Impact of COVID-19 Infection on Cognitive Function: History
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Contributor:
Sarah Houben
,
Bruno Bonnechère

There is mounting evidence that patients with severe COVID-19 disease may have symptoms that continue beyond the acute phase, extending into the early chronic phase. This prolonged COVID-19 pathology is often referred to as ‘Long COVID’. Simultaneously, case investigations have shown that COVID-19 individuals might have a variety of neurological problems. The accurate and accessible assessment of cognitive function in patients post-COVID-19 infection is thus of increasingly high importance for both public and individual health.

  • long-COVID
  • cognitive disorders
  • rehabilitation

1. Level of Cognitive Disorders in Patients with COVID-19

By analysing the results of different studies, there is clear evidence that people infected by SARS-CoV-2 show significant cognitive disorders (mean SMD −0.41 [95% CI −0.55; −0.27]), independently from the pathology stage or patients’ age. In addition, there is not a clear link between the severity of the infection and the degree of neurocognitive deficit. Before discussing the effect of rehabilitation, it is interesting to discuss other potential factors that could decrease the importance of the observed cognitive impairment in these patients.
The first potential aspect is vaccination. Most of the studies recruited the participants during the first wave, in 2020. Since fifty percent of the worldwide population was fully vaccinated (two doses of vaccine) at the beginning of January 2022, the vast majority of participants contracted COVID-19 before receiving any vaccination dose and it is therefore difficult to assess this point. To the authors’ best knowledge there is currently no study assessing the link between vaccination and a decrease in cognitive functions. It would be interesting to see new studies on long-COVID, among a fully vaccinated population. Nevertheless, it seems that vaccinated people with breakthrough infection were partially at lower risk of death and post-acute sequelae than people with a SARS-CoV-2 infection without prior vaccination, but cognition was not evaluated in this study [1]. Another study showed that vaccination may reduce the burden of long-COVID and this is already the case after one dose of vaccine [2]. Similar results were found in another study which concluded that people, especially older than 60 were more likely to be asymptomatic if they were infected by SARS-CoV-2 after being fully vaccinated [3]. So, if the pathology is less aggressive and the symptoms are reduced in vaccinated people, one could assume that the cognitive impairment in these infected people would be less important.
Nevertheless, according to OpenVAERS, 1,301,354 adverse events were reported after COVID-19 vaccine administrations and among that, there are more than 163,000 hospitalizations (data from the 20th of June 2022) [4]. Different vaccines were tested during this period and some of them were recalled or restricted due to side effect issues. One can easily imagine that cognitive impairments or reduced quality of life were among these adverse events and therefore cannot exclude a possible role of the vaccination in the observed neurological deficits. Another aspect to analyse is the age of the included participants. Here, the researchers chose adults as inclusion criteria, however, long-COVID pathology has been also reported in children and adolescents, but only a few studies have analysed long-COVID in the paediatric population [5][6][7]. It is however important to note that there are very limited cases of children with severe SARS-CoV-2 infection. Children and young adults affected by COVID-19 tend to be less sick than older adults and therefore one can assume that they presented a reduced risk of potential neurological disorders. It is also not clear whether the cognitive disorders that could be observed were due to the SARS-CoV-2 infection or to the pandemic situation where restrictions, isolation, and online teaching for example have been important stress factors that could also directly negatively impact cognitive functions. Studies in this population are surely necessary because they are still in a crucial phase of brain development.
Although some groups began to explore the neurophysiology [8][9] and the neuropathology [10][11] behind these cognitive impairments, the mechanism of action between SARS-CoV-2 infection and cognitive disorders is far from being understood. Current evidence suggests a highly multifactorial component: direct infection by SARS-CoV-2, the consequence of prolonged-time spent in intensive care units, persistent inflammation, brain hypoxia, ventilation mechanisms used, drugs, prior cognitive troubles, and peripheral organ dysfunction. The combination of these factors could lead to the so-called long-COVID statement. The uncontrolled inflammatory response, also named the cytokine storm may contribute to the severity of the disease. This increased level of inflammatory cytokines and chemokines was previously also observed during infection with other severe coronaviruses. High levels of IL-6, IL-8, and TNF-α were found in COVID-19 patients’ serum [8][12].
Some suggest that the sustained inflammatory response could contribute to psychiatric sequelae, such as cognitive impairment, after COVID-19 [9]. This persistence of inflammation was already correlated with depression [13] and can lead to a disruption of the blood–brain barrier (BBB), also resulting in neuronal and glial cells damages [14]. BBB permeability will permit cytokines like IL-6 to enter the brain giving rise to depression-like behaviours [15]. The disruption of the BBB can also directly permit SARS-CoV-2 to reach the central nervous system, in addition to the other pathway that would be the retrograde transport via the olfactory sensory neurons [16].
However, on the other hand, this cytokine storm is only observable in the most severe cases, and it has been seen that these cognitive impairments affect patients who have had either mild or severe forms of COVID-19 [1]. Therefore, this mechanism alone could not (fully) explain the neuropsychiatric deficits.
As with other coronaviruses, SARS-CoV-2 shows a neurotropism. The virus could enter into neurons and glial cells with the SPIKE protein, which binds to ACE2 receptors (angiotensin-converting enzyme 2) [17], which would result in neuronal death, and then, cause cognitive deficits [14]. As adult neurogenesis is not yet clearly demonstrated, this neuronal loss would be irreversible and could lead to an acceleration decline of brain functions, causing the typical symptoms observed in pathologies such as Alzheimer’s disease, and Parkinson’s, namely memory loss, learning deficits, and motor problems for example.

2. Rehabilitation Strategies

Different rehabilitation strategies have been proposed to improve the functions and the quality of life of patients suffering from COVID-19 infection both in the acute [18] and the chronic phase [19]. In the acute phase, rehabilitation seemed to improve dyspnoea, anxiety, and kinesiophobia. Results on pulmonary function were inconsistent, while improvements were detected in muscle strength, walking capacity, sit-to-stand performance, and quality of life, no information was available for cognitive functions [18].
Of course, most of the interventions, and therefore the current level of evidence, are focusing on pulmonary rehabilitation [20] and physical activity [21][22]. Significant differences were also found in quality-of-life related outcomes for both short and long term.
A new model of care has emerged, utilizing information and communication technologies to ensure the continuation of these services. Health services delivered via digital means are referred to as “telehealth”, “eHealth”, or “mHealth” [23]; about physiotherapy, the term “telerehabilitation” has been widely used in the literature to describe rehabilitation services delivered via mHealth [24]. Telerehabilitation can be provided through a variety of digital channels, including synchronous audio and/or video calls, as well as asynchronous channels such as recorded videos, text messages, emails, and links to educational materials [25]. Three randomized control trials (RCT) have been recently published on the use of telehealth in the management of COVID-19 patients.
In the acute phase of COVID-19, it has been shown in a large RCT that delivering breathing exercises via telerehabilitation was a promising, safe, and effective strategy for improving physical performance, dyspnoea, and perceived effort [26]. Patients performed breathing exercises at home once per day for one week, while a physiotherapist reinforced the program via videoconference; patients also received a daily text message to increase adherence.
In another study, the authors examined the effects of a 6-week unsupervised home-based exercise program consisting of breathing, aerobic, and lower limb muscle strength exercises delivered to COVID-19 patients via smartphone and remotely monitored by heart telemetry. At week 6 (post-treatment) and week 28 (follow-up), the intervention was superior in terms of exercise capacity, lower limb muscle strength, and quality of life [27].
In a last RCT the authors compared the efficacy of two different exercise-based programs (strengthening and breathing exercises) delivered via telerehabilitation in COVID-19 patients [28]. After the 14-day intervention, statistically significant differences were observed between the two intervention groups and the control group in all variables (fatigue, dyspnoea, perceived effort, and physical condition), with the breathing exercises group showing the greatest improvements in dyspnoea and aerobic capacity.
The three examples show that telerehabilitation proved to be an effective, safe, and feasible modality to facilitate the recovery of these patients, but it must be noted that specific outcomes related to cognition were never investigated in the above-mentioned studies. However, based on previous works and evidence, mainly studies on aging population, one can assume that physical exercises and an increased physical activity level will not only induce an increase in motor outcomes but will also improve cognition. It has indeed been shown that older people who are regularly engaged in exercise are more likely to maintain their cognitive functions compared to those who are physically inactive [29]: as a matter of fact, exercise has been shown to be a highly effective therapeutic strategy for age-related progressive neurodegenerative disorders, including dementia [30], with greater levels of physical activity seemingly protective against the onset of dementia in individuals who are healthy at baseline. In addition, physical activity yields significant improvements in cognition in individuals with dementia and mild cognitive impairment [31][32][33]. Interestingly a recent meta-analysis of randomized controlled trials has shown that combining cognitive intervention and physical exercise results in superior benefits over either intervention alone on global cognition, memory, executive function, and attention in older adults with mild cognitive impairment [34].

3. Implications for the Rehabilitation

The COVID-19 pandemic has drastically changed our lives. During the different peaks of the crisis, the continuity of care can no longer be guaranteed [35]. Therefore, rehabilitation services were forced to modify and adapt the way they provide and deliver services [36]. These measures were proposed and adopted in a large number of countries; the proposed changes included the following: A multidisciplinary team should administer early mobilization, respiratory, outpatient, and long-term care rehabilitation interventions to critically ill SARS-CoV-2 patients. Home- and community-based rehabilitation can be provided through various methods, such as telerehabilitation and direct care. COVID-19 transmission prevention and protection measures are required for all patients receiving rehabilitation care [37].
The COVID-19 pandemic has accelerated the development and implementation of telehealth, with the number of healthcare interventions delivered via digital devices increasing exponentially, also due to the widespread availability of mobile technology. This may open up new perspectives and opportunities in the healthcare industry, as previous research has shown that telehealth is well-received by patients, leading to greater adherence [38][39] and patient satisfaction [40][41]. So far, there is currently no study that has been specifically focusing on the rehabilitation of cognitive fatigue and disorders in COVID-19 patients. However, there is currently a growing body of evidence supporting the use of mHealth and brain training games or apps to train and challenge the brain in different ways. Recent systematic reviews and meta-analyses reported cognitive improvement after intervention using cognitive mobile games in various conditions such as healthy aging [42], mild cognitive impairment [43], stroke [44], Parkinson’s disease [45], and multiple sclerosis [46].
Technology and social media-based interventions appear to be promising techniques for promoting health and well-being and are the only effective methods for delivering an intervention during a pandemic situation [47]. However, there also appears a need for the development of guidelines for social media usage to prevent probable hazards and fake news.
However, a few issues must be resolved before these solutions can be implemented in daily practice. First, and likely most important, is the acceptance of mHealth applications as rehabilitation interventions. Not only has the COVID-19 pandemic disrupted healthcare systems, but it has also accelerated the development, implementation, and recognition of mHealth in clinical settings [48]. Notably, the majority of measures taken during the crisis may be temporary, and it is hoped that efforts will continue in this direction once the crisis has passed. For instance, it will be necessary to revise the nomenclature of interventions, as mobile solutions are currently placed in the same categories as pharmaceuticals, posing validation and reimbursement challenges [49]. A further limitation is that the majority of analysed mHealth is currently being developed as part of research projects and is therefore not readily available to patients. This brings us to the second major current limitation, which is the lack of social security reimbursement. The organization and participation of healthcare systems in the revalidation process varies by country, so reimbursement will not be discussed in detail here. However, it is known that the two most significant barriers to the implementation of telemedicine and telehealth for patients, regardless of their pathologies or specialties, are financial concerns and a lack of knowledge and experience with the use of (new) technology [50][51]. Most patients are familiar with smartphones, apps, and mobile technology, so familiarity with the technology should not be an issue for the majority of patients [52], whereas this can be a significant barrier for other diseases or patient groups (e.g., older adults with dementia) [53]. Efforts must also be directed toward the education of healthcare professionals, as they must be trained in the technology and know its limitations in order to encourage patients to utilize it.

This entry is adapted from the peer-reviewed paper 10.3390/ijerph19137748

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