title: Neuromagnetic mismatch negativity in individuals at clinical high risk state for psychosis
Creators: name: Mikanmaa, Emmi
Publisher: name: University of Glasgow
Year: 2020

description: Advances in electroencephalography (EEG) and magnetoencephalography (MEG) have allowed the investigation into the neurophysiological basis of perceptual and cognitive disturbances across different stages of psychosis. The EEG/MEG recorded (neuromagnetic) mismatch negativity (MMN(m)) is a component of the event-related potential/field reflecting early pre-attentive auditory processing. Reduced MMN amplitude is a well-replicated finding in chronic schizophrenia patients and there is evidence for a smaller MMN impairment in first episode patients. Interestingly, studies have suggested that MMN deficits may be present even prior to the onset of psychosis in individuals at clinical high risk state for developing psychosis (CHR), suggesting that MMN amplitude could be a potential marker of psychosis risk. However, in contrast to the robust finding of an attenuated MMN amplitude in schizophrenia, results are more inconsistent at the earliest stages of illness. Moreover, to date most studies have used a conventional analysis for assessing MMN amplitudes in different stages of psychosis although brain connectivity measures, such as dynamic causal modelling (DCM) allow investigating effective connectivity in the brain network underlying the MMN generation. Also, two decades of research into characteristics of CHR individuals has revealed that they are functioning poorly regardless of subsequent transition to psychosis. However, while MMN amplitude has been studied as a potential marker for predicting psychosis among CHR individuals in several studies, its utility to predict other clinically relevant outcomes remains unknown. In the current thesis, I sought to examine MEG-recorded MMNm peak amplitude in individuals at different stages of psychosis as well as its association with neuropsychological performance, attenuated psychotic symptoms and psychosocial functioning in CHR individuals (chapter 3). The aim was to assess the potential of MMNm amplitude as a marker for early stages of psychosis and to examine whether MMNm deficits are pronounced in CHR individuals with poor functioning and cognitive deficits. Secondly, I employed DCM to examine whether effective connectivity in the underlying network of duration change detection is altered in CHR individuals compared to controls (chapter 4). Lastly, I investigated whether baseline MMNm amplitude is able to predict the 12-month outcome of CHR individuals in terms of transition to psychosis or sustained subthreshold psychotic symptoms and poor functioning (chapter 5). Given that the current study is the first large study that recruited CHR individuals predominantly from the community, clinical findings will also be reviewed and compared to previous studies with CHR individuals recruited from special early detection and intervention services. The findings in chapter 3 show that compared to controls, MMNm peak amplitudes were intact in CHR individuals as well as in first episode patients. Chapter 3 also indicates a weak positive association between MMNm amplitudes and speed of information processing in CHR individuals. Chapter 4 results indicate that CHR individuals do not have abnormal duration deviant induced changes in frontotemporal connectivity network compared to controls. Collectively these findings suggest that neither the peak amplitude nor the measures of effective connectivity underlying the MMNm response are related to the CHR state. Lastly, chapter 5 indicates that baseline MMNm amplitude is not associated with progression to a first episode psychosis, although this finding needs to be considered limited due to the low transition rate to psychosis, or persistence of subthreshold psychotic symptoms and poor functioning in CHR individuals. Overall, the findings in the thesis do not support the utility of using MMNm as a marker for emerging psychosis. However, future longitudinal studies with several MEG recording time points are required to further determine the timing of MMN deficiency and whether it reflects emerging psychosis or illness progression. The clinical findings of the thesis demonstrate that CHR individuals recruited from the general population are characterised by several clinical concerns and despite the majority of them not developing psychosis and remitting symptomatically over 12 months, CHR individuals were characterised by persistent functional disability, highlighting the importance of evaluating and predicting more systematically psychosocial functioning in this clinically meaningful population. Finally, I discuss the key neurophysiological and clinical findings of the three data chapters in chapter 6 in the context of previous findings as well as the limitations and strengths of the current thesis. I also discuss the possibility and key challenges of implementing electrophysiological measures as part of a multivariate and sequential testing in clinical practice as well as proposals for moving beyond the current UHR paradigm.