Large-scale brain connectivity in schizophrenia in relation to auditory verbal hallucinations and familial liability

The research in this thesis aims to assess functional and structural connectivity in schizophrenia using MRI techniques, and to contribute new evidence to elucidate connectivity abnormalities in schizophrenia in relation to symptomology and familial risk for the disorder.
The results of chapter 2 and 3 show that schizophrenia patients with AVH have increased spontaneous functional connectivity among auditory cortex and associated brain regions, alongside decreased interhemispheric connectivity in these and other brain regions. As these two studies are based on first-episode, medication-naïve patients, our findings likely reflect an integral part of disease pathology, free from confounding factors such as medication and illness progression. Chapter 3 and 4 investigated interhemispheric functional connectivity abnormalities in relation to psychotic symptoms and familial risk for schizophrenia. The results suggest that schizophrenia patients as a group show altered functional connectivity between the two hemispheres, with different areas being implicated in AVH versus non-AVH patients. Moreover, the identified abnormalities seem to be effects of illness manifestation, rather than the expression of familial risk. Chapter 5 examined structural connectivity abnormalities in schizophrenia using the free-water imaging method (Pasternak et al., 2009). The free-water imaging technique was designed to reduce the influence of extracellular free-water in tensor fitting, which is particularly relevant in white matter near the ventricles (Alexander et al., 2001; Pierpaoli and Jones, 2004). Compared to controls, patients showed no significant group-difference of FAt, but exhibited a higher level of FW in three white matter ROIs in the left hemisphere relative to controls and siblings. Siblings did not differ from controls on FW, suggesting that the abnormalities in patients are likely to be disease-related effects rather than a reflection of familial risk for the illness. Global and voxel-wise group-comparisons revealed higher FAt in siblings relative to patients, consistent with a previous study by our group using fiber-based analysis based on a single tensor model in the same dataset (Boos et al., 2013). Moreover, examining the influence of ventricle volume on diffusion measurements, we found that although global FW was positively correlated with ventricle size, correcting for ventricle size in group-comparisons did not change our main results.
Our results show that patients have abnormalities in intrinsic functional connectivity patterns such as hemispheric integration and hemispheric specialization. Moreover, these abnormalities appear to differ in patients with and without AVH symptom, emphasizing that different neural mechanisms may exist in patients with distinct clinical profiles. In terms of structural connectivity, we found that schizophrenia patients show extracellular free-water accumulation in several white matter regions. We did not observe significant connectivity abnormalities in siblings in any of the connectivity measurements examined in this thesis. Taken together, using various neuroimaging techniques, we show abnormalities in both functional and structural cortico-cortical interactions in schizophrenia patients, and our findings suggest that these abnormalities are likely to be part of the biological substrate for behavioral symptoms of the illness, and expressions of disease manifestation rather than familial risk for schizophrenia.