CHAPTER 3
Insular connectivity in autistic and non-autistic development
interoception, emotional awareness, and mental health (Trevisan et al., 2019), including for individuals on the autism spectrum. Thus, considering the development of interoceptive brain systems in autistic and non-autistic individuals may be especially important to un- derstand the mixed interoceptive challenges reported by autistic individuals (DuBois et al., 2016; Failla et al., 2020; Fiene and Brownlow, 2015; Garfinkel et al., 2016; Palser et al., 2018; Quadt et al., 2021; Trevisan et al., 2021b; Williams et al., 2022).
The development of different aspects of interoception may be revealed by examining the specialized subregions along the insular cortex that coordinate to process, predict, and contextualize bodily sensations (Craig, 2008; Farb et al., 2013). Cytoarchitectural analysis of insular cortex reveals eight distinct subregions as divided by number of cortical lay- ers (granularity) and location relative to the long, short, and accessory insular gyri (Craig, 2008; Farb et al., 2013). These are commonly grouped into three major subdivisions that each map to a broader function: the posterior, middle, and anterior insula (Figure 1). The posterior insula receives inputs from subcortical regions about bodily sensations and these cell circuits involve the greatest number of cortical layers (dorsal and ventral granular in the 8-division model), which allows this area to process detailed information about bodily signals. The middle insula has a medium number of cortical layers (“dysgranular”) and re- ceives diverse multimodal sensory inputs which may then be associated with interoceptive cues. Ultimately, information that reaches the anterior insula reflects an abstracted “gist”
of bodily state as interpreted within the current environmental context and is processed at the broadest level of cell circuitry, reflected in its agranular (i.e., least layered) structure (Barrett and Simmons, 2015; Kleckner et al., 2017).
There also may be interesting patterns to consider based on laterality of interoceptive system development. Typically, the laterality of external sensory systems reflects the side of the body from which sensory information originates. However, interoceptive signals tend to originate from common (and often centralized) organs like the heart or lungs, but may be lateralized for distinct purposes. The most prominent model of insular lateraliza-
Figure 3.1: Correspondence of detailed and major subregions of the human insula
Subregions of the human insula are shown for both detailed (8-subregion) and major (posterior, middle, ante- rior) categorizations. The figure legend shows corresponding granularity (granular, dysgranular, or agranular) of each subregion.
tion comes from Craig (2005, 2008, 2002) neuroanatomic work establishing interoceptive pathways that the right insula specializes in sympathetic nervous system control and the left insula specializes in parasympathetic nervous system control. Evidence for this model comes from differential insular activation when stimulating the vagus nerve (Narayanan et al., 2002) and differential autonomic response patterns when stimulating the left ver- sus right insula in neurosurgery patients (Oppenheimer et al., 1992). Thus, differentiating between right and left insula development may inform the relationships between interocep- tion, stress, and anxiety.
Of the three major insular subregions, the anterior insula has been the best studied in autism (Di Martino et al., 2014; Uddin, 2015; Uddin and Menon, 2009). This region has received attention as it is considered part of the salience network for dynamically allocat- ing attention towards environmental stimuli that are deemed most relevant to the bodily self (Uddin and Menon, 2009), consistent with its status as a high-level hub of the inte- roceptive network (Klapwijk et al., 2017). Uddin (2015) reviews prominent differences in anterior insular connectivity in autism, though findings in terms of specific regions of differences have been heterogeneous between samples. Considering development is key to
finding patterns within this heterogeneity (Nomi et al., 2019; Uddin et al., 2013). In gen- eral neurodevelopment, connectivity patterns vary across the lifespan such that the num- ber of functional connections is increasing across childhood but prunes (i.e., selectively decreases) towards specialized communication patterns starting in adolescence and con- tinuing throughout adulthood (Hua and Smith, 2004; Innocenti and Price, 2005; Katz and Shatz, 1996). Nomi et al. (2019) model for anterior insular connectivity in autism is that aggregate findings suggest a shift from hyper- connected in childhood to hypo- connected in adolescence and adulthood. Mechanistically, this would suggest that anterior insular connections are pruned more readily in autism compared to neurotypical development.
These anterior insula findings suggest differences in autistic individuals in how the
“gist” of bodily information is constructed and developed. However, less is known about how communication patterns of primary interoceptive cortex in the posterior insula develop and whether that pattern diverges in autism. Whereas processing in the anterior insula re- flects an abstracted sense of bodily state, processing in the posterior insula reflects internal (bodily) signals that may or may not rise to the level of conscious awareness. Thus, these patterns may reveal insights about the subconscious parts of interoceptive processing that have been difficult to otherwise study. Failla et al. (2017) have found that altered anterior insula connectivity in autism may be related to posterior insular processing, specifically pinpointing differences in the white matter connecting the posterior to anterior insula in autistic compared to non-autistic individuals. As a complement to this structural approach, measuring functional communication patterns of the posterior insula may broaden our un- derstanding of how the insula coordinates with a variety of regions to adaptively tune inte- roceptive awareness.
Studies thus far of posterior insular (PI) functional connectivity in autism have mostly been completed in smaller adolescent samples. Findings included reduced PI connectivity with somatosensory areas in one autistic sample (Ebisch et al., 2011) and with visual, inte- grative, and striatal areas in another (Francis et al., 2019). Xu et al. (2018) analyzed con-
nectivity using an 8 subregion model and did not find significant connectivity differences in either their hypergranular or dorsal granular insula seed regions, which most closely align with the PI seeds used in other studies. Though Francis et al. (2019) combined left and right seeds, Ebisch et al. (2011) found differential pattern strength by insula seed hemisphere.
Though both left and right insula seeds showed reduced connectivity with somatosensory areas, they found that a greater number of somatosensory subregions were hypo-connected to the left posterior insula than to the right. These differences are interesting to consider within models of insular specialization for sympathetic (right) versus parasympathetic (left) specialization (Craig, 2005, 2008, 2002). Potentially, Ebisch et al. (2011) findings suggest that autistic individuals may maintain a greater number of sympathetic processing connec- tions relative to neurotypical individuals, as compared to parasympathetic.
Further, developmental patterns of connectivity differences have only been examined in a limited subset of these studies. These may be especially relevant to consider, given patterns of anterior insula connectivity with age (Nomi et al., 2019; Uddin et al., 2013) and other known developmental changes in surrounding limbic regions (Gabard-Durnam et al., 2014). Francis et al. (2019) found that in all three regions with which the autistic group showed reduced posterior insular connectivity (fusiform, putamen, and intraparietal lobule), connectivity within the autistic group increased with age, narrowing the difference between autistic and neurotypical samples at older ages. This mirrors patterns found in other behavioral (Feldman et al., 2018) and neural (Dunham et al., 2023) studies of multi- sensory processing in autism.
However, before we can understand how posterior insula development diverges in autism, we must better understand its typical development. Thus, in this sample we examine age- related trends in posterior insula connectivity across our autistic and non-autistic samples.
We will also examine dimensional relationships with self-reported body awareness. To be- gin to understand patterns in autism, we will further examine group-based differences in PI connectivity in autistic versus neurotypical individuals, independent of age. Though we
are underpowered to address age-specific group differences in the current sample, these findings will provide important background on how posterior insula connectivity develops across individuals, to compare with autistic development in the future.
3.2 Methods