A phylogenetic hypothesis for the origin of hiccough C. Straus, 1,2,3 * K. Vasilakos, 1 R. J. A. Wilson, 1 T. Oshima, 1,5 M. Zelter, 2,3 J-Ph. Derenne, 2,4 T. Similowski, 2,4 and W. A. Whitelaw 1 Summary The occurrence of hiccoughs (hiccups) is very wide- spread and yet their neuronal origin and physiological significance are still unresolved. Several hypotheses have been proposed. Here we consider a phylogenetic perspective, starting from the concept that the ventilatory central pattern generator of lower vertebrates provides the base upon which central pattern generators of higher vertebrates develop. Hiccoughs are characterized by glottal closure during inspiration and by early devel- opment in relation to lung ventilation. They are inhibited when the concentration of inhaled CO 2 is increased and they can be abolished by the drug baclofen (an agonist of the GABA B receptor). These properties are shared by ventilatory motor patterns of lower vertebrates, leading to the hypothesis that hiccough is the expression of archaic motor patterns and particularly the motor pattern of gill ventilation in bimodal breathers such as most frogs. A circuit that can generate hiccoughs may persist in mammals because it has permitted the development of pattern generators for other useful functions of the pharynx and chest wall muscles, such as suckling or eupneic breathing. BioEssays 25:182–188, 2003. ß 2003 Wiley Periodicals, Inc. Introduction Hiccoughs (or hiccups), combining a sudden inspiration im- mediately followed by an active closure of the glottis res- ponsible for a peculiar sound, are a common phenomenon. They are experienced by nearly everyone, yet their origin and significance remain elusive and hence debated. (1,2) Several hypotheses have been proposed. Hiccoughs could result from the activation of a reflex arc of which the afferent limb would comprise the phrenic and vagus nerves plus the sympathetic chain. The central link of this arc would be located within the spinal cord, the brainstem and the hypothalamus, and the cer- ebellum and cerebral hemispheres would possibly be in- volved. (3,4) Hiccough could also represent a form of epilepsy, although most patients with chronic hiccough do not have any cerebral dysfunction and although diazepam, a major anti- convulsant drug, can trigger or worsen hiccough (see the review in Ref. 1). It has also been suggested, from observa- tions made in patients with multiple sclerosis, that hiccough could be caused by the suppression of supraspinal inhibitory influences. (5) Another hypothesis is that hiccough could result from a dysfunction of the reciprocal inhibition of an ‘‘inspiratory complex’’ related to breathing and a ‘‘glottis closure complex’’ related to swallowing. (3) Some authors believe that hiccough represents the persistence of a fetal digestive reflex prevent- ing amniotic fluid aspiration. (6) For others, fetal hiccough may prepare respiratory muscles for their postnatal breathing function after birth. (7,8) We have taken a fresh look at hiccoughs by considering their past. We present here a phylogenetic hypothesis for their origin. It is based on the principle that neural mechanisms for rhythm generation in the brainstem are preserved through evolution and on the observation of numerous similarities between hiccoughs and ventilation in lower vertebrates such as the frogs. We begin by summing up the main characteristics of normal breathing at rest, eupnea, in humans and by review- ing what is known about hiccoughs, then discuss the phylo- genetic origin of respiration and the likelihood that hiccoughs are a by-product of earlier, but conserved, respiratory behaviours. Eupneic breathing in mammals Pulmonary gas exchanges in mammals depend upon the continuous renewal of the alveolar gas by a cyclical process called ventilation. This includes an inspiratory phase during which pulmonary inflation results from the contraction of ins- piratory muscles. This contraction generates a negative intra- thoracic pressure, aspiration, which pumps air into the lung. 182 BioEssays 25.2 BioEssays 25:182–188, ß 2003 Wiley Periodicals, Inc. 1 Respiratory Research Group, Department of Medical Physiology Faculty of Medicine, University of Calgary, Alberta, Canada. 2 UPRES EA 2397, Faculte ´ de Me ´ decine Pitie ´ -Salpe ˆ trie ` re, Universite ´ Paris, VI, France. 3 Service Central d’Explorations Fonctionnelles Respiratoires, Groupe Hospitalier Pitie-Salpetriere, Assistance Publique-Ho ˆpitaux de Paris, Paris, France. 4 Service de Pneumologie, Groupe Hospitalier Pitie-Salpetriere, Assistance Publique-Ho ˆ pitaux de Paris, Paris, France. 5 Department of Anesthesiology, Gifu University School of Medicine, Gifu-City, Japan. Funding agency: The Association pour le De ´ veloppement et l’Orga- nisation de la Recherche en Pneumologie (ADOREP). *Correspondence to: C. Straus, Explorations Fonctionnelles Respir- atoires, Groupe Hospitalier Pitie ´-Salpe ˆtre `re, 47-83, Boulevard de l’Ho ˆ pital, 75651 Paris Cedex 13, France. E-mail: christian.straus@psl.ap-hop-paris.fr DOI 10.1002/bies.10224 Published online in Wiley InterScience (www.interscience.wiley.com). Hypothesis