Identifying characteristics of thalamo-cortical changes and their relationship with symptoms in schizophrenia [Utvrđivanje obilježja talamo-kortikalnih promjena i njihovog odnosa sa simptomima u shizofreniji]

Hypothesis of the doctoral thesis was that, using resting-state functional magnetic resonance imaging (fMRI), patients diagnosed with schizophrenia would exhibit stable and specific patterns of thalamic connectivity changes that will show different relationship with specific symptoms of psychotic disorders. The aims of the study were to characterize in a more detailed way changes in thalamo-cortical connectivity (over- and under-connectivity) in a clinical sample compared to healthy controls, by using state-of-the-art resting-state functional resonance and Human Connectome Project protocols, as well as to more specifically determine within-thalamus differences and their relative contribution to described connectivity changes. Finally, the aim was to determine relationship between identified connectivity changes and specific symptoms of the disorder. Subjects for the study were pooled from multiple centers, as part of an existing initiative, Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium, created with a goal of investigating intermediate phenotypes across psychotic disorders. Study procedures and data analyses were done under the approved Yale University project Characterizing Clinical and Pharmacological Neuroimaging Biomarkers. Following identification of subjects that passed stringent quality controls for fMRI data, and matching with the clinical and healthy control populations, study included 436 psychosis probands (167 schizophrenia patients, 119 schizoaffective disorder patients, and 150 patients diagnosed with bipolar disorder with history of psychosis) and 219 matched healthy controls. Whole-thalamus seed-based analyses were used to determine thalamic connectivity changes, followed by parcellation of thalamus using a priori defined functional subnuclei, and data-driven clustering, to define details of the thalamo-cortical dysconnectivity in schizophrenia and psychotic disorders. Both in schizophrenia, and in the wider psychosis spectrum, there was a robust pattern of thalamic over-connectivity with sensory and motor regions, as well as with associative areas tasked with integration of lower-level inputs, and under-connectivity with cerebellar regions. Interestingly, previously reported under-connectivity with prefrontal regions was evident only in dorsal attention functional thalamic subnucleus connectivity map. Nine functional thalamic subnuclei showed relatively different thalamic connectivity changes, ranging from altogether missing effects to wide-spread over- /under-connectivity, but overall followed same general dysconnectivity pattern described for the whole thalamus. Clustering analyses revealed that the data-driven clustering, released from constraints of a priori defined thalamic subnuclei, resulted in solutions that significantly differed from existing functional subnuclei or anatomical divisions, with areas centered on mediodorsal nucleus and ventral lateral areas driving the dysconnectivity effect. In schizophrenia, thalamo-cortical connectivity changes showed relationship with negative symptoms, as well as with excitation and disorganization subscale scores, suggesting that a more pronounced over- or under-connectivity effect predicted more pronounced specific symptoms. Under-connectivity effect of the dorsal attention functional subnucleus (including reduced connectivity with prefrontal cortical regions) also correlated with disorientation. In conclusion, thalamo-cortical dysconnectivity patterns of seemingly correlated over- and under-connectivity effects seems to be robustly present in schizophrenia, but also across the psychosis spectrum. Although the same general pattern exists across different thalamic regions, its extent differs among different thalamic functional subnuclei suggesting that the effect is driven by specific associative functional subnuclei. Finally, although thalamo-cortical connectivity changes might be linked to a more non-specific disease severity or trait indicators, negative symptoms, disorganization, and excitation seem to be connected more directly to those changes than positive symptoms or emotional dysregulation