Insula functional connectivity in schizophrenia
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.
Section snippets
Participants
210 healthy individuals and 234 people with a schizophrenia spectrum disorder (i.e. schizophrenia, schizophreniform disorder, or schizoaffective disorder- hereafter referred to as “schizophrenia”) participated in one of three MRI studies (CT00762866; 1R01MH070560; 1R01MH102266) conducted in the Department of Psychiatry and Behavioral Sciences at Vanderbilt University Medical Center (VUMC) (include/exclusion criteria described in Supplement). Schizophrenia participants were recruited from the
Functional connectivity of insula sub-regions
Insula sub-regions demonstrated relatively distinct patterns of connectivity that were qualitatively similar in healthy controls and schizophrenia, and highly consistent with prior studies of insula connectivity (e.g. (Deen et al., 2011); Fig. 1). Briefly, dAI was connected with fronto-parietal regions, dACC, and temporal sulcus. Connectivity with vAI was seen in ventral ACC, inferior parietal lobe, and inferior temporal sulcus. The PI was largely connected with primary sensory and motor
Discussion
In contrast to well-documented structural abnormalities of the insula, comparatively little is known about functional connectivity disturbances of the insula in schizophrenia. This is especially true for insula sub-regions, including dAI, vAI, and PI divisions, which demonstrate distinct connectivity profiles in keeping with their divergent functional roles. To address this knowledge gap, we analyzed functional connectivity of insula sub-regions in a relatively large cohort of people with
Funding source
This work was supported by NIMH grants R01 MH102266 (awarded to NDW) and R01 MH070560 (awarded to SH), the Charlotte and Donald Test Fund, the Jack Martin, MD Research Professorship in Psychopharmacology (awarded to JUB), the Vanderbilt Psychiatric Genotype/Phenotype Project, and the Vanderbilt Institute for Clinical and Translational Research (through grant 1-UL-1-TR000445 from the National Center for Research Resources/NIH). JUB was partially supported by a Merit award (No. CX001226). This
Contributors
Julia Sheffield led the development of the research questions, performed data analysis and wrote the initial draft. Neil Woodward contributed to the development of research questions, provided consultation throughout the project, and edited the initial draft. Neil Woodward and Baxter Rogers led the development of methods and statistical design. Baxter Rogers performed data processing and wrote sections of the Methods section. Jennifer Blackford and Stephan Heckers contributed to development of
Declaration of competing interest
The authors declare no conflicts of interest.
Acknowledgement
The authors wish to acknowledge the contributions of the members of the Psychiatric Neuroimaging Program in the Vanderbilt University Medical Center Department of Psychiatry & Behavioral Sciences, who collected the data used in this study.
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