Submitted:
30 May 2025
Posted:
02 June 2025
You are already at the latest version
Preprints on COVID-19 and SARS-CoV-2
Abstract
Introduction: COVID-19, initially understood as a respiratory illness, has emerged as a multisystemic disease with persistent post-acute sequelae. Of growing concern is the impact of SARS-CoV-2 on the nervous system, particularly long after the acute infection has resolved. Objective: This review synthesizes emerging evidence regarding long-term neurologic sequelae of COVID-19, with emphasis on cognitive, psychiatric, and structural brain changes, and highlights novel mechanisms and future research directions. Methods: A literature review was conducted across PubMed, Scopus, and Google Scholar databases for peer-reviewed articles between 2020–2024. We focused on observational studies, imaging-based research, and reviews related to long COVID and its neurologic manifestations. Results: Long COVID is associated with brain fog, fatigue, memory deficits, and depression/anxiety persisting for months post-infection. Neuroimaging studies have revealed structural changes in the frontal cortex and limbic system, while pathophysiologic hypotheses include viral neuroinvasion, neuroinflammation, microvascular injury, and persistent immune dysregulation. Conclusion: COVID-19's neurologic footprint persists beyond the acute phase, resembling neurodegenerative and mood disorders. Understanding these effects is critical for developing targeted therapies and rehabilitation strategies. This review underscores the urgency of integrative research into post-viral neuropsychiatric conditions.
Keywords:
Long COVID
; Neuro-COVID
; neuroinflammation
; cognitive impairment
; Post-Viral syndromes
Introduction
As the acute phase of the COVID-19 pandemic recedes, attention is increasingly turning to the long-term sequelae of SARS-CoV-2 infection. Among the most pressing concerns is the growing body of evidence suggesting that even mild COVID-19 infections can lead to persistent neurologic and psychiatric complications—a phenomenon broadly termed “Long COVID” or “Post-Acute Sequelae of SARS-CoV-2 Infection” (PASC).
What sets COVID-19 apart from prior respiratory viruses is the extent and diversity of these post-acute neurologic effects. While cognitive fog, anxiety, and fatigue are common in viral convalescence, the persistence of structural brain changes, gray matter loss, and persistent cognitive impairment months after infection suggests unique neurobiological consequences.
This review highlights newly emerging imaging, mechanistic, and cohort-based data from 2020–2024 that further elucidate how COVID-19 leads to long-lasting neuropsychiatric impairment, reinforcing that PASC is not merely psychosomatic or post-viral fatigue but may share overlapping features with chronic neuroinflammatory and neurodegenerative conditions.
Methods
We searched PubMed, Scopus, and Google Scholar for literature published between January 2020 and April 2024 using terms including: “Long COVID,” “Post-acute COVID,” “Neuro-COVID,” “cognitive impairment,” “SARS-CoV-2 brain,” and “neuroinflammation.” Priority was given to peer-reviewed articles, systematic reviews, longitudinal studies, and neuroimaging research. Articles in English only were included. A total of 60 papers were reviewed, with 28 selected for detailed inclusion based on relevance and novelty.
Results
1. Epidemiology of Neurologic Long COVID
Large cohort studies estimate that 20–35% of individuals, including those with mild or asymptomatic infections, report persistent neurologic symptoms three to six months post-infection. These include:
- Fatigue
- Brain fog
- Impaired concentration
- Headache
- Insomnia
- Anxiety and depression
One of the largest retrospective cohorts (Taquet et al., Lancet Psychiatry, 2021) showed that nearly 1 in 3 COVID survivors received a neurologic or psychiatric diagnosis within 6 months.
2. Cognitive and Psychiatric Effects
Cognitive dysfunction (“brain fog”) is one of the most commonly reported symptoms, even among non-hospitalized patients (Graham et al., 2021). Cognitive domains affected include attention, memory, executive function, and language fluency. Psychiatric symptoms, including depression, anxiety, and PTSD-like features, may reflect shared neurobiological pathways such as limbic system inflammation and HPA axis dysregulation.
3. Neuroimaging and Structural Changes
Recent brain imaging studies have provided objective correlates to patient-reported symptoms, supporting a biological basis for cognitive impairment in long COVID. These neuroimaging findings reveal consistent alterations in brain structure and metabolism, particularly in regions involved in cognition and emotion. Key studies are summarized below:
| Study | Finding |
| Douaud et al. (Nature, 2022) | Reduction in gray matter thickness in orbitofrontal cortex and parahippocampal gyrus |
| Lu et al. (2020) | White matter microstructural changes on DTI (diffusion tensor imaging) |
| Hosp et al. (Brain, 2021) | Glucose hypometabolism in frontoparietal cortex |
| Nystad et al. (2023) | Systematic review showing MRI abnormalities in up to 30% of long COVID patients |
| Study | Sample | Imaging Modality | Key Findings |
| Douaud et al., 2022 | UK Biobank, N=401 | MRI (T1, structural) | Reduced gray matter thickness in orbitofrontal cortex and parahippocampal gyrus |
| Lu et al., 2020 | N=60 COVID patients | Diffusion Tensor Imaging (DTI) | White matter microstructural changes indicating disrupted connectivity |
| Hosp et al., 2021 | N=15 subacute COVID pts | 18F-FDG PET | Glucose hypometabolism in frontoparietal cortex correlated with cognitive deficits |
| Nystad et al., 2023 | Systematic Review (N=var) | MRI (various) | MRI abnormalities (e.g., white matter lesions, microbleeds) found in up to 30% of long COVID patients |
These findings support a biological basis for cognitive symptoms and may help in developing biomarkers.
4. Proposed Pathophysiology
- Direct neuroinvasion: SARS-CoV-2 may enter via the olfactory bulb, disrupting the limbic system.
- Neuroinflammation: Chronic microglial activation and cytokine dysregulation may underline cognitive and mood symptoms.
- Microvascular injury: Endothelial dysfunction and blood-brain barrier disruption may cause long-lasting damage.
- Autoimmunity: Cross-reactive antibodies have been found in CSF, raising concerns for post-infectious autoimmune encephalopathy.
These mechanisms may operate synergistically to create sustained neurologic injury long after viral clearance.
5. Comparison to Other Post-Viral Syndromes
While post-viral fatigue and depression are not unique to COVID-19, the scale and persistence of symptoms—particularly in mild cases—suggest a broader CNS impact. The spectrum overlaps with conditions like ME/CFS and even mild traumatic brain injury.
Discussion
The persistence of neurologic symptoms in COVID-19 survivors represents a looming public health challenge. Unlike transient post-viral fatigue, long COVID’s neurologic impact includes measurable structural brain changes and lasting impairment in daily function. Its resemblance to other neuroinflammatory disorders invites speculation about long-term risk for neurodegeneration.
Moreover, the broad demographic affected—often younger individuals with mild disease—raises concerns about workforce impact, educational interruption, and psychiatric comorbidity.
Clinicians should be aware that patients may present months after infection with vague but debilitating cognitive symptoms. Multidisciplinary care teams including neurology, psychiatry, rehabilitation, and primary care are crucial for comprehensive management.
Conclusion
SARS-CoV-2 infection can result in persistent neurologic symptoms that resemble neurodegenerative and neuroinflammatory conditions. As evidence mounts for structural brain changes and sustained immune dysregulation, long COVID should be understood not as a psychological phenomenon but as a bona fide neuropsychiatric syndrome.
Future research should focus on identifying biomarkers, risk factors, and interventional targets. Given the global scale of infection, the long-term neurologic impact of COVID-19 may be the next major wave of chronic disease burden.
Author Contributions
I: Brendan Jones, conceptualized the review, conducted the literature search, synthesized the findings, and wrote the manuscript.
Conflicts of Interest
The author declares no conflicts of interest.
Funding
No external funding was received for this work.
Use of AI Tools
This manuscript was prepared with the assistance of AI language models to enhance clarity, grammar, and structure. All intellectual content, critical analysis, and interpretation of data remain the sole responsibility of the author.
References
- Taquet M, Geddes JR, Husain M, Luciano S, Harrison PJ. 6-month neurological and psychiatric outcomes in 236,379 survivors of COVID-19: a retrospective cohort study using electronic health records. Lancet Psychiatry. 2021;8(5):416-427. [CrossRef]
- Graham EL, Clark JR, Orban ZS, et al. Persistent neurologic symptoms and cognitive dysfunction in non-hospitalized Covid-19 “long haulers.” Ann Clin Transl Neurol. 2021;8(5):1073-1085. [CrossRef]
- Douaud G, Lee S, Alfaro-Almagro F, et al. SARS-CoV-2 is associated with changes in brain structure in UK Biobank. Nature. 2022;604(7907):697-707. [CrossRef]
- Lu Y, Li X, Geng D, et al. Cerebral micro-structural changes in COVID-19 patients – an MRI-based 3-month follow-up study. EClinicalMedicine. 2020;25:100484. [CrossRef]
- Hosp JA, Dressing A, Blazhenets G, et al. Cognitive impairment and altered cerebral glucose metabolism in the subacute stage of COVID-19. Brain. 2021;144(4):1263-1276. [CrossRef]
- Nystad AE, Naesgaard PA, Sørhaug S, et al. Brain MRI findings in patients with long COVID: a systematic review. J Neuroradiol. 2023;50(2):114-122. [CrossRef]
- Nalbandian A, Sehgal K, Gupta A, et al. Post-acute COVID-19 syndrome. Nat Med. 2021;27(4):601-615. [CrossRef]
- Zhou H, Lu S, Chen J, et al. The landscape of cognitive function in recovered COVID-19 patients. J Psychiatr Res. 2020;129:98-102. [CrossRef]
- Petersen MS, Kristiansen MF, Hanusson KD, et al. Long COVID in the Faroe Islands: a longitudinal study among non-hospitalized patients. Clin Infect Dis. 2021;73(11):e4058-e4063. [CrossRef]
- Koralnik IJ, Tyler KL. COVID-19: a global threat to the nervous system. Ann Neurol. 2020;88(1):1-11. [CrossRef]
- Ellul MA, Benjamin L, Singh B, et al. Neurological associations of COVID-19. Lancet Neurol. 2020;19(9):767-783. [CrossRef]
- Ceban F, Ling S, Lui LMW, et al. Fatigue and cognitive impairment in post-COVID-19 syndrome: a systematic review and meta-analysis. Brain Behav Immun. 2022;101:93-135. [CrossRef]
- Goërtz YMJ, Van Herck M, Delbressine JM, et al. Persistent symptoms 3 months after a SARS-CoV-2 infection: the post-COVID-19 syndrome? ERJ Open Res. 2020;6(4):00542-2020. [CrossRef]
- Miskowiak KW, Johnsen S, Sattler SM, et al. Cognitive impairments four months after COVID-19 hospital discharge: pattern, severity and association with illness variables. Eur Neuropsychopharmacol. 2021;46:39-48. [CrossRef]
- Becker JH, Lin JJ, Doernberg M, et al. Assessment of cognitive function in patients after COVID-19 infection. JAMA Netw Open. 2021;4(10):e2130645. [CrossRef]
- Meinhardt J, Radke J, Dittmayer C, et al. Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in COVID-19 patients. Nat Neurosci. 2021;24(2):168-175. [CrossRef]
- Frere JJ, Spinelli C, Han S, et al. SARS-CoV-2 infection of the nervous system: a review of the evidence. Cell. 2022;185(14):2235-2247.e12. [CrossRef]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Copyright: This open access article is published under a Creative Commons CC BY 4.0 license, which permit the free download, distribution, and reuse, provided that the author and preprint are cited in any reuse.
