Abstract

1 Introduction

In March 2020, COVID-19 was declared a worldwide pandemic by the World Health Organization (WHO). From the first recorded case of COVID-19 until today, over 450 million cases worldwide have been counted. Within a few months of the initial outbreak of this predominantly pneumatological disease, several patients reported long-lasting symptoms for weeks to months after their acute infection, later described as Long- or Post-COVID (1, 2). Currently, there is no clear consensus regarding the taxonomy to describe COVID-19 sequelae. However, the majority of the literature refers to the British National Institute for Health and Care Excellence (NICE) guidelines that categorize COVID-19 sequelae into three separate definitions: (i) “acute COVID-19” for symptoms during the first month after infection, (ii) “ongoing symptomatic COVID-19” describing symptoms from four to twelve weeks after infection, and lastly, (iii) “Post-COVID-19 syndrome” for unresolved signs and symptoms of COVID-19 twelve weeks after infection (3). The term Long-COVID refers to any signs and symptoms that persist or develop after an acute COVID-19 infection. This includes both “ongoing symptomatic COVID-19” (4 to 12 weeks) and “Post-COVID-19 syndrome” (12 weeks or longer) (3). In the past two years, additional guidelines for patients and physicians have been published to help cope with these yet not fully understood secondary disorders (4, 5). Note that in the German S1-Guidelines, there is a clear distinction between Long- and Post-COVID syndrome. Here, the authors refer to Long-COVID syndrome, when patients report persistent symptoms for more than four weeks after the acute infection and to Post-COVID syndrome, when symptoms persist for more than twelve weeks (4). However, in this review, we will refer to the NICE guidelines and use the term Long-COVID as a general term referring to both time periods, four to twelve weeks, as well as persisting symptoms for more than twelve weeks.

Due to the novelty and complexity of Long-COVID, progress in understanding and treating Long-COVID is still limited. Two of the most frequently observed symptoms of Long-COVID are fatigue and cognitive impairments (6). The fatigue syndrome describes an overwhelming feeling of exhaustion that is manifested both cognitively and physically and does not resolve with rest or sleep (7). It is also frequently reported in other pathological conditions such as multiple sclerosis (MS, 8), Parkinson´s disease (9), stroke (10), and chronic fatigue syndrome (CFS, 11). Among people with MS, fatigue has been identified as the most detrimental symptom to quality of life (12), as is now similarly described by people with Long-COVID (13, 14).

Despite its clinical importance, there is a lack of effective therapeutic methods to alleviate fatigue. However, in recent years, numerous replicated studies, primarily conducted in people with MS, have demonstrated the efficacy of transcranial direct current stimulation (tDCS) as a promising, non-invasive, and non-pharmacological method of reducing fatigue (see 15 for a systematic review). Additionally, studies using transcranial alternating current stimulation (tACS) or transcutaneous vagus nerve stimulation (tVNS) show promising results (16–18). Therefore, the aim of this review article is to give a more detailed insight into Long-COVID-related fatigue and to discuss non-invasive brain stimulation (NIBS) techniques as a possible alternative therapeutic approach. The review includes data before August 2022, covering the first two and a half years of COVID-19 research and approximately the first two years of Long-COVID research.

2 Long-COVID

The main risk factors for Long-COVID are the amount and duration of symptoms at the acute stage of infection, body mass index, and female sex (19–21). Thus, according to Sudre et al. (21), Long-COVID was more likely to occur when patients reported more than five symptoms within the first week of infection. These included fatigue, headache, dyspnea, hoarse voice, and myalgia. Interestingly, the likelihood and severity of Long-COVID symptoms are not associated with the initial severity of the acute COVID-19 infection (19, 22).

The severity of Long-COVID varies greatly among individuals, from mild disturbances that last a few weeks to severe illnesses that keep a person from managing their everyday lives for an extended period of time (6). Additionally, symptoms can be persistent or undulant, meaning that they are present at all times or disappear and repeatedly return (23). There is a considerable variation in the incidence rates of Long-COVID among studies. Thus, Sudre et al. (21) reported that 13.3% of the participants reported symptoms lasting for over 28 days, 4.5% for over eight weeks, and 2.3% for over twelve weeks. Another study by Nalbandian et al. (6), reported that up to 55% of COVID-19 patients might develop persisting symptoms after their acute infection. Furthermore, persistent symptoms after an acute COVID-19 infection do not necessarily lead to a reduction in quality of life. Thus, in a study by Giszas et al. (24), 70.7% of the participants reported persistent symptoms, while only one-third of those also reported that these symptoms significantly reduced their quality of life. Giszas et al. (24) therefore proposed to distinguish between Long-COVID “disease”, in which quality of life is significantly diminished and Long-COVID “condition”, in which quality of life is near-normal. In summary, while not entirely conclusive, these rates indicate that a significant amount of individuals who have had COVID-19 may develop Long-COVID.

The mechanisms behind the onset of Long-COVID are etiologically complex and can affect different organ systems within the body. Correspondingly, Long-COVID can entail a plethora of signs and symptoms months after the acute infection (23, 25). Neurological symptoms of Long-COVID primarily include cognitive and physical fatigue, as well as cognitive impairment, also referred to as brain fog (26). Other symptoms include headaches, gustatory and olfactory disturbances, neuropathic pain, and motor-sensory symptoms like sensitization disturbances such as numbness or paresthesia (26).

3 Long-COVID-related fatigue

People affected by Long-COVID report severe cognitive and physical fatigue as well as brain fog that make it almost impossible to execute daily tasks (23). Fatigue is therefore identified as the most detrimental symptom to the quality of life of people suffering from Long-COVID (14, 27).

The emergence of Long-COVID and its main symptom of severe fatigue has brought up a topic that researchers have tried to explore in its entity and have not yet fully understood. Thus, although fatigue is a common symptom in many neurological disorders, the exact etiology and underlying pathophysiology still remains unclear. It has been attributed to a variety of pathomechanisms, including primary causes such as axonal demyelination or atrophy (28–33), as well as neuroendocrine dysregulation (34, 35) or an underlying immune system malfunction (36, 37), see Palotai and Guttmann (38) or Chalah and Ayache (39) for comprehensive reviews.

A dysregulated immune system, as experienced in fatigue-typical neurological diseases as well as after an acute COVID-19 infection (40), may cause severe and ongoing damage to the brain, even in the absence of the primary viral attack. Thus, an acute COVID-19 infection leads to an overwhelming immune response called systemic inflammatory response syndrome (SIRS). During SIRS, the immune system is activated, and pro-inflammatory cytokines are excessively released, resulting in a variety of symptoms, among others, fatigue (41). To return to immunologic homeostasis, this process is then followed by a compensatory anti-inflammatory response (compensatory anti-inflammatory response syndrome, CARS), a mirror-imaged counter-regulation to SIRS that dampens the pro-inflammatory state and deactivates the immune system. However, if this balance between SIRS and CARS is dysregulated and the inflammatory response is repressed too far, this may lead to a stage of prolonged immunosuppression, provoking chronic pro-inflammatory cytokines production and an impaired immune competence, thereby making individuals highly susceptible to secondary infections (41–43). Inflammatory responses and, in consequence, anti-inflammatory reactions vary from person to person depending on the viral load they were exposed to, the adequacy or inadequacy of their immune system prior to an infection and whether or not they are dealing with comorbidities (41). Persistent inflammation and simultaneous suppression of the immune system have been consistently reported in people with Long-COVID (42) and also in CFS. Like Long-COVID, CFS is characterized by immune and nervous system disorders that lead to persistent difficulty in physical and mental functioning (44). It usually starts in previously healthy individuals who have overcome a viral infection (45), and it is characterized by persisting symptoms that include fatigue, post-exertional malaise, low blood pressure, cognitive disturbances, sleep problems, hypersensitivity and pain, as well as symptoms that can be classified under immune dysfunction (11).

In addition to the dysregulated immune system, reduced cerebral blood flow (CBF) has been described as another inflammation-related component in the development of fatigue in neurological diseases, CFS and Long-COVID. Hence, Fluge et al. (45) proposed a framework model for the initiation and maintenance of CFS, in which an initial inflammatory response leads to a release of B-cells and antibodies. These, in turn, can affect the vascular system and impede neurovascular control, resulting in impaired blood flow autoregulation and, ultimately, tissue hypoxia. Moreover, reactive oxygen species might play an important role in this process as they have consistently been implicated as an integral aspect of CFS pathophysiology (46, 47). Thus, initially released after an immune response, they trigger a chain reaction that induces a vasoconstrictor response, which is then followed by a decreased regional CBF (46–48). The decrease in CBF and hypoxia, as well as the body’s attempt to compensate for the impairment and maintain vascular homeostasis, lead to the symptoms of persistent fatigue that we see in the suffering individuals. Often, the effects of fatigue are particularly noticeable after physical or cognitive exertion, as the higher oxygen demand cannot be met (45). CBF decline has been reported in several studies regarding MS-related fatigue (49), CFS (50, 51) as well as LCOF (52, 53).

Additionally, as shown in MS-related fatigue, evidence exists for the involvement of a frontoparietal dysfunction and a malfunctioning cortico-striato-thalamo-cortical network in people with Long-COVID (54). Thus, an MRI- and PET-based study conducted by Hosp et al. (55) assessed the cognition of hospitalized COVID-19 patients shortly after their acute infection as well as six months after recovery. Directly after the acute stage, they found impaired memory and disturbed concentration. Interestingly, scans of COVID-19 patients showed less activity in neocortical areas with a predominant frontoparietal hypometabolism and, in reverse, higher activity in the brainstem and cerebellum. Additionally, this pattern correlated with the severity of impaired cognitive functions. At a 6-month follow-up, the frontoparietal hypometabolism was reversible but still significantly reduced compared to healthy controls (56). Similar metabolic changes are also found in people with MS who suffer from fatigue (57, 58).

4 General obstacles in fatigue research

A possible explanation for the lack of progress in understanding fatigue can be attributed to the lack of a universal definition and classification of fatigue. Therefore, we and others proposed a unified taxonomy that is disease-nonspecific and universally applicable (7, 59). Accordingly, the fatigue syndrome can be subdivided into physical, cognitive, and psychosocial fatigue (8). In this review, we focus on cognitive fatigue. Cognitive fatigue is defined as a decrease in cognitive resources and can further be described as a trait and a state component. Cognitive trait fatigue refers to an ongoing overall status of mental exhaustion that changes slowly over time and does not resolve with rest or sleep, while cognitive state fatigue refers to the subjectively perceived level of mental fatigue at a particular time (60). In recent years, it has become increasingly evident that, in addition to a subjective component, there is also an objectively measurable performance decline while executing a cognitively demanding task, which is often referred to as mental fatigue or fatigability (59).

However, the fatigue diagnosis is still very subjective. It is carried out using self-report questionnaires that assess the severity of trait fatigue and retrospectively ask subjects how they have been feeling over the past two to four weeks. Noteworthy, these questionnaires exclusively focus on the subjective experience of people suffering from fatigue and assess retrospective statements that are mood-sensitive and susceptible to psychological errors. Additionally, it has been reported that in people with MS, the questionnaires show low correlations among each other and assess different aspects of fatigue (61). Subjective state fatigue is typically assessed via numerical rating scales or visual analog scales that ask the patient to rate how exhausted they feel “right now at this moment”. To provide a comprehensive clinical diagnosis of fatigue, it is imperative to combine the assessment of subjective fatigue with objective evaluations of fatigue’s impact on physical or cognitive functioning. As behavioral parameters, primarily reaction time and accuracy changes are used. However, these show inconsistent results since participants are often able to maintain their performance despite a pronounced subjective feeling of exhaustion. In recent years, electrophysiological parameters, such as event-related potentials (62–64), sensory and sensorimotor gating deficits (65–67), and increasing fronto-medial theta and occipital alpha power (59, 68, 69) have been established as promising objective fatigability markers that are not subject to psychological biases. However, to this date, the relationship between subjective fatigue and fatigability is still a topic of controversy. Both may occur simultaneously or independently and are rarely associated (59). This discrepancy between subjectively perceivable fatigue and objectively measurable fatigability is also shown in recent Long-COVID studies. In a study by Dressing et al. (27), people with Long-COVID reported that their symptoms severely interfered with their daily lives, and 67% had subjective fatigue scores above the critical cutoff score for cognitive fatigue. However, an exhaustive assessment of their cognitive performance revealed only mild impairments and no objective changes in PET scans compared to healthy controls.

Due to the complex pathogenesis and the multifactorial character of fatigue, the search for an optimal therapy remains challenging. Possible treatment options can be divided into pharmacological and non-pharmacological treatments. Amantadine and Modafinil are considered possibly useful for the management of fatigue in people with MS. However, both drugs are currently prescribed off-label and show inconsistent results in fatigue improvement as well as attention and daytime sleepiness (70). Some studies show short-term fatigue improvements in non-pharmacological therapy options, such as physical training, energy conservation strategies, and cognitive-behavioral therapy (71, 72). Wearing a cooling vest (73) or staying in a cooled room for a short time (74) has been shown to bring about relief in some heat-sensitive subjects. Additionally, more general lifestyle changes are suggested, such as abstaining from smoking, reducing caffeine intake, and adjusting daily routines with scheduled breaks (70, 71).

However, clear success in fatigue therapy is still lacking. The treatment approaches previously discussed report controversial results and are based on small sample sizes. The heterogeneity of the symptoms and the complex pathogenesis make finding an optimal treatment strategy difficult. In recent years, NIBS has gained much attention as a promising non-invasive and non-pharmacological approach to fatigue treatment.

5 Non-invasive brain stimulation as a therapeutic option for fatigue

During NIBS, usually small electrical currents are applied. The shape, intensity, and duration of the applied current produces acute or long-lasting effects on the brain’s excitability, activity, and connectivity (75). NIBS modalities that have been widely used are transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), and transcutaneous vagus nerve stimulation (tVNS). They offer the unique opportunity to manipulate the maladaptive neural activity underlying fatigue. The neuromodulatory potential of these modalities has already been widely shown in various neurological and psychiatric conditions, highlighting the potential for a clinical application of NIBS (76). When used and monitored according to the international safety guidelines (77), NIBS is considered safe and well-tolerated. Given its relatively low costs and risks, it can be made available to a broad range of people suffering from fatigue. Additionally, NIBS also has the considerable advantage that it can be used to specifically influence neuronal activity and directly observe resulting behavioral changes. Thus, direct causal relationships can be uncovered instead of showing only correlative relationships, which is of particular interest for a better understanding of pathomechanisms (78).

NIBS techniques can be used in any of the previously described NICE categories to treat the different symptoms (see 79 and 80 for comprehensive reviews). The purpose of this review, however, is to explore the potential use of NIBS to treat LCOF, in particular cognitive fatigue. Therefore, we will provide a summary of studies that have addressed this topic in the following sections. An overview of the NIBS techniques proposed to treat LCOF is illustrated in Figure 1 .

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Figure 1

Non-invasive brain stimulation (NIBS) techniques for the treatment of individual pathomechanisms of Long-COVID-related fatigue (LCOF). Transcutaneous auricular vagus nerve stimulation (taVNS) has been shown to have anti-inflammatory effects through its efferent projections, the so-called cholinergic anti-inflammatory pathway (¹ 81), and could have a stabilizing effect on the dysregulated immune-system after an acute COVID-19 infection that could lead to LCOF. First positive effects support this hypothesis and show a reduction of mental fatigue in people with LCOF after repetitive taVNS sessions (² 16). Transcranial direct current stimulation (tDCS) and alternating current stimulation (tACS) have been shown to modulate neuronal responsiveness (³ 78) and to induce long-term effects via long-term potentiation (⁴ 82). They could therefore be used to counteract the observed frontoparietal hypometabolism after an acute COVID-19 infection that has been associated with LCOF. Preliminary data to support this hypotheses show positive effects on self-reported fatigue scores after repetitive sessions in people with LCOF (⁵ 83, ⁶ 84). Following neuronal acitivity or via direct vascular responses, tDCS and tACS have also been shown to increase cerebral blood flow (⁷ 85). Therefore they might also be an optimal strategy to counteract the observed blood flow reduction in people with LCOF. However, while several data exists that has shown increased cerebral blood flow after tDCS and tACS in healthy subjects and other neurological diseases, no data exists for LCOF.

6 Conclusions

There are a large number of people who describe persistent symptoms after acute COVID-19 infection and are eventually diagnosed with Long-COVID. Fatigue is the most frequently observed symptom and represents a major threat to the medical health care system. In this review, we presented three NIBS methods that have the ability to modulate maladaptive fatigue-related neuronal activity that is shown in fatigued patients of several neurological diseases but also recently in people suffering from Long-COVID. Many of the presented studies have already been shown to improve fatigue, in particular cognitive fatigue, in healthy subjects as well as subjects with neurological disorders such as multiple sclerosis or Parkinson’s disease. Additionally, preliminary data also suggest positive effects on LCOF. Future studies need to systematically determine the parameters of an optimal stimulation setting, specifically pay attention to an established fatigue taxonomy and complement the effects on subjective fatigue with an objective and valid assessment of fatigability in Long-COVID. In the absence of an effective fatigue therapy, neuromodulation by NIBS provides a promising alternative treatment approach. The methods are safe and well-tolerated and allow for large-scale use in clinical practice.

Author contributions

SL and TZ conceived the idea. SL designed, coordinated, and wrote the review: LK wrote individual sections of the review. AH and TZ revised the manuscript and contributed to further drafts. All authors contributed to the final version of the manuscript. All authors contributed to the article and approved the submitted version.

Funding Statement

This work was funded by the Federal State of Saxony-Anhalt (21-04031-770/5/29915/2022).

References