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How COVID Impairs the Brain

Why does COVID affect the brain anyway?

If COVID-19 has robbed you of your reason and sanity you are not alone. A lot of people experience brain impairment after COVID-19 infection. A meta-analysis of 81 studies found that about 1/3 of the people experienced persistent fatigue and over 1/5 of people had cognitive impairment 12 or more weeks after COVID-19 diagnosis (Ceban et al. 2021).

*Shawn P. (22 years old): "I am now 14 months post-Covid. My brain is so tired it feels like the batteries are dead. Doctors can't help me. My family doesn't believe me and thinks I'm lazy and have hypochondria.

I feel like a dementia patient. I should be hanging out with my great grandma at the retirement home (at least I would get snacks). I forget people's names I've known for years, the words to old songs, why I drove to town. I don't have the energy to focus on anything like books, movies, TV. I don't have the energy for my hobbies. I don't even enjoy music like I used to. It just all seems too tiring. At this point I'm just gritting my teeth and hoping to get better soon."

COVID-19 crashes the brain

Back in the good old days when curing brain disorders meant removing madness stones: The Surgeon or The Extraction of the Stone of Madness (c. 1550) Jan Sanders van Hemessen oil on panel.

Jan Sanders van Hemessen, Public domain, via Wikimedia Commons

COVID-19 activates brain immune cells while impairing brain growth; this causes brain dysfunction

1) Increased cytokine production inhibits brain growth.

Even mild cases of COVID-19 can increase production of cerebrospinal fluid cytokines in the brain. Cytokines are small chemicals, usually proteins, that influence cell signaling.

Cytokines can impair neurogenesis; the growth of new brain cells. Higher concentrations of cytokines also activate the microglia. Microglia are brain immune cells in the hippocampus. The hippocampus is a part of the brain deeply involved in learning and memory (Bourgognon et al. 2022).

2) Microglia cells are activated and spew inflammatory cytokines.

Microglia cells activated due to COVID-19 became more reactive and stay more reactive even weeks later. Reactive microglia impair brain growth by sending out inflammatory cytokines themselves. This can create brain inflammation, called neuroinflammation. Spatial brain maps from 25 patients who died from COVID-19, showed neuroinflammation caused by strong immune cell activation.

3) Microglia cells lose communication with their neighbors.

Communication is disrupted because microglia lose their synapses and can no longer chat with each other. SARS-CoV-2 infection kills off neuronal cells and post-synaptic termini (Samudyata et al. 2022).

4) Immune cells invade the brain.

Compared to people who had died from non-infectious, non-inflammatory, and non-neurological related causes; the COVID-19 patient's brains contained infiltration of immune cells. These included distinct immune cell clusters, such as activated CD8 T cells which compromise the blood-brain-barrier and microglial nodules which mastermind immune activation (Schwabenland et al. 2021).

5) All this inflammation messes with your brain.

Brain inflammation causes problems with concentration, learning new tasks and memory. This is because when the microglia are more reactive, the brain has trouble keeping up with some of its regular tasks, such as making new neurons in the hippocampus, a region of the brain that plays an important role in learning and memory.

Read more about these topics in What Causes Long COVID: Brain Invasion!

COVID-19 decreases serotonin concentrations

People who reported that they have Long COVID and brain fog have lower levels of serotonin (Wong et al. 2023). Reduced serotonin signalling inhibits the vagus nerve which impairs hippocampal responses and memory. This could contribute to the memory problems and other health problems Long COVID patients report.

Serotonin is a neurotransmitter in the central nervous system (CNS) and responsible for many nonneuronal processes as well. This means physical symptoms seen in Long COVID could be

Serotonin regulates and helps modify: heart rate and remodeling, breathing, stomach and intestinal movement, digestion, pancreas secretions, pain, fat metabolism, wound healing, stress, blood pressure, body temperature, bladder control, bone health, milk production, uterine contractions, progesterone production, and erectile response in men. In the brain it regulates mood, memory, anxiety, appetite, sleep cycle, aggressiveness, stress response and more (for more see Berger et al. 2018).

COVID-19, and other inflammatory disorders, may cause brain lesions and microbleeds

Microbleeds are tiny chronic brain hemorrhages which may result from structural abnormalities in the brain's small blood vessels. Microbleeds are emerging as a marker of brain damage in people suffering from chronic stress, depressive disorders, diabetes, inflammatory disorders and age-associated illnesses.

COVID-19 may cause small bleeding lesions that exacerbate DNA damage in affected brain cells. This can result in accelerated aging of brain cells and activation of cell death mechanisms. Ultimately, the brain microstructure vasculature (blood vessel) network becomes abnormal. This pathological state resemble symptoms of neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. They are likely to cause or to make worse cognitive and motor deficits. (Schwabenland et al. 2021, Mitra et al. 2022).

Brain fog may be due to an increased density of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPARs)

AMPA receptors are essential for learning and memory. These glutamate receptors are responsible for fast excitatory neurotransmition in the central nervous system (CNS). It is called fast because it is triggered in less than a millisecond.

A study comparing 30 people with Long COVID (LC) to 80 people without LC found that LC may increase AMPA receptor activity. This could be due to brain inflammation (neuroinflammation) caused by elevated cytokines (Fujimoto et al. 2025).

This systemic increase in AMPK receptors was linked to cognitive impairment in people with LC. The greater the AMPK density the more executive function, attention and visual-motor coordination were negatively affected. In other words, more AMPK receptors = greater brain fog. It was so reliable that the researchers were able to tell from brain scans who had LC with brain fog.

AMPAR dysfunction has also been linked to dementia, depression, bipolar disorder, and schizophrenia. 

Blue Box of Science: Serotonin Reduction.

Serotonin seems to be reduced through three mechanisms:

1) MAO-mediated serotonin turnover is increased. Monoamine oxidase A (MOA) is an enzyme that helps to regulate and degrade serotonin and other neuroactive monoamines in the brain (such as dopamine, melatonin and norepinephrine)*. This process is not currently well understood (see Prah et al. 2020 if you love molecular calculations).

2) Inflammation caused by residue COVID viruses in the system causes less intestinal absorption of tryptophan, a serotonin precursor; and

3) platelet hyperactivation and thrombocytopenia impacts serotonin storage (Wong et al. 2023).

*So, if you are like me you are thinking; "if Long COVID increases MOA serotonin turnover which in turn reduces serotonin - does Long COVID also accelerate destruction of other monoamines like dopamine, melatonin and norepinephrine?"

Let's look at what happens when people have low amounts of these monoamines.

Low dopamine symptoms: unmotivated, depressed, tired, ADHD (problems with concentration, focus, and controlling impulsive behavior), memory issues, sleep disorders, muscle tremors, poor balance, constipation, back pain, hallucinations, obesity, low sex drive, and immunity (for more on dopamine see Franco et al. 2021).

Low dopamine is also responsible for the neurocognitive impairments seen in another chronic virus infection, HIV-1. These include apathy, forgetfulness, inability to concentrate, and muscle weakness (McLaurin et al. 2021).

Low melatonin symptoms: insomnia, daytime sleepiness, mood disorders, fatigue, brain fog, anxiety and weight gain.

Melatonin may help treat Long COVID. It improves sleep, enhances mood, lowers inflammation, and reduces oxidative stress. All of these symptoms can be present in Long COVID (Souissi et al. 2023, Lempesis et al. 2024). Melatonin also helps protect brain neurons.

Low norepinephrine symptoms: anxiety, ADHD, depression, headaches, memory issues, sleeping disorders, low blood sugar, changes in blood pressure and changes in heart rate.

Some of those symptoms above line up really well with the symptoms of long COVID.

Fun fact: Serotonin's more formal name is 5-hydroxytryptamine (known as 5-HT on it's best selling rap song "5-HT Busts Your Brain Wide Open").

Learn how to regenerate your brain here.

Definitions:

Global fatigue: a self-administered questionnaire that measures fatigue in terms of severity, distress, impact on daily life, and timing.

*Names and some minor identifying details in all stories in this website are changed to protect people's privacy.

This information is for informational purposes only and does not constitute medical advice, diagnosis, or treatment.

COVID-19 is associated with negative changes in the structure of the brain

COVID shrinks and damages the brain.

Brain scans that were done before and after someone had COVID-19 revealed that there was a significant, negative impact associated with the COVID-19 virus, SARS-CoV-2. Grey brain matter thickness decreased, overall brain volume shrunk, there was tissue damage and an increase in cerebrospinal fluid (CSF)  volume after COVID-19 (Douaud et al. 2022).

COVID-19 promoted negative changes in grey and white brain matter. Both grey and white matter are important components of the brain. Grey matter makes up the outer layer of the brain. It helps people retain memories, regulate emotions and control movement. White matter makes up more of the deeper parts of the brain and allow information to be transmitted between different areas of the grey matter within the brain and central nervous system. White matter is vital to active learning and memory.

Long COVID causes brain fatigue

People with Long COVID (129 women and men, mean age 49 years old) were evaluated for mental, physical and global fatigue using neuropsychological, and subjective cognitive complaints assessment. About 86% had fatigue.

Using fMRI brain scans, researchers assessed structural connectivity; this is how fiber tracts (axon bundles) are organized in the brain. People with mental fatigue showed distinct cerebral connectivity patterns when compared to people with physical and global fatigue.

There were patterns of structural and functional connectivity in frontal (strongest link), temporal, and cerebellar areas in fatigue. Mental fatigue had a different pattern of functional connectivity when compared to physical fatigue. White matter integrity was negatively associated with fatigue (Diez-Cirarda et al. 2024).

References:

Berger M, Gray JA, Roth BL. The expanded biology of serotonin. Annu Rev Med. 2009;60:355-66. doi: 10.1146/annurev.med.60.042307.110802. Full article.

Bourgognon J-M, Cavanagh J. The role of cytokines in modulating learning and memory and brain plasticity. Brain and Neuroscience Advances. 2020;4. doi:10.1177/2398212820979802 Full article.

Ceban F, Ling S, Lui LMW, Lee Y, Gill H, Teopiz KM, Rodrigues NB, Subramaniapillai M, Di Vincenzo JD, Cao B, Lin K, Mansur RB, Ho RC, Rosenblat JD, Miskowiak KW, Vinberg M, Maletic V, McIntyre RS. Fatigue and cognitive impairment in Post-COVID-19 Syndrome: A systematic review and meta-analysis. Brain Behav Immun. 2022 Mar;101:93-135. doi: 10.1016/j.bbi.2021.12.020. Full article.

Diez-Cirarda M, Yus-Fuertes M, Polidura C, Gil-Martinez L, Delgado-Alonso C, Delgado-lvarez A, Gomez-Ruiz N, Gil-Moreno MJ, Jorquera M, Oliver-Mas S, Gomez-Pinedo U, Matias-Guiu J, Arrazola J, Matias-Guiu JA. Neural basis of fatigue in post-COVID syndrome and relationships with cognitive complaints and cognition. Psychiatry Res. 2024 Oct;340:116113. doi: 10.1016/j.psychres.2024.116113. Full article.

Douaud G, Lee S, Alfaro-Almagro F, Arthofer C, Wang C, McCarthy P, Lange F, Andersson JLR, Griffanti L, Duff E, Jbabdi S, Taschler B, Keating P, Winkler AM, Collins R, Matthews PM, Allen N, Miller KL, Nichols TE, Smith SM. SARS-CoV-2 is associated with changes in brain structure in UK Biobank. Nature. 2022 Apr;604(7907):697-707. doi: 10.1038/s41586-022-04569-5. Full article.

Franco R, Reyes-Resina I, Navarro G. Dopamine in Health and Disease: Much More Than a Neurotransmitter. Biomedicines. 2021 Jan 22;9(2):109. doi: 10.3390/biomedicines9020109. Full article.

Fujimoto Y, Abe H, Eiro T, Tsugawa S, Tanaka M, Hatano M, Nakajima W, Ichijo S, Arisawa T, Takada Y, Kimura K, Sano A, Hirahata K, Sasaki N, Kimura Y, Takahashi T. Systemic increase of AMPA receptors associated with cognitive impairment of long COVID. Brain Commun. 2025 Oct 1;7(5):fcaf337. doi: 10.1093/braincomms/fcaf337. Full article.

Lempesis IG, Georgakopoulou VE, Reiter RJ, Spandidos DA. A mid-pandemic night's dream: Melatonin, from harbinger of anti-inflammation to mitochondrial savior in acute and long COVID-19 (Review). Int J Mol Med. 2024 Mar;53(3):28. doi: 10.3892/ijmm.2024.5352. Full article.

McLaurin KA, Harris M, Madormo V, Harrod SB, Mactutus CF, Booze RM. HIV-Associated Apathy/Depression and Neurocognitive Impairments Reflect Persistent Dopamine Deficits. Cells. 2021 Aug 21;10(8):2158. doi: 10.3390/cells10082158. Full article.

McNeill R, Marshall R, Fernando SA, Harrison O, Machado L. COVID-19 may Enduringly Impact Cognitive Performance and Brain Haemodynamics in Undergraduate Students. Brain Behav Immun. 2024 Dec 19;125:58-67. doi: 10.1016/j.bbi.2024.12.002. Full article.

Mitra J, Kodavati M, Provasek VE, Rao KS, Mitra S, Hamilton DJ, Horner PJ, Vahidy FS, Britz GW, Kent TA, Hegde ML. SARS-CoV-2 and the central nervous system: Emerging insights into hemorrhage-associated neurological consequences and therapeutic considerations. Ageing Res Rev. 2022 Sep;80:101687. doi: 10.1016/j.arr.2022.101687. Full article.

Prah A, Purg M, Stare J, Vianello R, Mavri J. How Monoamine Oxidase A Decomposes Serotonin: An Empirical Valence Bond Simulation of the Reactive Step. J Phys Chem B. 2020 Sep 24;124(38):8259-8265. doi: 10.1021/acs.jpcb.0c06502. Full article.

Samudyata, Oliveira AO, Malwade S, Rufino de Sousa N, Goparaju SK, Gracias J, Orhan F, Steponaviciute L, Schalling M, Sheridan SD, Perlis RH, Rothfuchs AG, Sellgren CM. SARS-CoV-2 promotes microglial synapse elimination in human brain organoids. Mol Psychiatry. 2022 Oct;27(10):3939-3950. doi: 10.1038/s41380-022-01786-2. Full article.

Schwabenland M, Salié H, Tanevski J, Killmer S, Lago MS, Schlaak AE, Mayer L, Matschke J, Püschel K, Fitzek A, Ondruschka B, Mei HE, Boettler T, Neumann-Haefelin C, Hofmann M, Breithaupt A, Genc N, Stadelmann C, Saez-Rodriguez J, Bronsert P, Knobeloch KP, Blank T, Thimme R, Glatzel M, Prinz M, Bengsch B. Deep spatial profiling of human COVID-19 brains reveals neuroinflammation with distinct microanatomical microglia-T-cell interactions. Immunity. 2021 Jul 13;54(7):1594-1610.e11. doi: 10.1016/j.immuni.2021.06.002. Full article.

Souissi A, Dergaa I, Romdhani M, Ghram A, Irandoust K, Chamari K, Ben Saad H. Can melatonin reduce the severity of post-COVID-19 syndrome? EXCLI J. 2023 Feb 2;22:173-187. doi: 10.17179/excli2023-5864. Full article.

Wong AC, Devason AS, Umana IC, Cox TO, Dohnalov L, Litichevskiy L, Perla J, Lundgren P, Etwebi Z, Izzo LT, Kim J, Tetlak M, Descamps HC, Park SL, Wisser S, McKnight AD, Pardy RD, Kim J, Blank N, Patel S, Thum K, Mason S, Beltra JC, Michieletto MF, Ngiow SF, Miller BM, Liou MJ, Madhu B, Dmitrieva-Posocco O, Huber AS, Hewins P, Petucci C, Chu CP, Baraniecki-Zwil G, Giron LB, Baxter AE, Greenplate AR, Kearns C, Montone K, Litzky LA, Feldman M, Henao-Mejia J, Striepen B, Ramage H, Jurado KA, Wellen KE, O'Doherty U, Abdel-Mohsen M, Landay AL, Keshavarzian A, Henrich TJ, Deeks SG, Peluso MJ, Meyer NJ, Wherry EJ, Abramoff BA, Cherry S, Thaiss CA, Levy M. Serotonin reduction in post-acute sequelae of viral infection. Cell. 2023 Oct 26;186(22):4851-4867.e20. doi: 10.1016/j.cell.2023.09.013. Full article.