Insula functional connectivity in schizophrenia

Abstract

The insula is structurally abnormal in schizophrenia, demonstrating reductions in volume, cortical thickness, and altered gyrification during prodromal, early and chronic stages of the illness. Despite compelling structural alterations, less is known about its functional connectivity, limited by studies considering the insula as a whole or only within the context of resting-state networks. There is evidence, however, from healthy subjects that the insula is comprised of sub-regions with distinct functional profiles, with dorsal anterior insula (dAI) involved in cognitive processing, ventral anterior insula (vAI) involved in affective processing, and posterior insula (PI) involved in somatosensory processing. The current study builds on this prior work and characterizes insula resting-state functional connectivity sub-region profiles in a large cohort of schizophrenia (N = 191) and healthy (N = 196) participants and hypothesizes specific associations between insula sub-region connectivity abnormalities and clinical characteristics related to their functional profiles. Functional dysconnectivity of the insula in schizophrenia is broadly characterized by reduced connectivity within insula sub-networks and greater connectivity with regions not normally connected with that sub-region, reflected in significantly greater similarity of dAI and PI connectivity profiles and significantly lower similarity of dAI and vAI connectivity profiles (p < .05). In schizophrenia, reduced connectivity of dAI correlates with cognitive function (r = 0.18, p = .014), whereas stronger connectivity between vAI and superior temporal sulcus correlates with negative symptoms (r = 0.27, p < .001). These findings reveal altered insula connectivity in all three sub-regions and converge with recent evidence of reduced differentiation of insula connectivity in schizophrenia, implicating functional dysconnectivity of the insula in cognitive and clinical symptoms.

Introduction

Abnormal structure of the insula is one of the most robust anatomical findings in schizophrenia. Meta-analyses have concluded that grey matter volume is reduced in bilateral insula and that smaller insula volume, while present in other mental illnesses, is most pronounced in psychotic disorders (Goodkind et al., 2015; Shepherd et al., 2012). Insula volume alterations are seen across the disease course (Ellison-Wright et al., 2008), demonstrating reductions in first-episode patients within the first few years of illness (Lee et al., 2016) with even more robust, progressive reductions during the chronic state (Chan et al., 2011). Neurobiological alterations of the insula may even represent a useful early marker of schizophrenia-risk, as smaller initial bilateral insula volume is seen in ultra-high risk patients who transition to psychosis, as compared to ultra-high risk patients who do not transition (Takahashi et al., 2009). Furthermore, structural abnormalities of the insula are associated with psychotic experiences (Krishnadas et al., 2014; Palaniyappan et al., 2011) and smaller insula volume at first episode predicts clinical course of positive and disorganized symptoms (M. Li et al., 2019). Combined, these findings implicate insula cortex integrity in the pathophysiology of schizophrenia.

Considerably less is known about functional abnormalities of the insula in schizophrenia. This critical knowledge gap is likely due to the fact that the insula is involved in a diverse range of functions (Wylie and Tregellas, 2010), including cognition (e.g. cognitive control, error processing), social and emotion processing (e.g. disgust), interoception, and pain (Craig, 2009; Namkung et al., 2017; Uddin, 2015). The functional diversity of the insula is reflected in its heterogeneous structure and connectivity. At the level of cytoarchitecture, there are at least three sub-divisions of the insula, including a dysgranular dorsal anterior region (dAI), an agranular ventral anterior region (vAI), and a granular posterior region (PI) (Mesulam and Mufson, 1982). Identification and specificity of these sub-regions in humans has been confirmed through convergent analysis of task-based activations and connectivity assessed with functional neuroimaging (Deen et al., 2011; Nelson et al., 2010). Meta-analysis of functional co-activation during performance of various tasks has revealed preferential involvement of the dAI in cognition, the vAI in affective processing, and the PI in somatosensory processes (Uddin et al. Moran et al., 2013). The different functional roles of insula sub-regions are recapitulated by their dissociable functional connectivity profiles (i.e. the regions with which they are reliably most strongly inter-connected). The dAI is functionally connected to regions associated with higher-level cognition, including the dorsal anterior cingulate cortex (dACC), prefrontal cortex, frontal eye fields and intraparietal sulcus (Deen et al., 2011). Consistent with its role in emotion, the vAI exhibits robust functional connectivity with other emotion-related brain areas, including the pregenual anterior cingulate, inferior frontal gyrus, portions of the superior temporal sulcus (Deen et al., 2011), and the amygdala (Mutschler et al., 2009). Similarly, the PI, which is involved in sensorimotor processing, is connected to primary and secondary somatosensory and motor cortices (Deen et al., 2011). The insula is also highly interconnected with itself, underscoring its role in integrating cognitive, emotion, and sensorimotor information (Deen et al., 2011; Uddin et al., 2013).

Studying the functional connectivity of insula sub-regions in schizophrenia may expand our understanding of the pathophysiology of the disorder and inform the neural substrate of clinical phenotypes (Wylie and Tregellas, 2010). However, the majority of studies looking at the insula in schizophrenia investigated either connectivity of the whole insula (Pang et al., 2017) or within the context of broader cortical resting-state networks that include the insula, such as the salience, cingulo-opercular, and somatosensory networks (Huang et al., 2019; Sheffield et al., 2015). Directed connectivity of the anterior insula (a hub of the salience network) to nodes within the default mode network (DMN) and central executive network is reduced in schizophrenia (Moran et al., 2013; Palaniyappan et al., 2013). Studies investigating connectivity of the insula with the whole brain have observed a range of findings in relatively small samples of schizophrenia participants (N < 50) including: reduced connectivity of the whole insula with the ACC, caudate, and Heschl's gyrus (Pang et al., 2017), increased connectivity between right PI and thalamus (Chen et al., 2016), and reduced connectivity of the vAI with regions of the DMN (Moran et al., 2013). Recent analysis also revealed reduced differentiation of insula connectivity sub-networks for anterior and posterior regions (Tian et al., 2019). Together, these studies indicate insula functional connectivity alterations in schizophrenia that have yet to be fully characterized in a large sample of patients.

The current study leverages a large resting-state fMRI dataset to characterize functional connectivity of insula sub-regions in schizophrenia and test specific a-priori hypotheses about the associations between dysconnectivity of specific insula sub-regions and clinical phenotypes. Given the dAI's well-defined role in higher-order cognition (Dosenbach et al., 2006; Moran et al., 2013), we hypothesized that dAI connectivity would be reduced in schizophrenia and associated with impaired general cognitive ability. The vAI is implicated in emotion processing (Simmons et al., 2013), a core feature of social cognition believed to underlie negative symptoms (Kohler et al., 2000; Martin et al., 2005). Therefore, we hypothesized that reduced vAI connectivity with affective regions would contribute to negative symptom severity. Finally, the PI plays a critical role in interoception, perception, and sensorimotor integration (Craig, 2009; Cauda et al., 2012), aspects of the human experience that are altered in psychosis. Greater interoceptive awareness in schizophrenia has been associated with more severe psychosis (Ardizzi et al., 2016) and a region in the insula that was activated during a symptom-capture study of auditory hallucinations was hyper-connected to the cerebellum and angular gyrus when compared to controls (Mallikarjun et al., 2018). We therefore hypothesized that stronger connectivity of the PI would be associated with more severe positive symptoms.