Hiccups are a manifestation of central respiratory arrhythmias

Abstract

Hiccups (singultus) comprise repeated episodes of sharp, large-volume inspiration followed by glottic closure, interspersed among normal inspiration. Hiccupping causes involuntary contractions of diaphragm and thoracic musculature. While generally short-lived and self-limiting, hiccupping can last hours, or days, or longer, and cause wide-ranging medical, quality of life, and economic burdens. A proposed mechanism for hiccups is a pathway comprising: 1) an afferent limb including ascending fibers of the vagus nerve, 2) a central processing component in the midbrain and brainstem, and 3) an efferent limb including motorneurons of the diaphragm, glottis, and intercostal muscles. We hypothesize that hiccups represent a disinhibition of vestigial neural circuitry in the central processing component, manifesting as a multi-stable state of abnormal respiratory rhythm: a “respiratory arrhythmia”. This hypothesis applies the concept of multi-stable (chaotic) systems to the respiratory cycle and stable, but aberrant, breathing rhythms. A system is multi-stable if, for a set of inputs, it has multiple potential stable states, depending on the system’s prior state and the effects of external perturbations. This hypothesis is predicated on Straus et al.’s suggestion that hiccups are an evolutionary preservation of gill ventilation, normally suppressed by neural circuitry controlling mammalian breathing. The respiratory system, it is proposed, could stably exhibit eupneic breathing motor patterns or a mix of eupneic and aquatic-like patterns (hiccups). That is, eupnea alone, or eupnea plus gill ventilation are alternative stable equilibrium points of a multi-stable system. Evidence supporting the hypothesis includes computational models of the respiratory control center manifesting hiccup-like patterns, and experimental data showing that medullary stimulation induces hiccups-like breathing in cats. Additional evidence includes clinical reports of therapeutic perturbations to, or near, the putative respiratory pattern generator resetting the breathing pattern to the default stable state, eupnea. These approaches, which provide strong afferent input to the brainstem regulatory network rather than disrupting aberrant afferent signaling, include elevating CO2 concentrations to excite central and peripheral chemoreceptors increasing respiratory drive. Other examples include nasopharyngeal stimulation or sudden administration of strong sweet or sour tastes. Viewing hiccups as a respiratory arrhythmia could prove helpful in developing targeted interventions.