John D. and
Catherine T. MacArthur
Research Network on Socioeconomic Status and Health
Parasympathetic Function This summary was prepared by Bruce McEwen, Karen Bulloch and Judith Stewart in collaboration with meeting participants. Participants included: Karen Bulloch, Firdaus Dhabhar, Ichiro Kawachi, Bruce McEwen, Tom Pickering, Steve Porges, Richard Sloan, Cliff Saper, Teresa Seeman and Gerald Smith. Last revised July, 1999. Table of Contents Context of Meeting Allostasis is the process of adaptation that helps the body to maintain homeostasis. Allostatic load is the cost of excessive adaptation and reflects over activity of chemical mediators involved in adaptation; it reflects an imbalance in the activities of mediators - e.g. inflammatory cytokines with inadequate glucocorticoids; or excess excitatory amino acids in brain after stress or during aging; or elevated glucocorticoids, insulin and catecholamines in relation to abdominal obesity and Type 2 diabetes. Most of our attention to allostasis focuses on the HPA axis and only one component of the autonomic nervous system (ANS), namely the sympathetic nervous system. Although acknowledged to be important, very little attention has been given to what role the other arm of the ANS, the parasympathetic nervous system, plays in the stress response. In order to amend this deficiency, and to gain a better understanding of the contribution of the whole ANS to the stress response and its resolution, the Mac Arthur Foundation has brought together distinguished scientists studying the anatomic and functional components of the ANS. A particular focus of this meeting was to examine the role of the vagus, the major highway of the parasympathetic nervous system. The vagus nerve has a substantial afferent component, which brings sensory information into the nervous system, as well as an efferent component that executes parasympathetic functions. The Autonomic Nervous System The autonomic nervous system (ANS), is divided anatomically into three components: the parasympathetic, with cranial and sacral connections; the sympathetic, with central nervous connections in the thoracic and lumbar segments of the spinal cord; and the enteric nervous system which occupies the digestive tract. The sensory nervous system is also included in any discussion of the ANS since its input can initiate changes in autonomic tone. The parasympathetic and sympathetic components of the ANS control the involuntary body functions via the distribution of nerve fibers to the various organs and glands, whereas the enteric nervous system is involved primarily with the internal regulation of the gustatory processes. The sensory nervous system is involved in generating messages of pain and other sensory modalities into the central nervous system to alert the brain of changes or challenges from the outside environment and to set the stage for the body’s response to these stimuli. Traditional concepts that the parasympathetic nervous system’s
control is inhibitory and sympathetic is excitatory have proven too simplistic, as we now
are aware of many exceptions in both systems. The best characterization is that the
sympathetic nervous system is a quick response mobilizing system and the parasympathetic
as a more slowly activated dampening system, but even these concepts do not hold up in all
cases of peripheral regulation since there are clear examples of where the two systems
work together to carry out physiological functions i.e. penile erection and ejaculation. Terminal Distribution in the ANS One of the most important features of the ANS innervation of target tissues is the manner in which neural signals are transmitted by ANS terminal nerve endings. In general, non-myelinated bundles of ANS neuronal fibers are dispersed between the stromal cells of the glands. The non-myelinated fibers of each axon form varicosities or swellings filled with vesicles containing signalling molecules such as acetylcholine, norepinerphrine neuropeptides etc. The Schwann cell sheath gives way at these varicosities so that the neurotransmitter substance can diffuse into the interstitial space of the tissue being innervated. This allows for the dissemination of CNS signal over large volumes of tissue effecting many cells that express the ANS transmitter receptors. Thus the one-to-one synaptic contacts derived from the classic neuromuscular junction model or the CNS models is not the standard mode of transmission for the post ganglionic autonomic nervous system. This is an extremely important concept when considering the impact of the nervous system on the immune system. Central control of the ANS The central nervous system controls the ANS from the cortex down through the brainstem and the spinal cord, but especially important is the hypothalamus, which is the integrator of autonomic function. The limbic system, comprised of the olfactory areas, the hippocampus and amygdaloid complex, the cingulate cortex and the septal region, in turn, has a regulatory input to the hypothalamus. The ANS includes regions within a central regulatory brainstem that determines special motor outputs via parasympathetic and sympathetic nerves to visceral organs after integrating information from sensory nerves regarding the status of an organ. Parasympathetic signals leave these brainstem centers and are distributed to peripheral organs and tissues, such as those of the cardiac and immune systems via the vagus nerve In mammals, two vagal components have evolved in the brainstem to regulate peripheral parasympathetic functions. The dorsal vagal complex (DVC), consisting of the dorsal motor nucleus (DMNX) and its connections, controls parasympathetic function below the level of the diaphragm, while the ventral vagal complex (VVC), comprised of nucleus ambiguus and nucleus retrofacial, controls functions above the diaphragm in organs such as the heart, thymus and lungs, as well as other glands and tissues of the neck and upper chest, and specialized muscles such as those of the esophageal complex. The VVC only appears in mammals and is associated with positive as well as negative regulation of heart rate, bronchial constriction, vocalization and contraction of the facial muscles in relation to emotional states (see below). The VVC inhibition is released (turned off) in states of alertness. This in turn causes cardiac vagal tone to decrease and heart rate to increase to support responses to environmental challenges. Thus novel and potentially dangerous situations can initiate an increase in heart rate and metabolic output for immediate mobilization through the parasympathetic nervous system without the participation of the sympathetic nervous system or adrenal system.
Another function of the VVC is somewhat more speculative. Its association with the 7th cranial (facial nerve) may be linked to facial expressions and the display of emotions. In particular, Stephen Porges postulates that the VVC is linked to social engagement and that withdrawal from social engagement is associated with impaired VVC function. A key question is whether this engagement and withdrawal, as seen in children and adults, represents a form of learning or plasticity, or an irreversible pathophysiological condition. In lower vertebrates the DMNX or DVC is the main component of the ANS, with the sympathetic nervous component (SNS) added later in evolution in teleosts and amphibia and the adrenal medulla added in reptiles. The DVC is linked to the final stages of ANS activity, leading, among other consequences, to inhibition cardiac function. In this respect, it is associated with the phenomenon of voodoo death, as well as with death in animals from defeat. According to the scheme summarized in the figure below, extreme terror brings about activation of the DVC and this leads to immobilization and potentially life-threatening bradycardia, apnea and cardiac arrhythmias. The DVC and sympathetic nervous system form opposing systems in their effects on heart rate, bronchial contraction and gastrointestinal function.
FIGURE 1: Stages of activation of the stress response
following the Jacksonian principle of dissolution: Three Aspects of Parasympathetic Function 
Karen Bulloch - Regional regulation of immunity. Primary, secondary and tertiary immune organs differ in the degree of innervation and regulation by the ANS as well as differing in production of and sensitivity to local immunomodulatory peptides, cytokines and circulating hormones. The thymus is an organ with considerable parasympathetic input and contains, among other receptors, cholinergic receptors. However, the function of parasympathetic input in thymus function is not clear at this time. CGRP, which is a potent peptide that is both a vasodialator and a suppressor of T cell and macrophage activation, is most likely derived from parasympathetic, sensory and paracrine cell that reside in the thymus. Cliff Saper - Peripheral immune responses signalling across the blood brain barrier. Prostaglandins appear to be the mediators that cross the blood-brain barrier and provide the link between circulating cytokines like IL-1 and CNS responses. Prostaglandins are produced by the blood vessels. IL-1 also acts in the microglia that lie outside of the blood brain barrier. He does not think that, except for injury, immune cells traffic freely into the brain. These types of signaling can occur at the level of the brain stem nuclei involved in ANS function, as well as at nerve endings of the afferent component of the vagus. Firdaus Dhabhar - Trafficking of immune cells into peripheral organs after immune challenge. The HPA axis and catecholamines are known to play a role. The role of the parasympathetic nervous system in the trafficking process is not known.
Tom Pickering - Blood pressure change patterns. Blood pressure normally falls during the night (the so-called dipper pattern) and this is associated with a nocturnal decrease of low frequency and increase of high frequency power. In some hypertensive patients the blood pressure does not dip at night (non-dippers), and this represents a form of allostatic load that may contribute to the damage caused by chronic hypertension. In non-dippers there is some disturbance of the sleep architecture, and a relatively high nocturnal low frequency power, together with a relatively low high frequency power. This would be consistent with a failure to reduce sympathetic and to increase parasympathetic activity during the night, and with the failure to lower blood pressure. We don't know (a) to what extent vagal tone can vary independently of sympathetic tone and (b) whether it plays any significant role in the pathogenesis of disease. Richard Sloan - HR variability is like a shock absorber against BP surges. Decreased heart rate variability is seen in those with depression, and higher hostility and/or anxiety. Similar decreases are seen with physical deconditioning and in aging. In healthy subjects low levels of high frequency power are associated with increased risk for cardiac disease. According to Sloan's hypothesis, this decreased variability contributes to increased allostatic load on the heart and acceleration of atherosclerosis among other pathophysiological changes. Ichiro Kawachi - HRV has been related to both anxiety and risk for CHD. Recent analyses suggest that HRV may serve as a mediator for anxiety effects on CHD risk. Michael Marmot has shown an association between SES and HRV by employment grade. A small but significant association between HRV and frequency of sudden death in those with clearly established heart disease has been shown. Low HR variability is a trait and has been related to higher hostility. Data also indicate that HRV is increased during positive social interactions and decreased under "stress" conditions. HRV may be a window on the relative growth/restorative versus mobilization levels. Stephen Porges - Polyvagal theory and ways to test it through studies of infants and autistic children. In infants at 9 months of age, poor regulation of the vagal brake during tests of attention in a social situation predicted behavior problems at age 3. Underlying the individual variations in vagal tone is the question of plasticity vs. damage and reversibility of defects in the vagal brake and in reduced heart rate variability. He reported that autistic children could be made to be more attentive and responsive to human stimulation by training with a toned system of listening exercises. Increasing attention to phoneme range sounds is hypothesized to positively impact the disordered functioning of the VVC, deemed by him to be the substrate for autism. The maintenance of such behavioral changes was reported to be contingent, however, on modification of the living environment of the child to reduce sound over stimulation (e.g. exposure to a circus can "shut the child back down"). In a similar vein it was suggested that HRV may be decreased in lower SES individuals as they are exposed to greater noise and, as a result of their environment, have a greater need for vigilance—i.e., similar to "predator monitoring", and consequently are less "tuned-in" to voices and prosocial activities. Gerard Smith - Regulation of satiety via vagus and gut. The GI tract as a sensory sheet: 98% vagal afferents; only 2% efferents. Transduction of sensory signals in afferent vagus represents an important area of current research to identify the chemical signals. CCK, gastrin, secretin, somatostatin, motilin are gut peptides with a signalling role. The NTS is a site of crosstalk between this sensory information and the cardiovascular system. General Model for VVC as it Relates to Other
Regulatory Systems The group discussed possible links between levels of VVC activity and the ANS and HPA axis: Is there a scientifically sound bridge here to link ‘social support/networks’ and biological consequences? For example, if a person’s environment operates against their ability to partake of social support (i.e. so turns off the VVC and the accompanying activation of the ‘social’ cranial nerves), then how might that translate into physical consequences? Here we must consider the reduction of the positive effects of social engagement and the negative downside, i.e., the allostatic load of the "unbraked" physiological systems. When hypothesizing about bridges between social factors and biological consequences (e.g., disregulation of VVC activity), it is often true that the most compelling case examples are those that are extreme ones. The inner city noise, pervasive threats of violence and strained interpersonal relations, which are assumed to characterize the lives of many low SES individuals are readily seen as imaginable derailers of VVC activity. However, the mechanisms of interest to the Network are those which operate to produce a social gradient, not just a threshold effect. So while extreme conditions are useful for theorizing and doing research (e.g., Porges's autism examples), the mechanisms proposed need to also be imaginable as producing the health differentials seen between other groups (e.g., the middle and upper classes). In this connection, and as an example of a more moderate and all-too-common situation, it does appear that work-related stress and lack of control (vital exhaustion) also can dysregulate VVC activity. On the flip side, it is also important to keep in mind Gerry Smith's concern that when using extreme examples there may be a tendency to caricature these social situations. For example, his concern that the characterizing of "ghetto parenting" as being marked by pervasive, predictable, dysfunction-producing practices may be so broad a generalization as to reach the level of caricature or stereotype. This brings to mind the important distinction between individuals and groups of individuals - within any population at any level of SES we can find people who cope well and others who do not! Thus our search at the individual level is for behavioral and physiological mechanisms for disregulated VVC activity, or other aspects of allostatic load, irrespective of SES, whereas the search at the group level is for average properties of groups based upon broader, average characterizations of their lives, that relate to SES characteristics.
General Discussion of HRV as a Component of Allostatic Load and Possibilities for Inclusion in Future Research The group discussed the possible protocols and equipment available for inclusion of HRV data in an assessment of allostatic load. General consensus appeared to be that it was quite feasible to get data in a clinical/laboratory setting but that available equipment do NOT exist for reliable ambulatory monitoring. To get HRV, only ECG with analog recording in lab is needed. It was suggested that the Network contact ARIC investigators and inquire about the possibility of looking at relationships between SES and HRV using their data. Bulloch, K. (1985). Neuroanatomy of Lymphoid Tissue: A Review. In R. Guillemin (Ed.), Neural Modulation of Immunity (pp. 111-141). New York: Raven Press. Bulloch, K., Sadamatsu, M., Patel, A., & McEwen, B. S. (1999). Calcitonin gene-related peptide immunoreactivity in the hippocampus and its relationship to cellular changes following exposure to trimethyltin. Journal of Neuroscience Research, 55, 441-457. Elmquist, J. K., Scammell, T. E., & Saper, C. B. (1997). Mechanisms of CNS response to systemic immune challenge: The febrile response. Trends in Neuroscience, 20(12), 565-570. Pine, D. S., Wasserman, G. A., Miller, L., Coplan, J. D., Bagiella, E., Kovelenku, P., Myers, M. M., & Sloan, R. P. (1998). Heart period variability and psychopathology in urban boys at risk for delinquency. Psychophysiology, 35, 521-529. Porges, S. W. (1995). Cardiac vagal tone: A physiological index of stress. Neuroscience and Biobehavioral Reviews, 19(2), 225-233. Porges, S. W. (1995). Orienting in a defensive world: Mammalian modifications of our evolutionary heritage. A Polyvagal Theory. Psychophysiology, 32, 301-318. Porges, S. W. (1997). Emotion: an evolutionary by-product of the neural regulation of the autonomic nervous system. Annual of the New York Academy of Science, 807, 62-77. Porges, S. W. (1998). Love: an emergent property of the mammalian autonomic nervous system. Psychoneuroendocrinology, 23(8), 837-861. Porges, S. W., Doussard-Roosevelt, J. A., & Greenspan, S. I. (1996). Infant regulation of the vagal "brake" predicts child behavior problems: A psychobiological model of social behavior. Developmental Psychobiology, 29(8), 697-712. Porges, S. W., Doussard-Roosevelt, J. A., Stifter, C. A., McClenny, B. D., & Riniolo, T. C. (1999). Sleep state and vagal regulation of heart period patterns in the human newborn: An extension of the polyvagal theory. Psychophysiology, 36, 14-21. Saul, H. P. (1990). Beat-to beat variations of heart rate reflect modulation of cardiac autonomic outflow. NIPS, 5, 32-37. Sloan, R. P., Shapiro, P. A., Bagiella, E., Myers, M. M., & Gorman, J. M. (1999). Cardiac autonomic control buffers blood pressure variability responses to challenge: A psychophysiologic model of coronary artery disease. Psychosomatic Medicine, 61, 58-68. Smith, G. P. (in press). Cholecystokinin-the first twenty-five years. In C. Bouchard & G. Bray (Eds.), Nutrition, Genetics, and Obesity : Louisiana State University Press. |
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Contact: Judith Stewart
Revised 25 July 2000