Mapping auditory hallucinations in schizophrenia using functional magnetic resonance imaging

BACKGROUND: Perceptions of speech in the absence of an auditory stimulus (auditory verbal hallucinations) are a cardinal feature of schizophrenia. Functional neuroimaging provides a powerful means of measuring neural activity during auditory hallucinations, but the results from previous studies have been inconsistent. This may reflect the acquisition of small numbers of images in each subject and the confounding effects of patients actively signaling when hallucinations occur. METHODS: We examined 6 patients with schizophrenia who were experiencing frequent auditory hallucinations, using a novel functional magnetic resonance imaging method that permitted the measurement of spontaneous neural activity without requiring subjects to signal when hallucinations occurred. Approximately 50 individual scans were acquired at unpredictable intervals in each subject while they were intermittently hallucinating. Immediately after each scan, subjects reported whether they had been hallucinating at that instant. Neural activity when patients were and were not experiencing hallucinations was compared in each subject and the group as a whole. RESULTS: Auditory hallucinations were associated with activation in the inferior frontal/insular, anterior cingulate, and temporal cortex bilaterally (with greater responses on the right), the right thalamus and inferior colliculus, and the left hippocampus and parahippocampal cortex (P<.0001). CONCLUSIONS: Auditory hallucinations may be mediated by a distributed network of cortical and subcortical areas. Previous neuroimaging studies of auditory hallucinations may have identified different components of this network.     

Functional anatomy of auditory verbal imagery in schizophrenic patients with auditory hallucinations

OBJECTIVE: This study investigated the functional neuroanatomy of inner speech and auditory verbal imagery in schizophrenic patients predisposed to auditory hallucinations. METHOD: Eight patients with schizophrenia with a history of prominent auditory hallucinations and six comparison subjects underwent functional magnetic resonance imaging while generating inner speech or imagining external speech. RESULTS: Patients showed no differences while generating inner speech but experienced a relatively attenuated response in the posterior cerebellar cortex, hippocampi, and lenticular nuclei bilaterally and the right thalamus, middle and superior temporal cortex, and left nucleus accumbens during auditory verbal imagery. CONCLUSIONS: Patients with schizophrenia who were prone to auditory hallucinations show attenuated activation when processing inner speech in areas implicated in verbal self-monitoring.     

Toward a brain map of auditory hallucinations.

OBJECTIVE: This study asks whether auditory hallucinations are reflected in a distinctive metabolic map of the brain. METHOD: Regional brain metabolism was measured by positron emission tomography with [18F]-fluorodeoxyglucose in 12 DSM-III schizophrenic patients who experienced auditory hallucinations during glucose uptake and 10 who did not. All patients were free of neuroleptics and 19 had never been treated with neuroleptics. Nine patients were reexamined after 1 year to assess effects of neuroleptic treatment. RESULTS: Compared with the patients who did not experience hallucinations, the patients who did experience hallucinations had significantly lower relative metabolism in auditory and Wernicke's regions and a trend toward higher metabolism in the right hemisphere homologue of Broca's region. Hallucination scores correlated positively and significantly with relative metabolism in the striatum and anterior cingulate regions. Neuroleptic treatment resulted in a significant increase in striatal metabolism and a reduced frontal-parietal ratio, which was significantly correlated with a decrease in hallucination scores. CONCLUSIONS: Auditory hallucinations involve language regions of the cortex in a pattern similar to that seen in normal subjects listening to their own voices but different in that left prefrontal regions are not activated. The striatum plays a critical role in auditory hallucinations.     

Cognitive triggers of auditory hallucinations: An experimental investigation

It has proved difficult to establish the internal process by which mental events are transformed into auditory hallucinations. The earlier stages of the generation of hallucinations may prove more accessible to research. Cognitions have been reported by patients as a trigger of auditory hallucinations, but the role of these preceding thoughts has not been causally determined. Therefore, the role of cognition in triggering auditory hallucinations was tested in an experimental study. Thirty individuals who experienced auditory hallucinations in social situations entered a neutral social situation presented using virtual reality. Participants randomised to the experimental condition were instructed to think their hallucination-preceding thoughts, and those randomised to the control condition were instructed to think neutral thoughts. Twenty-seven participants (93%) were able to spontaneously identify a cognition which preceded a hallucination. There was no difference between the experimental and control groups in the occurrence or severity of auditory hallucinations in virtual reality. Virtual reality did not lead to physical side effects or an increase in anxiety. The relationship between antecedent cognitions and auditory hallucinations is likely to be more complex than the one tested. It is argued that the effect of cognition on auditory hallucinations may be mediated by affect but this needs to be investigated through further experimental research.     

Specific and unspecific auditory hallucinations in patients with schizophrenia: a magnetoencephalographic study

BACKGROUND/AIMS: Different neuroimaging techniques have indicated that auditory association and language cortices are active in patients with schizophrenia and auditory hallucinations. Auditory verbal hallucinations are thought to arise from a disorder of inner speech, but little is known about their origin. METHODS: Spontaneous magnetoencephalographic (MEG) measurements were recorded with a 74-channel two-sensor system (BIOMAGNES II) in 16 patients with schizophrenia and 8 healthy subjects in frequency ranges from 2 to 6 and 12.5 to 30 Hz. Eight patients had auditory hallucinations during the MEG recordings. RESULTS: The total group of patients with schizophrenia showed a statistically significant elevation of the number of dipoles and dipole density maxima in slow frequency ranges compared to healthy subjects (p <0.001). Significant dipole activities in the fast frequency range were only found during auditory hallucinations (p <0.001). Dipole localization was concentrated in frontal and temporal regions depending on different qualities of hallucinations. In patients with external imperative voices we found a parallel activation of the dorsolateral frontal and temporal cortex. CONCLUSION: We conclude that various auditory hallucinations in schizophrenia are induced by different neuronal activities and may be represented by different cortical regions.     

The cognitive neuropsychology of auditory hallucinations: a parallel auditory pathways framework

Auditory hallucinations are generally defined as false perceptions. Recent developments in auditory neuroscience have rapidly increased our understanding of normal auditory perception revealing (partially) separate pathways for the identification ("what") and localization ("where") of auditory objects. The current review offers a reexamination of the nature of auditory hallucinations in schizophrenia using this object-based framework. First, the structural and functional organization of auditory what and where pathways is briefly described. Then, using recent functional neuroimaging data from healthy subjects and patients with schizophrenia, key phenomenological features of hallucinations are linked to abnormal processing both within and between these pathways. Finally, current cognitive explanations of hallucinations, based on intrusive cognitions and impaired source memory, are briefly outlined and set within this framework to provide an integrated cognitive neuropsychological model of auditory hallucinations.     

Central auditory processing in patients with auditory hallucinations

OBJECTIVE: Data from a full assessment of auditory perception in patients with schizophrenia were used to investigate whether auditory hallucinations are associated with abnormality of central auditory processing. METHOD: Three groups of subjects participated in auditory assessments: 22 patients with psychosis and a recent history of auditory hallucinations, 16 patients with psychosis but no history of auditory hallucinations, and 22 normal subjects. Nine auditory assessments, including auditory brainstem response, monotic and dichotic speech perception tests, and nonspeech perceptual tests, were performed. Statistical analyses for group differences were performed using analysis of variance and Kruskal-Wallis tests. The results of individual patients with test scores in the severely abnormal range (more than three standard deviations from the mean for the normal subjects) were examined for patterns that suggested sites of dysfunction in the central auditory system. RESULTS: The results showed significant individual variability among the subjects in both patient groups. There were no group differences on tests that are sensitive to low brainstem function. Both patient groups performed poorly in tests that are sensitive to cortical or high brainstem function, and hallucinating patients differed from nonhallucinating patients in scores on tests of filtered speech perception and response bias patterns on dichotic speech tests. Six patients in the hallucinating group had scores in the severely abnormal range on more than one test. CONCLUSIONS: Hallucinations may be associated with auditory dysfunction in the right hemisphere or in the interhemispheric pathways. However, comparison of results for the patient groups suggests that the deficits seen in hallucinating patients may represent a greater degree of the same types of deficits seen in nonhallucinating patients.     

Relationship of imprecise corollary discharge in schizophrenia to auditory hallucinations

CONTEXT: A forward model of intended thoughts and actions prepares sensory cortex for sensations that are a consequence of those actions. Imprecision of the corollary discharge in schizophrenia may contribute to the misperception of inner experiences and thoughts as "voices" or auditory hallucinations. OBJECTIVES: To assess the precision of the forward model in schizophrenia using the N100 component of the auditory event-related potential to speech that is altered or unaltered, in real time, as it is being spoken. To assess the relationship between auditory hallucinations and the imprecision of the corollary discharge. DESIGN: Prospective case-control study. SETTING: Community mental health centers and Palo Alto Veterans Affairs Health Care System, Palo Alto, Calif. PARTICIPANTS: Twenty patients with schizophrenia and 17 sex- and age-matched healthy control subjects. MAIN OUTCOME MEASURES: N100 responses to auditory feedback, which was altered by pitch-shifting the self-voice, substituting an alien voice, or pitch-shifting the alien voice. On each trial, subjects judged whether feedback was "self," "other," or "unsure." Clinical ratings were used to assess severity of auditory hallucinations in patients. RESULTS: In controls, N100 to unaltered self-voice feedback was dampened relative to N100 to altered self-voice or alien auditory feedback. This pattern was not seen in hallucinating patients. This imprecision correlated with the severity of hallucinations and with the percentage of misattribution errors. CONCLUSION: These data support a connection between auditory verbal hallucinations and the imprecision of the corollary discharge heralding the sensory consequences of thoughts and actions.     

Neurophysiological studies of auditory verbal hallucinations

We discuss 3 neurophysiological approaches to study auditory verbal hallucinations (AVH). First, we describe "state" (or symptom capture) studies where periods with and without hallucinations are compared "within" a patient. These studies take 2 forms: passive studies, where brain activity during these states is compared, and probe studies, where brain responses to sounds during these states are compared. EEG (electroencephalography) and MEG (magnetoencephalography) data point to frontal and temporal lobe activity, the latter resulting in competition with external sounds for auditory resources. Second, we discuss "trait" studies where EEG and MEG responses to sounds are recorded from patients who hallucinate and those who do not. They suggest a tendency to hallucinate is associated with competition for auditory processing resources. Third, we discuss studies addressing possible mechanisms of AVH, including spontaneous neural activity, abnormal self-monitoring, and dysfunctional interregional communication. While most studies show differences in EEG and MEG responses between patients and controls, far fewer show symptom relationships. We conclude that efforts to understand the pathophysiology of AVH using EEG and MEG have been hindered by poor anatomical resolution of the EEG and MEG measures, poor assessment of symptoms, poor understanding of the phenomenon, poor models of the phenomenon, decoupling of the symptoms from the neurophysiology due to medications and comorbidites, and the possibility that the schizophrenia diagnosis breeds truer than the symptoms it comprises. These problems are common to studies of other psychiatric symptoms and should be considered when attempting to understand the basic neural mechanisms responsible for them.     

Schizophrenia with auditory hallucinations: a voxel-based morphometry study

Many studies have shown widespread but subtle pathological changes in gray matter in patients with schizophrenia. Some of these studies have related specific alterations to the genesis of auditory hallucinations, particularly in the left superior temporal gyrus, but none has analysed the relationship between morphometric data and a specific scale for auditory hallucinations. The present study aims to define the presence and characteristics of structural abnormalities in relation with the intensity and phenomenology of auditory hallucinations by means of magnetic resonance voxel-based morphometry (MR-VBM) method applied on a highly homogeneous group of 18 persistent hallucinatory patients meeting DSM-IV criteria for schizophrenia compared to 19 healthy matched controls. Patients were evaluated using the PSYRATS scale for auditory hallucinations. Reductions of gray matter concentration in patients to controls were observed in bilateral insula, bilateral superior temporal gyri and left amygdala. In addition, specific relationships between left inferior frontal and right postcentral gyri reductions and the severity of auditory hallucinations were observed. All these areas might be implicated in the genesis and/or persistence of auditory hallucinations through specific mechanisms. Precise morphological abnormalities may help to define reliable MR-VBM biomarkers for the genesis and persistence of auditory hallucinations.     

Left superior temporal gyrus activation during sentence perception negatively correlates with auditory hallucination severity in schizophrenia patients

The left superior temporal cortex, which supports linguistic functions, has consistently been reported to activate during auditory-verbal hallucinations in schizophrenia patients. It has been suggested that auditory hallucinations and the processing of normal external speech compete for common neurophysiological resources. We tested the hypothesis of a negative relationship between the clinical severity of hallucinations and local brain activity in posterior linguistic regions while patients were listening to external speech. Fifteen right-handed patients with schizophrenia and daily auditory hallucinations for at least 3 months were studied with event-related fMRI while listening to sentences in French or to silence. Severity of hallucinations, assessed using the auditory hallucination subscales of the Psychotic Symptom Rating Scales (PSYRATS) and of the Scale for the Assessment of Positive Symptoms (SAPS-AH), negatively correlated with activation in the left temporal superior region in the French minus silence condition. This finding supports the hypothesis that auditory hallucinations compete with normal external speech for processing sites within the temporal cortex in schizophrenia.     

A controlled study of temporal lobe structure volumes and P300 responses in schizophrenic patients with persistent auditory hallucinations.

Recent studies of cerebral pathology in patients with schizophrenia have focused on symptomatological and electrophysiological correlates of reduced temporal lobe structure volumes. Volume deficits of the left superior temporal gyrus have been correlated with auditory hallucinations as well as to left-sided P300 amplitude reduction. However, caution is needed to interpret correlational data as evidence of a specific relationship. Therefore, a controlled study was undertaken on schizophrenic patients with and without auditory hallucinations. MRI-defined volumes of the left superior temporal gyrus and other temporal lobe structures were quantified from 3-mm coronal slices in 15 schizophrenic patients with chronic auditory hallucinations (hallucinators), 15 schizophrenic patients without auditory hallucinations (nonhallucinators) and 17 healthy controls. In all subjects a simple oddball paradigm was used to elicit P300 responses at temporal and centro-parietal electrode sites. No evidence was found for volume reductions of temporal lobe structures in the combined patient group compared with controls, or in the hallucinators compared with the nonhallucinators. The patients did show left P300 amplitude reduction compared with controls, particularly in the hallucinator group. Correlations between volumes of left temporal lobe structures and left P300 amplitudes were low and not significant. The results of the present study do not indicate that auditory hallucinations and associated abnormal electrophysiological activity are the consequence of atrophy of localized temporal lobe structures. However, replication in a larger sample of subjects is needed before firm conclusions can be drawn.     

Deep transcranial magnetic stimulation for the treatment of auditory hallucinations: a preliminary open-label study

Background  

Schizophrenia is a chronic and disabling disease that presents with delusions and hallucinations. Auditory hallucinations are usually expressed as voices speaking to or about the patient. Previous studies have examined the effect of repetitive transcranial magnetic stimulation (TMS) over the temporoparietal cortex on auditory hallucinations in schizophrenic patients. Our aim was to explore the potential effect of deep TMS, using the H coil over the same brain region on auditory hallucinations.     

Synch before you speak: auditory hallucinations in schizophrenia

OBJECTIVE: Synchronization of neural activity preceding self-generated actions may reflect the operation of the forward model, which acts to dampen sensations resulting from those actions. If this is true, pre-action synchrony should be related to subsequent sensory suppression. Deficits in this mechanism may be characteristic of schizophrenia and related to positive symptoms, such as auditory hallucinations. If so, schizophrenia patients should have reduced neural synchrony preceding movements, especially patients with severe hallucinations. METHOD: In 24 patients with schizophrenia or schizoaffective disorder and 25 healthy comparison subjects, the authors related prespeech neural synchrony to subsequent auditory cortical responsiveness to the spoken sound, compared prespeech neural synchrony in schizophrenia patients and healthy comparison subjects, and related prespeech neural synchrony to auditory hallucination severity in patients. To assess neural synchrony, phase coherence of single-trial EEG preceding talking was calculated at a single site across repeated trials. To assess auditory cortical suppression, the N1 event-related brain potentials to speech sound onset during talking and listening were compared. RESULTS: In healthy comparison subjects, prespeech neural synchrony was related to subsequent suppression of responsiveness to the spoken sound, as reflected in reduction of N1 during talking relative to listening. There was greater prespeech synchrony in comparison subjects than in patients, especially those with severe auditory hallucinations. CONCLUSIONS: These data suggest that EEG synchrony preceding speech reflects the action of a forward model system, which dampens auditory responsiveness to self-generated speech and is deficient in patients who hallucinate.     

Segmented volumes of cerebrum and cerebellum in first episode schizophrenia with auditory hallucinations

The volumes of cerebral and cerebellar regions were measured in first episode schizophrenic patients with (n = 17) and without (n = 8) auditory hallucinations. Magnetic resonance images of cerebral and cerebellar regions were segmented into gray and white fractions using an algorithm for semiautomated fuzzy tissue segmentation. They were defined by using the semiautomated Talairach atlas-based parcellation method. Patients with auditory hallucinations showed larger temporal white matter, frontal gray matter, and temporal gray matter volumes than patients without auditory hallucinations. These findings suggest that auditory hallucinations in schizophrenic patients may be associated with neuropathological abnormalities in frontal and temporal brain regions.     

Modality specific neural correlates of auditory and somatic hallucinations

Somatic hallucinations occur in schizophrenia and other psychotic disorders, although auditory hallucinations are more common. Although the neural correlates of auditory hallucinations have been described in several neuroimaging studies, little is known of the pathophysiology of somatic hallucinations. Functional magnetic resonance imaging (fMRI) was used to compare the distribution of brain activity during somatic and auditory verbal hallucinations, occurring at different times in a 36 year old man with schizophrenia. Somatic hallucinations were associated with activation in the primary somatosensory and posterior parietal cortex, areas that normally mediate tactile perception. Auditory hallucinations were associated with activation in the middle and superior temporal cortex, areas involved in processing external speech. Hallucinations in a given modality seem to involve areas that normally process sensory information in that modality.     

Reduced frontotemporal functional connectivity in schizophrenia associated with auditory hallucinations.

BACKGROUND: We used functional magnetic resonance imaging (fMRI) to investigate the frontotemporal disconnection hypothesis of schizophrenia. METHODS: Eight DSM-IV schizophrenia patients and 10 control subjects were studied with fMRI while they thought of the missing last word in 128 visually presented sentences. The fMRI data were analyzed comparing the effect of sentence completion (vs. rest) using a random effects analysis. RESULTS: There were no significant group differences in regional brain responses. Correlation coefficients between left temporal cortex (x = -54, y = -42, z = 3) and left dorsolateral prefrontal cortex (x = -39, y = 12, z = 24) were significantly lower in the schizophrenic group and were negatively correlated with the severity of auditory hallucinations. CONCLUSIONS: Previous demonstrations of hypofrontality in schizophrenia may reflect particular task requirements. Frontotemporal functional connectivity is reduced in schizophrenia and may be associated with auditory hallucinations.     

Effect of the benzodiazepine derivative estazolam in patients with auditory hallucinations. A multicentre double-blind, cross-over study

The main aim of this study was to test the effect of the triazolobenzodiazepine, estazolam, on auditory hallucinations. Fifty-eight patients (28 male, 30 female) with auditory hallucinosis that had responded poorly to neuroleptics alone, were included; most patients were chronic schizophrenics, and most patients were maintained on previous neuroleptic treatment during the trial. Each patient was treated for three consecutive 3-week periods, and randomly allocated to receive estazolam (1 + 1 + 4 mg) either in the first and third, or in the second period. Similar-looking placebo tablets were given in the control periods. These were seven drop-outs, three of them due to somnolence on estazolam. In both treatment groups there was a significant (but not significantly different) improvement during the first 3-week period, with regard to both global clinical state and auditory hallucinations. During the second and third periods, however, the two groups differed significantly, in that improvement of global state and hallucinosis was seen on estazolam, and deterioration on placebo. It is concluded that estazolam (as an addition to neuroleptics) had a significantly better effect than placebo on the global clinical state, on the frequency of, and attitude towards the hallucinations, and also on the single symptoms "Compulsive thoughts" and "Visual hallucinations" (items in the Comprehensive Psychopathological Rating Scale). There were few side effects except drowsiness. Possible pharmacokinetic and pharmacodynamic interactions between benzodiazepines and neuroleptics are discussed briefly.