Two Truths and a Lie, the “IHP Version”: Two Research Papers and a Totally Unrelated Article

I’m interrupting my regularly scheduled reading time and whatever it is that you were doing today to bring you the latest (and only) edition of our most popular (and only) game show: Two Research Papers and a Totally Unrelated Article!  For those who are unfamiliar (i.e. everyone), this is my own spin on the icebreaker game Two Truths and a Lie.  The only difference is that (1) my version is awesomer, and (2) you don’t have to guess which is which, because it should be pretty obvious.  I mean you technically could, so I guess if you’re that starved for entertainment then knock yourself out.  Anyway, without any further ado…

 

Research Paper #1

Title: Aerobic training improves vagal reactivation regardless of resting vagal control

Researchers: Duarte A, Soares PP, Pescatello L, and Farinatti P

Journal: Med Sci Sports Exerc

Publish Date: June 2015

 

Heart rate variability (HRV) has become more mainstream in recent years as a method to monitor and assess aerobic fitness, risk for cardiovascular disease and other illnesses, response to training loads, and general Autonomic Nervous System (ANS) balance.  For those unaware of exactly what HRV is, it is basically the measurement of the variance in the time between successive heart beats over a specific time period.  Because heart rate is regulated by the sympathetic and parasympathetic divisions of the ANS, changes in heart rate over time reflect variations in the respective inputs of the Sympathetic Nervous System (SNS) and the Parasympathetic Nervous System (PsNS).  Generally speaking, the PsNS is predominately in control of heart rate at rest, and it is especially active during the exhalation phase of the breathing cycle when heart rate tends to drop.  Greater PsNS input is reflected by an increase in variability in the time between successive heartbeats (i.e. a higher HRV).  With the introduction of stressors, PsNS input to the heart is typically withdrawn and SNS input is eventually cranked up.  Consequently, the “drop” in time between successive heart beats that provides the variability in heart rate at rest and that is seen during times of relatively high parasympathetic tone is diminished, and HRV is decreased.  While this is a crude overview of the mechanics of HRV, it will be sufficient for the paper I am about to discuss.  For those interested in a deeper discussion of the physiology of the ANS and its influence on HRV, I recommend reading the second installment in my Intro to PRI series as well as Joel Jamieson’s fantastic book “The Ultimate Guide to HRV Training”.

 

With regards to training, HRV can be used to assess the “readiness” of an athlete or trainee to take on certain training loads, as well as to plan out the distribution of training loads in a program over time.  As a rule of thumb, a high HRV score indicates that the body is in an aerobic/parasympathetic-dominant state of recovery and regeneration, while a low HRV score indicates that the body is in an anaerobic/sympathetic-dominant state of acute stress response.  In addition, a higher HRV generally indicates a higher level of aerobic fitness. (Again, I’m oversimplifying things here, but it’ll work for our purposes.)  The researchers in this study noted that in the current literature, however, there are reports of increased aerobic fitness as a result of training (as measured by VO2max) without concomitant improvements in resting cardiac vagal control (a term that is essentially analogous to PsNS control of the heart at rest, which is a desirable characteristic for general health as well as those looking to improve their fitness).  They also noted that other researchers have found that in highly fit individuals, resting HRV and heart rate recovery (the amount of reduction in the heart rate during a 60s time period immediately post-exercise, another measure that reflects parasympathetic control/aerobic fitness) become dissociated.  Placed within the context of our understanding that resting HRV and aerobic fitness are positively correlated, this seems to be a curious finding–we would expect heart rate recovery to increase roughly linearly with resting HRV.

 

Duarte et al., however, proposed that the pre-training resting HRV levels of the subjects might play a role in these findings.  They took 40 healthy young men (ages 18-22) and divided them into four groups: (1) a training group consisting of individuals with relatively high baseline HRV/parasympathetic control (TH), (2) a training group consisting of individuals with relatively low baseline HRV/parasympathetic control (TL), (3) a control group consisting of individuals with relatively high baseline HRV/parasympathetic control (CH), and (4) a control group consisting of individuals with relatively low baseline HRV/parasympathetic control (CL).  It should be noted that although the subjects all had a previous history of recreational physical activity, they had not engaged in regular exercise training (defined as 2 or more days per week) for the last year, as per the exclusion criteria; thus care should be taken in applying the results of this study to different populations.  The training groups underwent 12 weeks of aerobic training, which consisted of three weekly 40-minute running sessions at an intensity of 75-85% of their heart rate reserve.  (Heart rate reserve is defined as the difference between a person’s maximum heart rate and resting heart rate.)  Each group underwent pre- and post-testing to assess aerobic fitness (via VO2max), resting HRV, and “post-exercise vagal reactivation,” which you can basically think of as parasympathetic control immediately post-exercise (as assessed by HRV and heart rate recovery).

 

The researchers found that, as expected, both training groups saw improvements in their aerobic fitness.  The VO2max levels of the TH and TL groups increased by 11.7% (standard deviation of 5.4%) and 7.0% (standard deviation of 2.9%), respectively, while no change was observed in VO2max levels for the control groups.  In addition, post-exercise vagal reactivation improved in both the TH and TL groups.  The heart rate recovery of the TH group improved by about 8 beats per minute, while the heart rate recovery of the TL group improved by about 7 beats per minute.  The HRV analysis (the researchers used a variation of the rMSSD method, which I won’t get into the details of because it’s beyond the scope of this discussion) showed that post-exercise vagal reactivation similarly increased in both the TH and TL groups, with no statistical difference between the groups and no change observed in either of the control groups.  When looking at resting HRV measures, however, the researchers found a difference between the two training groups.  While the TL group showed significant increases in parasympathetic modulation of cardiac activity at rest as a result of training (which is to be expected if we accept that aerobic fitness and resting HRV are positively correlated), the TH group showed no difference.  This finding suggests that, as the researchers hypothesized, the baseline resting HRV levels of an individual may affect whether or not increases in resting HRV as a result of training will occur.  In the present study, those with high pre-training resting HRV levels saw no improvements in their resting HRV with training, while those with lower pre-training resting HRV levels did see a significant improvement.  Thus, Takeaway #1 from this study is that resting HRV alone may not be sufficient to assess improvements in aerobic fitness and/or autonomic control from training, especially in highly fit athletes and trainees.

 

So, what other measures can you include to complement measurements of resting HRV?  Well, as the title of the paper suggests and I already explained, the researchers observed that post-exercise vagal reactivation, another measure of aerobic fitness and autonomic control, improved as a result of training regardless of whether the subjects possessed a low or high pre-training resting HRV.  Takeaway #2, then, is that measuring indices of post-exercise vagal reactivation (via heart rate recovery and/or post-exercise HRV response) in addition to resting HRV likely provides a more complete picture of the aerobic and autonomic adaptations to training than resting HRV alone.  In addition, because it is possible for improvements in aerobic fitness to occur in the absence of changes in resting HRV, as the researchers note, “there may be some differences in the physiological determinants underlying the responses of these markers to training.”  In other words, the adaptations that result in the observed improvements (or lack thereof) in resting HRV and post-exercise vagal reactivation may have different physiological underpinnings.  The researchers go on to reference a 2007 paper by Dewland et al. that states that, “HRV would mostly express fluctuations of vagal outflow to the heart, whereas recovery of HR after an effort would reflect the mean cholinergic signaling at the sinoatrial nodal junction.”  Takeaway #3 is thus that these findings basically suggest that while resting HRV level reflects acute changes in parasympathetic tone, post-exercise vagal reactivation reflects the absolute level of parasympathetic outflow.

 

According to the researchers, this phenomenon could explain the lack of an increase in resting HRV despite the increase in post-exercise vagal reactivation in highly fit subjects/subjects with a high pre-training resting HRV: “When cardiac vagal control reaches high levels as a result of training, for example, further increasing vagal tone may eliminate respiratory modulation of the cardiac rhythm, leading to a saturation of HF power.”  In other words, once parasympathetic outflow reaches a certain level, the heart may cease responding to further increases.  In the literature, it has been suggested that this phenomenon may be due to the dose-response relationship of the heart to acetylcholine secreted by the vagal nerve at the sinoatrial node.  According to Goldberger et al. (2001), the heart’s dose-response relationship to acetylcholine “has been considered to be linear until its concentration reaches the level at which a further increase in acetylcholine concentration does not produce a change in the response. Rapid discharge of the vagal nerve during expiration may produce acetylcholine secretion intense enough to maintain a high parasympathetic effect even during inspiration, which results in the saturation of respiratory sinus arrhythmia and HF power.”  Thus, Takeaway #4 is that saturation of measures of resting HRV that might be interpreted as a lack of adaptation to training is a normal physiological phenomenon in people with high aerobic fitness and/or resting parasympathetic tone.

 

 

Research Paper #2

TitleSympathetic innervation of human muscle spindles

Researchers: Radovanovic D, Peikert K, Lindstrom M, and Domellof FP

Journal: J Anat

Publish Date: June 2015

 

If you read the first installment in my Intro to PRI series, then you’ll recall that I stated that while it is well-established that the Autonomic Nervous System (ANS) is capable of exerting indirect influence over skeletal muscle (via efferent neural circuits that pass through the reticular formation and the descending pathways of the reticulospinal tract), the evidence that the ANS can exert direct control over skeletal muscle is more limited.  There are several studies in animals that suggest that the Sympathetic Nervous System (SNS) can directly modulate metabolic and contractile properties of skeletal muscle (like resting muscle tone), but far less data to support that a pathway of this nature also exists in humans.  This is why I was excited (and grateful) to have this study forwarded to me by the brilliant Eric Oetter, since it provides new concrete evidence that the SNS does indeed exert direct influence over skeletal muscle.

 

Radovanovic et al. went about testing this theory by staining 232 muscle spindles from human lumbrical, biceps, levator scapulae, and deep neck muscles with antibodies against neuropeptide Y (NPY), NPY receptors, and tyrosine hydroxylase (TH).  (Antibodies are essentially proteins used by the immune system to identify and eventually neutralize specific pathogens and foreign molecules.)  The “identify” part is why they’re so commonly used in research, since exposing a sample to an antibody that binds to a specific compound (called an “antigen”) provides strong evidence for or against the presence of that compound in the sample.  In this case, five separate antibodies were used to detect three separate compounds:

 

– Neuropeptide Y is a neurotransmitter in the brain and ANS of humans that is mainly produced and stored in neurons of the SNS.  It is typically released in conjunction with the catecholamine and sympathetic stress hormone, norepinephrine, and is primarily responsible for vasoconstriction, though there is animal data to suggest that NPY also contributes to changes in muscle tension via muscle spindles.

– Neuropeptide Y receptors are, as the name indicates, responsible for binding NPY in target tissues and propagating its downstream effects.  There are four separate receptor subtypes, three of which were stained and tested for in this study.

– Tyrosine Hydroxylase is an enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine, more commonly known as L-DOPA.  This reaction is the rate-limiting step in a pathway that results in the synthesis of the catecholamines epinephrine (EPI) and norepinephrine (NE), as L-DOPA is converted to the neurotransmitter dopamine, which is a precursor to EPI and NE.  As such, TH is, as the researchers note, “a well-established marker for sympathetic nerve fibers.”

 

Upon analyzing the samples, the researchers divided each muscle spindle into three sections, according to methods used in previous studies: the “A region” was defined by the presence of the periaxial space, the “B region” was defined as the space on either side of the A region where the intrafusal fibers are closely surrounded by the capsule, and the “C region” was defined as the extracapsular portions of the spindles.  Specific immunofluorescence was detected in 12 out of 52 muscle spindles treated against NPY, in 17 out of 43 muscle spindles treated against NPY receptors, and in 31 out of 137 muscle spindles treated against TH.  The presence of NPY and NPY receptors was observed in the A and B regions of the muscle spindles, but not the C region.  The presence of TH, by contrast, was observed among the intrafusal fibers in the C region and (to a lesser degree) the far A and B regions, as well as “around the spindle vessel or capillaries found within the periaxial space and/or in small vessels in the capsular layers” in the A and B regions of several muscle spindles.  Most notably, in all three regions specific staining for NPY, NPY receptors, and TH was found on the nerves innervating the spindles as well as between the intrafusal fibers where no blood vessels could be seen.  As a result, the researchers concluded that, “this staining is most Iikely located on free nerve endings/nerves with varicose appearance.”  This finding is significant because it provides some of the first evidence of direct innervation of human muscle spindle fibers by sympathetic nerves.

 

Why does this matter?  To paraphrase the researchers’ comments in the Discussion section, it has been suggested that the ability of the SNS to modulate muscle spindle feedback to the CNS would allow the SNS to adjust motor acts during states of physical and emotional stress via motor reflex functions, coordination, and proprioception.  Specifically, since the precision and fine control of movements can be sacrificed in fight-or-flight reactions for stability and reliability of movement, depression of the feedback control of muscle length by increased sympathetic outflow may prove useful.

 

In addition, an established link between the SNS and muscle spindle discharge/regulation of resting muscle tone may help in understanding “motor and proprioceptive dysfunction seen under conditions of enhanced sympathetic activity, for example, during stress, which may lead to work-related myalgia and chronic muscle pain syndromes (Johansson et al. 1999; Passatore & Roatta, 2006), as well as the specific conditions grouped under the name of sympathetically maintained pain (e.g. Schwartzman & Kerrigan, 1990).”

 

As I commented to Eric, I wish that the researchers had included data on the distribution of the immunoreactive responses in the different muscles.  I think that it would have provided interesting insight into whether sympathetic influence over skeletal muscle is more prevalent in some muscle groups than others; this could have profound effects on our understanding of the development of various pathologies and how we treat them.  Alas, when I inquired with the researchers via email they responded that they did not have that data, so hopefully that is something that will be looked at in future studies.  In addition, it must be noted that this is a morphological study and not a functional study–the mere presence of sympathetic innervation does not prove that the SNS indeed has significant effects on muscle spindles.  Nonetheless, it does provides compelling evidence; hopefully the physiological effect that this innervation has on muscle spindles (if any) will be the subject of future research.

 

 

Totally Unrelated Article

Just when you thought it was impossible to sound any more nerdy, my totally unrelated article is a piece from The Independent on a Star Wars hero of old.  Or, more accurately, the actor who portrayed the hero of old.  Jake Lloyd, who avid Star Wars fans will recall played young Anakin Skywalker in Episode I: The Phantom Menace, recently decided to relive his reckless podracing days and took the local Charleston, South Carolina police on a lengthy chase that ended with him losing control of the vehicle and crashing into some trees.

You were the Chosen One, Anakin! You were supposed to destroy the Sith, not join them!

You were the Chosen One, Anakin! You were supposed to destroy the Sith, not join them! Bring balance to the Force, not leave it in Darkness! (photo from The Independent)

Luckily no one was harmed.  Lloyd was arrested and charged with reckless driving, failure to stop, resisting arrest, and driving without a license.  Apparently, having the highest recorded midichlorian count of all time doesn’t count for anything in the criminal justice system’s eyes.  No word yet on whether the Dark Side clouding Jake’s judgment was a factor in the incident.

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