COVID-19-associated neurological and psychological manifestations, 2025, Wilson et al.

[Chandelier]

COVID-19-associated neurological and psychological manifestations

Spoiler: Authors

Wilson, Jo Ellen; Gurdasani, Deepti; Helbok, Raimund; Ozturk, Serefnur; Fraser, Douglas D.; Filipović, Saša R.; Peluso, Michael J.; Iwasaki, Akiko; Yasuda, Clarissa Lin; Bocci, Tommaso; Priori, Alberto; Altmann, Daniel; Alwan, Nisreen A.; Wesley Ely, E.

Abstract​

Long COVID is an infection-associated chronic condition that typically occurs within 3 months of acute COVID-19 infection in which symptoms are intermittently or continuously present for at least 3 months.
Long COVID is estimated to affect between 80 and 400 million people globally, with an incidence of 5–20% in the community and up to 50% among hospitalized patients following acute SARS-CoV-2 infection.
Common neuropsychiatric and mental health symptoms of long COVID include memory deficits, executive dysfunction, anxiety, depression, recurring headaches, sleep disturbances, neuropathies, problems with taste and smell, and dizziness that accompanies erratic heart rates and severe post-exertional malaise.
Underlying pathophysiological mechanisms includes SARS-CoV-2 viral persistence, herpesvirus reactivation, microbiota dysbiosis, autoimmunity, clotting and endothelial abnormalities, and chronic immune activation.
Owing to the variability in the clinical presentation, management must be tailored based on a patient’s presenting symptoms.

Web | DOI | PDF | Nature Reviews Disease Primers
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[Utsikt]

Underlying pathophysiological mechanisms includes SARS-CoV-2 viral persistence, herpesvirus reactivation, microbiota dysbiosis, autoimmunity, clotting and endothelial abnormalities, and chronic immune activation.
Owing to the variability in the clinical presentation, management must be tailored based on a patient’s presenting symptoms.

Is this another review taking every abstract at face value?

We have no idea about the pathophysiology and there are no treatments so presumably there is no management to tailor other than helping with the practical consequences of their disability.

 

[SNT Gatchaman]

These are probably the relevant sections for us.

Pharmacological management
Studies of new treatments for long COVID should focus on particular organ systems and specific symptoms of long COVID160. Although many studies are ongoing, only a few have been completed (Supplementary Table 1); therefore, there is little evidence for definite recommendations, and more clinical trials are still needed. Most studies focusing on neurological manifestations of long COVID have investigated the treatment cognitive impairments, including brain fog and fatigue although, few studies have been completed (Table 2 and Supplementary Table 1).

There are many systematic and other reviews as well as guidelines published for assessing the efficacy of different approaches to the treatment of long COVID symptoms. Despite all these studies, only a few potential treatment options for long COVID are available with some evidence base.

All guidelines for long COVID recommend that specific symptoms are referred to a specialist for treatment according to management guidelines for that condition. For example, stroke should be managed by a stroke specialist during the acute and chronic stages and for secondary prevention. Similarly, brain fog and other cognitive disorders, headaches and sleep disorders should be treated according to relevant guidelines and specialist advice. Specific recommendations are not available for fatigue and myalgia.

Non-pharmacological management
Some manifestations of long COVID (such as fatigue, PEM, cognitive impairment, anxiety and depression) are treated via non-pharmacological approaches. The most promising non-pharmacological approaches include psychological therapies with behavioural interventions, physiotherapy with occupational therapy, and non-invasive brain stimulation (NIBS).

Fatigue and post-exertional malaise
Fatigue and PEM are the most frequently reported long COVID symptoms. Although these symptoms often occur together, they are separate phenomena that require specific management approaches. Fatigue is the subjective sensation of lack of physical and/or mental energy not related to or in disproportion with previous and/or ongoing levels of activity, whereas PEM is the worsening of long COVID symptoms after physical and/or cognitive exertion, including overexertion. Although the exact biological mechanisms underlying PEM are unclear, some studies have suggested that with physical activity, systemic oxygen extraction and oxidative phosphorylation capacities are exceeded, mediated by dysfunction in mitochondria and microcirculation, which is maintained by latent immune activation. Impaired metabolism leads to the accumulation of lactate, reactive oxygen species or prostaglandins following physical exertion, which further potentiate systemic immune activation.

For rehabilitation management of PEM in adults with long COVID, education and skills training on energy conservation techniques, such as pacing, are important. Pacing is an activity and energy management technique consisting of balancing activities and rests contingent on symptoms. However, interventions for rehabilitation based on fixed incremental increases in the time spent being physically active or graded exercise, which is often suggested to people with ME/CFS, should not be offered to people experiencing PEM, or if used it should be overseen by a specialist ME/CFS physiotherapist and include regular review. An evaluation by a physical medicine and rehabilitation physician or an occupational or physical therapist in the provision and training in the use of assistive products and environmental modifications (for example, a bath grab bar, raised toilet seat, etc.) may also be useful for people experiencing moderate to severe PEM.

For both fatigue and PEM, behavioural management techniques (rest breaks, cognitive behavioural therapy (CBT) and mindfulness-based stress reduction programmes), as well as educational and self-management programmes (such as relaxation, avoiding multitasking and improved sleep hygiene), are recommended by the major guidelines (Table 1). In addition, physical activity programmes (such as aerobic exercise, strengthening exercises, hydrotherapy, yoga and tai chi) are also of considerable importance for in the management of fatigue.

However, almost all the recommendations in existing guidelines are based on expert consensus and other conditions with similar symptoms to long COVID. Randomized clinical trials involving people with long COVID are scarce. A reasonably sized study (n = 114) involving people with severe post-COVID-19 fatigue found a significant benefit of CBT compared with routine care. Interestingly, two reasonably sized randomized placebo-controlled studies found beneficial effects of transcranial direct current stimulation (tDCS), a form of NIBS, on post-COVID-19 fatigue. In one study including 47 patients (23 in the active treatment group and 24 in the sham treatment group), tDCS of the left dorsolateral prefrontal cortex improved subjective measures of fatigue, and in another study including 70 patients with long-COVID-related fatigue, high-density tDCS of the left motor cortex improved subjective measures of fatigue, anxiety and quality of life.

Other alternative medical regimens have been studied for the management of fatigue, although they have limited supporting evidence. Hyperbaric oxygen therapy led to improved subjective symptoms of fatigue in a small case series. Moreover, a randomized trial investigating 2 weeks of aromatherapy (including thyme, orange, clove bud and frankincense) also showed benefit in improving energy levels in a small group of female patients compared with placebo.

 

[Jonathan Edwards]

I am afraid that I cannot take any of the authors of this paper seriously if they are prepared to put out drivel like this. A rehab psychologist seems somehow to have been able to recruit a string of celebrity Twitterati to produce the same old jobs for the boys and girls analysis.

 

[NelliePledge]

Frankincense - that’s a new one for the yoga and kale list of patronising have you tried suggestions

 

[Eleanor]

I am afraid that I cannot take any of the authors of this paper seriously if they are prepared to put out drivel like this. A rehab psychologist seems somehow to have been able to recruit a string of celebrity Twitterati to produce the same old jobs for the boys and girls analysis.

I'm particularly disappointed to see Altmann on there as I'd previously got the impression he had an understanding of the seriousness of the problem. And now his name's on this piffle about tai chi and clove buds.

 

[Dolphin]

Study details neuropsychiatric symptoms and biological mechanisms of long COVID

It is estimated that up to 400 million people worldwide and nearly 14 million in Brazil have the chronic condition. A review by an international panel of 14 experts, including Brazilians, highlights the need to standardize diagnosis and treatment.

www.eurekalert.org

NEWS RELEASE 23-MAR-2026

Study details neuropsychiatric symptoms and biological mechanisms of long COVID​

It is estimated that up to 400 million people worldwide and nearly 14 million in Brazil have the chronic condition. A review by an international panel of 14 experts, including Brazilians, highlights the need to standardize diagnosis and treatment

Peer-Reviewed Publication
FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO


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Nearly three years after the SARS-CoV-2 pandemic was declared over, conservative estimates suggest that between 80 million and 400 million people worldwide have long COVID. This chronic condition associated with the infection is linked to more than 200 symptoms, including fatigue and shortness of breath, as well as neuropsychiatric issues ranging from cognitive dysfunction and sleep disorders to depression and memory loss. These issues impact quality of life and hinder the performance of daily tasks and work.

Underlying pathophysiological mechanisms (processes that occur in the body and help explain certain symptoms and changes) include viral persistence of SARS-CoV-2, reactivation of herpesviruses (when immune stress allows latent viruses of the Herpesviridae family to become active), and chronic immune activation. Other mechanisms include immune system dysregulation, an imbalance in the function of microorganisms in the gut (microbiota dysbiosis), coagulation abnormalities, and endothelial damage. Regarding the brain, there are structural changes and abnormal functional connectivity.

However, significant progress in understanding long COVID requires further scientific studies to standardize definitions and nomenclature for the disorder, as well as more clinical trials with potential therapies.

The first review article published by the journal Nature Reviews Disease Primers provides an overview of this topic and is dedicated to the neurological, psychological, and psychiatric manifestations associated with COVID-19. The paper provides a comprehensive analysis of its epidemiology, biological mechanisms, diagnosis, therapeutic approaches, impact on quality of life, and the challenges facing science.

An international panel of 14 experts developed the article, which includes a single Brazilian author: professor and neurologist Clarissa Yasuda, from the Faculty of Medical Sciences at the State University of Campinas (UNICAMP) in the state of São Paulo. Yasuda is also a researcher at the Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), a FAPESP Research, Innovation, and Dissemination Center (RIDC). Since 2020, she has coordinated a series of studies on long COVID (read more at agencia.fapesp.br/41738).

“This disease is new and little understood. Many people are studying and trying to understand it, not only because of current cases, but also because humanity is susceptible to other viruses that could cause problems on the scale of that pandemic. We need to learn from it and investigate effectively and quickly. Long COVID greatly disrupts people’s lives, and currently, there’s no specific treatment. The important thing is to get vaccinated and avoid reinfection. That’s another message of the article,” Yasuda tells Agência FAPESP.

In the study, the researchers emphasize that avoiding SARS-CoV-2 infection is the only way to prevent long COVID so far. They note that diagnosis is based on clinical evaluation. Since there are no available biomarkers, a recent history of infection with the virus is required, as well as persistent or recurrent symptoms for at least three months. Other conditions must be ruled out, which may require blood and imaging tests, electrocardiography, and echocardiography.

In Brazil, the number of reported cases of COVID-19 has been falling year after year but remains high. In 2025, the Ministry of Health reported approximately 432,400 cases, compared to 984,000 the previous year. Between January and the second week of February of this year, approximately 25,200 cases were reported.

Quality of life

In the section on quality of life, the article discusses the effects of long COVID on the labor market and the stigmas associated with the disease, in addition to its health impacts.

The authors point out that individuals may experience job and income loss, as well as difficulty returning to work due to a lack of support from social welfare systems. They also mention that affected individuals may experience periods of “ups and downs,” “breakdowns,” “depression,” and “lows,” which can leave them feeling unable to maintain the same level of activity.

In 2024, scientists from U.S. institutions published an article in Nature Medicine estimating that long COVID resulted in over 803 million lost work hours in Brazil alone that year, with a potential cost of more than USD 11 billion. This equates to approximately 400,000 full-time workers being out of the labor market for a year. The same study estimated that long COVID could have an annual global economic impact of approximately USD 1 trillion – about 1% of the global economy.

Professor Yasuda herself experienced difficulties resuming her activities after having long COVID. She contracted the virus in August 2020 and experienced mild symptoms without a fever. However, about a month later, she realized that cognitive dysfunction was hindering her academic work.

In the article “I Want My Brain Back,” published in the Scielo Brasil digital library in June 2022, she recounted her experience. “At the time, I described my recovery efforts and the strategies I used to cope with the persistent limitations in cognitive performance. After a lot of effort and discipline, I improved,” she says.

Long COVID, also known as “post-COVID-19 condition,” has been monitored by Brazil’s national public health system, the SUS (Sistema Único de Saúde), since 2021, with an update in 2023 via Technical Note No. 57. An epidemiological bulletin on the topic released in 2025 estimated that there were 13.8 million cases of “post-COVID conditions” in the country, the majority of whom were female (8.58 million). The most affected age group was 30 to 49 (6.2 million Brazilians).

Stigma

Regarding stigma, the scientists note that patients face multiple barriers when trying to have their condition recognized and gain access to care and support. These experiences can range from discrimination and inadequate treatment to blame. Individuals from ethnic minorities experience particularly high levels of stigma.

They also note that there can be serious implications for social and educational interactions for children and adolescents.

Therefore, they recommend multidisciplinary teams, including professionals from various health fields, provide patient care.

For future studies, they recommend recruiting a diverse and representative patient population and taking the perspectives of people with long COVID and the role of social and health determinants into account.

In this context, Yasuda’s group is conducting a longitudinal study to understand how the disease changes the brain. “Being invited to participate in this review was very important and an international recognition of the work we’re developing at the BRAINN RIDC,” says Yasuda, who also receives support from the National Council for Scientific and Technological Development (CNPq), a funding agency linked to the Ministry of Science, Technology, and Innovation.

About São Paulo Research Foundation (FAPESP)
The São Paulo Research Foundation (FAPESP) is a public institution with the mission of supporting scientific research in all fields of knowledge by awarding scholarships, fellowships and grants to investigators linked with higher education and research institutions in the State of São Paulo, Brazil. FAPESP is aware that the very best research can only be done by working with the best researchers internationally. Therefore, it has established partnerships with funding agencies, higher education, private companies, and research organizations in other countries known for the quality of their research and has been encouraging scientists funded by its grants to further develop their international collaboration. You can learn more about FAPESP at www.fapesp.br/en and visit FAPESP news agency at www.agencia.fapesp.br/en to keep updated with the latest scientific breakthroughs FAPESP helps achieve through its many programs, awards and research centers. You may also subscribe to FAPESP news agency at http://agencia.fapesp.br/subscribe.

JOURNAL​

Nature Reviews Disease Primers

DOI​

10.1038/s41572-025-00674-7

ARTICLE TITLE​

COVID-19-associated neurological and psychological manifestations

ARTICLE PUBLICATION DATE​

24-Dec-2025