Skip to main content

A Neural Systems Approach to the Study of the Respiratory-Type Panic Disorder

  • Chapter
  • First Online:

Abstract

Panic disorder (PD) patients are exquisitely and specifically sensitive to inhalations of 5–7 % carbon dioxide and infusions of 0.5 M sodium lactate. Another startling feature of clinical panic is the lack of increments of the ‘stress hormones’ corticotropin, cortisol and prolactin. PD is also more frequent in women and shows high comorbidity with childhood separation anxiety, late luteal period dysphoric disorder and depression. The hypothalamus-pituitary-adrenal axis is nevertheless activated in fear-like panics marked by palpitations, tremor and sweating, that are devoid of suffocation symptoms. These and other data suggest the existence of both respiratory and non-respiratory types of panic attacks. Increasing evidence suggests, on the other hand, that panics are mediated at midbrain’s dorsal periaqueductal grey matter (DPAG). Therefore, here we summarized data showing that: (1) the DPAG harbors a suffocation alarm system which is activated by low intravenous doses of potassium cyanide (KCN); (2) KCN evokes defensive behaviors that are facilitated by hypercapnia, blocked by lesions of DPAG and attenuated by clinically effective treatments with panicolytics; (3) DPAG stimulations do not change the stress hormones when escape is prevented by stimulating the rats in a small compartment; (4) DPAG-evoked panics responses are facilitated in neonatally-isolated adult rats, a model of childhood separation anxiety; (5) DPAG-evoked panic-like behaviors are facilitated in diestrus phase of rat ovulatory cycle. It is proposed a neural model of panic attacks in which the PAG is the fulcrum of threatening signals from both forebrain and hindbrain. This model emphasizes the role of PAG as a suffocation alarm system.

This is a preview of subscription content, log in via an institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Freud S. On the right to separate from neurasthenia a definite symptom-complex as anxiety neurosis. In: Brill JAA, editor. Selected papers on hysteria and other psychoneuroses. New York: The Journal of Nervous and Mental Disease Publishing Company; 1912. p. 133–54. Chapter VI.

    Google Scholar 

  2. Freud S. The psychotherapy of hysteria. In: Brill JAA, editor. Selected papers on hysteria and other psychoneuroses. New York: The Journal of Nervous and Mental Disease Publishing Company; 1912. p. 75–120. Chapter IV.

    Google Scholar 

  3. Freud S. Obsessions and phobias: their psychical mechanism and their aetiology. Complete psychological works, standard edition. London: Hogarth Press; 1962. p. 81.

    Google Scholar 

  4. APA. Diagnostic and statistical manual of mental disorders. 3rd ed. Washington, DC: American Psychiatry Association; 1980.

    Google Scholar 

  5. Drury A. The percentage of carbon dioxide in the alveolar air, and the tolerance to accumulating carbon dioxide in cases of so-called “irritable heart” of soldiers. Heart. 1920;7:165–73.

    Google Scholar 

  6. Cohen ME, White PD. Life situations, emotions and neurocirculatory asthenia (anxiety neurosis, neurasthenia, effort syndrome). Res Publ Assoc Res Nerv Ment Dis. 1949;29:832–69.

    CAS  PubMed  Google Scholar 

  7. Pitts FN, McClure JN. Lactate metabolism in anxiety neurosis. N Engl J Med. 1967;277:1329–36.

    Article  PubMed  Google Scholar 

  8. Cowley DS, Roy-Byrne PP. Hyperventilation and panic disorder. Am J Med. 1987;83:929–37.

    Article  CAS  PubMed  Google Scholar 

  9. Klein DF, Fink M. Psychiatric reaction patterns to imipramine. Am J Psychiatry. 1962;119:432–8.

    Article  CAS  PubMed  Google Scholar 

  10. Klein DF. Delineation of two drug-responsive anxiety syndromes. Psychopharmacologia. 1964;5:397–408.

    Article  CAS  PubMed  Google Scholar 

  11. Bowlby J. Attachment, separation anxiety, loss. 2nd ed. NY: Basic Books; 1969.

    Google Scholar 

  12. Gorman JM, Askanazi J, Liebowitz MR, Fyer AJ, Stein J, Kinney JM, et al. Response to hyperventilation in a group of patients with panic disorder. Am J Psychiatry. 1984;141:857–61.

    Article  CAS  PubMed  Google Scholar 

  13. Liebowitz MR, Gorman JM, Fyer AJ, Levitt M, Dillon D, Levy G, et al. Lactate provocation of panic attacks: II. Biochemical and physiological findings. Arch Gen Psychiatry. 1985;42:709–19.

    Article  CAS  PubMed  Google Scholar 

  14. Cameron OG, Lee MA, Curtis GC, McCann DS. Endocrine and physiological changes during “spontaneous” panic attacks. Psychoneuroendocrinology. 1987;12:321–31.

    Article  CAS  PubMed  Google Scholar 

  15. Levin AP, Doran AR, Liebowitz MR, Fyer AJ, Gorman JM, Klein DF, et al. Pituitary adrenocortical unresponsiveness in lactate-induced panic. Psychiatry Res. 1987;21:23–32.

    Article  CAS  PubMed  Google Scholar 

  16. Woods SW, Charney DS, McPherson CA, Gradman AH, Heninger GR. Situational panic attacks. Behavioral, physiologic, and biochemical characterization. Arch Gen Psychiatry. 1987;44:365–75.

    Article  CAS  PubMed  Google Scholar 

  17. Woods SW, Charney DS, Goodman WK, Heninger GR. Carbon dioxide-induced anxiety. Behavioral, physiologic, and biochemical effects of carbon dioxide in patients with panic disorders and healthy subjects. Arch Gen Psychiatry. 1988;45:43–52.

    Article  CAS  PubMed  Google Scholar 

  18. Hollander E, Liebowitz MR, Cohen B, Gorman JM, Fyer AJ, Papp LA, et al. Prolactin and sodium lactate-induced panic. Psychiatry Res. 1989;28:181–91.

    Article  CAS  PubMed  Google Scholar 

  19. Hollander E, Liebowitz MR, Gorman JM, Cohen B, Fyer A, Klein DF. Cortisol and sodium lactate-induced panic. Arch Gen Psychiatry. 1989;46:135–40.

    Article  CAS  PubMed  Google Scholar 

  20. Hollander E, Liebowitz MR, DeCaria C, Klein DF. Fenfluramine, cortisol, and anxiety. Psychiatry Res. 1989;31:211–3.

    Article  Google Scholar 

  21. Ehlers A, Margraf J, Roth WT, Taylor CB, Maddock RJ, Sheikh J, et al. Lactate infusions and panic attacks: do patients and controls respond differently? Psychiatry Res. 1986;17:295–308.

    Article  CAS  PubMed  Google Scholar 

  22. Margraf J, Ehlers A, Roth WT. Sodium lactate infusions and panic attacks: a review and critique. Psychosom Med. 1986;48:23–51.

    Article  CAS  PubMed  Google Scholar 

  23. Clark DM, Salkovskis PM, Ost LG, Breitholtz E, Koehler KA, Westling BE, et al. Misinterpretation of body sensations in panic disorder. J Consult Clin Psychol. 1997;65:203–13.

    Article  CAS  PubMed  Google Scholar 

  24. Klein DF. False suffocation alarms, spontaneous panics, and related conditions. An integrative hypothesis. Arch Gen Psychiatry. 1993;50:306–18.

    Article  CAS  PubMed  Google Scholar 

  25. Klein DF. Panic may be a misfiring suffocation alarm. In: Montgomery SA, editor. Psychopharmacology of panic. 1st ed. New York: Oxford University Press; 1993. p. 67–73.

    Google Scholar 

  26. Shavitt RG, Gentil V, Mandetta R. The association of panic/agoraphobia and asthma. Contributing factors and clinical implications. Gen Hosp Psychiatry. 1992;14:420–3.

    Article  CAS  PubMed  Google Scholar 

  27. Preter M, Klein DF. Panic, suffocation false alarms, separation anxiety and endogenous opioids. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32:603–12.

    Article  CAS  PubMed  Google Scholar 

  28. Griez E, Schruers K. Experimental pathophysiology of panic. J Psychosom Res. 1998;45:493–503.

    Article  CAS  PubMed  Google Scholar 

  29. Liebowitz MR, Fyer AJ, Gorman JM, Dillon D, Davies S, Stein JM, et al. Specificity of lactate infusions in social phobia versus panic disorders. Am J Psychiatry. 1985;142:947–50.

    Article  CAS  PubMed  Google Scholar 

  30. Rifkin A, Klein DF, Dillon D, Levitt M. Blockade by imipramine or desipramine of panic induced by sodium lactate. Am J Psychiatry. 1981;138:676–7.

    Article  CAS  PubMed  Google Scholar 

  31. Liebowitz MR, Fyer AJ, Gorman JM, Dillon D, Appleby IL, Levy G, et al. Lactate provocation of panic attacks: I. Clinical and behavioral findings. Arch Gen Psychiatry. 1984;41:764–70.

    Article  CAS  PubMed  Google Scholar 

  32. Woods SW, Charney DS, Delgado PL, Heninger GR. The effect of long-term imipramine treatment on carbon dioxide-induced anxiety in panic disorder patients. J Clin Psychiatry. 1990;51:505–7.

    CAS  PubMed  Google Scholar 

  33. Yeragani VK, Pohl R, Balon R, Rainey JM, Berchou R, Ortiz A. Sodium lactate infusion after treatment with tricyclic antidepressants: behavioral and physiological findings. Biol Psychiatry. 1988;24:767–74.

    Article  CAS  PubMed  Google Scholar 

  34. Gittelman-Klein R, Klein DF. School phobia: diagnostic considerations in the light of imipramine effects. J Nerv Ment Dis. 1973;156:199–215.

    Article  CAS  PubMed  Google Scholar 

  35. Battaglia M, Bertella S, Politi E, Bernardeschi L, Perna G, Gabriele A, et al. Age at onset of panic disorder: influence of familial liability to the disease and of childhood separation anxiety disorder. Am J Psychiatry. 1995;152:1362–4.

    Article  CAS  PubMed  Google Scholar 

  36. Klein RG. Is panic disorder associated with childhood separation anxiety disorder? Clin Neuropharmacol. 1995;18 Suppl 2:S7–14.

    Article  Google Scholar 

  37. Battaglia M, Ogliari A, D'Amato F, Kinkead R. Early-life risk factors for panic and separation anxiety disorder: insights and outstanding questions arising from human and animal studies of CO sensitivity. Neurosci Biobehav Rev. 2014;46:455–64.

    Article  PubMed  Google Scholar 

  38. Bernstein GA, Borchardt CM, Perwien AR, Crosby RD, Kushner MG, Thuras PD, et al. Imipramine plus cognitive-behavioral therapy in the treatment of school refusal. J Am Acad Child Adolesc Psychiatry. 2000;39:276–83.

    Article  CAS  PubMed  Google Scholar 

  39. Roberson-Nay R, Klein DF, Klein RG, Mannuzza S, Moulton III JL, Guardino M, et al. Carbon dioxide hypersensitivity in separation-anxious offspring of parents with panic disorder. Biol Psychiatry. 2010;67:1171–7.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Battaglia M, Pesenti-Gritti P, Spatola CA, Ogliari A, Tambs K. A twin study of the common vulnerability between heightened sensitivity to hypercapnia and panic disorder. Am J Med Genet B Neuropsychiatr Genet. 2008;147B:586–93.

    Article  PubMed  Google Scholar 

  41. Roberson-Nay R, Eaves LJ, Hettema JM, Kendler KS, Silberg JL. Childhood separation anxiety disorder and adult onset panic attacks share a common genetic diathesis. Depress Anxiety. 2012;29:320–7.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Preter M, Klein DF. Lifelong opioidergic vulnerability through early life separation: a recent extension of the false suffocation alarm theory of panic disorder. Neurosci Biobehav Rev. 2014;46:10–351.

    Article  Google Scholar 

  43. Lawson EE, Waldrop TG, Eldridge FL. Naloxone enhances respiratory output in cats. J Appl Physiol. 1979;47:1105–11.

    CAS  PubMed  Google Scholar 

  44. Bonham AC. Neurotransmitters in the CNS control of breathing. Respir Physiol. 1995;101:219–30.

    Article  CAS  PubMed  Google Scholar 

  45. van der Schier R, Roozekrans M, van VM, Dahan A, Niesters M. Opioid-induced respiratory depression: reversal by non-opioid drugs. F1000Prime Rep 2014;6:79.

    Google Scholar 

  46. Kalin NH, Shelton SE, Barksdale CM. Opiate modulation of separation-induced distress in non-human primates. Brain Res. 1988;440:285–92.

    Article  CAS  PubMed  Google Scholar 

  47. Kalin NH, Shelton SE, Lynn DE. Opiate systems in mother and infant primates coordinate intimate contact during reunion. Psychoneuroendocrinology. 1995;20:735–42.

    Article  CAS  PubMed  Google Scholar 

  48. Panksepp J, Herman B, Conner R, Bishop P, Scott JP. The biology of social attachments: opiates alleviate separation distress. Biol Psychiatry. 1978;13:607–18.

    CAS  PubMed  Google Scholar 

  49. Panksepp J, Herman BH, Vilberg T, Bishop P, DeEskinazi FG. Endogenous opioids and social behavior. Neurosci Biobehav Rev. 1980;4:473–87.

    Article  CAS  PubMed  Google Scholar 

  50. Deakin JFW, Graeff FG. 5-HT and mechanisms of defence. J Psychopharmacol. 1991;5:305–15.

    Article  CAS  PubMed  Google Scholar 

  51. Graeff FG. Serotonin, the periaqueductal gray and panic. Neurosci Biobehav Rev. 2004;28:239–59.

    Article  CAS  PubMed  Google Scholar 

  52. Canteras NS, Graeff FG. Executive and modulatory neural circuits of defensive reactions: implications for panic disorder. Neurosci Biobehav Rev. 2014;46:352–64.

    Article  PubMed  Google Scholar 

  53. Goetz RR, Klein DF, Gorman JM. Symptoms essential to the experience of sodium lactate-induced panic. Neuropsychopharmacology. 1996;14:355–66.

    Article  CAS  PubMed  Google Scholar 

  54. Dillon DJ, Gorman JM, Liebowitz MR, Fyer AJ, Klein DF. Measurement of lactate-induced panic and anxiety. Psychiatry Res. 1987;20:97–105.

    Article  CAS  PubMed  Google Scholar 

  55. Shioiri T, Someya T, Murashita J, Takahashi S. The symptom structure of panic disorder: a trial using factor and cluster analysis. Acta Psychiatr Scand. 1996;93:80–6.

    Article  CAS  PubMed  Google Scholar 

  56. Perna G, Caldirola D, Namia C, Cucchi M, Vanni G, Bellodi L. Language of dyspnea in panic disorder. Depress Anxiety. 2004;20:32–8.

    Article  PubMed  Google Scholar 

  57. Briggs AC, Stretch DD, Brandon S. Subtyping of panic disorder by symptom profile. Br J Psychiatry. 1993;163:201–9.

    Article  CAS  PubMed  Google Scholar 

  58. Nardi AE, Nascimento I, Valenca AM, Lopes FL, Mezzasalma MA, Zin WA, et al. Respiratory panic disorder subtype: acute and long-term response to nortriptyline, a noradrenergic tricyclic antidepressant. Psychiatry Res. 2003;120:283–93.

    Article  CAS  PubMed  Google Scholar 

  59. Roberson-Nay R, Latendresse SJ, Kendler KS. A latent class approach to the external validation of respiratory and non-respiratory panic subtypes. Psychol Med. 2012;42:461–74.

    Article  CAS  PubMed  Google Scholar 

  60. Schenberg LC, Bittencourt AS, Sudré ECM, Vargas LC. Modeling panic attacks. Neurosci Biobehav Rev. 2001;25:647–59.

    Article  CAS  PubMed  Google Scholar 

  61. Schenberg LC, Schimitel FG, Armini RS, Bernabe CS, Rosa CA, Tufik S, et al. Translational approach to studying panic disorder in rats: hits and misses. Neurosci Biobehav Rev. 2014;46:472–96.

    Article  PubMed  Google Scholar 

  62. Mobbs D, Petrovic P, Marchant JL, Hassabis D, Weiskopf N, Seymour B, et al. When fear is near: threat imminence elicits prefrontal-periaqueductal gray shifts in humans. Science. 2007;317:1079–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Gorman JM, Kent JM, Sullivan GM, Coplan JD. Neuroanatomical hypothesis of panic disorder, revised. Am J Psychiatry. 2000;157:493–505.

    Article  CAS  PubMed  Google Scholar 

  64. Smoller JW, Gallagher PJ, Duncan LE, McGrath LM, Haddad SA, Holmes AJ, et al. The human ortholog of acid-sensing ion channel gene ASIC1a is associated with panic disorder and amygdala structure and function. Biol Psychiatry. 2014;76:902–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Shekhar A, Keim SR. The circum ventricular organs form a potential neural pathway for lactate sensitivity: implications for panic disorder. J Neurosci. 1997;17:9726–35.

    CAS  PubMed  Google Scholar 

  66. Johnson PL, Federici LM, Shekhar A. Etiology, triggers and neurochemical circuits associated with unexpected, expected, and laboratory-induced panic attacks. Neurosci Biobehav Rev. 2014;46:429–54.

    Article  PubMed  Google Scholar 

  67. Gorman JM, Liebowitz MR, Fyer AJ, Stein J. A neuroanatomical hypothesis for panic disorder. Am J Psychiatry. 1989;146:148–61.

    Article  CAS  PubMed  Google Scholar 

  68. Blanchard DC, Griebel G, Blanchard RJ. The mouse defense test battery: pharmacological and behavioral assays for anxiety and panic. Eur J Pharmacol. 2003;463:97–116.

    Article  CAS  PubMed  Google Scholar 

  69. Beitman BD, Basha I, Flaker G, DeRosear L, Mukerji V, Lamberti J. Non-fearful panic disorder: panic attacks without fear. Behav Res Ther. 1987;25:487–92.

    Article  CAS  PubMed  Google Scholar 

  70. Fleet RP, Martel JP, Lavoie KL, Dupuis G, Beitman BD. Non-fearful panic disorder: a variant of panic in medical patients? Psychosomatics. 2000;41(4):311–20.

    Article  CAS  PubMed  Google Scholar 

  71. Fleet RP, Lavoie KL, Martel JP, Dupuis G, Marchand A, Beitman BD. Two-year follow-up status of emergency department patients with chest pain: was it panic disorder? CJEM. 2003;5:247–54.

    Article  PubMed  Google Scholar 

  72. Figueiredo HF, Bodie BL, Tauchi M, Dolgas CM, Herman JP. Stress integration after acute and chronic predator stress: differential activation of central stress circuitry and sensitization of the hypothalamo-pituitary-adrenocortical axis. Endocrinology. 2003;144(12):5249–58.

    Article  CAS  PubMed  Google Scholar 

  73. Hauger RL, Millan MA, Lorang M, Harwood JP, Aguilera G. Corticotropin-releasing factor receptors and pituitary adrenal responses during immobilization stress. Endocrinology. 1988;123:396–405.

    Article  CAS  PubMed  Google Scholar 

  74. Fredrikson M, Sundin O, Frankenhaeuser M. Cortisol excretion during the defense reaction in humans. Psychosom Med. 1985;47:313–9.

    Article  CAS  PubMed  Google Scholar 

  75. Furlan PM, DeMartinis N, Schweizer E, Rickels K, Lucki I. Abnormal salivary cortisol levels in social phobic patients in response to acute psychological but not physical stress. Biol Psychiatry. 2001;50:254–9.

    Article  CAS  PubMed  Google Scholar 

  76. Wiest G, Lehner-Baumgartner E, Baumgartner C. Panic attacks in an individual with bilateral selective lesions of the amygdala. Arch Neurol. 2006;63:1798–801.

    Article  PubMed  Google Scholar 

  77. Feinstein JS, Buzza C, Hurlemann R, Follmer RL, Dahdaleh NS, Coryell WH, et al. Fear and panic in humans with bilateral amygdala damage. Nat Neurosci. 2013;16:270–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Wilent WB, Oh MY, Buetefisch CM, Bailes JE, Cantella D, Angle C, et al. Induction of panic attack by stimulation of the ventromedial hypothalamus. J Neurosurg. 2010;112:1295–8.

    Article  PubMed  Google Scholar 

  79. Charney DS, Redmond DE. Neurobiological mechanism in human anxiety: evidence supporting central noradrenergic hyperactivity. Neuropharmacology. 1983;22:1531–6.

    Article  CAS  PubMed  Google Scholar 

  80. Charney DS, Heninger GR, Redmond Jr DE. Yohimbine induced anxiety and increased noradrenergic function in humans: effects of diazepam and clonidine. Life Sci. 1983;33:19–29.

    Article  CAS  PubMed  Google Scholar 

  81. Charney DS, Woods SW, Goodman WK, Heninger GR. Neurobiological mechanisms of panic anxiety: biochemical and behavioral correlates of yohimbine-induced panic attacks. Am J Psychiatry. 1987;144:1030–6.

    Article  CAS  PubMed  Google Scholar 

  82. Elam M, Yao T, Thoren P, Svensson TH. Hypercapnia and hypoxia: chemoreceptor-mediated control of locus coeruleus neurons and splanchnic, sympathetic nerves. Brain Res. 1981;222:373–81.

    Article  CAS  PubMed  Google Scholar 

  83. Liebowitz MR, Fyer AJ, McGrath PA, Klein DF. Clonidine treatment of panic disorder. Psychopharmacol Bull. 1981;17:122–3.

    Google Scholar 

  84. Hoehn-Saric R, Merchant AF, Keyser ML, Smith VK. Effects of clonidine on anxiety disorders. Arch Gen Psychiatry. 1981;38:1278–82.

    Article  CAS  PubMed  Google Scholar 

  85. Pineda J, Aghajanian GK. Carbon dioxide regulates the tonic activity of locus coeruleus neurons by modulating a proton- and polyamine-sensitive inward rectifier potassium current. Neuroscience. 1997;77:723–43.

    Article  CAS  PubMed  Google Scholar 

  86. Teppema LJ, Veening JG, Kranenburg A, Dahan A, Berkenbosch A, Olievier C. Expression of c-fos in the rat brainstem after exposure to hypoxia and to normoxic and hyperoxic hypercapnia. J Comp Neurol. 1997;388:169–90.

    Article  CAS  PubMed  Google Scholar 

  87. Nutt DJ. Altered central alpha 2-adrenoceptor sensitivity in panic disorder. Arch Gen Psychiatry. 1989;46:165–9.

    Article  CAS  PubMed  Google Scholar 

  88. Glue P, Nutt DJ. Benzodiazepine receptor sensitivity in panic disorder. Lancet. 1991;337:563.

    Article  CAS  PubMed  Google Scholar 

  89. Muskin PR, Fyer AJ. Treatment of panic disorder. J Clin Psychopharmacol. 1981;1:81–90.

    Article  CAS  PubMed  Google Scholar 

  90. Reiman EM, Raichle ME, Butler FK, Herscovitch P, Robins E. A focal brain abnormality in panic disorder, a severe form of anxiety. Nature. 1984;310:683–5.

    Article  CAS  PubMed  Google Scholar 

  91. Reiman EM, Raichle ME, Robins E, Butler FK, Herscovitch P, Fox P, et al. The application of positron emission tomography to the study of panic disorder. Am J Psychiatry. 1986;143:469–77.

    Article  CAS  PubMed  Google Scholar 

  92. Gray JA, McNaughton N. The neuropsychology of anxiety. 2nd ed. Oxford: Oxford Medical Publications; 2000.

    Google Scholar 

  93. Kaplan JS, Arnkoff DB, Glass CR, Tinsley R, Geraci M, Hernandez E, et al. Avoidant coping in panic disorder: a yohimbine biological challenge study. Anxiety Stress Coping. 2012;25:425–42.

    Article  PubMed  Google Scholar 

  94. Kaitin KI, Bliwise DL, Gleason C, Nino-Murcia G, Dement WC, Libet B. Sleep disturbance produced by electrical stimulation of the locus coeruleus in a human subject. Biol Psychiatry. 1986;21:710–6.

    Article  CAS  PubMed  Google Scholar 

  95. Libet B, Gleason CA. The human locus coeruleus and anxiogenesis. Brain Res. 1994;634:178–80.

    Article  CAS  PubMed  Google Scholar 

  96. Ledoux JE, Iwata J, Cicchetti P, Reis DJ. Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear. J Neurosci. 1988;8:2517–29.

    CAS  PubMed  Google Scholar 

  97. Ledoux JE, Cicchetti P, Xagoraris A, Romanski LM. The lateral amygdaloid nucleus: sensory interface of the amygdala in fear conditioning. J Neurosci. 1990;10:1062–9.

    CAS  PubMed  Google Scholar 

  98. Hitchcock J, Davis M. Lesions of the amygdala, but not of the cerebellum or red nucleus, block conditioned fear as measured with the potentiated startle paradigm. Behav Neurosci. 1986;100:11–22.

    Article  CAS  PubMed  Google Scholar 

  99. Nashold Jr BS, Wilson WP, Slaughter DG. Sensations evoked by stimulation in the midbrain of man. J Neurosurg. 1969;30:14–24.

    Article  PubMed  Google Scholar 

  100. Amano K, Tanikawa T, Iseki H, Kawabatake H, Notani M, Kawamura H, et al. Single neuron analysis of the human midbrain tegmentum. Appl Neurophysiol. 1978;41:66–78.

    CAS  PubMed  Google Scholar 

  101. Young RF. Brain and spinal stimulation: how and to whom! Clin Neurosurg. 1989;35:429–47.

    CAS  PubMed  Google Scholar 

  102. Fernandez de Molina A, Hunsperger RW. Organization of the subcortical system governing defence and flight reactions in the cat. J Physiol. 1962;160:200–13.

    Article  CAS  PubMed  Google Scholar 

  103. Adams DB. Brain mechanisms for offense, defense and submission. Behav Brain Sci. 1979;2:201–41.

    Article  Google Scholar 

  104. Hilton SM, Redfern WS. A search for brain stem cell groups integrating the defence reaction in the rat. J Physiol. 1986;378:213–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Graeff FG. The anti-aversive action of drugs. In: Thompson T, Dews PB, Barret JE, editors. Neurobehavioral Pharmacology, Advances in Behavioral Pharmacology, vol.6. Hillsdale: Lawrence Erlbaum Associates Inc.; 1987. p. 129–56.

    Google Scholar 

  106. Graeff FG. Animal models of aversion. In: Simon P, Soubrie P, Wildlocher D, editors. Selected models of anxiety, depression and psychosis. 1st ed. Basel: Karger AG; 1988. p. 115–41.

    Google Scholar 

  107. Paul ED, Lowry CA. Functional topography of serotonergic systems supports the Deakin/Graeff hypothesis of anxiety and affective disorders. J Psychopharmacol. 2013;27:1090–106.

    Article  CAS  PubMed  Google Scholar 

  108. Paul ED, Johnson PL, Shekhar A, Lowry CA. The Deakin/Graeff hypothesis: focus on serotonergic inhibition of panic. Neurosci Biobehav Rev. 2014;46:379–96.

    Article  CAS  PubMed  Google Scholar 

  109. Tanaka KF, Samuels BA, Hen R. Serotonin receptor expression along the dorsal-ventral axis of mouse hippocampus. Philos Trans R Soc Lond B Biol Sci. 2012;367:2395–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Pitkänen A, Pikkarainen M, Nurminen N, Ylinen A. Reciprocal connections between the amygdala and the hippocampal formation, perirhinal cortex, and postrhinal cortex in rat. A review. Ann N Y Acad Sci. 2000;911:369–91.

    Article  PubMed  Google Scholar 

  111. Nutt DJ, Glue P, Lawson C, Wilson S. Flumazenil provocation of panic attacks. Evidence for altered benzodiazepine receptor sensitivity in panic disorder. Arch Gen Psychiatry. 1990;47:917–25.

    Article  CAS  PubMed  Google Scholar 

  112. Barnard EA, Skolnick P, Olsen RW, Mohler H, Sieghart W, Biggio G, et al. International union of pharmacology: XV. Subtypes of gamma-aminobutyric acid-A receptors: classification on the basis of subunit structure and receptor function. Pharmacol Rev. 1998;50:291–313.

    CAS  PubMed  Google Scholar 

  113. Olsen RW, Sieghart W. International union of pharmacology: LXX. Subtypes of gamma-aminobutyric acid(A) receptors: classification on the basis of subunit composition, pharmacology, and function. Update. Pharmacol Rev. 2008;60:243–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Ströhle A, Kellner M, Yassouridis A, Holsboer F, Wiedemann K. Effect of flumazenil in lactate-sensitive patients with panic disorder. Am J Psychiatry. 1998;155:610–2.

    Article  PubMed  Google Scholar 

  115. Ströhle A, Kellner M, Holsboer F, Wiedemann K. Behavioral, neuroendocrine, and cardiovascular response to flumazenil: no evidence for an altered benzodiazepine receptor sensitivity in panic disorder. Biol Psychiatry. 1999;45:321–6.

    Article  PubMed  Google Scholar 

  116. Potokar J, Lawson C, Wilson S, Nutt D. Behavioral, neuroendocrine, and cardiovascular response to flumazenil: no evidence for an altered benzodiazepine receptor sensitivity in panic disorder (Comment on). Biol Psychiatry. 1999;46:1709–11.

    Article  CAS  PubMed  Google Scholar 

  117. Kaschka W, Feistel H, Ebert D. Reduced benzodiazepine receptor binding in panic disorders measured by iomazenil SPECT. J Psychiatr Res. 1995;29:427–34.

    Article  CAS  PubMed  Google Scholar 

  118. Malizia AL, Cunningham VJ, Bell CJ, Liddle PF, Jones T, Nutt DJ. Decreased brain GABA(A)-benzodiazepine receptor binding in panic disorder: preliminary results from a quantitative PET study. Arch Gen Psychiatry. 1998;55:715–20.

    Article  CAS  PubMed  Google Scholar 

  119. Schlegel S, Steinert H, Bockisch A, Hahn K, Schloesser R, Benkert O. Decreased benzodiazepine receptor binding in panic disorder measured by IOMAZENIL-SPECT. A preliminary report. Eur Arch Psychiatry Clin Neurosci. 1994;244:49–51.

    Article  CAS  PubMed  Google Scholar 

  120. Preter M, Lee SH, Petkova E, Vannucci M, Kim S, Klein DF. Controlled cross-over study in normal subjects of naloxone-preceding-lactate infusions; respiratory and subjective responses: relationship to endogenous opioid system, suffocation false alarm theory and childhood parental loss. Psychol Med. 2011;41:385–93.

    Article  CAS  PubMed  Google Scholar 

  121. Roncon CM, Biesdorf C, Santana RG, Zangrossi Jr H, Graeff FG, Audi EA. The panicolytic-like effect of fluoxetine in the elevated T-maze is mediated by serotonin-induced activation of endogenous opioids in the dorsal periaqueductal grey. J Psychopharmacol. 2012;26:525–31.

    Article  CAS  PubMed  Google Scholar 

  122. Roncon CM, Biesdorf C, Coimbra NC, Audi EA, Zangrossi Jr H, Graeff FG. Cooperative regulation of anxiety and panic-related defensive behaviors in the rat periaqueductal grey matter by 5-HT1A and mu-receptors. J Psychopharmacol. 2013;27:1141–8.

    Article  CAS  PubMed  Google Scholar 

  123. Breuer J, Freud S. Studien über Hysterie. Vienna: Franz Deudicke; 1895.

    Google Scholar 

  124. Bowlby J. A secure base: parent-child attachment and healthy human development. New York: Basic Books; 1988.

    Google Scholar 

  125. Heim C, Shugart M, Craighead WE, Nemeroff CB. Neurobiological and psychiatric consequences of child abuse and neglect. Dev Psychobiol. 2010;52:671–90.

    Article  PubMed  Google Scholar 

  126. Ladd CO, Owens MJ, Nemeroff CB. Persistent changes in corticotropin-releasing factor neuronal systems induced by maternal deprivation. Endocrinology. 1996;137:1212–8.

    CAS  PubMed  Google Scholar 

  127. Ladd CO, Huot RL, Thrivikraman KV, Nemeroff CB, Plotsky PM. Long-term adaptations in glucocorticoid receptor and mineralocorticoid receptor mRNA and negative feedback on the hypothalamo-pituitary-adrenal axis following neonatal maternal separation. Biol Psychiatry. 2004;55:367–75.

    Article  CAS  PubMed  Google Scholar 

  128. Rots NY, de Jong J, Workel JO, Levine S, Cools AR, de Kloet ER. Neonatal maternally deprived rats have as adults elevated basal pituitary-adrenal activity and enhanced susceptibility to apomorphine. J Neuroendocrinol. 1996;8:501–6.

    Article  CAS  PubMed  Google Scholar 

  129. Anisman H, Zaharia MD, Meaney MJ, Merali Z. Do early-life events permanently alter behavioral and hormonal responses to stressors? Int J Dev Neurosci. 1998;16:149–64.

    Article  CAS  PubMed  Google Scholar 

  130. Biagini G, Pich EM, Carani C, Marrama P, Agnati LF. Postnatal maternal separation during the stress hyporesponsive period enhances the adrenocortical response to novelty in adult rats by affecting feedback regulation in the CA1 hippocampal field. Int J Dev Neurosci. 1998;16:187–97.

    Article  CAS  PubMed  Google Scholar 

  131. van Oers HJ, de Kloet ER, Levine S. Early vs. late maternal deprivation differentially alters the endocrine and hypothalamic responses to stress. Brain Res Dev Brain Res. 1998;111:245–52.

    Article  PubMed  Google Scholar 

  132. Kinkead R, Gulemetova R. Neonatal maternal separation and neuroendocrine programming of the respiratory control system in rats. Biol Psychol. 2010;84:26–38.

    Article  PubMed  Google Scholar 

  133. Meaney MJ, Diorio J, Francis D, Weaver S, Yau J, Chapman K, et al. Postnatal handling increases the expression of cAMP-inducible transcription factors in the rat hippocampus: the effects of thyroid hormones and serotonin. J Neurosci. 2000;20:3926–35.

    CAS  PubMed  Google Scholar 

  134. Gardner KL, Thrivikraman KV, Lightman SL, Plotsky PM, Lowry CA. Early life experience alters behavior during social defeat: focus on serotonergic systems. Neuroscience. 2005;136:181–91.

    Article  CAS  PubMed  Google Scholar 

  135. Gardner KL, Hale MW, Lightman SL, Plotsky PM, Lowry CA. Adverse early life experience and social stress during adulthood interact to increase serotonin transporter mRNA expression. Brain Res. 2009;1305:47–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Gardner KL, Hale MW, Oldfield S, Lightman SL, Plotsky PM, Lowry CA. Adverse experience during early life and adulthood interact to elevate tph2 mRNA expression in serotonergic neurons within the dorsal raphe nucleus. Neuroscience. 2009;163:991–1001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Quintino-Dos-Santos JW, Muller CJ, Bernabe CS, Rosa CA, Tufik S, Schenberg LC. Evidence that the periaqueductal gray matter mediates the facilitation of panic-like reactions in neonatally-isolated adult rats. PLoS One. 2014;9:e90726.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. Dumont FS, Biancardi V, Kinkead R. Hypercapnic ventilatory response of anesthetized female rats subjected to neonatal maternal separation: insight into the origins of panic attacks? Respir Physiol Neurobiol. 2011;175:288–95.

    Article  PubMed  Google Scholar 

  139. Grosz HJ, Farmer BB. Pitts’ and McClure’s lactate-anxiety study revisited. Br J Psychiatry. 1972;120:415–8.

    Article  CAS  PubMed  Google Scholar 

  140. Gorman JM, Battista D, Goetz RR, Dillon DJ, Liebowitz MR, Fyer AJ, et al. A comparison of sodium bicarbonate and sodium lactate infusion in the induction of panic attacks [published erratum appears in Arch Gen Psychiatry 1991;48:772]. Arch Gen Psychiatry. 1989;46:145–50.

    Article  CAS  PubMed  Google Scholar 

  141. Gorman JM, Goetz RR, Dillon D, Liebowitz MR, Fyer AJ, Davies S, et al. Sodium d-lactate infusion of panic disorder patients. Neuropsychopharmacology. 1990;3:181–9.

    CAS  PubMed  Google Scholar 

  142. Ewaschuk JB, Naylor JM, Zello GA. d-Lactate in human and ruminant metabolism. J Nutr. 2005;135:1619–25.

    CAS  PubMed  Google Scholar 

  143. Dager SR, Rainey JM, Kenny MA, Artru AA, Metzger GD, Bowden DM. Central nervous system effects of lactate infusion in primates. Biol Psychiatry. 1990;27:193–204.

    Article  CAS  PubMed  Google Scholar 

  144. Dager SR, Marro KI, Richards TL, Metzger GD. Localized magnetic resonance spectroscopy measurement of brain lactate during intravenous lactate infusion in healthy volunteers. Life Sci. 1992;51:973–85.

    Article  CAS  PubMed  Google Scholar 

  145. Stein JM, Papp LA, Klein DF, Cohen S, Simon J, Ross D, et al. Exercise tolerance in panic disorder patients. Biol Psychiatry. 1992;32:281–7.

    Article  CAS  PubMed  Google Scholar 

  146. Ströhle A, Feller C, Onken M, Godemann F, Heinz A, Dimeo F. The acute antipanic activity of aerobic exercise. Am J Psychiatry. 2005;162:2376–8.

    Article  PubMed  Google Scholar 

  147. 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;108:473–82.

    Article  CAS  PubMed  Google Scholar 

  148. Hackett PH, Roach RC. High-altitude illness. N Engl J Med. 2001;345:107–14.

    Article  CAS  PubMed  Google Scholar 

  149. Fagenholz PJ, Murray AF, Gutman JA, Findley JK, Harris NS. New-onset anxiety disorders at high altitude. Wilderness Environ Med. 2007;18:312–6.

    Article  PubMed  Google Scholar 

  150. Tweed JL, Schoenbach VJ, George LK, Blazer DG. The effects of childhood parental death and divorce on six-month history of anxiety disorders. Br J Psychiatry. 1989;154:823–8.

    Article  CAS  PubMed  Google Scholar 

  151. Stein MB, Walker JR, Anderson G, Hazen AL, Ross CA, Eldridge G, et al. Childhood physical and sexual abuse in patients with anxiety disorders and in a community sample. Am J Psychiatry. 1996;153:275–7.

    Article  CAS  PubMed  Google Scholar 

  152. Battaglia M, Pesenti-Gritti P, Medland SE, Ogliari A, Tambs K, Spatola CA. A genetically informed study of the association between childhood separation anxiety, sensitivity to CO(2), panic disorder, and the effect of childhood parental loss. Arch Gen Psychiatry. 2009;66:64–71.

    Article  PubMed  Google Scholar 

  153. Spatola CA, Scaini S, Pesenti-Gritti P, Medland SE, Moruzzi S, Ogliari A, et al. Gene-environment interactions in panic disorder and CO(2) sensitivity: effects of events occurring early in life. Am J Med Genet B Neuropsychiatr Genet. 2011;156B:79–88.

    Article  PubMed  CAS  Google Scholar 

  154. Angst J, Wicki W. The epidemiology of frequent and less frequent panic attacks. In: Montgomery SA, editor. Psychopharmacology of panic. New York: Oxford University Press; 1993. p. 7–24.

    Google Scholar 

  155. Lovick TA. Sex determinants of experimental panic attacks. Neurosci Biobehav Rev. 2014;46:465–71.

    Article  PubMed  Google Scholar 

  156. Nashold Jr BS, Wilson WP, Slaughter GS. The midbrain and pain. In: Bonica JJ, editor. International symposium on pain. New York: Raven; 1974. p. 191–6.

    Google Scholar 

  157. Kumar K, Toth C, Nath RK. Deep brain stimulation for intractable pain: a 15-year experience. Neurosurgery. 1997;40:736–46.

    Article  CAS  PubMed  Google Scholar 

  158. Bandler R, Depaulis A. Midbrain periaqueductal gray control of defensive behavior in the cat and rat. In: Depaulis A, Bandler R, editors. The midbrain periaqueductal gray matter. New York: Plenum Press; 1991. p. 175–98.

    Chapter  Google Scholar 

  159. Bandler R, Keay KA. Columnar organization in the midbrain periaqueductal gray and the integration of emotional expression. Prog Brain Res. 1996;107:285–300.

    Article  CAS  PubMed  Google Scholar 

  160. Carrive P. Functional organization of PAG neurons controlling regional vascular beds. In: Depaulis A, Bandler R, editors. The midbrain periaqueductal gray matter: functional, anatomical, and neurochemical organization. New York: Plenum Press; 1991. p. 67–100.

    Chapter  Google Scholar 

  161. Carrive P. The periaqueductal gray and defensive behavior: functional representation and neuronal organization. Behav Brain Res. 1993;58:27–47.

    Article  CAS  PubMed  Google Scholar 

  162. Keay KA, Bandler R. Periaqueductal gray. In: Paxinos G, editor. The rat nervous system. 3rd ed. San Diego: Elsevier; 2004. p. 243–57.

    Chapter  Google Scholar 

  163. Kingsbury MA, Kelly AM, Schrock SE, Goodson JL. Mammal-like organization of the avian midbrain central gray and a reappraisal of the intercollicular nucleus. PLoS One. 2011;6:e20720.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Jansen AS, Farkas E, Mac SJ, Loewy AD. Local connections between the columns of the periaqueductal gray matter: a case for intrinsic neuromodulation. Brain Res. 1998;784:329–36.

    Article  CAS  PubMed  Google Scholar 

  165. Bittencourt AS, Carobrez AP, Zamprogno LP, Tufik S, Schenberg LC. Organization of single components of defensive behaviors within distinct columns of periaqueductal gray matter of the rat: role of N-methyl-d-aspartic acid glutamate receptors. Neuroscience. 2004;125:71–89.

    Article  CAS  PubMed  Google Scholar 

  166. Teixeira KV, Carobrez AP. Effects of glycine or (+/−)-3-amino-1-hydroxy-2-pyrrolidone microinjections along the rostrocaudal axis of the dorsal periaqueductal gray matter on rats’ performance in the elevated plus-maze task. Behav Neurosci. 1999;113:196–203.

    Article  CAS  PubMed  Google Scholar 

  167. Mota-Ortiz SR, Sukikara MH, Felicio LF, Canteras NS. Afferent connections to the rostrolateral part of the periaqueductal gray: a critical region influencing the motivation drive to hunt and forage. Neural Plast. 2009; ID612698.

    Google Scholar 

  168. Holstege G, Kerstens L, Moes MC, Vanderhorst VG. Evidence for a periaqueductal gray-nucleus retroambiguus-spinal cord pathway in the rat. Neuroscience. 1997;80:587–98.

    Article  CAS  PubMed  Google Scholar 

  169. Ruiz-Torner A, Olucha-Bordonau F, Valverde-Navarro AA, Martinez-Soriano F. The chemical architecture of the rat's periaqueductal gray based on acetylcholinesterase histochemistry: a quantitative and qualitative study. J Chem Neuroanat. 2001;21:295–312.

    Article  CAS  PubMed  Google Scholar 

  170. Onstott D, Mayer B, Beitz AJ. Nitric oxide synthase immunoreactive neurons anatomically define a longitudinal dorsolateral column within the midbrain periaqueductal gray of the rat: analysis using laser confocal microscopy. Brain Res. 1993;610:317–24.

    Article  CAS  PubMed  Google Scholar 

  171. Bandler R, Tork I. Midbrain periaqueductal grey region in the cat has afferent and efferent connection with solitary tract nuclei. Neurosci Lett. 1987;74:1–6.

    Article  CAS  PubMed  Google Scholar 

  172. Lv BC, Ji GL, Huo FQ, Chen T, Li H, Li YQ. Topographical distributions of endomorphinergic pathways from nucleus tractus solitarii to periaqueductal gray in the rat. J Chem Neuroanat. 2010;39:166–74.

    Article  CAS  PubMed  Google Scholar 

  173. Iwata J, Ledoux JE, Reis DJ. Destruction of intrinsic neurons in the lateral hypothalamus disrupts the classical conditioning of autonomic but not behavioral emotional responses in the rat. Brain Res. 1986;368:161–6.

    Article  CAS  PubMed  Google Scholar 

  174. Kiser RS, Brown CA, Sanghera MK, German DC. Dorsal raphe nucleus stimulation reduces centrally elicited fearlike behavior. Brain Res. 1980;191:265–72.

    Article  CAS  PubMed  Google Scholar 

  175. Lovick TA. Stimulation in the ventral periaqueductal grey matter modulates the cardiovascular response evoked from the midbrain defence area in anaesthetized rats. J Physiol. 1990;91P.

    Google Scholar 

  176. Lovick TA. Inhibitory modulation of the cardiovascular defence response by ventrolateral periaqueductal grey matter in rats. Exp Brain Res. 1992;89:133–9.

    Article  CAS  PubMed  Google Scholar 

  177. Lovick TA. Influence of the dorsal and median raphe nuclei on neurons in the periaqueductal gray matter: role of 5-hydroxytryptamine. Neuroscience. 1994;59:993–1000.

    Article  CAS  PubMed  Google Scholar 

  178. Lovick TA, Parry DM, Stezhka VV, Lumb BM. Serotonergic transmission in the periaqueductal gray matter in relation to aversive behaviour: morphological evidence for direct modulatory effects on identified output neurons. Neuroscience. 2000;95:763–72.

    Article  CAS  PubMed  Google Scholar 

  179. Pobbe RL, Zangrossi Jr H. 5-HT(1A) and 5-HT(2A) receptors in the rat dorsal periaqueductal gray mediate the antipanic-like effect induced by the stimulation of serotonergic neurons in the dorsal raphe nucleus. Psychopharmacology (Berl). 2005;183:314–21.

    Article  CAS  Google Scholar 

  180. Schenberg LC, Graeff FG. Role of the periaqueductal gray substance in the antianxiety action of benzodiazepines. Pharmacol Biochem Behav. 1978;9:287–95.

    Article  CAS  PubMed  Google Scholar 

  181. Spyer KM, Gourine AV. Chemosensory pathways in the brainstem controlling cardiorespiratory activity. Philos Trans R Soc Lond B Biol Sci. 2009;364:2603–10.

    Article  PubMed  PubMed Central  Google Scholar 

  182. Finley JC, Katz DM. The central organization of carotid body afferent projections to the brainstem of the rat. Brain Res. 1992;572(1–2):108–16.

    Article  CAS  PubMed  Google Scholar 

  183. Loeschcke HH, Koepchen HP, Gertz KH. Über den Einflub von Wasserstoffionenkonzentration und CO2-Druck im Liquor cerebrospinalis auf die Atmung. Pflugers Arch. 1958;266:569–85.

    Article  CAS  PubMed  Google Scholar 

  184. Loeschcke HH. Central chemosensitivity and the reaction theory. J Physiol. 1982;332:1–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Schlaefke ME, See WR, Loeschcke HH. Ventilatory response to alterations of H+ ion concentration in small areas of the ventral medullary surface. Respir Physiol. 1970;10:198–212.

    Article  CAS  PubMed  Google Scholar 

  186. Schlaefke ME. Central chemosensitivity: a respiratory drive. Rev Physiol Biochem Pharmacol. 1981;90:171–244.

    CAS  PubMed  Google Scholar 

  187. Ricardo JA, Koh ET. Anatomical evidence of direct projections from the nucleus of the solitary tract to the hypothalamus, amygdala, and other forebrain structures in the rat. Brain Res. 1978;153:1–26.

    Article  CAS  PubMed  Google Scholar 

  188. Luft U. Aviation physiology-the effects of altitude. In: Handbook of physiology. Washington, DC: Am. Physiol. Soc.; 1965. p. 1099–145.

    Google Scholar 

  189. Moosavi SH, Golestanian E, Binks AP, Lansing RW, Brown R, Banzett RB. Hypoxic and hypercapnic drives to breathe generate equivalent levels of air hunger in humans. J Appl Physiol. 2003;94:141–54.

    Article  CAS  PubMed  Google Scholar 

  190. Banzett RB, Lansing RW, Evans KC, Shea SA. Stimulus-response characteristics of CO2-induced air hunger in normal subjects. Respir Physiol. 1996;103:19–31.

    Article  CAS  PubMed  Google Scholar 

  191. Banzett RB, Lansing RW, Reid MB, Adams L, Brown R. ‘Air hunger’ arising from increased PCO2 in mechanically ventilated quadriplegics. Respir Physiol. 1989;76:53–67.

    Article  CAS  PubMed  Google Scholar 

  192. Gandevia SC, Killian K, McKenzie DK, Crawford M, Allen GM, Gorman RB, et al. Respiratory sensations, cardiovascular control, kinaesthesia and transcranial stimulation during paralysis in humans. J Physiol. 1993;470:85–107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. van den Hout MA, Boek C, van der Molen GM, Jansen A, Griez E. Rebreathing to cope with hyperventilation: experimental tests of the paper bag method. J Behav Med. 1988;11:303–10.

    Article  PubMed  Google Scholar 

  194. Moosavi SH, Banzett RB, Butler JP. Time course of air hunger mirrors the biphasic ventilatory response to hypoxia. J Appl Physiol. 2004;97:2098–103.

    Article  CAS  PubMed  Google Scholar 

  195. Spengler CM, Banzett RB, Systrom DM, Shannon DC, Shea SA. Respiratory sensations during heavy exercise in subjects without respiratory chemosensitivity. Respir Physiol. 1998;114:65–74.

    Article  CAS  PubMed  Google Scholar 

  196. Shea SA, Andres LP, Shannon DC, Guz A, Banzett RB. Respiratory sensations in subjects who lack a ventilatory response to CO2. Respir Physiol. 1993;93:203–19.

    Article  CAS  PubMed  Google Scholar 

  197. Banzett RB, Mulnier HE, Murphy K, Rosen SD, Wise RJ, Adams L. Breathlessness in humans activates insular cortex. Neuroreport. 2000;11:2117–20.

    Article  CAS  PubMed  Google Scholar 

  198. Craig AD. How do you feel? Interoception: the sense of the physiological condition of the body. Nat Rev Neurosci. 2002;3:655–66.

    Article  CAS  PubMed  Google Scholar 

  199. Craig AD. Human feelings: why are some more aware than others? Trends Cogn Sci. 2004;8:239–41.

    Article  PubMed  Google Scholar 

  200. Casanova JP, Contreras M, Moya EA, Torrealba F, Iturriaga R. Effect of insular cortex inactivation on autonomic and behavioral responses to acute hypoxia in conscious rats. Behav Brain Res. 2013;253:60–7.

    Article  PubMed  Google Scholar 

  201. Prabhakar NR. Sensing hypoxia: physiology, genetics and epigenetics. J Physiol. 2013;591:2245–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Katzman MA, Struzik L, Vijay N, Coonerty-Femiano A, Mahamed S, Duffin J. Central and peripheral chemoreflexes in panic disorder. Psychiatry Res. 2002;113:181–92.

    Article  PubMed  Google Scholar 

  203. Corfield DR, Fink GR, Ramsay SC, Murphy K, Harty HR, Watson JD, et al. Evidence for limbic system activation during CO2-stimulated breathing in man. J Physiol. 1995;488:77–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Brannan S, Liotti M, Egan G, Shade R, Madden L, Robillard R, et al. Neuroimaging of cerebral activations and deactivations associated with hypercapnia and hunger for air. Proc Natl Acad Sci U S A. 2001;98:2029–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Liotti M, Brannan S, Egan G, Shade R, Madden L, Abplanalp B, et al. Brain responses associated with consciousness of breathlessness (air hunger). Proc Natl Acad Sci U S A. 2001;98:2035–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Reiman EM, Fusselman MJ, Fox PT, Raichle ME. Neuroanatomical correlates of anticipatory anxiety. Science. 1989;243:1071–4.

    Article  CAS  PubMed  Google Scholar 

  207. Drevets WC, Videen TQ, MacLeod AK, Haller JW, Raichle ME. PET images of blood flow changes during anxiety: correction. Science. 1992;256:1696.

    Article  CAS  PubMed  Google Scholar 

  208. Benkelfat C, Bradwejn J, Meyer E, Ellenbogen M, Milot S, Gjedde A, et al. Functional neuroanatomy of CCK4-induced anxiety in normal healthy volunteers. Am J Psychiatry. 1995;152:1180–4.

    Article  CAS  PubMed  Google Scholar 

  209. Javanmard M, Shlik J, Kennedy SH, Vaccarino FJ, Houle S, Bradwejn J. Neuroanatomic correlates of CCK-4-induced panic attacks in healthy humans: a comparison of two time points. Biol Psychiatry. 1999;45:872–82.

    Article  CAS  PubMed  Google Scholar 

  210. Reiman EM, Raichle ME, Robins E, Mintun MA, Fusselman MJ, Fox PT, et al. Neuroanatomical correlates of a lactate-induced anxiety attack. Arch Gen Psychiatry. 1989;46:493–500.

    Article  CAS  PubMed  Google Scholar 

  211. Goossens L, Leibold N, Peeters R, Esquivel G, Knuts I, Backes W, et al. Brainstem response to hypercapnia: a symptom provocation study into the pathophysiology of panic disorder. J Psychopharmacol. 2014;28:449–56.

    Article  PubMed  Google Scholar 

  212. Brust RD, Corcoran AE, Richerson GB, Nattie E, Dymecki SM. Functional and developmental identification of a molecular subtype of brain serotonergic neuron specialized to regulate breathing dynamics. Cell Rep. 2014;9:2152–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Bett K, Sandkuhler J. Map of spinal neurons activated by chemical stimulation in the nucleus raphe magnus of the unanesthetized rat. Neuroscience. 1995;67:497–504.

    Article  CAS  PubMed  Google Scholar 

  214. Schenberg LC, Lovick TA. Attenuation of the midbrain-evoked defense reaction by selective stimulation of medullary raphe neurons in rats. Am J Physiol. 1995;269:R1378–89.

    CAS  PubMed  Google Scholar 

  215. Beitz AJ, Clements JR, Mullett MA, Ecklund LJ. Differential origin of brainstem serotoninergic projections to the midbrain periaqueductal gray and superior colliculus of the rat. J Comp Neurol. 1986;250:498–509.

    Article  CAS  PubMed  Google Scholar 

  216. Fischer H, Andersson JL, Furmark T, Fredrikson M. Brain correlates of an unexpected panic attack: a human positron emission tomographic study. Neurosci Lett. 1998;251:137–40.

    Article  CAS  PubMed  Google Scholar 

  217. Sato M, Severinghaus JW, Basbaum AI. Medullary CO2 chemoreceptor neuron identification by c-fos immunocytochemistry. J Appl Physiol. 1992;73:96–100.

    CAS  PubMed  Google Scholar 

  218. Erickson JT, Millhorn DE. Hypoxia and electrical stimulation of the carotid sinus nerve induce Fos-like immunoreactivity within catecholaminergic and serotoninergic neurons of the rat brainstem. J Comp Neurol. 1994;348:161–82.

    Article  CAS  PubMed  Google Scholar 

  219. Haxhiu MA, Yung K, Erokwu B, Cherniack NS. CO2-induced c-fos expression in the CNS catecholaminergic neurons. Respir Physiol. 1996;105:35–45.

    Article  CAS  PubMed  Google Scholar 

  220. Hirooka Y, Polson JW, Potts PD, Dampney RA. Hypoxia-induced Fos expression in neurons projecting to the pressor region in the rostral ventrolateral medulla. Neuroscience. 1997;80:1209–24.

    Article  CAS  PubMed  Google Scholar 

  221. Larnicol N, Wallois F, Berquin P, Gros F, Rose D. c-fos-like immunoreactivity in the cat’s neuraxis following moderate hypoxia or hypercapnia. J Physiol Paris. 1994;88:81–8.

    Article  CAS  PubMed  Google Scholar 

  222. Berquin P, Bodineau L, Gros F, Larnicol N. Brainstem and hypothalamic areas involved in respiratory chemoreflexes: a Fos study in adult rats. Brain Res. 2000;857:30–40.

    Article  CAS  PubMed  Google Scholar 

  223. Johnson PL, Fitz SD, Hollis JH, Moratalla R, Lightman SL, Shekhar A, et al. Induction of c-Fos in ‘panic/defence’-related brain circuits following brief hypercarbic gas exposure. J Psychopharmacol. 2011;25:26–36.

    Article  CAS  PubMed  Google Scholar 

  224. Mitchell RA, Herbert DA. The effect of carbon dioxide on the membrane potential of medullary respiratory neurons. Brain Res. 1974;75:345–9.

    Article  CAS  PubMed  Google Scholar 

  225. Horn EM, Kramer JM, Waldrop TG. Development of hypoxia-induced Fos expression in rat caudal hypothalamic neurons. Neuroscience. 2000;99:711–20.

    Article  CAS  PubMed  Google Scholar 

  226. Feldman JL, Mitchell GS, Nattie EE. Breathing: rhythmicity, plasticity, chemosensitivity. Annu Rev Neurosci. 2003;26:239–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Raff H, Roarty TP. Renin, ACTH, and aldosterone during acute hypercapnia and hypoxia in conscious rats. Am J Physiol. 1988;254:R431–5.

    CAS  PubMed  Google Scholar 

  228. Argyropoulos SV, Bailey JE, Hood SD, Kendrick AH, Rich AS, Laszlo G, et al. Inhalation of 35 % CO(2) results in activation of the HPA axis in healthy volunteers. Psychoneuroendocrinology. 2002;27:715–29.

    Article  CAS  PubMed  Google Scholar 

  229. Kaye J, Buchanan F, Kendrick A, Johnson P, Lowry C, Bailey J, et al. Acute carbon dioxide exposure in healthy adults: evaluation of a novel means of investigating the stress response. J Neuroendocrinol. 2004;16:256–64.

    Article  CAS  PubMed  Google Scholar 

  230. van Duinen MA, Schruers KR, Maes M, Griez EJ. CO2 challenge induced HPA axis activation in panic. Int J Neuropsychopharmacol. 2007;10:797–804.

    PubMed  Google Scholar 

  231. Johnson P, Lowry C, Truitt W, Shekhar A. Disruption of GABAergic tone in the dorsomedial hypothalamus attenuates responses in a subset of serotonergic neurons in the dorsal raphe nucleus following lactate-induced panic. J Psychopharmacol. 2008;22:642–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Ryan JW, Waldrop TG. Hypoxia sensitive neurons in the caudal hypothalamus project to the periaqueductal gray. Respir Physiol. 1995;100:185–94.

    Article  CAS  PubMed  Google Scholar 

  233. Shams I, Avivi A, Nevo E. Oxygen and carbon dioxide fluctuations in burrows of subterranean blind mole rats indicate tolerance to hypoxic-hypercapnic stresses. Comp Biochem Physiol A Mol Integr Physiol. 2005;142:376–82.

    Article  PubMed  CAS  Google Scholar 

  234. Teppema LJ, Veening JG, Berkenbosch A. Expression of c-fos in the brain stem of rats during hypercapnia. Adv Exp Med Biol. 1995;393:47–51.

    Article  CAS  PubMed  Google Scholar 

  235. Bodineau L, Larnicol N. Brainstem and hypothalamic areas activated by tissue hypoxia: Fos-like immunoreactivity induced by carbon monoxide inhalation in the rat. Neuroscience. 2001;108:643–53.

    Article  CAS  PubMed  Google Scholar 

  236. Dillon GH, Waldrop TG. In vitro responses of caudal hypothalamic neurons to hypoxia and hypercapnia. Neuroscience. 1992;51:941–50.

    Article  CAS  PubMed  Google Scholar 

  237. Coates EL, Li A, Nattie EE. Widespread sites of brain stem ventilatory chemoreceptors. J Appl Physiol. 1993;75:5–14.

    CAS  PubMed  Google Scholar 

  238. Kramer JM, Nolan PC, Waldrop TG. In vitro responses of neurons in the periaqueductal gray to hypoxia and hypercapnia. Brain Res. 1999;835:197–203.

    Article  CAS  PubMed  Google Scholar 

  239. Kim Y, Bang H, Kim D. TASK-3, a new member of the tandem pore K(+) channel family. J Biol Chem. 2000;275:9340–7.

    Article  CAS  PubMed  Google Scholar 

  240. Rajan S, Wischmeyer E, Xin LG, Preisig-Muller R, Daut J, Karschin A, et al. TASK-3, a novel tandem pore domain acid-sensitive K+ channel. An extracellular histiding as pH sensor. J Biol Chem. 2000;275:16650–7.

    Article  CAS  PubMed  Google Scholar 

  241. Buckler KJ. TASK-like potassium channels and oxygen sensing in the carotid body. Respir Physiol Neurobiol. 2007;157:55–64.

    Article  CAS  PubMed  Google Scholar 

  242. Talley EM, Solorzano G, Lei Q, Kim D, Bayliss DA. CNS distribution of members of the two-pore-domain (KCNK) potassium channel family. J Neurosci. 2001;21:7491–505.

    CAS  PubMed  Google Scholar 

  243. Bayliss DA, Talley EM, Sirois JE, Lei Q. TASK-1 is a highly modulated pH-sensitive ‘leak’ K(+) channel expressed in brainstem respiratory neurons. Respir Physiol. 2001;129:159–74.

    Article  CAS  PubMed  Google Scholar 

  244. Washburn CP, Sirois JE, Talley EM, Guyenet PG, Bayliss DA. Serotonergic raphe neurons express TASK channel transcripts and a TASK-like pH- and halothane-sensitive K+ conductance. J Neurosci. 2002;22:1256–65.

    CAS  PubMed  Google Scholar 

  245. Washburn CP, Bayliss DA, Guyenet PG. Cardiorespiratory neurons of the rat ventrolateral medulla contain TASK-1 and TASK-3 channel mRNA. Respir Physiol Neurobiol. 2003;138:19–35.

    Article  CAS  PubMed  Google Scholar 

  246. Schimitel FG, de Almeida GM, Pitol DN, Armini RS, Tufik S, Schenberg LC. Evidence of a suffocation alarm system within the periaqueductal gray matter of the rat. Neuroscience. 2012;200:59–73.

    Article  CAS  PubMed  Google Scholar 

  247. Vianna DM, Landeira-Fernandez J, Brandão ML. Dorsolateral and ventral regions of the periaqueductal gray matter are involved in distinct types of fear. Neurosci Biobehav Rev. 2001;25:711–9.

    Article  CAS  PubMed  Google Scholar 

  248. Subramanian HH, Balnave RJ, Holstege G. The midbrain periaqueductal gray control of respiration. J Neurosci. 2008;28:12274–83.

    Article  CAS  PubMed  Google Scholar 

  249. Schenberg LC, Póvoa RMF, Costa AL, Caldellas AV, Tufik S, Bittencourt AS. Functional specializations within the tectum defense systems of the rat. Neurosci Biobehav Rev. 2005;29:1279–98.

    Article  CAS  PubMed  Google Scholar 

  250. Steeves JD, Jordan LM. Autoradiographic demonstration of the projections from the mesencephalic locomotor region. Brain Res. 1984;307:263–76.

    Article  CAS  PubMed  Google Scholar 

  251. Franchini KG, Krieger EM. Cardiovascular responses of conscious rats to carotid body chemoreceptor stimulation by intravenous KCN. J Auton Nerv Syst. 1993;42:63–9.

    Article  CAS  PubMed  Google Scholar 

  252. Franchini KG, Oliveira VL, Krieger EM. Hemodynamics of chemoreflex activation in unanesthetized rats. Hypertension. 1997;30:699–703.

    Article  CAS  PubMed  Google Scholar 

  253. Hayward LF, Von Reitzentstein M. c-Fos expression in the midbrain periaqueductal gray after chemoreceptor and baroreceptor activation. Am J Physiol Heart Circ Physiol. 2002;283:H1975–84.

    Article  CAS  PubMed  Google Scholar 

  254. Schimitel FG, Muller CJ, Tufik S, Schenberg LC. Evidence of a suffocation alarm system sensitive to clinically-effective treatments with the panicolytics clonazepam and fluoxetine. J Psychopharmacol. 2014;28:1184–8.

    Article  CAS  PubMed  Google Scholar 

  255. Spiacci Jr A, de Oliveira ST, da Silva GS, Glass ML, Schenberg LC, Garcia-Cairasco N, et al. Serotonin in the dorsal periaqueductal gray inhibits panic-like defensive behaviors in rats exposed to acute hypoxia. Neuroscience. 2015;307:191–8.

    Article  CAS  PubMed  Google Scholar 

  256. Suchecki D, Mozaffarian D, Gross G, Rosenfeld P, Levine S. Effects of maternal deprivation on the ACTH stress response in the infant rat. Neuroendocrinology. 1993;57:204–12.

    Article  CAS  PubMed  Google Scholar 

  257. Suchecki D, Rosenfeld P, Levine S. Maternal regulation of the hypothalamic-pituitary-adrenal axis in the infant rat: the roles of feeding and stroking. Brain Res Dev Brain Res. 1993;75:185–92.

    Article  CAS  PubMed  Google Scholar 

  258. Suchecki D, Nelson DY, Van OH, Levine S. Activation and inhibition of the hypothalamic-pituitary-adrenal axis of the neonatal rat: effects of maternal deprivation. Psychoneuroendocrinology. 1995;20:169–82.

    Article  CAS  PubMed  Google Scholar 

  259. Schenberg LC. Towards a translational model of panic attack. Psychol Neurosci. 2010;3:9–37.

    Article  Google Scholar 

  260. Johnson PL, Lightman SL, Lowry CA. A functional subset of serotonergic neurons in the rat ventrolateral periaqueductal gray implicated in the inhibition of sympathoexcitation and panic. Ann N Y Acad Sci. 2004;1018:58–64.

    Article  CAS  PubMed  Google Scholar 

  261. Sachs E. On the relation of the optic thalamus to respiration, circulation, temperature, and the spleen. J Exp Med. 1911;14:408–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Tan ES. Brain-stem regions for stimulus-bound and stimulus-related respiration. Exp Neurol. 1967;17:517–28.

    Article  CAS  PubMed  Google Scholar 

  263. Paydarfar D, Eldridge FL. Phase resetting and dysrhythmic responses of the respiratory oscillator. Am J Physiol. 1987;252:R55–62.

    CAS  PubMed  Google Scholar 

  264. Hayward LF, Swartz CL, Davenport PW. Respiratory response to activation or disinhibition of the dorsal periaqueductal gray in rats. J Appl Physiol. 2003;94:913–22.

    Article  PubMed  Google Scholar 

  265. Cohen MI. Neurogenesis of respiratory rhythm in the mammal. Physiol Rev. 1979;59:1105–73.

    CAS  PubMed  Google Scholar 

  266. Schenberg LC, de Aguiar JC, Graeff FG. GABA modulation of the defense reaction induced by brain electrical stimulation. Physiol Behav. 1983;31:429–37.

    Article  CAS  PubMed  Google Scholar 

  267. Bizzi E, Libretti A, Malliani A, Zanchetti A. Reflex chemoceptive excitation of diencephalic sham rage behavior. Am J Physiol. 1961;200:923–6.

    Google Scholar 

  268. Hilton SM, Joels N. Facilitation of chemoreceptor reflexes during the defence reaction. J Physiol. 1965;176:20–2.

    Google Scholar 

  269. Guyenet PG, Koshiya N. Working model of the sympathetic chemoreflex in rats. Clin Exp Hypertens. 1995;17:167–79.

    Article  CAS  PubMed  Google Scholar 

  270. Hayward LF, Castellanos M, Davenport PW. Parabrachial neurons mediate dorsal periaqueductal gray evoked respiratory responses in the rat. J Appl Physiol. 2004;96:1146–54.

    Article  PubMed  Google Scholar 

  271. Zhang W, Hayward LF, Davenport PW. Respiratory responses elicited by rostral versus caudal dorsal periaqueductal gray stimulation in rats. Auton Neurosci. 2007;134:45–54.

    Article  PubMed  Google Scholar 

  272. Haibara AS, Tamashiro E, Olivan MV, Bonagamba LG, Machado BH. Involvement of the parabrachial nucleus in the pressor response to chemoreflex activation in awake rats. Auton Neurosci. 2002;101:60–7.

    Article  PubMed  Google Scholar 

  273. Adams DB, Baccelli G, Mancia G, Zanchetti A. Relation of cardiovascular changes in fighting to emotion and exercise. J Physiol. 1971;212:321–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  274. Hilton SM. The defence-arousal system and its relevance for circulatory and respiratory control. J Exp Biol. 1982;100:159–74.

    CAS  PubMed  Google Scholar 

  275. Lovick TA. Interactions between descending pathways from the dorsal and ventrolateral periaqueductal gray matter in the rat. In: Depaulis A, Bandler R, editors. The midbrain periaqueductal gray matter. New York: Plenum Press; 1991. p. 101–20.

    Chapter  Google Scholar 

  276. Lovick TA. Midbrain and medullary regulation of defensive cardiovascular functions. Prog Brain Res. 1996;107:301–13.

    Article  CAS  PubMed  Google Scholar 

  277. Carobrez AP, Schenberg LC, Graeff FG. Neuroeffector mechanisms of the defense reaction in the rat. Physiol Behav. 1983;31:439–44.

    Article  CAS  PubMed  Google Scholar 

  278. Subramanian HH, Holstege G. Stimulation of the midbrain periaqueductal gray modulates pre-inspiratory neurons in the ventrolateral medulla in the in vivo rat. J Comp Neurol. 2013;521:3083–98.

    Article  PubMed  PubMed Central  Google Scholar 

  279. Hilton SM. Inhibition of baroreceptor reflexes on hypothalamic stimulation. J Physiol. 1963;165:56P–7.

    Article  Google Scholar 

  280. Coote JH, Hilton SM, Zbrozyna AW. The ponto-medullary area integrating the defence reaction in the cat and its influence on muscle blood flow. J Physiol. 1973;229:257–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  281. Schenberg LC, Vasquez EC, da Costa MB. Cardiac baroreflex dynamics during the defence reaction in freely moving rats. Brain Res. 1993;621:50–8.

    Article  CAS  PubMed  Google Scholar 

  282. Lopes LT, Patrone LG, Bicego KC, Coimbra NC, Gargaglioni LH. Periaqueductal gray matter modulates the hypercapnic ventilatory response. Pflugers Arch. 2012;464:155–66.

    Article  CAS  PubMed  Google Scholar 

  283. Lopes LT, Biancardi V, Vieira EB, Leite-Panissi C, Bicego KC, Gargaglioni LH. Participation of the dorsal periaqueductal grey matter in the hypoxic ventilatory response in unanaesthetized rats. Acta Physiol (Oxf). 2014;211:528–37.

    Article  CAS  Google Scholar 

  284. Krout KE, Jansen AS, Loewy AD. Periaqueductal gray matter projection to the parabrachial nucleus in rat. J Comp Neurol. 1998;401:437–54.

    Article  CAS  PubMed  Google Scholar 

  285. Hayward LF, Castellanos M. Increased c-Fos expression in select lateral parabrachial subnuclei following chemical versus electrical stimulation of the dorsal periaqueductal gray in rats. Brain Res. 2003;974:153–66.

    Article  CAS  PubMed  Google Scholar 

  286. Potts JT, Rybak IA, Paton JF. Respiratory rhythm entrainment by somatic afferent stimulation. J Neurosci. 2005;25:1965–78.

    Article  CAS  PubMed  Google Scholar 

  287. Orwin A. ‘The running treatment’: a preliminary communication on a new use for an old therapy (physical activity) in the agoraphobic syndrome. Br J Psychiatry. 1973;122:175–9.

    Article  CAS  PubMed  Google Scholar 

  288. Sun MK, Reis DJ. Hypoxia-activated Ca2+ currents in pacemaker neurones of rat rostral ventrolateral medulla in vitro. J Physiol. 1994;476:101–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  289. Pascual O, Morin-Surun MP, Barna B, Deavit-Saubie M, Pequignot JM, Champagnat J. Progesterone reverses the neuronal responses to hypoxia in rat nucleus tractus solitarius in vitro. J Physiol. 2002;544:511–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  290. Peano CA, Shonis CA, Dillon GH, Waldrop TG. Hypothalamic GABAergic mechanism involved in respiratory response to hypercapnia. Brain Res Bull. 1992;28:107–13.

    Article  CAS  PubMed  Google Scholar 

  291. Panneton WM, Loewy AD. Projections of the carotid sinus nerve to the nucleus of the solitary tract in the cat. Brain Res. 1980;191:239–44.

    Article  CAS  PubMed  Google Scholar 

  292. Sandkuhler J, Herdegen T. Distinct patterns of activated neurons throughout the rat midbrain periaqueductal gray induced by chemical stimulation within its subdivisions. J Comp Neurol. 1995;357:546–53.

    Article  CAS  PubMed  Google Scholar 

  293. Morgan MM, Carrive P. Activation of the ventrolateral periaqueductal gray reduces locomotion but not mean arterial pressure in awake, freely moving rats. Neuroscience. 2001;102:905–10.

    Article  CAS  PubMed  Google Scholar 

  294. Loewy AD, Wallach JH, Kellar S. Efferent connections of the ventral medulla oblongata in the rat. Brain Res Rev. 1981;3:63–80.

    Article  Google Scholar 

  295. Sandner G, Dessort D, Schmitt P, Karli P. Distribution of GABA in the periaqueductal gray matter. Effects of medial hypothalamic lesions. Brain Res. 1981;224:279–90.

    Article  CAS  PubMed  Google Scholar 

  296. Van den Bergh P, Wu P, Jackson IM, Lechan RM. Neurons containing a N-terminal sequence of the TRH-prohormone (preproTRH53-74) are present in a unique location of the midbrain periaqueductal gray of the rat. Brain Res. 1988;461:53–63.

    Article  PubMed  Google Scholar 

  297. Beitz AJ, Williams FG. Localization of putative amino acid transmitters in the PAG and their relationship to the PAG-raphe magnus pathway. The midbrain periaqueductal gray matter. New York: Plenum Press; 1991. p. 305–27.

    Google Scholar 

  298. Smith GST, Savery D, Marden C, Costa JJL, Averill S, Priestley JV, et al. Distribution of messenger RNAs encoding enkephalin, substance P, somatostatin, galanin, vasoactive intestinal polypeptide, neuropeptide Y, and calcitonin gene related peptide in the midbrain periaqueductal grey in the rat. J Comp Neurol. 1994;350:23–40.

    Article  CAS  PubMed  Google Scholar 

  299. Mihaly E, Legradi G, Fekete C, Lechan RM. Efferent projections of ProTRH neurons in the ventrolateral periaqueductal gray. Brain Res. 2001;919:185–97.

    Article  CAS  PubMed  Google Scholar 

  300. Mennicken F, Hoffert C, Pelletier M, Ahmad S, O'Donnell D. Restricted distribution of galanin receptor 3 (GalR3) mRNA in the adult rat central nervous system. J Chem Neuroanat. 2002;24:257–68.

    Article  CAS  PubMed  Google Scholar 

  301. Harding A, Paxinos G, Halliday G. The serotonin and tachykinin systems. In: Paxinos G, editor. The rat nervous system. 3rd ed. San Diego: Elsevier; 2004. p. 1205–56.

    Chapter  Google Scholar 

  302. Darwinkel A, Stanic D, Booth LC, May CN, Lawrence AJ, Yao ST. Distribution of orexin-1 receptor-green fluorescent protein- (OX1-GFP) expressing neurons in the mouse brain stem and pons: co-localization with tyrosine hydroxylase and neuronal nitric oxide synthase. Neuroscience. 2014;278:253–64.

    Article  CAS  PubMed  Google Scholar 

  303. Jenck F, Moreau JL, Martin JR. Dorsal periaqueductal gray-induced aversion as a simulation of panic anxiety: elements of face and predictive validity. Psychiatry Res. 1995;57:181–91.

    Article  CAS  PubMed  Google Scholar 

  304. Brandão ML, de Aguiar JC, Graeff FG. GABA mediation of the anti-aversive action of minor tranquilizers. Pharmacol Biochem Behav. 1982;16:397–402.

    Article  PubMed  Google Scholar 

  305. Graeff FG, Brandão ML, Audi EA, Milani H. Role of GABA in the anti-aversive action of anxiolytics. Adv Biochem Psychopharmacol. 1986;42:79–86.

    CAS  PubMed  Google Scholar 

  306. Behbehani MM, Jiang MR, Chandler SD, Ennis M. The effect of GABA and its antagonists on midbrain periaqueductal gray neurons in the rat. Pain. 1990;40:195–204.

    Article  CAS  PubMed  Google Scholar 

  307. Lovick TA, Stezhka VV. Neurones in the dorsolateral periaqueductal grey matter in coronal slices of rat midbrain: electrophysiological and morphological characteristics. Exp Brain Res. 1999;124:53–8.

    Article  CAS  PubMed  Google Scholar 

  308. Brandao ML, Lopez-Garcia JA, Graeff FG, Roberts MH. Electrophysiological evidence for excitatory 5-HT2 and depressant 5-HT1A receptors on neurones of the rat midbrain tectum. Brain Res. 1991;556:259–66.

    Article  CAS  PubMed  Google Scholar 

  309. Jeong HJ, Lam K, Mitchell VA, Vaughan CW. Serotonergic modulation of neuronal activity in rat midbrain periaqueductal gray. J Neurophysiol. 2013;109:2712–9.

    Article  CAS  PubMed  Google Scholar 

  310. Stezhka VV, Lovick TA. Inhibitory and excitatory projections from the dorsal raphe nucleus to neurons in the dorsolateral periaqueductal gray matter in slices of midbrain maintained in vitro. Neuroscience. 1994;62:177–87.

    Article  CAS  PubMed  Google Scholar 

  311. Thompson RH, Canteras NS, Swanson LW. Organization of projections from the dorsomedial nucleus of the hypothalamus: a PHA-L study in the rat. J Comp Neurol. 1996;376:143–73.

    Article  CAS  PubMed  Google Scholar 

  312. Veening J, Buma P, Ter Horst GJ, Roeling TAP, Luiten PGM, Nieuwenhuys R. Hypothalamic projections to the PAG in the rat: topographical, immuno-electronmicroscopical and functional aspects. In: Depaulis A, Bandler R, editors. The midbrain periaqueductal gray matter. New York: Plenum Press; 1991. p. 387–415.

    Chapter  Google Scholar 

  313. Barbaresi P. Immunocytochemical localization of substance P receptor in rat periaqueductal gray matter: a light and electron microscopic study. J Comp Neurol. 1998;398:473–90.

    Article  CAS  PubMed  Google Scholar 

  314. Drew GM, Mitchell VA, Vaughan CW. Postsynaptic actions of substance P on rat periaqueductal grey neurons in vitro. Neuropharmacology. 2005;49:587–95.

    Article  CAS  PubMed  Google Scholar 

  315. Brodin E, Rosen A, Schott E, Brodin K. Effects of sequential removal of rats from a group cage, and of individual housing of rats, on substance P, cholecystokinin and somatostatin levels in the periaqueductal grey and limbic regions. Neuropeptides. 1994;26:253–60.

    Article  CAS  PubMed  Google Scholar 

  316. Bassi GS, Nobre MJ, Carvalho MC, Brandão ML. Substance P injected into the dorsal periaqueductal gray causes anxiogenic effects similar to the long-term isolation as assessed by ultrasound vocalizations measurements. Behav Brain Res. 2007;182:301–7.

    Article  CAS  PubMed  Google Scholar 

  317. Shekhar A, DiMicco JA. Defense reaction elicited by injection of GABA antagonists and synthesis inhibitors into the posterior hypothalamus in rats. Neuropharmacology. 1987;26:407–17.

    Article  CAS  PubMed  Google Scholar 

  318. Shekhar A, Hingtgen JN, DiMicco JA. Selective enhancement of shock avoidance responding elicited by GABA blockade in the posterior hypothalamus of rats. Brain Res. 1987;420:118–28.

    Article  CAS  PubMed  Google Scholar 

  319. Shekhar A, Hingtgen JN, DiMicco JA. GABA receptors in the posterior hypothalamus regulate experimental anxiety in rats. Brain Res. 1990;512:81–8.

    Article  CAS  PubMed  Google Scholar 

  320. Shekhar A. GABA receptors in the region of the dorsomedial hypothalamus of rats regulate anxiety in the elevated plus-maze test. I Behav Meas Brain Res. 1993;627:9–16.

    CAS  Google Scholar 

  321. Shekhar A, Johnson PL, Sajdyk TJ, Fitz SD, Keim SR, Kelley PE, et al. Angiotensin-II is a putative neurotransmitter in lactate-induced panic-like responses in rats with disruption of GABAergic inhibition in the dorsomedial hypothalamus. J Neurosci. 2006;26:9205–15.

    Article  CAS  PubMed  Google Scholar 

  322. Johnson PL, Shekhar A. Panic-prone state induced in rats with GABA dysfunction in the dorsomedial hypothalamus is mediated by NMDA receptors. J Neurosci. 2006;26:7093–104.

    Article  CAS  PubMed  Google Scholar 

  323. Shekhar A. Effects of treatment with imipramine and clonazepam on an animal model of panic disorder. Biol Psychiatry. 1994;36:748–58.

    Article  CAS  PubMed  Google Scholar 

  324. Shekhar A, Keim SR, Simon JR, McBride WJ. Dorsomedial hypothalamic GABA dysfunction produces physiological arousal following sodium lactate infusions. Pharmacol Biochem Behav. 1996;55:249–56.

    Article  CAS  PubMed  Google Scholar 

  325. Swanson LW, Lind RW. Neural projections subserving the initiation of a specific motivated behavior in the rat: new projections from the subfornical organ. Brain Res. 1986;379:399–403.

    Article  CAS  PubMed  Google Scholar 

  326. Shekhar A, Sajdyk TS, Keim SR, Yoder KK, Sanders SK. Role of the basolateral amygdala in panic disorder. Ann N Y Acad Sci. 1999;877:747–50.

    Article  CAS  PubMed  Google Scholar 

  327. Shekhar A, Keim SR. LY354740, a potent group II metabotropic glutamate receptor agonist prevents lactate-induced panic-like response in panic-prone rats. Neuropharmacology. 2000;39:1139–46.

    Article  CAS  PubMed  Google Scholar 

  328. Sajdyk TJ, Schober DA, Gehlert DR, Shekhar A. Role of corticotropin-releasing factor and urocortin within the basolateral amygdala of rats in anxiety and panic responses. Behav Brain Res. 1999;100:207–15.

    Article  CAS  PubMed  Google Scholar 

  329. Sajdyk TJ, Shekhar A. Sodium lactate elicits anxiety in rats after repeated GABA receptor blockade in the basolateral amygdala. Eur J Pharmacol. 2000;394:265–73.

    Article  CAS  PubMed  Google Scholar 

  330. Johnson PL, Truitt W, Fitz SD, Minick PE, Dietrich A, Sanghani S, et al. A key role for orexin in panic anxiety. Nat Med. 2010;16:111–5.

    Article  CAS  PubMed  Google Scholar 

  331. Antunes-Rodrigues J, Castro M, Elias LL, Valenca MM, McCann SM. Neuroendocrine control of body fluid metabolism. Physiol Rev. 2004;84:169–208.

    Article  CAS  PubMed  Google Scholar 

  332. Fitzsimons JT. Angiotensin, thirst, and sodium appetite. Physiol Rev. 1998;78:583–686.

    CAS  PubMed  Google Scholar 

  333. Rodgers RJ, Ishii Y, Halford JC, Blundell JE. Orexins and appetite regulation. Neuropeptides. 2002;36:303–25.

    Article  CAS  PubMed  Google Scholar 

  334. Siegel JM. Narcolepsy: a key role for hypocretins (orexins). Comment. Cell. 1999;98:409–12.

    Article  CAS  PubMed  Google Scholar 

  335. Taheri S, Zeitzer JM, Mignot E. The role of hypocretins (orexins) in sleep regulation and narcolepsy. Ann Rev Neurosci. 2002;25:283–313.

    Article  CAS  PubMed  Google Scholar 

  336. Molosh AI, Johnson PL, Fitz SD, DiMicco JA, Herman JP, Shekhar A. Changes in central sodium and not osmolarity or lactate induce panic-like responses in a model of panic disorder. Neuropsychopharmacology. 2010;35:1333–47.

    Article  PubMed  PubMed Central  Google Scholar 

  337. Kellner M, Wiedemann K, Holsboer F. Atrial natriuretic factor inhibits the CRH-stimulated secretion of ACTH and cortisol in man. Life Sci. 1992;50:1835–42.

    Article  CAS  PubMed  Google Scholar 

  338. Tannure RM, Bittencourt AS, Schenberg LC. Short-term full kindling of the amygdala dissociates natural and periaqueductal gray-evoked flight behaviors of the rat. Behav Brain Res. 2009;199:247–56.

    Article  PubMed  Google Scholar 

  339. Bailey TW, DiMicco JA. Chemical stimulation of the dorsomedial hypothalamus elevates plasma ACTH in conscious rats. Am J Physiol Regul Integr Comp Physiol. 2001;280:R8–15.

    CAS  PubMed  Google Scholar 

  340. Zaretskaia MV, Zaretsky DV, Shekhar A, DiMicco JA. Chemical stimulation of the dorsomedial hypothalamus evokes non-shivering thermogenesis in anesthetized rats. Brain Res. 2002;928:113–25.

    Article  CAS  PubMed  Google Scholar 

  341. Johnson PL, Truitt WA, Fitz SD, Lowry CA, Shekhar A. Neural pathways underlying lactate-induced panic. Neuropsychopharmacology. 2008;33:2093–107.

    Article  CAS  PubMed  Google Scholar 

  342. Olsson M, Ho HP, Annerbrink K, Thylefors J, Eriksson E. Respiratory responses to intravenous infusion of sodium lactate in male and female Wistar rats. Neuropsychopharmacology. 2002;27:85–91.

    Article  CAS  PubMed  Google Scholar 

  343. 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;293:540–80.

    Article  CAS  PubMed  Google Scholar 

  344. Chamberlin NL, Saper CB. Topographic organization of respiratory responses to glutamate microstimulation of the parabrachial nucleus in the rat. J Neurosci. 1994;14:6500–10.

    CAS  PubMed  Google Scholar 

  345. Chamberlin NL. Functional organization of the parabrachial complex and intertrigeminal region in the control of breathing. Respir Physiol Neurobiol. 2004;143:115–25.

    Article  PubMed  Google Scholar 

  346. Kaur S, Pedersen NP, Yokota S, Hur EE, Fuller PM, Lazarus M, et al. Glutamatergic signaling from the parabrachial nucleus plays a critical role in hypercapnic arousal. J Neurosci. 2013;33:7627–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  347. Yokota S, Kaur S, Vanderhorst VG, Saper CB, Chamberlin NL. Respiratory-related outputs of glutamatergic, hypercapnia-responsive parabrachial neurons in mice. J Comp Neurol. 2015;523:907–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  348. Huang GF, Besson JM, Bernard JF. Intravenous morphine depresses the transmission of noxious messages to the nucleus centralis of the amygdala. Eur J Pharmacol. 1993;236:449–56.

    Article  CAS  PubMed  Google Scholar 

  349. Huang GF, Besson JM, Bernard JF. Morphine depresses the transmission of noxious messages in the spino(trigemino)-ponto-amygdaloid pathway. Eur J Pharmacol. 1993;230:279–84.

    Article  CAS  PubMed  Google Scholar 

  350. Beitz AJ. Possible origin of glutamatergic projections to the midbrain periaqueductal grey and deep layer of the superior colliculus of the rat. Brain Res Bull. 1989;23:25–35.

    Article  CAS  PubMed  Google Scholar 

  351. da Silva LG, de Menezes RC, dos Santos RA, Campagnole-Santos MJ, Fontes MA. Role of periaqueductal gray on the cardiovascular response evoked by disinhibition of the dorsomedial hypothalamus. Brain Res. 2003;984:206–14.

    Article  PubMed  CAS  Google Scholar 

  352. da Silva LG, Menezes RC, Villela DC, Fontes MA. Excitatory amino acid receptors in the periaqueductal gray mediate the cardiovascular response evoked by activation of dorsomedial hypothalamic neurons. Neuroscience. 2006;139:1129–39.

    Article  PubMed  CAS  Google Scholar 

  353. Allen GV, Saper CB, Hurley KM, Cechetto DF. Organization of visceral and limbic connections in the insular cortex of the rat. J Comp Neurol. 1991;311:1–16.

    Article  CAS  PubMed  Google Scholar 

  354. Shipley MT, Ennis M, Rizvi TA, Behbehani MM. Topographical specificity of forebrain inputs to the midbrain periaqueductal gray: evidence for discrete longitudinally organized input columns. In: Depaulis A, Bandler R, editors. The midbrain periaqueductal gray matter. New York: Plenum Press; 1991. p. 417–48.

    Chapter  Google Scholar 

  355. Floyd NS, Price JL, Ferry AT, Keay KA, Bandler R. Orbitomedial prefrontal cortical projections to distinct longitudinal columns of the periaqueductal gray in the rat. J Comp Neurol. 2000;422:556–78.

    Article  CAS  PubMed  Google Scholar 

  356. Selye H. A syndrome produced by diverse nocuous agents. Nature. 1936;138:31.

    Article  Google Scholar 

  357. Selye H. Forty years of stress research: principal remaining problems and misconceptions. Can Med Assoc J. 1976;115:53–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  358. Strohle A, Holsboer F. Stress responsive neurohormones in depression and anxiety. Pharmacopsychiatry. 2003;36 Suppl 3:S207–14.

    PubMed  Google Scholar 

  359. Jovanovic T, Norrholm SD, Fennell JE, Keyes M, Fiallos AM, Myers KM, et al. Posttraumatic stress disorder may be associated with impaired fear inhibition: relation to symptom severity. Psychiatry Res. 2009;167:151–60.

    Article  PubMed  PubMed Central  Google Scholar 

  360. Jovanovic T, Norrholm SD, Blanding NQ, Phifer JE, Weiss T, Davis M, et al. Fear potentiation is associated with hypothalamic-pituitary-adrenal axis function in PTSD. Psychoneuroendocrinology. 2010;35:846–57.

    Article  CAS  PubMed  Google Scholar 

  361. Jovanovic T, Norrholm SD, Blanding NQ, Davis M, Duncan E, Bradley B, et al. Impaired fear inhibition is a biomarker of PTSD but not depression. Depress Anxiety. 2010;27:244–51.

    Article  PubMed  PubMed Central  Google Scholar 

  362. Keen-Rhinehart E, Michopoulos V, Toufexis DJ, Martin EI, Nair H, Ressler KJ, et al. Continuous expression of corticotropin-releasing factor in the central nucleus of the amygdala emulates the dysregulation of the stress and reproductive axes. Mol Psychiatry. 2009;14:37–50.

    Article  CAS  PubMed  Google Scholar 

  363. Neill JD. Effects of “stress” on serum prolactin and luteinizing hormone levels during the estrous cycle of the rat. Endocrinology. 1970;87:1192–7.

    Article  CAS  PubMed  Google Scholar 

  364. Siegel RA, Conforti N, Chowers I. Neural pathways mediating the prolactin secretory response to acute neurogenic stress in the male rat. Brain Res. 1980;198:43–53.

    Article  CAS  PubMed  Google Scholar 

  365. Dijkstra H, Tilders FJH, Hiehle MA, Smelik PG. Hormonal reactions to fighting in rat colonies prolactin rises during defence, not during offence. Physiol Behav. 1992;51:961–8.

    Article  CAS  PubMed  Google Scholar 

  366. 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;86:93–8.

    Article  CAS  PubMed  Google Scholar 

  367. Bandelow B, Wedekind D, Pauls J, Broocks A, Hajak G, Ruther E. Salivary cortisol in panic attacks. Am J Psychiatry. 2000;157:454–6.

    Article  CAS  PubMed  Google Scholar 

  368. Kamilaris TC, Johnson EO, Calogero AE, Kalogeras KT, Bernardini R, Chrousos GP, et al. Cholecystokinin-octapeptide stimulates hypothalamic-pituitary-adrenal function in rats: role of corticotropin-releasing hormone. Endocrinology. 1992;130:1764–74.

    CAS  PubMed  Google Scholar 

  369. Graeff FG, Garcia-Leal C, Del-Ben CM, Guimaraes FS. Does the panic attack activate the hypothalamic-pituitary-adrenal axis? An Acad Bras Cienc. 2005;77:477–91.

    Article  CAS  PubMed  Google Scholar 

  370. De Montigny C. Cholecystokinin tetrapeptide induces panic-like attacks in healthy volunteers. Preliminary findings. Arch Gen Psychiatry. 1989;46:511–7.

    Article  PubMed  Google Scholar 

  371. Bradwejn J, Koszycki D, Annable L, Couetoux DT, Reines S, Karkanias C. A dose-ranging study of the behavioral and cardiovascular effects of CCK-tetrapeptide in panic disorder. Biol Psychiatry. 1992;32:903–12.

    Article  CAS  PubMed  Google Scholar 

  372. Abelson JL, Liberzon I. Dose response of adrenocorticotropin and cortisol to the CCK-B agonist pentagastrin. Neuropsychopharmacology. 1999;21:485–94.

    Article  CAS  PubMed  Google Scholar 

  373. Kobelt P, Paulitsch S, Goebel M, Stengel A, Schmidtmann M, van der Voort I, et al. Peripheral injection of CCK-8S induces Fos expression in the dorsomedial hypothalamic nucleus in rats. Brain Res. 2006;1117:109–17.

    Article  CAS  PubMed  Google Scholar 

  374. Shlik J, Aluoja A, Vasar V, Vasar E, Podar T, Bradwejn J. Effects of citalopram treatment on behavioural, cardiovascular and neuroendocrine response to cholecystokinin tetrapeptide challenge in patients with panic disorder. J Psychiatry Neurosci. 1997;22:332–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  375. Depot M, Caille G, Mukherjee J, Katzman MA, Cadieux A, Bradwejn J. Acute and chronic role of 5-HT3 neuronal system on behavioral and neuroendocrine changes induced by intravenous cholecystokinin tetrapeptide administration in humans. Neuropsychopharmacology. 1999;20:177–87.

    Article  CAS  PubMed  Google Scholar 

  376. Chen DY, Deutsch JA, Gonzalez MF, Gu Y. The induction and suppression of c-fos expression in the rat brain by cholecystokinin and its antagonist L364,718. Neurosci Lett. 1993;149:91–4.

    Article  CAS  PubMed  Google Scholar 

  377. Schenberg LC, Dos Reis AM, Ferreira Povoa RM, Tufik S, Silva SR. A panic attack-like unusual stress reaction. Horm Behav. 2008;54:584–91.

    Article  CAS  PubMed  Google Scholar 

  378. Lim LW, Blokland A, van DM, Visser-Vandewalle V, Tan S, Vlamings R, et al. Increased plasma corticosterone levels after periaqueductal gray stimulation-induced escape reaction or panic attacks in rats. Behav Brain Res. 2011;218:301–7.

    Article  CAS  PubMed  Google Scholar 

  379. Armini RS, Bernabe CS, Rosa CA, Siller CA, Schimitel FG, Tufik S, et al. In a rat model of panic, corticotropin responses to dorsal periaqueductal gray stimulation depend on physical exertion. Psychoneuroendocrinology. 2015;53:136–47.

    Article  CAS  Google Scholar 

  380. Beckett S, Marsden CA. Computer analysis and quantification of periaqueductal grey- induced defence behaviour. J Neurosci Methods. 1995;58:157–61.

    Article  CAS  PubMed  Google Scholar 

  381. Neophytou SI, Graham M, Williams J, Aspley S, Marsden CA, Beckett SR. Strain differences to the effects of aversive frequency ultrasound on behaviour and brain topography of c-fos expression in the rat. Brain Res. 2000;854:158–64.

    Article  CAS  PubMed  Google Scholar 

  382. Soya H, Mukai A, Deocaris CC, Ohiwa N, Chang H, Nishijima T, et al. Threshold-like pattern of neuronal activation in the hypothalamus during treadmill running: establishment of a minimum running stress (MRS) rat model. Neurosci Res. 2007;58:341–8.

    Article  CAS  PubMed  Google Scholar 

  383. Pittman QJ, Blume HW, Renaud LP. Connections of the hypothalamic paraventricular nucleus with the neurohypophysis, median eminence, amygdala, lateral septum and midbrain periaqueductal gray: an electrophysiological study in the rat. Brain Res. 1981;215:15–28.

    Article  CAS  PubMed  Google Scholar 

  384. Ziegler DR, Edwards MR, Ulrich-Lai YM, Herman JP, Cullinan WE. Brainstem origins of glutamatergic innervation of the rat hypothalamic paraventricular nucleus. J Comp Neurol. 2012;520:2369–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  385. Klein S, Nicolas LB, Lopez-Lopez C, Jacobson LH, McArthur SG, Grundschober C, et al. Examining face and construct validity of a noninvasive model of panic disorder in Lister-hooded rats. Psychopharmacology (Berl). 2010;211:197–208.

    Article  CAS  Google Scholar 

  386. Feldman S, Weidenfeld J. The excitatory effects of the amygdala on hypothalamo-pituitary-adrenocortical responses are mediated by hypothalamic norepinephrine, serotonin, and CRF-41. Brain Res Bull. 1998;45:389–93.

    Article  CAS  PubMed  Google Scholar 

  387. Bhatnagar S, Viau V, Chu A, Soriano L, Meijer OC, Dallman MF. A cholecystokinin-mediated pathway to the paraventricular thalamus is recruited in chronically stressed rats and regulates hypothalamic-pituitary-adrenal function. J Neurosci. 2000;20:5564–73.

    CAS  PubMed  Google Scholar 

  388. Koolhaas JM, Bartolomucci A, Buwalda B, de Boer SF, Flugge G, Korte SM, et al. Stress revisited: a critical evaluation of the stress concept. Neurosci Biobehav Rev. 2011;35:1291–301.

    Article  CAS  PubMed  Google Scholar 

  389. Raff H, Shinsako J, Dallman MF. Renin and ACTH responses to hypercapnia and hypoxia after chronic carotid chemodenervation. Am J Physiol. 1984;247:R412–7.

    CAS  PubMed  Google Scholar 

  390. Raff H, Shinsako J, Keil LC, Dallman MF. Vasopressin, ACTH, and corticosteroids during hypercapnia and graded hypoxia in dogs. Am J Physiol. 1983;244:E453–8.

    CAS  PubMed  Google Scholar 

  391. Raff H, Shinsako J, Keil LC, Dallman MF. Vasopressin, ACTH, and blood pressure during hypoxia induced at different rates. Am J Physiol. 1983;245:E489–93.

    CAS  PubMed  Google Scholar 

  392. Raff H, Sandri RB, Segerson TP. Renin, ACTH, and adrenocortical function during hypoxia and hemorrhage in conscious rats. Am J Physiol. 1986;250:R240–4.

    CAS  PubMed  Google Scholar 

  393. Kossowsky J, Wilhelm FH, Schneider S. Responses to voluntary hyperventilation in children with separation anxiety disorder: implications for the link to panic disorder. J Anxiety Disord. 2013;27:627–34.

    Article  PubMed  Google Scholar 

  394. Vargas LC, Marques TA, Schenberg LC. Micturition and defensive behaviors are controlled by distinct neural networks within the dorsal periaqueductal gray and deep gray layer of the superior colliculus of the rat. Neurosci Lett. 2000;280:45–8.

    Article  CAS  PubMed  Google Scholar 

  395. Schenberg LC, Marcal LPA, Seeberger F, Barros MR, Sudré ECM. L-type calcium channels selectively control the defensive behaviors induced by electrical stimulation of dorsal periaqueductal gray and overlying collicular layers. Behav Brain Res. 2000;111:175–85.

    Article  CAS  PubMed  Google Scholar 

  396. Goetz RR, Klein DF, Gorman JM. Consistencies between recalled panic and lactate-induced panic. Anxiety. 1994;1:31–6.

    Article  CAS  PubMed  Google Scholar 

  397. APA. Diagnostic and statistical manual of mental disorders. 4th-R ed. Washington, DC: American Psychiatry Association; 2000.

    Google Scholar 

  398. WHO. The ICD-10 classification of mental and behavioral disorders. Diagnostic criteria for research. Geneva: 1993.

    Google Scholar 

  399. D'Amato FR, Zanettini C, Lampis V, Coccurello R, Pascucci T, Ventura R, et al. Unstable maternal environment, separation anxiety, and heightened CO2 sensitivity induced by gene-by-environment interplay. PLoS One. 2011;6:e18637.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  400. Kinkead R, Genest SE, Gulemetova R, Lajeunesse Y, Laforest S, Drolet G, et al. Neonatal maternal separation and early life programming of the hypoxic ventilatory response in rats. Respir Physiol Neurobiol. 2005;149:313–24.

    Article  PubMed  Google Scholar 

  401. Genest SE, Gulemetova R, Laforest S, Drolet G, Kinkead R. Neonatal maternal separation and sex-specific plasticity of the hypoxic ventilatory response in awake rat. J Physiol. 2004;554:543–57.

    Article  CAS  PubMed  Google Scholar 

  402. Genest SE, Gulemetova R, Laforest S, Drolet G, Kinkead R. Neonatal maternal separation induces sex-specific augmentation of the hypercapnic ventilatory response in awake rat. J Appl Physiol. 2007;102:1416–21.

    Article  PubMed  Google Scholar 

  403. Francis DD, Meaney MJ. Maternal care and the development of stress responses. Curr Opin Neurobiol. 1999;9:128–34.

    Article  CAS  PubMed  Google Scholar 

  404. Abelson JL, Curtis GC. Hypothalamic-pituitary-adrenal axis activity in panic disorder. 24-Hour secretion of corticotropin and cortisol. Arch Gen Psychiatry. 1996;53:323–31.

    Article  CAS  PubMed  Google Scholar 

  405. Schreiber W, Lauer CJ, Krumrey K, Holsboer F, Krieg JC. Dysregulation of the hypothalamic-pituitary-adrenocortical system in panic disorder. Neuropsychopharmacology. 1996;15:7–15.

    Article  CAS  PubMed  Google Scholar 

  406. Rentesi G, Antoniou K, Marselos M, Fotopoulos A, Alboycharali J, Konstandi M. Long-term consequences of early maternal deprivation in serotonergic activity and HPA function in adult rat. Neurosci Lett. 2010;480:7–11.

    Article  CAS  PubMed  Google Scholar 

  407. Fournier S, Allard M, Gulemetova R, Joseph V, Kinkead R. Chronic corticosterone elevation and sex-specific augmentation of the hypoxic ventilatory response in awake rats. J Physiol. 2007;584(Pt 3):951–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  408. Gorman JM, Coplan JD. Comorbidity of depression and panic disorder. J Clin Psychiatry. 1996;57 Suppl 10:34–41.

    PubMed  Google Scholar 

  409. Kaufman J, Charney D. Comorbidity of mood and anxiety disorders. Depress Anxiety. 2000;12 Suppl 1:69–76.

    Article  PubMed  Google Scholar 

  410. Safadi G, Bradwejn J. Relationship of panic disorder to posttraumatic stress disorder. Arch Gen Psychiatry. 1995;52:76–8.

    CAS  PubMed  Google Scholar 

  411. Koenen KC, Lyons MJ, Goldberg J, Simpson J, Williams WM, Toomey R, et al. A high risk twin study of combat-related PTSD comorbidity. Twin Res. 2003;6:218–26.

    Article  PubMed  Google Scholar 

  412. Nixon RD, Resick PA, Griffin MG. Panic following trauma: the etiology of acute posttraumatic arousal. J Anxiety Disord. 2004;18:193–210.

    Article  PubMed  PubMed Central  Google Scholar 

  413. Hinton D, Hsia C, Um K, Otto MW. Anger-associated panic attacks in Cambodian refugees with PTSD; a multiple baseline examination of clinical data. Behav Res Ther. 2003;41:647–54.

    Article  CAS  PubMed  Google Scholar 

  414. Cougle JR, Feldner MT, Keough ME, Hawkins KA, Fitch KE. Comorbid panic attacks among individuals with posttraumatic stress disorder: associations with traumatic event exposure history, symptoms, and impairment. J Anxiety Disord. 2010;24:183–8.

    Article  PubMed  Google Scholar 

  415. McGrath PJ, Stewart JW, Liebowitz MR, Markowitz JM, Quitkin FM, Klein DF, et al. Lactate provocation of panic attacks in depressed outpatients. Psychiatry Res. 1988;25:41–7.

    Article  CAS  PubMed  Google Scholar 

  416. Quintino-Dos-Santos JW, Muller CJ, Santos AMC, Tufik S, Rosa CA, Schenberg LC. Long-lasting marked inhibition of periaqueductal gray-evoked defensive behaviors in inescapably-shocked rats. Eur J Neurosci. 2014;39:275–86.

    Article  PubMed  Google Scholar 

  417. de Paula Soares V, Zangrossi Jr H. Involvement of 5-HT1A and 5-HT2 receptors of the dorsal periaqueductal gray in the regulation of the defensive behaviors generated by the elevated T-maze. Brain Res Bull. 2004;64:181–8.

    Article  PubMed  CAS  Google Scholar 

  418. Maier SF, Seligman ME. Learned helplessness: theory and evidence. J Exp Psychol. 1975;105:3–46.

    Article  Google Scholar 

  419. Maier SF. Learned helplessness and animal models of depression. Prog Neuropsychopharmacol Biol Psychiatry. 1984;8:435–46.

    Article  CAS  PubMed  Google Scholar 

  420. Maier SF, Watkins LR. Stressor controllability, anxiety, and serotonin. Cogn Ther Res. 1998;22:595–613.

    Article  Google Scholar 

  421. Maier SF, Watkins LR. Stressor controllability and learned helplessness: the roles of the dorsal raphe nucleus, serotonin, and corticotropin-releasing factor. Neurosci Biobehav Rev. 2005;29:829–41.

    Article  CAS  PubMed  Google Scholar 

  422. Porsolt RD, Lenegre A, McArthur RA. Pharmacological models of depression. In: Olivier B, Slangen JL, Mos J, editors. Animal models in psychopharmacology. Basle: Birkhaeuser-Verlag; 1991. p. 137–61.

    Chapter  Google Scholar 

  423. Maier SF, Grahn RE, Kalman BA, Sutton LC, Wiertelak EP, Watkins LR. The role of the amygdala and dorsal raphe nucleus in mediating the behavioral consequences of inescapable shock. Behav Neurosci. 1993;107:377–88.

    Article  CAS  PubMed  Google Scholar 

  424. Amat J, Matus-Amat P, Watkins LR, Maier SF. Escapable and inescapable stress differentially and selectively alter extracellular levels of 5-HT in the ventral hippocampus and dorsal periaqueductal gray of the rat. Brain Res. 1998;797:12–22.

    Article  CAS  PubMed  Google Scholar 

  425. Hammack SE, Richey KJ, Watkins LR, Maier SF. Chemical lesion of the bed nucleus of the stria terminalis blocks the behavioral consequences of uncontrollable stress. Behav Neurosci. 2004;118:443–8.

    Article  PubMed  Google Scholar 

  426. Leshner AI, Segal M. Fornix transection blocks “learned helplessness” in rats. Behav Neural Biol. 1979;26:497–501.

    Article  CAS  PubMed  Google Scholar 

  427. Petty F, Sherman AD. Learned helplessness induction decreases in vivo cortical serotonin release. Pharmacol Biochem Behav. 1983;18:649–50.

    Article  CAS  PubMed  Google Scholar 

  428. Joca SR, Padovan CM, Guimaraes FS. Activation of post-synaptic 5-HT(1A) receptors in the dorsal hippocampus prevents learned helplessness development. Brain Res. 2003;978:177–84.

    Article  CAS  PubMed  Google Scholar 

  429. Joca SR, Zanelati T, Guimaraes FS. Post-stress facilitation of serotonergic, but not noradrenergic, neurotransmission in the dorsal hippocampus prevents learned helplessness development in rats. Brain Res. 2006;1087:67–74.

    Article  CAS  PubMed  Google Scholar 

  430. Malberg JE, Duman RS. Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment. Neuropsychopharmacology. 2003;28:1562–71.

    Article  CAS  PubMed  Google Scholar 

  431. Zhou J, Li L, Tang S, Cao X, Li Z, Li W, et al. Effects of serotonin depletion on the hippocampal GR/MR and BDNF expression during the stress adaptation. Behav Brain Res. 2008;195:129–38.

    Article  CAS  PubMed  Google Scholar 

  432. Wu J, Kramer GL, Kram M, Steciuk M, Crawford IL, Petty F. Serotonin and learned helplessness: a regional study of 5-HT1A, 5-HT2A receptors and the serotonin transport site in rat brain. J Psychiatr Res. 1999;33:17–22.

    Article  CAS  PubMed  Google Scholar 

  433. Yang LM, Hu B, Xia YH, Zhang BL, Zhao H. Lateral habenula lesions improve the behavioral response in depressed rats via increasing the serotonin level in dorsal raphe nucleus. Behav Brain Res. 2008;188:84–90.

    Article  PubMed  Google Scholar 

  434. Lino-de-Oliveira C, De Lima TC, Carobrez AP. Dorsal periaqueductal gray matter inhibits passive coping strategy elicited by forced swimming stress in rats. Neurosci Lett. 2002;335:87–90.

    Article  CAS  PubMed  Google Scholar 

  435. Lino-de-Oliveira C, De Oliveira RM, Padua CA, De Lima TC, Del Bel EA, Guimaraes FS. Antidepressant treatment reduces Fos-like immunoreactivity induced by swim stress in different columns of the periaqueductal gray matter. Brain Res Bull. 2006;70:414–21.

    Article  CAS  PubMed  Google Scholar 

  436. Jang DP, Lee SH, Lee SY, Park CW, Cho ZH, Kim YB. Neural responses of rats in the forced swimming test: [F-18]FDG micro PET study. Behav Brain Res. 2009;203:43–7.

    Article  PubMed  Google Scholar 

  437. Strong PV, Christianson JP, Loughridge AB, Amat J, Maier SF, Fleshner M, et al. 5-Hydroxytryptamine 2C receptors in the dorsal striatum mediate stress-induced interference with negatively reinforced instrumental escape behavior. Neuroscience. 2011;197:132–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  438. Krout KE, Loewy AD. Periaqueductal gray matter projections to midline and intralaminar thalamic nuclei of the rat. J Comp Neurol. 2000;424:111–41.

    Article  CAS  PubMed  Google Scholar 

  439. Macchi G, Bentivoglio M, Molinari M, Minciacchi D. The thalamo-caudate versus thalamo-cortical projections as studied in the cat with fluorescent retrograde double labeling. Exp Brain Res. 1984;54:225–39.

    Article  CAS  PubMed  Google Scholar 

  440. Kaufman J, Plotsky PM, Nemeroff CB, Charney DS. Effects of early adverse experiences on brain structure and function: clinical implications. Biol Psychiatry. 2000;48:778–90.

    Article  CAS  PubMed  Google Scholar 

  441. Faravelli C, Pallanti S. Recent life events and panic disorder. Am J Psychiatry. 1989;146:622–6.

    Article  CAS  PubMed  Google Scholar 

  442. Falsetti SA, Resnick HS. Frequency and severity of panic attack symptoms in a treatment seeking sample of trauma victims. J Trauma Stress. 1997;10:683–9.

    CAS  PubMed  Google Scholar 

  443. Sherman AD, Sacquitne JL, Petty F. Specificity of the learned helplessness model of depression. Pharmacol Biochem Behav. 1982;16:449–54.

    Article  CAS  PubMed  Google Scholar 

  444. Maier SF. Exposure to the stressor environment prevents the temporal dissipation of behavioral depression/learned helplessness. Biol Psychiatry. 2001;49:763–73.

    Article  CAS  PubMed  Google Scholar 

  445. Yonkers KA, Pearlstein T, Rosenheck RA. Premenstrual disorders: bridging research and clinical reality. Arch Womens Ment Health. 2003;6:287–92.

    Article  CAS  PubMed  Google Scholar 

  446. Le Mellédo JM, Van DM, Coupland NJ, Lott P, Jhangri GS. Response to flumazenil in women with premenstrual dysphoric disorder. Am J Psychiatry. 2000;157:821–3.

    Article  PubMed  Google Scholar 

  447. Gorman JM, Kent J, Martinez J, Browne S, Coplan J, Papp LA. Physiological changes during carbon dioxide inhalation in patients with panic disorder, major depression, and premenstrual dysphoric disorder: evidence for a central fear mechanism. Arch Gen Psychiatry. 2001;58:125–31.

    Article  CAS  PubMed  Google Scholar 

  448. Kent JM, Papp LA, Martinez JM, Browne ST, Coplan JD, Klein DF, et al. Specificity of panic response to CO2 inhalation in panic disorder: a comparison with major depression and premenstrual dysphoric disorder. Am J Psychiatry. 2001;158:58–67.

    Article  CAS  PubMed  Google Scholar 

  449. Lovick TA. Plasticity of GABA-A receptor subunit expression during the oestrous cycle of the rat: implications for premenstrual syndrome in women. Exp Physiol. 2006;91:655–60.

    Article  CAS  PubMed  Google Scholar 

  450. Lovick TA. GABA in the female brain—oestrous cycle-related changes in GABAergic function in the periaqueductal grey matter. Pharmacol Biochem Behav. 2008;90:43–50.

    Article  CAS  PubMed  Google Scholar 

  451. Lovick TA, Devall AJ. Progesterone withdrawal-evoked plasticity of neural function in the female periaqueductal grey matter. Neural Plast. 2009;2009:730902.

    CAS  PubMed  Google Scholar 

  452. Lovick TA, Griffiths JL, Dunn SM, Martin IL. Changes in GABA-A receptor subunit expression in the midbrain during the oestrous cycle in Wistar rats. Neuroscience. 2005;131:397–405.

    Article  CAS  PubMed  Google Scholar 

  453. Griffiths J, Lovick T. Withdrawal from progesterone increases expression of alpha4, beta1, and delta GABA(A) receptor subunits in neurons in the periaqueductal gray matter in female Wistar rats. J Comp Neurol. 2005;486:89–97.

    Article  CAS  PubMed  Google Scholar 

  454. Griffiths JL, Lovick TA. GABAergic neurones in the rat periaqueductal grey matter express alpha4, beta1 and delta GABAA receptor subunits: plasticity of expression during the estrous cycle. Neuroscience. 2005;136:457–66.

    Article  CAS  PubMed  Google Scholar 

  455. Brack KE, Jeffery SM, Lovick TA. Cardiovascular and respiratory responses to a panicogenic agent in anaesthetised female Wistar rats at different stages of the oestrous cycle. Eur J Neurosci. 2006;23:3309–18.

    Article  CAS  PubMed  Google Scholar 

  456. Brack KE, Lovick TA. Neuronal excitability in the periaqueductal grey matter during the estrous cycle in female Wistar rats. Neuroscience. 2007;144:325–35.

    Article  CAS  PubMed  Google Scholar 

  457. Smith SS, Woolley CS. Cellular and molecular effects of steroid hormones on CNS excitability. Cleve Clin J Med. 2004;71 Suppl 2:S4–10.

    Article  PubMed  Google Scholar 

  458. Gallo MA, Smith SS. Progesterone withdrawal decreases latency to and increases duration of electrified prod burial: a possible rat model of PMS anxiety. Pharmacol Biochem Behav. 1993;46:897–904.

    Article  CAS  PubMed  Google Scholar 

  459. Gulinello M, Gong QH, Li X, Smith SS. Short-term exposure to a neuroactive steroid increases alpha4 GABA-A receptor subunit levels in association with increased anxiety in the female rat. Brain Res. 2001;910:55–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  460. Gulinello M, Gong QH, Smith SS. Progesterone withdrawal increases the alpha4 subunit of the GABA-A receptor in male rats in association with anxiety and altered pharmacology—a comparison with female rats. Neuropharmacology. 2002;43:701–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  461. Smith SS. Withdrawal properties of a neuroactive steroid: implications for GABA(A) receptor gene regulation in the brain and anxiety behavior. Steroids. 2002;67:519–28.

    Article  CAS  PubMed  Google Scholar 

  462. Smith SS, Gong QH, Hsu FC, Markowitz RS, Ffrench-Mullen JM, Li X. GABA-A receptor alpha4 subunit suppression prevents withdrawal properties of an endogenous steroid. Nature. 1998;392:926–30.

    Article  CAS  PubMed  Google Scholar 

  463. Freeman EW, Frye CA, Rickels K, Martin PA, Smith SS. Allopregnanolone levels and symptom improvement in severe premenstrual syndrome. J Clin Psychopharmacol. 2002;22:516–20.

    Article  CAS  PubMed  Google Scholar 

  464. Redgrave P, Dean P. Does the PAG learn about emergencies from the superior colliculus? In: Depaulis A, Bandler R, editors. The midbrain periaqueductal gray matter. New York: Plenum Press; 1991. p. 199–209.

    Chapter  Google Scholar 

  465. King SM, Shehab S, Dean P, Redgrave P. Differential expression of fos-like immunoreactivity in the descending projections of superior colliculus after electrical stimulation in the rat. Behav Brain Res. 1996;78:131–45.

    Article  CAS  PubMed  Google Scholar 

  466. Canteras NS, Chiavegatto S, Valle LE, Swanson LW. Severe reduction of rat defensive behavior to a predator by discrete hypothalamic chemical lesions. Brain Res Bull. 1997;44:297–305.

    Article  CAS  PubMed  Google Scholar 

  467. Dielenberg RA, Hunt GE, McGregor IS. “When a rat smells a cat”: the distribution of Fos immunoreactivity in rat brain following exposure to a predatory odor. Neuroscience. 2001;104:1085–97.

    Article  CAS  PubMed  Google Scholar 

  468. Bittencourt AS, Nakamura-Palacios EM, Mauad H, Tufik S, Schenberg LC. Organization of electrically and chemically evoked defensive behaviors within the deeper collicular layers as compared to the periaqueductal gray matter of the rat. Neuroscience. 2005;133:873–92.

    Article  CAS  PubMed  Google Scholar 

  469. Jenck F, Broekkamp CL, Van Delft AML. The effect of antidepressants on aversive periaqueductal gray stimulation in rats. Eur J Pharmacol. 1990;177:201–4.

    Article  CAS  PubMed  Google Scholar 

  470. Hogg S, Michan L, Jessa M. Prediction of anti-panic properties of escitalopram in the dorsal periaqueductal grey model of panic anxiety. Neuropharmacology. 2006;51:141–5.

    Article  CAS  PubMed  Google Scholar 

  471. Schenberg LC, Capucho LB, Vatanabe RO, Vargas LC. Acute effects of clomipramine and fluoxetine on dorsal periaqueductal grey-evoked unconditioned defensive behaviours of the rat. Psychopharmacology (Berl). 2002;159:138–44.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Luiz Carlos Schenberg .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Schenberg, L.C. (2016). A Neural Systems Approach to the Study of the Respiratory-Type Panic Disorder. In: Nardi, A., Freire, R. (eds) Panic Disorder. Springer, Cham. https://doi.org/10.1007/978-3-319-12538-1_2

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-12538-1_2

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-12537-4

  • Online ISBN: 978-3-319-12538-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics