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The Autonomic Nervous System and ME/CFS. The HRV patterns in CFS patients suggest they have increased sympathetic nervous system (SNS) and decreased parasympathetic nervous system activity (PNS).

The SNS plays an excitatory role - it boosts heart activity during stressful situations to ensure adequate flows of oxygen and nutrients get to our tissues. The CDC and others believe the stress response is impaired in CFS and we’ve heard a lot about the HPA axis but the other branch of the HPA axis, the SNS, is equally important. When we are cold, for instance, the SNS is partially responsible for maintaining our core body temperatures by shunting blood flows away from our skin. When we stand SNS activity keeps blood from pooling in our legs.

The parasympathetic nervous system, on the other hand, plays an inhibitory role; it regulates heart and other activity when we're at rest. One might think of the SNS as a kind of warrior that helps the body react to stressful situations and the PNS as a kind of caretaker that puts the body in a restful mode so that it can heal. Could an imbalance in these systems cause many of the symptoms in ME/CFS? Let’s find out.

As a patient group we are well known for our ‘edginess’. I have long noticed that particularly after I exercise I am prone to fly off the handle. If someone calls to me when I’m working in the garden I just about jump out of my skin. My mind seems to be all over the place and my body seems far from relaxed - my muscles, particularly in my upper body, seem so tight and stiff that I tend to breathe shallowly. I have to work to concentrate.

The ability to control oneself, for instance, to not eat too much or to not eat the wrong things, to control one’s emotions, to make decisions and follow through on them, is called self regulation. We take these activities for granted but there is evidence that some people are better self-regulators than others.

These researchers believe that HRV levels reflect one’s self regulatory capacities; that the lower the HRV the more difficult it is to exert control over certain aspects of one’s behavior (e.g. overeating), emotions (anger, sadness) and to make decisions and perform cognitively. High HRV levels, on the other hand, have been associated with better performance in cognitive tests, less negative emotions during stress, more effective coping with stress and better impulse control.

How is HRV connected with ‘self regulation’? It turns out that the parts of the brain that control autonomic nervous system activity (ANS) are very similar to those we use when we control our emotions, make decisions and engage in cognitive activity. This part of the brain, which is called the ‘central autonomic network’ (CAN) is connected to or located in the prefrontal cortex. If you’ve been reading Phoenix Rising for long you may recognize these brain structures as CFS researchers are interested in each of them; they are the anterior cingulate, insula, amygdale and hypothalamus.

The Study. These researchers wanted to know if our autonomic nervous system is indeed activated when we engage in these types of activities. If it is this will suggest that problems in autonomic nervous system functioning may not only affect physical factors such as heart rate variability but also the emotions, cognition and ‘self regulation’. It will establish a connection between the mind and the body – or perhaps more accurately between the body and the mind.

They used one of the most powerfully evocative stimuli known to man to test their theory; warm chocolate chip cookies. One group was ordered to ignore the chocolate chip cookies placed before them and eat carrots while other got to eat the chocolate chip cookies. Both groups rated themselves on their experiences and then did cognitive tests to determine if engaging in self regulation affected their cognitive abilities and endurance.

The Findings. Higher HRVs in the carrot eaters indicated that self regulation does activate the ANS. Simply forcing people to not eat the (warm) chocolate chip cookies caused the ANS to turn on and this showed up in higher HRV readings.

The carrot eaters also performed more poorly than the chocolate chip eaters at the cognitive test. This suggested that the self regulatory system is like a muscle that one can wear out – by denying themselves the chocolate chip cookies the study participants slightly weakened their ability to think.

The people who had higher resting HRVs to begin with showed greater persistence or endurance in trying to solve the cognitive tests. This suggests that low HRV is associated with reduced mental endurance, i.e. fatigue.

Relevance to CFS. This study suggested that people with lower HRVs (such as ME/CFS patients) may have more difficulty ‘self regulating’, i.e. have more trouble controlling their emotions, inhibiting compulsive behavior (such as eating), and performing cognitively.

How to connect reduced cognition and impaired control with low HRV? Remember the idea that low parasympathetic nervous system (PNS) activity may prevent the body from relaxing properly during sleep? This authors suggest that an unrelaxed body can affect the mind as well. We apparently don’t have enough energy for both the body and the brain to function at optimal levels – one of them must turned down for the other function well. In order for the brain to engage in calm reflective thought the energy needs of the body need to be turned down.

This, of course, is the job of the PNS. If PNS activity in ME/CFS is indeed low it’s possible it may never turn down the activity levels of the body down enough for the brain to engage in calm, reflective thought or to easily engage in ‘self regulatory’ behaviors.

Interestingly, a model incorporating the above scenario has already been suggested by ME/CFS researchers. Some CDC researchers participating in the Pharmacogenomics studies suggested that the ‘energy set point’ of the brains of CFS patients is too low. (See

Several central nervous studies imply that an energy starved brain may be present in CFS. The low cerebral glucose levels, low blood flows, low energy production, high lactate levels and grey matter atrophy are the kinds of findings that might be expected in people with ‘energy starved’ brains.

The low HRV readings in ME/CFS suggest that low levels of parasympathetic nervous system (PNS) are present. As noted earlier PNS regulates many bodily functions when we are at rest or asleep. But what if it never really steps in? Could an overactive sympathetic nervous system and underactive PNS also contribute to the unrefreshing sleep ME/CFS patients report? Could the ‘wired but tired’ feeling ME/CFS patients experience come from the excitatory side of the autonomic nervous system (the SNS) always being turned on and the inhibitory or ‘relaxing’ side of it (the PNS) being always turned down. Is this why many ME/CFS patients never really rest when they sleep?

There is some evidence it could be. The CDC found low HRV in one set of ME/CFS patients during sleep in one of its Pharmacogenomics studies and a Japanese researcher reported at the 2007 IACFS Conference that HRV tests indicated that PNS activity was decreased during sleep in ME/CFS patients. In just the last week the CDC published a full paper on HRV and the sympathetic nervous system functioning during sleep.

Increased heart rates and lower HRVs were strongly associated with activity limitations. They also found increased levels of a main SNS factor, norepinephrine (noradrenaline) and reduced levels of aldosterone. The increased heart rate, lower HRV and increased norepinephrine levels were all indicators of increased sympathetic nervous system activity. Their findings also suggested that not all these abnormalities were due simply to reduced activity levels.　

This is the second time the CDC has found lowered levels of aldosterone, a hormone that could contribute to the blood volume, inflammation, oxidative stress and cardiovascular problems in ME/CFS. A year ago Pharmacogenomics study authors zeroed in on aldosterone as a possible indicator that the energy set point of the ME/CFS patient’s body is altered. See A Selfish Brain in CFS.

Conclusion: We can add sleep to our growing list of problems autonomic nervous system dysfunction could contribute to in CFS.

This group from Norway used much the same protocol that Dr. Peckerman and Dr. Cheney have; they put their patients on a Tilt board and measured their heart and cardiovascular functioning. They came to similar results but their conclusions were very different. (This study used young people who were chronically fatigued but did not require that they met the more restrictive 1994 International criteria for ME/CFS; thus they will be referred to chronically fatigued not ME/CFS patients)

It appeared that their hearts were pumping faster in order to maintain a higher blood pressure upon tilting. The researchers noted that a significantly decreased stroke index (p<.05) indicated their hearts were pumping less blood than their healthy counterparts. It appears that their hearts compensated for the less blood available to them by pumping faster. The increased heart rate, blood pressure and TPRI suggest increased sympathetic nervous system activity.

Diastolic dysfunction. The end diastolic volume index (EDVI) test indicated these patients had reduced diastolic filling when they were lying down. The heart first expands to fill with blood before it ejects it. The diastolic process is the filling stage. Because more blood is available to the heart when one is lying down, problems with filling show up more readily in that position. A similar pattern (poorer diastolic function while supine) was found in Dr. Peckerman’s study.

Acceleration Index. These chronically fatigued patients also had an increased ‘acceleration index’ when standing. The acceleration index measures the rate at which the heart ejects blood. Because the heart actually has less blood available to it when we’re standing (some of it falls to the legs) it may need to pump faster in order to keep blood flowing to the brain, but it doesn’t have to pump harder. Thus the acceleration index decreases when we stand. It decreased in the healthy controls but it actually increased in the CFS patients.

The increased acceleration index in the chronically fatigued patients indicated that their heart muscles were contracting more forcefully at the very time they had less blood to pump; i.e. their hearts were ‘overworking’. (Could this cause ‘heart pounding’ sensations ME/CFS patients commonly experience?) Since the SNS controls the force of the hearts contractions these authors suggested that this ‘overwork’ was due to an overactive sympathetic nervous system.

Cardiac Damage or Autonomic Nervous System Dysfunction? - Dr. Cheney believes that heart muscle damage causes diastolic abnormalities he has been observing. These researchers believe the heart muscle is not damaged but that it’s getting bad signals. Specifically they believe that the increased heart rates, increased total peripheral resistance index, reduced diastolic filling and increased acceleration index were caused by increased sympathetic nervous system activity (SNS).

They are not the first heart researchers to suspect the SNS or PNS involvement in the cardiovascular problems in chronically fatigued or ME/CFS patients. Dr. Peckerman posited that underactive PNS activity may have caused the decreased stroke volume he saw.

The Cause of the Increased SNS Activity  – The authors believe that the increased SNS activity could be due either to problems in the peripheral nerves that connect to the heart or to problems with the cardiovascular control mechanisms in the brainstem. They note, however, that low blood volume or deconditioning could cause many of the same results.

The brainstem is the integration point for many signals coming from the body. It processes them and then sends them up to the brain. An autopsy revealed inflammation in the brainstem of a CFS/ME patient in the UK who died of dehydration. Apparently the control mechanism involving hydration failed in her brainstem.

The blood volume scenario is fascinating. If low blood volume is present the hearts must pump faster to maintain blood flows to the tissues. We know that low blood volume is present in many ME/CFS patients. Interestingly, while low blood volume can result in increased SNS activity, increased SNS activity can also cause low blood volume!

Provisos. This study has two provisos; the subjects were adolescents and they had chronic fatigue not CFS; that is they had severe fatigue but not necessarily other symptoms associated with CFS (joint, muscle pains, etc.).

The Study. In this study several ANS factors (norepinephrine, epinephrine, metaepinephrine) and dopamine were measured while one hand was slowly cooled in water. They expected skin blood flows to decrease and levels of the ANS agents to increase as the hands steadily cooled.

Findings. Even before the cooling test commenced increased norepinephrine levels and increased heart rates suggested ME/CFS patients had (yes) increased sympathetic nervous system activity. The ME/CFS patients did not begin to turn off the blood flows to their skin until their hands were much cooler than those of the controls and during cooling their skin blood flows decreased much more slowly. According to eardrum temperature measurements the ME/CFS patients’ core body temperatures were higher than the controls.

Explanations: Several things could explain these findings. The increased core body temperatures could explain the slowed skin cooling response. If the CFS patients body temperatures were increased they would be less quick to turn off their cooling mechanism – than would people with normal body temperatures. Alternately these abnormalities might reflect problems with constricting the blood vessels – something that has been found before in some CFS patients. Whatever the case this study again suggests that autonomic nervous system abnormalities are present in ME/CFS.

Background. In primary biliary cirrhosis (PBC) the bile ducts of the liver are slowly destroyed. The fatigue seen in primary biliary cirrhosis has several intriguing qualities; it is not severe in all patients and it is not a function of the severity of the disease; i.e. some PBC patients with low levels of bile duct destruction have more fatigue than others with high bile duct destruction. This pattern – which is found in multiple sclerosis as well – indicates the fatigue is not due to the bile duct destruction per se but to some process associated with it, a process that some people are susceptible to and others are not.

One could argue a similar scenario occurs in CFS/ME. The Dubbo studies, for instance, have shown that infection triggers CFS/ME in some people but not others. It’s possible that the same process may be causing fatigue and other problems in CFS, as well as fatigued PBC, multiple sclerosis and post-cancer patients. This and other studies suggest that low HRV could have something to do with it.

PBC is a nasty disease with high enough mortality rates that researchers have begun to look specifically at what is causing these patients to die. Surprisingly enough, they’ve found many PBC patients are not dying of liver failure or liver cancer but of sudden cardiac failure (heart attack). This is what directed their attention to HRV; low HRV levels have been associated with an increased risk for sudden cardiac death in healthy people.

Study Purpose. They wanted to know if HRV was reduced in biliary cirrhosis patients, and, if so, whether it was associated with high rates of fatigue. One interesting note - in their broad outlines these patients look very much like CFS patients; all were female and most had a high waist:hip ratio.

Study Findings: PBC patients had significantly lower HRV levels than did the healthy controls but more importantly for our purposes, the patients with with very high fatigue had lower HRV than did those with lower fatigue.

Just as in CFS patients most of the HRV abnormalities occurred in the lower frequency domains – those involved in sympathetic/parasympathetic nervous system activity. The authors suggested this reflected abnormal neuro-hormonal or neuro-endocrine activity– two subjects the CDC and others are currently interested in in CFS. Intriguingly the authors zeroed in on serotonin neurotransmission in particular – another subject of high interest in CFS.

Serotonin and CFS. At the 2007 IACFS conference, Dr. Lange stated that CFS patients appear to have problems with serotonin activity in two areas of the brain, the hippocampus and the anterior cingulate. At the same conference the leader of the Japanese effort on CFS, Dr. Kuratsune, singled out serotonin in his theory of CFS pathophysiology as well

 The second study found that fatigued PBC patients tended to have both low HRV and orthostatic intolerance – another common finding in ME/CFS (!). This study concluded that autonomic nervous system dysfunction probably played a significant role in producing the fatigue found in many PBC patients. Furthermore they suggested a similar process occurs in CFS/ME (yes they called it CFS/ME), multiple sclerosis and Parkinson’s disease.

Possible Causes of Autonomic Nervous System Dysfunction in PBC, CFS and Others

They proposed it could be due to deconditioning or basal ganglia dysfunction

Basal Ganglia Dysfunction  

Studies indicate that impaired detoxification (a natural consequence of bile duct destruction) in PBC patients has lead to manganese deposition in the basal ganglia - a part of the brain involved in autonomic nervous system regulation. This is an exciting finding given evidence of basal ganglia abnormalities in ME/CFS. Recent reports suggest that the CDC, in its first foray into brain imaging in ME/CFS, has also found basal ganglia dysfunction in their ME/CFS patients.

Some Remarkable Similarities: These research efforts establish more commonalities between CFS and fatigued PBC patients. Beside low HRV, female predominance, and increased waist:hip ratios, fatigued PBC patients also display increased rates of orthostatic intolerance, basal ganglia abnormalities and heavy metal loading – all of which may occur in CFS.

The Newton research group is now examining the role that impaired blood flows to the muscles may play in producing the fatigue found in many PBC patients and they have broadened their scope to assess cognitive dysfunction – two areas of great interest in CFS. Its almost uncanny how similar the paths several research groups are taking to determine the cause of fatigue and other problems in PBC, CFS and other diseases. This suggests they are all on the right track and presents hope for ME/CFS patients.

Not all ANS studies have found abnormalities in ME/CFS. While one CDC study did find low HRV in one set of ME/CFS patients during sleep another found no differences in the levels of ANS agents called catecholamines (epinephrine, norepinephrine, etc.) in ME/CFS. Still, the interest in the ANS in ME/CFS and other fatiguing diseases is increasing and the future should tell us much more about how much of a role this part of our nervous system plays in producing fatigue and other problems.

Ongoing Studies

A fantastic study from the Neuroimmune RFA Grants will explore the intersection between low blood volume, reduced blood flows to the tissues, oxidative stress and SNS activity. Dr. Biaggioni will examine if microcirculatory problems involving the SNS, nitric oxide and other factors shut down the blood vessels and thus impede blood flows to the tissues. This could explain a lot in ME/CFS.

Another study from the Neuroimmune RFA by Dr. Fletcher will examine the SNS-immune connection – a connection that has been well established in the literature but has yet to receive any interest in ME/CFS. Both branches of the stress response, the HPA axis and the SNS, regulate immune system. There is some evidence that the HPA axis does a poor job in doing so. If Dr. Fletcher finds abnormalities as well, this could mean that the immune system is getting it from both sides in ME/ CFS.