Subcortical gray matter volumes in asthma: associations with asthma duration, control, and anxiety

  • Thomas RitzEmail author
  • Juliet L. Kroll
  • Sina Aslan
  • Thomas Janssens
  • David A. Khan
  • Amy E. Pinkham
  • E. Sherwood Brown
Original Research


Asthma as a chronic inflammatory disease can be expected to affect central nervous system structures but little is known about subcortical structures in asthma and their potential association with illness-specific outcomes and anxiety. A total of 40 young adults (20 with asthma and 20 gender- and age-matched controls) underwent high-resolution T1-weighted MRI scan, viewed short distressing film clips, and filled in questionnaires about anxious and depressed mood, as well as asthma history, control, and catastrophizing thoughts about asthma, for those with asthma. The structural scans were processed in FSL’s FIRST program to delineate subcortical structures of interest: amygdala, hippocampus, putamen, pallidum, caudate nucleus, nucleus accumbens, and thalamus. Findings showed no general reduction in subcortical gray matter volumes in asthma compared to controls. Asthma duration, asthma control, and catastrophizing of asthma and asthma attacks were negatively associated with volumes of putamen and pallidum, and to a weaker extent thalamus and amygdala, while controlling for gender, age, and corticosteroid inhaler use. In addition, stronger anxiety in response to distressing films was associated with lower volume of the pallidum, whereas general anxious and depressed mood was unrelated to subcortical structures. Thus, although there are no subcortical structural differences between young adults with asthma and healthy controls, longer asthma history, suboptimal management, and illness-related anxiety are reflected in lower gray matter volumes of subcortical structures, further emphasizing the importance of maintaining optimal asthma control.


Structural magnetic resonance imaging Gray matter volume Asthma Limbic system Basal ganglia Asthma management Anxiety 



Asthma Control Questionnaire


Catastrophizing of Asthma Scale


Central nervous system


Fractional exhaled nitric oxide


Forced expiratory volume in the 1st second


Hospital Anxiety and Depression Scale


Magnetic resonance imaging


National Heart, Lung, and Blood Institute/National Asthma Education and Prevention Program



Partial funding for this study was provided by the National Institute on Aging (NIA, R24 AG048024), the University Research Council grant (URC 413876) at Southern Methodist University (SMU), and seed funds from Dedman College at SMU. We thank Binu Thomas, Lilly Yang, and Salvador Pena (University of Texas Southwestern Medical Center, Advanced Imaging Research Center) for their help with image acquisitions; Ashton Steele, Sheenal V. Patel, Justin R. Chen, Steve Dorman, Maryam Saifi, Sharon Deol, and Julie Kim for their help in data collection; and Alexandra Kulikova and Brittany Mason for their administrative support.

Author contributions

Conception and design of the study: TR, ESB, and TJ; acquisition of the data: JLK and DAK; analysis and interpretation: TR, SA, and ESB; drafting the article and/or revising it critically for important intellectual content: TR, SA, JLK, TJ, AEP, DAK, and ESB; approval of the final version to be published: TR, SA, JLK, TJ, AEP, DAK, and ESB.


Partial funding for this study was provided by the National Institute on Aging (NIA, R24 AG048024), the University Research Council grant (URC 413876) at Southern Methodist University (SMU), and seed funds from Dedman College at SMU.

Compliance with ethical standards

Conflict of interest

TR, SA, JLK, TJ, AEP, and DAK, report no biomedical financial interests or potential conflicts of interest. ESB reports having received research funding from Otsuka and lecture fees from Genentech.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

11682_2019_188_MOESM1_ESM.docx (17 kb)
ESM 1 (DOCX 16 kb)


  1. Ahmed-Leitao, F., Spies, G., van den Heuvel, L., & Seedat, S. (2016). Hippocampal and amygdala volumes in adults with posttraumatic stress disorder secondary to childhood abuse or maltreatment: A systematic review. Psychiatry Research: Neuroimaging, 256, 33–43.CrossRefGoogle Scholar
  2. Albéri, L. (2013). Asthma: a clinical condition for brain health. Experimental Neurology, 248, 338–342.CrossRefGoogle Scholar
  3. Alving, K., Jansson, C., & Nordvall, L. (2006). Performance of a new hand-held device for exhaled nitric oxide measurement in adults and children. Respiratory Research, 7, 67.CrossRefGoogle Scholar
  4. Baxter, M. G., & Murray, E. A. (2002). The amygdala and reward. Nature Reviews Neuroscience, 3, 563573.CrossRefGoogle Scholar
  5. Berkowitz, R. L., Coplan, J. D., Reddy, D. P., & Gorman, J. M. (2007). The human dimension: how the prefrontal cortex modulates the subcortical fear response. Reviews in the Neurosciences, 18, 191–207.CrossRefGoogle Scholar
  6. Brown, E. S., Woolston, D., Frol, A., Bobadilla, L., Khan, D. A., Hanczyc, M., Rush, A. J., Fleckenstein, J., Babcock, E., & Cullum, C. M. (2004). Hippocampal volume, spectroscopy, cognition, and mood in patients receiving corticosteroid therapy. Biological Psychiatry, 55, 538–545.CrossRefGoogle Scholar
  7. Brown, E. S., Woolston, D. J., & Frol, A. B. (2008). Amygdala volume in patients receiving chronic corticosteroid therapy. Biological Psychiatry, 63, 705–709.CrossRefGoogle Scholar
  8. Cacciaglia, R., Nees, F., Grimm, O., Ridder, S., Pohlack, S. T., Diener, S. J., Liebscher, C., & Flor, H. (2017). Trauma exposure relates to heightened stress, altered amygdala morphology and deficient extinction learning: implications for psychopathology. Psychoneuroendocrinology, 76, 19–28.CrossRefGoogle Scholar
  9. Carlson, S. M., Kim, J., Khan, D. A., King, K., Lucarelli, R. T., McColl, R., Peshock, R., & Brown, E. S. (2017). Hippocampal volume in patients with asthma: results from the Dallas Heart study. Journal of Asthma, 54, 9–16.CrossRefGoogle Scholar
  10. Dai, X. J., Jiang, J., Zhang, Z., Nie, X., Liu, B. X., Pei, L., Gong, H., Hu, J., Lu, G., & Zhan, Y. (2018). Plasticity and susceptibility of brain morphometry alterations to insufficient sleep. Frontiers in Psychiatry, 9, 266.CrossRefGoogle Scholar
  11. Damasio, A., & Carvalho, G. B. (2013). The nature of feelings: evolutionary and neurobiological origins. Nature Reviews Neuroscience, 14, 143–152.CrossRefGoogle Scholar
  12. Davenport, P. W., Cruz, M., Stecenko, A. A., & Kifle, Y. (2000). Respiratory-related evoked potentials in children with life-threatening asthma. American Journal of Respiratory and Critical Care Medicine, 161, 1830–1835.CrossRefGoogle Scholar
  13. Davis, M. (1992). The role of the amygdala in fear and anxiety. Annual Review of Neuroscience, 15, 353–375.CrossRefGoogle Scholar
  14. De Peuter, S., Lemaigre, V., Van Diest, I., Verleden, G., Demedts, M., & Van den Bergh, O. (2007). Differentiation between the sensory and affective aspects of histamine-induced bronchoconstriction in asthma. Respiratory Medicine, 101, 925–932.CrossRefGoogle Scholar
  15. De Peuter, S., Lemaigre, V., Van Diest, I., & Van den Bergh, O. (2008). Illness-specific catastrophic thinking and overperception in asthma. Health Psychology, 27, 93–99.CrossRefGoogle Scholar
  16. Esser, R. W., Stoeckel, M. C., Kirsten, A., Watz, H., Taube, K., Lehmann, K., Petersen, S., Magnussen, H., & von Leupoldt, A. (2016). Structural brain changes in patients with COPD. Chest, 149, 426–434.CrossRefGoogle Scholar
  17. Favreau, H., Bacon, S. L., Labrecque, M., & Lavoie, K. L. (2014). Prospective impact of panic disorder and panic-anxiety on asthma control, health service use, and quality of life in adult patients with asthma over a 4-year follow-up. Psychosomatic Medicine, 76, 147–155.CrossRefGoogle Scholar
  18. Fisler, M. S., Federspiel, A., Horn, H., Dierks, T., Schmitt, W., Wiest, R., de Quervain, D. J., & Soravia, L. M. (2013). Spider phobia is associated with decreased left amygdala volume: a cross-sectional study. BMC Psychiatry, 13, 70.CrossRefGoogle Scholar
  19. Frodl, T., & Amico, F. (2014). Is there an association between peripheral immune markers and structural/functional neuroimaging findings? Progress in Neuro-Psychopharmacology & Biological Psychiatry, 48, 295–303.CrossRefGoogle Scholar
  20. Frodl, T., & Skokauskas, N. (2012). Meta-analysis of structural MRI studies in children and adults with attention deficit hyperactivity disorder indicates treatment effects. Acta Psychiatrica Scandinavica, 125, 114–126.CrossRefGoogle Scholar
  21. Goodwin, R. D., Bandiera, F. C., Steinberg, D., Ortega, A. N., & Feldman, J. M. (2012). Asthma and mental health among youth: etiology, current knowledge and future directions. Expert Reviews in Respiratory Medicine, 6, 397–406.CrossRefGoogle Scholar
  22. Gorka, A. X., Hanson, J. L., Radtke, S. R., & Hariri, A. R. (2014). Reduced hippocampal and medial prefrontal gray matter mediate the association between reported childhood maltreatment and trait anxiety in adulthood and predict sensitivity to future life stress. Biology of Mood & Anxiety Disorders, 4, 12.CrossRefGoogle Scholar
  23. Grieve, S. M., Korgaonkar, M. S., Koslow, S. H., Gordon, E., & Williams, L. M. (2013). Widespread reductions in gray matter volume in depression. Neuroimage Clinical, 3, 332–339.CrossRefGoogle Scholar
  24. Gu, Y., Vorburger, R., Scarmeas, N., Luchsinger, J. A., Manly, J. J., Schupf, N., Mayeux, R., & Brickman, A. M. (2017). Circulating inflammatory biomarkers in relation to brain structural measurements in a nondemented elderly population. Brain, Behavior, and Immunity, 65, 150–160.CrossRefGoogle Scholar
  25. Günther, V., Ihme, K., Kersting, A., Hoffmann, K. T., Lobsien, D., & Suslow, T. (2018). Volumetric associations between amygdala, nucleus accumbens, and socially anxious tendencies in healthy women. Neuroscience, 374, 25–32.CrossRefGoogle Scholar
  26. Hassan, W., Silva, C. E., Mohammadzai, I. U., da Rocha, J. B., & Landeira-Fernandez, J. (2014). Association of oxidative stress to the genesis of anxiety: implications for possible therapeutic interventions. Current Neuropharmacology, 12, 120–139.CrossRefGoogle Scholar
  27. Hayano, F., Nakamura, M., Asami, T., Uehara, K., Yoshida, T., Roppongi, T., Otsuka, T., Inoue, T., & Hirayasu, Y. (2009). Smaller amygdala is associated with anxiety in patients with panic disorder. Psychiatry and Clinical Neurosciences, 63, 266–276.CrossRefGoogle Scholar
  28. Hilbert, K., Pine, D. S., Muehlhan, M., Lueken, U., Steudte-Schmiedgen, S., & Beesdo-Baum, K. (2015). Gray and white matter volume abnormalities in generalized anxiety disorder by categorical and dimensional characterization. Psychiatry Research, 234, 314–320.CrossRefGoogle Scholar
  29. Hölzel, B.K., Carmody, J., Evans, K.C., Hoge, E.A., Dusek, J.A., Morgan, L., Pitman, R.K., & Lazar, S.W. (2010). Stress reduction correlates with structural changes in the amygdala. Social Cognitive and Affective Neuroscience, 5, 11-17.Google Scholar
  30. Huber, A. K., Giles, D. A., Segal, B. M., & Irani, D. N. (2018). An emerging role for eotaxins in neurodegenerative disease. Clinical Immunology, 189, 29–33.CrossRefGoogle Scholar
  31. Hyland, M. E., Kenyon, C. A. P., Taylor, M., & Morice, A. H. (1993). Steroid prescribing for asthmatics: relationship with asthma symptom checklist and living with asthma questionnaire. British Journal of Clinical Psychology, 32, 505–511.CrossRefGoogle Scholar
  32. Janssens, T., Verleden, G., De Peuter, S., Van Diest, I., & Van den Bergh, O. (2009). Inaccurate perception of asthma symptoms: a cognitive-affective framework and implications for asthma treatment. Clinical Psychology Review, 29, 317–327.CrossRefGoogle Scholar
  33. Janssens, T., Verleden, G., & Van den Bergh, O. (2012). Symptoms, lung function, and perception of asthma control: an exploration into the heterogeneity of the asthma control construct. Journal of Asthma, 49, 63–69.CrossRefGoogle Scholar
  34. Janssens, T., Steele, A. M., Rosenfield, D., & Ritz, T. (2017). Airway reactivity in response to repeated emotional film clip presentation in asthma. Biological Psychology, 123, 1–7.CrossRefGoogle Scholar
  35. Joëls, M (2018). Corticosteroids and the brain. Journal of Endocrinology, 238, R121-R130.Google Scholar
  36. Juniper, E. F., O'Byrne, P. M., Guyatt, G. H., Ferrie, P. J., & King, D. R. (1999). Development and validation of a questionnaire to measure asthma control. European Respiratory Journal, 14, 902–907.CrossRefGoogle Scholar
  37. Kinsman, R. A., Dahlem, N. W., Spector, S., & Staudenmayer, H. (1977). Observations on subjective symptomatology, coping behavior, and medical decisions in asthma. Psychosomatic Medicine, 36, 102–119.CrossRefGoogle Scholar
  38. Kuo, S. S., & Pogue-Geile, M. F. (2019). Variation in fourteen brain structure volumes in schizophrenia: A comprehensive meta-analysis of 246 studies. Neuroscience and Biobehavioral Reviews, 98, 85–94.CrossRefGoogle Scholar
  39. Lago, T., Davis, A., Grillon, C., & Ernst, M. (2017). Striatum on the anxiety map: Small detours into adolescence. Brain Research, 1654, 177–184.CrossRefGoogle Scholar
  40. LeDoux, J. E., Iwata, J., Cicchetti, P., & Reis, D. J. (1988). Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear. Journal of Neuroscience, 8, 2517–2519.CrossRefGoogle Scholar
  41. Lupien, S.J., Juster, R.P., Raymond, C., & Marin, M.F. (2018). The effects of chronic stress on the human brain: From neurotoxicity, to vulnerability, to opportunity. Frontiers in Neuroendocrinology, 49, 91-105.Google Scholar
  42. Månsson, K. N. T., Salami, A., Carlbring, P., Boraxbekk, C. J., Andersson, G., & Furmark, T. (2017). Structural but not functional neuroplasticity one year after effective cognitive behaviour therapy for social anxiety disorder. Behavioral Brain Research, 318, 45–51.CrossRefGoogle Scholar
  43. McEwen, B. S., & Gianaros, P. J. (2011). Stress- and allostasis-induced brain plasticity. Annual Review of Medicine, 62, 431–445.CrossRefGoogle Scholar
  44. McEwen, B. S., Bowles, N. P., Gray, J. D., Hill, M. N., Hunter, R. G., Karatsoreos, I. N., & Nasca, C. (2015). Mechanisms of stress in the brain. Nature Neuroscience, 18, 1353–1363.CrossRefGoogle Scholar
  45. McEwen, B.S., Nasca, C., & Gray, J.D. (2016). Stress effects on neuronal structure: Hippocampus, amygdala, and prefrontal cortex. Neuropsychopharmacology, 41, 3-23.Google Scholar
  46. Meijer, O.C., Buurstede, J.C., & Schaaf, M.J.M. (2019). Corticosteroid receptors in the brain: Transcriptional mechanisms for specificity and context-dependent effects. Cellular and Molecular Neurobiology, 39, 539-549.Google Scholar
  47. Meuret, A. E., Kroll, J., & Ritz, T. (2017). Panic disorder comorbidity with medical conditions and treatment implications. Annual Review of Clinical Psychology, 13, 209–240.CrossRefGoogle Scholar
  48. Morey, R.A., Gold, A.L., LaBar, K.S., Beall, S.K., Brown, V.M., Haswell, C.C., Nasser, J.D., Wagner, H.R., McCarthy, G. & Mid-Atlantic MIRECC Workgroup. (2012). Amygdala volume changes in posttraumatic stress disorder in a large case-controlled veterans group. Archives of General Psychiatry, 69, 1169-1178.Google Scholar
  49. Morrison, S. E., & Salzman, C. D. (2010). Re-valuing the amygdala. Current Opinion in Neurobiology, 20, 221–230.CrossRefGoogle Scholar
  50. National Heart, Lung, and Blood Institute/National Asthma Education and Prevention Program (2007). Expert panel report: Guidelines for the diagnosis and management of asthma. Full report 2007. NIH Publication No. 07–4051. National Institutes of Health, Bethesda, MD, 2007.Google Scholar
  51. Panksepp, J. (2011). Cross-species affective neuroscience decoding of the primal affective experiences of humans and related animals. PLoS One, 6(9), e21236.CrossRefGoogle Scholar
  52. Patenaude, B., Smith, S. M., Kennedy, D., & Jenkinson, M. (2011). A Bayesian model of shape and appearance for subcortical brain. NeuroImage, 56, 907–922.CrossRefGoogle Scholar
  53. Riedl, M. A., & Nel, A. E. (2008). Importance of oxidative stress in the pathogenesis and treatment of asthma. Current Opinion in Allergy and Clinical Immunology, 8, 49–56.CrossRefGoogle Scholar
  54. Ritz, T., Kullowatz, A., Goldman, G. D., Smith, H.-J., Kanniess, F., Dahme, B., & Magnussen, H. (2010). Airway response to emotional stimuli in asthma: the role of the cholinergic pathway. Journal of Applied Physiology, 108, 1542–1549.CrossRefGoogle Scholar
  55. Ritz, T., Wilhelm, F. H., Meuret, A. E., Gerlach, A. L., & Roth, W. T. (2011). Airway response to emotion- and disease-specific films in asthma, blood phobia, and health. Psychophysiology, 48, 121–135.CrossRefGoogle Scholar
  56. Romero-Frais, E., Vázquez, M. I., Sández, E., Blanco-Aparicio, M., Otero, I., & Verea, H. (2005). Prescription of oral corticosteroids in near-fatal asthma patients: relationship with panic-fear, anxiety and depression. Scandinavian Journal of Psychology, 46, 459–465.CrossRefGoogle Scholar
  57. Rosenkranz, M. A., Esnault, S., Christian, B. T., Crisafi, G., Gresham, L. K., Higgins, A. T., Moore, M. N., Moore, S. M., Weng, H. Y., Salk, R. H., Busse, W. W., & Davidson, R. J. (2016). Mind-body interactions in the regulation of airway inflammation in asthma: a PET study of acute and chronic stress. Brain, Behavior, and Immunity, 58, 18–30. Scholar
  58. Schienle, A., Wabnegger, A., & Scharmüller, W. (2014). Effects of cognitive behavior therapy on regional brain volume in spider-phobic patients: preliminary results. Journal of Anxiety Disorders, 28, 276–279.CrossRefGoogle Scholar
  59. Scott, K. M., Von Korff, M., Ormel, J., Zhang, M. Y., Bruffaerts, R., Alonso, J., Kessler, R. C., Tachimori, H., Karam, E., Levinson, D., Bromet, E. J., Posada-Villa, J., Gasquet, I., Angermeyer, M. C., Borges, G., de Girolamo, G., Herman, A., & Haro, J. M. (2007). Mental disorders among adults with asthma: results from the world mental health survey. General Hospital Psychiatry, 29, 123–133.CrossRefGoogle Scholar
  60. Uono, S., Sato, W., Kochiyama, T., Kubota, Y., Sawada, R., Yoshimura, S., & Toichi, M. (2017). Putamen volume is negatively correlated with the ability to recognize fearful facial expressions. Brain Topography, 30, 774–784.CrossRefGoogle Scholar
  61. von Leupoldt, A., Sommer, T., Kegat, S., Eippert, F., Baumann, H. J., Klose, H., Dahme, B., & Büchel, C. (2009). Down-regulation of insular cortex responses to dyspnea and pain in asthma. American Journal of Respiratory and Critical Care Medicine, 180, 232–238.CrossRefGoogle Scholar
  62. von Leupoldt, A., Brassen, S., Baumann, H. J., Klose, H., & Büchel, C. (2011). Structural brain changes related to disease duration in patients with asthma. PLoS One, 6, e23739.CrossRefGoogle Scholar
  63. Wagner, P. D., Hedenstierna, G., & Rodriguez-Roisin, R. (1996). Gas exchange, expiratory flow obstruction and the clinical spectrum of asthma. European Respiratory Journal, 9, 1278–1282.CrossRefGoogle Scholar
  64. Wang, Q., Verweij, E. W., Krugers, H. J., Joels, M., Swaab, D. F., & Lucassen, P. J. (2014). Distribution of the glucocorticoid receptor in the human amygdala; changes in mood disorder patients. Brain Structure and Function, 219, 1615–1626.CrossRefGoogle Scholar
  65. Webster, K. E., & Colrain, I. M. (2002). P3-specific amplitude reductions to respiratory and auditory stimuli in subjects with asthma. American Journal of Respiratory and Critical Care Medicine, 166, 47–52.CrossRefGoogle Scholar
  66. Yoo, H. K., Kim, M. J., Kim, S. J., Sung, Y. H., Sim, M. E., Lee, Y. S., Song, S. Y., Kee, B. S., & Lyoo, I. K. (2005). Putaminal gray matter volume decrease in panic disorder: an optimized voxel-based morphometry study. European Journal of Neuroscience, 22, 2089–2094.CrossRefGoogle Scholar
  67. Yoon, S., Kim, J. E., Kim, G. H., Kang, H. J., Kim, B. R., Jeon, S., Im, J. J., Hyun, H., Moon, S., Lim, S. M., & Lyoo, I. K. (2016). Subregional shape alterations in the amygdala in patients with panic disorder. PLoS One, 11, e0157856.CrossRefGoogle Scholar
  68. Zhang, H., Wang, X., Lin, J., Sun, Y., Huang, Y., Yang, T., Zheng, S., Fan, M., & Zhang, J. (2012). Grey and white matter abnormalities in chronic obstructive pulmonary disease: a case control study. BMJ Open, 2, e000844.CrossRefGoogle Scholar
  69. Zigmond, A. S., & Snaith, R. P. (1983). The hospital anxiety and depression scale. Acta Psychiatrica Scandinavica, 67, 361–370.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Thomas Ritz
    • 1
    Email author
  • Juliet L. Kroll
    • 1
  • Sina Aslan
    • 2
    • 3
    • 4
  • Thomas Janssens
    • 5
  • David A. Khan
    • 2
  • Amy E. Pinkham
    • 4
  • E. Sherwood Brown
    • 2
  1. 1.Department of PsychologySouthern Methodist UniversityDallasUSA
  2. 2.The University of Texas Southwestern Medical CenterDallasUSA
  3. 3.Advance MRI LLCFriscoUSA
  4. 4.The University of Texas at DallasDallasUSA
  5. 5.KU LeuvenLeuvenBelgium

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