Marketing Scoops: New Long COVID Study Zeroes In On Possible Biological Cause of Brain Fog

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Millions of “long COVID” patients coping with debilitating “brain fog” and chronic fatigue, who are looking for answers to what’s at the root of their illness, received a hopeful sign through a new study released Thursday. The answers, though somewhat complex, appear to be biological and neurological, authors of the study said. In other words, it’s not just in patients’ heads……..Continue reading…..

By Don Jacobson

Source: UPI

Critics:

Fatigue is complex and can be driven and maintained by a potentially wide range of biopsychosocial factors. Tiredness is a common medically unexplained symptom. In up to a third of fatigue primary care cases, no medical or psychiatric diagnosis is found. Adverse life events have been associated with fatigue. A 2021 study in a Korean city found that alcohol consumption was the variable with the most correlation with overall fatigue.

A 2020 Norway study found that 69% of substance use disorder patients had severe fatigue symptoms, and particularly those with extensive use of benzodiazepines. Causality, as opposed to correlation, were not proven in these studies. Fatigue can often be traced to poor sleep habits. Sleep deprivation and disruption is associated with subsequent fatigue. Sleep disturbances due to disease may impact fatigue. Caffeine and alcohol can disrupt sleep, causing fatigue.

Fatigue may be a side effect of certain medications (e.g., lithium salts, ciprofloxacin); beta blockers, which can induce exercise intolerance, medicines used to treat allergies or coughs, and many cancer treatments, particularly chemotherapy and radiotherapy. Use of benzodiazepines has been found to correlate with higher fatigue. Fatigue is often associated with diseases and conditions. Some major categories of conditions that often list fatigue as a symptom include physical diseases, substance use illness, mental illnesses, and other diseases and conditions.

In some areas, it has been proposed that fatigue be separated into

primary fatigue, caused directly by a disease process, and
ordinary or secondary fatigue, caused by a range of causes including exertion and also secondary impacts on a person of having a disease (such as disrupted sleep).

The ICD-11 MG22 definition of fatigue captures both types of fatigue; it includes fatigue that “occur[s] in the absence of… exertion… as a symptom of health conditions.” Obesity correlates with higher fatigue levels and incidence. In somatic symptom disorder the patient is overfocused on a physical symptom, such as fatigue, that may or may not be explained by a medical condition. The concept of adrenal fatigue is often raised in media but no scientific basis has been found for it.

The mechanisms that cause fatigue are not well understood. Several mechanisms may be in operation within a patient, with the relative contribution of each mechanism differing over time. Proposed fatigue explanations due to permanent changes in the brain may have difficulty in explaining the “unpredictability” and “variability” (i.e. appearing intermittently during the day, and not on all days) of the fatigue associated with inflammatory rheumatic diseases and autoimmune diseases (such as multiple sclerosis).

Inflammation distorts neural chemistry, brain function and functional connectivity across a broad range of brain networks, and has been linked to many types of fatigue. Findings implicate neuroinflammation in the etiology of fatigue in autoimmune and related disorders. Low-grade inflammation may cause an imbalance between energy availability and expenditure. Cytokines are small protein molecules that modulate immune responses and inflammation (as well as other functions) and may have causal roles in fatigue. However a 2019 review was inconclusive as to whether cytokines play any definitive role in ME/CFS.

Fatigue has been correlated with reductions in structural and functional connectivity in the brain. This has included in post-stroke, MS, NMOSD and MOG, and ME/CFS. This was also found for fatigue after brain injury, including a significant linear correlation between self-reported fatigue and brain functional connectivity. Areas of the brain for which there is evidence of relation to fatigue are the thalamus and middle frontal cortex, fronto-parietal and cingulo-opercular, and default mode network, salience network, and thalamocortical loop areas.

A 2024 review found that structural connectivity changes may underlie fatigue in pwRRMS but that the overall results were inconclusive, possibly explained by heterogeneity and limited number of studies. A small 2023 study found that infratentorial lesion volume (cerebellar and brainstem) was a relatively good predictor of RRMS fatigue severity. Studies have found MS fatigue correlates with damage to NAWM (normal appearing white matter) (which will not show on normal MRI but will show on DTI (diffusion tensor imaging)).The correlation becomes unreliable in patients aged over 65 due to damage due to ageing.

A small 2016 study found that primary Sjögren’s syndrome patients with high fatigue, when compared with those with low fatigue, had significantly higher plasma concentrations of HSP90α, and a tendency to higher concentrations of HSP72. A small 2020 study of Crohn’s disease patients found that higher fatigue visual analogue scale (fVAS) scores correlated with higher HSP90α levels. A related small 2012 trial investigating if application of an IL-1 receptor antagonist (anakinra) would reduce fatigue in primary Sjögren’s syndrome patients was inconclusive.

Fatigue is currently measured by many different self-measurement surveys. Examples are the Fatigue Symptom Inventory (FSI) and the Fatigue Severity Scale. There is no consensus on best practice, and the existing surveys do not capture the intermittent nature of some forms of fatigue. Physical fatigue, or muscle fatigue, is the temporary physical inability of muscles to perform optimally.

The onset of muscle fatigue during physical activity is gradual, and depends upon an individual’s level of physical fitness – other factors include sleep deprivation and overall health. Physical fatigue can be caused by a lack of energy in the muscle, by a decrease of the efficiency of the neuromuscular junction or by a reduction of the drive originating from the central nervous system, and can be reversed by rest.

The central component of fatigue is triggered by an increase of the level of serotonin in the central nervous system. During motor activity, serotonin released in synapses that contact motor neurons promotes muscle contraction. During high level of motor activity, the amount of serotonin released increases and a spillover occurs. Serotonin binds to extrasynaptic receptors located on the axonal initial segment of motor neurons with the result that nerve impulse initiation and thereby muscle contraction are inhibited.

Muscle strength testing can be used to determine the presence of a neuromuscular disease, but cannot determine its cause. Additional testing, such as electromyography, can provide diagnostic information, but information gained from muscle strength testing alone is not enough to diagnose most neuromuscular disorders. Mental fatigue is a temporary inability to maintain optimal cognitive performance.

The onset of mental fatigue during any cognitive activity is gradual, and depends upon an individual’s cognitive ability, and also upon other factors, such as sleep deprivation and overall health. Mental fatigue has also been shown to decrease physical performance. It can manifest as somnolence, lethargy, directed attention fatigue, or disengagement. Research also suggests that mental fatigue is closely linked to the concept of ego depletion, though the validity of the concept is disputed.

For example, one pre-registered study of 686 participants found that after exerting mental effort, people are likely to disengage and become less interested in exerting further effort. Decreased attention can also be described as a more or less decreased level of consciousness. In any case, this can be dangerous when performing tasks that require constant concentration, such as operating large vehicles. For instance, a person who is sufficiently somnolent may experience microsleep.

However, objective cognitive testing can be used to differentiate the neurocognitive deficits of brain disease from those attributable to tiredness. The perception of mental fatigue is believed to be modulated by the brain’s reticular activating system (RAS). Fatigue impacts a driver’s reaction time, awareness of hazards around them and their attention. Drowsy drivers are three times more likely to be involved in a car crash, and being awake over 20 hours is the equivalent of driving with a blood-alcohol concentration level of 0.08%.