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Panic disorder: from respiration to the homeostatic brain

  • Giampaolo Perna (a1), Daniela Caldirola (a1) and Laura Bellodi (a1)

There is some experimental evidence to support the existence of a connection between panic and respiration. However, only recent studies investigating the complexity of respiratory physiology have revealed consistent irregularities in respiratory pattern, suggesting that these abnormalities might be a vulnerability factor to panic attacks. The source of the high irregularity observed, together with unpleasant respiratory sensations in patients with panic disorder (PD), is still unclear and different underlying mechanisms might be hypothesized. It could be the result of compensatory responses to abnormal respiratory inputs or an intrinsic deranged activity in the brainstem network shaping the respiratory rhythm. Moreover, since basic physiological functions in the organism are strictly interrelated, with reciprocal modulations and abnormalities in cardiac and balance system function having been described in PD, the respiratory findings might arise from perturbations of these other basic systems or a more general dysfunction of the homeostatic brain. Phylogenetically ancient brain circuits process physiological perceptions/sensations linked to homeostatic functions, such as respiration, and the parabrachial nucleus might filter and integrate interoceptive information from the basic homeostatic functions. These physiological processes take place continuously and subconsciously and only occasionally do they pervade the conscious awareness as ‘primal emotions’. Panic attacks could be the expression of primal emotion arising from an abnormal modulation of the respiratory/homeostatic functions.

Corresponding author
Giampaolo Perna MD PhD, Anxiety Disorders Clinical and Research Unit, Istituto Scientifico H. San Raffaele, Vita-Salute University, 20 Via Stamira d'Ancona, 20127, Milan, Italy. Tel.(39)-02-26433211; Fax: (39)-02 26433265. E-mail:
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1.Bellodi, L, Perna, G.The Panic Respiration Connection. Milan, Italy: Medical Media, 1998.
2.Griez, E, Perna, G.Anxiety and respiration. In: Davidson, JR, Nutt, D, eds. Anxiety Disorders. Oxford, UK: Blackwell Science Ltd, 2003.
3.Freud, S.The Justification for Detaching from Neurasthenia a Particular Syndrome: the Anxiety Neurosis (1894). Collected Papers. London: Hogart Press 1950: 76127.
4.Anderson, DJ, Noyes, R Jr, Crowe, RR.A comparison of panic disorder and generalized anxiety disorder. Am J Psychiatry 1984;141: 572575.
5.Ley, R.Agoraphobia, the panic attack and the hyperventilation syndrome. Behav Res Ther 1985;23: 7981.
6.Klein, DF.False suffocation alarms, spontaneous panics, and related conditions. An integrative hypothesis. Arch General Psychiatry 1993;50: 306317.
7.Garssen, B, Van Veenendaal, W, Bloemink, R.Agoraphobia and the hyperventilation syndrome. Behav Res Ther 1983;21: 643649.
8.Cowley, DS, Roy-Byrne, PP.Hyperventilation and panic disorder. Am J Med 1987;83: 929937. Ruiter, C, Garssen, B, Rijken, H, Kraaimaat, F.The hyperventilation syndrome in panic disorder, agoraphobia and generalized anxiety disorder. Behav Res Ther 1989;27: 447452.
10.Gorman, JM, Askanazi, J, Liebowitz, MRet al. Response to hyperventilation in a group of patients with panic disorder. Am J Psychiatry 1984;141: 857861.
11.Griez, E, Zandbergen, J, Lousberg, H, Van Den Hout, M.Effects of low pulmonary CO2 on panic anxiety. Compr Psychiatry 1988;29: 490497.
12.Antony, MM, Brown, TA, Barlow, DH.Response to hyperventilation and 5.5% CO2 inhalation of subjects with types of specific phobia, panic disorder, or no mental disorder. Am J Psychiatry 1997;154: 10891095.
13.Liebowitz, MR, Gorman, JM, Fyer, AJet al. Lactate provocation of panic attacks. II. Biochemical and physiological findings. Arch General Psychiatry 1985;42: 709719.
14.Gorman, JM, Liebowitz, MR, Fyer, AJ, Fyer, MR, Klein, DF.Possible respiratory abnormalities in panic disorder. Psychopharmacol Bull 1986;22: 797801.
15.van Den Hout, MA, Hoekstra, R, Arntz, A, Christiaanse, M, Ranschaert, W, Schouten, E.Hyperventilation is not diagnostically specific to panic patients. Psychosom Med 1992;54: 182191.
16.Gorman, JM, Papp, LA, Coplan, JDet al. Anxiogenic effects of CO2 and hyperventilation in patients with panic disorder. Am J Psychiatry 1994;151: 547553.
17.Zandbergen, J, Lousberg, Hh, Pols, H, De Loof, C, Griez, EJ.Hypercarbia versus hypocarbia in panic disorder. J Affect Disord 1990;18: 7581.
18.Gorman, JM, Papp, LA, Martinez, Jet al. High-dose carbon dioxide challenge test in anxiety disorder patients. Biol Psychiatry 1990;28: 743757.
19.Carr, RE.Panic disorder and asthma. J Asthma 1999;36: 143152.
20.Perna, G, Bertani, A, Politi, E, Colombo, G, Bellodi, L.Asthma and panic attacks. Biol Psychiatry 1997;42: 625630.
21.Smoller, JW, Otto, MW.Panic, dyspnea, and asthma. Curr Opin Pulm Med 1998;4: 4045.
22.Davies, SJ, Jackson, PR, Ramsay, LE.Dysfunctional breathing and asthma. Panic disorder needs to be considered. Br Med J 2001;323: 631 (discussion: 631–632).
23.Karajgi, B, Rifkin, A, Doddi, S, Kolli, R.The prevalence of anxiety disorders in patients with chronic obstructive pulmonary disease. Am J Psychiatry 1990;147: 200201.
24.Yellowlees, PM, Haynes, S, Potts, N, Ruffin, RE.Psychiatric morbidity in patients with life-threatening asthma: initial report of a controlled study. Med J Aust 1988;149: 246249.
25.Perna, G, Marconi, C, Battaglia, M, Bertani, A, Panzacchi, A, Bellodi, L.Subclinical impairment of lung airways in patients with panic disorder. Biol Psychiatry 1994;36: 601605.
26.Spinhoven, P, Ros, M, Westgeest, A, Van der Does, AJ.The prevalence of respiratory disorders in panic disorder, major depressive disorder and V-code patients. Behav Res Ther 1994;32: 647649.
27.Verburg, K, Griez, E, Meijer, J, Pols, H.Respiratory disorders as a possible predisposing factor for panic disorder. J Affect Disord 1995;33: 129134.
28.Verburg, C, Perna, G, Griez, E.A case study of the 35% CO2 challenge. In: Griez, E, Faravelli, C, Nutt, D, Zohar, J, eds. Anxiety Disorders. An Introduction to Clinical Management and Research. Chichester, UK: John Wiley, 2001: 341356.
29.Beck, JG, Ohtake, PJ, Shipherd, JC.Exaggerated anxiety is not unique to CO2 in panic disorder: a comparison of hypercapnic and hypoxic challenges. J Abnorm Psychol 1999;108: 473482.
30.Beck, JG, Shipherd, JC, Ohtake, P.Do panic symptom profiles influence response to a hypoxic challenge in patients with panic disorder? A preliminary report. Psychosom Med 2000;62: 678683.
31.Klein, DF.Testing the suffocation false alarm theory of panic disorder. Anxiety 1994;1: 17.
32.Klein, DF.Panic disorder and agoraphobia: hypothesis hothouse. J Clin Psychiatry 1996;57(Suppl. 6):2127.
33.Gorman, JM, Fyer, MR, Goetz, Ret al. Ventilatory physiology of patients with panic disorder. Arch General Psychiatry 1988;45: 3139.
34.Fishman, SM, Carr, DB, Beckett, A, Rosenbaum, JF.Hypercapneic ventilatory response in patients with panic disorder before and after alprazolam treatment and in pre- and postmenstrual women. J Psychiatr Res 1994;28: 165170.
35.Lousberg, H, Griez, E, Van Den Hout, MA.Carbon dioxide chemosensitivity in panic disorder. Acta Psychiatr Scand 1988;77: 214218.
36.Bocola, V, Trecco, MD, Fabbrini, G, Paladini, C, Sollecito, A, Martucci, N.Antipanic effect of fluoxetine measured by CO2 challenge test. Biol Psychiatry 1998;43: 612615.
37.Papp, LA, Martinez, JM, Klein, DF, Coplan, JD, Gorman, JM.Rebreathing tests in panic disorder. Biol Psychiatry 1995;38: 240245.
38.Zandbergen, J, Pols, H, De Loof, C, Griez, EJ.Ventilatory response to CO2 in panic disorder. Psychiatry Res 1991;39: 1319.
39.Woods, SW, Charney, DS, Loke, J, Goodman, WK, Redmond, DE Jr, , Heninger, GR.Carbon dioxide sensitivity in panic anxiety. Ventilatory and anxiogenic response to carbon dioxide in healthy subjects and patients with panic anxiety before and after alprazolam treatment. Arch General Psychiatry 1986; 43: 900909.
40.Katzman, MA, Struzik, L, Vijay, N, Coonerty-Femiano, A, Mahamed, S, Duffin, J.Central and peripheral chemoreflexes in panic disorder. Psychiatry Res 2002;113(1–2):181192.
41.Zandbergen, J, Strahm, M, Pols, H, Griez, EJ.Breath-holding in panic disorder. Compr Psychiatry 1992;33: 4751.
42.Asmundson, GJ, Stein, MB.Triggering the false suffocation alarm in panic disorder patients by using a voluntary breath-holding procedure. Am J Psychiatry 1994;151: 264266.
43.Van der Does, WA J.Voluntary breath holding: not a suitable probe of the suffocation alarm in panic disorder. Behav Res Ther 1997;35: 779784.
44.Roth, WT, Wilhelm, FH, Trabert, W.Voluntary breath holding in panic and generalized anxiety disorders. Psychosom Med 1998;60: 671679.
45.Berkenbosch, A, Bovill, JG, Dahan, A, Degoed, J, Olievier, IC W.The ventilatory CO2 sensitivities from Read's rebreathing method and the steady-state method are not equal in man. J Physiol 1989;411: 367377.
46.Holt, PEm Andrews, G.Hyperventilation and anxiety in panic disorder, social phobia, GAD and normal controls. Behav Res Ther 1989;27: 453460.
47.Papp, LA, Klein, DF, Gorman, JM.Carbon dioxide hypersensitivity, hyperventilation, and panic disorder. Am J Psychiatry 1993;150: 11491157.
48.Maddock, RJ, Carter, CS.Hyperventilation-induced panic attacks in panic disorder with agoraphobia. Biol Psychiatry 1991;29: 843854.
49.Papp, LA, Martinez, JM, Klein, DFet al. Respiratory psychophysiology of panic disorder: three respiratory challenges in 98 subjects. Am J Psychiatry 1997;154: 15571565.
50.Hegel, MT, Ferguson, RJ.Psychophysiological assessment of respiratory function in panic disorder: evidence for a hyperventilation subtype. Psychosom Med 1997; 59: 224230.
51.Lum, LC.The syndrome of habitual chronic hyperventilation. In: Hill, OW, ed. Modern Trends in Psycosomatic Medicine. Saint Louis, MO, USA: Elsevier Science & Technology Books , 1976.
52.Clark, DM.A cognitive approach to panic. Behav Res Ther 1986;24: 441470.
53.Holloway, W, McNally, RJ.Effects of anxiety sensitivity on the response to hyperventilation. J Abnorm Psychol 1987;96: 330334.
54.McNally, RJ, Eke, M.Anxiety sensitivity, suffocation fear, and breath-holding duration as predictors of response to carbon dioxide challenge. J Abnorm Psychol 1996;105: 146149.
55.Gorman, JM, Kent, JM, Sullivan, GM, Coplan, JD.Neuroanatomical hypothesis of panic disorder, revised. Am J Psychiatry 2000;157: 493505.
56.Sinha, S, Papp, LA, Gorman, JM.How study of respiratory physiology aided our understanding of abnormal brain function in panic disorder. J Affect Disord 2000;61: 191200.
57.Sinha, SS, Coplan, JD, Pine, DS, Martinez, JA, Klein, DF, Gorman, JM.Panic induced by carbon dioxide inhalation and lack of hypothalamic-pituitary-adrenal axis activation. Psychiatry Res 1999;86: 9398.
58.Uhde, TW, Boulenger, JP, Roy-Byrne, PP, Geraci, MF, Vittone, BJ, Post, RM.Longitudinal course of panic disorder: clinical and biological considerations. Prog Neuropsychopharmacol Biol Psychiatry 1985;9: 3951.
59.Coplan, JD, Goetz, R, Klein, DFet al. Plasma cortisol concentrations preceding lactate-induced panic. Psychological, biochemical, and physiological correlates. Arch General Psychiatry 1998;55: 130136.
60.Abelson, JA, Weg, JG, Nesse, RM, Curtis, GC.Neuroendocrine response to laboratory panic: cognitive intervention in the doxapram model. Psychoneuroendocrinology 1996;21: 375390.
61.Carr, DB, Sheehan, DV, Surman, OSet al. Neuroendocrine correlates of lactate-induced anxiety and their response to chronic alprazolam therapy. Am J Psychiatry 1986;143: 483494.
62.Hollander, E, Liebowitz, M, Gorman, J, Cohen, B, Fyer, A, Klein, DF.Cortisol and sodium lactate induced panic. Arch General Psychiatry 1989;46: 135140.
63.Seier, FE, Kellner, M, Yassuridis, A, Hesse, R, Strian, F, Wiedermann, K.Automatic reactivity and hormonal secretion in lactate induced panic attacks. Am J Physiol 1997;272: H2630H2638.
64.Perna, G, Bertani, A, Caldirola, D, Di Pasquale, D, Migliarese, G, Bellodi, L.Modulation of hyperreactivity to 35% CO2 after one-week of treatment with paroxetine and reboxetine: a double-blind, randomized study. J Clin Psychopharmacology, submitted.
65.Bertani, A, Perna, G, Migliarese, Get al. Comparison of treatment with paroxetine and reboxetine in panic disorder. A randomized, single-blind study. Pharmacopsychiatry, submitted.
66.Bellodi, L, Caldirola, D, Bertani, A.Does the brain noradrenaline network mediate the effects of the CO2 challenge. J Psychopharmacology 2003;17(263–4):267268.
67.Klein, DF.Response differences of spontaneous panic and fear. Arch General Psychiatry 2002;59: 567569.
68.Pincus, SM.Approximate entropy as a measure of system complexity. Proc Natl Acad Sci USA 1991;88: 22972301.
69.Stein, MB, Millar, TW, Larsen, DK, Kryger, Mh.Irregular breathing during sleep in patients with panic disorder. Am J Psychiatry 1995;152: 11681173.
70.Martinez, JM, Papp, LA, Coplan, JDet al. Ambulatory monitoring of respiration in anxiety. Anxiety 1996;2: 296302.
71.Bystritsky, A & Shapiro, D.Continuous physiological changes and subjective reports in panic patients: a preliminary methodological report. Biol Psychiatry 1992;32: 766777.
72.Bystritsky, A, Craske, M, Maidenberg, E, Vapnik, T, Shapiro, D.Autonomic reactivity of panic patients during a CO2 inhalation procedure. Depress Anxiety 2000; 11: 1526.
73.Abelson, JA.Respiratory irregularity in panic patients may reflect excessive sighing. Biol Psychiatry 2000; 47(Suppl. 1):157158.
74.Abelson, JL, Weg, JG, Nesse, RM, Curtis, GC.Persistent respiratory irregularity in patients with panic disorder. Biol Psychiatry 2001;49: 588595.
75.Wilhelm, Fh, Trabert, W, Roth, WT.Characteristics of sighing in panic disorder. Biol Psychiatry 2001;49: 606614.
76.Coryell, W, Fyer, A, Pine, D, Martinez, J, Arndt, S.Aberrant respiratory sensitivity to CO (2) as a trait of familial panic disorder. Biol Psychiatry 2001;49: 582587.
77.Pine, DS, Klein, RG, Coplan, JDet al. Differential carbon dioxide sensitivity in childhood anxiety disorders and nonill comparison group. Arch General Psychiatry 2000;57: 960967.
78.Pine, DS, Coplan, JD, Papp, LAet al. Ventilatory physiology of children and adolescents with anxiety disorders. Arch General Psychiatry 1998;55: 123129.
79.Pincus, SM, Gladstone, IM, Ehrenkranz, RA.A regularity statistic for medical data analysis. J Clin Monit 1991;7: 335345.
80.Yeragani, VK, Radhakrishna, RK, Tancer, M, Uhde, T.Nonlinear measures of respiration: respiratory irregularity and increased chaos of respiration in patients with panic disorder. Neuropsychobiology 2002;46: 111120.
81.Caldirola, D, Bellodi, L, Caumo, A, Migliarese, G, Perna, G.Approximate entropy of respiratory patterns in panic disorder. Am J Psychiatry 2004;161: 7987.
82.Perna, G, Ieva, A, Caldirola, D, Bertani, A, Bellodi, L.Respiration in children at risk for panic disorder. Arch General Psychiatry 2002;59: 185186.
83.Capra, F.The Web of Life. New York: Anchor Books, 1996.
84.Goldberger, AL.Non-linear dynamics for clinicians: chaos theory, fractals, and complexity at the bedside. Lancet 1996;347(9011):13121314.
85.Prigogine, I.The philosophy of instability. Futures 1989;21: 396400.
86.Remmers JE. Central neural control of breathing. In: Altose MD, Kawakami Y (eds). Control of Breathing in Health and Disease (Lung Biology in Health and Disease). New York: Marcel Dekker, 1999.
87.Horn, EM, Waldrop, TG.Suprapontine control of respiration. Respiration Physiol 1998;114: 201211.
88.Lieske, SP, Thoby-Brisson, M, Telgkamp, P, Ramirez, JM.Reconfiguration of the neural network controlling multiple breathing patterns: eupnea, sighs and gasps. Neural Neuroscience 2000;3: 600607.
89.St-John, WM & Paton, JF R.Respiratory-modulated neuronal activities of the rostral medulla which may generate gasping. Respiratory Physiology and Neurobiology 2003;135: 97101.
90.Katz, DM.Neuronal growth factors and development of respiratory control. Respiratory Physiol Neurobiol 2003;135: 155165.
91.Boiten, FA, Frijda, NH, Wientjes, CJ.Emotions and respiratory patterns: review and critical analysis. Int J Psychophysiol 1994;17: 103128.
92.Orem, J.The activity of late inspiratory cells during the behavioral inhibition of inspiration. Brain Res 1988;458: 224230.
93.Himle, J, Thyer, BA, Fischer, DJ.Prevalence of smoking among anxious patients. Phobia Prac Res J 1988;1: 2531.
94.Breslau, N, Kilbey, M, Andreski, P.Nicotine dependence, major depression and anxiety in young adults. Arch General Psychiatry 1991;48: 10691074.
95.Breslau, N, Klein, DF.Smoking and panic attacks: an epidemiologic investigation. Arch General Psychiatry 1999;56: 11411147.
96.Khoo, MC.Determinants of ventilatory instability and variability. Respir Physiol 2000;122(2–3):167182.
97.Ferini-Strambi, L, Spera, A, Oldani, A, Battaglia, M, Bianchi, A, Cerutti, S.Cardiac autonomic regulation during sleep in panic disorder. J Neurol Neurosurg Psychiatry 1996;61: 421422.
98.Yeragani, VK, Sobolewski, E, Igel, Get al. Decreased heart-period variability in patients with panic disorder. a study of Holter ECG records. Psychiatry Res 1998; 78(1–2):8999.
99.Yeragani, VK, Nadella, R, Hinze, B, Yeragani, S, Jampala, VC.Nonlinear measures of heart period variability: decreased measures of symbolic dynamics in patients with panic disorder. Depress Anxiety 2000; 12: 6777.
100.Radhakrishna, RK, Yeragani, VK.Decreased measures of chaos and increased nonlinearity in patients with panic disorder. Auton Neurosci 2001;88: 99108.
101.McCraty, R, Atkinson, M, Tomasino, D, Stuppy, WP.Analysis of twenty-four hour heart rate variability in patients with panic disorder. Biol Psychol 2001;56: 131150.
102.Srinivasan, K, Ashok, MV, Vaz, M, Yeragani, VK.Decreased chaos of heart rate time series in children of patients with panic disorder. Depression Anxiety 2002;15: 159167.
103.Yeragani, VK, Radhakrishna, KA.Non linear measures of QT interval series: novel indices of cardiac repolarization lability: MEDqthr LLEqthr. Psychiatry Res 2003;117: 177190.
104.Balaban, CD.Vestibular nucleus projections to the parabrachial nucleus in rabbits: implications for vestibular influences on the autonomic nervous system. Exp Brain Res 1996;108: 367381.
105.Balaban, CD, Thayer, JF.Neurological bases for balance-anxiety links. J Anxiety Disord 2001; 15(1–2):5379.
106.Yardley, L, Gresty, M, Bronstein, A, Beyts, J.Changes in heart rate and respiration rate in patients with vestibular dysfunction following head movements which provoke dizziness. Biol Psychol 1998;49 (1–2):95108.
107.Perna, G, Dario, A, Caldirola, D, Stefania, B, Cesarani, A, Bellodi, L.Panic disorder: the role of the balance system. J Psychiatr Res 2001;35: 279286.
108.Perna, G, Alpini, D, Caldirola, D, Raponi, G, Cesarani, A, Bellodi, L.Serotonergic modulation of the balance system in panic disorder: an open study. Depression Anxiety 2003;17: 101106.
109.Damasio, AR. The feeling of what happens. Body, Emotion and the Making of Consciousness. New York, NY, USA: Harcourt, 1999.
110.Parson, LM, Egan, G, Liotti, M, Brannan, S, Denton, D.Neuroimaging evidence implicating cerebellum in the experience of hypercapnia and hunger for air. Proc Natl Acad Sci 2001;98: 20412046.
111.Liotti, M, Brannan, S, Egan, Get al. Brain responses associated with consciousness of breathlessness (air hunger). Proc Natl Acad Sci USA 2001;98: 20352040.
112.Brannan, S, Liotti, M, Egan, Get al. Neuroimaging of cerebral activations and deactivations associated with hypercapnia and hunger for air. Proc Natl Acad Sci USA 2001;98: 20292034.
113.Denton, D, Shade, R, Zamarippa, Fet al. Neuroimaging of genesis and satiation of thirst and an interoceptor-driven theory of origins of primary consciousness. Proc Natl Acad Sci USA 1999;96: 53045309.
114.Herbert, H, Moga, MM, Saper, CB.Connections of the parabrachial nucleus with the nucleus of the solitary tract and the medullary reticular formation in the rat. J Comp Neurol 1990;293: 540580.
115.Fulwiler, CE, Saper, CB.Subnuclear organization of the efferent connections of the parabrachial nucleus in the rat. Brain Res 1984;319: 229259.
116.Shapiro, RE, Miselis, RR.The central neural connections of the area postrema of the rat. J Comp Neurol 1985;234: 344364.
117.Morillo, AM, NUNEZ-ABADES, PA, Gaytan, SP, Pasaro, R.Brain stem projections by axonal collaterals to the rostral and caudal ventral respiratory group in the rat. Brain Res Bull 1995;37: 205211.
118.Dobbins, EG, Feldman, JL.Brainstem network controlling descending drive to phrenic motoneurons in rat. J Comp Neurol 1994;347: 6486.
119.Saleh, TM, Connell, BJ.The parabrachial nucleus mediates the decreased cardiac baroreflex sensitivity observed following short-term visceral afferent activation. Neuroscience 1998;87: 135146.
120.Mutolo, D, Bongianni, F, Carfi, M, Pantaleo, T.Respiratory responses to chemical stimulation of the parabrachial nuclear complex in the rabbit. Brain Res 1998;807(1–2):182186.
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