Title: Large-scale Functional Connectivity in the Human Brain Reveals Fundamental Mechanisms of Cognitive, Sensory and Emotion Processing in Health and Psychiatric Disorders
Description: Functional connectivity networks that integrate remote areas of the brain as working functional units are thought to underlie fundamental mechanisms of perception and cognition, and have emerged as an active area of investigation. However, traditional approaches of measuring functional connectivity are limited in that they rely on a priori specification of one or a few brain regions. Therefore, the development of data-driven and exploratory approaches that assess functional connectivity on a large-scale are required in order to further understand the functional network organization of these processes in both health and disease. In this thesis project, I investigate the roles of functional connectivity in visual search (Chapter 2, (Pantazatos, Yanagihara et al., 2012)) and bistable perception (Chapter 3, (Karten et al., 2013)) using traditional functional connectivity approaches, and develop and apply new approaches to characterize the large-scale networks underlying the processing of supraliminal (Chapter 4, (Pantazatos et al., 2012a)) and subliminal (Chapter 5, (Pantazatos, Talati et al., 2012b)) emotional threat signals, speech and song processing in autism (Chapter 6, (Lai et al., 2012)), and face processing in social anxiety disorder (Chapter 7, (Pantazatos et al., 2013)).

Finally, I complement the latter study with an investigation of structural morphological abnormalities in social anxiety disorder (Chapter 8, (Talati et al., 2013)). Each of these chapters has been or is about to be published in peer reviewed journals and this thesis provides an overview of the entire body of investigation, based on advances in understanding the role of large-scale neural processes as fundamental organizational units that underlie behavior. In Chapter 2, Independent Components Analysis (ICA), Psychophysiological Interactions (PPI) and Dynamic Causal Modeling (DCM) analyses were used to investigate the hypothesis that expectation and attention-related interactions between ventral and medial prefrontal cortex and association visual cortex underlie visual search for an object. Results extend previous models of visual search processes to include specific frontal-occipital neuronal interactions during a natural and complex search task. In Chapter 3, PPI analyses revealed percept-dependent changes in connectivity between visual cortex, frontoparietal attention and default mode networks during bistable image perception.

These findings advance neural models of bistable perception by implicating the default mode and frontoparietal networks during image segmentation. In Chapters 4 and 5, an exploratory approach based on multivariate pattern analysis of large-scale, condition-dependent functional connectivity was developed and applied in order to further understand the neural mechanisms of threat-related emotion processing. This approach was successful in extracting sufficient information to "brain-read" both unattended supraliminal (Chapter 4) and subliminal (Chapter 5) fear perception in healthy subjects. Informative features for supraliminal fear perception included functional connections between thalamus and superior temporal gyrus, angular gyrus and hippocampus, and fusiform and amygdala, while informative features for subliminal fear perception included middle temporal gyrus, cerebellum and angular gyrus. In psychiatric disorders, large-scale functional connectivity is typically assessed during resting-state (i.e. no task or stimulus).

However, disorder-dependent alterations in functional network architecture may be more or less prominent during a stimulus or task that is behaviorally relevant to the disorder, as is exemplified by enhanced long-range, frontal-posterior connectivity during song (vs. speech) perception in autism (Chapter 6). In the case of social anxiety disorder (SAD), pattern analysis of large-scale, functional connectivity during neutral face perception was sensitive enough to discriminate individual subjects with SAD from both healthy controls and panic disorder (Chapter 7). The most informative feature was functional connectivity between left hippocampus and left temporal pole, which was reduced in medication-free SAD subjects, and which increased following 8-weeks SSRI treatment, with greater increases correlating with greater decreases in symptom severity. This finding parallels results from observed neuroanatomical abnormalities in SAD, which include reduced grey matter volume in the temporal pole, in addition to increased grey matter volume in cerebellum and fusiform (Chapter 8).

The above findings suggest promise for emerging functional connectivity and structural-based neurobiomarkers for SAD diagnosis and treatment effects.