Anneleen Malfliet, Roselien Pas, Raf Brouns, Joris De Win, Samar M. Hatem, Mira Meeus, Kelly Ickmans, Robbert-Jan van Hooff and Jo Nijs


Department of Physiotherapy, Human Physiology and Anatomy (KIMA), Vrije Universiteit Brussel, Brussels, Belgium


Background: Pain, fatigue, and concentration difficulties are typical features of chronic fatigue syndrome (CFS). The exact underlying mechanisms of these symptoms are still unknown, but available evidence suggests an important role for impaired pain modulation. As evidence also suggests that pain modulation is related to cardiovascular mechanisms, it seems logical to investigate whether cerebral blood flow (CBF) and heart rate variability (HRV) are altered in these patients.

Objectives: We aimed to investigate the role of the cardiovascular system in pain modulation and symptoms of CFS; the response of CBF and HRV to physical stress and their relation to the change in temporal summation (TS) of pressure pain and self-reported symptoms was evaluated.

Study Design: A controlled, randomized cross-over trial.

Setting: University Hospital Brussels.

Methods: Twenty CFS patients and 20 sedentary healthy controls were included in this study. In both of the groups, the change in TS of pressure pain, CBF (using transcranial Doppler), and HRV (using finger plethysmography) was examined during physical and emotional stress (to control for potential bias), as well as their association mutually and with self-reported symptoms of pain, fatigue, and concentrations difficulties.

Results: There was no significant interaction or group (F-values ranging from .100 to 1.862, P-values ranging from .754 to .181) effect in CBF or HRV parameters. HRV and CBF did change during physical exercise, but the changes did not differ between patients and controls. While pain scores during TS at the trapezius site reduced in the control group after the physical exercise protocol (P = .037), they did not change in the CFS group (P = .108), suggesting impaired pain modulation. There were no significant correlations between CBF, HRV, TS, and self-reported symptoms (all P-values of correlation analyses > .01).

Limitations: Although effect sizes were medium to large, the study sample was relatively low. Also, the mild nature of the exercise bout is discussable. Nonetheless, this mild exercise was able to provoke endogenous pain modulation in the control group, which endorsed a proper execution of the cycling exercise. Moreover, mild exercises are more applicable to daily physical activities in CFS patients than vigorous exercises.

Conclusion: These results seem to refute the previously suggested alterations of CBF/HRV in CFS patients. These cardiovascular parameters appear not to explain pain before, during, and following exercise.


Malfliet et al, Pain Physician, 2018 Jan; 21(1):E13–24


The study was funded by ME Research UK, a national charity funding biomedical research into Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Comment by ME Research UK

Chronic widespread pain is a fact of life for many people with ME/CFS, and around a third of patients report that pain limits their everyday activities and can be more disabling than fatigue. But we are only just beginning to understand what the causes might be.

One idea that may help to explain the mechanisms underlying the pain in ME/CFS is that of central sensitisation. Briefly, central sensitisation is an increased sensitivity of cells in the spinal cord and brain to stimuli such as pressure, heat, cold or chemicals. The concept is believed to underlie many chronic pain conditions, and has been extensively explored in fibromyalgia research.

A few years ago, Prof. Jo Nijs and colleagues at Vrije Universiteit Brussel in Belgium reviewed the scientific evidence for central sensitisation in ME/CFS, and concluded that its presence is consistent with many of the symptoms of the illness.

Since then, the team has since continued work in this area and has recently completed two studies looking at different aspects of central sensitisation in ME/CFS. The results of one strand of this work were published in 2018 in the journal Pain Physician.

Under experimental conditions, a painful stimulus has been shown to result in a decrease in cerebral blood flow (supplying the brain), leading to symptoms such as fatigue, dizziness, memory loss and headaches. These symptoms are also characteristic of ME/CFS and can be induced by physical exercise, suggesting that cerebral blood flow might play a significant role in the illness.

The researchers’ hypothesis was that ME/CFS patients may have an inadequate cerebral blood flow response to exercise, thereby altering pain sensitivity in these individuals. To test this, they asked 20 women with ME/CFS and 20 healthy, pain-free sedentary women to undergo a number of measurements while performing a 12-minute cycling test.

Throughout the experiments, cerebral blood flow was monitored using an ultrasound technique, while heart rate variability was measured using finger plethysmography. Heart rate variability is the natural variation in the intervals between consecutive heartbeats, and is another indication of cardiovascular health which has been shown to be abnormal in chronic pain. To control for the effects of emotional stress, the measurements were repeated while participants underwent an emotional stress test.

In addition, before and after each cycling or emotional stress test, the investigators measured the temporal summation of pressure pain. This is essentially a measure of the accumulation in pain experienced following repeated pressure stimuli, and is a useful way of evaluating the excitability of sensory nerves.

As perhaps expected, pain scores during the temporal summation test reduced following exercise in the healthy control group, indicating active modulation the painful stimuli. However, there was no change after exercise in the ME/CFS group, suggesting that pain modulation is dysfunctional in these patients.

Cerebral blood flow increased during physical exercise, while heart rate variability decreased, but these changes were what one would normally expect, and there were no differences between the ME/CFS patients and healthy controls. Furthermore, there were no significant associations between any of the parameters assessed.

So these results seem to contradict the original hypothesis of the study, and indicate that cerebral blood flow and heart rate variability changes after exercise are not altered in ME/CFS, and are unlikely to be the cause of the abnormal pain response in these individuals.

The researchers point out that this was a relatively small number of participants and the exercise was fairly mild, although the changes seen were fairly substantial, and normal pain modulation was seen in the healthy controls.

In conclusion, cerebral blood flow and heart rate variability do not appear to play a role in the increase in pain experienced following exercise in ME/CFS patients. It is disappointing when a promising idea leads to a dead end, but there are still plenty of other threads to pursue in ongoing research into central sensitization.