Functional Imaging

Metabolic and functional abnormalities, particularly in speech and language areas, have been widely reported by positron emission tomography (PET) fluorodexyglucose (FDG-PET) imaging studies of schizophrenia patients with AH.¹ Increased cerebral blood flow (rCBF) in the left STG and right temporoparietal cortex in patients with relative to patients without AH has also been reported using magnetic resonance perfusion imaging.¹⁰ The recruitment of the secondary auditory cortex during AH (reported by “state” or “capture” studies) is a widely replicated finding¹ and has been recently confirmed by a coordinate-based meta-analysis of the hallucinatory state.² This meta-analysis included 10 functional imaging studies investigating state activation during AH and evidenced that hallucinators showed increased activation likelihoods in a distributed bilateral frontotemporal network including Broca’s area, anterior insula, precentral gyrus, frontal operculum, middle and STGs, inferior parietal lobule, hippocampus, and parahippocampal region. These findings emphasize the involvement of a disrupted network of frontal production and temporoparietal language perception areas in AH occurrence.^1,11 Interestingly, when such a pattern of activation in inferior frontal and temporoparietal language areas during AH is compared with that of normal language production, the lack of lateralization of AH-related activity becomes apparent.¹² Of note, an imaging study in a group of nonpatients with AH suggests that altered lateralization may be specific to schizophrenia rather than AH per se.¹³ Another interesting finding of this meta-analysis is the activation seen in hippocampus/parahippocampal regions. Previous studies investigating cortical activations prior to the onset of AH reported deactivation of the parahippocampal cortex before symptom emergence as opposed to activation during hallucinations,¹⁴ leading some authors to consider such oscillations to be an aberrant trigger of activations in language-related areas responsible for AH.² The parahippocampus is thought 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 language areas during AH.² Results from the meta-analysis thus support 2 hypotheses: (1) aberrant activations within frontal-temporal language areas during AH and (2) a dysfunction of the verbal memory systems which could lead to the occurrence of AH. Moreover, these results invite new theoretical reflections about the involvement of primary and secondary auditory regions in AH experiences. While some brain-imaging studies failed to identify PAC activations during AH,^12,15 others do report activation in this region (eg, van de Ven et al¹⁶), questioning the exact role of this structure in AH. A meta-analysis of structural imaging studies also shows volume reduction in the PAC.³ The fact that activations of the PAC found in some reports did not survive the quantitative functional meta-analysis suggest that this structure is not necessary for AH emergence and could be more related to specific clinical or phenomenological features, such as the vividness of hallucinatory experiences.

Two recent “state” studies have also investigated AH in cohorts of nonpatient hallucinators.^17,18 The study by Diederen and colleagues¹⁷ revealed multiple common areas of AH-related activation in nonpatients and psychosis patients, consisting of the bilateral IFGs, insula, STGs, supramarginal gyri and postcentral gyri, left precentral gyrus, inferior parietal lobule, superior temporal pole, and right cerebellum. Moreover, there were no significant differences in AH-related activation between the patient and nonpatient hallucinators. Using a similar experimental design in nonpatients, Linden and colleagues¹⁸ report activation in human voice areas in the superior temporal sulcus as well as frontotemporal language areas and the supplementary motor area (SMA) during both AH and an auditory imagery task. Interestingly, AH were critically distinguished from imagery by lack of voluntary control reflected in the relative activation timing of prefrontal and sensory areas. Activity of the SMA preceded that of auditory areas during imagery, whereas during AH, the 2 processes occurred instantaneously.

However, a major issue with state studies is that the roles of many cortical regions in the generation of AH can only be inferred. For example, while activation in language areas during AH is intuitive and fits well with inner speech models of AH, the role of areas such as the cerebellum, hippocampus, parahippocampal, SMA, and parietal regions is more speculative. Cognitive or “trait” studies may be a more suitable approach to address these questions. Early cognitive studies investigating AH were usually based upon verbal self-monitoring, verbal imagery, and source memory paradigms, designed to engage specific cognitive processes that purportedly overlap with those impaired in schizophrenia patients with AH. These studies have shown that patients with AH demonstrate attenuated activation in temporal, cingulate, premotor, cerebellar, and subcortical regions thought to subserve the monitoring of inner speech and/or verbal imagery.¹ A study utilizing a reality discrimination task, in which participants were asked to remember whether or not they had earlier generated a target word, showed reduced medial prefrontal cortex (mPFC) activity in schizophrenia patients.¹⁹ The mPFC is thought to be involved in the evaluation of self-referential stimuli and is selectively engaged in the self-related task conditions.⁶ However, this study did not directly compare patients with and without AH and impaired function in these regions may be the basis for the self-other confusion characteristic of schizophrenia in general.

A small number of functional imaging studies have begun to examine the neural correlates of the phenomenological and emotional characteristics associated with the AH. Vercammen and colleagues²⁰ examined the subjective physical characteristics (loudness and reality) of AH using a metrical stress evaluation task, which has been shown to activate both inner speech production and perception regions. Loudness of voices correlated with reduced task-related activity in bilateral angular gyri, anterior cinculate cortex (ACC), left IFG and insula, and the left temporal cortex while reality of AH was found to be associated with reduced language lateralization.²⁰ In a study by Raij and colleagues,²¹ the subjective reality of patients’ voices correlated with hallucination-related activation in the left IFG and coupling between the IFG and other cortical and subcortical regions including the ACC. Two studies have investigated emotional dysfunction in patients with AH. During the presentation of emotional auditory stimuli, relative to control subjects and patients without AH, patients with AH showed increased activity in the parahippocampal gyrus and the amygdala.²² Conversely, in a similar study, during a task in which patients listened to emotional sounds, patients with AH showed reduced activation in the amygdala and bilateral hippocampus, relative to patients without AH.²³

Gyrification Studies

“Postmortem” brain photographs of patients with “Dementia Praecox” proposed a relation between “auditory hallucinosis” and cortical folding in the temporal lobe. The advent of magnetic resonance imaging (MRI)-based computational tools for visualization and measurement in vivo of brain structure has confirmed abnormalities in cortical surface morphology (or gyrification) in schizophrenia patients and subtle gyrification deviations associated to AH.³⁷ The cortical folding process begins from the 10th week of fetal life, and during the third trimester of pregnancy, the cerebral cortex changes from a relatively smooth lissencephalic surface, to a complex folded structure.³⁸ Several factors contribute to developmental processes that influence the shape of the folded cerebral cortex, including structural connectivity through axonal tension forces leading to a compact layout that optimizes the transit of neuronal signals between brain regions.³⁹

Early gyrification studies of AH were based on the assessment of hand-traced regions of interest derived from 2-dimensional MRI slices. Analysis of the insular cortex surface of drug-naïve first-episode schizophrenia patients revealed a specific correlation with delusions and hallucinations.⁴⁰ A recent study using exactly the same methodology, but in a large and heterogeneous sample of 225 schizophrenia-spectrum patients, indicated that AH were the most correlated clinical dimensions to insular surface area.⁴¹ Functional abnormalities in language system, including frontal motor-speech and temporal semantic areas, have repeatedly been associated to AH pathophysiology.¹ Involvement of the PAC remains, however, controversial. The comparison of the folding pattern of Heschl’s gyrus (HG), the cortical region hosting the PAC, revealed that schizophrenia patients with a history of AH show a trend toward a higher number of duplicated HG in comparison with both patients without history of AH and healthy controls.⁴² This finding suggests specific early morphogenesis PAC deviations in schizophrenia patients with history of AH. The development of computer-based methods now allows the automated extraction of the cortical folds across the whole cortex, reliably measuring their complexity, variability, and 3-dimensional shape.³⁷ Based on this approach, a significant sulcal area decrease was detected in 30 schizophrenia patients with resistant AH in comparison with 28 healthy controls⁴³ in language-related cortex. No correlation was detected between the sulcal areas and AH severity, patients’ age or drug dose. Taken together, these findings suggest that the detected sulcal deviations could be better viewed as a “trait” feature of AH vulnerability rather than a state feature of AH severity. The same morphometrical approach was recently used to investigate a phenomenological aspect of AH, the neural substate of spatial location.⁴⁴ In comparison with healthy subjects, opposite sulcus displacements were detected in patients with inner space AH and patients with outer space AH in the right Temporoparietal junction (rTPJ), a key region of the “where” auditory pathway. The detected tilt in the junction of the superior temporal sulcus and its anterior terminal branch (or angular sulcus) suggests deviations during early brain maturation.⁴⁴ As sulcus morphology in an adult subject can be seen as the integration of both normative and pathological influences exerted on brain development, such “sulcal dysjunction” might reflect an illness-associated developmental variation. These findings lead to the speculation that the preference for attaching either an “external” or “internal” location to AVH could be associated with particularities of early rTPJ neurodevelopmental trajectory.

State vs Trait

Interpretation of findings is made difficult by state and trait factors. The different ways hallucinating and nonhallucinating patients are defined could potentially lead to the same patient meeting the criteria for a hallucinator in one study and a nonhallucinator in another. This is why it may be important to study patients with severe hallucinations as a separate group.

Temporal Course

In terms of hallucination events, it is often hard to differentiate between activation triggering hallucinations, vs activation involved in the genesis of these experiences, vs activation reflecting downstream consequences (such as secondary shifts in auditory attention). Determination of the fMRI time course of activation could provide informative clues regarding the sequencing of these activations. However, the temporal resolution of fMRI is rather coarse for hallucination events, which may only last a few seconds. A useful parallel approach would be to use electroencephalography or magnetoencephalography for such studies, where temporal resolution is much greater.

Cognition

Cognitive studies generally address processes that share overlapping cognitive operations. The role of secondary auditory cortex is fairly clear (although the majority of studies report secondary involvement only); however, the role of the PAC is less clear and its involvement could be more related to specific clinical or phenomenological features. The role of nonsensory regions in AH is also largely speculative giving rise to issues with construct validity. While these studies may help us to understand anatomical and functional underpinnings that overlap, deficits in these processes are not the basis of AH. Deficits in several processes are likely to contribute to the AH (ie, self-monitoring, source monitoring, episodic memory, etc). Furthermore, the neural substrates that underpin these processes in healthy subjects are not well understood.

Specificity

The specificity of these cognitive operations (and their neural correlates) to AH is not clear. For example, dysfunction in language networks is seen generally across schizophrenia and is particularly associated with thought disorder.

Medication Confounds

Many studies negate this problem by either using a nonhallucinating patient group matched for medication or by studying the same patients when they are actively hallucinating and then again when their symptoms have remitted. However, a substantial number of studies do not control for the effects of medication (usually antipsychotics) upon neural activation measured by either fMRI or PET making these studies more difficult to interpret. Antipsychotic medication makes investigating the role of dopamine in AH particularly difficult. Plasmatic nicotine levels can also interfere with BOLD signal, and patients suffering from schizophrenia smoke a larger amount of cigarettes than healthy controls.

Connectivity Studies

The challenge of selecting optimal seed regions is paramount; many candidate regions can be proposed based on the literature, including Wernicke’s area, primary or secondary auditory association cortex, superior and middle temporal regions activated during hallucination events themselves, and the thalamus. Moreover, it is entirely plausible that a hyperconnected neurocircuitry involving some brain regions will secondarily induce hypoconnected neurocircuitry in other overlapping brain regions—and vice versa. Therefore, the question of what is cause and what is effect again becomes critical.

The authors have declared that there are no conflicts of interest in relation to the subject of this study.