Schizophrenia is a common and disabling neuropsychiatric disorder associated with cognitive dysfunction. The latest in vivo data suggests patients with schizophrenia have lower synaptic terminal levels in the frontal cortex and in the anterior cingulate cortex, as well as in other brain regions. Functional magnetic resonance imaging (fMRI) studies of cognitive function show that aberrant activation of these and other regions is associated with cognitive dysfunction, both during cognitive tasks and at rest in people with schizophrenia. Given that fMRI signal has been shown to have a synaptic origin, this thesis focussed on testing a set of hypotheses around the potential link between synaptic terminal levels, measured by [11C]UCB-J positron emission tomography (PET), and brain function during cognitive tasks and at rest, measured by fMRI in patients with schizophrenia and controls. I additionally tested whether [11C]UCB-J distribution volume ratio (DVRCS), which measures synaptic vesicle protein 2A (SV2A) levels, was associated with task performance during task switching and during a working memory N-Back task.

The main contributions of this thesis to the field are that aberrant brain function in schizophrenia at rest, during working memory and during task switching is not associated with interindividual differences in SV2A levels/synaptic density in controls or in patients with schizophrenia. In healthy controls, I found that working memory performance is associated with SV2A levels/synaptic density in a working memory specific prefrontal cortex region, but not with the magnitude of activation of this region under working memory load. In addition, in healthy controls switch cost is associated with SV2A/synaptic density in the parietal cortex, but not with brain activity during task switching. Importantly, neither relationship between cognitive function and SV2A levels was seen in patients with schizophrenia. Possible explanations for this may be that despite having comparable SV2A levels, patients with schizophrenia have different types of synapses contributing to total synaptic density, excitatory-inhibitory imbalance, or other factors that disrupt this relationship. At rest, associations between amplitude of low frequency fluctuations and SV2A levels were significantly different between patients with schizophrenia and control subjects, further supporting that schizophrenia may be associated with synaptic changes that are not captured by a general measure of synaptic density.