Researchers used a broad brush when they focused on the most easily understood aspect of the disorder – fatigue. Now, in this bold and provocative blog, the first part of a four-part series called “A Neuroinflammatory Model of ME/CFS”, guest blogger Marco proposes that other symptoms, none of which are in the Fukuda definition of CFS, may provide more insights into the causes of Chronic ‘Fatigue’ Syndrome than the fatigue its been so firmly linked with. Only time will tell if Marco’s theory is correct but it’s good to get a fresh perspective on this disorder.
Voices Rising! – Many talented people with ME/CFS who do not have medical degrees have spent considerable time and effort trying to understand this disorder – sometimes with very fresh perspectives. Marco’s essays are the first to appear in the ‘Voices Rising’ series of rigorous research and treatment reviews, advocacy essays and others from members of the ME/CFS community. Health Rising will provide each author with 40% of Paypal donations through its first six months on the site. Each author will retain full copyright of their material and will be able to post it on other sites. Thanks to Marco for kicking off the Health Rising Series:)
A Neuroinflammatory Model of ME/CFS
This document is the first in a series of four in which I hope to set out a hypothesis for a single neuroinflammatory process as the core pathophysiology underpinning ME/CFS as well as a range of other conditions.
I have written this in ‘blog’ format rather than in the more traditional format of a scientific paper for two reasons. Firstly, it was always my intention to put together a ‘short’ paper that I could open up for discussion amongst ourselves. Every hypothesis must be critically tested and who better to do this than those who live with ME/CFS on a daily basis.
Secondly, this material has evolved over the course of just over a year. The initial impetus came from several threads on Phoenix Rising where I and others were discussing several ‘atypical’ symptoms we experienced including various types of ‘sensory defensiveness’ or ADHD or ASD like behaviours or symptoms that are rarely if ever mentioned in the ME/CFS literature and which seemed more appropriate to an alternative ‘diagnosis’.
Comparing conditions in which various forms of ‘sensory overload’ featured brought up some startling commonalities and led to neuroinflammation as a potential common pathophysiology.
I hope to present this under the following headings :
- Part I – Sensory Gating
- Part II – Glutamate – One More Piece in the Puzzle?
- Part III – Glutamate/GABA Imbalance – Stiff Person Syndrome
- Part IV – Symptoms, heterogeneity and onset
My many thanks to Cort Johnson who has worked with me on this over a period of many months in the capacity of ‘contributing editor’ and who has now kindly agreed to host this material here as one of what will hopefully become a growing list of ‘guest bloggers’.
I hope this ‘hypothesis’ resonates with at least some of you.
- Learn more about Marco’s background and his experiences with ME/CFS here.
‘Sensory Gating’ – A Key to Chronic Fatigue Syndrome (ME/CFS)?
First a short questionnaire….. Would you agree or disagree with below statements?
- My hearing is so sensitive that ordinary sounds become uncomfortable
- There have been times when it seems that sounds and sights are coming in too fast
- It’s not bad when just one person is speaking but if others join in, then I can’t pick it up at all. I just can’t get into tune with that conversation
- There are days when indoor lights seem so bright that they bother my eyes.
- I have more trouble concentrating than others seem to have
- I seem to hear the smallest details of sound
- When I’m tired sounds seem amplified
These statements are taken from a questionnaire developed to assess problems with something called ‘sensory gating’. If you answered yes to several of these or other similar questions you could have problems with sensory gating. (Other possible sensory gating problems include over-sensitization to such things as touch (allodynia), smell (environmental sensitivities) and taste.)
Breaking out of the bunker. Systemic diseases and vague non-specific symptoms
Why focus on these kind of odd sensory issues when the medical community overwhelmingly associates chronic fatigue syndrome with fatigue? Because there is a tendency in science and medicine to use ‘cardinal symptoms’ (the most obvious and pressing symptoms’ found in a disorder) to pigeon-hole it. Once a diagnosis is made and a condition named both researchers and physicians tend to focus on these symptoms, largely ignoring minor symptoms or those that tend to overlap with other conditions. This ‘bunker mentality’ approach may be appropriate for single organ, single pathogen diseases but increasingly research points to multi-pathogen (or stressor) systemic diseases or physiological pathologies that may underlie a whole range of illnesses.
The problem is that cardinal symptoms such as fatigue or pain that are almost ubiquitous in chronic illnesses may offer little insight into a disorder’s underlying pathology. Minor and overlap symptoms, that are downplayed or often ignored, may in fact offer greater insights. It’s possible that neurological symptoms, in particular a condition called ‘sensory overload’ could provide a better ‘key’ to ME/CFS than fatigue and pain.
Sensory overload, of course, is a well-known feature of chronic fatigue syndrome that is described in the Canadian Consensus Criteria for ME/CFS as :
“cognitive, sensory- e.g., photophobia an hypersensitivity to noise – and/or emotional overload, which may lead to crash periods and/or anxiety.”
The Canadian Consensus Criteria Manual also mentions many cognitive problems such as confusion, impairment of concentration and short-term memory consolidation, disorientation, difficulty with information processing, categorizing and word retrieval, and perceptual and sensory disturbances. e.g., spatial instability and disorientation and inability to focus vision.
Note that many cognitive problems in ME/CFS could be impacted, if not caused, by high levels of ‘sensory overload’ interfering with the ability to effectively process ‘outside information’ (i.e. understanding conversations, understanding reading materials, navigating through physical space etc) as well as difficulty processing bodily sensations, which brings us to the question ….. could sensory overload contribute to many of the symptoms found in ME/CFS? The marked reduction in the speed of decision making, frequently noted in ME/CFS, for instance, might be expected if people with ME/CFS are being constantly being bombarded with sensory ‘noise’.
Too much information? – What is sensory gating and what does a deficit imply?
“Sensory gating describes neurological processes of filtering out redundant or unnecessary stimuli in the brain from all possible environmental stimuli. Also referred to as filtering, or sensorimotor gating, sensory gating prevents an overload of irrelevant information in the higher cortical centres of the brain”
Sensory gating is a basic physiological/neurological mechanism (present in all, at least, vertebrate species) that allows an organism to attend to salient stimuli (from all the senses) important to survival while filtering out routine, on-going and irrelevant signals.
Cocktail Party Syndrome, Seat of the Pants Phenomenon and the Startle Reflex
Three common phenomena that may be disturbed if there is a problem with sensory gating are ‘the Cocktail Party Syndrome’, the ‘Seat of the Pants’ phenomenon and the ‘Startle Reflex.’ Perhaps they apply to you?
In the ‘cocktail party syndrome’ it’s difficult to carry on a conversation with in a room because we have difficulty filtering out the noise of others. In the ‘seat of the pants’ phenomenon we have difficulty attending to the outside world because nerve impulses signalling the body is in contact with a surface don’t get filtered out as they should.
If we hear a loud bang we jump but if the noise is repeated several times and nothing untoward happens then eventually we learn to ignore it through a process of habituation and it becomes just so much more background noise. However, if our brains keep attending to the jackhammer or the door shutting or banging or whatever, again we don’t have much room left to attend to what’s in from of us.
It’s easy to imagine the ‘information overload’ if all these signals and others, reached the conscious mind on an on-going basis.
An important point to note though is that these mechanisms operate at the pre-conscious level. For example a sudden loud noise will elicit a startle response regardless of whether or not we had previously identified the noise as dangerous or harmless. It also appears that the strength of the startle response varies between individuals.
Measures of sensory gating
Two commonly used and related measures of sensory gatingare PPI (pre-pulse inhibition)in which a weaker prestimulus (prepulse) inhibits the reaction of an organism to a subsequent strong startling stimulus (pulse) and determines the strength of the startle response and the ERP (event-related potential) which reflects the habituation of repeated stimuli. Both measures involve recording the brain’s electrical response to auditory, visual or tactile signals.
Sensory Gating Deficits
It may be hypothesised that ME/CFS patients, if tested, would show a deficit in neurological sensory gatingand that this gating deficit may give an insight into many of our common and not so common symptoms.
It doesn’t take very long to identify a fairly long list of neurological/psychiatric conditions in which a gating deficit has been identified. They include Autism; Asperger’s; Bipolar disorder; Post Traumatic Stress Disorder; Alzheimer’s Disease; Obsessive Compulsive Disorder; Huntington’s Disease; Parkinson’s Disease; Fibromyalgia; IBS; Interstitial Cystitis/Painful Bladder Syndrome, Schizophrenia and Treatment Resistant Depression.
Sensory gating problems are also present in Attention Deficit Hyperactivity Disorder (ADHD). High rates of ADHD have been found in Fibromyalgia and just recently in ME/CFS and sensory gating questionnaires were recently proposed as easy diagnostic tools for ADHD. A recent study found a drug, methylphenidate used in ME/CFS can ameliorate sensory gating problems to some extent in ADHD. Methylphenidate (Ritalin, Concerta) is a psychostimulant that increases the levels of dopamine and norepinephrine in the brain. Another psychostimulant study involving Vyvanse found improved cognition and, interestingly enough, fatigue and pain levels in ME/CFS patients (Young, 2012).
Gating issues may produce different kinds of ‘overload phenomena’ in different disorders. Gating problems appear to cause or contribute to pain issues in Fibromyalgia and Interstitial Cystitis, fullness and urgency feelings in Irritable Bowel Syndrome, sensory integration problems in Autism; auditory hallucinations in Schizophrenia; the manic phase of Bipolar Disorder; and cognitive/memory/multi-tasking difficulties (Alzheimers); or ataxia (Huntington’s).
Evidence of Sensory Gating Problems in ME/CFS
in his 1996 book ‘Betrayal by the Brain’ Dr J A Goldstein proposed that a sensory gating deficit played a key role in ME/CFS and set out (in numbing detail) how it could account for many of the symptoms and physiological findings in ME/CFS. Unfortunately, it doesn’t appear that Dr Goldstein has published any research which investigated whether a gating deficit really is associated with ME/CFS.
One study (Geisser et al, 2008) found that ME/CFS patient’s brains have trouble turning off their attention to innocuous stimuli. Dr. Baraniuk reported he believes the sensory filtering processes are broken down in this disorder. The Lights propose that sensory ganglia that transmit sensory data to the spinal cord may be dysfunctional in ME/CFS.
A dissertation “Sensory Gating in Adolescents with Chronic Fatigue Syndrome” by EM Van de Putte et al found that adolescent CFS (Fukuda) patients showed a sensory gating deficit using the P50 ERP (sensory) paradigm but not on the PPI ‘Startle reflex (sensorimotor). The deficit only reached borderline significance once they controlled for confounding variables such as age; gender; depression and anxiety. They suggested, however, that co-morbid symptoms of anxiety and depression may mask a gating deficit in CFS.
Another point to note is that in the study that found a gating deficit in Fibromyalgia patients, the researchers used both an auditory and somatosensory stimulus (painless pressure) and significant results were found only for the somatosensory stimulus. It is entirely possible that, while some of us report increased sensitivity to sounds, an increased sensitivity to internal body signals may be a more important test in disorders like fibromyalgia and ME/CFS. Indeed, several studies suggest that an area of the brain called the insula which regulates awareness of one’s body, pain and perception may not be working properly in ME/CFS and fibromyalgia.
Causes I: Chemotherapy toxicity –A Model for a breakdown in Gating?
ME/CFS patients obviously aren’t typically exposed to chemotherapy drugs but they may arrive at the same endpoints as cancer patients. Chemotherapy is known to often lead to long term fatigue and cognitive problems in a significant number of patients. Studies suggest that up to 50% of cancer survivors exhibit signs of ‘Cancer-Related Fatigue’ and 12% have severe CRF two years after their cancer treatment. Cognitive issues are so prevalent that the term ‘chemo-fog’ (similar to ‘brain-fog’ in ME/CFS and ‘fibro-fog’ in Fibromyalgia) has entered the cancer lexicon.
One astounding fact is that as many as 41% of women receiving chemotherapy for breast cancer develop symptoms of Post-Traumatic Stress Disorder (which you recall is associated with a gating deficit) with 3-18% going on to develop full PTSD – with one of the key symptoms being ‘hyperarousal’ (which some evidence suggests is found in ME/CFS as well.) Several studies have associated ‘CFS’ with trauma or reported high levels of co-morbidity between PTSD and CFS (Dansie et al, 2012).
One assumption has been that the psychological trauma of dealing with a life threatening illness is causal but some evidence suggests the drugs could spark sensory gating and cognitive problems.
Gandal et al, 2008, demonstrated that administering a common breast cancer chemotherapy drug to mice results in significantly impaired ERP gating with reduced sensory habituation, reflected in behavioural changes such as increased pain sensitivity and reduced habituation to novel objects. To quote their discussion:
“In the present situation, gating deficits may underlie the qualitative observations of neurocognitive dysfunction reported in the clinical literature. An inability to filter out extraneous sensory stimuli in the pre-attentive stages of sensory processing could overwhelm an individual with a flood of incoming stimuli and interfere with the ability to mount a selective attentive response to the most salient information”
“Future studies should employ this animal model to probe underlying mechanisms of chemotherapy induced cognitive impairments. While definitive mechanisms for these cognitive changes have yet to be established, there are several potential hypotheses. Leading candidates include disruption of the blood brain barrier, cytokine upregulation and neuroinflammation, DNA damage, oxidative stress, and dysfunction of the neurohormonal axis”
Many of the causes suggested for ‘Cancer related fatigue’ are under discussion in ME/CFS as well; they include inflammatory cytokines, HPA axis problems, alterations in central nervous system serotonergic systems, problems with melatonin secretion, genetic predispositions, problems with energy metabolism and problems with muscular activation.
ME/CFS research also increasingly points to evidence of systemic inflammation/oxidative stress; immune dysfunction and, perhaps to a lesser degree (on the basis of the volume of published evidence), mitochondrial dysfunction.
Causes II: Psychological Stress
Thankfully (for us if not the mice) sensory gating can be readily studied in animal models and the effects of various stressors and their physiological effects elucidated.
It does indeed appear that, in animal models, a sensory gating deficit (PPI) can be induced, by stress induced by Social Isolation Rearing (SIR). The isolation results in increased levels of oxidative stress including increased superoxide dismutase activity, decreased oxidized: reduced glutathione ratio and increased lipid peroxidation in brain regions.
Causes III: Oxidative Stress/Mitochondrial dysfunction
Another study shows that systemic administration of the mitochondrial toxin 3-nitropropionic acid (3NP) induces a similar gating deficit (PPI) to that seen in Huntington’s Disease.
Schizophrenics may provide another clue. A very high proportion of schizophrenics smoke tobacco as a form of self medication as nicotine can help ameliorate a sensory gating deficit and the resulting psychotic episodes. Peroxisome proliferator-activated receptors (PPARs) are important regulators of mitochondrial function and may provide neuroprotection. Watt et al (2004) demonstrated that nicotinic acid could induce the production of mitochondrial regulating PPARs as effectively as exercise.
Further support for oxidative stress and mitochondrial dysfunction playing a role in sensory gating may come from the finding that the antioxidant and glutathione precursor (and glutamate antagonist) N-acteylcysteine can ameliorate sensory gating deficits (PPI) in knockout mice (Chen et al, 2010). While this study was primarily concerned with glutamate metabolism other studies have noted reduced glutathione levels in schizophrenia and that administration of NAC reduced symptoms in schizophrenia (Berk et al, 2008) and bipolar disorder (Magalhães et al, 2012).
Causes IV: Genetic Risk
Many now consider Bipolar Disorder and Schizophrenia to be the same or similar conditions and both show an associated sensory gating deficit. Dopamine is believed to play a key role in these conditions. In a large study of dopamine metabolism associated genes , Ancin et al, 2011 found that a particular polymorphism of the COMT gene was associated with Bipolar Disorder and the associated gating deficit (P50 ERP).
The 2011 Wyller study linked COMT gene alterations (rs4860) in adolescents with increased sympathetic nervous system (‘fight or flight’) activity and both Light studies have shown increased expression of the COMT genes after exercise.
Although it now appears that attempts to link a single genetic polymorphism to a particular disease were overoptimistic, it does appear that individuals who carry the COMT val to met mutation and in particular the low COMT activity met/met genotype may be predisposed to greater pain sensitivity and a loss of higher cognitive function when put under stress. It may be that ME/CFS patients carrying the met allele (particularly met/met) are more likely to experience higher levels of pain and/or cognitive fatiguability and may represent a sub-set with greater overlap with Fibromyalgia symptomology. The same genotype also appears to represent a risk factor for developing ADHD in males only.
Note that the loss of cognitive functions and increased pain sensitivity are to be expected when sensory overload is present.
Focus on Immune Dysfunction, Oxidative Stress and Mitochondrial Dysfunction
Returning to those conditions already associated with a sensory gating deficit, a quick search (Pubmed and similar sources) finds that immune dysfunction, oxidative stress and mitochondrial dysfunction are often found in these disorders. (Only those terms were used rather than specific markers such as TNF-alpha or terms such as glutathione so papers may easily have been missed).
An asterisk indicates that a positive association has been reported.
|Immune dysfunction||Oxidative stress||Mitochondrial dysfunction|
Psychiatric Disorders or Neuroinflammatory Ones?
It appears that many of the illnesses previously regarded as ‘psychiatric’ are increasingly explained by underlying neuroinflammatory pathologies that may be amenable to treatment with no need to resort to ‘theories of the mind’.
A recent paper reviewing trends in Autism Spectrum Disorder research over the past 40 years concluded that there had been a move away from traditional areas such as neuropathology and ‘theory of mind’ and a rapid increase in papers on immune dysfunction/inflammation; oxidative stress; mitochondrial dysfunction and environmental toxin exposure; that a high proportion of papers confirmed a link and were of increasingly high quality.
They also noted similar associations for other psychiatric/neurological disorders :
“Immune dysregulation and inflammation has been implicated in several psychiatric disorders”. For example, “neuroinflammation, which generally refers to CNS-specific, chronic glial reactions…. has been implicated in several psychiatric disorders,including Alzheimer’s disease,schizophrenia, bipolar disorder,and depressionas well as ASD.”
These are not isolated observations. A further review (Bitanihirwe and Woo, 2010) discusses the rationale for and effects of treating Schizophrenia with antioxidants :
“Currently available evidence points towards an alteration in the activities of enzymatic and nonenzymatic antioxidant systems in schizophrenia. In fact, experimental models have demonstrated that oxidative stress induces behavioral and molecular anomalies strikingly similar to those observed in schizophrenia. Recent clinical studies have shown antioxidant treatment to be effective in ameliorating schizophrenic symptoms. Hence, identifying viable therapeutic strategies to tackle oxidative stress and the resulting physiological disturbances provide an exciting opportunity for the treatment and ultimately prevention of schizophrenia.”
Dantzer et al (2009) reports on recommendations from a multidisciplinary conference held in 2007 to consider how best to identify and treat medically ill patients with a range of conditions in which inflammation played a key role in the symptomology.
“The most harmful and costly health problems in the Western World are originating from a few diseases that include coronary heart disease, cancer, obesity, type II diabetes, physical disability and neurodegenerative disorders associated with ageing. In addition to the specific symptoms that are characteristic of each of these conditions, most patients experience non-specific symptoms that are similar in all these conditions and include depressed mood, altered cognition, fatigue, and sleep disorders.”
Conclusions and….Treatments (?)
Concentrating almost exclusively on fatigue and/or pain whilst ignoring minor and overlap symptoms may only serve to ‘ring-fence’ ME/CFS research in a way that is artificial and unproductive.
There are tentative findings that a sensory gating deficit is also associated with ME/CFS. This is a testable hypothesis that, if confirmed, might suggest common physiological aberrations and understanding the pathology of these other conditions may help unearth the core pathology of ME/CFS.
Research is increasingly implicating oxidative stress in a wide range of neuroinflammatory conditions as it is with ME/CFS. These conditions are all associated with a neurological sensory gating deficit which may be induced by oxidative stress.
Interventions to attenuate oxidative stress have shown promise in a number of conditions. Additionally, it’s not uncommon for drugs to find uses well outside of their originally intended use.
Trazodone, a commonly used sleep drug in ME/CFS is also used, for instance in central nervous system degenerative diseases (behavioral disorders in dementia and other organic disorders), schizophrenia, chronic pain disease and diabetic neuropathy and sexual dysfunction.
An anti-psychotic, Quetiapine, used in the treatment of schizophrenia can enhance sleep in healthy people and is suggested as a sleep aid and pain reducer in fibromyalgia and ME/CFS. Clozapine (an antipsychotic agent used in the treatment of Schizophrenia and off-label for Bipolar Disorder) reverses the gating deficit produced in rats.
As a final example, it appears that a number of antidepressants also have the effect of reducing inflammatory cytokines and the reduction in depressive symptoms may be due to this anti-inflammatory action.
More importantly, given their vastly greater levels of funding, a major breakthrough is more likely to come from research into one or more of these other neuroinflammatory conditions. One promising candidate is the gene RORA which is involved in several key processes including brain cell differentiation; protection of neurons against chemical stress; suppression of inflammation and regulation of circadian rhythms.
RORA has already been implicated in bipolar disorder, ADHD, depression and autism and lately variants of the RORA gene have been shown to be a risk factor for developing post-traumatic stress disorder. Of particular interest is the RORA gene’s responsiveness to sex hormones which has been proposed as the explanation for gender prevalence differences in ASD.
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