Anxiety is often considered a natural response to stress by most people around the world. However, in many cases, it is a form of disorder. According to Statistics Canada, Anxiety Disorder, which includes: Generalize Anxiety Disorder, Phobia, Post Traumatic Stress Disorder, Social Anxiety Disorder, Obssessive Compulsive Disorder, and Panic Disorder; not only affects but also cause mild to several impairment of 12% of Canada’s population. [1]

In most cases, Anxiety disorder physically manifests itself in forms of respiratory and cardiovascular symptoms.[2] Heavy and quickened respiratory activity and increased heart rate suggests the hyperactivation of sympathetic nervous system. However, not many of the instigators of this response are known. One of the initiators that is being closely examined is, surprisingly, CO2-> Carbon Dioxide.

CO2 is the waste product of human respiratory system and it also controls the pH of the blood, regulate oxygen intake, and regulate our respiratory and cardiovascular system. The homeostasis of the body with CO2 is visible also in the brain, where there is an abundance of CO2 sensitive cells.

external image clip_image001.gifThis leads to the hypothesis that function or dysfunction of these CO2-sensitive cells is the cause of anxiety and panic attacks. Recent studies have shown that patients who suffer from general anxiety disorder might have abnormally high sensitivity to CO2. Other studies have found that the mechanism of CO2 induced panic attacks might be correlated to the noradrenergic system/locus coeruleus system; in particular, elevated respiratory and cardiovascular response in anxiety disorder patients correlate to the NA/LC system .









Carbon Dioxide in the Human Brain


Chemosensitivity

The term chemosenitivity, according to Merriam-Webster medical dictionary refers to the “susceptibility (as of a disease-causing bacterium or a cancer cell) to the action of a chemical agent (as a therapeutic drug).”[3] Chemosensitivity of a chemical agent can be quantified with the abundance of the receptors for that agent in the region of the body

CO2-sensitive receptors in human brain

There are number of chemoreceptors in human brain that is sensitive to different gases such as oxygen and carbon dioxide. Much of the CO2 and O2 receptors are located near the medulla oblongata to control respiratory by detecting the change in the carbon dioxide levels.

According to previous researches by Feldmen et al, CO2 sensing mainly relies on the central chemoreceptors which are located around the brain stem area.[4].

Many of the neurons in the brainstems are CO­­2 sensitive.[5] Some of the examples of these neurons are: serotonergic neurons in the midline raphe nuclei, glutamatergic neurons in the retrotrapezoid nucleus, and catecholaminergic neurons in the locus coeruleus.[6] These neurons are not respiratory modulated, although they act as though they are respiratory-modulated neurons. This indicates that that these CO2 chemosensitive cells are presynaptic.

Brainstem respiratory-modulated neurons are also CO2 chemosensitive. During the body’s response to hypercapnia, inspiratory neurons are depolarized, and expiratory cells are hyperpolarized.[7]. The retainment of these neuronal responses after blockade of synaptic transmission, indicates that the postsynaptic cells are CO2 chemosensitive.[8] The susceptibility of CO2 in both pre and postsynaptic neurons may indicate a potential amplification mechanism by these neurons.

Respiratory and cardiovascular response to CO2


As previously stated, the respiratory and cardiovascular system is directly related to the level of carbon dioxide in a human body. The partial pressure asserted by CO2 controls the cerebral blood flow [9] and the change of pH[10] caused by the reaction CO2 + H2O → H2CO3 → H+ + HCO−[11] regulates the breathing. When affected by anxiety disorder, the respiratory and cardiovascular system usually hyperactivates to deal with the perceived stress.



Regular Response

During a normal process of respiration, oxygen is inhaled into the body through the lungs, carried by the blood cells to the tissue of the organism , and removes carbon dioxide from the body by exhalation. During this process, gas exchanges occurs in the pulmonary alveoli between the alveolar gas and the blood in the capillaries in the lungs. These gases are pumped throughout the body by the heart via circulatory system. The amount of carbon dioxide exhaled with each breath is believed to be about 480mL~500mL.[12]

Irregular Response

One form of irregular response that is closely associated with many forms of anxiety disorder is hyperventilation syndrome.[13] Studies have shown that irregular respiratory response, (elevation of exhalation rate, increased heart rate) is induced by applying 7.5% CO2 to patients with generalized anxiety disorder.[14] The experiment gathered healthy volunteers for the control group and patients who were diagnosed with generalized anxiety disorder(GAD) from the age of 18-65 and performed a single blind, randomized, placebo-controlled cross-over study, performed twice in GAD patients. On each study occasion 20-minute inhalations of both placebo (compressed air) and 7.5% CO2 mixture were administered according to a randomization list, at least 30 min apart. At least seven days separated each study day.


The Finapres (Ohmeda, Englewood,CO, USA) technique was used to continuously record systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR). The Finapres cuff was attached prior to the inhalations and a recording obtained during each gas inhalation. [14]


Although the response was not as severe as hyperventilation, the patients had greater sense of anxiety and stress and showed it physiologically by increased systolic blood pressure. The control group however, those who was never diagnosed with any form of anxiety disorder, felt ‘uncomfortable’ and had slight rise in their blood pressure, but it was incomparable to those suffering from anxiety disorder.


Prevalence of CO2 induced panic attacks in PD and SAD


Those who suffer from Panic Disorder (PD) and Separation Anxiety Disorder (SAD) showed to be more affected by the CO2 patients than other form of general anxiety disorder. Not only that, but the child who suffer from SAD and the parent who suffer from PD seemed to be linked. In an experiment designed by Roberson et al. showed that the child suffering from SAD who has a parent who suffers from PD are more susceptible to CO2­ induced panic attacks.

They had four groups: child with SAD with parents who had PD, child with SAD with parents who did not have PD, child that did not SAD but had parents who had PD, and a group where neither the child or the parent was suffering from any form of Anxiety disorder.

Two hundred and twelve 9-20 year old children were exposed to 5% CO­­2 in their home continuously for 15 min. Anxiety symptoms, panic attacks, and respiratory physiology (respiratory frequency and tidal volume) were monitored during baseline and the 15 min of 5% CO­2. Significant offspring SAD_parent PD interactions were obtained for anxiety symptoms, respiratory frequency,tidal volume, and a panting index during CO2 inhalation. The child with both SAD and parental PD exhibited more anxiety symptoms from 5% CO2 breathing than the other offspring groups and had the most extreme values on measures of respiratory physiology.[15]

Possible Mechanisms of CO2 induced panic attacks NA/LC system



The locus coeruleus is a nucleus in the pons that is involved with physiological responses to stress and anxiety. It is the main site of norepinephrine synthesis. Which is why the locus coeruleus and the areas affected by norepinephrine it produces are called the locus coeruleus-noradrenergic system or LC-NA system.


This NA/LC system was closely looked into by Griez and Schruers in their search for the cause and the mechanisms of the CO2 intolerance in patients with Anxiety Disorders. Based on the results of other experiments done by Argyropoulos et al and Bailey et al., where the NA/LC system was triggered during CO2 induced panic attack, they hypothesized this system which is located in the CO2 sensitive part of the brain and regulates stress and panic responses, must have to do with the intolerance of CO2.[16] LC neurons are particularly CO2 sensitive and their firing rate are direct function of increasing pCO2. Also its function of the sympathetic responses leads many to believe that those with anxiety disorders might have defective NA/LC system. However, the accuracy of this hypothesis has not been proven and the exact mechanism of the CO2 induced panic attack have yet to be found.

Treatment

A benzodiazepine drug having anxiolytic, anticonvulsant, muscle relaxant, and hypnotic properties called clonazepam is a popular anti-anxiety drug. This drug enchances effects of gamma-aminobutyric acid (GABA), which causes the body to relax by blocking the neuronal signalling. In a paper by Nardi, A. E., and Perna, G., it shows that clonazepam has shown to block CO­­2 induced panic.

References

1. Statistics Canada. “A report on Mental Illness in Canada”. Anxiety Disorders. http://www.phac-aspc.gc.ca/publicat/miic-mmac/chap_4-eng.php (12 Mar, 2012)

2. Simpson, H.B., et al. (2010) Anxiety disorders : theory, research, and clinical perspectives. Cambridge University Press, Cambridge, U.K

3. Merriam-Webster Medical Dictionary. Chemosensitivity http://www.merriam-webster.com/medical/chemosensitivity (24,Mar, 2012)

4. Feldman, J.L., Mitchell, G.S., Nattie, E.E., (2003). Breathing: rhythmicity, plasticity, chemosensitivity. Annu Rev Neurosci 26, 239266

5. Su, J., et al. (2007). High CO2 chemosensitivity versus wide sensing spectrum: a paradoxical problem and its solutions in cultured brainstem neurons. The Journal of Physiology. 578. 831-832

6. Ritucci, N. A., Erlichman, J.S., Leiter, J.C. Putnam, R.W., (2005). Response of membrane potential and intracellular pH to hypercapnia in neurons and astrocytes from rat retrotrapezoid nucleus. Am J Physiol Regul Integr Comp Physiol 289, R851–R861

7. Guyenet ,P.G., Mulkey, D.K., Stornetta, R.L., Bayliss, D.A., (2005). Regulation of ventral surface chemoreceptors by the central respiratory pattern generator. J Neurosci 25, 89388947

8. Kawai, A., Onimaru, H., Homma I., (2006). Mechanisms of CO2/H+ chemoreception by respiratory rhythm generator neurons in the medulla from newborn rats in vitro. J Physiol 572, 525537

9. Gersten, A., (2010). Peculiarities of Brain’s Blood Flow: Role of Carbon Dioxide. Department of Physics, Ben-Gurion University 84-105.

10. Richerson, G.B., (2004). Serotonergic neurons as carbon dioxide sensors that maintain pH homeostasis. Nat Rev Neurosci 5, 449461.

11. Nattie, E. (1999). CO2, brainstem chemoreceptors and breating. Department of Physiology, Dartmouth Medical School. NU 03756-0001.

12. Alberts, B., et al (2002) Molecular biology of the cell, 4th edition. Garland Science, New York

13. Freire, R. C., et al., (2008) Panic disorder respiratory subtype: A comparison between responses to hyperventilation and CO2 challenge tests. Psychiatry Research (Vol. 157, Issue 1, Pages 307-310)

14. Seddon, K., (2011) Effects of 7.5% CO2 challenge in generalized anxiety disorder. Journal of Psychopharmacology. 25(1) 43–51

15. Roberson-Nay, R., et al. (2010) Carbon Dioxide Hypersensitivity in Separation Anxious Offspring of Parents with Panic Disorder. BIOL PSYCHIATRY 67:1171–1177

16. Griez, E., Schruers, K., (2003) Mechanisms of CO2 Challenges. J Psychopharmacologyvol. 17 no. 3 260-262