The Insular Cortex Dynamically Maps Changes in Cardiorespiratory Interoception

Abstract

Palpitations and dyspnea are fundamental to the human experience of panic anxiety, but it remains unclear how the brain dynamically represents changes in these interoceptive sensations. We used isoproterenol, a rapidly acting peripheral beta-adrenergic agonist similar to adrenaline, to induce sensations of palpitation and dyspnea in healthy individuals (n=23) during arterial spin labeling functional magnetic resonance imaging (fMRI). We hypothesized that the right mid-insular cortex, a central recipient of viscerosensory input, would preferentially respond during the peak period of cardiorespiratory stimulation. Bolus infusions of saline and isoproterenol (1 or 2 μg) were administered in a blinded manner while participants continuously rated the intensity of their cardiorespiratory sensation using a dial. Isoproterenol elicited dose-dependent increases in cardiorespiratory sensation, with all participants reporting palpitations and dyspnea at the 2 μg dose. Consistent with our hypothesis, the right mid-insula was maximally responsive during the peak period of sympathetic arousal, heart rate increase, and cardiorespiratory sensation. Furthermore, a shift in insula activity occurred during the recovery period, after the heart rate had largely returned to baseline levels, with an expansion of activation into anterior and posterior sectors of the right insula, as well as bilateral regions of the mid-insula. These results confirm the right mid-insula is a key node in the interoceptive network, and inform computational models proposing specific processing roles for insula subregions during homeostatic inference. The combination of isoproterenol and fMRI offers a powerful approach for evaluating insula function, and could be a useful probe for examining interoceptive dysfunction in psychiatric disorders.

Figure 1

(a–c) Group averages of continuous heart rate (red curve) and cardiorespiratory intensity ratings (blue curve) during saline, 1 μg, and 2 μg isoproterenol infusions. (d) Cardiorespiratory detection rates at different doses. (e) Zero-order cross correlation between interoceptive dial rating and heart rate response. Error bars indicate s.e.’s. (f) Maximum cardiorespiratory intensity dial ratings vs heart rate increases during peak period for saline (blue), 1 μg (orange), and 2 μg (dark brown), along with the corresponding R-squares and associated p-values for linear regression. b.p.m., beats per minute; HR, heart rate.

Figure 2

Retrospective ratings of (a) palpitations, (b) dyspnea, (c) negative emotion, and (d) positive emotion experienced at different doses. Error bars show s.e.’s. p-values for one-way ANOVA analysis of dose effect are reported.

Figure 3

Cortical activity during different stages of cardiorespiratory interoceptive processing following 2 μg isoproterenol infusion. (a) A voxelwise whole-brain analysis showed an increase in right mid-insula activity during the peak period relative to the baseline period (shown with the red and blue bars on the left side of the plot). (b) A voxelwise whole-brain analysis showed bilateral increases in insula activity during the recovery period (shown with the purple bar), at multiple subregions, including the right and left mid-insula, the right anterior insula, and the right posterior insula.

Figure 4

Insula activations for the peak and recovery periods displayed against the backdrop of all relevant probabilistic cytoarchitectonic insula subregions (thresholded at 25% probability, as per Fan et al (2016)). (a) During the peak period, the cluster in the right mid-insula spans mostly the dorsal dysgranular insula. (b) During the recovery period, the cluster in the right posterior insula spans mostly the hypergranular insula, the cluster in the right anterior mid-insula spans both the dorsal dysgranular and agranular insula, and the cluster in the left mid-insula spans mostly the dorsal dysgranular insula (see Supplementary Table 2 for a breakdown of the percentage overlap for each cluster with each subregion).

Figure 5

(a) Insula response to peak cardiorespiratory interoceptive stimulation from our prior BOLD fMRI study (top left), the current ASL fMRI study (top middle), and a recent meta-analysis of BOLD fMRI studies assessing attention to the heartbeat under physiological resting conditions (maximum overlap in yellow). In each case, the right mid-insula showed the most response. Reproduced with permission as follows: BOLD fMRI study (Hassanpour et al, 2016); and BOLD fMRI meta-analysis (Schulz, 2016). (b) Comparison between the right mid-insula response to cardiorespiratory interoceptive stimulation in the current ASL fMRI study (bottom left) and a large meta-analysis (n=7381 patients and 8511 matched healthy comparisons) identifying shared patterns of decreased gray matter across different psychiatric diagnoses in the same region, as well as the dorsal anterior cingulate cortex (bottom right), reproduced with permission from Goodkind et al (2015).