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Anterior insular cortex plays a critical role in interoceptive attention

  1. Xingchao Wang
  2. Qiong Wu
  3. Laura Egan
  4. Xiaosi Gu
  5. Pinan Liu
  6. Hong Gu
  7. Yihong Yang
  8. Jing Luo
  9. Yanhong Wu  Is a corresponding author
  10. Zhixian Gao  Is a corresponding author
  11. Jin Fan  Is a corresponding author
  1. Beijing Tiantan Hospital, Capital Medical University, China
  2. China National Clinical Research Center for Neurological Diseases, China
  3. Capital Normal University, China
  4. Peking University, China
  5. The City University of New York, United States
  6. Icahn School of Medicine at Mount Sinai, United States
  7. The James J. Peter Veterans Affairs Medical Center, United States
  8. National Institute on Drug Abuse, United States
Research Article
Cite this article as: eLife 2019;8:e42265 doi: 10.7554/eLife.42265
13 figures, 9 tables and 1 additional file

Figures

Figure 1 with 2 supplements
Experimental setup, trial structure of the tasks, and stimulus conditions.

(a) The respiratory effort is converted into electronic signal changes using a respiratory transducer, amplified by BIOPAC, digitized using an A/D converter, and sent to the test computer for the final visual display as a dynamic breath curve, with or without a 400 ms delay. (b) This panel shows two trials for the breath detection task (BDT) and flash dot detection task (DDT) runs, respectively. Each trial begins with a 3 s blank display, followed by a 12 s display of respiratory curve presented with or without a 400 ms delay and with or without a 30 ms red dot flashed at a random position on the curve, and ends with a 3 s response window during which participants make a forced-choice button-press response to two alternative choices depending on the block type (BDT or DDT) to indicate whether the feedback curve is synchronous or delayed (for the BDT run) or whether a dot has appeared (for the DDT run). (c) The task represents a 2 × 2 × 2 factorial design with the factors of attention to breath or dot (block design), presence or absence of breath curve delay, and presence or absence of a dot flashed. The dashed line represents the actual breath curve, while the solid line represents the feedback breath curve displayed on the screen.

https://doi.org/10.7554/eLife.42265.002
Figure 1—figure supplement 1
Raincloud plots visualizing the five-number summary (minimum, lower quartile, median, upper quartile, and maximum) for (a) accuracy, (b) reaction time, (c) d’, and (d) β for the BDT and DDT tasks in the first sample of the fMRI study.
https://doi.org/10.7554/eLife.42265.003
Figure 1—figure supplement 1—source data 1

Behavioral data for the first sample of the fMRI study.

https://doi.org/10.7554/eLife.42265.004
Figure 1—figure supplement 2
Raincloud plots visualizing the five-number summary (minimum, lower quartile, median, upper quartile, and maximum) for (a) accuracy, (b) reaction time, (c) d’, and (d) β for the BDT and DDT tasks in the second sample of the fMRI study.
https://doi.org/10.7554/eLife.42265.005
Figure 1—figure supplement 2—source data 1

Behavioral data for the second sample of the fMRI study.

https://doi.org/10.7554/eLife.42265.006
Main effects and the interaction effect of the whole brain analysis of the first sample.

(a) Main effect of interoceptive vs. exteroceptive attention contrast (BDT vs. DDT). (b) Main effect of breath curve feedback condition (delayed curve vs. non-delayed curve). (c) Interaction between attention type and breath-curve feedback condition ([delayed – non-delayed] BDT – [delayed – non-delayed] DDT). Here we showed the left AIC for the visualization of the seed for the ROI analysis in the second fMRI sample, although the cluster with 210 voxels did not survive GRF correction. Red color represents an increased activation; Blue color represents a decreased activation. (d) Activation of the left and the right AIC under the four task conditions, and the pattern of the interaction.

https://doi.org/10.7554/eLife.42265.010
Figure 2—source data 1

CSV file containing data for Figure 2d.

https://doi.org/10.7554/eLife.42265.011
Relationship between brain activation and behavioral performance across participants.

(a) This was revealed in a regression analysis of contrast images for the interaction between interoceptive attention deployment (BDT vs. DDT) and breath curve feedback condition (delayed vs. no-delayed), with performance accuracy on interoceptive and exteroceptive tasks as regressor-of-interest and covariate, respectively. AIC, anterior insular cortex; MTG, middle temporal gyrus. (b) Correlational patterns between the interaction effect of bilateral AIC activation and relative interoceptive accuracy. Data were normalized as z-scores.

https://doi.org/10.7554/eLife.42265.015
Figure 3—source data 1

CSV file containing data for Figure 3b.

https://doi.org/10.7554/eLife.42265.016
Figure 4 with 2 supplements
PPI and DCM results of the first fMRI sample.

(a) Regions showing positive (red) and negative (blue) associations with AIC activation modulated by interoceptive attention relative to exteroceptive attention (BDT vs. DDT). (b) An increase in activation in the right AIC was associated with an increase in activation in the postcentral gyrus (PoCG) and a decrease in activation in the visual cortex (VC, V2/3) under the condition of interoceptive attention compared with exteroceptive attention. (c) Five base models generated by specifying possible modulations of interoceptive and exteroceptive attention (BDT and DDT) on the four endogenous connections between ROIs. The model surrounded by a rectangle in dashed-line indicates the winning model out of 52 variant models revealed by random-effects Bayesian model selection (BMS). (d) Intrinsic efferent connection from the AIC to the PoCG was significant. The modulatory effect of interoceptive attention (BDT) on the connection from the AIC to the PoCG was significant. The modulatory effect of exteroceptive attention (DDT) on the connection from AIC to V2/3 was significant (uncorrected).

https://doi.org/10.7554/eLife.42265.018
Figure 4—source data 1

CSV file containing data for Figure 4b.

https://doi.org/10.7554/eLife.42265.021
Figure 4—figure supplement 1
Regions showed positive (red) and negative (blue) association with the left AIC (as the seed) modulated by interoceptive attention relative to exteroceptive attention (BDT vs DDT) for the first fMRI sample.
https://doi.org/10.7554/eLife.42265.019
Figure 4—figure supplement 2
Exceedance probability of RFX BMS for the first fMRI sample.

Across all 52 models, M20 outperformed the other models and thus was identified as the optimal model. M20 denotes the model with the modulatory effects of interoceptive and exteroceptive attention (BDT and DDT) exerting on the connection from the AIC to the PoCG and to the V2/3.

https://doi.org/10.7554/eLife.42265.020
Figure 5 with 3 supplements
ROI results of the second fMRI sample.

(a) ROI analysis of the parameter estimates of the left and the right AIC under the four experimental conditions. Raincloud plots were used for visualization. (b) Correlation between the interaction effect of bilateral AIC and relative interoceptive accuracy. The values of the variable in b were normalized as z-scores.

https://doi.org/10.7554/eLife.42265.023
Figure 5—source data 1

CSV file containing data for Figure 5b.

https://doi.org/10.7554/eLife.42265.027
Figure 5—figure supplement 1
Raincloud plot visualization of respiratory volumes under the four experimental conditions from the second fMRI sample.
https://doi.org/10.7554/eLife.42265.024
Figure 5—figure supplement 1—source data 1

CSV file containing data for Figure 5—figure supplement 1.

https://doi.org/10.7554/eLife.42265.029
Figure 5—figure supplement 2
Activation maps without and with RETROICOR +RVHRCOR correction for the second fMRI sample.

(a) Main effect of interoceptive vs. exteroceptive attention (BDT vs. DDT). (b) Main effect of breath curve feedback condition (delayed vs. non-delayed). (c) Interaction between attention type and breath-curve feedback condition ([delayed – non-delayed] BDT – [delayed – non-delayed] DDT). Pink purple contours indicate corresponding activation in the first sample. We used an extremely liberal threshold of voxelwise p<0.05 for visualization.

https://doi.org/10.7554/eLife.42265.025
Figure 5—figure supplement 3
Paired t-test of beta maps obtained without and with RETROICOR + RVHRCOR correction for the second fMRI sample.

The difference of the signals of the AIC between the analyses with and without physiological corrections was only evident under the main effect of interoceptive vs. exteroceptive attention (BDT vs. DDT), but not under the interaction contrast, confirming that the interaction effect of the AIC was not significantly impacted by the physiological noises. (a) Main effect of interoceptive vs. exteroceptive attention (BDT vs. DDT). (b) Main effect of breath curve feedback condition (delayed vs. non-delayed). (c) Interaction between attention type and breath-curve feedback condition ([delayed – non-delayed] BDT – [delayed – non-delayed] DDT). Pink purple contours indicate corresponding activation in the first sample. We used an extremely liberal threshold of voxelwise p<0.05 for visualization.

https://doi.org/10.7554/eLife.42265.026
Reconstruction of anterior insular cortex lesions of six patients.

Red color indicates 100% overlap. Left lesions were flipped to the right side to map the lesion overlap.

https://doi.org/10.7554/eLife.42265.028
Behavioral results of the lesion study.

(a, b, c) the interoceptive performance on the BDT, and (d, e, f) the exteroceptive performance on the DDT. On the BDT, patients with AIC lesions had significantly lower performance in accuracy and compared with the NC and BDC groups but did not show significant alteration in β during the BDT. On the DDT, patients with AIC lesions did not show significant abnormality in performance in accuracy, , and β compared with either the NC or BDC groups. NC, normal control; BDC, brain damage control. Dashed line: chance level. * p < 0.05; ** p < 0.01; *** p < 0.001.

https://doi.org/10.7554/eLife.42265.030
Figure 7—source data 1

CSV file containing behavioral data for lesion study.

https://doi.org/10.7554/eLife.42265.031
Author response image 1
Activation maps with and without including individual heart rate and respiratory volume as covariates in the 2nd GLM.

(a) Main effect of interoceptive attention (interoceptive task vs. exteroceptive task). (b) Interaction between attention type and breath-curve feedback condition ([delayed – non-delayed]interoceptive task – [delayed – non-delayed]exteroceptive task).

Author response image 2
The pattern of respiratory parameters under different task conditions.
Author response image 3
Activation maps with and without physiological correction for the 1st level GLM.

(a) Main effect of interoceptive attention (interoceptive task vs. exteroceptive task). (b) Interaction between attention type and breath-curve feedback condition ([delayed – non-delayed]interoceptive task – [delayed – non-delayed]exteroceptive task). (c) The interaction patterns of the left and right anterior insular cortex (AIC) activity without physiological correction. (d) The interaction patterns of the left and right AIC activity with physiological correction.

Author response image 4
Paired t-test on beta maps obtained without and with physiological correction.

(a) using interoceptive vs. exteroceptive contrast maps. (b) using interaction effect beta maps.

Author response image 5
Author response image 6
The F-test across all RETROICOR regressors.

Voxelwise p < 0.001.

Tables

Table 1
Statistics of behavioral results of the fMRI studies.
https://doi.org/10.7554/eLife.42265.008
First sampleSecond sample
DfTCohen’s dDfTCohen’s d
accuracyintero vs. 0.54314.51***2.182713.77***2.59
intero vs. extero43−2.36*0.3527−1.830.35
intero vs. 04313.09***2.02712.89***2.67
intero vs. extero43-2.31*0.3527-2.83**0.50
βintero vs. extero43−2.31*0.3527−2.83**0.50
RTintero vs. extero432.89**0.44270.60.12
  1. * p<0.05; **p<0.01; ***p<0.001.

Table 2
Pearson correlation coefficients (and Bayes Factors) between the behavioral measurements for the first, the second, and across the two samples.
https://doi.org/10.7554/eLife.42265.009
Relative accuracySubjective difficultyBPQPositive PANASHAMABDI
Relative accuracy-
1st sampleSubjective difficulty−0.43**
(10.38)
-
BPQ0.27
(0.17)
−0.15
(0.29)
-
Positive PANAS0.31
(1.38)
−0.04
(0.19)
−0.006
(0.19)
-
HAMA−0.006
(0.19)
−0.14
(0.28)
0.25
(0.69)
−0.12
(0.25)
-
BDI−0.002
(0.19)
−0.004
(0.19)
0.16
(0.32)
−0.06
(0.20)
0.70***
(>100)
-
Relative accuracy-
2nd sampleSubjective difficulty--
BPQ−0.17
(0.33)
--
Positive PANAS0.12
(0.27)
-0.07
(0.25)
-
HAMA0.29
(0.69)
-0.40
(1.90)
−0.034
(0.24)
-
BDI0.034
(0.24)
-0.075
(0.25)
−0.43
(2.84)
0.47*
(4.96)
-
Relative accuracy-
1st + 2nd samplesSubjective difficulty--
BPQ0.06
(0.17)
--
Positive PANAS0.25
(1.16)
-0.03
(0.15)
-
HAMA0.12
(0.25)
-0.31*
(4.91)
−0.09
(0.20)
-
BDI0.008
(0.15)
-0.14
(0.28)
−0.20
(0.56)
0.60***
(>100)
-
  1. * corrected p<0.05; ** corrected p<0.01; *** corrected p<0.001; value in brackets represents Bayes factor. BPQ, body perception questionnaire; PANAS, positive and negative affective schedule; HAMA, Hamilton anxiety scale; BDI, Beck depression inventory.

Table 3
Activation and deactivation of the brain regions involved in interoceptive attention (interoception – exteroception).
https://doi.org/10.7554/eLife.42265.012
MNI
RegionL/RBAXYZTZK
Positive
Cerebelum crus IL−30−70−2413.02Inf.73834
Middle occipital gyrusR1932−682211.99Inf.
Cerebelum crus IIL−20−78−4811.727.80
Inferior frontal gyrusR4452142411.247.63
Inferior parietal lobuleR4036−484411.197.62
Inferior parietal lobuleL40−38−464210.417.32
Postcentral gyrusR246−405410.297.27
Supramarginal gyrusR4048−344210.007.15
Superior occipital gyrusR722−72469.997.15
Cerebelum VIIBL−32−70−529.787.06
Superior parietal lobule (Intraparietal sulcus)R716−78529.697.02
Cerebelum VIIIR22−74−509.616.99
Middle frontal gyrusL46−4450129.206.80
Middle frontal gyrusR464242249.166.78
Supplementary motor areaR684768.926.68
Inferior occipital gyrusR3752−66−128.686.56
Cerebelum crus IIR2−76−368.666.56
Middle occipital gyrus (Intraparietal sulcus)R1932−76348.586.52
ThalamusR18−20208.556.50
Inferior temporal gyrusR2056−38−208.416.43
Inferior frontal gyrusR454438128.316.38
Superior parietal lobule (Intraparietal sulcus)L7−20−72468.216.33
Supplementary motor areaL6-2-4748.086.27
Inferior frontal gyrusL44−5412268.076.26
CaudateR16-8247.896.17
Anterior cingulate cortexR32218447.786.12
Vermis-2−74−127.766.10
Middle frontal gyrusR465014407.756.10
Middle frontal gyrusL46−4034347.726.08
Supramarginal gyrusL40−60−36287.475.95
Middle frontal gyrusR6282487.015.69
Anterior insular cortexR342046.985.68
Postcentral gyrusL2−62−26366.875.62
Inferior frontal gyrusL6−528126.845.59
Superior frontal gyrusL6−264666.735.53
Middle occipital gyrus (Intraparietal sulcus)L7−24−66366.665.49
Lingual gyrusL18−18−90−186.615.46
Superior parietal lobuleL1−24−44726.555.42
CaudateL-82246.455.37
Precentral gyrusL6−402566.235.23
Superior occipital gyrusL18−22−92286.205.21
Middle occipital gyrusL18−24−94166.095.14
Middle occipital gyrusR1830−86166.095.14
Fusiform gyrusL37−46−46−225.824.97
Anterior insular cortexL−302085.504.76
CuneusL190−88345.224.57
Superior parietal lobuleL5−18−60665.184.54
Fusiform gyrusR3744−32−204.964.39
Negative
Anterior cingulate cortexR32438-47.475.953232
Anterior cingulate cortexL32-638-47.105.94
Superior frontal gyrusL9−1638545.975.07
Medial superior frontal gyrusR321052205.334.65
Medial superior frontal gyrusL32-850265.324.63
Middle frontal gyrusL8−2430565.124.50
Superior frontal gyrusL9−2032484.544.08
PrecuneusL23−10−44406.455.37819
PrecuneusR236−60244.243.85
Middle temporal gyrusL21−60−10−145.895.02787
Table 4
Activation and deactivation of the brain regions involved in feedback delay (delay – non-delay).
https://doi.org/10.7554/eLife.42265.013
MNI
RegionL/RBAXYZTZK
Positive
Anterior insular cortexR3026-45.264.60618
Inferior frontal gyrusR45422284.403.98
CaudateR82444.293.90
Inferior parietal lobuleL40−38−54425.234.58598
Angular gyrusR3944−44304.994.411317
Inferior parietal lobuleR4056−54444.173.80
Middle frontal gyrusR6348464.784.26780
Middle frontal gyrusR93418344.744.23
Middle frontal gyrusR463428324.323.92
Negative
Lingual gyrusL17−10−78-46.215.22443
Table 5
Activation of brain regions related to the interaction between interoceptive attention and feedback delay ([delayed – non-delayed] interoception – [delayed – non-delayed] exteroception).
https://doi.org/10.7554/eLife.42265.014
MNI
RegionL/RBAXYZTZK
Positive
Anterior insular cortexR282805.524.77516
Inferior frontal gyrusR474026−104.664.17
Middle frontal gyrusR94014405.364.672330
Supplementary motor areaR8422545.194.55
Anterior cingulate cortexR32636385.124.5
Superior frontal gyrusR8630444.714.21
Inferior frontal gyrusR454622164.504.05
Middle frontal gyrusR6344524.273.88
Supplementary motor areaL6−128523.643.38
Anterior cingulate cortexR321030283.493.25
Supramarginal gyrusR4054−46264.914.351748
Middle temporal gyrusR2166−32−104.704.20
Inferior parietal lobuleR1960−48424.564.10
Superior temporal gyrusR4258−40164.494.04
Table 6
Relationship between the interaction effect ([delayed – non-delayed] interoception – [delayed – non-delayed] exteroception) of the brain and behavioral performance (interoceptive accuracy) across participants.
https://doi.org/10.7554/eLife.42265.017
MNI
RegionL/RBAXYZTZK
Positive
Middle temporal gyrusR2054−20−103.853.53232
Middle temporal gyrusL22−48−24-23.693.41170
Anterior insular cortexL−4212-63.643.37168
Anterior insular cortexR4216-63.413.18119
Angular gyrusR2258−50263.102.92128
Table 7
Positive and negative psychophysiological interaction effects with the right AIC as the seed.
https://doi.org/10.7554/eLife.42265.022
MNI
RegionL/RBAXYZTZK
Positive
Inferior frontal operculumR44528267.495.965895
Precentral gyrusR65810366.715.52
Insula cortexR380146.355.30
PutamenR208106.335.29
Rolandic operculumR48484106.015.09
CaudateR81045.865.00
Inferior frontal gyrusR454236104.353.94
Postcentral gyrusR4358−16326.956.552078
Supramarginal gyrusR266−22346.045.11
Superior temporal gyrusR4262−32205.284.61
Precentral gyrusL6−5810306.895.6311155
PutamenL−2010126.045.11
Supplementary motor areaL6-8-4645.905.02
CaudateL-81625.414.70
Triangle Inferior fronal gyrusL48−3832245.214.56
Superior temporal gyrusL44−48−42245.194.55
Insula cortexL−36-285.194.55
Supplementary motor areaR644645.194.55
Supramarginal gyrusL2−56−28405.134.50
Superior frontal gyrusL6−24-2584.734.22
Postcentral gyrusL3−56−20344.534.07
Middle frontal gyrusL6−28-8524.484.04
Middle temporal gyrusR3748−6085.444.72569
Cerebelum VIIbL−16−74−484.954.38427
Cerebelum VIIIL−24−66−524.754.24
Negative
CuneusL17−10−96167.305.855904
CuneusR1814−90286.805.40
Lingual gyrusR1814−62-26.055.11
Lingual gyrusL18−18−74-85.264.60
CalcarineL180−76185.114.49
Fusiform gyrusL18−24−80−164.954.38
CalcarineR1720−5464.724.22
Cerebelum Crus IL−38−78−184.373.95
Middle occipital gyrusL18−16−86-44.223.84
Table 8
Statistics of the results of the lesion study.
https://doi.org/10.7554/eLife.42265.032
Accuracy
TBFTBF
BDTAIC vs. NC−3.47***14.71−3.62***13.78
AIC vs. BDC−2.35**3.95−2.22*3.40
BDC vs. NC00.420.110.43
DDTAIC vs. NC0.180.380.180.38
AIC vs. BDC−0.990.98−0.830.85
BDC vs. NC1.74*0.821.460.69
  1. * p<0.05; **p<0.01; ***p<0.001; one- tailed; BF, Bayes factor.

Table 9
Demographic characteristics of the participants in lesion experiment.
https://doi.org/10.7554/eLife.42265.007
Lesion lateralityLesion size (ml)Chronicity (months)Age (years)GenderEducation (years)MMSEBDI
IC1Right3.73839M15284
IC2Right5.5633M16281
IC3Left11.2938M12264
IC4Left9.01253M12268
IC5Left16.0651M16291
IC6Left9.23740M16260
BDC3 Left/3 Right18 ± 1421 ± 1639 ± 73F/3M12 ± 328 ± 12 ± 2
NCN/AN/AN/A46 ± 78F/4M14 ± 228 ± 11 ± 1
  1. IC, insular cortex; BDC, brain damage control; NC, normal control; MMSE, mini-mental state examination; BDI, Beck depression inventory.

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