HISTORICAL PERSPECTIVES ON THE AUTONOMIC NERVOUS SYSTEM
Central nervous system regulation of visceral organs is the focus of several historic publications that have shaped the texture of physiological inquiry. For example, in 1872 Darwin acknowledged the dynamic neural relationship between the heart and the brain:
. . .when the heart is affected it reacts on the brain; and the state of the brain again reacts through the pneumo-gastric [vagus] nerve on the heart; so that under any excitement there will be much mutual action and reaction between these, the two most important organs of the body.1
Although Darwin acknowledged the bidirectional communication between the viscera and the brain, subsequent formal description of the autonomic nervous system (eg, by Langley2) minimized the importance of central regulatory structures and afferents. Following Langley, medical and physiological research tended to focus on the peripheral motor nerves of the autonomic nervous sytem, with a conceptual emphasis on the paired antagonism between sympathetic and parasympathetic efferent pathways on the target visceral organs. This focus minimized interest in both afferent pathways and the brainstem areas that regulate specific efferent pathways.
The early conceptualization of the vagus focused on an undifferentiated efferent pathway that was assumed to modulate “tone” concurrently to several target organs. Thus, brainstem areas regulating the supradiaphragmatic (eg, myelinated vagal pathways originating in the nucleus ambiguus and terminating primarily above the diaphragm) were not functionally distinguished from those regulating the subdiaphragmatic (eg, unmyelinated vagal pathways originating in the dorsal motor nucleus of the vagus and terminating primarily below the diaphragm). Without this distinction, research and theory focused on the paired antagonism between the parasympathetic and sympathetic innervation to target organs. The consequence of an emphasis on paired antagonism was an acceptance in physiology and medicine of global constructs such as autonomic balance, sympathetic tone, and vagal tone.
More than 50 years ago, Hess proposed that the autonomic nervous system was not solely vegetative and automatic but was instead an integrated system with both peripheral and central neurons.3 By emphasizing the central mechanisms that mediate the dynamic regulation of peripheral organs, Hess anticipated the need for technologies to continuously monitor peripheral and central neural circuits involved in the regulation of visceral function.
THE VAGAL PARADOX
In 1992, I proposed that an estimate of vagal tone, derived from measuring respiratory sinus arrhythmia, could be used in clinical medicine as an index of stress vulnerability.4 Rather than using the descriptive measures of heart rate variability (ie, beat-to-beat variability) frequently used in obstetrics and pediatrics, the paper emphasized that respiratory sinus arrhythmia has a neural origin and represents the tonic functional outflow from the vagus to the heart (ie, cardiac vagal tone). Thus, it was proposed that respiratory sinus arrhythmia would provide a more sensitive index of health status than a more global measure of beat-to-beat heart rate variability reflecting undetermined neural and nonneural mechanisms. The paper presented a quantitative approach that applied time-series analyses to extract the amplitude of respiratory sinus arrhythmia as a more accurate index of vagal activity. The article provided data demonstrating that healthy full-term infants had respiratory sinus arrhythmia of significantly greater amplitude than did preterm infants. This idea of using heart rate patterns to index vagal activity was not new, having been reported as early as 1910 by Hering.5 Moreover, contemporary studies have reliably reported that vagal blockade via atropine depresses respiratory sinus arrhythmia in mammals.6,7
In response to this article,4 I received a letter from a neonatologist who wrote that, as a medical student, he learned that vagal tone could be lethal. He argued that perhaps too much of a good thing (ie, vagal tone) could be bad. He was referring, of course, to the clinical risk of neurogenic bradycardia. Bradycardia, when observed during delivery, may be an indicator of fetal distress. Similarly, bradycardia and apnea are important indicators of risk for the newborn.
My colleagues and I further investigated this perplexing observation by studying the human fetus during delivery. We observed that fetal bradycardia occurred only when respiratory sinus arrhythmia was depressed (ie, a respiratory rhythm in fetal heart rate is observable even in the absence of the large chest wall movements associated with breathing that occur postpartum).8 This raised the question of how vagal mechanisms could mediate both respiratory sinus arrhythmia and bradycardia, as one is protective and the other is potentially lethal. This inconsistency became the “vagal paradox” and served as the motivation behind the polyvagal theory.
With regard to the mechanisms mediating bradycardia and heart rate variability, there is an obvious inconsistency between data and physiological assumptions. Physiological models assume vagal regulation of both chronotropic control of the heart (ie, heart rate) and the amplitude of respiratory sinus arrhythmia.9,10 For example, it has been reliably reported that vagal cardio-inhibitory fibers to the heart have consistent functional properties characterized by bradycardia to neural stimulation and a respiratory rhythm.9 However, although there are situations in which both measures covary (eg, during exercise and cholinergic blockade), there are other situations in which the measures appear to reflect independent sources of neural control (eg, bradycardic episodes associated with hypoxia, vasovagal syncope, and fetal distress). In contrast to these observable phenomena, researchers continue to argue for a covariation between these two parameters. This inconsistency, based on an assumption of a single central vagal source, is what I have labeled the vagal paradox.
THE POLYVAGAL THEORY: THREE PHYLOGENETIC RESPONSE SYSTEMS
Investigation of the phylogeny of the vertebrate autonomic nervous system provides an answer to the vagal paradox. Research in comparative neuroanatomy and neurophysiology has identified two branches of the vagus, with each branch supporting different adaptive functions and behavioral strategies. The vagal output to the heart from one branch is manifested in respiratory sinus arrhythmia, and the output from the other branch is manifested in bradycardia and possibly the slower rhythms in heart rate variability. Although the slower rhythms have been assumed to have a sympathetic influence, they are blocked by atropine.7
The polyvagal theory7,11–15 articulates how each of three phylogenetic stages in the development of the vertebrate autonomic nervous system is associated with a distinct autonomic subsystem that is retained and expressed in mammals. These autonomic subsystems are phylogenetically ordered and behaviorally linked to social communication (eg, facial expression, vocalization, listening), mobilization (eg, fight–flight behaviors), and immobilization (eg, feigning death, vasovagal syncope, and behavioral shutdown).
The social communication system (ie, social engagement system; see below) involves the myelinated vagus, which serves to foster calm behavioral states by inhibiting sympathetic influences to the heart and dampening the hypothalamic-pituitary-adrenal (HPA) axis.16 The mobilization system is dependent on the functioning of the sympathetic nervous system. The most phylogenetically primitive component, the immobilization system, is dependent on the unmyelinated vagus, which is shared with most vertebrates. With increased neural complexity resulting from phylogenetic development, the organism’s behavioral and affective repertoire is enriched. The three circuits can be conceptualized as dynamic, providing adaptive responses to safe, dangerous, and life-threatening events and contexts.
Only mammals have a myelinated vagus. Unlike the unmyelinated vagus, originating in the dorsal motor nucleus of the vagus with pre- and postganglionic muscarinic receptors, the mammalian myelinated vagus originates in the nucleus ambiguus and has preganglionic nicotinic receptors and postganglionic muscarinic receptors. The unmyelinated vagus is shared with other vertebrates, including reptiles, amphibians, teleosts, and elasmobranchs.
We are now investigating the possibility of extracting different features of the heart rate pattern to dynamically monitor the two vagal systems. Preliminary studies in our laboratory support this possibility. In these studies we have blocked the nicotinic preganglionic receptors with hexamethonium and the muscarinic receptors with atropine. The data were collected from the prairie vole,17 which has a very high ambient vagal tone. These preliminary data demonstrated that, in several animals, nicotinic blockade selectively removes respiratory sinus arrhythmia without dampening the amplitude of the lower frequencies in heart rate variability. In contrast, blocking the muscarinic receptors with atropine removes both the low and respiratory frequencies.