The double breath challenge induced an instant affect with a negative valence. As rated on the eVAAS, the healthy volunteers experienced a significant sense of “fear” or “discomfort” while reporting substantial panic symptomatology on the PSL. Both eVAAS and PSL were strictly based on DSM-IV semantics. The picture as a whole was a mathematical function of CO2 intake.
It may therefore be inferred that a double breath of increasing concentrations of CO2 dose dependently induced a condition complying with the formal criteria of panic in current psychiatric nosology.
There has been a wealth of evidence showing that experimental hypercapnia triggers PA's in patients diagnosed with PD 
, and conditions which are closely related to PD 
. In contrast, the same procedure failed to affect patients with other disorders 
, in particular those with Generalized Anxiety Disorder 
, Obsessive-Compulsive Disorder 
, Eating Disorders 
, Major Depression 
and control groups of healthy volunteers. First-degree relatives of PD patients however share a significant degree of CO2
. In fact, the liability to experience panic with CO2
exposure discriminates between individuals at high and low risk for PD 
Recent reports have suggested that healthy individuals breathing a low 7% concentration of CO2
may display signs of generalized anxiety 
. Yet, the present results are the first to demonstrate that CO2
dose dependently activates a condition identical to panic in healthy volunteers, regardless of any constitutional predisposition to psychiatric pathology.
induce a true emotion? While formally meeting all the criteria of a PA according to modern psychiatric nosology, the CO2
induced state we observed in our healthy subjects may have been a “phenocopy” of panic, the amalgam of autonomic symptoms of hypercapnia and some resulting physical discomfort. Amongst the 13 PSL items, we therefore separately analyzed the specific cognitive symptoms of “derealization” and “fear of loosing control”. Several studies have identified these symptoms as belonging to a specific psychological/cognitive cluster on basis of factor analysis 
. Our results show that both “derealization” and “fear of loosing control” were linked to the doses of inhaled carbon dioxide in a significant linear and quadratic pattern. Across the procedure, “derealization/depersonalisation” displayed more than one point increase (on a five point scale) in about half of the subjects, and “fear of loosing control” in about one fourth of them. Fear of dying did not belong to the cognitive dimension in Meuret and Cox's studies 
, nevertheless, from a conceptual point of view, it may refer to an extreme type of emotion. In the present study “fear of dying” remained very infrequent. However, when reported, we noted a significant dose-response relationship. It should be born in mind that all subjects were in a safe laboratory environment, and all had received ample reassurance regarding the safety of the intervention trough the informed consent procedure. This obviously influenced the psychological impact of CO2
. Yet, modest as they are, cognitive shifts did occur, they were a function of the experimental procedure, and their occurrence was statistically significant.
This lends support to the idea that, beyond a particular threshold, carbon dioxide may yield genuine psychotropic properties in healthy individuals.
Influential authors have increasingly referred to emotions as evolutionarily derived, “organism-ready solutions” to face major survival problems 
, as brain representations of internal body states 
, and more specifically, as images of the “material me” arising from “the homeostatic condition of each individual's body” 
. The idea that panic may proceed from a suffocation alarm disrupted by acute CO2
loading is perfectly consonant with such views. Several pieces of evidence point to a connection between hypercapnia and emotion. For instance, it appears that central chemosensitivity is not restricted to medullary respiratory neurons. Severson and co-workers 
have shown that midbrain raphe serotonergic neurons are CO2
sensors, and midbrain neurons are not believed to have any direct function in the control of ventilation. Instead these midbrain chemosensors head mainly in the rostral direction. They have been proposed to participate in the homeostasis of the brain via non-respiratory responses to hypercapnia, including behavioural reactions as hyperarousal and anxiety 
. Liotti et al. have produced neuroimaging evidence linking directly CO2
inhalation with brain structures related to emotions 
. Following CO2
induced breathlessness, healthy volunteers displayed limbic and paralimbic activation, and neuronal firing in the affective brain correlated with the sense of suffocation. The authors comment that this neuronal activity may reflect a primal emotion, in other words “a compelling interoceptor-driven affect, rooted in metabolic distress, and aimed at signalling that the existence of the organism is endangered.” In an earlier study on the characteristics of CO2
induced responses, healthy volunteers spontaneously described their subjective experience as “frightening”, “panicky” or “scaring”, while authors noted that the sensitivity of the feeling, which was poorly correlated with the ventilatory response, varied threefold among individuals 
Our study shows that CO2 intake induces an affective state, which is similar to the psychiatric picture of panic. Within subjects, we observe a significant interaction between the intensity of the affective response and the CO2 concentration of the inhaled mixture.
We show older subjects to display less behavioural vulnerability to CO2,
compared to younger individuals. To the extent that CO2
intake is a valid model of panic, this difference between younger and older subjects strikingly evokes the decline of natural PA's and the progressive blunting of panic symptomatology in PD patients when they grow older 
. Most studies have found a lower prevalence of PD amongst elderly people 
. The decreased CO2
susceptibility in the elderly revealed by the present data reminds of a similar age effect found with experimental cholecystokinin provocation of panic 
. If midbrain serotonergic chemosensors are at work in the chain of events leading from CO2
to panic, the phenomenon observed in our study might be related to an age dependent decline of serotonergic activity 
No gender differences were found. This is somewhat surprising in view of all epidemiological data showing women to be at greater risk for panic than men 
. Yet, a recent study in a nonclinical population shows women reporting more fear and panic than men after CO2
. Interestingly, when asked to rate their experience on a “like or dislike” dimension (which dimension has a conceptual overlap with “discomfort”), the gender difference disappeared. This suggests women being more prone than men to report a feeling as “anxiety”. Therefore, lumping together anxiety and discomfort in our eVAAS may have blunted a gender effect. It is noteworthy that the few existing reports about sex differences in the so-called condition “non fearful PD”, which diagnosis relies on “discomfort” rather than on “anxiety”, suggest that both genders have similar prevalence 
A final comment applies to the potential of further work with CO2
challenges in healthy individuals. The panic model of CO2
, in particular the single breath 35% CO2
procedure, has proven to be both valid and reliable 
. It has undergone extended pharmacological validation, e.g. Bertani, Perna et al. 
. Assuming that higher doses of CO2
activate the same physiologic chain of events in panic free individuals, CO2
challenges in healthy volunteers may have a strong potential as a substitute to early clinical trials in testing novel pharmacological compounds.
In conclusion, it appears that healthy individuals display a distinct behavioural vulnerability to increasing levels of acute hypercapnia. This effect is dose-dependent and shares a striking similarity with the psychiatric condition of panic.
CO2 susceptibility, sensed as acute affective distress may represent an evolutionarily evolved protective mechanism in case of impending asphyxia.