The Brain-basis of Large-scale Learning Processes in Schizophrenia

Learning impairments are common in schizophrenia and relate to functional outcome. This thesis explored the brain-basis of learning in schizophrenia in spatial and temporal domains as it unfolded across two fMRI sessions. During fMRI scanning, healthy controls and participants with schizophrenia completed a lexicon-learning task and a comparative reaction-time task. Using multivariate analytic approaches, the thesis used three vantage points on the fMRI-BOLD signal to characterize the brain-learning relationships. Using reaction-time tasks bookending the learning tasks on both scanning days, Study 1 examined task-independent linear changes in the BOLD signal that could potentially interfere with accurate interpretation in fMRI learning studies. It showed that these effects are stronger in schizophrenia in brain areas associated with cognitive control, default mode networks, perceptual and semantic processing. Results suggested that some of the ‘hyperactivation’ attributed to learning processes in the practice-related literature is better attributed to task-independent effects associated with impaired modulation of the BOLD signal during task switching. Study 2 used a brain-behaviour analysis to examine BOLD activity related to learning-success. With practice, controls shifted between early and late learning processes with a switch between early frontotemporal engagement to later subcortically-focused engagement. Persons with schizophrenia failed to show this same pattern; they were differentiated by level of engagement with perceptual processing regions and an overall suggestion of prolonged, early-learning brain processes. Whole-brain functional connectivity patterns related to learning accuracy showed between-groups similarities, differences and a group-by-time interaction in study 3. While again the controls showed two patterns capturing early and late learning, the pattern for the schizophrenia group spanned both days and did not vary with learning stage. Strong differences in schizophrenia included over-connected intra-cerebellar regions, under-connected frontal-cerebellar regions, over-connected sensorimotor-thalamus connection and under-connected prefrontal-thalamus regions. These patterns mirror many resting-state findings in the extant literature, but here we showed how this dysconnectivity pattern impacted directly on learning performance. Together, these three studies showed how learning in schizophrenia is associated with different large-scale interactions that emerge in different spatial and temporal brain-behaviour distributions. The thesis showed how an overall pattern of brain inflexibility underlies learning challenges in schizophrenia.Ph.D