. It also indicates that local rTMS treatment may have global therapeutic effects, suggesting an effect on multiple brain regions in a distributed network. Although a placebo effect cannot be ruled out, this case warrants further investigation of the effects of rTMS treatment in AIWS.
[show abstract][hide abstract] ABSTRACT: 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.
[show abstract][hide abstract] ABSTRACT: 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.
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.
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.
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.
American Journal of Psychiatry 04/2010; 167(4):427-35. · 14.72 Impact Factor