There seems to be no universally accepted definition of biological fatigue 1, although it is often defined as a reduction in the force output and/or energy-generating capacity of skeletal muscle after exertion, which may manifest itself as an inability to continue exercise or usual activities at the same intensity 1234. Fatigue is thought to be associated with a diminished contractile ability of muscles due to accumulation of lactic acid and depletion of energy stores (glycogen) 56 as well as with a reduction in motor neurotransmission delivered to skeletal muscle by the central nervous system (CNS), all of which can result in diminished force output 78. At the level of the CNS, precise mechanisms of fatigue are not well understood, although there is some evidence that it may be associated with diminished activity of a brainstem structure called reticular activating system 91011 and with increased levels of serotonin in the frontal cortex and hippocampus 1213.

A typical fatigue-related disorder is chronic fatigue syndrome (CFS), a complex and disabling condition characterized by extended periods of severe fatigue unexplained by known medical causes 14. Currently, there are no specific diagnostic tests and etiology of CFS remains elusive, although some progress has been made in elucidating its pathophysiology 1516. A number of studies have reported insufficient function of the hypothalamic-pituitary-adrenal (HPA) axis (e.g. lowered production of cortisol 1617) and a rather frequent occurrence of autonomic nervous system dysfunction in patients with CFS 1618. Neither lowered production of cortisol nor dysautonomia appears to be a causative factor in most CFS patients because cortisol injections and various therapeutic approaches to autonomic nervous system abnormalities have so far shown a rather limited effect on CFS symptoms 171920. Other findings about the pathophysiology of CFS suggest that abnormal fatigability in this disorder is associated with a reduced ability of the CNS to recruit motor neurons 212223 and with some biochemical abnormalities in skeletal muscle 242526. In addition, there is some evidence that CFS patients may have a low opioid tone (27282930, contrary evidence: 3132), as well as an increased level of serotonergic activity in the brain (333435363738, contrary evidence: 3940). The latter has been shown to correlate with fatigue in animal models of exercise-related fatigue 134142434445.

This paper describes a physiological treatment, namely, exposure to moderate cold, which could have a beneficial effect on some of the above-mentioned pathological changes as explained in more detail below.

It is known that small amounts of stressful or harmful agents can be beneficial for animals, a phenomenon known as hormesis 4647. In particular, exposure to cold can transiently reverse several physiological changes that are often associated with CFS and therefore, the hypothesis is that repeated cold stress can reduce fatigue in CFS patients. The following is detailed theoretical evidence that appears to support this hypothesis.

1) Insufficient function of the HPA axis has been found to correlate with fatigue 48, for example, a lowered plasma level of stress hormone cortisol (secreted by adrenal glands) is one of the few consistent endocrine changes found in CFS in numerous studies 17, although the level of cortisol in CFS patients is within the normal range and therefore cannot be used as a diagnostic tool 16. Cold stress is known to transiently activate the HPA axis 4950 as evidenced by a brief increase in the plasma levels of adrenocorticotropic hormone 5152 and beta-endorphin (the latter is a secreted by the pituitary gland) 5354, as well as a modest elevation in the level of cortisol 5556. Some studies reported no significant change in cortisol levels following cold stress 5758, which may be due to gender and diurnal variation of this effect 5556. In addition, there is some evidence of another deficiency of the HPA axis in various disorders associated with fatigue: hypofunction of corticotropin-releasing hormone-producing neurons (located in hypothalamus) 485960. Therefore, "exercising" the HPA system by repeated exposure to cold could potentially restore its normal function in CFS, or at least increase the net HPA activity (without a change in baseline activity 61) and, possibly, reduce fatigue. For example, repeated cold stress has been shown to enhance HPA axis responsiveness to other stressors 6263 and to enhance cortisol responses to cold stress 64.

2) Cold hydrotherapy is known to produce a significant analgesic effect 656667, which could be beneficial in CFS, where pain symptoms are rather common 6869. The cold stress-induced analgesia is believed to be mediated by increased production of opioid peptide beta-endorphin, which is an endogenous pain-killer 53557071.

3) Exposure to cold is known to increase metabolic rate: for instance, head-out immersion in cold water of 20°C almost doubles metabolic rate, while at 14°C it is more than quadrupled 72. Theoretically, the high metabolic rate may accelerate 7374 the process of recovery of muscle tissues from fatigue in CFS 24257576 and some studies indeed show accelerated muscle recovery following immersion in cold water 7778. In combination with cold-induced analgesia described above, the increased metabolic rate would be expected to reduce fatigue by both improving muscle recovery after exertion and by reducing muscle pain 79. A cold-induced increase in cerebral metabolic rate 80 may also be consistent with reduced fatigue (781 contrary evidence: 8283).

4) There is evidence that exposure to cold can activate some components of the brainstem arousal system 848586 (also known as the reticular activating system 8788). In particular, cold stress appears to stimulate activity of serotonergic neurons of raphe nuclei 84899091 and noradrenergic neurons of locus ceruleus 8492, the situation that would be consistent with activation of behavior and enhanced somatomotor function of the brain 98793949596. This could be beneficial in CFS because abnormally high fatigability of CFS patients appears to be mediated by a reduction in the ability of the CNS to generate motor neurotransmission 212223. It is noteworthy that in polio survivors and patients with multiple sclerosis, the presence of minor lesions in the reticular activating system correlates with severe chronic fatigue 1097. This kind of lesions can also cause lethargy in laboratory animals 98898. Reduced electrical activity in the reticular activating system also appears to correlate with fatigue in laboratory animals 99100101. At present, there is no evidence that CFS patients have lesions in the reticular activating system 9102, although there is some limited evidence of abnormalities of metabolism, blood flow, and electrical activity in the brainstem 81103104105, the anatomical site of the reticular activating system 8788.

5) While the increased level of serotonin in the brainstem 85 is thought to correlate with arousal and increased cortical activity 1194106, high levels of serotonin in other areas of the brain, particularly in the hippocampus and frontal cortex, are believed to be associated with fatigue, which is the basis of "the serotonin hypothesis of central fatigue" 12134142434445. Whether high levels of brain serotonin actually cause fatigue or are merely an epiphenomenon is a subject of controversy 1213. With respect to cold stress, studies suggest that it reduces the level of serotonin in most regions of the brain 107108 except the rostral brainstem 85, which would be consistent with diminished fatigue 1213 and could be beneficial in CFS (333435363738, contrary evidence: 3940).

6) Exposure to cold typically causes activation of the sympathetic nervous system (SNS) 49109, which, theoretically, can be undesirable in CFS because there is evidence of hyperactivity of some components of the SNS in CFS patients 18110. It should be noted that physical exercise is also known to transiently activate the SNS 111 and graded exercise appears to be beneficial in CFS 112113. Therefore, brief cold stress will not necessarily have adverse effects on CFS patients (more detailed discussion can be found in Additional file 1).

7) As described previously, brief cold hydrotherapy appears to be safe and does not seem to have either short-term or long-term adverse effects on health 109114115116117. The effect of moderately cold hydrotherapy (16–23°C) on core body temperature is expected to be very small and therefore hypothermia is hardly a concern 118119120.

To test the hypothesis, a treatment is proposed that consists of adapted cold showers (20°C, 3 minutes, preceded by 5-minute gradual adaptation) twice a day. The detailed study protocol can be found in Additional file 2. Statistically insignificant preliminary evidence is described in Additional file 3.

If statistically significant studies confirm (or refute) the hypothesis, this could further our understanding of the mechanisms of physiological fatigue and possibly contribute to the development of new therapeutic approaches to CFS.

The author(s) declare that they have no competing interests.

The idea and writing are solely N.A.S.'s.