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Altered interoceptive activation before, during, and after aversive breathing load in women remitted from anorexia nervosa

Published online by Cambridge University Press:  17 July 2017

L. A. Berner
Department of Psychiatry, University of California, San Diego, CA, USA
A. N. Simmons
Department of Psychiatry, University of California, San Diego, CA, USA VA San Diego Healthcare System, San Diego, CA, USA
C. E. Wierenga
Department of Psychiatry, University of California, San Diego, CA, USA VA San Diego Healthcare System, San Diego, CA, USA
A. Bischoff-Grethe
Department of Psychiatry, University of California, San Diego, CA, USA
M. P. Paulus
Department of Psychiatry, University of California, San Diego, CA, USA Laureate Institute for Brain Research, Tulsa, Oklahoma, USA
U. F. Bailer
Department of Psychiatry, University of California, San Diego, CA, USA Department of Psychiatry and Psychotherapy, Division of General Psychiatry, Medical University of Vienna, Vienna, Austria
A. V. Ely
Department of Psychiatry, University of California, San Diego, CA, USA
W. H. Kaye*
Department of Psychiatry, University of California, San Diego, CA, USA
*Address for correspondence: W. H. Kaye, M.D., UCSD Department of Psychiatry, UCSD Eating Disorder Research and Treatment Program , Chancellor Park, 4510 Executive Dr., Suite 315, San Diego, CA 92121-3021, USA. (Email:



The neural mechanisms of anorexia nervosa (AN), a severe and chronic psychiatric illness, are still poorly understood. Altered body state processing, or interoception, has been documented in AN, and disturbances in aversive interoception may contribute to distorted body perception, extreme dietary restriction, and anxiety. As prior data implicate a potential mismatch between interoceptive expectation and experience in AN, we examined whether AN is associated with altered brain activation before, during, and after an unpleasant interoceptive state change.


Adult women remitted from AN (RAN; n = 17) and healthy control women (CW; n = 25) underwent functional magnetic resonance imaging during an inspiratory breathing load paradigm.


During stimulus anticipation, the RAN group, relative to CW, showed reduced activation in right mid-insula. In contrast, during the aversive breathing load, the RAN group showed increased activation compared with CW in striatum and cingulate and prefrontal cortices (PFC). The RAN group also showed increased activation in PFC, bilateral insula, striatum, and amygdala after stimulus offset. Time course analyses indicated that RAN responses in interoceptive processing regions during breathing load increased more steeply than those of CW. Exploratory analyses revealed that hyperactivation after breathing load was associated with markers of past AN severity.


Anticipatory deactivation with a subsequent exaggerated brain response during and after an aversive body state may contribute to difficulty predicting and adapting to internal state fluctuation. Because eating changes our interoceptive state, restriction may be one method of avoiding aversive, unpredictable internal change in AN.

Original Articles
Copyright © Cambridge University Press 2017 

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Bailer, UF, Frank, GK, Henry, SE, Price, JC, Meltzer, CC, Weissfeld, L, Mathis, CA, Drevets, WC, Wagner, A, Hoge, J, Ziolko, SK, McConaha, CW, Kaye, WH (2005). Altered brain serotonin 5-HT1A receptor binding after recovery from anorexia nervosa measured by positron emission tomography and [carbonyl11C]WAY-100635. Archives of General Psychiatry 62, 10321041.CrossRefGoogle ScholarPubMed
Bailer, UF, Price, JC, Meltzer, CC, Mathis, CA, Frank, GK, Weissfeld, L, McConaha, CW, Henry, SE, Brooks-Achenbach, S, Barbarich, NC, Kaye, WH (2004). Altered 5-HT(2A) receptor binding after recovery from bulimia-type anorexia nervosa: relationships to harm avoidance and drive for thinness. Neuropsychopharmacology 29, 11431155.CrossRefGoogle ScholarPubMed
Barrett, LF, Simmons, WK (2015). Interoceptive predictions in the brain. Nature Reviews Neuroscience 16, 419429.CrossRefGoogle ScholarPubMed
Beck, AT, Steer, RA, Brown, GK (1996). Manual for the Beck Depression Inventory-II. Psychological Corporation: San Antonio, TX.Google Scholar
Berk, L, Stewart, JL, May, AC, Wiers, RW, Davenport, PW, Paulus, MP, Tapert, SF (2015). Under pressure: adolescent substance users show exaggerated neural processing of aversive interoceptive stimuli. Addiction 110, 20252036.CrossRefGoogle ScholarPubMed
Brand-Gothelf, A, Parush, S, Eitan, Y, Admoni, S, Gur, E, Stein, D (2016). Sensory modulation disorder symptoms in anorexia nervosa and bulimia nervosa: a pilot study. International Journal of Eating Disorders 49, 5968.CrossRefGoogle ScholarPubMed
Cloninger, CR, Przybeck, TR, Svrakic, DM (1994). The Temperament and Character Inventory (TCI): a Guide to its Development and Use. Center for Psychobiology of Personality, Washington University: St. Louis, MO.Google Scholar
Courty, A, Godart, N, Lalanne, C, Berthoz, S (2015). Alexithymia, a compounding factor for eating and social avoidance symptoms in anorexia nervosa. Comprehensive Psychiatry 56, 217228.CrossRefGoogle ScholarPubMed
Cowdrey, FA, Park, RJ, Harmer, CJ, McCabe, C (2011). Increased neural processing of rewarding and aversive food stimuli in recovered anorexia nervosa. Biological Psychiatry 70, 736743.CrossRefGoogle ScholarPubMed
Craig, AD (2002). How do you feel? Interoception: the sense of the physiological condition of the body. Nature Reviews Neuroscience 3, 655666.CrossRefGoogle Scholar
Craig, AD (2003). Interoception: the sense of the physiological condition of the body. Current Opinion in Neurobiology 13, 500505.CrossRefGoogle ScholarPubMed
Critchley, HD, Wiens, S, Rotshtein, P, Ohman, A, Dolan, RJ (2004). Neural systems supporting interoceptive awareness. Nature Neuroscience 7, 189195.CrossRefGoogle ScholarPubMed
Desikan, RS, Ségonne, F, Fischl, B, Quinn, BT, Dickerson, BC, Blacker, D, Buckner, RL, Dale, AM, Maguire, RP, Hyman, BT, Albert, MS, Killiany, RJ (2006). An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage 31, 968980.CrossRefGoogle ScholarPubMed
Eklund, A, Nichols, T, Knutsson, H (2016). Cluster failure: why fMRI inferences for spatial extent have inflated false-positive rates. Proceedings of the National Academy of Sciences of the United States of America 113, 79007905.CrossRefGoogle ScholarPubMed
Frank, GK, Bailer, UF, Henry, SE, Drevets, W, Meltzer, CC, Price, JC, Mathis, CA, Wagner, A, Hoge, J, Ziolko, S, Barbarich-Marsteller, N, Weissfeld, L, Kaye, WH (2005). Increased dopamine D2/D3 receptor binding after recovery from anorexia nervosa measured by positron emission tomography and [11c]raclopride. Biological Psychiatry 58, 908912.CrossRefGoogle ScholarPubMed
Frank, GK, Collier, S, Shott, ME, O'Reilly, RC (2016). Prediction error and somatosensory insula activation in women recovered from anorexia nervosa. Journal of Psychiatry and Neuroscience 41, 150103.CrossRefGoogle ScholarPubMed
Frank, GKW (2015). Advances from neuroimaging studies in eating disorders. CNS Spectrums 20, 391400.CrossRefGoogle ScholarPubMed
Frank, GKW, Reynolds, JR, Shott, ME, Jappe, L, Yang, TT, Tregellas, JR, O'Reilly, RC (2012). Anorexia nervosa and obesity are associated with opposite brain reward response. Neuropsychopharmacology 37, 20312046.CrossRefGoogle ScholarPubMed
Galli, G, Shukla, A, Simmons, AN, Davenport, PW, Paulus, MP (2013). Sex differences in the neural processing of aversive interoceptive events: the benefit of relief. PLoS ONE 8, e84044.CrossRefGoogle ScholarPubMed
Garner, DM (1991). Eating Disorder Inventory-2 Professional Manual. Psychological Assessment Resources: Odessa, FL.Google Scholar
Haase, L, May, AC, Falahpour, M, Isakovic, S, Simmons, AN, Hickman, SD, Liu, TT, Paulus, MP (2015). A pilot study investigating changes in neural processing after mindfulness training in elite athletes. Frontiers in Behavioral Neuroscience 9, 229.CrossRefGoogle ScholarPubMed
Haase, L, Stewart, JL, Youssef, B, May, AC, Isakovic, S, Simmons, AN, Johnson, DC, Potterat, EG, Paulus, MP (2016). When the brain does not adequately feel the body: links between low resilience and interoception. Biological Psychology 113, 3745.CrossRefGoogle Scholar
Haase, L, Thom, NJ, Shukla, A, Davenport, PW, Simmons, AN, Paulus, MP, Johnson, DC (2014). Mindfulness-based training attenuates insula response to an aversive interoceptive challenge. Social Cognitive and Affective Neuroscience 11, 182190.CrossRefGoogle Scholar
Hayes, DJ, Northoff, G (2012). Common brain activations for painful and non-painful aversive stimuli. BMC Neuroscience 13, 60.CrossRefGoogle ScholarPubMed
Huber, P (1964). Robust estimation of location parameter. Annals of Mathematical Statistics 35, 73101.CrossRefGoogle Scholar
Kerr, KL, Moseman, SE, Avery, JA, Bodurka, J, Zucker, NL, Simmons, WK (2016). Altered insula activity during visceral interoception in weight-restored patients with anorexia nervosa. Neuropsychopharmacology 41, 521528.CrossRefGoogle ScholarPubMed
Khalsa, SS, Craske, MG, Li, W, Vangala, S, Strober, M, Feusner, JD (2015). Altered interoceptive awareness in anorexia nervosa: effects of meal anticipation, consumption and bodily arousal. International Journal of Eating Disorders 48, 889897.CrossRefGoogle ScholarPubMed
Khalsa, SS, Rudrauf, D, Feinstein, JS, Tranel, D (2009). The pathways of interoceptive awareness. Nature Neuroscience 12, 14941496.CrossRefGoogle ScholarPubMed
Klein, TA, Ullsperger, M, Danielmeier, C (2013). Error awareness and the insula: links to neurological and psychiatric diseases. Frontiers in Human Neuroscience 7, 14.CrossRefGoogle ScholarPubMed
Leknes, S, Lee, M, Berna, C, Andersson, J, Tracey, I (2011). Relief as a reward: hedonic and neural responses to safety from pain. PLoS ONE 6, e17870.CrossRefGoogle ScholarPubMed
Merwin, RM, Moskovich, AA, Wagner, HR, Ritschel, LA, Craighead, LW, Zucker, NL (2013). Emotion regulation difficulties in anorexia nervosa: relationship to self-perceived sensory sensitivity. Cognition and Emotion 27, 441452.CrossRefGoogle ScholarPubMed
Nunn, K, Framptom, I, Fuglset, T, Torzsok-Sonnevend, M, Lask, B (2011). Anorexia nervosa and the insula. Medical Hypotheses 76, 353357.CrossRefGoogle ScholarPubMed
Oberndorfer, T, Simmons, A, McCurdy, D, Strigo, I, Matthews, S, Yang, T, Irvine, Z, Kaye, W (2013 a). Greater anterior insula activation during anticipation of food images in women recovered from anorexia nervosa versus controls. Psychiatry Research: Neuroimaging 214, 132141.CrossRefGoogle ScholarPubMed
Oberndorfer, TA, Frank, GK, Simmons, AN, Wagner, A, McCurdy, D, Fudge, JL, Yang, TT, Paulus, MP, Kaye, WH (2013 b). Altered insula response to sweet taste processing after recovery from anorexia and bulimia nervosa. The American Journal of Psychiatry 170, 11431151.CrossRefGoogle ScholarPubMed
Paulus, MP, Flagan, T, Simmons, AN, Gillis, K, Kotturi, S, Thom, N, Johnson, DC, Van Orden, KF, Davenport, PW, Swain, JL (2012). Subjecting elite athletes to inspiratory breathing load reveals behavioral and neural signatures of optimal performers in extreme environments. PLoS ONE 7, e29394.CrossRefGoogle ScholarPubMed
Paulus, MP, Stein, MB (2006). An insular view of anxiety. Biological Psychiatry 60, 383387.CrossRefGoogle ScholarPubMed
Paulus, MP, Stein, MB (2010). Interoception in anxiety and depression. Brain Structure and Function 214, 451463.CrossRefGoogle ScholarPubMed
Peiffer, C (2009). Dyspnea relief: more than just the perception of a decrease in dyspnea. Respiratory Physiology & Neurobiology 167, 6171.CrossRefGoogle ScholarPubMed
Pollatos, O, Kurz, A-L, Albrecht, J, Schreder, T, Kleemann, A, Schopf, V, Kopietz, R, Weismann, M, Schandry, R (2008). Reduced perception of bodily signals in anorexia nervosa. Eating Behaviors 9, 381388.CrossRefGoogle ScholarPubMed
Schultz, W, Dayan, P, Montague, PR (1997). A neural substrate of prediction and reward. Science 275, 15931599.CrossRefGoogle ScholarPubMed
Seidel, E, Pfabigan, DM, Hahn, A, Sladky, R, Grahl, A, Paul, K, Kraus, C, Kublbock, M, Kranz, GS, Hummer, A, Lanzenberger, R, Windischberger, C, Lamm, C (2015). Uncertainty during pain anticipation: the adaptive value of preparatory processes. Human Brain Mapping 36, 744755.CrossRefGoogle ScholarPubMed
Shott, ME, Pryor, TL, Yang, TT, Frank, GKW (2015). Greater insula white matter fiber connectivity in women recovered from anorexia nervosa. Neuropsychopharmacology 41, 498507.CrossRefGoogle ScholarPubMed
Simmons, WK, Avery, JA, Barcalow, JC, Bodurka, J, Drevets, WC, Bellgowan, P (2013). Keeping the body in mind: insula functional organization and functional connectivity integrate interoceptive, exteroceptive, and emotional awareness. Human Brain Mapping 34, 29442958.CrossRefGoogle ScholarPubMed
Spielberger, CD, Gorsuch, RL, Lushene, RD (1970). State-Trait Anxiety Inventory Manual. Consulting Psychologists Press: Palo Alto, CA.Google Scholar
Steinglass, JE, Sysko, R, Mayer, L, Berner, LA, Schebendach, J, Wang, Y, Chen, H, Albano, AM, Simpson, HB, Walsh, BT (2010). Pre-meal anxiety and food intake in anorexia nervosa. Appetite 55, 214218.CrossRefGoogle ScholarPubMed
Stewart, JL, May, AC, Poppa, T, Davenport, PW, Tapert, SF, Paulus, MP (2014). You are the danger: attenuated insula response in methamphetamine users during aversive interoceptive decision-making. Drug and Alcohol Dependence 142, 110119.CrossRefGoogle ScholarPubMed
Strigo, IA, Matthews, SC, Simmons, AN, Oberndorfer, T, Klabunde, M, Reinhardt, LE, Kaye, WH (2013). Altered insula activation during pain anticipation in individuals recovered from anorexia nervosa: evidence of interoceptive dysregulation. International Journal of Eating Disorders 46, 2333.CrossRefGoogle ScholarPubMed
Tchanturia, K, Davies, H, Roberts, M, Harrison, A, Nakazato, M, Schmidt, U, Treasure, J, Morris, R (2012). Poor cognitive flexibility in eating disorders: examining the evidence using the Wisconsin card sorting task. PLoS ONE 7, e28331.CrossRefGoogle ScholarPubMed
Wagner, A, Aizenstein, H, Mazurkewicz, L, Fudge, J, Frank, GK, Putnam, K, Bailer, UF, Fischer, L, Kaye, WH (2008). Altered insula response to taste stimuli in individuals recovered from restricting-type anorexia nervosa. Neuropsychopharmacology 33, 513523.CrossRefGoogle ScholarPubMed
Wagner, A, Aizenstein, H, Venkatraman, VK, Fudge, J, May, JC, Mazurkewicz, L, Frank, GK, Bailer, UF, Fischer, L, Nguyen, V, Carter, C, Putnam, K, Kaye, WH (2007). Altered reward processing in women recovered from anorexia nervosa. American Journal of Psychiatry 164, 18421849.CrossRefGoogle ScholarPubMed
Wierenga, CE, Bischoff-Grethe, A, Melrose, AJ, Irvine, Z, Torres, L, Bailer, UF, Simmons, A, Fudge, JL, McClure, SM, Ely, A (2015). Hunger does not motivate reward in women remitted from anorexia nervosa. Biological Psychiatry 77, 642652.CrossRefGoogle Scholar
Zucker, NL, Merwin, RM, Bulik, CM, Moskovich, A, Wildes, JE, Groh, J (2013). Subjective experience of sensation in anorexia nervosa. Behaviour Research and Therapy 51, 256265.CrossRefGoogle ScholarPubMed
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