Exploring the Neural Correlates of Auditory Hallucinations Duration in Schizophrenia
Auditory verbal hallucinations (AVH) are a major symptom of schizophrenia, estimated to occur in around 70% of patients. While the clinical features of the phenomenon are well established-AVH may be single or multiple, are often but not always derogatory, and may be experienced inside or outside the head (or both)-the mechanism or mechanisms underlying them remain obscure.
Theoretical approaches to AVH include so-called ‘cognitive’ models, which argue that they are a manifestation of non-perceptual processes, for example inner speech that fails to be labeled as internally generated, or memories whose vividness and/or intrusiveness leads them to be misinterpreted as perceptions.
The other main approach, the ‘neurological’ or ‘perceptual’ model, proposes that AVH are in some sense genuinely perceptual in nature. In its simplest form this approach dates back to the beginning of the twentieth century as the idea that they are due to pathological (‘irritative’) neuronal activity in the auditory cortex. A current version of this approach proposes that, in addition to there being such a ‘bottom-up’ abnormal perceptual process, ‘top-down’ influences on perception act to confer additional features on AVH, leading them to be interpreted as the voices of family, friends or people involved in a conspiracy against the patient, etc.
Complex perceptual experiences are known to occur in neurological disorders such as epilepsy and migraine, and electrical stimulation of the temporal lobe cortex in patients undergoing brain surgery can also result in auditory experiences up to and including speech. Beyond such clinical observations, the neurological/perceptual model of AVH is testable using functional imaging, specifically the symptom capture paradigm, which compares brain activations at times when hallucinating patients hear a voice (which they typically signal by a button press) to periods when the voices are silent.
Several studies of this type have found evidence of AVH-related activations in the superior temporal cortex, the posterior part of which contains the primary auditory cortex (Heschl’s gyrus). Others, however, have not found auditory cortex activation, or found activation only in a very small cluster (11 voxels) or activation which appeared to be localized to temporal lobe white matter.
Image depicting the location of the temporal lobe in the human brain.
We employed a novel variant of the symptom capture paradigm and 3 T fMRI to examine 30 right-handed adult patients with a DSM-5 diagnosis of schizophrenia or schizoaffective disorder. Fifteen of these patients (the AVH + group) reported experiencing AVH nearly continually. The remaining 15 patients (the AVH- group) had been free of AVH for at least six months. The two groups were matched for age (t = 1.53, p = 0.14), sex (χ2 = 0.75, p = 0.39), and premorbid IQ, as estimated using a word pronunciation test (t = 0.25, p = 0.81).
During the functional run (lasting 10 min 10 s) the AVH + patients were instructed to press a button with their right index finger each time they heard a voice (frequency of button press during scanning ranged from 5 to 174 times, mean 43.53, SD = 49.20, median = 23). During the same run 40 randomly timed examples of real speech were also delivered to both ears via MRI-compatible headphones, to which the patients had to respond with the left index finger (see Fig. 1). The real speech was individually tailored to be similar in form to each patient’s AVH.
To achieve this, prior to scanning the patients were asked to repeat out loud what their voices said, as they heard them, over a 5-min period, and their verbatim responses were tape-recorded and transcribed. Examples, which took the form of single words, short phrases or sentences such as ‘The good boy’ or ‘You will change the world’, were then recorded for presentation during scanning in a neutral voice by an individual of the same gender of the hallucinated voice, as reported by each patient. The real speech stimuli were separated by random intervals ranging from 3 to 30 s (mean = 14.94 s, SD = 7.06); stimulus duration ranged from 0.53 to 3.22 s (mean = 1.33, SD = 0.67).
Overview of the experimental paradigm. Throughout the 10 min, 10 s scanning period, participants pressed a button with their right index finger when they experienced an auditory hallucination (red), and with their left index finger when real speech was presented through headphones (black).
The AVH− patients performed the second part of the fMRI task only. The real speech stimuli presented to these patients were the same as the ones presented to AVH + patients: for each patient, the stimuli that were used were taken from an AVH + patient who was as similar as possible in terms of age, sex and estimated premorbid IQ.
Activations in response to AVH and real auditory stimuli
Findings using whole brain, voxel-based analyses, with an initial threshold of z = 3.1 (p < 0.001) and cluster-corrected for multiple comparisons at p < 0.05, are shown in Fig. 2. As a group, the AVH + patients showed no activation in most of the superior temporal cortex when they experienced AVH, including its posterior portion which contains the primary auditory cortex (Heschl’s gyrus). The only exception was a bilateral cluster in the extreme posterior superior temporal gyrus and the adjacent supramarginal gyrus, which on the left includes the regions usually identified as Wernicke’s area.
Group activation maps for experience of auditory hallucinations (A) and real speech (B) in 15 hallucinating patients. Activations to real speech in 15 non-hallucinating patients are shown in row (C). Colour bar depicts Z values.
Experience of AVH was, however, associated with activations in circumscribed regions outside the temporal lobe. As well as Wernicke’s area and its right homologue, these included the bilateral inferior frontal gyrus (Broca’s area and its right homologue), the precentral gyrus and the supplementary motor area, both bilaterally.
In contrast, when hearing real speech, the AVH + patients showed activation along the length of the superior temporal cortex bilaterally, as well as in areas outside this (see Fig. 2, panel B). The extra-temporal areas activated largely overlapped with, but were more extensive than, the regions activated by experience of hallucinations. As shown in Fig. 3, Heschl’s gyrus was robustly activated in response to real speech, but activation barely rose above baseline in response to AVH. In contrast, activation levels for both real speech and AVH were similar in the two regions generally accepted as comprising Broca’s area, the left inferior frontal gyrus, pars opercularis and pars triangularis, and in its homologue on the right. This was also the case for the anterior and posterior portions of the supramarginal gyrus, which on the left overlap with Wernicke’s area.
Finally, activations were similar for AVH and real speech in the precentral gyrus and supplementary motor area; these activations may have reflected the effect of button-pressing, but the ventral premotor cortex has also been suggested to play a role in speech perception.
Task-related activation in anatomically-defined ROIs for auditory perception, language processing and motor regions. Dot plots show individual mean activation levels (beta values) for real auditory stimuli and AVH in Heschl’s gyrus (A), the inferior frontal gyrus, pars opercularis (B), the inferior frontal gyrus, pars triangularis (C), the anterior portion of the supramarginal gyrus (D), the posterior supramarginal gyrus (E), the precentral gyrus (F) and the supplementary motor area (G). Time-series plots show group signal change in the same ROIs relative to the region’s average, in the time window spanning 4 s before to 10 s after stimulus presentation (estimated stimulus occurrence time in the case of AVH).
Examination of possible interfering effects of real auditory stimuli on activations to AVH
Given that the design of the study meant that AVH occurred in the same blocks as the presentation of real auditory stimuli, it needs to be considered whether auditory cortex activations produced by real speech might have obscured activations to AVH occurring very soon afterwards. As a first test of this, we measured the correlation between the regressors for AVH and real speech in the individual GLMs in our first-level model. In all cases, this was close to zero or negative (mean = − 0.14, range = + 0.04 to − 0.48). This finding does not suggest that temporal co-occurrence between AVH and the real speech stimuli was playing an important role.
Secondly, we ran an additional analysis to minimize any interfering effects of auditory stimuli on AVH-related activations occurring very shortly afterwards. At the first level, we defined three regressors: real auditory stimuli, hallucinations occurring more than 10 s after a preceding auditory stimulus, and hallucinations occurring up to 10 s after a preceding auditory stimulus (a 10-s separation was chosen based on the time-series plots shown in Fig. 3, which indicate that activation linked to real auditory stimuli had returned to baseline levels after this interval). The last regressor was considered a nuisance regressor. Motion regressors were also included as covariates, as in the original model. At the second level, we examined activations to AVH occurring more than 10 s after a preceding auditory stimulus with a one-sample t-test (p < 0.05, cluster-corrected, with a cluster-defining threshold of z > 3.1).
The findings are shown in Supplementary Figure S1 and Supplementary Table S4; the pattern of activation remained similar, although with smaller cluster sizes reflecting the smaller number of events captured, and the auditory cortex continued to be uninvolved. As in the original analysis, we found a small cluster of activation in the extreme posterior superior temporal gyrus, in this case only in the right hemisphere, roughly overlapping with Wernicke’s area right homologue.
Discussion
Contradicting several earlier studies using the symptom capture paradigm as well as meta-analyses of such studies, we found nothing to suggest that the experience of AVH is associated with auditory cortex activation. This failure, coupled with the fact that perception of formally similar real speech strongly activated a large expanse of the superior temporal cortex, would seem to exclude theoretical approaches to AVH in schizophrenia that invoke abnormal neuronal activity in the auditory cortex.
This then implies that some version of the cognitive model of AVH must be correct. It should be noted that the findings of our study make one theory of this type-that AVH are misinterpreted vivid/intrusive memories-unlikely. The brain functional correlates of the conscious re-experiencing of memories, or autobiographical recall, are well established and prominent among them are activations in two midline cortical regions, the medial frontal cortex and the posterior cingulate gyrus/precuneus. These two areas are a key part of the default mode network, a set of brain regions that typically de-activate during the performance of most cognitive tasks; autobiographical recall is one of a small number of tasks that have been found to activate rather than de-activate this network. There was no hint of a default mode network pattern of activation in response to AVH in our study. Nor have meta-analyses of symptom capture studies suggested such an activation pattern.
We did find activations outside the temporal lobe during experience of AVH: these involved Wernicke’s area and its right homologue, Broca’s area and its right homologue, and the precentral gyrus and supplementary motor area bilaterally. While, as noted above, activations in motor areas may simply have reflected the act of button-pressing, our finding of activations in Broca’s and Wernicke’s areas (and perhaps also the activations in the ventral premotor cortex, which has been considered to play a role in speech perception) could be taken to suggest that the experience of AVH involves mechanisms that normally participate in the processing of speech. Given the lack of accompanying auditory cortex activation, this would presumably be at the level of decoding of the linguistic properties of speech rather than its initial detection and analysis of its auditory perceptual qualities.
There is also another possible interpretation of the pattern of AVH-related activations we found. Based on functional imaging studies, Broca’s area, the precentral cortex and the supplementary motor area are regarded as core regions subserving working memory, specifically its verbal non-executive component, the articulatory or phonological loop. Interestingly, a further region is implicated in verbal short-term memory, the left supramarginal gyrus, which has been argued to fulfil the temporary storage or ‘buffering’ function of the articulatory/phonological loop. This region was also activated in our study, as part of the cluster of activation in Wernicke’s area (which includes the supramarginal gyrus according to current views). Since verbal short-term memory equates to some extent with the concept of inner speech, our findings could therefore be interpreted as providing support for Frith’s mislabelled inner speech theory of AVH.
Our findings pertain to AVH as experienced by patients with schizophrenia. However, it is now well documented that around 6% of healthy adults also report having experienced AVH. To date, two symptom capture studies have examined the functional imaging correlates of AVH in such ‘healthy voice hearers’. Using whole brain analysis in seven AVH-experiencing individuals, Linden et al found a pattern of activations that was not dissimilar to the one we found, in that it included Broca’s and Wernicke’s areas and their right homologues; however, regions of the prefrontal, parietal and temporal lobe cortex were also activated. Interestingly, the temporal lobe activation did not appear to involve the primary auditory cortex but rather the superior temporal sulcus and the planum temporale, which lies immediately posterior to Heschl’s gyrus. Rather differently, Diederen et al examined 21 healthy voice hearers and 21 matched hallucinating patients with schizophrenia or other psychotic disorders. Examination of ROIs previously reported to be involved in the experience of AVH revealed evidence of bilateral superior temporal gyrus activation in the two groups combined, with no differences between the psychotic and healthy individuals in a conjunction analysis.