How functional neuroimaging is informing cognitive neurobiological models of auditory verbal hallucinations

Introduction

Auditory verbal hallucinations (AVHs), or “hearing voices”, are a complex phenomenon characterised by abnormal perceptions of speech occurring in the absence of an appropriate external stimulus.1 Hallucinations of this modality hold great diagnostic significance, with Schneider’s (1959) first-rank symptoms of schizophrenia (including AVHs) still recognised today by major classification systems such as the International Classification of Diseases (ICD)-10 and the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV.2–4 AVHs also occur in other mental illnesses, including bipolar disorder (20-50%), post-traumatic stress disorder (40%) and major depression with psychotic features (10%),5 as well as being reported by 10-20% of the general population.6 These hallucinations vary over a number of dimensions (e.g. in frequency, clarity, content), but are frequently intrusive and malevolent, thus very debilitating.7 Additionally, in mental illness, the patient’s insight into their condition is often limited, leaving them convinced of the voices objective reality.2,8

Hallucinations have long been recognised as a hallmark of mental illness, with literature on their aetiology dating back to the 19th century.2,9 Advances in medicine over the last hundred years saw the introduction of new treatments for AVHs, such as electroconvulsive therapy (ECT) and anti-psychotic medication. However, in 1964, psychiatrist R. D. Laing expressed his belief of the importance of the content of these hallucinations, and criticised the views of other psychiatrists stating that these hallucinations were “more socially intelligible than has come to be supposed by most psychiatrists”.10,11 This has led to an alternative view of AVHs; that these experiences have important meaning to the hearer, allowing one to reflect on past experiences and guide future direction.12 This has led to debate over the role of trauma in these experiences, illustrated by Laing’s iconic quote: “Insanity – a perfectly rational adjustment to an insane world”.

Our understanding of the aetiology of AVHs has come a long way since the Ancient Greeks implicated an excess of black bile humour, but it is still limited.10 Advances in technology over the past 20 years have allowed us to utilise neuroimaging to better our understanding of these experiences, through both visualising the brain structurally, and exploring activity during AVHs using functional techniques. By first describing the cognitive neurobiological theories of AVHs, this essay will explore how functional neuroimaging studies have informed these views, and discuss the direction for future research in this area.

Cognitive neurobiological models of AVHs

There are four main cognitive neurobiological models of AVHs. Firstly, that AVHs are spontaneously generated by auditory regions of the brain. This theory arose when patients experienced hearing voices during perioperative electrical stimulation of the temporal cortex,13 and is supported by recent studies reporting metabolic changes in areas of the brain involved in language during AVHs.14–16 Secondly, that these experiences stem from dysfunctional monitoring of episodic verbal memory, leading to activation of language processing regions and creating a sensory experience.15,16 Unlike the previous theory, this explains the personal content of some hallucinations, fuelling the debate of whether subconsciously attributing these memories to an external source reduces the distress they cause.17 However, this theory does not explain hallucinations that are neutral in temperament, providing a running commentary of one’s actions (a 3rd person hallucination).18

Thirdly, a self-monitoring deficit of inner speech may cause misattribution of the “inner voice” to an external source.19 Proposed by Frith in 1988,20 this theory is based on impaired internal monitoring, and could explain multiple core symptoms of psychosis e.g. hallucinations and delusions.19 However, this model does not explain complex AVHs, e.g. hearing multiple voices in the third person.21 Finally, that these hallucinations are due to early sensory processing errors; the cognitive deficits seen in schizophrenia could lead to one inappropriately labelling any auditory stimulus as a voice.22,23 However, as with the previous theory, this does not explain the complexity of AVHs, or why they arise in people that do not have schizophrenia.

Functional neuroimaging studies

Brain states

AVHs are the hallucination most frequently addressed by neuroimaging studies,15,16 with a common technique being exploration of resting brain state (when the brain is not performing an explicit task) differences. Studies comparing resting brain state activity of patients with schizophrenia experiencing AVHs to patients with schizophrenia without AVHs, or healthy controls, have reported reduced connectivity in language processing areas such as the primary and secondary auditory cortex.15,24–26 The primary auditory cortex is the region of the brain responsible for processing auditory sensations into perceptions, whilst the secondary auditory cortex plays a role in localising sound and processing complex sounds such as language.27,28 A 2013 study by Mou29 coupled a voice recognition task with functional magnetic resonance imaging (fMRI) in schizophrenic patients with and without AVHs, and healthy controls. They found that patients with schizophrenia that also experienced AVHs had altered frontotemporal connectivity and comparatively poorer voice-recognition. This echoes the results of two previous studies that report disrupted intrinsic connectivity of speech-related networks and impaired functional integration of areas involved in speech appraisal, which could indicate deficient perception of inner speech.30,31 These findings support models of cognitive deficiency and misattribution of inner speech as causal of AVHs.

In addition to finding reduced connectivity of language processing areas, studies into resting state activity have reported elevated activity in the default mode network (DMN). This network is active when the brain is at wakeful rest (e.g. not taking in information from the external surroundings; it is made up of the medial temporal lobe, medial prefrontal cortex, posterior cingulate cortex and areas of the parietal cortex.32 Northoff et al. proposed that AVHs are generated by an abnormal interaction between the DMN and auditory cortex, whereby high resting state activity in the DMN induces activity in the auditory cortex, causing one to perceive internally processed functions as external events, or voices.33 This too is in keeping with a misattribution of inner speech model of AVHs. Furthermore, increased connectivity in the DMN may be correlated with severity of AVHs.15

In actuality, studies comparing topological organisation of structural and functional networks in brains of people with and without schizophrenia have highlighted a number of differences including reduced hierarchy of the multimodal cortex (involved in processing sensory information) and indicators of inefficient axonal wiring.34,35 Differences between the spatially distinct regions that make up functional networks can be seen in figure 1.35 Abnormalities in ‘top-down’ modulation have also proven to be significant in AVHs.36 ‘Top-down’ mechanisms refer to those generated through mental processing in the cerebral cortex, as opposed to ‘bottom-up’ mechanisms that are initiated by sensory receptor stimulation.37 A change in balance between ‘top-down’ modulation and ‘bottom-up’ functional processing in schizophrenia as significant to AVHs has been highlighted before.26 Abnormal ‘top-down’ modulation may cause a person to attribute inappropriate significance to background noise, a factor possibly made worse by increased resting state activity in the secondary auditory cortex,33,38 and the decreased task induced deactivation (reducing activity in regions of the brain that are not in use during an activity) seen in psychosis.39 On the other hand, inappropriate ‘bottom-up’ activity in auditory regions of the brain may lead to errors of perception when processed by higher regions.15,40 Our understanding of how the occurrence of ‘bottom-up’ activity is still limited, however ongoing research is providing increasing evidence of differences in the resting brains states of this population. This research may better our understanding of why people with schizophrenia experience AVHs, but may not be applicable to non-clinical AVHs.

Symptom capture studies

Few studies have explored the neural correlates of AVHs during an episode itself.41 One method that has shown increasing popularity over the last two decades is that of a symptom capture design, whereby a person self-reports AVHs whilst in a scanner; this is most commonly done by pressing a button or squeezing a balloon to indicate the time period over which a hallucination persists. It is then possible to separate neuroimaging data into hallucinating and non-hallucinating (resting) brain states, and compare the two ‘within’ a person, as a self-comparison. The results of these studies have highlighted number of regions of the brain that may be involved in AVHs. A number of studies have reported spontaneous activity in the superior temporal and transverse temporal (Heschyl’s) gyri. These regions of the brain are associated with processing sound and language (the primary auditory cortex and Wernicke’s area respectively).24,25,42–48 Activity has also been noted in parietal regions involved in language and sensory processing,24,25,43,47,49 and in motor regions such as those involved in language production.24,25,42–44,47,49–51 (It should be noted that some studies have attributed motor activity to the physical act of button-pressing in self reporting AVHs.)42,49,51 This data suggests aberrant activations within sensorimotor regions of the brain may play a role in AVHs, but could indicate that these brain regions are involved in another mechanism of generation.

Furthermore, using a symptom capture method, Dierks reported increased resting state activity in the superior and middle temporal gyri of voice-hearers, including the primary auditory cortex during AVHs.25,52 These results suggest that the auditory cortex of voice-hearers shows more activity whilst at rest, and orientates one’s perception towards internal activity as opposed to external stimuli,33,53 which could lead to abnormal attribution of inner speech to external stimuli. This agrees with the previously stated theory that increased DMN activity may affect resting state activity in language areas. However, these results do not indicate whether the activity we see is causative of the hallucinations, or occurs as a result of the association cortex recruiting these brain regions during AVHs.41

Symptom capture studies have also reported increased activity in the limbic system and hippocampus during AVHs. These regions of the brain are involved in emotion and memory respectively.24,25,44,54,55 These findings are echoed by the 2011 meta-analysis of positron emission tomography (PET) and fMRI symptom capture studies by Jardri (figure 2), which also reported activation in areas involved in language generation and perception. Abnormal memory retrieval could activate dispersed storage sites within language regions of the brain, implicating dysfunction of memory retrieval as causative of AVHs.16

Future directions for research

There are some recurrent limitations across neuroimaging studies to date. It has been recommended that a minimum of 12 participants be recruited for a neuroimaging study to be valid,56 meaning many are underpowered.24,25,42–44,46,49,54 Furthermore, most studies have targeted the chronic schizophrenia population, meaning results will be impacted by factors such as medication and length of illness.15 To address this, researchers could target early AVH presenters, e.g. those with first episode psychosis (the first time a patient presents with a clinically significant symptom of psychosis, e.g. a hallucination, delusion etc.).57 Additionally, research into non-clinical AVHs is sparse,26,58 questioning whether the proposed models of AVHs are applicable to this population; further research into this population would address this and increase generalisability.

The temporal course of activity measured is also an issue, namely whether the activity we see is causal of a hallucination or vice versa. Understanding the time course of activation would better inform the sequence of activations in AVHs. Allen15 proposed the use of techniques with higher temporal resolution, such as electroencephalography, alongside other imaging techniques to combat this. However, participants self-reporting AVHs also limits our understanding of temporal course, as they may not press the button immediately at onset if unaware whether the sound they heard was hallucinated.

Finally, the cognitive biological theories that we have today do not account for the rich content of hallucinations.15,59 By combining neuroimaging studies with detailed phenomenological descriptions of AVHs, attributing the nature of the hallucination to the neural correlates identified may inform current models and provide a stronger scientific basis for future research.

Conclusion

Over the past 20 years, functional neuroimaging studies have bettered our understanding of AVHs, informing existing cognitive biological models. Functional resting brain state scans have implicated abnormal connectivity and resting brain state activity in those that experience AVHs, whilst symptom capture studies have identified regions of the brain that are active during these experiences: those involved in language, memory and emotion. Future researchers should aim to address the limitations of previous studies, e.g. population targeted and sample size, and put thought into the challenges of imaging studies, such as determining the temporal course of events in AVHs. Ultimately, there is a need for an integrative neurobiological model that accounts for both the biological mechanism underlying AVHs, and the phenomenology of the experiences. A biopsychosocial model of this nature would adhere to the holistic view of modern medicine, inform as to whether content of these experiences is of importance (and whether they are indeed in some cases a “rational adjustment to an insane world”), and set a stronger scientific background for the development and assessment of new interventions.

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