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Perception of voices that do not exist: Tracking the temporal signatures of auditory hallucinations

Periodic Reporting for period 4 - ONOFF (Perception of voices that do not exist: Tracking the temporal signatures of auditory hallucinations)

Reporting period: 2021-03-01 to 2021-12-31

The problem addressed in ONOFF ERC AdG project is the underlying neuronal and cognitive mechanisms for auditory verbal hallucinations(AVH) in schizophrenia, using behavioral and brain imaging methods. A subsidiary problem is how to understand the spontaneous fluctuations over time of hallucinatory episodes, and in particular what causes the "voices" to temporarily go away, with a long-term goal of contributing to development of new interventions, targeted on a symptom rather than on a diagnosis as such. Schizophrenia is one of the most severe mental disorders, which affects about 1% of the European population, and with enormous costs for the society. There is a changing demographic pattern of the incidence of schizophrenia which goes together with the increasing urbanization and migration into the major European cities. Thus, understanding the the most severe symptom, AVH, in one of the most severe mental disorders, schizophrenia, is of major societal importance. The overall objective of the project follows a model called "Levels of explanation", which seeks to understand AVH at different explanatory levels, from the clinical to the neuronal levels. A major issue in the ONOFF project is the fluctuations of hallucinatory episodes, and if these are related to changes in excitatory/inhibitory influences at the level of neurochemistry in the brain. Using MR spectroscopy (MRS), our group was the first to report increased levels of the excitatory neurotransmitter Glutamate in brain regions which are activated during AVH episodes. We have recently followed-up these initial results, showing that frequency and severity of auditory hallucinations correlate positively with increased levels of glutamate in temporal (STG) brain regions, but negatively in frontal (ACC) regions, as would be predicted from the VOICE model proposed by Hugdahl in 2009. In order to relate these findings to findings at the level of neuroimaging, we have developed a new MR sequence to simultaneously assessing brain transmitters and functional changes seen in fMRI BOLD data. Preliminary validations show that the simultaneously acquired MRS and BOLD data is a feasible way forward. As stated in the proposal, there is a need for new approaches to cognitive training of auditory hallucinations, as well as new ways of acquiring data on frequency and content of auditory hallucinations in real-time. We have for this purpose developed two smartphone apps, one for training, and another for symptom capture screening
A hypothesis put forward in the ONOFF proposal is that the spontaneous fluctuations of hallucinatory episodes are caused by changing influences of excitatory and inhibitory neuronal effects. Using the MRS method we have preliminary evidence of a positive correlation between Glutamate levels and frequency and severity of auditory hallucinations in the left upper posterior temporal lobe, and a corresponding negative correlation in the medial frontal lobe. For the BOLD fMRI part of the project we are using an Eriksen Flanker paradigm which is a cognitive task that loads on attention and executive function. In 2020 we found that fMRI-BOLD activation in a region medially in the ventromedial prefrontal cortex (VMPFC) correlated with the subjective experience of the presence or absence of AVH episodes, BioRxiv pre-print server). A surprising effect was however that activation in this region increased a few seconds before the onset of an AVH episode, but it decreased a few seconds before the offset of an AVH episode. It was as if this region in the brain act like a "switch" to turn an episode on or off, and that this happened a few seconds before the patient made a conscious decision (by pressing a hand-held button) that the "voice" was present or absent. This result, which is currently under review for publication) must be replicated, but it nevertheless provides a first answer to the main question asked in the ONOFF project, "why do auditory hallucinations fluctuate". A second achievement is related to up- and down-regulation of the Default Mode Network (DMN) which was hypothesized to be aberrant in hallucinatory patients, and that this could interact with the up- and down-regulation of another, task-positive network, labelled EMN, originally discovered by our group (Hugdahl et al. 2015). A hypothesis is that fluctuations of AVH also correspond with how these networks are in- or out-of-phase with each other, which in turn could be driven by the interaction of excitatory and inhibitory neurotransmitters such as Glutamate and GABA, respectively. In a first publication (Weber et al., 2020) we used an approach to network analysis called dynamic functional connectivity analysis, which includes the time domain into the analysis of spatial data. This showed that AVH patients had a more rigid network patterns across time, potentially correlating with AVH episode frequency. We have further been working on analyzing data from white matter tracts, using DTI and tractography techniques, which would provide evidence on how functional network connectivity relate to underlying fiber structure connectivity. The Covid-19 pandemic has had the effect that recruitment and MR scanning has been delayed and it has been difficult to have participants come to Bergen from other parts of the country because of travel restrictions. This has the consequence that we still have data to process, analyze and report, which will go on during 2022.
Progress beyond the state-of-the-art is that we have moved the study of neurobiological correlates of auditory hallucinations (AH) beyond a traditional brain imaging approach by asking the question how changes at the underlying transmitter and receptor level of explanation may contribute to changes in brain activation as observed with e.g. fMRI. By adding a MR spectroscopy sequence to the traditional EPI-sequence we have been able to study how excitatory (Glutamate) and inhibitory (GABA) factors correlate with frequency and severity of AH, and are in the process to take the MRS approach one step further by setting the stage for simultaneous BOLD and MRS data acquisitions from the same brain region in real-time, using MEGA PRESS MRS sequence with insufficient water suppression. So far we have found that temporal lobe Glu concentration is positively correlated with frequency and severity of AH, while frontal lobe Glu is correspondinglynbegatively correlated. We expect to have results for the GABA transmitter as well by the end of the project period. Another progress beyond state-of-the-art is the discovery of the Extrinsic Mode Network (EMN) by Hugdahl et al. (2015) as a generalized task-positive cortical network, that is independent of the cognitive task. We have been able to show that the EMN is anti-correlated with the well-known Default Mode Network (DMN), discovered by Raichle and colleagues (2001), and that this happens when environmental demands change from rest to active processing. We will now use this new discovery to analyze data from the ONOFF project to explore if AH abrupt the EMN/DMN dynamics, and if this is related to the fluctuations of AH. A third beyond state-of-the-art progress is the continuing development and improvement of smartphone apps for cognitive training and real-time AH symptom capturing.
The MR scanner environment at the Haukeland University Hospital, Bergen, Norway
Group picture, from Bergens Tidende newspaper article
PI Kenneth Hugdahl, University of Bergen, Norway