Hemispheric divergence of interoceptive processing across psychiatric disorders
- Laureate Institute for Brain Research, United States
- Department of Biological Sciences, University of Tulsa, United States
- Laboratory of Brain and Cognition, National Institute of Mental Health, United States
- Laboratory for Autonomic Neuroscience, Imaging, and Cognition (LANIC), Department of Psychosomatic Medicine and Psychotherapy, Jena University Hospital, Germany
- Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California at Los Angeles, United States
Figures
Figure 1
Experimental design.
During a single functional neuroimaging scanning session two neuroimaging tasks were used to localize the convergence between bottom-up and top-down interoceptive processing. The isoproterenol infusion (ISO) task manipulated interoceptive input in a bottom-up manner, while the visceral interoceptive attention (VIA) task manipulated interoceptive attention in a top-down manner. During the ISO task, participants were asked to attend to their cardiorespiratory sensations while receiving double-blinded infusions of either isoproterenol 2.0 micrograms (mcg, solid line) or 0.5 mcg (not pictured), a rapidly acting peripheral beta-adrenergic agonist eliciting transiently increased cardiovascular and respiratory signals in a manner akin to adrenaline, or infusions of saline (dashed line), resulting in no physiological change. During the VIA task, on-screen cues directed participants to shift their attention towards naturally occurring body sensations from a particular internal organ (heart, lungs, or stomach, the interoceptive attention conditions) or the word ‘TARGET’ (the exteroceptive attention condition) that would flash at different intensities. No infusions were given during this task, so the body remained at physiological rest. Both tasks were preceded and followed by a resting state scan.
Figure 2
Convergence between bottom-up and top-down interoceptive processing in healthy comparisons (HC, top row) and individuals with anxiety, depression, and/or eating disorders (ADE, bottom row).
Each convergence map reflects the only cluster of voxels that were co-activated across the whole brain during the isoproterenol nfusion infusion (ISO) task, involving perturbation of cardiorespiratory signals, and the visceral interoceptive attention (VIA) task, involving goal-directed interoceptive attention towards cardiac and respiratory signals at rest. Numbers on the left and right reflect the Dice similarity coefficient, which is used to quantify the degree of spatial overlap between groups. Relative to HCs, the ADE group showed lower spatial similarity for the left insular cortex (Dice coefficient of 0.58), than the right insular cortex (Dice coefficient of 0.78).
Figure 3
Hemispheric divergence of bottom-up and top-down interoceptive processing across psychiatric disorders.
(A) Hemisphere-specific convergence maps (white outlines) overlaid on a tripartite probabilistic cytoarchitectonic division of the insular cortex. (B) Quantification of convergence within each cytoarchitectonic subregion (i.e. number of co-activated voxels in relation to the total number of voxels within that subregion), showing asymmetric proportional voxel co-activation in the left and right dysgranular insula between the groups. *indicates significant group difference for the proportion of co-activated voxels in each subregion via chi-square test. HC: healthy comparison. ADE: anxiety, depression, and/or eating disorders.
Figure 4
Hemispheric differences in the activation magnitude of the convergent dysgranular insula subregion.
(A) Co-activated voxels within the right dysgranular insula subregion exhibited a greater degree of percent signal change during the Peak period of the 2.0 mcg dose in the isoproterenol infusion (ISO) task (left sub-panel) and during the Heart and Lung attention condition in the visceral interoceptive attention (VIA) task (right sub-panel). As there were no main effects of group, the mean percent signal change is collapsed across groups. *indicates p<0.05 for the left versus right post-hoc contrast, following a main effect of the hemisphere in the linear mixed-effects regression. (B) Across both groups, the mean percent signal change within the right but not left convergent dysgranular insula subregion was correlated with real-time cardiorespiratory intensity ratings during the Peak period of the 2.0 mcg dose in the ISO task. *indicates p<0.05 for the Pearson’s R correlation coefficient, separately for each hemisphere.
Figure 5
Changes in whole-brain functional connectivity of convergent dysgranular insula subregions following the performance of the interoceptive tasks.
(A) Functional connectivity between the right convergent dysgranular insula subregion and the left middle frontal gyrus showed opposing effects in the anxiety, depression, and/or eating disorders (ADE) versus healthy comparisons (HC) groups. (B) While functional connectivity between these regions increased from baseline following interoception in the ADE group, it decreased in the HC group, resulting in a significant interaction effect. (C) Across the entire sample changes in functional connectivity were associated with trait measures of anxiety and depression. When examined in each group individually, associations between connectivity change and trait anxiety occurred in opposite directions (left and middle panel).
Figure 6
Divergence of top-down processing during interoceptive uncertainty in individuals with anxiety, depression, and/or eating disorders (ADE) and healthy comparisons (HC).
(A) Selective activation of the bilateral agranular anterior insula during the Anticipation period (top) and Saline Peak period (bottom) of the isoproterenol (ISO) task. Both epochs demarcate periods of maximal expectancy about future changes in body state while the body remains at physiological rest (i.e. no ensuring evidence of heart rate or breathing rate increases). These brain areas showed activity only during these periods of the ISO task and were not active during the Heart and Lung attention part of the visceral interoceptive attention (VIA) task, indicating they have specialized roles. (B) Quantifying the spatial extent of this agranular activation (i.e. number of active voxels in relation to total number of voxels in that subregion) revealed that greater right hemisphere activation during the anticipation window occurred for both groups, and more so in the HC than the ADE group. During the peak period of Saline, this activation covered more of the bilateral agranular insula in both groups. However, the right hemisphere was activated more than the left in both groups, and the HC group exhibited more active voxels in the right hemisphere than the left, and more than the ADE group in both hemispheres, while the ADE group showed no hemispheric difference during this window. (C) Increased ISO-specific activation of agranular insular during the anticipation period versus the saline peak period. This pattern, occurring for both hemispheres and across both groups, was greater in the right than the left hemisphere.
Figure 7
Time courses of heart rate (A) and continuous dial ratings (B) during the 2.0 mcg (solid lines) and Saline (dotted lines) doses of the isoproterenol (ISO) task.
Heart rate changes observed during both infusions were generally similar between both groups across the majority of the infusion period. The cluster-based permutation analysis showed a 2 s instance of significantly higher heart rate in the anxiety, depression, and/or eating disorders (ADE) group starting at the 98th second of the 2.0 mcg dose only during the Peak period, followed by a prolonged increase in dial rating for large portions of the Peak and Recovery periods (110 s through 142 s, shown via the shaded area). No heart rate differences were observed during the Saline infusion. *indicates p<0.05 for significant group differences using permutation analysis. (C) Retrospective ratings on the ISO task showed no significant group differences in cardiac or respiratory intensity or excitement following saline or the 2.0 mcg infusion, while the ADE group reported increased anxiety following both infusions. (D) Sensation ratings during the visceral interoceptive attention (VIA) task. The ADE group reported higher cardiac intensity ratings than the healthy comparison (HC) group but lower exteroceptive ratings, with no group difference in respiratory or gastric sensation ratings. *indicates p<0.05 for a two-sample t-test between groups, separately for each condition. Where appropriate, both the p-value and Cohen’s d are shown.
Author response image 1
(A) Interoceptive accuracy during 2.0mcg isoproterenol perturbation, as measured by the maximum (left panel) and zero-lag (right panel) cross-correlation between the time series of heart rate and perceptual dial rating. There were no differences between groups. (B) There were no associations between interoceptive accuracy ratings and signal intensity within the convergence dysgranular insula during the Peak period of 2.0mcg perturbation.
Author response image 2
(A) Post-trial ratings during the Visceral Interoceptive attention task, for reference. This is also shown in Figure 7D. (B) The same post-trial ratings in (A), but with the ADE group separated by primary diagnoses. Importantly, although assigned to one diagnostic category on the basis of most prominent symptom expression, most patients had one or more comorbidities across disorders. GAD = Generalized Anxiety Disorder. MDD = major depressive disorder. AN = anorexia nervosa. HC = healthy comparison.
Tables
Table 1
Demographic information for the transdiagnostic anxiety, depression, and/or eating disorders (ADE) group and the propensity-matched healthy comparison (HC) group.
GAD=generalized anxiety disorder, MDD=major depressive disorder, AN=anorexia nervosa, PTSD=post-traumatic stress disorder, OCD=obsessive-compulsive disorder, SUD=substance use disorder, BMI=body mass index, STAI=State-Trait Anxiety Inventory, ASI=Anxiety Sensitivity Index, with a Total Score, and Physical, Cognitive, and Social subscales, PHQ-9=depression module of the Patient Health Questionnaire, SCOFF=‘Sick, Control, One, Fat, Food’ eating disorder questionnaire.
| HC (n=46) | ADE (n=46) | t | df | p-value | |
|---|---|---|---|---|---|
| Sex | 41 Female | 45 Female | - | - | - |
| 5 Male | 1 Male | ||||
| Age | 24 (5) | 25 (7) | 0.57 | 80.49 | 0.57 |
| BMI | 23.48 (3.26) | 23.34 (3.33) | –0.20 | 89.97 | 0.84 |
| STAI | 30.0 (1.1) | 56.0 (1.4) | –14.43 | 83.01 | <0.0001 |
| ASI-Total | 7.39 (5.26) | 13.98 (8.89) | 8.89 | 57.47 | <0.0001 |
| ASI-Physical | 1.15 (1.59) | 5.19 (5.81) | 5.81 | 53.38 | <0.0001 |
| ASI-Cognitive | 0.98 (1.47) | 7.41 (6.53) | 6.52 | 49.54 | <0.0001 |
| ASI-Social | 5.26 (4.04) | 13.83 (6.08) | 7.96 | 78.28 | <0.0001 |
| PHQ-9 | 0.78 (1.11) | 10.39 (5.98) | 10.72 | 48.12 | <0.0001 |
| SCOFF | 0 (0) | 1.09 (1.23) | 6.01 | 45 | <0.0001 |
| Diagnoses | No psychiatric disorders | 67% GAD | - | - | - |
| 72% MDD (current or remitted) | |||||
| 35% AN | |||||
| 13% Social anxiety disorder | |||||
| 11% PTSD | |||||
| 4% OCD | |||||
| 4% SUD | |||||
| Medication use | None | Taking one or more psychiatric medication: | - | - | - |
| Serotonergic*: 35% | |||||
| Histaminergic†: 11% | |||||
| Dopaminergic‡: 7% | |||||
| SNRI§: 7% | |||||
| Benzodiazepene¶: 4% | |||||
| Miscellaneous**: 2% | |||||
| Beta-blocker††: 2% |
-
*
Escitalopram, Fluoxetine, Trazodone, Sertraline, Paroxetine, Duloxetine.
-
†
Lamotrigine, Hydroxyzine, Doxepin.
-
‡
Olanzapine, Aripiprazole, Quetiapine.
-
§
Atomoxetine, Buproprion, Desvenlafaxine.
-
¶
Clonazepam, Alprazolam.
-
**
Vortioxetine.
-
††
Propranolol (as needed usage).
Table 2
Insular regions demonstrate convergent processing between top-down and bottom-up interoception.
| MNI coordinates (center of mass) | Volume (mm3) | |||
|---|---|---|---|---|
| X | Y | Z | ||
| Left Insula: ADE | –39 | –0.1 | –8.2 | 1736 (217 voxels) |
| Left Insula: HC | –40 | –1.3 | –4.8 | 1240 (155 voxels) |
| Right Insula: ADE | 39 | 2.3 | –12.9 | 1088 (136 voxels) |
| Right Insula: HC | 39.9 | 2.2 | –10.3 | 1960 (245 voxels) |
Table 3
Agranular anterior insular regions demonstrate divergent processing during periods of increased bodily expectancies.
| MNI coordinates (center of mass) | Volume (mm3) | ||||
|---|---|---|---|---|---|
| X | Y | Z | |||
| Anticipation | Left: ADE | –31.6 | 17.9 | 4.8 | 1168 (146 voxels) |
| –31.9 | 9.2 | 344 (43 voxels) | |||
| Left: HC | –31.5 | 15.2 | –1.2 | 1688 (211 voxels) | |
| Right: ADE | 35.4 | 19.1 | 1.4 | 1648 (206 voxels) | |
| Right: HC | 37 | 13 | –9 | 1744 (218 voxels) | |
| 35 | 7 | –19 | 368 (46 voxels) | ||
| Saline (Peak) | Left: ADE | –33.1 | 16.7 | –1.6 | 2264 (283 voxels) |
| Left: HC | –33.2 | 15.7 | –2.7 | 2760 (345 voxels) | |
| Right: ADE | 35.4 | 18.6 | –0.9 | 2120 (265 voxels) | |
| Right: HC | 34.3 | 16.7 | –4.7 | 3024 (378 voxels) | |
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Hemispheric divergence of interoceptive processing across psychiatric disorders
eLife 13:RP92820.
https://doi.org/10.7554/eLife.92820.3
