A multimodal approach to investigate the hallucinating brain

Abstract

The pathophysiology of auditory verbal hallucinations (AVH) is still largely unknown. However, there is evidence that a disturbed language system is involved. Two theories explanations exist for this phenomenon. First, AVH might arise from a misattribution of inner speech. Second, these voices might originate from spontaneous right hemispheric language related activation, which is not prevented due to decreased hemispheric inhibition. In a large group of patients with schizophrenia, these AVH are resistant to medication. For this group of patients, repetitive transcranial magnetic stimulation (rTMS) has been suggested as a possible therapy for AVH. In this thesis, several neuroimaging modalities and brain stimulation were used to investigate the pathophysiology of AVH. In the first part of this thesis, intra-hemispheric connectivity within the language system was investigated in a group of patients with schizophrenia and non-psychotic individuals with AVH. With diffusion tensor imaging (DTI), the arcuate fasciculus (AF), a white matter tract which connects the primary language regions, was reconstructed. Integrity of this white matter tract was expressed in diffusion parameters and magnetization transfer ratio (MTR). In the second part, high frequency rTMS was applied as a therapeutic tool for AVH and compared with traditional low frequency protocols. In the final chapters, a setup was developed that allows investigating of inter- and intra-hemispheric connectivity by means of applying TMS during the acquisition of functional MRI (fMRI). This setup is unique, because it allows the stimulation of language related regions, which are located at the more lateral sites of the head. Finally, to investigate if this setup can be used to investigate connectivity in the language system, TMS was applied on the temporoparietal language region in a small group of healthy subjects. The main finding was the association of AVH with impaired white matter integrity of the AF, the main tract between primary cortical language regions. This finding supports the model of aberrant connectivity within the language network as a pathophysiological mechanism underlying AVH. The second conclusion was that rTMS treatment in schizophrenia needs to be thoroughly re-evaluated regarding its therapeutic potential. Finally, we demonstrated the potential of a concurrent TMS-fMRI setup to investigate the inter- and intra-hemispheric connectivity of the language network, which may yield valuable knowledge regarding the pathophysiology of AVH.