Just before Xmas 2010 I was overcome by a bout of Swine Flu. After the holiday, which was a complete blur due to sickness, I went back to work in January feeling very weak. Over the course of the next 8 months, up until my diagnosis of ME, I was afflicted by a bewildering variety of symptoms which caused a great deal of physical and mental suffering. The symptoms which affected me the most in some respects were the unrefreshing sleep and acute insomnia which made me fear that I would lose my job. I was working over 50 hours a week in a very stressful and physically demanding job which I increasingly struggled to keep onto partly due to the lack of sleep/unrefreshing sleep. I noticed a considerable decline in my ability to do some of the basics of my job as I struggled to concentrate and felt increasingly unable to keep up with the very demanding target driven regime at work. Trying to teach a class of 30 teenagers can be hard work at the best of times but when you’re getting 4 hours of unrefreshing sleep it can be a nightmare. Once I received my diagnosis of ME one of the first things I asked my GP for was a course of sleeping tablets to help me overcome the worst of the insomnia.
Since my diagnosis unrefreshing sleep and insomnia have been my constant companions. Sadly, none of the health professionals and scientists I’ve spoken to over the years have been able to offer much insight as to what is causing this and what might help treat it.
There is lack of research into this important aspect of ME. As we all know sleep is the foundation stone of good health for anyone. Those of us who live with dysfunctional sleep all the time it can be very debilitating and have a considerable knock on effect on the other symptoms of our illness.
In a 2012 paper which investigated sleep abnormalities in pwME Professor Bruck noted that they experience insomnia, disturbed sleep, an increased number and duration of intermittent awakenings during the night besides the non-restorative nature of their sleep. She further observed that pwME have a disrupted sleep architecture which is found in the reduced slow wave sleep of pwME compared to healthy controls.
A 2023 review of sleep studies found that ME/CFS patients spend a longer time in bed, take longer to fall asleep, spend more time awake after they’ve fallen asleep, have reduced sleep efficiency, decreased stage 2 sleep, more Stage 3 sleep, and longer rapid eye movement sleep latency. That study suggested that altered sympathetic and parasympathetic nervous system activity was keeping people with ME/CFS from getting good sleep.
That conclusion echoed the results of several studies. Back in 2007, a CDC study found that a similar sympathetic ANS dominance prevailed in ME/CFS patients during sleep. A small 2018 study concluded that people with ME/CFS had lower parasympathetic tone in deep sleep (less “rest and digest” during deep sleep) and higher sympathetic nervous system activity (more “fight or flight) overall while asleep. Finally, in 2020, an Australian sleep study concluded that “Autonomic hypervigilance during the deeper, recuperative stages of sleep is associated with poor quality sleep and self-reported wellbeing.”; i.e. the deep, restorative stages of sleep weren’t as deep or restorative in ME/CFS as they were in healthy controls.
Professor Dorothy Bruck
I recently spoke with Professor Dorothy Bruck about her insights into some of the sleep issues which affect people with ME.
Emeritus Professor Bruck’s main area of research interest and expertise is sleep and sleep health. She has been thinking about, and working with, many aspects of sleep for about 40 years. Professor Bruck has had a long academic career at Victoria University in Melbourne, with particular expertise in sleep/wake behaviour, mental health, chronic fatigue syndrome, waking thresholds and human behaviour in emergencies. She has an international research reputation, with over 120 peer-reviewed full-length publications, $2.5 million in competitive grant income, dozens of invited international and national professional speaking engagements, and numerous awards. Professor Bruck’s research has been regularly featured in the media, including Time Magazine and New Scientist. Apart from her academic work Professor Bruck has worked as a sleep psychologist and most recently she was Chair of the Sleep Health Foundation (Australia). She is now semi-retired and lives in the Far South of Tasmania, Australia.
Dr. Bruck’s larger 2018 follow-up erythromycin/probiotic trial in ME/CFS patients with high gram-negative bacterial counts (Streptococcus) again suggested that the gut may play a role in the poor sleep found in ME. The study found that reduced Streptococcus levels were associated with better sleep (fewer awakenings, greater sleep efficiency and quality) and cognition (attention, processing speed, cognitive flexibility, story memory, and verbal fluency). (Mood and fatigue, however, were not altered.)
Other studies have shown that people with insomnia typically have dysregulated gut flora – a common finding in ME/CFS. Similarly, reduced levels of short-chain fatty acids such as butyrate have been found in both ME/CFS and insomnia. Studies suggest that alterations in the gut microbiome may even be contributing to the changes in circadian rhythms and sleep patterns that Dr. Bruck outlines below, and some studies suggest that gut flora or microbiome manipulation could help. A study using a probiotic bifidobacterium called Longum 1714 improved sleep quality and increased energy/vitality in healthy controls.
5-Hydroxytryptophan (5-HTP) was able to improve gut health and sleep in older adults who were experiencing poor sleep. Similarly, a recent animal study found that sleep deprivation both altered the gut flora and increased anxiety levels. Melatonin, a common sleep supplement used in ME/CFS, may work, when it does, in part by benefitting the gut flora. On the whole, though, a review of probiotic and prebiotic use to enhance sleep concluded that while some evidence suggests that altering the gut flora may help with sleep, more and better studies are needed.
How did you get involved in the field of M.E. research?
I have been a sleep researcher since undertaking my Honours degree in 1978, with a particular interest in disorders of excessive daytime sleepiness such as narcolepsy. In 2010 my teenage son was diagnosed with ME/CFS, which left him bed and recliner bound for about 10 of the next 15 years. Remarkably he has now improved sufficiently to hold a job with flexible hours. While he was very sick I met ME/CFS clinicians and researchers in Melbourne and we managed to obtain funding for a series of studies focussing on sleep and gut microbes. We have since published this research with Melinda Jackson and Amy Wallis as the first authors.
In October 2021 the National Institute for Clinical Excellence in the UK issued a new guideline for the treatment and care of people with M.E. This guideline recognised that for a diagnosis of M.E. to be made people had to suffer from four key symptoms. Unrefreshing sleep or non-restorative sleep is recognised as one of the core symptoms of the illness. The sleep disturbance experienced by pwME can be broken down into two categories: disturbed sleep patterns and unrefreshing sleep. Despite this, there is remarkably little research being conducted into this core symptom of the illness. Amongst the limited studies that have been done into this issue there appears to be no consensus as to what is causing the sleep dysfunction among pwME. How would you explain the sleep dysfunction experienced by pwME?
I think the dichotomy between disturbed sleep patterns and unrefreshing sleep is quite useful, keeping in mind however, that a pwME/CFS may have both. Neither are unique to ME/CFS.
Disturbed sleep patterns (where the person is unable to sleep when they want to) may arise from co-morbidities with ME/CFS, such as sleep apnea, insomnia and circadian rhythm disorders. Sometimes the latter two disorders may begin with, or be perpetuated by, behavioural changes in sleep/wake behaviours that lead to disturbed sleep.
Unrefreshing sleep occurs across the population, both in people with a range of clinical conditions and sometimes in people with no diagnosed medical problem. It is usually described by self-report. It is likely to be a very heterogenous phenomenon. A study by El-Mekkawy Leqaa et al (2022) noted a significant change in delta wave power (deep sleep) in the temporal brain region in those with unrefreshing sleep arising from sleep apnea, compared to controls. In our review of sleep patterns in ME/CFS (Jackson and Bruck, 2012) we concluded that technological advances in the assessment/monitoring of sleep may lead to further understanding of how the micro-structure of sleep may differ between those with self-reported unrefreshing sleep compared to quality sleep.
Anecdotal evidence from some pwME and a few research studies suggest that the sleep disturbance that people experience can have a significant impact on their cognitive abilities. How prevalent is this? What may be causing the sleep disturbance to impact people’s cognitive function?
Any ongoing sleep disturbance will affect a person’s cognitive abilities. Attention, concentration, memory and reaction time may all be affected in some way depending on (a) their overall health (physical and/or mental) and (b) individual differences in how poor sleep quality affects an individual. It seems reasonable to think that a pwME/CFS that includes the symptom of brain fog would be affected by the cognitive impairments we associate with poor sleep in an additive way.
Is there any evidence that non-restorative sleep is impacting other symptoms which pwME experience such as pain?
I believe that ANY ongoing poor quality sleep, whether it is unrestorative sleep or disturbed sleep will affect a range of ME/CFS symptoms, possibly all. Pain and brain fog are likely to be particularly affected.
With regard to pain we know that sleep loss increases the experience of pain. Krause et al (2019) showed that acute sleep deprivation amplifies pain reactivity within the human primary somatosensory cortex, lowers pain thresholds and that ‘even modest nightly changes in sleep quality within an individual determine consequential day-to-day changes in experienced pain’.
Having a clearer understanding about the pathophysiology of non-restorative sleep in pwME may lead to better treatment options for patients. Are you aware of any clinical trials which are exploring treatment issues for non-restorative sleep in pwME?
Unfortunately not.
Many people with M.E. report that there is a direct link between the degree of their non-restorative sleep and the depth of the fatigue they experience the next day. What research has been done into this particular issue and what were their findings?
To my knowledge this issue has not yet been investigated in pwME/CFS. However, cognitive fatigue as measured on a range of working memory tests (Benkirane et al, 2022) found that the main effect of sleep fragmentation was to increase subjectively reported fatigue rather than reduce cognitive test performance. This study, using healthy participants, highlights the difficulties in objectively measuring fatigue, as many people can rally their mental resources for short-term testing in a research setting. This may have little to do with how fatigue is experienced in real-life settings.
What further research is required to investigate the causes of non-restorative sleep and the impact this has on cognitive function, fatigue and pain in pwME?
There are so many unanswered questions. The first step for any such research is to have a standard definition of non-restorative sleep. Is it a certain level of sleep fragmentation? Sleep disruption? Lower EEG delta power? Subjective report in the light of an otherwise normal sleep diary? Is reported non-restorative sleep the same for someone with sleep apnea, vivid dreaming or ME/CFS?
Many thanks go to Cort Johnson for his important contribution to this article.
Since my diagnosis unrefreshing sleep and insomnia have been my constant companions. Sadly, none of the health professionals and scientists I’ve spoken to over the years have been able to offer much insight as to what is causing this and what might help treat it.
There is lack of research into this important aspect of ME. As we all know sleep is the foundation stone of good health for anyone. Those of us who live with dysfunctional sleep all the time it can be very debilitating and have a considerable knock on effect on the other symptoms of our illness.
In a 2012 paper which investigated sleep abnormalities in pwME Professor Bruck noted that they experience insomnia, disturbed sleep, an increased number and duration of intermittent awakenings during the night besides the non-restorative nature of their sleep. She further observed that pwME have a disrupted sleep architecture which is found in the reduced slow wave sleep of pwME compared to healthy controls.
A 2023 review of sleep studies found that ME/CFS patients spend a longer time in bed, take longer to fall asleep, spend more time awake after they’ve fallen asleep, have reduced sleep efficiency, decreased stage 2 sleep, more Stage 3 sleep, and longer rapid eye movement sleep latency. That study suggested that altered sympathetic and parasympathetic nervous system activity was keeping people with ME/CFS from getting good sleep.
That conclusion echoed the results of several studies. Back in 2007, a CDC study found that a similar sympathetic ANS dominance prevailed in ME/CFS patients during sleep. A small 2018 study concluded that people with ME/CFS had lower parasympathetic tone in deep sleep (less “rest and digest” during deep sleep) and higher sympathetic nervous system activity (more “fight or flight) overall while asleep. Finally, in 2020, an Australian sleep study concluded that “Autonomic hypervigilance during the deeper, recuperative stages of sleep is associated with poor quality sleep and self-reported wellbeing.”; i.e. the deep, restorative stages of sleep weren’t as deep or restorative in ME/CFS as they were in healthy controls.
Professor Dorothy Bruck
I recently spoke with Professor Dorothy Bruck about her insights into some of the sleep issues which affect people with ME.
Emeritus Professor Bruck’s main area of research interest and expertise is sleep and sleep health. She has been thinking about, and working with, many aspects of sleep for about 40 years. Professor Bruck has had a long academic career at Victoria University in Melbourne, with particular expertise in sleep/wake behaviour, mental health, chronic fatigue syndrome, waking thresholds and human behaviour in emergencies. She has an international research reputation, with over 120 peer-reviewed full-length publications, $2.5 million in competitive grant income, dozens of invited international and national professional speaking engagements, and numerous awards. Professor Bruck’s research has been regularly featured in the media, including Time Magazine and New Scientist. Apart from her academic work Professor Bruck has worked as a sleep psychologist and most recently she was Chair of the Sleep Health Foundation (Australia). She is now semi-retired and lives in the Far South of Tasmania, Australia.
The Gut-Sleep Connection in ME/CFS
Noting that increased levels of faecal gram-positive bacteria have been associated with ME/CFS symptoms (cognitive problems – concentration, excessive irritability, confusion as well as impaired motor coordination), Dr Bruck’s 2015 study used erythromycin to reduce down gram-positive bacteria in individuals with high levels of them. The antibiotic substantially improved sleep times and sleep quality in some individuals, but other symptoms remained.Dr. Bruck’s larger 2018 follow-up erythromycin/probiotic trial in ME/CFS patients with high gram-negative bacterial counts (Streptococcus) again suggested that the gut may play a role in the poor sleep found in ME. The study found that reduced Streptococcus levels were associated with better sleep (fewer awakenings, greater sleep efficiency and quality) and cognition (attention, processing speed, cognitive flexibility, story memory, and verbal fluency). (Mood and fatigue, however, were not altered.)
Other studies have shown that people with insomnia typically have dysregulated gut flora – a common finding in ME/CFS. Similarly, reduced levels of short-chain fatty acids such as butyrate have been found in both ME/CFS and insomnia. Studies suggest that alterations in the gut microbiome may even be contributing to the changes in circadian rhythms and sleep patterns that Dr. Bruck outlines below, and some studies suggest that gut flora or microbiome manipulation could help. A study using a probiotic bifidobacterium called Longum 1714 improved sleep quality and increased energy/vitality in healthy controls.
5-Hydroxytryptophan (5-HTP) was able to improve gut health and sleep in older adults who were experiencing poor sleep. Similarly, a recent animal study found that sleep deprivation both altered the gut flora and increased anxiety levels. Melatonin, a common sleep supplement used in ME/CFS, may work, when it does, in part by benefitting the gut flora. On the whole, though, a review of probiotic and prebiotic use to enhance sleep concluded that while some evidence suggests that altering the gut flora may help with sleep, more and better studies are needed.
How did you get involved in the field of M.E. research?
I have been a sleep researcher since undertaking my Honours degree in 1978, with a particular interest in disorders of excessive daytime sleepiness such as narcolepsy. In 2010 my teenage son was diagnosed with ME/CFS, which left him bed and recliner bound for about 10 of the next 15 years. Remarkably he has now improved sufficiently to hold a job with flexible hours. While he was very sick I met ME/CFS clinicians and researchers in Melbourne and we managed to obtain funding for a series of studies focussing on sleep and gut microbes. We have since published this research with Melinda Jackson and Amy Wallis as the first authors.
In October 2021 the National Institute for Clinical Excellence in the UK issued a new guideline for the treatment and care of people with M.E. This guideline recognised that for a diagnosis of M.E. to be made people had to suffer from four key symptoms. Unrefreshing sleep or non-restorative sleep is recognised as one of the core symptoms of the illness. The sleep disturbance experienced by pwME can be broken down into two categories: disturbed sleep patterns and unrefreshing sleep. Despite this, there is remarkably little research being conducted into this core symptom of the illness. Amongst the limited studies that have been done into this issue there appears to be no consensus as to what is causing the sleep dysfunction among pwME. How would you explain the sleep dysfunction experienced by pwME?
I think the dichotomy between disturbed sleep patterns and unrefreshing sleep is quite useful, keeping in mind however, that a pwME/CFS may have both. Neither are unique to ME/CFS.
Disturbed sleep patterns (where the person is unable to sleep when they want to) may arise from co-morbidities with ME/CFS, such as sleep apnea, insomnia and circadian rhythm disorders. Sometimes the latter two disorders may begin with, or be perpetuated by, behavioural changes in sleep/wake behaviours that lead to disturbed sleep.
- For example, the fatigue associated with ME/CFS may lead to irregular sleep patterns where the person sleeps episodically (i.e. naps) across the 24 hour period and the circadian (24 hour) rhythm becomes confused. The person’s sleep quality suffers because they are no longer getting their main sleep period in a single block at the time the body clock expects it. A different pattern that we may see in ME./CFS is Delayed Sleep Phase Disorder, where the person is very much an ‘evening’ type, going to bed late and getting up late. People who get insufficient outdoor light during the daytime are particularly susceptible to this. Sometimes their body clock begins to ‘free run’ and each night they may go to bed later than the previous night, so their ‘day’ may be 25 hours instead of 24 hours.
- Behavioural changes that may precipitate insomnia include decreased sleep drive (or sleep pressure) arising from reduced activity, significant napping during the day, reduced exposure to daytime light, worry at night about the consequences of having ME/CFS, and/or longer time in bed trying to sleep than the actual sleep duration that person may need. For example, due to boredom and/or feelings of fatigue, turning lights off from 9pm to 8am each night (i.e. 11 hours trying to sleep) when the person may only need 8 hours of actual sleep. Best if lights-out time equals sleep time required. The research shows quite clearly that treatment with Cognitive Behavioural Therapy for Insomnia can provide significant improvements in people whose sleep has been impaired by such behavioural factors and online programs are available.
Unrefreshing sleep occurs across the population, both in people with a range of clinical conditions and sometimes in people with no diagnosed medical problem. It is usually described by self-report. It is likely to be a very heterogenous phenomenon. A study by El-Mekkawy Leqaa et al (2022) noted a significant change in delta wave power (deep sleep) in the temporal brain region in those with unrefreshing sleep arising from sleep apnea, compared to controls. In our review of sleep patterns in ME/CFS (Jackson and Bruck, 2012) we concluded that technological advances in the assessment/monitoring of sleep may lead to further understanding of how the micro-structure of sleep may differ between those with self-reported unrefreshing sleep compared to quality sleep.
Anecdotal evidence from some pwME and a few research studies suggest that the sleep disturbance that people experience can have a significant impact on their cognitive abilities. How prevalent is this? What may be causing the sleep disturbance to impact people’s cognitive function?
Any ongoing sleep disturbance will affect a person’s cognitive abilities. Attention, concentration, memory and reaction time may all be affected in some way depending on (a) their overall health (physical and/or mental) and (b) individual differences in how poor sleep quality affects an individual. It seems reasonable to think that a pwME/CFS that includes the symptom of brain fog would be affected by the cognitive impairments we associate with poor sleep in an additive way.
Is there any evidence that non-restorative sleep is impacting other symptoms which pwME experience such as pain?
I believe that ANY ongoing poor quality sleep, whether it is unrestorative sleep or disturbed sleep will affect a range of ME/CFS symptoms, possibly all. Pain and brain fog are likely to be particularly affected.
With regard to pain we know that sleep loss increases the experience of pain. Krause et al (2019) showed that acute sleep deprivation amplifies pain reactivity within the human primary somatosensory cortex, lowers pain thresholds and that ‘even modest nightly changes in sleep quality within an individual determine consequential day-to-day changes in experienced pain’.
Having a clearer understanding about the pathophysiology of non-restorative sleep in pwME may lead to better treatment options for patients. Are you aware of any clinical trials which are exploring treatment issues for non-restorative sleep in pwME?
Unfortunately not.
Many people with M.E. report that there is a direct link between the degree of their non-restorative sleep and the depth of the fatigue they experience the next day. What research has been done into this particular issue and what were their findings?
To my knowledge this issue has not yet been investigated in pwME/CFS. However, cognitive fatigue as measured on a range of working memory tests (Benkirane et al, 2022) found that the main effect of sleep fragmentation was to increase subjectively reported fatigue rather than reduce cognitive test performance. This study, using healthy participants, highlights the difficulties in objectively measuring fatigue, as many people can rally their mental resources for short-term testing in a research setting. This may have little to do with how fatigue is experienced in real-life settings.
What further research is required to investigate the causes of non-restorative sleep and the impact this has on cognitive function, fatigue and pain in pwME?
There are so many unanswered questions. The first step for any such research is to have a standard definition of non-restorative sleep. Is it a certain level of sleep fragmentation? Sleep disruption? Lower EEG delta power? Subjective report in the light of an otherwise normal sleep diary? Is reported non-restorative sleep the same for someone with sleep apnea, vivid dreaming or ME/CFS?
Many thanks go to Cort Johnson for his important contribution to this article.
