Dr. Erin Cvejic is a Senior Lecturer in Biostatistics at the School of Public Health, University of Sydney, Australia, and an Adjunct Lecturer in Psychiatry at UNSW Sydney. Over the last eight years he has written several articles on the issue of unrefreshing sleep and cognitive function in people with myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS).
I had an opportunity to interview Dr. Cvejic for Phoenix Rising.
How did you get involved in the field of ME/CFS research?
Dr. Erin Cvejic:
I completed my Ph.D. in the field of experimental psychology, but was eager to pursue a program of research that had greater potential for real-world impact that could eventually help people.
A post-doctoral position became available at the University of New South Wales (UNSW) to work with Associate Professor Uté Vollmer-Conna and Professor Andrew Lloyd. This provided the opportunity to develop and contribute to existing projects in the field of ME/CFS — most notably to analyses of the Dubbo Infection Outcomes Study.
To date, this study provides the sole validated model for studies of the onset and evolution of ME/CFS following infection.
My doctoral work had equipped me with the necessary technical skills to acquire, process, and analyse high-dimensional data, with my post-doctoral appointment providing the opportunity to apply these skills to a range of ME/CFS research projects.
The Dubbo Infection Outcomes Study (DIOS) was a National Health and Medical Research Council (NHRMC) and Mason Foundation-funded prospective cohort study run in the Dubbo region (New South Wales, Australia) and surrounding towns, which ran from 1999.
Participants were recruited into DIOS after presenting to their family physician with an acute febrile illness, with serological testing for Epstein Barr Virus, Ross River Virus, or Q-Fever infection. They were recruited as soon as possible after the initial onset of the acute febrile phase of their illness.
After initial intake, participants were followed up at semi-regular intervals until recovery. Some of them did not recover within the follow-up period. The main cohort comprises 502 participants.
There have been several publications that describe or detail DIOS or its findings, some of which I have listed below:
- Initial cohort description (BMJ)
- Case-control study of cytokine production alterations (Clinical Infectious Diseases)
- Synergistic effect of cytokine polymorphisms on acute sickness response to infections (Clinical Infectious Diseases)
- Contribution of individual psychological and psychosocial factors to symptom severity and time-to-recovery (Brain Behaviour and Immunity)
- Genetic associations of fatigue (Brain Behaviour and Immunity)
- Inflammatory and genetic correlates of neurocognitive disturbances associated with acute illness (Brain Behaviour and Immunity)
DIOS (and the Sydney Infectious Outcomes Study [SIOS], which builds on DIOS and was a project I ran as part of my time at UNSW) is included as part of the International Collaborative on Fatigue Following Infection (COFFI)
Unrefreshing sleep is a core symptom of ME. Anecdotal evidence from people with ME suggests that unrefreshing sleep may be a key factor in the degree of pain, fatigue or poor social functioning they experience. Does your research support this?
Sleep is the great equaliser — regardless of someone’s clinical status, having unrefreshing (or insufficient) sleep, even if only for a few nights, can take a toll on various aspects of the way we feel and function.
It is not then surprising that experiencing this constantly impacts heavily on an individuals’ physical, social, emotional, and cognitive functioning. Over the five years of working with people with ME/CFS, this was absolutely a consistent anecdotal theme.
As researchers, one of the challenges we find in this area lies in how to measure sleep quality or the refreshing nature of sleep when no “gold standard” objective measure exists yet. We need to rely on other measures of observable behaviour that serve as proxy measures (e.g., time to sleep onset, number of awakenings during the night), or use subjective self-reported information.
Over the years, a number of explanations have been put forward by different researchers to explain the unrefreshing sleep/insomnia that is experienced by people with ME. These explanations range from hypothalamic dysfunction to nocturnal hypoglycaemia, melatonin dysfunction, or sleep apnea, amongst many others.
In the Journal of Clinical Sleep Medicine, you and a group of colleagues published an article about unrefreshing sleep in people with ME. You put forward the hypothesis that nocturnal parasympathetic activity reflected by heart rate variability (HRV) is diminished in individuals with ME, suggesting hyper-vigilant sleep.
Can you explain this concept?
There are quite a few elements at play here, so I will try and explain the concept without getting too bogged down in the technical details.
Heart rate variability (HRV) is the small variations in the time between successive heart beats. This can be used as a non-invasive way to measure activity of the autonomic nervous system (ANS), from which we can calculate an index of parasympathetic nervous system activity (the “rest-and-digest” division of the ANS).
When we sleep, we go through several different “sleep stages”, each characterised by changes in neural and autonomic activity (including parasympathetic activity as measured by HRV) which are cycled through over the course of the period of sleep.
In “healthy” non-disordered sleep, HRV increases during the transition from wakefulness to sleep onset. It then increases gradually through two different sleep stages (non-rapid-eye-movement-1 [NREM1] and non-rapid-eye-movement-2 [NREM2]). HRV peaks during slow-wave sleep (SWS), which is generally considered to be the most restorative stage of sleep. Finally, it decreases during rapid eye movement (REM) sleep — often to levels at or below wakeful rest.
Previous studies have suggested that people with ME/CFS have reduced HRV during the night, but few have explored whether this reduction is specific to any particular sleep stages.
We hypothesised that people with ME/CFS may not be “switching off” during those deeper, restorative stages of sleep, which in turn may be contributing to the feeling of waking unrefreshed.
What measurable differences did you observe between how people with ME/CFS sleep and how healthy controls sleep?
We used a portable sleep monitoring device (SleepProfiler) to record a range of parameters while participants slept in their own homes, as well as administering some self-reported questions in the morning when they woke up.
In terms of sleep timing, although people with ME/CFS spent a comparable amount of time asleep compared to control participants, they spent a longer time in bed, took longer to initially get to sleep, and then spent almost twice as long awake after sleep onset (and therefore had lower “sleep efficiency”).
Notably, people with ME/CFS actually spent a greater proportion of their time in the slow wave sleep stage than controls, but rated their sleep quality and level of refreshment when they awoke as lower than controls. Consistent with previous studies, people with ME/CFS had lower HRV on average across the night.
When we looked at each of the sleep stages individually, we identified reduced HRV during NREM2 and SWS (but no differences during daytime wakeful rest, wake before sleep onset, NREM1 or REM sleep stages) for people with ME/CFS compared to controls.
In the conclusion to your study it states that autonomic hyper-vigilance during the deeper, recuperative stages of sleep is associated with poor quality sleep and self-reported well-being. How might this finding help provide medical interventions to alleviate unrefreshing sleep in people with ME?
As the study was cross-sectional, we can demonstrate associations but cannot establish causal links. To do this would require longitudinal studies that monitor people with ME/CFS over time, or experimental (interventional) studies. What our findings do provide is a potential novel target for such interventional studies.
The exact nature of what these interventions could (or should) be is outside the scope of my own expertise. But it could include pharmacological, electrical stimulation (e.g., vagus nerve stimulation [VNS] or the less invasive transcutaneous auricular VNS) or manual (e.g., focused deep breathing) interventions that increase parasympathetic nervous system activity — either in general, or during particular sleep stages.
What further research is needed to help develop treatments for unrefreshing sleep in people with ME?
While our reported research findings are novel, they do require independent replication (something that many studies of the pathophysiology of ME/CFS lack) and preferably in a much larger sample.
Further, a caveat of this work is that while our people with ME/CFS were functionally limited compared to demographically similar healthy controls, they were not at the most extreme end of the severity spectrum. All were capable of traveling to and attending our assessment laboratory to be given instructions and the equipment.
A better understanding of the neural and autonomic aspects of sleep across the ME/CFS severity spectrum is needed, and an understanding of whether these differences relative to healthy controls are further exaggerated in people with ME/CFS who have greater functional impairment.
Finally, as I suggested before, a better understanding of whether alterations in parasympathetic activity during sleep is causally linked to the symptomatology, or simply a by-product of some other mechanism of the illness, is still needed.
Dr. Cvejic’s latest article on sleep and people with ME/CFS can be found below:
Parasympathetic activity is reduced during slow-wave sleep, but not resting wakefulness, in patients with chronic fatigue syndrome.
Journal of Clinical Sleep Medicine, vol. 16, issue 1, online Jan 15, 2020.