Suffocation Alarm Research Articles

Locus coeruleus noradrenaline depletion and its differential impact on CO2-induced panic and hyperventilation in male and female mice

CO2 exposure has been used to investigate the panicogenic response in patients with panic disorder. These patients are more sensitive to CO2, and more likely to experience the "false suffocation alarm" which triggers panic attacks. Imbalances in locus coeruleus noradrenergic (LC-NA) neurotransmission are responsible for psychiatric disorders, including panic disorder. These neurons are sensitive to changes in CO2/pH. Therefore, we investigated if LC-NA neurons are differentially activated after severe hypercapnia in mice. Further, we evaluated the participation of LC-NA neurons in ventilatory and panic-like escape responses induced by 20% CO2 in male and female wild type mice and two mouse models of altered LC-NA synthesis. Hypercapnia activates the LC-NA neurons, with males presenting a heightened level of activation. Mutant males lacking or with reduced LC-NA synthesis showed hypoventilation, while animals lacking LC noradrenaline present an increased metabolic rate compared to wild type in normocapnia. When exposed to CO2, males lacking LC noradrenaline showed a lower respiratory frequency compared to control animals. On the other hand, females lacking LC noradrenaline presented a higher tidal volume. Nevertheless, no change in ventilation was observed in either sex. CO2 evoked an active escape response. Mice lacking LC noradrenaline had a blunted jumping response and an increased freezing duration compared to the other groups. They also presented fewer racing episodes compared to wild type animals, but not different from mice with reduced LC noradrenaline. These findings suggest that LC-NA has an important role in ventilatory and panic-like escape responses elicited by CO2 exposure in mice.

Response to Singh et al. 2023: It is premature for a unified hypothesis of sudden unexpected death in epilepsy: A great amount of research is still needed to understand the multisystem cascade.

In response to the comments by Singh and colleagues about our recent paper proposing a unified hypothesis of SUDEP, we definitely agree that more research is needed. This research should include studies in other models, including Dravet mice, emphasized by Singh et al. However, we strongly believe the hypothesis is timely, because it is based on the continuing progress on SUDEP-related research on serotonin (5-HT) and adenosine as well as neuroanatomical findings.We propose testing of 5-HT enhancing drugs, neurotoxicity blocking drugs, such as N-methyl-D-aspartate (NMDA) antagonists and periaqueductal gray (PAG) electrical stimulation for SUDEP prevention. There are FDA-approved drugs that enhance the action of 5-HT, including fluoxetine and fenfluramine, which is approved for Dravet syndrome. NMDA antagonists, including memantine and ketamine, are also approved for other disorders. PAG electrical stimulation, which is proposed to activate a suffocation alarm, is also approved to treat other conditions and is known to enhance respiration. Experiments using these methods are currently being carried out in animal studies. If these approaches are validated in SUDEP models, treatments could be evaluated relatively quickly in patients with epilepsy (PWE) who exhibit a biomarker for high SUDEP risk, such as peri-ictal respiratory abnormalities. An example of such a study is the ongoing clinical trial of a selective serotonin reuptake inhibitor in PWE. Although, gene-based therapies may ultimately become treatments of choice to prevent SUDEP, as Singh et al suggested, one or more of the approaches we proposed could become temporizing treatments before gene-based therapies can be available. Establishing genetic treatments would require extensive time for each of the genetic abnormalities associated with SUDEP, and too many PWE are likely to die in the meantime.The temporizing treatments may help to reduce the incidence of SUDEP sooner, which is urgently needed.

Estrogens, age, and, neonatal stress: panic disorders and novel views on the contribution of non-medullary structures to respiratory control and CO2 responses.

CO2 is a fundamental component of living matter. This chemical signal requires close monitoring to ensure proper match between metabolic production and elimination by lung ventilation. Besides ventilatory adjustments, CO2 can also trigger innate behavioral and physiological responses associated with fear and escape but the changes in brain CO2/pH required to induce ventilatory adjustments are generally lower than those evoking fear and escape. However, for patients suffering from panic disorder (PD), the thresholds for CO2-evoked hyperventilation, fear and escape are reduced and the magnitude of those reactions are excessive. To explain these clinical observations, Klein proposed the false suffocation alarm hypothesis which states that many spontaneous panics occur when the brain's suffocation monitor erroneously signals a lack of useful air, thereby maladaptively triggering an evolved suffocation alarm system. After 30years of basic and clinical research, it is now well established that anomalies in respiratory control (including the CO2 sensing system) are key to PD. Here, we explore how a stress-related affective disorder such as PD can disrupt respiratory control. We discuss rodent models of PD as the concepts emerging from this research has influenced our comprehension of the CO2 chemosensitivity network, especially structure that are not located in the medulla, and how factors such as stress and biological sex modulate its functionality. Thus, elucidating why hormonal fluctuations can lead to excessive responsiveness to CO2 offers a unique opportunity to gain insights into the neuroendocrine mechanisms regulating this key aspect of respiratory control and the pathophysiology of respiratory manifestations of PD.

An apnea-hypothesis of anxiety generation: Novel, respiratory, and falsifiable

The Apnea-induced Anxiety model of Feinstein et al. continues a line of respiratory theories of panic, extending Klein's false suffocation alarm theory to a broader range of fear and anxiety states. It draws on neurobiological evidence including the underappreciated role of the amygdala in eliciting periods of apnea and CO2 tolerance. Further progress can be expected from empirical testing and integration with neuromodulatory systems that support respiration, activity, fear and anxiety, in particular the orexin system.

The amygdala might be the main target for Donald Klein´s “Real” False Suffocation Alarm hypothesis for triggering panic attacks

In this issue Feinsteinet al. (2022) proposed in a large and detailed review of an interesting neurosurgical evidence a model of apnea-induced anxiety (AiA) which could predict the recurring episodes of apnea are being unconsciously elicited by amygdala activation which might result in transient spikes in CO 2 that provoke panic attacks (PAs) and lead to agoraphobia and some other problems with anxiety disorders patients. Respiratory tests have been fruitful in generating hypotheses about PD, indicating that CO 2 sensitivity would be part of a hypersensitive suffocation detector.

Les modèles théoriques actuels du trouble panique : examen conceptuel et implications cliniques

Parmi les troubles anxieux, le trouble panique est associé à certains des plus grands fardeaux en termes de souffrance personnelle, de déficience professionnelle et de coût sociétal. Cet article passe en revue les modèles théoriques de ce trouble afin de déterminer leurs évolutions, leurs limites et les perspectives théoriques et cliniques qui en découlent. Pour ce faire, une revue de la littérature a été entreprise à partir de la base de données PsycINFO. Sur les 928 articles identifiés, 54 faisaient référence à 14 modèles théoriques du trouble panique. Les résultats montrent que la plupart des modèles ne sont pas empiriquement bien étayés et que peu ont été utilisés de manière cohérente pour guider le traitement de ce trouble. Bien que les traitements basés sur ces modèles bénéficient à un grand pourcentage de patients, au moins 25 % des patients sont classés comme résistants à ces traitements. De plus, les rechutes ne sont pas rares. La conclusion discute des limites des modèles existants et propose des recommandations pour améliorer les modèles actuels du trouble panique. Panic disorder (PD) is defined by recurring and unexpected panic attacks accompanied by anticipatory anxiety about future attacks and their consequences. This generally involves avoiding situations and behaviors that can produce panic attacks (American Psychiatric Association [APA], 2013). Among anxiety disorders, PD is associated with some of the greatest burdens in terms of personal suffering, occupational disability, and societal cost. Since the introduction of PD in the DSM-III (1980) and the distinction of PD from generalized anxiety disorder following the work of Klein (1964), several biological and psychological theories of PD have been developed. These theories have highlighted several risk factors (for the onset, maintenance and relapse associated with the disorder) that have strongly influenced research on PD and have guided its treatment. However, a comprehensive and universally accepted theoretical framework of PD to guide its treatment is lacking. This article reviews the previously described theoretical frameworks of PD and related treatments while examining the strength of the scientific evidence supporting their validity as well as their limitations. A review of the literature was undertaken by searching PsycINFO database to list all the articles published between January 2000 and November 2020 and referring to a theoretical model or a conceptual framework of PD. The conceptual frameworks identified were reviewed based on the recent scientific researches to determine the strength of the evidence supporting their validity. Of the 928 articles initially identified, 54 referred to fourteen different conceptual frameworks relating to PD. Two models are exclusively biological: the false suffocation alarm and the neuroanatomical hypothesis of PD. Six models are psychological, one of which is psychodynamic and five are derived from the cognitive-behavioral paradigm. Finally, six models are integrative: triple vulnerability of Barlow, integrated cognitive vulnerability of Schmidt & Woolaway-Bickel, unified model of vulnerability of McGinn, causal model of Fava & Morton, causal model based on the evidence by Pilecki and integrated model of Busch. These models highlight biological, environmental, developmental and psychological vulnerability factors. The analysis of these different models shows that few conceptual frameworks have been used consistently to guide the treatment of PD, and that not all frameworks are empirically well supported. The theoretical approaches that have strongly influenced the treatment of PD are the cognitive model of Clark, the expectation model of Reiss as well as the triple vulnerability model of Barlow. Although treatments based on these models benefit a large percentage of patients, at least 25% of patients are classified as resistant to these treatments. In addition, relapses and persistence of symptoms remain common results of these treatments. This suggests that other vulnerability factors such as emotional regulation skills should be taken into consideration and integrated into these models especially as several studies have suggested that research focused on emotion regulation may improve our understanding of panic.

A systematic review and network meta-analysis of carbon dioxide provocation in psychiatric disorders

False suffocation alarm hypothesis has been widely used to explain carbon dioxide hypersensitivity in panic disorder (PD). However, hypersensitivity to carbon dioxide has been observed in other psychiatric disorders. We explored the specificity of carbon dioxide inhalation as a panic provocation test among psychiatric disorders via network meta-analysis. A systematic literature search on PubMed, EMBASE, and PsycNET was performed to acquire the studies using the carbon dioxide provocation test in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and checklists. Odds ratios (OR) for a panic attack (PA) induced by the carbon dioxide inhalation tests were extracted from each of the original studies and were pooled using the random-effects model. Network meta-analysis on a pool of 2181 participants from 41 studies was used to compare the efficacy of carbon dioxide provocation tests among psychiatric disorders. The network meta-analysis showed that the odds for PA in response to carbon dioxide inhalation are higher in patients with PD, premenstrual dysphoric syndrome (PMDD), and social anxiety disorder (SAD) than healthy controls (HC). The odds for PA were not significantly different among patients with generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), major depressive disorder (MDD), and healthy controls (HC). The vulnerability to the carbon dioxide provocation test is not limited to PD. The specificity of the test for PD is questionable, as individuals suffering from PMDD and SAD are also significantly more responsive to carbon dioxide inhalation compared to HC, OCD, MDD, and GAD. There may be shared underpinning biological mechanisms between PD, PMDD, and SAD.

The Role of Respiratory Noradrenergic Neurons Projecting to the Basal Lateral Amygdala in Anxiety‐related Behavior

The most commonly reported symptom of panic attacks is respiratory dysfunction, such as hyperventilation. It has been shown that subsets of patients with anxiety disorders show a lower threshold for carbon dioxide level imbalances and exposure to high levels of carbon dioxide (hypercapnia) can induce anxiety‐like behavior such as panic attacks. The false suffocation alarm hypothesis posits that inappropriate activation of respiratory chemoreceptors in response to benign indices triggers an alarm of suffocation danger and may contribute to anxiety and panic disorders. Two potential candidates that may link anxiogenic and respiratory circuitry are the central noradrenergic (NA) system and the amygdala, both of which have been shown to play roles in both breathing and anxiety. Therefore, we hypothesize that projections from the brainstem NA nuclei to the amygdala play a functional role in modulating the hypercapnic ventilatory response and anxiety‐like behavior in mice.To test this hypothesis, we targeted NA projections to the amygdala by using a Cre‐expressing retrograde virus applied to the amygdala of our intersectional DBH‐p2a‐FLPo; RR5, multicolor reporter line to conduct projection mapping of NA neurons to the amygdala and DBH‐p2a‐FLPo; RR1 and RR2 DREADD mice to specifically inhibit or stimulate NA neurons that project to the amygdala. In these mice, we measured respiratory output using whole‐body plethysmography and anxiety‐like behavior using open field, light dark, and elevated plus maze.Preliminary results indicate that DREADD mediated inhibition of NA neurons projecting to the amygdala may result in a decreased hypercapnic ventilatory response. However, upon stimulation of the NA neurons that project to the amygdala, there was no change in the hypercapnic ventilatory response. Inhibition and stimulation of NA neurons projecting to the amygdala result in a possible decrease in anxiety‐like behavior. Our preliminary results demonstrate the feasibility of delineating and accessing NA neurons based on the their projection target and suggest that NA neurons that project to the amygdala may play a role in the hypercapnic ventilatory response, as well as anxiety‐related behavior. Future directions will include the role of amygdala‐projecting NA neurons in behavior, such as fear learning and anxiety‐related behavior, under higher CO2 concentrations.Support or Funding InformationMcNair Medical InstituteR01HL130249R01HL130249‐02S1This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

On the verge of a respiratory-type panic attack: Selective activations of rostrolateral and caudoventrolateral periaqueductal gray matter following short-lasting escape to a low dose of potassium cyanide

Intravenous injections of potassium cyanide (KCN) both elicit escape by its own and facilitate escape to electrical stimulation of the periaqueductal gray matter (PAG). Moreover, whereas the KCN-evoked escape is potentiated by CO2, it is suppressed by both lesions of PAG and clinically effective treatments with panicolytics. These and other data suggest that the PAG harbors a hypoxia-sensitive alarm system the activation of which could both precipitate panic and render the subject hypersensitive to CO2. Although prior c-Fos immunohistochemistry studies reported widespread activations of PAG following KCN injections, the employment of repeated injections of high doses of KCN (>60µg) in anesthetized rats compromised both the localization of KCN-responsive areas and their correlation with escape behavior. Accordingly, here we compared the brainstem activations of saline-injected controls (air/saline) with those produced by a single intravenous injection of 40-µg KCN (air/KCN), a 2-min exposure to 13% CO2 (CO2/saline), or a combined stimulus (CO2/KCN). Behavioral effects of KCN microinjections into the PAG were assessed as well. Data showed that whereas the KCN microinjections were ineffective, KCN intravenous injections elicited escape in all tested rats. Moreover, whereas the CO2 alone was ineffective, it potentiated the KCN-evoked escape. Compared to controls, the nucleus tractus solitarius was significantly activated in both CO2/saline and CO2/KCN groups. Additionally, whereas the laterodorsal tegmental nucleus was activated by all treatments, the rostrolateral and caudoventrolateral PAG were activated by air/KCN only. Data suggest that the latter structures are key components of a hypoxia-sensitive suffocation alarm which activation may trigger a panic attack.

Serotonin in the dorsal periaqueductal gray inhibits panic-like defensive behaviors in rats exposed to acute hypoxia

It has been proposed that spontaneous panic attacks are the outcome of the misfiring of an evolved suffocation alarm system. Evidence gathered in the last years is suggestive that the dorsal periaqueductal gray (dPAG) in the midbrain harbors a hypoxia-sensitive suffocation alarm system. We here investigated whether facilitation of 5-HT-mediated neurotransmission within the dPAG changes panic-like defensive reactions expressed by male Wistar rats submitted to a hypoxia challenge (7% O2), as observed in other animal models of panic. Intra-dPAG injection of 5-HT (20 nmol), (±)-8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide (8-OH-DPAT) (8 nmol), a 5-HT1A receptor agonist, or (±)-2,5-dimethoxy-4-iodo amphetamine hydrochloride (DOI) (16 nmol), a preferential 5-HT2A agonist, reduced the number of upward jumps directed to the border of the experimental chamber during hypoxia, interpreted as escape attempts, without affecting the rats' locomotion. These effects were similar to those caused by chronic, but not acute, intraperitoneal administration of the antidepressant fluoxetine (5-15 mg/kg), or acute systemic administration of the benzodiazepine receptor agonist alprazolam (1-4 mg/kg), both drugs clinically used in the treatment of panic disorder. Our findings strengthen the view that the dPAG is a key encephalic area involved in the defensive behaviors triggered by activation of the suffocation alarm system. They also support the use of hypoxia-evoked escape as a model of respiratory-type panic attacks.

Testosterone Increase Hypercapnic Ventilatory Response of Adult Male Rats Subjected to Panic Attack Model

Panic attacks occur when the brain wrongly detects a lack of air triggering a false suffocation alarm system. Panic disorder (PD) patients exhibit greater CO2 chemo-sensitivity and an increasedventilatory response to CO2 compared to normal individuals. Interestingly, the prevalence of PD is ~3 times greater in women than men. Neonatal Maternal Separation (NMS) is a form of stress that disrupts respiratory control development in a sex-specific fashion. We showed that NMS augments the ventilatory response to CO2 in females but not males. These results brought us to propose that testosterone prevents NMS-induced enhancement of the ventilatory response to CO2. Pups subjected to NMS were placed in an incubator for 3 h/day from postnatal day 3 to 12. Control pups remained undisturbed. Rats were reared until adulthood, and the ventilatory response to CO2 was measured by whole-body plethysmography (FICO2 = 0.10, for 10 min). We used gonadectomy to evaluate the effects of reducing testosterone on the hypercapnic response. By comparison with sham-operated animals, gonadectomy augmented the hypercapnic ventilatory response of control rats; an opposite (albeit modest) effect was observed in NMS rats. While these results do not support our initial hypothesis, they highlight the importance of testosterone in regulating the CO2-related respiratory drive in normal rats. Further experiments (hormone measurements) will help elucidate the mechanisms underlying the sexual dimorphism of stress-related respiratory disorder such as PD. Supported by: Canadian Institutes of Health Research.

Evidence of a suffocation alarm system sensitive to clinically-effective treatments with the panicolytics clonazepam and fluoxetine.

Dyspnea, 'hunger for air', and the urge to flee are the cardinal symptoms of respiratory-type panic attacks. Patients also show baseline respiratory abnormalities and a higher rate of comorbid and antecedent respiratory diseases. Panic attacks are also precipitated by both the infusion of 0.5 M sodium lactate and the inhalation of 5-7% carbon dioxide (CO2) in predisposed patients, but not in healthy volunteers nor patients without panic disorder. Further studies show that patients with panic are also hyper-responsive to hypoxia. These and other observations led Klein (1993) to suggest that clinical panic is the misfiring of a suffocation alarm system. In rats, cytotoxic hypoxia of chemoreceptor cells by intravenous injection of potassium cyanide (KCN) produces short-lasting flight behaviors reminiscent of panic attacks. KCN-induced flight behaviors are blocked both by denervation of chemoreceptor cells and lesion of dorsal periaqueductal gray matter, a likely substrate of panic. Herein, we show that KCN-evoked flight behaviors are also attenuated by both acute and chronic treatment with clonazepam (0.01-0.3 mg/kg, intraperitoneally (i.p.)) and fluoxetine (1-4 mg/kg/day, i.p. for 21 days), respectively. Attenuation of KCN-evoked panic-like behaviors by clinically-effective treatment with panicolytics adds fresh evidence to the false suffocation alarm theory of panic disorder.

Evidence of a suffocation alarm system within the periaqueductal gray matter of the rat

Dyspnea, hunger for air, and urge to flee are the cardinal symptoms of panic attacks. Patients also show baseline respiratory abnormalities and a higher rate of comorbid and antecedent respiratory diseases. Panic attacks are also precipitated by infusion of sodium lactate and inhalation of 5% CO₂ in predisposed patients but not in healthy volunteers or patients without panic disorder. Accordingly, Klein [Klein (1993) Arch Gen Psychiatry 50:306-317] suggested that clinical panic is the misfiring of an as-yet-unidentified suffocation alarm system. In rats, selective anoxia of chemoreceptor cells by potassium cyanide (KCN) and electrical and chemical stimulations of periaqueductal gray matter (PAG) produce defensive behaviors, which resemble panic attacks. Thus, here we examined the effects of single or combined administrations of CO₂ (8% and 13%) and KCN (10-80 μg, i.v.) on spontaneous and PAG-evoked behaviors of rats either intact or bearing electrolytic lesions of PAG. Exposure to CO₂ alone reduced grooming while increased exophthalmus, suggesting an arousal response to non-visual cues of environment. Unexpectedly, however, CO₂ attenuated PAG-evoked immobility, trotting, and galloping while facilitated defecation and micturition. Conversely, KCN produced all defensive behaviors of the rat and facilitated PAG-evoked trotting, galloping, and defecation. There were also facilitatory trends in PAG-evoked exophthalmus, immobility, and jumping. Moreover, whereas the KCN-evoked defensive behaviors were attenuated or even suppressed by discrete lesions of PAG, they were markedly facilitated by CO₂. Authors suggest that the PAG harbors an anoxia-sensitive suffocation alarm system which activation precipitates panic attacks and potentiates the subject responses to hypercapnia.

An Integrated Model of Panic Disorder

Clinicians are shifting away from dualistic conceptions of mind and brain toward a view of psychiatric illnesses as involving interactions between biology, mind, and environment. Our understanding of panic disorder benefits from such an integrative analysis. We review genetic, neurochemical, and neuroimaging data on panic disorder, along with a series of biological and psychological models. We propose that separation and suffocation alarm systems cut across various models, and we suggest how biological, psychological, and environmental interactions can lead to panic onset and persistence. Separation and suffocation alarm systems may become sensitized due to environmental events, an inborn vulnerability, or both. These oversensitized systems create a vulnerability to environmental experiences of loss and intrusion and to frightening psychological experiences of separation and suffocation. In individuals with this vulnerability, angry feelings and fantasies, often unconscious, further intensify fears of loss of or intrusion by attachment figures, triggering separation and suffocation alarms and associated panic attacks. This model provides a basis for understanding how psychological and biological approaches affect different components of these interactive systems, leading to relief of panic symptoms. We discuss implications of this integrative model for current clinical practice and future research.

Towards a translational model of panic attack.

years ago, Deakin and Graeff proposed that whereas generalized anxiety disorder is produced by the overactivity of 5-HT excitatory projections from dorsal raphe nucleus to the areas of prefrontal cortex and amygdala which process distal threat, panic attacks are a dysfunction of 5-HT inhibitory projections from dorsal raphe nucleus to the dorsal periaqueductal gray matter, thereby releasing the responses to proximal threat, innate fear or anoxia. Besides, they suggested that the decrease in 5-HT1A neurotransmission in the hippocampus results in learned helplessness and depression. Accordingly, the Deakin Graeff hypothesis provided a unified frame to the widespread use of 5-HT selective reuptake inhibitors in generalized anxiety, panic disorder and depression. Competitor hypotheses implicate panic attacks with the abnormal functioning of locus coeruleus, basolateral amygdala, dorsomedial hypothalamus or an as-yet-unknown suffocation alarm system. Conversely, cognitive psychologists suggest that panic attacks result from the catastrophic (cortical) interpretation of bodily symptoms. In any event, translational models of panic attack are expected to reproduce the main features of clinical panic, namely, the patient's higher sensitivity to both lactate and CO2, the drug specific sensitivity, the lack of stress hormone responses during panic attacks, the higher vulnerability of women and the high comorbidity with agoraphobia, major depression and childhood separation anxiety. Therefore, here we review the main steps in the experimental approach to anxiety disorders which are paving the route towards a translational model of panic attack. Keywords: Panic, Anxiety, Stress, Suffocation, Serotonin, Periaqueductal Gray Matter

Panic Disorder: The Psychobiology of External Treat and Introceptive Distress

Panic disorder seems to be mediated by the neuronal circuitry and neurochemical systems that have evolved to respond to external threatening stimuli. Distant threats activate prefrontal cortex (involved in complex planning of avoidance strategies), while immediate threats activate midbrain structures (involved in fast reflexive behaviors). Panic disorder may, however, also involve more specific interoceptive mechanisms. For example, the association between respiratory dysfunction and panic disorder has bolstered a false suffocation alarm hypothesis. Genetic and environmental contributors to panic disorder are beginning to be delineated. Effective pharmacotherapy and psychotherapy are able to normalize the relevant psychobiology.

Some notes on a historical perspective of panic disorder

This article aims to describe important points in the history of panic disorder concept, as well as to highlight the importance of its diagnosis for clinical and research developments. Panic disorder has been described in several literary reports and folklore. One of the oldest examples lies in Greek mythology - the god Pan, responsible for the term panic. The first half of the 19th century witnessed the culmination of medical approach. During the second half of the 19th century came the psychological approach of anxiety. The 20th century associated panic disorder to hereditary, organic and psychological factors, dividing anxiety into simple and phobic anxious states. Therapeutic development was also observed in psychopharmacological and psychotherapeutic fields. Official classifications began to include panic disorder as a category since the third edition of the American Classification Manual (1980). Some biological theories dealing with etiology were widely discussed during the last decades of the 20th century. They were based on laboratory studies of physiological, cognitive and biochemical tests, as the false suffocation alarm theory and the fear network. Such theories were important in creating new diagnostic paradigms to modern psychiatry. That suggests the need to consider a wide range of historical variables to understand how particular features for panic disorder diagnosis have been developed and how treatment has emerged.

Physiological markers for anxiety: Panic disorder and phobias

Physiological activation is a cardinal symptom of anxiety, although physiological measurement is still not used for psychiatric diagnosis. An ambulatory study of phobics who were afraid of highway driving showed a concordance between self-reported anxiety during driving, autonomic activation, hypocapnia, and sighing respiration. Patients with panic attacks do not exhibit autonomic activation when they are quietly sitting and not having panic attacks, but do have the same respiratory abnormalities as driving phobics, suggesting that these abnormalities could be a marker for panic disorder. Such abnormalities are compatible with both the false suffocation alarm (D. Klein) and hyperventilation (R. Ley) theories of panic. Hypocapnia, however, is often absent during full-blown panic attacks. Since activation functions as preparation for physical activity, it may not occur when a patient has learned that avoidance of fear by flight or fight is futile. We developed a capnometry feedback assisted breathing training therapy for panic disorder designed to reduce hyperventilation and making breathing regular. Without feedback, conventional therapeutic breathing instructions may actually increase hyperventilation by increasing dyspnea. Five weekly therapy sessions accompanied by daily home practice with a capnometer produced marked clinical improvement compared to changes in an untreated group. Improvement was sustained over a 12-month follow-up period. The therapist avoided any statements or procedures designed to alter cognitions. Improvement occurred regardless of whether patients initially reported mostly respiratory or non-respiratory symptoms during their attacks. There is evidence that modifying any of the three systems comprising a fear network can be therapeutic, as exemplified by cognitive therapy modifying thoughts, exposure therapy modifying avoidance, and breathing training procedures modifying pCO(2).

Central and peripheral chemoreflexes in panic disorder

Klein (Arch Gen Psychiatry, 50, 1993, 306-317) has suggested that panic disorder patients have a false suffocation alarm that may be associated with a lowered threshold for carbon dioxide detection. We compared the thresholds and sensitivities of the central and peripheral chemoreflexes between panic disorder patients and age- and sex-matched healthy volunteers to test this aspect of the hypothesis. We used a modified version of Read's rebreathing technique in 11 panic disorder patients and 10 healthy volunteers to examine the peripheral and central chemoreflex characteristics in these two populations. Subjects were examined during three rebreathing tests: training, hyperoxic (central chemoreflex alone) and hypoxic (combined central and peripheral chemoreflex). Panic symptoms were retrospectively assessed between groups using a DSM-IV derived Panic Symptom Scale. Comparisons of panic disorder patients with agoraphobia and healthy volunteers showed no significant differences in sensitivities or thresholds. Klein's hypothesis is not supported by these data. If a false suffocation alarm exists, its triggering may not be implemented within the respiratory chemoreflexes.

Slow recovery from voluntary hyperventilation in panic disorder.

Because hyperventilation has figured prominently in theories of panic disorder (PD) but not of social phobia (SP), we compared predictions regarding diagnosis-specific differences in psychological and physiological measures before, during, and after voluntary hyperventilation. Physiological responses were recorded in 14 patients with PD, 24 patients with SP, and 24 controls during six cycles of 1-minute of fast breathing alternating with 1 minute of recovery, followed by 3 minutes of fast breathing and 10 minutes of recovery. Speed of fast breathing was paced by a tone modulated at 18 cycles/minute, and depth by feedback aimed at achieving an end-tidal pCO2 of 20 mm Hg. These values were reached equally by all groups. During fast breathing, PD and SP patients reported more anxiety than controls, and their feelings of dyspnea and suffocation increased more from baseline. Skin conductance declined more slowly in PD over the six 1-minute fast breathing periods. At the end of the final 10-minute recovery, PD patients reported more awareness of breathing, dyspnea, and fear of being short of breath, and their pCO2s, heart rates, and skin conductance levels had returned less toward normal levels than in other groups. Their lower pCO2s were associated with a higher frequency of sigh breaths. PD and SP patients report more distress than controls to equal amounts of hypocapnia, but PD differ from SP patients and controls in having slower symptomatic and physiological recovery. This finding was not specifically predicted by hyperventilation, cognitive-behavioral, or suffocation alarm theories of PD.