Intervention modalities for brain fog caused by long-COVID: systematic review of the literature

Abstract

Individuals suffering from long-COVID can present with "brain fog", which is characterized by a range of cognitive impairments, such as confusion, short-term memory loss, and difficulty concentrating. To date, several potential interventions for brain fog have been considered. Notably, no systematic review has comprehensively discussed the impact of each intervention type on brain fog symptoms. We included studies on adult (aged > 18 years) individuals with proven long- COVID brain-fog symptoms from PubMed, MEDLINE, Central, Scopus, and Embase. A search limit was set for articles published between 01/2020 and 31/12/2023. We excluded studies lacking an objective assessment of brain fog symptoms and patients with preexisting neurological diseases that affected cognition before COVID-19 infection. This review provided relevant information from 17 studies. The rehabilitation studies utilized diverse approaches, leading to a range of outcomes in terms of the effectiveness of the interventions. Six studies described noninvasive brain stimulation, and all showed improvement in cognitive ability. Three studies described hyperbaric oxygen therapy, all of which showed improvements in cognitive assessment tests and brain perfusion. Two studies showed that the use of Palmitoylethanolamide and Luteolin (PEA-LUT) improved cognitive impairment. Noninvasive brain stimulation and hyperbaric oxygen therapy showed promising results in the treatment of brain fog symptoms caused by long-COVID, with improved perfusion and cortical excitability. Furthermore, both rehabilitation strategies and PEA-LUT administration have been associated with improvements in symptoms of brain fog. Future studies should explore combinations of interventions and include longer follow-up periods to assess the long-term effects of these treatments.

Keywords: Brain fog; Intervention; Non-invasive brain stimulation; Oxygen therapy hyperbaric; Post-acute sequelae of COVID-19.

Fig. 1

Revised Cochrane risk-of-bias (ROB2) tool for RCTs

Fig. 2

Preferred reporting items for systematic reviews and meta-analyses (PRISMA) Flow Chart

Fig. 3

Potential mechanism underlying brain-fog symptoms caused by COVID-19. When COVID-19 patients gain access to the central nervous system (CNS), various pathways are activated, including direct invasion of CNS cells, retrograde axonal transport, and penetration through the endothelial cells of the blood‒brain barrier. Once inside the CNS, COVID-19 can prompt microglia to release proinflammatory agents, leading to mitochondrial dysfunction and oxidative stress. This cascade of events can lead to neuroinflammation, demyelination, and neurodegeneration. Moreover, systemic hypoxia and organ-related ischemia also participate in pathogenesis