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EDITORIAL |
The author is with the Integrative Neural Immune Program and the Section on Neuroendocrine Immunology and Behavior, National Institute of Mental Health, National Institutes of Health, Bethesda, Md.
Correspondence: Requests for reprints should be sent to Esther M. Sternberg, MD, Bldg 36, Rm 1A-23, 36 Convent Dr, MSC 4020, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-4020 (e-mail: ems{at}codon.nih.gov).
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INTRODUCTION |
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 TOP INTRODUCTION References |
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If submitted to a scientific journal today, this paper would not make it beyond the review process, as it would be described (probably with some disdain) as simply "anecdotal" and hypothetical. However, fortunately for our generation, our predecessors were apparently not averse to recording oral reports of inexplicable phenomena in detail—even down to the names of the individuals who experienced or perpetrated these events.
Thus, Cannon starts his article with several anecdotal case reports, all of which share several important features that lead him to propose, first, that there may indeed be a physiological basis for the phenomenon of voodoo death and, second, what that physiological basis might be.
The dramatic suddenness of the illness following the threat, coupled with a lack of any apparent injury, exposure to toxins, or infection suggested to Cannon that merely the fear of death could, through physiological response mechanisms initiated by fear, precipitate death itself.
Cannon focused on the "sympathetic" and "sympathicoadrenal" divisions of the nervous system—terms still in use today (although "sympatho-adrenal" is now the more common term). He outlines all the aspects of bodily function over which this arm of the nervous system exerts control—blood vessel contraction, dilation of bronchioles, adrenaline release, release of sugar from the liver—all effects that together prepare the animal to attack or run—to "fight or flee." Cannon thus elegantly lays out both the physiology and the evolutionary rationale for the "fight or flight response," a term still in use today that he coined to describe this neurophysiological–behavioral response pattern.
We could not have provided a better rationale for this aspect of the phenomenon today. This piece has stood the test of time. In the 60 years since Cannon first published his work, we have simply gained a clearer understanding of the brain regions that become activated when a fearful stimulus is experienced and a better road map of the pathways linking those brain centers involved in receiving sensory signals (in Cannon’s example, seeing a bone pointed at one) to the part of the brain that processes the emotional component of fear—the amygdala. In today’s terms, we would call this the "vision-to-fear pathway" or "auditory-to-fear pathway," depending on the sense through which the threat is initially received.
We have a deeper understanding of the neurotransmitters and neuropeptides involved in initiating these responses and perpetuating them through learning and memory. We know how such chemical signals are translated into electrical impulses and how quickly or slowly they are conveyed along nerve fibers. And we now know that such nerve chemicals and proteins are made by genes within the nucleus of nerve cells, that are switched on and off by all sorts of chemical and physical signals. We know that when we learn to fear something there are permanent changes in the shape and wiring of nerve cells that make it more likely that the next time we experience the fearful stimulus, those same pathways will be switched on all the more rapidly.
Strikingly absent, however, from Cannon’s explanation is the hormonal stress response—the cascade of hormones released from the brain, pituitary gland, and adrenal gland within minutes of exposure to any sort of stressor. This is because in 1942, when the article was written, many of these hormones were yet to be discovered. Furthermore, the term "stress," popularized by Cannon’s admirer Hans Selye and others in the postwar period, was not yet in general use. The structure of cortisol, the hormone released from the cortex of the adrenal glands during stress, was identified in 1936 by Edward Kendall and Tadeus Reichstein,2,3 who received the Nobel Prize for their discoveries in 1950 together with Philip Hench. However, the full cascade of hormones involved in the hormonal stress response was not fully elucidated until the identity of the brain’s hypothalamic stress hormone, corticotropin releasing hormone or CRH, was discovered by Wylie Vale in 1981.4
Thus, Cannon could not have included in his scenario of the possible causes of voodoo death the role of hypothalamic CRH released after signals from the amygdala, the brain’s fear center, reached the hypothalamus. Nor could he include how the cross-talk between the brain stem adrenaline centers involved in initiation of the sympathetic response could coordinate with hormones released from the brain’s hypothalamic stress center5 to cause a massive release of both adrenaline-like nerve chemicals and stress hormones. Together these might well cause illness,6–9 including loss of appetite, weakness, cardiac arrhythmias, and even vascular collapse that could result in death.
Thus, Cannon’s rather simplistic explanation of how shock could ensue simply by removal of blood volume through sympathetic clamping of peripheral arterioles is in part correct, but he could not know of the complexity of hormones and nerve chemicals that, when all released together, might be more likely to produce the cardiac arrhythmias and vascular collapse than he predicted.
Finally, he did not have the tools to go beyond hypothesis into the experimental stage in humans—to measure the responses he predicted and to prove through such measures which parts of his hypotheses were correct. He could not, as we can today, use neuroimaging technologies, electroencephalograms, and even single neuron recordings to measure nerve cell activation in different stress- and fear-related brain regions. He could not use telemetry devices and complex computer-generated mathematical analyses to noninvasively measure changes in heart rate variability, blood pressure, and cardiac blood flow in humans while they are going about their daily routines. Nor could he ask his subjects to respond to questions, programmed in their palm-pilots and synchronized with their heart rate monitors, about their moment-tomoment emotional states, to indicate within milliseconds whether a given threat caused a particular arrhythmia. He could not imagine that one could measure minute amounts of stress hormones and nerve chemicals released into the saliva during fear, simply by asking the subject to chew on a lemon-soaked cotton swab and spit into a cup. And he could not imagine how such hormones and nerve chemicals could possibly affect cells of the immune system to cause chronic wasting or disease.
Cannon could not imagine how one could accomplish all this because the tools of neuroscience, molecular biology, computational mathematics, bioengineering, neuroimaging, endocrinology, and cellular immunology had not yet been invented or discovered. But, on the basis of observation, logic, and deduction, he did imagine that there could be a biological basis to the seemingly magical phenomenon of voodoo death. And, what’s more, he had the courage to predict and record in writing that there should be, some day, a way to get the answers. In this, Cannon was perhaps among the first physiologists to apply his scientific background to attempt to explain otherwise inexplicable illnesses and phenomena that seemed to link emotions and disease. This approach, combining open-mindedness and scientific rigor, is the essence of modern complementary and alternative medicine research.
Accepted for publication June 7, 2002.
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References |
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TOPINTRODUCTIONReferences |
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2. Mason HL, Myers CS, Kendall EC. The chemistry of crystalline substances isolated from the suprarenal gland. J Biol Chem. 1936;114:613–631.
3. Hench PS, Kendall EC, Slocumb CH, et al. Effects of cortisone acetate and primary ACTH on rheumatoid arthritis, rheumatic fever and certain other conditions. Arch Intern Med. 1950;85:545–666.
4. Spiess J, Rivier J, Rivier C, Vale W. Primary structure of corticotropinreleasing factor from ovine hypothalamus. Proc Natl Acad Sci USA. 1981;78:6517–6521.
5. Sawchenko PE, Li HY, Ericsson A. Circuits and mechanisms governing hypothalamic responses to stress: a tale of two paradigms. Prog Brain Res. 2000;122:61–78.[Medline]
6. Webster JI, Tonelli L, Sternberg EM. Neuroendocrine regulation of immunity. Annu Rev Immunol. 2002;20:125–163.[Medline]
7. Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. The sympathetic nerve—an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev. 2000;52:595–638.
8. Goldstein, DS. The Autonomic Nervous System in Health and Disease. New York, NY: Marcel Dekker Inc; 2001.
9. Sternberg EM. The Balance Within: The Science Connecting Health and Emotions. New York, NY: W. H. Freeman and Co; 2000.
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