and to sort of illustrate the way I interpret how heart rate variability has evolved over the years, I have put together the five stages, and this is based on the prevailing scientific paradigms that existed in each of these stages. Unfortunately, I won't be able to go through all of these five stages; it will probably take three talks overall to go over all of them. But you know, I think as of today, we'll just largely focus on part one: understanding heart rate variability. The stages are first understanding heart rate variability, and then heart rate variability as a marker of the autonomic nervous system, then heart rate variability as a marker of body-wide function, heart rate variability within the construct of mind-body interaction, and then finally the heart rate variability itself as a desirable target. So the first stage, understanding heart rate variability, happened in the 1970s and 1980s. Predominantly, there was a focus in physiology and the development of methods. In my view, the 1970s

and 1980s was the golden age of physiology. Uh, about, you know, this occurred about 20 years after Hodgkin and Huxley finalized their axon signal transduction had gone along the squid axons. This was also 20 years after Watson and Crick figured out the DNA double helix structure, and there was enough time for development of imaging stains such as ELISA in 1971, electrophysiology techniques such as voltage clamps, and machines that are important for obtaining electrophysiological measures, neural transmitter blockades such as atropine and propranolol, and you also have infrastructure for animal studies. So, it is only natural that you would see a significant development or advancement of our physiological understanding of the autonomic nervous system around this time. And by this time, by the 1970s, they really had a pretty good understanding of the autonomic nervous system, and they have divided it into two divisions. Actually, there are probably three because there's

the parasympathetic nervous system, the sympathetic nervous system, and the third one is the enteric nervous system, which we don't talk about too much here. Um, and during the 1970s and 80s, they've very much outlined the various physiological roles that each of these nervous systems play and also, importantly, understood the anatomical pathways that were responsible for the execution and functions of both of these nervous systems. In regards to the heart, we knew that the parasympathetic nerves slow heart rates and the sympathetic nerves increase heart rate. Now, the contracting functions of the heart are coordinated basically through the electrical conduction system, as depicted here in blue and purple. The part that sets the pace for the heartbeats is the sinoatrial node, or the SA node, located in the right atrium, and it helps sense the rate of the heartbeat. The conduction, the electrical conductions, you have

essentially, pacemaker cells in the SA node send electrical signals down the atrium to the AV node and then down the Purkinje fibers, the His-Purkinje cells, and then down the bundles that lead to the contractions of various chambers. Both the parasympathetic and the sympathetic nervous system act at the SA node and help set the rate of the heartbeat, and they both have sort of opposing effects. The sympathetic nervous system increases heart rate, which is shown here going up to 200 beats per minute. The vagal system, on the other hand, slows heart rate. And if you have exact cancellation of each other, and if you let the heart beat intrinsically on its own, the intrinsic heart rate is about 100-110 beats per minute. And since our resting heart rate is around 70 beats per minute, that indicates that the vagal tone is greater than the sympathetic tone at rest. And we knew that actually in the 1970s and even as early as the 1950s, actually was because um they

had done some experimentations with transplanted hearts, and you could see here the heart rate over time in a healthy heart. You can see that the average heart rate is about 71 beats per minute, and then when they transplanted the heart either in a dog or a human, you could see that the heart rate was much higher, about 99 beats per minute or even higher, 110 beats per minute. And the other thing that you know is that the variability that you see in the heart rate disappears in a transplanted heart. And the reason is that's the case is because the transplanted part, in order to transfer that part from the donor to the recipient, you need to disconnect all the autonomic nervous connections to that heart. So, that includes the parasympathetic nervous system, sympathetic nervous system, and so you lose this variability, and you have a significant rise in your heart rate. And this was known as early as the 1960s because the first human cardiac transplantation

was done by Christian Barnard in South Africa in December of 1967. So, we knew this way early on, and this is an example of sort of the complexity that you get with heart rate variability. This is our interval, which is the inverse of heart rate, and you can see the changes in the R interval with time or with the number of beats, and the average of this graph gives you the resting B2B interval, or in the analogy that I like to say, is sort of like the C level. The fluctuations that you can see around this quote-unquote sea level is the tides and the waves, and this is the heart and brake variability that we're talking about. And as early as the 1970s, clearly physiologists were able to identify the important factors that were involved in heart rate variability and even developed a schematic representation, and this is a pretty good representation, and this was a publication in 1973.

they've identified sort of the central neural controls, which included the brainstem control centers and triple mechanical factors, and they even developed a schematic to help understand how these various factors interacted with each other. And as noted, they identified the important factors, which included the control centers of the autonomic nervous system in the brainstem, the baroreceptors, which were important for maintaining a stable blood pressure, and also the effect of breathing by changing the intrapleural pressures. And so, they've clearly developed a very good understanding of this in the 1970s. And one of the important parts, sort of physiological contributions to this heart rate variability, is respiratory sinus arrhythmia. This is the change in your heart rate as you take a breath in and out. And you may notice as you breathe in, your heart rate, which is illustrated here by the gray, increases with inspiration or inhalation, and it goes down with exhalation. And there are certain sort of time dynamical time parameters or

information about the typical time scales is about every three to seven seconds that you take a breath or about nine to twenty-four cycles per minute. So this is the respiratory sinus arrhythmia, and then the other important physiological factor in heart rate variability is the baroreflex. The baroreflex is a way to control or stabilize blood pressure, and you have essentially these mechanical receptors located in the aorta and the carotid sinus. And then through the vagus nerve and the glossopharyngeal nerve, you have signals sent to the brain stem, and then this brainstem signals then gets sent to the autonomic nervous system nuclei, including the parasympathetic and the sympathetic systems, and then they feedback that response so that affects the SA node in other regions of the heart. The time scale for the baroreflex is a little longer; it's about three to twenty seconds, and it happens to be greatest problems approximately about six cycles per minute or every 10 seconds.

and around this time in the 1970s, in order to capture these variability dynamics, physiologists began to create multiple measures. And it's very hard to see sort of this in sort of granular detail here, but what's important to note is already by the 1970s, they've established important time domain measures and frequency domain measures. And this is a summation of the multiple heart rate variability measures that are out there in the literature right now. This was in Shaper in 2017. These are sort of highlighting the most important ones. There are at least 60 to 70 different heart rate variability measures now, and they're categorized into three big buckets. One is heart rate variability by the time domain measures, the second is heart rate variability by frequency domain measures, and the third one is non-linear measures. And I'm going to talk about each of these in a little more detail. The first one that I want to talk about is the

frequency domain, and the way I want to help you understand how this works is to sort of imagine light. So, if you take a prism and then you shine white light onto it, then the prism actually breaks down the white light into its different components of spectral light. You have different speeds of light secondary to the refraction within the prism, and as a result, it divides the light into its different frequencies. You could imagine that if you had a photo sensor in this wall, and you let that photo sensor accumulate the amount of light that goes onto that sensor over time, you would develop an idea of how strong each of these individual components of light are. You could do the same thing with heart rate time series, and we use different techniques, and sort of analogous to the prism, you have something called Fourier transform and auto-regressive spectrum analysis. There are some others as well, and what these techniques do is it permits us to identify the spectral power of each frequency range, so you can

Imagine this heart rate variability is composed of multiple signals with different frequencies, and these techniques enable us to sort of divide them and to identify which component is the strongest. And what you see here is you can essentially produce a spectral power, and you can see that the spectral power is divided according to the frequency. Now, frequency, the higher it is, that means the faster the cycle. So, the higher frequency is on the right here, and the lower frequency is on the left. And over time, we've got a pretty good understanding of the various categories of the cycles of the frequencies that are involved in heart rate variability, and we've divided them into several categories. There's high frequency, low frequency, very low frequency, and ultra-low frequency. And then we have a ratio of lower frequency versus high frequencies. And the frequencies that are associated with each of these frequency ranges are listed here. The ones that I want to have you pay attention to is the high frequency and the low frequency.

so high frequency is 0.5 to 0.4 hertz, which is about 9 to 24 cycles per minute. uh low frequency is three to nine cycles per minute. very low frequency is 25 seconds to five minutes per cycle, five minutes to 24 hours through the ultra-low frequencies per cycle. and in order to evaluate these cycles, you would need to acquire the heart rate over time. and because these cycles are shorter high frequency low frequency, oftentimes you just need five minutes in order to get information about these cycles, whereas for longer cycles, you would definitely need to require as long as 24 hours. and each of these cycles has physiological significance, so high frequency is associated with respiratory sinus rhythmia. the low frequency is associated with bare reflex and vascular sympathetic nerves um, and there's something called mirror waves, which is the oscillations, the intrinsic oscillations that you see in the vessels um, when I'm talking about the artery system. very low frequencies have slower physiological systems.

involved such as temperature regulation hormones such as region tension thyroxine reproductive forms and steroids and then the heart has an intrinsic nervous system as well which is believed to have a very low frequency range and then at the ultra-low frequency range it involves thermoregulation other hormones such as cortisol and growth hormones in the circulating rhythm and they knew a lot of this um as early as the 1970s and this is a publication in ergonomics and again they have created this frequency spectral analysis of heart rate variability and I'm going to read this to you because it may be small on your screen but they have already noticed that the respiratory activity is largely predominantly near 0.35 perch which falls into our high-frequency range the vase and mortar activity lies in the 0.1 hertz which lies in the low-frequency range and thermal activity at 0.025 hertz which is in the very low-frequency range so already they knew this in the 1970s

1.2 Fundamental HRV Physiology & Frequency Domain

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