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The Science Behind Long COVID Brain Fog

The Science Behind Long COVID Brain Fog

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Introduction
Potential Causes of Long COVID Brain Fog
Brain Fog Symptoms and Impact
Insights from Current Research
Emerging Treatments
Clearing the COVID Fog

The coronavirus disease 2019 (COVID-19) pandemic caused unprecedented mortality worldwide and had higher morbidity rates than any disease in the past few decades. However, the detrimental impacts of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections continued long after the pandemic was brought under control through concerted vaccination efforts across the globe.

Headache, pain and senior man with migraine, mental health risk, retirement stress or mind problem at home.Image Credit: PeopleImages.com – Yuri A/Shutterstock.com

Introduction

Post-acute sequelae of SARS-CoV-2 infection or PASC, commonly known as Long COVID, has been recognized as a significant public health concern. Among its many symptoms, “brain fog” is one of the most reported and debilitating cognitive impairments, affecting memory, concentration, and executive function.1

Studies suggest that memory problems and cognitive dysfunction occur in up to 88% of individuals with Long COVID, regardless of their age or the severity of their initial infection.2

The emergence of Long COVID brain fog has raised concerns among healthcare professionals due to its impact on cognitive abilities and daily functioning. Many patients describe it as persistent mental cloudiness that affects their ability to think clearly, remember information, and perform routine tasks efficiently. Unlike typical cognitive fatigue, Long COVID brain fog appears to persist for months, sometimes years, following an acute COVID-19 infection.3

This article explores the potential underlying mechanisms of Long COVID brain fog, its symptoms and their impact on overall quality of life, current research findings on the neurological impairments caused by Long COVID, and emerging treatment options.

Mythbusting: COVID-19 Misconceptions

Potential Causes of Long COVID Brain Fog

Several hypotheses have been proposed to explain the underlying mechanisms of brain fog in Long COVID patients. These include neurological, inflammatory, and vascular factors.4

The interplay between these factors suggests that brain fog is a multifaceted condition, influenced by immune responses, brain metabolism, and oxygen delivery.

Neurological Factors

Evidence suggests that SARS-CoV-2 can impact the brain indirectly through neuroinflammation and altered neurochemical signaling. Numerous studies have demonstrated using animal models that even mild COVID-19 infections can lead to sustained microglial activation, which disrupts neural networks and impairs cognitive function.5

Research also indicates that brain fog may be linked to persistent changes in neurotransmitter levels, particularly involving dopamine and serotonin. These neurotransmitters play essential roles in cognition, attention, and emotional regulation.

Disruptions in their balance could contribute to symptoms such as slowed thinking, poor concentration, and mood disturbances, which are frequently reported in Long COVID patients.2,4

Inflammatory Factors

Neuroinflammation is suspected to be one of the major drivers of brain fog in Long COVID. Elevated levels of pro-inflammatory cytokines, particularly the chemokine CCL11, have been linked to cognitive impairments observed in patients with persistent symptoms.5

This inflammatory response is thought to interfere with neurogenesis and synaptic plasticity, leading to cognitive dysfunction.

In some cases, a phenomenon known as “cytokine storm“—a hyperactive immune response—has been observed in COVID-19 patients. Even after recovering from acute infection, residual inflammation may persist in the brain, leading to prolonged cognitive impairment.

This ongoing inflammatory state may alter the blood-brain barrier’s integrity, allowing immune cells to enter the central nervous system and further exacerbate cognitive dysfunction.3,6

Vascular and Hypoxic Mechanisms

Another biological mechanism proposed to explain brain fog during Long COVID is associated with vascular dysfunction, particularly in patients who experienced respiratory distress during acute infection.

Studies have identified microvascular damage, including micro-hemorrhages and endothelial dysfunction, in individuals with persistent cognitive symptoms.7 Such changes can impair cerebral blood flow, potentially leading to sustained cognitive deficits.

Hypoxia, or reduced oxygen levels, is another contributing factor. Severe COVID-19 infections can cause oxygen deprivation, which may lead to neuronal damage. Even in cases where oxygen levels do not drop to critical levels, subtle but chronic reductions in oxygenation can negatively impact brain function over time, leading to symptoms such as confusion, difficulty concentrating, and memory lapses.1,8

Trinity team discovers underlying cause of brain fog linked with Long COVID

Brain Fog Symptoms and Impact

Brain fog manifests as a constellation of cognitive impairments that significantly affect daily life. Individuals with Long COVID often have trouble with sustained attention, memory lapses, slowed processing speed, and challenges in executive function, such as impaired decision-making.9

Many patients have also reported increased mental fatigue following cognitive exertion, as well as difficulty in concentrating on tasks for prolonged periods. Impaired word-finding abilities or vocabulary recall and challenges in multitasking are also commonly reported symptoms, leading to frustration and decreased confidence in completing work-related or personal tasks.10

These cognitive impairments often result in a decline in work performance, social interactions, and overall quality of life. Many individuals with Long COVID reported struggling to return to their pre-pandemic cognitive baseline, with some experiencing prolonged disability and social isolation.1

Patients have also reported that previously simple activities, such as reading, writing, or following conversations, require significantly more effort, leading to emotional distress and anxiety.

Additionally, research has shown that cognitive symptoms may be exacerbated by sleep disturbances and mental health conditions, including depression and anxiety, further compounding the burden of Long COVID.8

The persistence of these symptoms for almost a year or more after the initial SARS-CoV-2 infection highlights the urgent need for effective interventions to mitigate the cognitive effects of Long COVID and improve the daily lives of affected individuals.

Impact of COVID-19 on Parkinson’s Disease

Insights from Current Research

Recent studies have sought to quantify and characterize the cognitive deficits in Long COVID patients. A systematic review found that neuropsychological assessments confirm objective impairments in attention, working memory, and processing speed in Long COVID patients.3

Numerous other studies have utilized neuroimaging techniques to reveal structural and functional changes in the hippocampus and prefrontal cortex, supporting the hypothesis that COVID-19 resulted in neurodegeneration.3,11,12

Furthermore, recent research has also indicated that even individuals with mild COVID-19 infections exhibit increased neuroinflammation markers, underscoring the need for further investigation into potential long-term neurological consequences.5

Additional research suggests that cognitive impairments associated with Long COVID may share similarities with neurodegenerative conditions such as Alzheimer’s disease, although the exact pathological mechanisms remain unclear.13

Emerging Treatments

Several therapeutic interventions are under investigation to treat cognitive impairments and brain fog in Long COVID cases. These include medications and therapies that address many of the underlying mechanisms that are potential causes of long COVID, as well as cognitive and stimulative therapies to restore brain function.

Pharmacological Approaches

Anti-inflammatory drugs targeting neuroinflammation, such as corticosteroids and cytokine inhibitors, are being explored for their potential to alleviate cognitive symptoms.14

Medications such as modafinil, which has been used to treat narcolepsy, are also being tested to explore whether they can be repurposed to enhance cognitive function in Long COVID patients.15

Additionally, neuroprotective agents that support neuronal health, such as antioxidants and mitochondrial enhancers, are also being investigated for their potential role in cognitive recovery.16

Non-Pharmacological Interventions

Therapies that do not involve medications, such as cognitive rehabilitation, and noninvasive brain stimulation are also being explored in current research.

Techniques such as transcranial magnetic stimulation and transcranial direct current stimulation have been found to enhance cortical excitability and improve cognitive function in preliminary trials.8

Furthermore, hyperbaric oxygen therapy has also demonstrated potential in improving brain perfusion and cognitive function in patients with Long COVID-related cognitive impairment.8

COVID-19 and Headaches

Clearing the COVID Fog

To conclude, a growing body of research indicates that brain fog is a persistent and disabling symptom of Long COVID that significantly impacts the quality of life of patients.

Multiple potential mechanisms, including neuroinflammation, vascular dysfunction, and direct neurological effects of SARS-CoV-2 have been proposed for these cognitive impairments.

While emerging treatments show promise, further studies are needed to develop targeted therapies and optimize clinical management strategies. Increased recognition of Long COVID brain fog within the medical community is also essential for managing symptoms and improving patient outcomes.

References

  1. Nordvig, A. S., Rajan, M., Lau, J. D., Kingery, J. R., Mahmud, M., Chiang, G. C., De Leon, M. J., & Goyal, P. (2023). Brain fog in long COVID limits function and health status, independently of hospital severity and preexisting conditions. Frontiers in neurology, 14, 1150096. https://doi.org/10.3389/fneur.2023.1150096
  2. Kavanagh E. (2022). Long Covid brain fog: a neuroinflammation phenomenon?. Oxford open immunology, 3(1), iqac007. https://doi.org/10.1093/oxfimm/iqac007
  3. Nouraeinejad A. (2023). Brain fog as a Long-term Sequela of COVID-19. SN comprehensive clinical medicine, 5(1), 9. https://doi.org/10.1007/s42399-022-01352-5
  4. Al-Aly, Z., & Rosen, C. J. (2024). Long Covid and Impaired Cognition – More Evidence and More Work to Do. The New England journal of medicine, 390(9), 858–860. https://doi.org/10.1056/NEJMe2400189
  5. Venkataramani, V., & Winkler, F. (2022). Cognitive Deficits in Long Covid-19. The New England journal of medicine, 387(19), 1813–1815. https://doi.org/10.1056/NEJMcibr2210069
  6. Asadi-Pooya, A. A., Akbari, A., Emami, A., Lotfi, M., Rostamihosseinkhani, M., Nemati, H., Barzegar, Z., Kabiri, M., Zeraatpisheh, Z., Farjoud-Kouhanjani, M., Jafari, A., Sasannia, S., Ashrafi, S., Nazeri, M., Nasiri, S., & Shahisavandi, M. (2022). Long COVID syndrome-associated brain fog. Journal of medical virology, 94(3), 979–984. https://doi.org/10.1002/jmv.27404
  7. Taube M. (2023). Depression and brain fog as long-COVID mental health consequences: Difficult, complex and partially successful treatment of a 72-year-old patient-A case report. Frontiers in psychiatry, 14, 1153512. https://doi.org/10.3389/fpsyt.2023.1153512
  8. Gorenshtein, A., Liba, T., Leibovitch, L., Stern, S., & Stern, Y. (2024). Intervention modalities for brain fog caused by long-COVID: systematic review of the literature. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 45(7), 2951–2968. https://doi.org/10.1007/s10072-024-07566-w
  9. Arbula, S., Pisanu, E., Bellavita, G., Menichelli, A., Lunardelli, A., Furlanis, G., Manganotti, P., Cappa, S., & Rumiati, R. (2024). Insights into attention and memory difficulties in post-COVID syndrome using standardized neuropsychological tests and cognitive tasks. Scientific reports, 14(1), 4405. https://doi.org/10.1038/s41598-024-54613-9
  10. Azcue, N., Gómez-Esteban, J. C., Acera, M., Tijero, B., Fernandez, T., Ayo-Mentxakatorre, N., Pérez-Concha, T., Murueta-Goyena, A., Lafuente, J. V., Prada, Á., López de Munain, A., Ruiz-Irastorza, G., Ribacoba, L., Gabilondo, I., & Del Pino, R. (2022). Brain fog of post-COVID-19 condition and Chronic Fatigue Syndrome, same medical disorder?. Journal of translational medicine, 20(1), 569. https://doi.org/10.1186/s12967-022-03764-2
  11. Choi, Y., & Lee, M. K. (2020). Neuroimaging findings of brain MRI and CT in patients with COVID-19: A systematic review and meta-analysis. European journal of radiology, 133, 109393. https://doi.org/10.1016/j.ejrad.2020.109393
  12. Kesler, S. R., Franco-Rocha, O. Y., De La Torre Schutz, A., Lewis, K. A., Aziz, R. M., Henneghan, A. M., Melamed, E., & Brode, W. M. (2024). Altered functional brain connectivity, efficiency, and information flow associated with brain fog after mild to moderate COVID-19 infection. Scientific reports, 14(1), 22094. https://doi.org/10.1038/s41598-024-73311-0
  13. Pszczołowska, M., Walczak, K., Misków, W., Antosz, K., Batko, J., Karska, J., & Leszek, J. (2024). Molecular cross-talk between long COVID-19 and Alzheimer’s disease. GeroScience, 46(3), 2885–2899. https://doi.org/10.1007/s11357-024-01096-1
  14. Whitaker-Hardin, B., McGregor, K. M., Uswatte, G., & Lokken, K. (2025). A Narrative Review of the Efficacy of Long COVID Interventions on Brain Fog, Processing Speed, and Other Related Cognitive Outcomes. Biomedicines, 13(2), 421. https://doi.org/10.3390/biomedicines13020421
  15. Pliszka, A. G. (2022). Modafinil: A Review and Its Potential Use in the Treatment of Long COVID Fatigue and Neurocognitive Deficits. American Journal of Psychiatry Residents’ Journal, 17(4), 5–7. https://doi.org/10.1176/appi.ajp-rj.2022.170402
  16. Akanchise, T., & Angelova, A. (2023). Potential of Nano-Antioxidants and Nanomedicine for Recovery from Neurological Disorders Linked to Long COVID Syndrome. Antioxidants (Basel, Switzerland), 12(2), 393. https://doi.org/10.3390/antiox12020393

Further Reading

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