Exploring function in the hallucinating brain
Chapter 2 describes the presentation of VAH in a single patient, highlighting the diagnostic and co-morbidity issues involved. Functional MRI (fMRI) revealed activation of the primary auditory cortex, speech areas (Broca, Broca’s homologue and Wernicke), basal ganglia, anterior cingulate gyrus and dorsolateral prefrontal cortex; these results are in line with earlier studies (for a meta-analysis see Jardri et al. 1). In this particular patient, VAH were in full remission after treatment with repetitive transcranial magnetic stimulation directed at Wernicke’s area, together with remission of a range of metamorphopsia and depressive symptoms. Although current knowledge on the pathophysiology of VAH on a neural level is still at an early stage, the studies presented here show the potential of fMRI to guide novel treatment. These studies also indicate that the brain is an integrated network within which local influence can spread across different brain functions.
The study in Chapter 3 investigated whether neurophysiological differences exist between internal VAH and external VAH. This is highly relevant, because the clinical tradition generally considers internal VAH to be less pathological and atypical for psychotic disorders. According to this tradition, internal VAH are often referred to as ‘pseudohallucinations’ 2. Our hypothesis is that the difference between internally perceived versus externally perceived VAH is limited to additional activation in the auditory ‘where’ pathway, i.e. a network of brain regions dedicated to locating sounds in our environment 3. Results from fMRI show increased activation of the right-sided medial frontal gyrus and the left-sided planum temporale in persons experiencing external VAH. This indicates that the ‘where’ pathway could indeed play a substantial role in the projection of hallucinated voices into external space. Correspondingly, internal VAH are neurophysiologically distinguished from external VAH by their lack of activity within the ‘where’ pathway. Considering that a small amount of auxiliary activation can explain the difference between internal and external VAH, we suggest that caution is required when applying the term ‘pseudohallucinations’. This recommendation is in line with clinical studies reporting that there is no evidence for a differential impact or effect in patients experiencing either internal or external VAH 4.Chapter 4 steps back from the phenomenological level of studying VAH. The increasing amount of research on schizophrenia and psychotic symptoms has identified a range of factors suggested to be causal to the psychotic state. Although these explorative studies are highly valuable (providing data on, amongst others, genetics, neurodevelopmental trauma, altered brain connectivity, and/or social factors) they should be viewed within a larger context. In our work, an integrative model is proposed for psychosis based on network theory. This model states that the human brain is a ‘scale-free’ structure in which the multilevel and (complex structural/functional) organization contributes to the formation of hallucinations. Within the scale-free biological network, functional brain dysconnectivity is viewed as an intermediary scale level, under reciprocal influence from microlevel and macrolevel states. This ‘integrated network model of psychotic symptoms’ (INMOPS) is described, together with various possibilities for its application in clinical practice.
Based on our INMOPS theory (Chapter 4), an exploratory study was conducted in Chapter 5 to investigate the occurrence of VAH from the perspective of the multilevel and complex (functional) organization of the human brain. The aim was to develop a mechanistic account of the way in which the interaction of multiple functional networks leads to VAH in schizophrenia spectrum disorder. An Independent Component Analysis (ICA) of fMRI data was performed for a large group of persons experiencing frequent VAH, decomposing the overall general function of the brain of these patients into a set of constituent functional subnetworks. The interaction between these functional networks was further studied using network analysis to estimate the flow of activity in the brain circuits that subserve VAH. Firstly, it was found that our rigorous procedure for denoising the data in combination with ICA, decomposed the data into a fine-grained system of 98 functional networks in which 7 higher-level modules could be identified mathematically. These modules constituted plausible functional networks which, in an unsupervised layout produced by a force-directed orientation algorithm, neatly positioned themselves according to global brain anatomy. These so-called large-scale networks of the brain, i.e. default mode network (DMN), central executive network (CEN), and salience network (SN), decomposed into several subunits, each with their own interaction profiles and degrees of correspondence with hallucinatory activity as reported by the patients. These findings show that the commonly reported large-scale networks should not only be studied in their entirety, but also that their constituent parts serve important subfunctions that contribute differentially to the global psychotic phenotype. These results also fit our INMOPS theory, by showing that multiple levels of (functional) organization indeed contribute to the formation of hallucinations. Interestingly, several subparts of the global cerebellar network contributed differentially to the experience of VAH, indicating a more complex pathogenesis of VAH than previously thought. The functional networks showing the most direct involvement with VAH experience were the bilateral anterior cingulate cortex, the right anterior insula, the cerebellum, and the homologue of Broca’s area. Based on the causal structure of their mutual connections, we hypothesize that the right-sided insula and Broca’s homologue are responsible for the production of preconscious linguistic constructs (‘error’) to which superfluous importance is assigned by the salience network, producing a conscious experience that matches this disproportionately high level of salience.