Jo Nijs

Jo Nijs, PT, MT, PhD, is a Belgian professor of physiotherapy at the Vrije Universiteit Brussel and physiotherapist/manual therapist at the University Hospital Brussels. He is Scientific Chair of the executive committee of the Pain, Mind and Movement Special Interest Group of the International Association for the Study of Pain (IASP) and holder of the Chair 'Exercise immunology and chronic fatigue in health and disease' funded by the European College for Decongestive Lymphatic Therapy. Nijs plays a leading role in the Pain in Motion research group, an international collaborative that studies the interplay between chronic pain and movement. While he advocates graded exercise as a treatment for ME/CFS, he argues that it should be preceded by a stabilization phase in which patients pace themselves to find the right balance between rest and activity. Nijs is mostly known for espousing the theory of central sensitization : he suspects ME/CFS to be a dysfunction of the central nervous system, characterized by a heightened sensitivity to pain and other stimuli such as light, sounds and chemical substances.

Under the guidance of De Meirleir: a biomedical approach
After graduating in rehabilitations sciences, Nijs started working as a physiotherapist in private practice where he came into contact with ME/CFS patients. He was intruiged by their condition and decided to do a PhD about it. At the Vrije Universiteit Brussel (VUB)Nijs started working under the guidance of Dr. Kenny De Meirleir, who is known for his biomedical approach to the illness. In the mid-2000s De Meirleir and Nijs published a number of studies together regarding the infectious and immunologic aspects of ME/CFS, including mycoplasma infection and defects in the 2.5A Synthetase RNase L antiviral pathway.

The Chronic fatigue syndrome activities and participation questionnaire (CFS-APQ)
In his PhD, Nijs took on the task of devising a new activities questionnaire for ME/CFS. Many of the surveys that were used at the time such as the Short Form 36-Item Health Survey (SF-36), Karnofsky scores and the Symptom Checklist (SCL-90) were not specific to this illness, so they might overlook important aspects of ME/CFS-disability. By analyzing various questionnaires retrospectively, Nijs came up with 26 new questions that map out the particular limitations ME/CFS-patients face (e.g. making the bed, preparing meals, reading etc.). The questionnaire, called the ‘Chronic Fatigue Syndrome Activities and Participation Questionnaire’ (CFS-APQ), showed good construct validity and internal consistency but was unable to differentiate between ME/CFS- and fibromyalgia-patients.

Daily physical activity in ME/CFS
Nijs has researched how a reliable measurement of the daily activities of ME/CFS patients could be obtained. He has agued that the ‘International Physical activity questionnaire-short form’ (IPAQ-sf) might be inappropriate since it focused mostly on strenuous efforts and vigorous activities, which are hardly performed by ME/CFS patients. As an alternative, Nijs proposes to use more direct measures such as an accelerometer that tracks step counts and an activity diary. In a 2011 study, Nijs used these techniques to follow up on the activities of 67 ME/CFS patients and 66 healthy controls. Patients were significantly less active compared to sedentary controls. The study was however unable to confirm the fluctuating activity pattern of ME/CFS patients; they did not concentrate their activities more in peaks, as was suggested by Leonard Jason. Nijs’ study showed a correlation between time spent being more active on the one hand and pain, fatigue and concentration difficulties on the other hand. According to the authors “this can be interpreted as more physical activity resulting in more complaints and more fluctuations in the fatigue.” A 2013 study by Nijs’ research group showed that there was no significant correlation between activity levels and cognitive performance in 31 ME/CFS patients. Another study suggested increased physical activity to have beneficial effects on sleep quality in ME/CFS.

The value of exercise testing in ME/CFS
Nijs has worked on the issue of exercise testing in ME/CFS. Because of post-exertional malaise, it is not always possible for ME/CFS-patients to reach their VO2 Max. Based on the exercise testing of more than 200 ME/CFS-patients, Nijs demonstrated (in succession to Mullis et al. ) that other values such as peak workload or VO2 submax can be used to correctly predict VO2 Max.

In a review of exercise testing in ME/CFS, Nijs concluded that despite some conflicting studies, “the weighted available evidence points towards a reduced physiological exercise capacity in CFS". The authors concluded that a lack of uniformity in diagnostic criteria, could explain for the differences between studies. Yet, while ME/CFS patients showed a reduced physiological exercise capacity, there was only a minor correlation between exercise test results and employment rate, suggesting this might not be a reliable measure to assess disability.

Exercise limits
Nijs tested the use of exercise limits as a method to prevent post-exertional setbacks in ME/CFS patients. In a 2008 study, patients had to estimate the amount of exercise (walking) they could handle without triggering post-exertional malaise. Because it was assumed patients would overestimate their capacities, this amount was reduced by 25% if the person was having a good day and 50% if she was having a bad day. Another exercise limit involved a maximal heart rate (the heart rate that corresponded with a respiratory exchange ratio of 1 on an exercise test), that patients could not exceed during walking. Despite these precautions, patients still experienced a worsening of their symptoms after exertion. Because this relapse was short-lived, Nijs concluded that the exercise limits had worked and prevented important health status changes.

Two years later the Nijs’ research group conducted a similar study. Twenty-two ME/CFS test-subjects had to perform a submaximal exercise test and a paced cycling regime. Patients could only do 75% (on a good day) or 50% (on a bad day) of what they thought they could handle without triggering a relapse, while a maximal heart rate was set at 80% of their anaerobe threshold. Once again, despite these precautions, patients experienced a worsening of their condition after both pacing and the submaximal exercise test, a deterioration that was not seen in healthy controls.

A symptom-contingent exercise program
In 2008, Nijs collaborated with Karen Wallman and Lorna Paul to work out an exercise program for ME/CFS that took into account post-exertional malaise. Although it was still instructed to exercise progressively and to build up stamina, the key advice was that patients should listen to their body while doing so. They could for example change their schedule if they were having a bad day. Nijs et al. criticized earlier approaches that used a time-contingent approach where patients have to follow a pre-set plan, regardless of how they were feeling. "“Early approaches to graded exercise therapy advised patients to continue exercising at the same level when they developed symptoms in response to the exercise. This led to exacerbation of symptoms and adverse feedback from patients and patient charities.”"To prevent relapses, Nijs, Paul and Wallman advised to build in a long stabilization phase in which patients had to find the right balance between rest and activity. With this approach, symptom fluctuation has to be reduced to a manageable level first. Only when the patient feels that she can cope with a certain level, can it be decided to build up exercises. This form of self-management combined with graded exercise was criticized by Lucy Clark and Peter White. They emphasized that a graded exercise program has to be time-contingent to be effective: "“[…] a central concept of GET is that patients maintain their level of exercise as much as possible even after a CFS/ME setback. This is to reduce the many negative consequences of rest and allow the body to habituate to the increase in activity.”"In 2011, Nijs & Wallman collaborated with Leonard Jason, who had helped develop the Energy Envelope Theory, and Ellen Goudsmit, who had studied the use of pacing. Together they worked out a ‘consensus document’ about the main principles of the pacing in ME/CFS. According to the authors there was a “lack of information on the efficacy of time-contingent protocols in people with evidence of neurological or immunological disease.” Nijs and colleagues proposed an approach where patients limited their activities in response to internal cues of post-exertional malaise. Patients were only advised to gently increase their activity levels if their health had stabilized and they were close to about 60 to 70% of their former functioning.

A U-turn towards time contingent-exercise
In 2012 (after the first results of the controverial PACE-trial were published) the research group of Nijs made a U-turn and started advocating a time-contingent form of graded exercise. This position was criticized by Tom Kindlon who pointed out that studies supporting graded exercise therapy were almost solely based on subjective measures. Nijs et al. responded: "“We agree with Tom Kindlon that such evidence is based on self-report rather than on objective measures, but in the end of the day, patients prefer treatments that make them feel better (subjectively) over treatments that improve objective blood results (but at the same time leave them feeling sick).”"Regarding the argument that numerous patients surveys had shown that GET can have detrimental effects on the health of ME/CFS patients, Nijs et al. replied: "“Such surveys have value, but from a scientific viewpoint, it remains an unanswered question who filled out these surveys (nothing but patients with ME ⁄ CFS diagnosed by a physician?), to what extent selection bias, suggestion and recall bias have contributed to the study findings, etc. One cannot exclude the possibility that the survey results reflect the difficulty of clinicians around the globe to apply exercise therapy for patients with ME ⁄ CFS.”"

Activity pacing self-management (APSM)
According to Nijs, the PACE-authors made a mistake by placing GET in opposition to pacing. He argues the two can and should be used together, in what he calls ‘Activity Pacing Self-Management’ (APSM). In a first phase, pacing is used to stabilize the health condition of the patient and let her know that exercise doesn’t always have to result in a relapse. Only when this is achieved (and this can take several weeks) is it advised to move on to a second, graded phase where a progressive time-contingent approach is used. According to APSM, activities should only be increased incrementally according to a personalized, pre-set schedule. Sufficient rest periods are included after each activity to prevent serious relapses.

Nijs tested his APSM approach in a 2015 randomized controlled trial in which the control group received relaxation therapy. The results were favorable, though no objective performance measures were used. The study was also rather small as only 16 ME/CFS patients were involved in the experimental APSM group, of which 4 (25%) stopped the treatment prematurely.

Kinesiophobia and catastrophizing: testing the fear-avoidance model
Nijs has investigated the fear avoidance model in ME/CFS. In this model, originally developed for chronic low back pain, it is believed patients worsen their condition by holding an irrational fear of movement called kinesiophobia. When Nijs tested this in 64 ME/CFS patients, the results contradicted the theory:"“Our data do not support the view that kinesiophobia is associated with disability (ie, activity limitations and participation restrictions) in patients with CFS who experience pain. Our results, therefore bring into question the clinical importance of kinesiophobia.”"Two other studies by Nijs, both published in 2004, did find a relationship between kinesiophobia and activity limitations measured with the CFS-APQ, but there was no correlation with exercise test results.

Another concept of the fear avoidance model is catastrophizing, a tendency to interpret events negatively or to assume the worst will happen. In a group of 36 ME/CFS patients, Nijs found that “catastrophizing accounted for 41% of the variance in bodily pain.” These results were questioned by Tom Kindlon who pointed out the study could not prove the assumed direction of causation. The lack of correlation between catastrophizing and the large drop in employment rate seen in the ME/CFS patients studied, suggests other factors might be more important in determining their condition."

In 2011, Nijs collaborated with Gijs Bleijenberg to test the effect of kinesiophobia and catastrophizing in ME/CFS before a threatening activity, in this case, stair climbing. Both factors were unrelated to symptom expectancies, but they did correlate with actual stair climbing performance, i.e. the time required to complete the task. Two years later the study was repeated using a larger sample of 49 ME/CFS patients. Findings contradicted those of the previous study as kinesiophobia and catastrophizing were no longer related to stair-climbing duration.

In 2012, Nijs’ research group concluded that catastrophizing is a long-term predictor of pain in ME/CFS patients. In a 2013 review Nijs concluded that fear of movement was a highly prevalent and a clinically relevant factor in ME/CFS.

Searching for a PEM-biomarker
In several studies, the Nijs research group investigated the nature of post-exertional malaise, often with funding of ME research UK (MERUK). One of their studies looked at immune factors after exercise and found a relationship between the change in complement C4a split product levels and the increase in pain and fatigue. According the authors this suggested C4a has the potential to become a biomarker for post-exertional malaise in ME⁄CFS. In two other studies, the Pain in Motion research group showed that heart rates of ME/CFS patients recovered more slowly after exercise compared to controls. A 2018 study looked at cerebral blood flow and heart rate variability after exercise, but did not reveal meaningful results.

With or without FM
In 2014, Nijs researched the recovery of muscle in function and its relationship to cognitive performance in ME/CFS. The most important finding was the difference between patients with and without comorbid fibromyalgia. In the former group, recovery of upper limb muscle function was found to be slower and a significant predictor of cognitive performance. In a study comparing various ME/CFS criteria using objective measures, Nijs and colleagues found that neither the old ME-criteria, nor the Canadian Consensus criteria selected patients were worse off than those who fulfilled the Fukuda-criteria. Only the subgroup with comorbid fibromyalgia scored significantly worse on objective tests, as the recovery of their muscles was slower than in ME/CFS patients without FM.

Chronic pain might be more disabling than chronic fatigue
Most of Jo Nijs’ research focuses on the treatment of chronic pain. He argues that fatigue has been arbitrarily put forward as the primary symptom of ME/CFS patients. In his own research, he found that pain explained as much of the activity limitations and participation restrictions of ME/CFS patients as fatigue, concluding that chronic pain might thus be more disabling than chronic fatigue in this disease.

An increased reactivity of the central nervous system
Nijs suspects pain in ME/CFS might be explained be the process of ‘central sensitization’ (CS). This refers to a heightened responsiveness of the central nervous system (CNS) to nociceptive stimuli. Because no lesions or neural damage can be found to explain the pain of ME/CFS patients, it is assumed that the CNS overreacts to normal stimuli, seeing them as more threatening than they are. According to Nijs this might explain why ME/CFS patients often perceive painful stimuli as more intense (hyperalgesia) or experience pain after normally innocuous stimuli (allodynia). Nijs has argues that CS might also explain other symptoms besides pain, such as the sensitivity to light, sound and various chemicals that many ME/CFS patients display.

Secondary hyperalgesia
Researchers use various methods to evaluate if the CNS overreacts to stimuli. The easiest way is to measure pain thresholds all over the body, using an algometer. The research team of Nijs tested this in 30 ME/CFS patients who were suffering from chronic pain. Pain pressure thresholds were significantly lower compared to those of the control group when pain-free areas of the body were tested (a phenomenon known as secondary hyperalgesia). In an additional study it was shown that ME/CFS patients experienced more pain following heat stimuli.

Wind-up and temporal summation
Another method to test CS is to look at ‘temporal summation’, also called wind up. This refers to the process where neurons of the CNS respond to a repeated stimuli with an increased reactivity. If one quickly repeats a fixed noxious stimulus 10 times, then the last one will be experienced as more painful that the first. Researchers can measure the amount of ‘wind up’ of the neurons by looking at the difference between the first and the last stimulus. In chronic pain conditions like fibromyalgia, that difference is greater than in normal controls, suggesting these patients experience a heightened form of temporal summation. Nijs’ research group tested this procedure in 48 ME/CFS patients, but the results were ambiguous. There was only a difference in windup compared to control subjects if the pain stimuli were administered to the finger and not to the shoulder.

Conditioned pain modulation: pain inhibits pain
Central sensitization doesn’t necessary involve an increased susceptibility to stimuli. It can also be explained by a defect in the inhibitory pain pathways of the body. One highly researched mechanism in this respect is called ‘conditioned pain modulation’ or CPM (an older name is ‘diffuse noxious inhibitory control’). This refers to the fact that pain in one area of the body can decrease pain in another area. Nijs’ research group tested this in 2009 using heat stimuli showing that conditioned pain modulation was normal but delayed in ME/CFS patients. In two other studies, Nijs’ research group tested CPM using the pressure of an inflatable occlusion cuff as the conditioning stimulus. In both cases there were no differences between ME/CFS patients and healthy controls.

Endogenous pain inhibition after exercise
Another way to induce endogenous inhibition is to exercise. When healthy people exercise, their brain induces the production of endorphins that increase pain thresholds. In some chronic pain patients like fibromyalgia and whiplash associated disorders, this endogenous pain inhibition is defective and pain thresholds decrease shortly after exercise (i.e. they experience more pain while they should be feeling less). In 2004, Whiteside et al. first showed this defect in ME/CFS patients, though their study only involved five patients. The Pain in Motion group of Nijs and colleagues confirmed these results in two of their studies. While pain thresholds increased in normal controls, they decreased in the ME/CFS patient group. These studies however, only included ME/CFS that were suffering from chronic pain. It therefore remains uncertain whether similar results will also show up in ME/CFS patients that do not have comorbid FM.

Criteria for the classification of central sensitization pain
Jo Nijs is regarded as an international expert in central sensitization. He has researched CS in patients with chronic spinal pain, chronic low back pain, shoulder pain , knee osteoarthritis , cancer-related pain and chronic whiplash. In 2014, he was first author of a consensus paper in which 18 experts set out criteria for the diagnosis of central sensitivity. After neuropathic pain has been ruled out, the criteria propose to assess if the severity of pain is “disproportionate to the nature and extent of injury and pathology”. This is an obligatory criterion; if pain is not disproportionate, then it doesn’t involve CS. Secondly it is proposed to look at the pain distribution; if pain is widespread and diffuse then the clinician can diagnose CS in his patient. If this is not the case, then the clinician can use the central sensitization inventory (CSI), a questionnaire that has been developed to assess CS and mostly looks at secondary symptoms like sensitivity to light, bad sleep and concentration problems. If the patient scores 40 or more on the CSI, than the clinician can make the diagnosis of CS.

Treating central sensitization
Together with long-time collaborator Mira Meeus, Nijs wrote two reviews on the treatment of CS. Special attention goes to medications that target central pathways of the pain response. One example is acetaminophen (paracetamol) that reinforces the inhibitory serotonergic pathway. Meeus & Nijs tested this in ME/CFS patients with comorbid fibromyalgia. Though pain thresholds rose, there was no influence on temporal summation or conditioned pain modulation.

Selective serotonin reuptake inhibitors (SSRI) also activate the serotonergic descending pathways. In a 2011 study, Meeus & Nijs gave their test subjects intravenous SRRI (citalopram) but the trial had to be stopped prematurely, since the medication caused too many side-effects.

Opioids form another option, although these drugs are rather controversial because they can lead to addiction and cause selective pain sensitization. In 2017 Meeus & Nijs tested morphine and naloxone (an opioid antagonist) against a placebo, but the results were rather bleak: "“[...] neither morphine nor naloxone influenced deep tissue pain, temporal summation or CPM. Therefore, these results suggest that the opioid system is not dominant in (enhanced) bottom-up sensitization (temporal summation) or (impaired) endogenous pain inhibition (CPM) in patients with CFS/FM or RA.”"There are other therapeutic options to treat central sensitization like N-methyl-D-aspartate –receptor antagonists (e.g. ketamine), GABA-antagonists  (e.g. pregabalin) or a ketogenic diet. Nijs & Meeus also propose exercise therapy and emphasize that a time-contingent approach is preferable in treating CS:"“A symptom-contingent approach may facilitate the brain in its production of nonspecific warning signs like pain, whereas a time-contingent approach may deactivate brain-orchestrated top-down pain facilitatory pathways.”"The authors do however caution that this approach might not work in every CS-patient group: "“[...] some patients with CS pain, including those with chronic whiplash associated disorders, chronic fatigue syndrome and fibromyalgia, are unable to activate endogenous analgesia following exercise. It remains to be established whether long-term exercise therapy accounting for the dysfunctional endogenous analgesia is able to ‘treat’ CS in these patients.”"

Pain neurophysiology education
Before starting exercise therapy in CS patients, Nijs promotes the use of ‘pain neurophysiology education’, in which the patient is told that pain doesn’t always involve nociceptive input and vice versa. Nijs emphasized that this method might convince patients wary of a psychological approach:"“The innovative aspect of pain physiology education is the use of physiology (i.e., the mechanism of central sensitization) to change perceptions and cognitions. This makes it appropriate even for CFS cases reluctant to the biopsychosocial model.”"Tom Kindlon questioned ‘neurophysiology education’ since it advises to ignore chronic pain while little is known about the mechanisms and etiology of pain in ME/CFS. Kindlon also criticized one of the primary justifications for the pain management program; that it might increase therapy adherence - that is adherence to graded exercise therapy:"“Until a particular exercise regimen has been shown to be safe in CFS, in the interim it seems questionable, and indeed possibly unethical, to have adherence to such an intervention as the goal of any educational program.”"

Is it unethical to question GET?
In 2013, Nijs’ position towards GET was questioned by Twisk & Arnoldus. Nijs reposted that it was ‘unethical’ to downplay the effectiveness of GET for ME/CFS patients:"“[…] at the group level, there is no doubt that graded exercise therapy and cognitive behavioural therapy are effective treatments for ME ⁄ CFS. Saying the reverse might prevent clinicians from applying these treatments to their ME ⁄ CFS patients. In the absence of alternative treatment options (recall that besides graded exercise therapy and cognitive behavioural therapy, no other treatment has proven to be beneficial to ME ⁄ CFS patients), this would be unethical.”"Nijs also suggested that opposition to GET might be fuelled by a conflict of interest of patient advocates: "“At the same time, one can imagine that refuting the evidence favouring conservative interventions for ME ⁄ CFS might be inspired by a conflict of interest (e.g. personal interest in biopharmaceutical companies or as a ME ⁄ CFS patient running for a disability payment).”"

Are ME/CFS and fibromyalgia the same?
The publications of Nijs and collagues often lump ME/CFS and fibromyalgia together as if they are one disorder. For example in their 2013 book on the treatment of persistent fatigue directed at clinicians (written in Dutch), no distinction is made between ME/CFS and fibromyalgia. The rationale behind this is that both disorders have similar symptoms and are (supposedly) characterized by central sensitization. Most researchers however emphasize the importance of dealing with ME/CFS and fibromyalgia separately, since there might be biological differences between the two.

Research studies

 * 2002, High prevalence of Mycoplasma infections among European chronic fatigue syndrome patients. Examination of four Mycoplasma species in blood of chronic fatigue syndrome patients (Full Text)
 * 2002, Activity Limitations and Participation Restrictions in Patients with Chronic Fatigue Syndrome—Construction of a Disease Specific Questionnaire (Abstract)
 * 2003, Associations between bronchial hyperresponsiveness and immune cell parameters in patients with chronic fatigue syndrome (Abstract)
 * 2003, Deregulation of the 2,5A Synthetase RNase L Antiviral Pathway by Mycoplasma spp. in Subsets of Chronic Fatigue Syndrome (Full Text)
 * 2003, Comparison of Activity Limitations/Participation Restrictions Among Fibromyalgia and Chronic Fatigue Syndrome Patients (Abstract)
 * 2003, Immunophenotyping Predictive of Mycoplasma Infection in Patients with Chronic Fatigue Syndrome? Abstract)
 * 2003, Monitoring a Hypothetical Channelopathy in Chronic Fatigue Syndrome: Preliminary Observations (Abstract)
 * 2004, Review - Gulf War Veterans: Evidence for Chromosome Alterations and Their Significance (Abstract)
 * 2010, Unravelling the nature of postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: the role of elastase, complement C4a and interleukin-1beta. (Full text)
 * 2011, Tired of being inactive: a systematic literature review of physical activity, physiological exercise capacity and muscle strength in patients with chronic fatigue syndrome (Abstract)
 * 2012, Pacing as a strategy to improve energy management in myalgic encephalomyelitis/chronic fatigue syndrome: a consensus document (Full text - downloadable pdf)
 * 2013, The role of mitochondrial dysfunctions due to oxidative and nitrosative stress in the chronic pain or chronic fatigue syndromes and fibromyalgia patients: peripheral and central mechanisms as therapeutic targets? (Abstract)
 * 2014, Altered immune response to exercise in patients with chronic fatigue syndrome/myalgic encephalomyelitis: a systematic literature review (Full Text)
 * 2016, Editorial Comment - Rehabilitation for patients with myalgic encephalomyelitis/chronic fatigue syndrome: time to extent the boundaries of this field (Full Text)
 * 2017, Influence of morphine and naloxone on pain modulation in Rheumatoid Arthritis, Chronic Fatigue Syndrome/Fibromyalgia and controls: a double blind randomized placebo-controlled cross-over study (Abstract)
 * 2017, Endogenous Pain Facilitation Rather Than Inhibition Differs Between People with Chronic Fatigue Syndrome, Multiple Sclerosis, and Controls: An Observational Study (Full Text)
 * 2017, The Role of Autonomic Function in Exercise-induced Endogenous Analgesia: A Case-control Study in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Healthy People (Full Text)
 * 2018, Cerebral Blood Flow and Heart Rate Variability in Chronic Fatigue Syndrome: A Randomized Cross-Over Study (Full Text)
 * 2018, Exercise-induce hyperalgesia, complement system and elastase activation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - a secondary analysis of experimental comparative studies
 * 2019, Relationship Between Exercise-induced Oxidative Stress Changes and Parasympathetic Activity in Chronic Fatigue Syndrome: An Observational Study and in Patients and Healthy Subjects

Talks and interviews

 * 2014, Treatment of central sensitization pain: targeting bottom-up or top-down mechanisms?
 * 2015, Exercise therapy for chronic pain: retraining mind & brain

Online presence

 * RearchGate
 * PubMed
 * The World Confederation for Physical Therapy Biography

Learn more

 * Pain in Motion Research Group