3 Causes of Brain Fog

What causes brain fog associated with chronic fatigue syndrome and fibromyalgia?

What is Brain Fog?

Brain Fog. It’s a vague term for one of the most debilitating symptoms of ME/CFS, fibromyalgia, and other conditions. If you experience brain fog, you know exactly how to describe it in detail. Forgetfulness. Difficulty focusing on simple tasks. Inability to multitask. Forgetfulness. (Point proven!) Trouble learning new things. Trouble with reading comprehension. The list goes on.

No matter how you experience it, the question remains: what causes brain fog? What drives these cognitive problems? I’ll take a stab at 3 of the likeliest perpetrators specific to ME/CFS and Fibro.

1. Oxidative Stress & Neuroinflammation

In the context of cancer patients, brain fog is better understood and recognized. Chemo brain occurs in up to 75% of patients receiving treatment. Various chemotherapeutic agents induce oxidative DNA damage (oxidative stress) in the body to reduce cancerous cells, but also stress in the brain.

In chemo brain fog, growth and repair of neurons is blocked and microglia activated to produce inflammatory cytokines. In chemo brain imaging studies, there are distinct changes in key brain areas related to memory, learning, and abstract thinking. In this way, brain oxidative stress—a stimulator of neuroinflammation—drives processes that cause brain fog. Learn more about neuroinflammation in a prior post.

2. Ammonia

Ammonia is constantly produced by the body and is non-toxic to all tissues except the brain. Metabolism converts ammonia to urea for excretion. Excess ammonia can cause severe, lifethreatening encephalopathy. Yet even minimal levels (minimal hepatic encephalopathy) can drive generalized brain fog. Even small fluctuations in ammonia levels can lead to dramatic cognitive troubles that are contingent on which region of the brain is affected.

Ammonia that enters the brain causes neurons like astrocytes to swell and disrupt the blood-brain barrier. In severe ammonia toxicity, the brain swells and the cerebellum can even swell to displace from the skull (akin to Chiari malformation). In mild states of excess ammonia, subtle neurological and psychiatric disturbances occur. Even subtle increases in brain ammonia can disrupt normal brain metabolism to increase lactate and compromise normal energy production.

 

Excess ammonia is classically only considered in those with liver disease. However, several metabolic faults may disrupt the balance of normal ammonia processing with a normal functioning liver. In-born errors of metabolism, such as these, are not always outright detected and may be involved in ME/CFS pathology as evidenced by recent metabolomics studies. These studies show increases in metabolites related to ammonia processing—the urea cycle. Lastly, medication usage can increase ammonia burden. This includes popular drugs such as benzodiazepines and the anti-convulsants topiramate and sodium valproate.

Most importantly, ammonia is also produced by bacteria in the large intestine. Chronic, low level overproduction of ammonia by gut bacteria is a risk factor in a number of neurodegenerative diseases including Alzheimer’s. Ammonia is seldom measured in ME/CFS patients but measuring ammonia in serum and stool may be a best practice especially in those with the most severe cognitive problems. Anecdotally, I’ve seen elevated ammonia in stool studies of several patients.

Not all gut microbiota produce ammonia. Certain bacterial strains containing the enzyme urease increase ammonia production. Some of these include Proteus mirabillis, Staphylococcus saprophyticus, Helicobacter pylori, Klebsiella pneumonie, Clostridium perfringens, Salmonella spp., and Yersenia enterocolitica. Also fungi such as Cryptococcus neoformans and Coccidiodes posadasii produce urease and therefore ammonia. Overproduction of these bacteria can overburden ammonia detoxification. Antimicrobial treatment is a first-line treatment in those with liver disease with ammonia excesses.

3. Environmental Pollutants

Organic chemicals, pesticides, and other environmental pollutants are known to have detrimental effects on the central nervous system. Ultrafine particles from these chemicals may pass the blood-brain barrier or breach the nasal passages by way of the olfactory bulb where they can damage neurons.

Pollutants may also indirectly damage brain tissues through a lung-brain axis. Here, inhalation of particles trigger lung tissues to release signaling molecules--cytokines—which traverse to the brain amplifying the inflammatory message. Central to these effects are microglia, the brains specialized immune cells, which may “reprogram” after long term exposure to pollutants and thereby drive chronic inflammation and oxidative stress. Even spores from mold can activate microglia to drive inflammatory pathways.

 

Generalized neuroinflammation, as seen in ME/CFS and fibromyalgia, perpetuate symptoms of brain fog. Overgrowth of gut bacteria that produce excess ammonia may drive brain fog. Chemicals and other pollutants in our external environment have the potential to create brain fog. All 3 have the potential to create serious, debilitating brain fog that may be a major risk factor for development of age-related neurodegenerative disease.

In the next post, learn ways to battle brain fog based on these 3 causes.

Walker, V (2012) Severe hyperammonaemia in adults not explained by liver disease. Annals of Clinical Biochemistry: International Journal of Laboratory Medicine. 49(3): 214-228.

Nardone, R., Taylor, A. C., Höller, Y., Brigo, F., Lochner, P., & Trinka, E. (2016). Minimal hepatic encephalopathy: A review. Neuroscience Research, 111, 1–12.

Jin YY, et al (2018) Blood Ammonia as a Possible Etiological Agent for Alzheimer's Disease. Nutrients. 10(5). pii: E564.

Yamano, E et al. (2016) Index markers of chronic fatigue syndrome with dysfunction of TCA and urea cycles. Nature Scientific Reports volume 6, Article number: 34990.

Mora D. & Arioli S. (2014) Microbial Urease in Health and Disease. PLoS Pathog. 10(12): e1004472.

Schmidt S. (2019) Brain Fog: Does Air Pollution Make Us Less Productive? Environmental Health Perspective. 127:5.