Ayna Baladi Nejad, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, Copenhagen University

Assessment by:

Kerstin von Plessen, Prof, MD, Copenhagen University, Denmark

Nick Ramsey, Prof, PhD, University Medical Center Utrecht, The Netherlands

Siegfried Kasper, Prof, MD, Medical University of Vienna, Austria

Thesis work has been supervised by:

Hartwig R. Siebner, Prof, DMSc, Danish Research Centre of Magnetic Resonance, Hvidovre Hospital

William F.C. Baaré, PhD, Danish Research Centre of Magnetic Resonance; Hvidovre Hospital

Birte Y. Glenthøj, Prof, DMSc, Center for Neuropsychiatric Schizophrenia Research & Lundbeck Foundation Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Glostrup Hospital

Abstract

Working memory dysfunction is one of the most consistently found cognitive deficits in schizophrenia. Studies employing functional neuroimaging techniques have shown that these working memory deficits are associated with abnormal brain activity patterns. The relationship between working memory-related brain activity and effects of antipsychotic treatment have been inadequately investigated and teased apart. This PhD thesis compiles two studies which follow a cohort of initially antipsychotic-naïve patients with first-episode schizophrenia who received seven months of treatment with quetiapine (a second-generation antipsychotic). These patients were clinically assessed and functionally MRI scanned while performing a verbal working memory task at baseline and seven-month follow-up. A group of healthy control subjects were also followed up during the same time interval.  

In Study 1, I tested the hypothesis that the inability to suppress activity in task-irrelevant brain regions is a primary feature of schizophrenia that is already expressed at disease onset prior to initiation of antipsychotic medication. Patients were found impaired in deactivating large bilateral clusters centred on the superior temporal gyrus. Interestingly, most of these brain regions were increasing activation in the 0-back condition relative to resting baseline suggesting that these regions were responding to the experimental verbal stimuli. In healthy control subjects, these regions deactivated with working memory load. Consequently, we interpreted the patients’ persistent activation of these regions in the low (1-back) and high (2-back) working memory load conditions to point to an inability to shift away from a verbal strategy with the onset of working memory demands. In contrast to previous studies, attenuated task-induced deactivations in the default mode network were not found in the current cohort of antipsychotic-naïve patients. This could be due to the high performance of the patients as well as their drug-free state which are two things that have confounded previous studies that find default mode network dysfunction during working memory.

In Study 2, I employed multivariate pattern classification to assess whether the functional connectivity of networks involved in working memory at baseline were predictive of patients’ clinical improvement at seven months follow-up. Specifically, I focused on negative symptoms (e.g. alogia and anhedonia) since these symptoms share many characteristics (e.g. time course, severity, and associated brain regions) with the cognitive deficits found in schizophrenia. Our findings indicate that functional connectivity of frontoparietal, working memory networks differentiated patients who improved in negative symptoms at follow-up from those who did not. These findings are promising for the stratification of schizophrenia patients and the possible personalisation of their treatment.

In conclusion, functional working memory networks seem to exhibit a primary dysfunction in schizophrenia and contain predictive information for improvement in clinical symptoms that are important for the functional outcome of patients. Overall, this work has contributed to the understanding of primary brain activity dysfunction from those mediated by drug effects, as well as opened avenues for further research into the personalisation of treatment in schizophrenia.