(In a second of four-part series of papers elucidating a neuro-inflammatory model of chronic fatigue syndrome, Marco examines a possibility that could explain many symptoms and issue not just in ME/CFS but in other neurological disorders. Learn more about Marco here – Cort).
- Pt 1 of the Neuroinflammatory Series: Not Fatigue After All: New Model Suggests Other Symptoms Better Explain Chronic Fatigue Syndrome (ME/CFS)
Glutamate plays a beneficial and indeed crucial role as the primary excitatory neurotransmitter powering the transmission of messages between neurons. Without glutamate we’d be unable to respond quickly to events but too much glutamate can lead to a condition called excitotoxicity which can damage or destroy neurons.
“Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate…. This occurs when receptors receptors for the excitatory neurotransmitter such as the NMDA and AMPA receptors are overactivated.”
Interestingly, given the low blood flow problems in chronic fatigue syndrome, central nervous system ischemia (low blood flows) increases glutamate levels and contributes to cellular death.
High glutamate levels shift the central nervous system towards seizure, and indeed, researchers have known for over 50 years that directly applying glutamate to the central nervous system causes seizures. Dr. Paul Cheney has long proposed that a shift towards seizure brought on by overstimulated, overly sensitive neurons explains the ‘wired but tired’ symptoms and sensory overload often experienced in ME/CFS.
“Our neurons (nerve cells) are sensing stimuli and firing when they should not. This causes amplification of sensory input. Light, noise, motion and pain are all magnified. At the beginning of their illness, many patients report feeling exhausted, yet also strangely “wired.” The “wired” feeling is the slight shift towards seizure that occurs as a result of the excitatory neurotoxicity.” From Carol Sieverlings reports
Cheney proposed that overly activated NMDA (glutamate) receptors cause neurons to fire at the slightest stimulation. He suggested people with ME/CFS use Klonopin, Doxepin elixir and magnesium to reduce receptor activation and indeed Klonopin is widely used in ME/CFS.
Normally glutamate is balanced by the inhibitory neurotransmitter GABA. It is likely that the balance between glutamate and GABA may determine the excitatory/inhibitory balance in the central nervous system and hence the ratio of ‘signal’ to ‘noise’. It seems logical that an excess of glutamate might result in increased noise and a deficit in signal gating leading to various ‘overload phenomena’.
Evidence For Excessive Glutamate in Chronic Fatigue Syndrome
Links with Other Disorders
In addition to an inflammatory milieu, oxidative stress and mitochondrial dysfunction (all of which interact), diabetes is a final condition not discussed as yet (and for which no research has been conducted on sensory gating) but which may hold a clue to glutamate as a key driver involved in ME/CFS and other neuroinflammatory conditions.
You may recall that the CDC (Maloney et al, 2010) suggested an association between metabolic syndrome (a precursor to type II diabetes) and ME/CFS, albeit in a study using the empirical criteria. Recent research has identified excess glutamate as a potential mechanism leading to the onset of type II diabetes via the destruction of pancreatic cells by glutamate (Eliana et al, 2011). Kogelnik, in an interview coming up, has reported increased levels of diabetes in his chronic fatigue syndrome patients.
This suggests excess glutamate could be triggering sensory gating problems, diabetes and mood disorders in some patients. Type II diabetes rates are three times higher in patients with bipolar disorder compared to the general population (Calkin et al 2012). In the same vein it’s intriguing that diabetic mothers have a higher risk of having children on the autism spectrum (Krakowiak et al, 2012). .
Notably excess glutamate has also been implicated in most if not all of the conditions discussed here including ME/CFS – indirectly via allostatic load (Goertzel et al, 2006) and the concept of the ‘selfish brain’ (Peters et al, 2004). Glutamate’s key role in neuronal plasticity suggests it could help remodel the nervous systems in people with ME/CFS.
Murrough (2010) did not find altered levels of glutamate or GABA in an ‘exploratory’ analysis of ME/CFS patients. However increased central nervous system glutamate levels have been well-documented in fibromyalgia patients and a study analysing the effects of a glutamate blocker called memantine on pain and glutamate levels is underway. Australian researchers propose that inactivation of glutamate limiting enzyme called GAD plays a key role in FM, and note that being female, poor sleep, sedentariness, anxiety and depression can all depress GAD functioning. Interestingly, given the alcohol intolerance in ME/CFS, alcohol depresses GAD functioning as well.
N-acetylcsysteine (NAC) is usually thought of as an antioxidant but it also acts as a glutamate antagonist through facilitating the production of GABA. A number of small clinical trials have shown promising results for NAC administration in another disorder with sensory gating issues, Autism Spectrum Disorder (ASD) (Hardan et al, 2012). NAC is also fairly well established in the treatment of trichotillomania (compulsive hair pulling – a form of obsessive compulsive disorder (OCD).
NAC’s effectiveness in ameliorating a sensory gating deficit may therefore lie in its role as a glutamate antagonist instead of (or indeed as well as) its antioxidant properties and role as a glutathione precursor.
Oral GABA supplementation has also been shown to have potential to prevent metabolic syndrome and type II diabetes in a mouse model (Tian et al, 2011). Even more promising, neuronal damage caused by glutamate in ASD may be reversible by attenuating the over proliferation of glutamate receptors in the brain (Baudouin et al, 2012).
Another glutamate inhibitor, low dose naltrexone (LDN) has shown some efficacy with pain and mood in fibromyalgia.
Glutamate and ‘Neuroinflammation’
In fact, research is increasingly suggesting that oxidative stress, mitochondrial dysfunction and glutamate excitotoxicity are intrinsically linked in a range of neuroinflammatory conditions (Coyle and Puttfarcken, 1993) presenting as various symptom complexes
“Thus, two broad mechanisms–oxidative stress and excessive activation of glutamate receptors–are converging and represent sequential as well as interacting processes that provide a final common pathway for cell vulnerability in the brain.
The broad distribution in brain of the processes regulating oxidative stress and mediating glutamatergic neurotransmission may explain the wide range of disorders in which both have been implicated. Yet differential expression of components of the processes in particular neuronal systems may account for selective neurodegeneration in certain disorders.”
In short, the same pathological process can result in a different constellation of symptoms and therefore result in a range of eventual diagnoses.
Oxidative stress, mitochondrial dysfunction and glutamate excitotoxicity may also interact as a ‘feed-forward’ vicious cycle (Nguyen et al, 2011) :
“Our results conclusively demonstrate that not only glutamate excitotoxicity and/or oxidative stress alters mitochondrial fission/fusion, but that an imbalance in mitochondrial fission/fusion in turn leads to NMDA receptor upregulation and oxidative stress. Therefore, we propose a new vicious cycle involved in neurodegeneration that includes glutamate excitotoxicity, oxidative stress, and mitochondrial dynamics.”
Stablon (tianeptine) is an atypical antidepressant that has demonstrated remarkable clinical effectiveness in major depressive disorder that is often resistant to treatment with traditional SSRI’s. The interesting fact about tianeptine is that its efficacy does not conform to the monoamine hypothesis of depression as tianeptine may actually lower serotonin levels. An investigation into the neurobiological properties of tianeptine (McEwen et al, 2010) concludes :
“Converging lines of evidences demonstrate actions of tianeptine on the glutamatergic system, and therefore offer new insights into how tianeptine may be useful in the treatment of depressive disorders.”
Intriguingly the antidepressant and anxiolytic effects (plus protection against cognitive defects) appear to be due to its ability to protect the brain (particularly in the amygdala and hippocampus) against stress induced glutamate excitotoxicity :
“A modification of glutamatergic mechanisms by tianeptine may therefore be implicated in its ability to oppose the negative influence of chronic stress upon hippocampal neurogenesis, cell proliferation, and dendritic remodeling, processes profoundly disrupted in depressive states”
Similarly ketamine has a rapid and sustained antidepressant effect through modulation of glutamate neurotransmission as does the novel compound GLYX-13 which has the same beneficial effects without inducing dissociative symptoms usually associated with schizophrenia (Burgdorf et al, 2012)
Wrapped up within the vague notion of ‘fatigue’ in ME/CFS is the rather more specific description contained in the Canadian Consensus Criteria of a “Low threshold of physical and mental fatigability (lack of stamina)”. Mental fatigue is a common symptom following brain trauma and encephalitis and is associated with a number of neuroinflammatory and neurodegenerative disorders and can also result from sleep deprivation. Ongoing research at the University of Gothenburg, Sweden has implicated glutamate dysregulation in mental fatigue (Rönnbäck, Hansson, 2004) which they define as :
“a decreased ability to intake and process information over time. Mental exhaustion becomes pronounced when cognitive tasks have to be performed for longer time periods with no breaks (cognitive loading).”
“In addition to the fatigue itself, the patient with mental fatigue often suffers from loudness and light sensitivity, irritability, affect lability, stress intolerance, and headaches”
The researchers’ University of Gothenburg home page also describes over-exertion leading to a state of mental “deadlock” :
“Intense mental activity with high glutamate signalling can lead to astrocytes swelling, especially if their glutamate uptake capacity is impaired. This state, which is locked, may resemble the feeling of cramp in a muscle and the signalling takes a long time to be restored. This may explain the total exhaustion experienced by a person suffering from mental fatigue, when being too active and doing too many things.”
Rönnbäck and Hansson propose an inflammatory state where the efficient transmission of information via glutamate is disrupted with a decrease in the ability to discriminate signal from noise; in effect, the sensory filter ‘disintegrates’ :
“Based on this literature and observations from our own laboratory and others on the role of astroglial cells in the fine-tuning of glutamate neurotransmission we present the hypothesis that the proinflammatory cytokines tumor necrosis factor-α, IL-1β and IL-6 could be involved in the pathophysiology of mental fatigue through their ability to attenuate the astroglial clearance of extracellular glutamate, their disintegration of the blood brain barrier, and effects on astroglial metabolism and metabolic supply for the neurons, thereby attenuating glutamate transmission.”
The authors go on to note that, in some cases, mental fatigue persists long after the identified neural trauma has been resolved (perhaps due to a genetic predisposition or due to dendritic remodelling) and emphasise the importance of early treatment to prevent the problem becoming chronic :
“Providing information about mental fatigue, its cause and the prognosis, is of utmost importance for breaking the vicious circle, which comes with the risk for secondary anxiety and depression.
Furthermore, it is important for the patient to imagine and learn how much sensory stimulation they can tolerate prior to feeling too exhausted.
Due to recent results on changes in cell signaling and neuronal plasticity, it may be important to identify the symptoms and treat them as early as possible to avoid formation of new and functionally disturbing neuronal circuits due to overstimulation of neuronal-glial units.
If our hypothesis is correct, it may be possible to further improve the symptoms by suppressing the production of proinflammatory cytokines and, thereby, restoring the normal astroglial glutamate uptake.”
It goes without saying that exacerbation of symptoms in response to physical or mental stressors is as emblematic of ME/CFS as the PEM that follows and that, by definition (with most case definitions requiring new onset ‘fatigue’ of at least 6 months duration), in ME/CFS mental fatigue may have already become a chronic condition. Studies and anecdotal reports from doctors suggest that early treatment leads to better results in this disorder.
A Predisposition to Glutamate Excitotoxicity in Chronic Fatigue Syndrome?
If such a vicious cycle of glutamate excitotoxicity, oxidative stress, and mitochondrial dysfunction does indeed underpin ME/CFS pathology, it may not be clear where exactly the root problem lies.
Oxidative stress/weak or compromised antioxidant capacity; mitochondrial dysfunction or glutamate/GABA imbalances could all be the initiating factor.
Again gene studies may shed some light on what could be a predisposing factor for developing ME/CFS and other neuroinflammatory conditions.
A recent CDC study (Smith et al 2011) carried out a genome-wide mapping of gene SNPs and gene expression in 40 CFS patients and 40 controls. Following statistical analysis to reduce the risk of ‘false positive’ associations two genes remained that showed statistically significant differences between patients and controls on both SNP and gene expression analysis.
The genes identified were NPAS2 – involved in circadian rhythms and GRIK2 – a gene involved in glutamatergic neurotransmission.
The authors note that these genes are not only associated with key functions such as cognition, sleep and memory that are impaired in ME/CFS but also with those symptoms (mood disorders and anxiety) in which ME/CFS symptomology often overlaps with ‘psychiatric’ disorders raising the possibility of shared neurological underpinnings.
They also note that the same polymorphisms of glutamate receptors:
“have also been associated with a number of neuropsychiatric disorders including autism, Huntington’s disease, ADHD, OCD …”
The authors conclude that
“Replication of these findings will open novel avenues for the study of CFS pathogenesis”
Research into the genetics of Huntington’s disease suggest that a combination of polymorphisms in the GRIK2 gene and PPARGC1A (also called PGC1-alpha – the master regulator of mitochondrial biogenesis and function) may determine the age of onset of the disease (Gusella, Macdonald, 2009).
Notably, in animal (rodent) models of schizophrenia and autism, maternal infection with the H1N1 virus results in prenatal alterations in the genes of the offspring which include changes to GRIK2 and GABAergic genes leading to structural changes in the brain and adverse effects on behaviour (Hossein Fatemi, Powerpoint presentation, 2011).
An imbalance between GABA and glutamate can also result in a phenomenon called kindling, defined in neurology as :
“a process in which repeated stimuli sensitize the brain to react when the stimulus is re-applied. Used in explaining increased frequency of seizures in epilepsy and progression of bipolar disorder in humans.”
Jason et al have recently (2011) proposed kindling as an etiological model for ME/CFS :
“Kindling might represent a heuristic model for understanding the etiology of Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Kindling occurs when an organism is exposed repeatedly to an initially sub-threshold stimulus resulting in hypersensitivity and spontaneous seizure-like activity. Among patients with ME/CFS, chronically repeated low-intensity stimulation due to an infectious illness might cause kindling of the limbic-hypothalamic-pituitary axis. Kindling might also occur by high-intensity stimulation (e.g., brain trauma) of the limbic-hypothalamic-pituitary axis.
Once this system is charged or kindled, it can sustain a high level of arousal with little or no external stimulus and eventually this could lead to hypocortisolism. Seizure activity may spread to adjacent structures of the limbic-hypothalamic-pituitary axis in the brain, which might be responsible for the varied symptoms that occur among patients with ME/CFS. In addition, kindling may also be responsible for high levels of oxidative stress, which has been found in patients with ME/CFS.”
Once ‘primed’ (which may reflect structural changes to the brain) very little stimulus is needed to trigger a flare of neuroinflammation.
Neurological kindling is frequently encountered in the clinical or recreational use and/or abuse of certain GABA modulating drugs, most notably benzodiazepines and alcohol.
Withdrawal from GABAergic acting sedative-hypnotic drugs causes acute GABA-under-activity as well as glutamate over-activity which can lead to sensitization and hyper-excitability of the central nervous system, excito-neurotoxicity and increasingly profound neuroadaptions.”
Wikipedia – Kindling (sedative-hypnotic withdrawal)
Similarities Between Kindling in ME/CFS and Other Kindling Disorders
ME/CFS shares many symptoms with ‘benzodiazepine withdrawal syndrome’ including: agitation, chest pain, dizziness, fatigue and weakness, flu-like symptoms, irritable bowel syndrome, hot and cold flushes, orthostatic intolerance, restless leg syndrome, stiffness, tachycardia, sensitivity to touch and sound, indecision, etc.
Reports have recently appeared in the press suggesting that the routine use of benzodiazepines as a sleep aid in care homes for the elderly increase the risk of developing Alzheimers disease as each cycle of benzo withdrawal results in a rebound ‘spike’ of excitotoxic glutamate.
Similarly glutamate kindling in chronic alcohol abuse leads to multiple physical and neurological impairments and can result in permanent brain damage which impacts on important cognitive capacities such as executive function (decision making) a deficit also found in ME/CFS (Prasher et al, 1990, Jason, 2011). Chronic alcohol abuse is, of course, one of the exclusionary conditions in most if not all ME/CFS case definitions which might suggest that without this disclosure they might meet the criteria for a ME/CFS diagnosis.
Baclofen is a GABA-B receptor agonist (originally used as an antispasmodic) that has recently been licensed for use in France for the treatment of alcohol dependence and withdrawal. This resulted from an intriguing tale of how Olivier Ameisen, M.D, a lone French-American doctor, self-treated his own lifelong anxiety and alcoholism with high dose Baclofen, wrote a book and spawned a growing on-line community who, following his lead, also found in many cases that their lifelong anxiety (and potentially the root cause of their alcohol abuse) was resolved. Presumably the fact that Baclofen acts on GABA-B receptors rather than GABA-A (like benzodiazepines) and/or the particular treatment regime used avoids kindling due to repeated administration and withdrawal.
Glutamate Induced Peripheral Damage
Neural damage due to glutamate excitotoxicity may not be restricted to the central nervous system. Peripheral neuropathy is a common complication in diabetes (and metabolic syndrome) and often results from chronic alcohol abuse.
Small fibre polyneuropathy can result not only in neuropathic pain and other sensations such as pins and needles or itching but also, interestingly, in a very wide range of (familiar) autonomic symptoms including (but not restricted to) dry eyes, dry mouth, orthostatic dizziness, constipation, bladder incontinence, sexual dysfunction, trouble sweating etc (Tavee, Zhou, 2009).
One recent study (Oaklander, 2012, press article) reports that almost 50% of a cohort of fibromyalgia patients showed objective evidence of small fibre polyneuropathy via skin biopsy sufficient to meet strict diagnostic criteria for that condition. A study at CDMRP Boston is currently recruiting to study small fibre polyneuropathy in Gulf War veterans.
Glutamate, Chemotherapy, Fatigue, Cognition and HHV6
As discussed earlier, chemotherapy treatment frequently results in ‘chemo fog’ and ‘chemo fatigue’ and a high proportion of those treated for breast cancer develop the symptoms of post-traumatic stress disorder or full-blown PTSD. Peripheral neuropathy is also a common complication of chemotherapy which places an upper limit on the dosages used (Pachman et al 2011).
Glutamate is strongly implicated in chemotherapy neurotoxicity (Carozzi et al, 2009) and compounds that inhibit glutamate production have been shown to reduce neuronal damage (particularly in the dorsal root ganglia) in rat models (Carozzi et al). Intriguingly, the Light’s believe damage to the dorsal root ganglia (DRG) in chronic fatigue syndrome patients may contribute to the sensory overload present there. The dorsal root ganglia also often harbor herpesvirus infections. Could glutamate excitotoxicity in the DRG lay the foundation for herpesvirus activation there?
Or vice versa? HHV6 can cause dysregulation of glutamate transport in neural astrocytes with the potential for similar effects on the peripheral sensory neurons in the DRG : Human herpesvirus 6 (HHV-6) induces dysregulation of glutamate uptake and transporter expression in astrocytes.
Inhibition of the glutamate forming enzyme glutamate carboxypeptidase II (GCP II), may help prevent both peripheral and central nervous system damage during chemotherapy and has been proposed as a possible treatment for amyotrophic lateral sclerosis (ALS), stroke, and even Multiple Sclerosis plus other ‘neuropsychiatric’ diseases (Rahn et al, 2012).
The Multiple Sclerosis Connection
Multiple sclerosis has several intriguing associations with ME/CFS including an infectious mononucleosis trigger, a relapsing/remitting nature, possible herpesvirus activation and high rates of fatigue (that are not associated with demyelination). The neuroprotective effects of a novel oral treatment, BG12 (dimethyl fumarate) has been recently shown to slow disease progression in relapsing/remitting MS in phase III trials. Neural degeneration in MS is believed to be mediated by oxidative stress and an analysis of the neuroprotective effects of dimethyl fumarate suggests that these effects are due to enhancing the recycling of glutathione, a key antioxidant. (Lee et al, 2012).
This is intriguing because the experimental model used to simulate neurodegeneration in MS involves both glutamate toxicity and glutathione depletion. It suggests that extracellular glutamate leads to deprivation of cystine and its reduced form cysteine, which is the rate-limiting substrate for the synthesis of glutathione. The subsequent glutathione depletion gives rise to the accumulation of reactive oxygen species and cell death by oxidative stress (Albrecht et al, 2012).
An Autoimmune Disorder?
As a final thought, the potential efficacy of Rituximab in treating ME/CFS (Fluge et al, 2011) has not only raised hopes amongst patients but also suggests that ME/CFS may be an autoimmune disease although Fluge and Mella themselves have not yet reached this conclusion.
To examine the potential mechanisms of the reported efficacy of Rituximab for ME/CFS, a recent study (Bradley et al, 2012) compared B cell subpopulations in ME/CFS patients and healthy controls and found subtle yet significant differences that they could not explain but which prompted them to conclude that this “may suggest a subtle tendency to autoimmunity”.
In the context of the association between neuroinflammatory conditions and metabolic syndrome/type II diabetes (in which glutamate may pay a key role), Stanford researchers (Winer et al, 2011) have demonstrated the effectiveness of Rituximab treatment in mice in an autoimmune model of type II diabetes :
“B cell effects on glucose metabolism are mechanistically linked to the activation of proinflammatory macrophages and T cells and to the production of pathogenic IgG antibodies.
Treatment with a B cell-depleting CD20 antibody attenuates disease, whereas transfer of IgG from DIO mice rapidly induces insulin resistance and glucose intolerance. Moreover, insulin resistance in obese humans is associated with a unique profile of IgG autoantibodies.
These results establish the importance of B cells and adaptive immunity in insulin resistance and suggest new diagnostic and therapeutic modalities for managing the disease.”
Anti-NMDA receptor encephalitis and late onset autism are recently recognised and related autoimmune disorders involving antibodies to NMDA (glutamatergic) receptors with prodromal symptoms reminiscent of a viral infection and that result in a wide range of movement and neuropsychiatric symptoms and neuroinflammation. (Dalmau et al, 2011).
Autoimmune encephalitis (where symptoms include psychiatric features, confusion, memory loss and seizures followed by a movement disorder, loss of consciousness and autonomic fluctuations) and related disorders have also been associated with anti GABA-B receptor antibodies and/or glutamic acid decarboxylase (GAD – the enzyme responsible for converting glutamic acid to GABA) antibodies (Boronat et al, 2011). One recent hypothesis (Fitzgerald, Carter, 2011) proposes decreased GAD expression or activity as playing a key role in fibromyalgia.
Rituximab has also been used to treat anti-NMDA receptor encephalitis (Ikeguchi et al, 2012) supporting a close link between autoimmunity, glutamate/GABA and encephalitis.
A range of neuroinflammatory/neurodegenerative and ‘psychiatric’ conditions show evidence of various overload phenomena and when tested show evidence of a sensory gating deficit. These conditions have also been associated with immune dysregulation, inflammation/oxidative stress and mitochondrial dysfunction. Similar markers have also been found in ME/CFS patients who also experience various forms of ‘overload’.
A glutamate/GABA imbalance is increasingly implicated in most if not all of these conditions which results in a disruption in the brain’s ability to efficiently process information and in time can lead to lasting neuronal damage both centrally and peripherally. A sensory gating deficit is likely an epiphenomenon resulting from this loss of efficient sensory ‘filtering’ due to an imbalance of glutamate and GABA.
Dopamine as the ‘Gatekeeper’?
Dopamine may still play a role in this scenario. Despite the recent focus on glutamate, the ‘dopamine hypothesis’ of schizophrenia is well established and compounds that raise dopamine levels (e.g. Ritalin and Adderall) are standard treatments for ADHD and have also shown some promise in relieving fatigue and concentration difficulties in ME/CFS (Blockmans et al, 2006). It appears that dopamine plays a key role in regulating glutamate neurotransmission. Dopamine acts as a sort of ‘gatekeeper’ of glutamatergic input, boosting strong glutamate signals while suppressing weaker ones (Horvitz, 2002). Again an adequate level of dopamine is necessary for the efficient filtering of salient information from extraneous noise.
A Gender Effect?
Additionally, as might be expected, dopamine, glutamate and GABA do not act independently. In Part I we discussed the potential role of the COMT gene in disorders such as schizophrenia, bipolar disorder and possibly ME/CFS and that the RORA gene may help explain the gender imbalance in ASD. As previously discussed, COMT polymorphisms affect dopamine levels and recent research strongly suggests that gender (or more specifically the effects of estrogen) impact on COMT function leading to sexually dimorpic effects on brain function (Tunbridge, Harrison, 2011). Sex differences in ‘psychiatric’ disorders have long been recognised :
“ the Val(158)Met polymorphism in COMT is associated with obsessive-compulsive disorder in men, with anxiety phenotypes in women, and has a greater impact on cognitive function in boys than girls”
…… with COMT activity, on average, being lower in women than men due partly to its suppression by estrogen (Harrison, Tunbridge, 2008).
Of particular relevance to the current discussion is the fact that the COMT and GAD genes (where, as discussed above, antibodies to GAD are found in autoimmune encephalitis) regulate cortical GABA function (which opposes glutamate) although sometimes not in the expected direction (Marenco et al, 2010) :
“These results support the importance of genetic variation in GAD1 and COMT in regulating prefrontal cortical GABA function. The directionality of the effects, however, is inconsistent with earlier evidence of decreased GABA activity in schizophrenia.”
Thus, gender may influence the type of condition that results from the same neuroinflammatory process through the modulating effect of estrogen on genes. Could it be that the effects of estrogen on RORA provide protection against developing ASD while its effects on COMT predispose more females to developing conditions like ME/CFS?
A Neuroinflammatory Vicious Cycle
Glutamate excitotoxicity, oxidative stress, and mitochondrial dynamics may represent a self-perpetuating ‘vicious cycle’ which in time may lead to neural remodelling making future excitoxicity more likely and requiring little outside stimulus.
Because glutamate signalling is ubiquitous in the brain (and concentrated in other tissues such as the heart, adrenal glands and the gastrointestinal tract – Julio-Pieper et al 2011) this neuroinflammatory cycle can result in a wide range of symptoms that then result in a variety of ‘differential diagnoses’.
Identifying a sensory gating deficit in ME/CFS may help to identify the core pathology as the same neuroinflammatory cycle identified in other conditions and better insights (and treatment options) might come from those other conditions that share the same basic pathophysiology but where the pathological process is expressed as a different constellation of symptoms, perhaps due to individual variations in genetic predisposition, developmental stage, environmental stressors and perhaps gender.
- Check out Pt I of the Neuroinflammatory Series: Not Fatigue After All: New Model Suggests Other Symptoms Better Explain Chronic Fatigue Syndrome (ME/CFS)
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