What do we know about covid-19’s effects on the brain? (2024)

1. Katharine Lang, freelance journalist

1. Bristol

1. lang.kathj26{at}gmail.com

What are the neurological symptoms of covid-19?

Covid may be primarily a respiratory infection, but a common symptom is “brain fog”—problems with memory or concentration—which can persist for weeks or months as part of long covid.1 And it’s not the only neurological effect.

Giovanni Schifitto, professor of neurology at the University of Rochester Medical School in New York, explains that neurological symptoms are widespread. “In the acute phase, common things like lack of smell, changes in taste, increase in headaches, cognitive dysfunction, and strokes have been reported, and there are effects on the peripheral nervous system,” he says.

Although these complications are more likely in people with severe covid—a 2021 study found that 80% of people admitted to hospital with covid-19 experienced neurological symptoms2—they can also affect people who experience only mild covid symptoms.3 These neurological symptoms were also found to be more likely in people who were older, male, or white and in people with pre-existing neurological disorders.

The most common neurological symptoms are loss of smell (anosmia) and loss of taste (ageusia). Studies have suggested that during a bout of covid as many as 68% of people experience loss of smell and 44% lose their sense of taste.45 But no evidence suggests that these effects are due to the virus entering the brain.

Other studies have reported a range of neurological symptoms alongside general fatigue. These symptoms are much like those experienced after a “mild traumatic brain injury” (as defined in one study6) or from concussion—including dizziness, headaches, seizures, stroke, delirium, and balance disturbances.

The UK Covid and Cognition study (Covcog, from the University of Cambridge) reported cognitive dysfunction in some 70% of people with signs of long covid (or “post-covid condition,”7 although it’s worth noting that there are no agreed international diagnostic criteria for long covid), and brain fog and difficulty concentrating were found to be more common than lasting respiratory symptoms.8 The Covcog study found that the severity of lasting symptoms was related to the severity of symptoms during acute covid.

Data from the UK Coronavirus (Covid-19) Infection Survey from March 20239 showed that difficulty concentrating was the second most common symptom in long covid (after fatigue) and was experienced by 51% of respondents. More recently, a community based study used online assessments to evaluate cognitive impairment after covid infection.10 Participants who had been infected showed measurable long term cognitive deficits not evident in the no-covid group.

What causes these symptoms? Is it the virus entering the brain?

This is a complex issue and the subject of much debate. In vitro studies have found that the virus disrupts the blood-brain barrier, although this was seen only with the original wild-type SARS-CoV-2 and omicron variants.11 This research also found that the virus may affect the function of cells in the central nervous system.

Because loss of smell is a common symptom, some researchers have suggested that the virus may enter the brain through the olfactory system. Stephen Griffin, virologist at the University of Leeds, notes that the UK Biobank study12 recorded “reduced grey matter thickness—comprised of the main cellular ‘bodies’ of neurons, rather than their tendril-like projections—in parts of the brain linked with olfactory sensing, namely the limbic system and primary olfactory cortex,” which could be evidence for this route of entry.

However, there’s little other evidence that the virus enters cells in the brain. Schifitto says, “There’s been one report suggesting the virus gets into astrocytes13; others have not really found the virus in specific cells.”

But he adds, “The virus can cause damage without infecting cells. If it’s activating other cells in the brain that cause inflammation, you don’t need the virus to be there to cause problems. The amount of cytokines in the blood could activate, for example, microglia, a classical cell type involved in chronic neuroinflammation.”

Does inflammation play a role?

The consensus is that inflammation, rather than invasion by the virus, is highly likely to be responsible for the neurological symptoms seen in both acute and long covid. One 2023 study found raised levels of brain injury markers and inflammatory mediators during the acute phase of covid.14

Daniel Altmann, professor of immunology at Imperial College London, says, “Many ideas have been put forward, but just as there can be immunopathology in any other organ—for example, through excessive inflammatory cytokines—so it is for the brain.”

He cites a 2022 study in mice and people15 that showed lasting post-covid cytokine activity, particularly CCL11 (eotaxin 1) in the central nervous system. CCL11 is known to play a role both in allergic conditions and in brain disorders.16 Studies in mice revealed that, as well as elevated cytokines/chemokines in the cerebrospinal fluid, the myelin on nerve cells was damaged, which could be one explanation for cognitive issues. Little evidence suggests that demyelination has been seen in people after covid.

Another study, published in October 2023, has proposed an alternative theory: that peripheral serotonin reduction after covid impedes the vagus nerve—impairing the responses of the hippocampus, which is involved in learning, memory, and emotion.17

What about microbleeds and strokes associated with covid-19?

Many people have reported microbleeds and strokes after infection. Schifitto says that the virus often infects endothelial cells anywhere in the body, including those in the brain vessels. He explains, “It’s not surprising, if something is affecting the endothelial cells, that this may predispose people to small strokes, large strokes, or dysregulation of the blood-brain barrier, which then could predispose to additional inflammation coming from the bloodstream into the brain.”

Altmann says, “There is massive evidence for this. Many mechanisms have been demonstrated for endothelial, prothrombotic effects of the virus, so the effect is fairly easily rationalised.”

What’s the effect of covid-19 on dementia?

Schifitto expresses concern that covid may lead to an increase in dementias, telling The BMJ that dementias are “almost always a mix with vascular disease included—so if SARS-CoV-2 has had an impact on the microcirculation, we may see an increase in vascular disease in the brain, which may contribute to earlier or more aggressive dementia. That’s a concern, but there’s no evidence so far.”

Benedict Michael, professor of neuroscience at the University of Liverpool, says that this risk may well not apply to the whole population but could potentially increase the likelihood of dementia in people already at increased risk of neurodegenerative disease.

Schifitto adds, “Most dementias do not progress rapidly, so it would be unlikely that we’d see a surge within a few years.” He’s currently investigating neuroimaging biomarkers to see if these might give early warning of small vessel disease or microcirculation problems in people who have had covid.

Can vaccination help reduce the neurological effects of covid-19?

The only way to avoid neurological symptoms during and after infection is to avoid catching covid in the first place, says Altmann. But vaccination could also reduce the risk.

Griffin points to preclinical studies18 indicating that vaccination can prevent SARS-CoV-2 from damaging the brain in some experimental models. He adds, “Plus, we know that vaccination is one of the few things that reduce the risk of long covid.”

Griffin warns that the long term consequences of covid aren’t being considered enough when planning vaccination and other prevention strategies in the UK—“which would seem most unwise given the accumulating evidence of long term harm in neurological and indeed other tissues.”

Footnotes

• Competing interests: None declared.

• Provenance and peer review: Commissioned; peer reviewed.

This article is made freely available for personal use in accordance with BMJ's website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.

https://bmj.com/coronavirus/usage

References

1. ↵
   1. Davis HE,
   2. McCorkell L,
   3. Vogel JM,
   4. Topol EJ

   . Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol2023;21:133-46. doi:10.1038/s41579-022-00846-2.pmid:36639608

   OpenUrlCrossRefPubMed

2. ↵
   1. Chou SH,
   2. Beghi E,
   3. Helbok R,
   4. et al.,
   5. GCS-NeuroCOVID Consortium and ENERGY Consortium

   . Global Incidence of neurological manifestations among patients hospitalized with covid-19—a report for the GCS-NeuroCOVID Consortium and the ENERGY Consortium. JAMA Netw Open2021;4:e2112131. doi:10.1001/jamanetworkopen.2021.12131pmid:33974053

   OpenUrlCrossRefPubMed

3. ↵
   1. Marshall M

   . How covid-19 affects the brain. New Sci2023;257:14-5. doi:10.1016/S0262-4079(23)00189-6.pmid:36776697

   OpenUrlCrossRefPubMed

4. ↵
   1. Meng X,
   2. Deng Y,
   3. Dai Z,
   4. Meng Z

   . COVID-19 and anosmia: A review based on up-to-date knowledge. Am J Otolaryngol2020;41:102581. doi:10.1016/j.amjoto.2020.102581.pmid:32563019

   OpenUrlCrossRefPubMed

5. ↵
   1. Tong JY,
   2. Wong A,
   3. Zhu D,
   4. Fastenberg JH,
   5. Tham T

   . The prevalence of olfactory and gustatory dysfunction in covid-19 patients: a systematic review and meta-analysis. Otolaryngol Head Neck Surg2020;163:3-11. doi:10.1177/0194599820926473.pmid:32369429

   OpenUrlCrossRefPubMed

6. ↵
   1. Granholm AC

   . Long-term effects of SARS-CoV-2 in the brain: clinical consequences and molecular mechanisms. J Clin Med2023;12:3190. doi:10.3390/jcm12093190.pmid:37176630

   OpenUrlCrossRefPubMed

7. ↵

   World Health Organization. Post-covid 19 condition (long covid). 7 Dec 2022. https://www.who.int/europe/news-room/fact-sheets/item/post-covid-19-condition

8. ↵
   1. Guo P,
   2. Benito Ballesteros A,
   3. Yeung SP,
   4. et al

   . COVCOG 1: factors predicting physical, neurological and cognitive symptoms in long covid in a community sample. A first publication from the Covid and Cognition Study. Front Aging Neurosci2022;14:804922. https://www.frontiersin.org/articles/10.3389/fnagi.2022.804922. doi:10.3389/fnagi.2022.804922pmid:35370617

   OpenUrlCrossRefPubMed

9. ↵

   Office for National Statistics. Prevalence of ongoing symptoms following coronavirus (covid-19) infection in the UK: 30 March 2023. 30 Mar 2023. https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/bulletins/prevalenceofongoingsymptomsfollowingcoronaviruscovid19infectionintheuk/30march2023

10. ↵
    1. Hampshire A,
    2. Azor A,
    3. Atchison C,
    4. et al

    . Cognition and memory after covid-19 in a large community sample. N Engl J Med2024;390:806-18. doi:10.1056/NEJMoa2311330.pmid:38416429

    OpenUrlCrossRefPubMed

11. ↵
    1. Taquet M,
    2. Skorniewska Z,
    3. Hampshire A,
    4. et al.,
    5. PHOSP-COVID Study Collaborative Group

    . Acute blood biomarker profiles predict cognitive deficits 6 and 12 months after COVID-19 hospitalization. Nat Med2023;29:2498-508. doi:10.1038/s41591-023-02525-y.pmid:37653345

    OpenUrlCrossRefPubMed

12. ↵
    1. Douaud G,
    2. Lee S,
    3. Alfaro-Almagro F,
    4. et al

    . SARS-CoV-2 is associated with changes in brain structure in UK Biobank. Nature2022;604:697-707. doi:10.1038/s41586-022-04569-5.pmid:35255491

    OpenUrlCrossRefPubMed

13. ↵
    1. Huang S,
    2. Fishell G

    . In SARS-CoV-2, astrocytes are in it for the long haul. Proc Natl Acad Sci U S A2022;119:e2209130119. doi:10.1073/pnas.2209130119.pmid:35858460

    OpenUrlCrossRefPubMed

14. ↵
    1. Michael BD,
    2. Dunai C,
    3. Needham EJ,
    4. et al.,
    5. ISARIC4C Investigators,
    6. COVID-CNS Consortium

    . Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses. Nat Commun2023;14:8487. doi:10.1038/s41467-023-42320-4.pmid:38135686

    OpenUrlCrossRefPubMed

15. ↵
    1. Fernández-Castañeda A,
    2. Lu P,
    3. Geraghty AC,
    4. et al

    . Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation. Cell2022;185:2452-68.e16. doi:10.1016/j.cell.2022.06.008.pmid:35768006

    OpenUrlCrossRefPubMed

16. ↵
    1. Ivanovska M,
    2. Abdi Z,
    3. Murdjeva M,
    4. Macedo D,
    5. Maes A,
    6. Maes M

    . CCL-11 or eotaxin-1: an immune marker for ageing and accelerated ageing in neuro-psychiatric disorders. Pharmaceuticals (Basel)2020;13:230. doi:10.3390/ph13090230.pmid:32887304

    OpenUrlCrossRefPubMed

17. ↵
    1. Wong AC,
    2. Devason AS,
    3. Umana IC,
    4. et al

    . Serotonin reduction in post-acute sequelae of viral infection. Cell2023;186:4851-67.E20. doi:10.1016/j.cell.2023.09.013

    OpenUrlCrossRefPubMed

18. ↵
    1. Villadiego J,
    2. García-Arriaza J,
    3. Ramírez-Lorca R,
    4. et al

    . Full protection from SARS-CoV-2 brain infection and damage in susceptible transgenic mice conferred by MVA-CoV2-S vaccine candidate. Nat Neurosci2023;26:226-38. doi:10.1038/s41593-022-01242-y.pmid:36624276

    OpenUrlCrossRefPubMed