Neuroimmune Mechanisms and Emerging Intervention Strategies for Post-Stroke Fatigue: A Narrative Review

Introduction

Post-stroke fatigue (PSF) is common and disabling, affecting approximately 2 in 5 stroke survivors and independently predicting worse quality of life, slower rehabilitation, and greater long-term disability [1]. Despite its frequency and clinical importance, a unified definition and measurement framework are still evolving, contributing to heterogeneity in reported prevalence and outcomes [2]. Clinically, PSF comprises persistent, disproportionate exhaustion and reduced energy that are not fully relieved by rest; these manifestations are out of proportion to recent physical or cognitive effort. The presentation should be differentiated from depression, apathy, sleep disorders, medication effects, post-stroke pain, and deconditioning, each of which warrants targeted evaluation and management before symptoms are attributed to PSF.

Against this clinical backdrop, emerging evidence implicates neuroimmune pathways in PSF, including chronic low-grade inflammation; dysregulated neurotransmitter systems, particularly dopamine and serotonin [3]; and neuroendocrine dysregulation [4], especially involving the hypothalamic-pituitary-adrenal (HPA) axis. Elevated levels of pro-inflammatory cytokines such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-1β (IL-1β) play a crucial role in these pathways and can exacerbate fatigue [5,6]. These pathways are often distinct but overlap with conditions such as post-stroke depression (PSD) and sleep disorders, suggesting testable mechanistic targets for intervention.

Although mechanisms are documented, treatment strategies targeting these pathways remain under investigation. Various interventions show promise, including pharmacological agents (eg, selective serotonin reuptake inhibitors [SSRIs] and modafinil [7]) and non-pharmacological approaches such as transcranial direct current stimulation (tDCS) [8], repetitive transcranial magnetic stimulation (rTMS) [9], and aerobic exercise [10]. However, early clinical trials have shown mixed results – some therapies exhibit limited or short-lived effects – underscoring the need for standardized phenotyping, rigorous study designs, and adequately powered trials.

This review synthesizes the neuroimmune framework and appraises these emerging mechanism-targeted strategies to inform future study design and clinical translation.

Mechanisms and Interventions for Post-Stroke Fatigue

Definition and Epidemiology of Post-Stroke Fatigue

CLINICAL DEFINITION AND DIAGNOSTIC CRITERIA OF POST-STROKE FATIGUE: PSF is clinically defined as a persistent and disproportionate sense of fatigue that is not commensurate with the level of physical activity undertaken by the individual. This condition is often accompanied by cognitive impairments, including difficulties with attention and concentration, as well as emotional fluctuations such as mood swings and feelings of frustration or helplessness. The subjective nature of fatigue can hinder quantification, highlighting the importance of standardized diagnostic criteria and assessment tools. Currently, the Fatigue Severity Scale (FSS) and the Fatigue Assessment Scale (FAS) are among the most commonly used instruments for evaluating fatigue in stroke survivors. The FSS consists of a series of statements that patients rate based on their fatigue over the preceding week, allowing quantitative evaluation of fatigue severity. In contrast, the FAS assesses both physical and mental fatigue, providing broader characterization of the patient’s fatigue experience. The use of these scales facilitates identification of PSF and enables clinicians to develop tailored interventions. Research indicates that PSF affects a substantial proportion of stroke survivors, with prevalence estimates ranging from 25% to 73%, depending on the population studied and methodologies used [1,2].

The clinical implications of accurate PSF diagnosis are considerable, given that fatigue can substantially impact rehabilitation outcomes and overall quality of life. Inadequate recognition and management of PSF can lead to increased disability, reduced participation in rehabilitation programs, and a higher likelihood of readmission to healthcare facilities. Therefore, clinicians should be vigilant in screening for PSF using validated tools such as the FSS and FAS to identify patients who may benefit from targeted fatigue management strategies. Furthermore, an understanding of the multifaceted nature of PSF – encompassing biological, psychological, and social components – is essential to develop comprehensive treatment plans. Such an approach not only addresses fatigue itself but also considers underlying factors that contribute to its persistence, including depression, anxiety, and cognitive dysfunction [3,4].

In summary, the clinical definition and diagnostic criteria for PSF underscore the importance of recognizing this condition as a clinically significant and independent symptom after stroke. The use of standardized assessment tools such as the FSS and FAS can enhance PSF identification, ultimately supporting improved management strategies and better outcomes for stroke survivors. As research continues to advance, further exploration of the neurobiological mechanisms underlying PSF and the development of effective interventions will be essential for addressing this pervasive issue within the stroke recovery landscape.

EPIDEMIOLOGICAL CHARACTERISTICS OF POST-STROKE FATIGUE: PSF is a prevalent and debilitating condition affecting a substantial proportion of stroke survivors, with reported incidence rates ranging from 30% to 70% across studies. This wide variability in prevalence likely reflects differences in study populations, methodologies, and the specific criteria used to define fatigue. Notably, a systematic review reported that PSF is more common among female stroke survivors, with significantly higher incidence relative to male stroke survivors [11]. Data directly comparing PSF risk by ethnicity remain sparse; however, inequities in post-stroke care and social stressors may interact with stress–inflammation pathways to influence fatigue burden. These observations underscore the need for prespecified analyses by sex and ethnicity, as well as the inclusion of social determinants in future studies. The observed sex disparity in PSF prevalence may involve biological and psychosocial factors, including hormonal influences, differences in social support, and the psychological burden of stroke recovery [12]. PSF occurrence is also closely linked to stroke severity, lesion location, and comorbid conditions. Patients who experience more severe strokes, particularly those involving the basal ganglia and frontal lobes, commonly report higher fatigue levels. Additionally, comorbid depression, anxiety, and sleep disorders are associated with greater fatigue in stroke survivors. PSF affects not only physical health but also substantially influences quality of life and rehabilitation outcomes. There is evidence that fatigue can reduce motivation for rehabilitation, increase dependency in daily activities, and heighten the likelihood of depressive symptoms. Therefore, an understanding of these epidemiological characteristics is critical when developing targeted interventions that address the specific needs of stroke survivors and support fatigue management as a core component of post-stroke care. Future studies should aim to standardize PSF assessment and further investigate mechanisms contributing to its prevalence – such knowledge will be essential for developing effective treatment strategies and improving overall quality of life among stroke survivors [5,6]. Evidence that obesity and type 2 diabetes serve as independent PSF risk factors remains limited. Metabolic–inflammatory and neuroendocrine pathways provide biological plausibility; some longitudinal work suggests an association between obesity and the persistence of fatigue over time. However, definitive PSF-specific associations require prespecified, metabolically stratified cohorts.

IMPACT OF POST-STROKE FATIGUE ON PATIENT PROGNOSIS: Research indicates that PSF greatly decreases patients’ overall quality of life and contributes to increased rates of depression and anxiety. Individuals with PSF report higher levels of depressive symptoms and anxiety, both of which are closely linked to perceived reductions in quality of life [7,8]. The psychological burden associated with PSF can create a vicious cycle in which fatigue exacerbates mental health concerns, further diminishing patients’ ability to participate in rehabilitation and daily activities. PSF is also associated with delayed recovery because patients with higher fatigue levels often struggle to engage fully in rehabilitation programs, leading to longer hospital stays and increased rates of readmission [8,9]. These delays not only prolong rehabilitation but also heighten healthcare utilization – patients with PSF more frequently require additional clinical interventions and support services.

The implications of PSF extend beyond its immediate psychological and physical effects, influencing long-term functional outcomes. Studies have demonstrated a negative correlation between PSF and functional independence, indicating that patients with fatigue are less likely to regain their pre-stroke level of functioning [8,10]. This relationship emphasizes the need for healthcare providers to monitor and address fatigue proactively to optimize rehabilitation outcomes. For example, patients with substantial fatigue have shown worse performance on functional assessments, supporting a direct link between fatigue severity and functional recovery [8,9].

In summary, PSF significantly diminishes quality of life, exacerbates mental health concerns, delays recovery, and increases healthcare costs. The interplay among fatigue, psychological well-being, and functional outcomes highlights the importance of early identification and targeted interventions for PSF. These factors must be addressed to improve overall outcomes and support more effective rehabilitation. Future studies should prioritize the development of comprehensive management strategies that integrate psychological support and fatigue-directed interventions to enhance recovery trajectories for stroke survivors.

INFLAMMATORY RESPONSE AND POST-STROKE FATIGUE: The relationship between inflammatory responses and PSF has received substantial attention in recent years as research continues to elucidate the complex neuroimmune mechanisms involved in stroke recovery. After a stroke, both the peripheral and central nervous systems exhibit activation of inflammatory pathways, characterized by elevated levels of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α [13–15]. These cytokines play a pivotal role in mediating the body’s response to injury and infection, but their dysregulation can produce detrimental effects, including exacerbation of fatigue. When their levels are elevated, these cytokines can cross the blood–brain barrier and influence neuronal activity and synaptic plasticity, both of which are critical for cognitive function and emotional well-being [16].

The chronic phase of stroke recovery has also been associated with persistent inflammation. Studies have demonstrated correlations between elevated cytokine levels and fatigue severity in stroke survivors [15,16]. For instance, a study showed that 60% of stroke survivors exhibited clinically significant fatigue that was correlated with increased serum levels of IL-6 and high-sensitivity C-reactive protein [13]. These findings suggest that systemic inflammation can serve as a biomarker for fatigue during the chronic recovery phase. The interplay between inflammation and fatigue may be further influenced by factors such as sleep disturbances, which are prevalent among stroke survivors and have been associated with both elevated fatigue and increased levels of inflammatory markers [15].

The mechanisms linking inflammation and PSF are multifaceted. Chronic inflammation can lead to alterations in neurotransmitter systems, particularly those involving dopamine and serotonin, which are crucial for mood regulation and energy levels [16]. Neuroinflammation can also impair neuroplasticity, the brain’s capacity to adapt and reorganize, which is essential for post-stroke recovery. Such impairments may contribute to sustained fatigue because they affect both cognitive and physical rehabilitation outcomes [16,17].

Overall, the inflammatory response after a stroke is a key contributor to the development of PSF. Elevated levels of pro-inflammatory cytokines indicate the presence of inflammation and are correlated with fatigue severity, highlighting the need for targeted interventions that address neuroimmune dysregulation. Future research should focus on clarifying the mechanisms that link inflammation to PSF and exploring therapeutic strategies that modulate inflammatory responses to improve recovery outcomes in stroke survivors (Figure 1).

NEUROTRANSMITTER IMBALANCE AND POST-STROKE FATIGUE: The relationship between neurotransmitter imbalances – specifically serotonin, dopamine, and norepinephrine – and PSF is complex and multifaceted. After a stroke, homeostasis of these critical neurotransmitters is often disrupted, leading to altered synthesis, release, and reuptake. Such disruptions can substantially contribute to the fatigue experienced by stroke survivors. Serotonin, which is vital for mood regulation and energy levels, is frequently reduced in individuals with PSF, exacerbating fatigue and lethargy; this exacerbation creates a cycle that impairs recovery and rehabilitation [18]. Dopamine, a key mediator of motivation and reward, is similarly affected post-stroke; its dysregulation may lead to anhedonia and intensify fatigue symptoms [19]. Norepinephrine, involved in arousal and alertness, also shows altered levels after stroke, contributing to cognitive impairments and diminished energy. The interplay among these neurotransmitters is critical. For example, reduced serotonin levels can diminish dopamine activity, which may subsequently affect norepinephrine levels, creating a cascade of neurochemical changes that intensify fatigue [20].

The neuroinflammatory response that follows a stroke further complicates neurotransmitter dynamics. Elevated pro-inflammatory cytokines can interfere with neurotransmitter synthesis and receptor sensitivity, fostering a state of neuroinflammation that exacerbates PSF [21]. This inflammatory milieu can disrupt the blood–brain barrier and promote neurodegeneration, which manifests as increased fatigue and cognitive dysfunction. The chronic nature of neuroinflammation may also impede the recovery of neurotransmitter systems, perpetuating fatigue and limiting rehabilitation outcomes.

In addition to the biochemical aspects, psychological factors must be considered. The experience of a stroke is often accompanied by substantial emotional distress, which can influence neurotransmitter levels and contribute to fatigue. Depression and anxiety, common comorbidities among stroke survivors, are associated with alterations in serotonin and dopamine pathways, further complicating the clinical presentation of PSF [22]. Biochemical and psychological components of neurotransmitter imbalance must be addressed to develop effective interventions that alleviate PSF.

Emerging therapeutic strategies aim to restore neurotransmitter balance as a means to reduce fatigue. Pharmacological approaches that enhance serotonin reuptake or increase dopamine receptor sensitivity are under investigation for their potential to improve energy levels in patients with stroke. Non-pharmacological interventions, including cognitive behavioral therapy (CBT) and structured physical rehabilitation, may modulate neurotransmitter activity and improve overall energy and motivation [23]. Given the increasing understanding of the neurochemical basis of PSF, there is a growing need for a multifaceted approach that targets neurotransmitter imbalances while addressing inflammatory and psychological factors. Such an approach will be crucial for improving recovery and quality of life in stroke survivors.

NEUROENDOCRINE DYSREGULATION AND POST-STROKE FATIGUE: The HPA axis plays a central role in the neuroendocrine response to stress, and its dysregulation is increasingly regarded as a key contributor to PSF. After a stroke, HPA axis overactivation is common and leads to elevated cortisol levels. This hypercortisolism can exacerbate fatigue symptoms, creating a cycle in which fatigue impairs recovery, increases stress, and triggers additional cortisol release. Cortisol, a glucocorticoid hormone essential for the body’s stress response, can be detrimental when elevated for prolonged periods. Chronic cortisol elevation can produce immune suppression and increased inflammation – both implicated in fatigue among stroke survivors [21]. The interaction between cortisol and inflammatory cytokines may also promote neuroinflammation, which contributes to fatigue and cognitive dysfunction. Importantly, the relationship between HPA axis dysregulation and PSF may not be solely a consequence of stroke. Underlying vulnerabilities in neuroendocrine regulation may predispose certain individuals to fatigue. For instance, chronic stress prior to a stroke may have influenced HPA axis function, creating conditions that heighten susceptibility to fatigue during recovery.

In addition to cortisol, abnormalities in the secretion of growth hormone and thyroid hormones have also been implicated in the development of PSF. Growth hormone, which is critical for tissue repair and metabolism, may be inadequately produced after a stroke, leading to impaired recovery and increased fatigue. Similarly, thyroid hormones play key roles in regulating energy metabolism and overall vitality. Dysregulation of the hypothalamic-pituitary-thyroid axis can result in hypothyroidism, which is characterized by fatigue, lethargy, and cognitive impairment – symptoms that closely resemble those of PSF [19]. The interaction between thyroid function and fatigue is complex because thyroid hormones influence the metabolism of neurotransmitters that are critical for mood and energy regulation. Thus, assessment of thyroid function in patients with stroke is crucial – restoration of normal thyroid hormone levels may alleviate some aspects of fatigue.

Emerging research suggests that interventions targeting the neuroendocrine system may benefit PSF management. Pharmacological strategies that modulate cortisol levels or enhance growth hormone secretion could offer new therapeutic options. Lifestyle interventions, including structured exercise and stress management, may help normalize HPA axis function and improve fatigue outcomes. Furthermore, understanding the influence of the gut–brain axis on neuroendocrine regulation may yield innovative therapeutic strategies, given that gut microbiota can affect both HPA axis activity and immune function [24].

In conclusion, neuroendocrine dysregulation, particularly involving the HPA and hypothalamic-pituitary-thyroid axes, plays a central role in the development of PSF after stroke. The interplay of elevated cortisol, abnormal growth hormone secretion, and thyroid hormone dysregulation creates a multifaceted challenge in fatigue management. Future research should clarify the mechanisms by which these neuroendocrine changes contribute to PSF and explore targeted interventions to mitigate these effects, ultimately improving quality of life for patients with stroke.

CHANGES IN SYNAPTIC PLASTICITY: After a stroke, extensive alterations occur in synaptic plasticity, particularly in the processes of long-term potentiation (LTP) and long-term depression (LTD). These processes are essential for the normal functioning of neural networks because they support learning and memory by enabling the strengthening and weakening of synaptic connections. In the context of stroke, disruption of LTP and LTD can impair communication between neurons; it may manifest as cognitive and behavioral deficits, including fatigue. Microglia, the resident immune cells of the brain, have emerged as key contributors to these changes. In addition to their roles in immune surveillance and phagocytosis, microglia participate in synapse formation, elimination, and overall plasticity. Their abilities to monitor the central nervous system and respond to environmental changes are vital for maintaining synaptic integrity and function [25].

Microglial activation, commonly observed after stroke, can initiate inflammatory cascades that exacerbate synaptic dysfunction. This activation may result in excessive synaptic pruning, further impairing synaptic plasticity and contributing to cognitive decline and fatigue. The balance between synaptic formation and elimination becomes disrupted, leading to a net loss of synaptic connections required for efficient neural communication. Furthermore, activated microglia release signaling molecules that influence synaptic plasticity, either promoting or inhibiting LTP and LTD depending on the nature of the injury and surrounding neuroinflammatory environment [25].

The implications of these changes in synaptic plasticity are substantial. Disrupted plasticity affects cognitive functions and contributes to the overall experience of fatigue in stroke survivors. Fatigue is characterized by a persistent sense of tiredness that is not relieved by rest and can greatly reduce quality of life. Cognitive and behavioral impairments arising from altered synaptic plasticity can create a feedback loop in which fatigue worsens cognitive deficits, leading to greater disengagement from activities and social interactions. This cycle highlights the importance of understanding the neuroimmune mechanisms that underlie synaptic changes after stroke, given that such insights may guide the development of therapeutic interventions to alleviate fatigue and enhance recovery.

Emerging strategies to address these issues include targeting neuroinflammatory processes mediated by microglia, with the aim of restoring appropriate synaptic function and plasticity. Modulation of microglial activity may enhance LTP and LTD processes, thereby improving cognitive outcomes and reducing fatigue in patients with stroke. This approach emphasizes the need for continued investigation into neuroimmune interactions and underscores the potential for novel therapies that could considerably improve rehabilitation outcomes for individuals recovering from stroke. Overall, the study of changes in synaptic plasticity after stroke and their relationship with fatigue represents a promising area of research that may lead to innovative interventions addressing both cognitive and physical challenges faced by stroke survivors.

NEURAL REGENERATION AND POST-STROKE FATIGUE: Post-stroke neural regeneration is strongly influenced by the inflammatory environment, which can inhibit the differentiation and migration of neural stem cells. After a stroke, the brain undergoes a cascade of inflammatory responses characterized by microglial activation and the infiltration of peripheral immune cells. These immune cells release pro-inflammatory cytokines and chemokines that create a hostile microenvironment for neural stem cells, impeding their ability to differentiate into neurons and migrate to sites of injury. For instance, inflammatory factors such as TNF-α and IL-1β can suppress the proliferation and differentiation of neural progenitor cells, reducing neurogenesis and adversely affecting recovery outcomes [21]. This inhibition of neural regeneration is not transient; it may lead to long-term deficits in neuronal repair and functional recovery, thereby contributing to persistent symptoms such as fatigue, which is common among stroke survivors.

PSF is increasingly recognized as a debilitating condition that can significantly impair quality of life. The mechanisms underlying PSF are complex and multifactorial, with growing evidence that neurogenesis disruption plays an important role. When neural stem cells cannot effectively differentiate or migrate due to the inflammatory milieu, the brain’s capacity for self-repair is compromised. This lack of self-repair can result in sustained neuronal loss and dysfunction, which may manifest as fatigue. Furthermore, chronic inflammation can establish a cycle of neurodegeneration and fatigue; the ongoing inflammatory response may continue to inhibit neurogenesis and exacerbate cognitive and physical impairments [22].

Additionally, the interplay between the immune system and neural regeneration is critical for understanding PSF. The activation of immune cells after stroke contributes to tissue damage and influences regenerative processes within the brain. Recent studies have highlighted the role of CD8+ T cells, indicating that these cells can both exacerbate inflammation and modulate neurogenesis in the post-stroke environment [20]. This dual role complicates therapeutic strategies because approaches that reduce inflammation must also consider the potential benefits of immune modulation to support regeneration.

In conclusion, the inhibition of neural stem cell differentiation and migration by inflammatory factors represents a substantial barrier to effective neural regeneration after stroke. This barrier impedes recovery and is closely linked to the persistence of fatigue symptoms in stroke survivors. An understanding of the relationship among neuroinflammation, neural regeneration, and PSF is essential to develop targeted therapeutic interventions. Future research should focus on elucidating the molecular pathways involved in these processes, as well as exploring strategies that mitigate inflammation while promoting neurogenesis to improve recovery and reduce fatigue [18] (Table 1).

POTENTIAL ROLE OF ANTI-INFLAMMATORY DRUGS: The use of anti-inflammatory drugs, particularly non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids, has attracted attention for their potential to alleviate PSF by modulating inflammatory responses. In the context of ischemic stroke, neuroinflammation plays a central role in the progression of brain injury and subsequent recovery. NSAIDs such as ibuprofen and aspirin act by inhibiting cyclooxygenase enzymes, which are essential for the synthesis of pro-inflammatory prostaglandins. These drugs have been shown to reduce inflammation and may help mitigate fatigue in stroke survivors, given the established link between inflammation and fatigue mechanisms [18]. Glucocorticoids – steroid hormones with broad immunomodulatory effects – have also been examined for potential benefits in stroke recovery. Their anti-inflammatory properties may help restore homeostasis within the neuroimmune environment, thus addressing PSF symptoms [21].

However, the long-term use of these medications is not without risks. Chronic NSAID use is associated with gastrointestinal complications, cardiovascular events, and renal impairment, emphasizing the need for careful evaluation of the risk–benefit ratio in patients with stroke [24]. Glucocorticoids, while effective in modulating inflammation, can lead to adverse effects such as weight gain, osteoporosis, and increased susceptibility to infection, particularly when used at high doses or for extended periods [20]. These considerations highlight the importance of individualized treatment plans that consider overall health status and potential adverse effects.

The timing and duration of anti-inflammatory treatment are also critical determinants of clinical outcomes. Early intervention with NSAIDs or glucocorticoids may be beneficial during the acute phase of stroke, when inflammation is most pronounced; prolonged use during recovery may not confer additional benefit and could potentially hinder neuroplasticity and repair processes [26]. Thus, although the anti-inflammatory properties of these medications offer a promising avenue for the management of PSF, appropriate balance between symptom relief and risk mitigation is essential.

In summary, the potential role of anti-inflammatory drugs in managing PSF underscores the need for further research to determine optimal therapeutic strategies. Future studies should identify patient populations that may benefit most from these interventions and explore alternative anti-inflammatory approaches that offer more favorable safety profiles. The integration of anti-inflammatory therapy into comprehensive post-stroke care may enhance recovery and improve quality of life, provided that the risks associated with long-term use are carefully managed and monitored.

RESEARCH PROGRESS ON CYTOKINE ANTAGONISTS: Cytokine antagonists, particularly TNF-α antagonists such as infliximab and interleukin-1 receptor antagonists (IL-1Ra) such as anakinra, have emerged as promising therapeutic agents for the management of PSF. Preclinical studies in animal models have demonstrated that these agents can significantly alleviate fatigue symptoms associated with stroke. Infliximab, a monoclonal antibody that specifically binds to TNF-α, has been shown to reduce neuroinflammation and improve functional recovery in multiple stroke models. This reduction in inflammation is crucial because elevated TNF-α levels are linked to increased fatigue and worse recovery outcomes. Similarly, IL-1Ra, which inhibits the action of interleukin-1 (IL-1), has been associated with improved neurological function and reduced fatigue in preclinical studies. The therapeutic effects of these agents appear to involve modulation of inflammatory pathways that contribute to fatigue. Both TNF-α and IL-1 exacerbate neuroinflammation, leading to neuronal damage and subsequent fatigue. Inhibition of these cytokines mitigates fatigue and supports neurological recovery. Clinical trials are underway to evaluate the efficacy and safety of cytokine antagonists in human stroke populations; preliminary results have shown promise. A systematic review indicated that IL-1Ra administration in acute ischemic stroke was safe and associated with favorable clinical outcomes, including lower levels of inflammatory markers and improved functional recovery [27]. Ongoing studies are examining optimal timing and dosing strategies to maximize therapeutic benefit while minimizing adverse effects. Early findings from these trials are encouraging and suggest that cytokine antagonists may play a pivotal role in the future management of PSF and overall recovery. As research progresses, continued investigation of the mechanisms by which cytokine antagonists exert their effects will be essential. Such knowledge will support the development of targeted therapies that can address the multifaceted biological drivers of PSF.

TRANSCRANIAL MAGNETIC STIMULATION: Transcranial magnetic stimulation, particularly rTMS, has emerged as a promising non-invasive intervention for addressing PSF, a common and debilitating symptom among stroke survivors. rTMS modulates cortical excitability, thereby influencing cognitive and emotional symptoms associated with fatigue. The technique utilizes magnetic fields to stimulate neuronal activity in targeted brain regions, promoting neural plasticity and functional recovery. There is evidence that high-frequency rTMS can significantly improve cognitive function and alleviate emotional disturbances such as depression and anxiety, which frequently accompany PSF. Small-scale clinical studies have supported its efficacy, demonstrating reductions in fatigue and improvements in overall cognitive performance. For example, a randomized controlled trial showed that patients receiving high-frequency rTMS exhibited greater improvements in fatigue compared with those who received sham stimulation, suggesting that rTMS may serve as an effective adjunct in stroke rehabilitation programs [18]. Furthermore, the neurophysiological effects of rTMS on the brain’s excitatory and inhibitory balance provide a compelling rationale for its use in managing fatigue, given that disrupted neuroimmune interactions and altered neurotransmitter levels are often implicated in PSF. Modulation of cortical excitability through rTMS not only provides symptomatic relief but also addresses associated cognitive and emotional deficits. The integration of rTMS into stroke recovery protocols could represent a meaningful advancement in therapeutic strategies aimed at improving patient outcomes. However, additional research is needed to establish optimal stimulation parameters, including frequency, duration, and target regions, to maximize clinical benefit. Further exploration of the neuroimmune mechanisms underlying rTMS efficacy may also clarify how this intervention facilitates recovery through modulation of inflammatory pathways and enhancement of neuroplasticity. As the field advances, the potential for rTMS to become a standard component of post-stroke rehabilitation remains a critical area of investigation, with the promise of improving quality of life for individuals affected by the long-term consequences of stroke.

TRANSCRANIAL DIRECT CURRENT STIMULATION: tDCS is an emerging non-invasive brain stimulation technique that has gained attention for its potential to alleviate PSF by modulating neuronal activity. This technique applies a low electrical current to the scalp, altering neuronal membrane potentials, enhancing synaptic plasticity, and potentially improving cognitive and motor functions. Its mechanism of action is primarily attributed to anodal stimulation, which depolarizes neuronal membranes and increases excitability in targeted brain regions. Targeting the left dorsolateral prefrontal cortex (DLPFC) has shown considerable promise, such that anodal tDCS can reduce fatigue symptoms and enhance cognitive performance. Improvements have been demonstrated through changes in FSS scores and neurophysiological assessments of cortical excitability [28,29].

The benefits of tDCS in stroke rehabilitation extend beyond symptom relief. By reducing fatigue and improving attention, tDCS may facilitate greater engagement in rehabilitation activities. For instance, a study of stroke survivors showed that individuals receiving anodal tDCS completed more rehabilitation therapy sessions than those receiving sham stimulation, although the difference was not statistically significant [30]. These findings suggest that tDCS enhances the quality, rather than the quantity, of rehabilitation engagement. Furthermore, physiological effects of tDCS have been documented, including alterations in motor cortex excitability and improved perceived effort during task performance, both of which are integral to rehabilitation success [31,32].

The safety and feasibility of tDCS have been established in outpatient settings, where it has been well tolerated with minimal reported adverse effects [33]. This favorable safety profile supports its potential integration into standard stroke rehabilitation protocols. However, individual variability in response to tDCS indicates a need for further research to optimize stimulation parameters and clarify the mechanisms underlying its effects on PSF [11,34].

In conclusion, tDCS represents a promising intervention for addressing PSF, particularly through targeted application over the DLPFC. By enhancing neuronal excitability and synaptic plasticity, tDCS has the potential to improve fatigue symptoms and support greater engagement in rehabilitation efforts. Continued exploration of into optimal stimulation parameters – including session duration, frequency, and individual patient characteristics – will be essential to establish its role as a standard therapeutic option in stroke care. The integration of tDCS into comprehensive rehabilitation strategies may substantially improve quality of life for stroke survivors affected by fatigue.

APPLICATION OF ANTIDEPRESSANTS: SSRIs such as fluoxetine and sertraline have received considerable attention for their potential to alleviate PSF by modulating serotonin levels. Serotonin imbalance is believed to contribute to fatigue, and SSRIs may improve mood and energy by increasing serotonin availability in the synaptic cleft. A longitudinal study of 847 patients with acute ischemic stroke examined SSRI effects on the time course of PSF. Although no significant association was observed across the entire cohort, subgroup analyses indicated that SSRIs reduced the risk of incident and persistent PSF specifically in patients with PSD [35]. Reported odds ratios suggested a benefit from early SSRI administration, with reductions in both PSF risk (odds ratio 0.955) and severity (β=−0.018) in the PSD subgroup. These findings highlight the potential utility of SSRIs not only in treating depressive symptoms but also in addressing fatigue, a common and debilitating consequence of stroke.

However, the application of SSRIs is not without challenges. Major concerns include the development of drug tolerance and occurrence of side effects, which considerably vary among individuals. Some patients experience gastrointestinal disturbances, sexual dysfunction, or increased anxiety, complicating adherence and diminishing quality of life. Response variability may lead to a trial-and-error approach when prescribing SSRIs, making the selection of an appropriate agent and dosage time-consuming and frustrating for both patients and clinicians. It is also important to recognize that although SSRIs may provide symptomatic relief for some individuals, they are not universally effective for PSF, particularly in patients without concurrent depressive symptoms. These limitations underscore the need for personalized treatment plans that consider each individual’s psychological and physiological profile.

Beyond small and heterogeneous studies, 3 large pragmatic multicenter randomized trials – FOCUS [36], AFFINITY [37], and EFFECTS [38] – evaluated fluoxetine 20 mg daily for 6 months. These trials did not show improved functional recovery after stroke; they identified safety concerns, including increased bone fractures, with higher rates of falls and seizures in some cohorts. Although the trials were not designed to treat PSF, and fatigue was typically a secondary or exploratory outcome, longer-term follow-up showed no durable functional benefit [39]. Overall, the level of evidence supporting SSRIs solely for PSF remains low. Routine use should be avoided in the absence of a clear indication, such as PSD or another compelling clinical need. Current evidence suggests that SSRIs should not be prescribed solely for PSF in patients without comorbid PSD. Modafinil has shown short-term benefit in a small randomized crossover trial and may be considered in selected patients with appropriate monitoring. Methylphenidate remains investigational; findings have been inconsistent across studies.

In summary, although SSRIs such as fluoxetine and sertraline may mitigate PSF, particularly in patients with underlying depression, their effectiveness is limited by tolerance and side effects. Continued research is crucial to clarify the neuroimmune mechanisms underlying PSF and refine intervention strategies that enhance quality of life for stroke survivors. As the field advances, development of comprehensive treatment protocols integrating pharmacological and non-pharmacological approaches will be vital to ensure holistic management of PSF that addresses both neurochemical imbalance and psychological well-being.

RESEARCH ON CENTRAL STIMULANTS: The use of central stimulants such as modafinil and methylphenidate has gained attention for their potential to alleviate PSF, particularly in addressing daytime sleepiness and attention deficits that commonly accompany the condition. PSF contributes to decreased participation in stroke rehabilitation and diminished quality of life. Modafinil, a wakefulness-promoting agent, has been shown to improve voluntary activation and reduce central fatigue in patients with chronic stroke. One study demonstrated increased isometric muscle strength and voluntary activation after modafinil administration [40]. Methylphenidate has also been investigated for its ability to enhance cognitive function and reduce fatigue. A retrospective study indicated that modafinil use was associated with improved discharge disposition among patients with stroke who were experiencing lethargy and fatigue, suggesting that central stimulants facilitate better rehabilitation outcomes [41]. Despite such encouraging findings, the long-term safety and efficacy of these medications remain uncertain. Concerns regarding adverse effects and the potential for dependency require careful evaluation of their safety profiles in the context of post-stroke recovery. Existing literature highlights the need for randomized controlled trials to define optimal dosing, treatment duration, and patient selection criteria for stimulant therapy. Economic considerations are also relevant because preliminary analyses suggest that modafinil can produce cost savings by improving productivity among working-age stroke survivors [41]. Although central stimulants show potential for improving PSF and related cognitive impairments, comprehensive studies are essential to clarify their clinical role and ensure that benefits outweigh risks associated with long-term use.

GLUTAMATERGIC MODULATORS:

Ketamine and esketamine have not yet been evaluated in PSF-specific randomized trials. Given ketamine’s N-methyl-D-aspartate (NMDA) receptor antagonism, rapid antidepressant effects, and reported immunomodulatory actions, there is mechanistic overlap with pathways implicated in PSF. However, any benefit for fatigue after stroke remains hypothetical and must be weighed against safety considerations. Accordingly, ketamine should be regarded as investigational for PSF pending phenotype-stratified, parallel-group randomized controlled trials.

EXERCISE THERAPY: Exercise therapy, particularly aerobic exercise and resistance training, has emerged as a promising intervention for alleviating PSF. Aerobic exercise enhances cardiovascular function and promotes neuroplasticity, contributing to improved recovery outcomes. Structured aerobic exercise programs have been shown to reduce fatigue levels and increase overall physical endurance, thereby improving quality of life for stroke survivors [42]. For instance, graded activity training combined with cognitive therapy led to effective reduction of fatigue symptoms, with significant improvements in endurance among participants [43]. These findings highlight the potential of aerobic exercise not only to enhance physical capacity but also to address psychological aspects of recovery, including motivation and self-efficacy.

Resistance training also plays a key role in improving muscle strength and functional independence, both of which are often compromised after a stroke. Tailored resistance training programs have been shown to increase muscle mass and strength, thereby reducing fatigue and improving the ability to perform daily activities [44]. The integration of aerobic and resistance training into rehabilitation protocols is essential because these modalities complement each other and address distinct components of recovery. Aerobic exercise improves cardiovascular health and endurance, whereas resistance training focuses on building strength and preventing muscle atrophy – both critical elements of post-stroke rehabilitation [45].

Personalized exercise regimens are paramount to maximizing the effectiveness of these interventions. Individualized plans that consider each survivor’s needs, capabilities, and preferences can enhance adherence and improve overall outcomes. Research indicates that personalized approaches support better engagement in rehabilitation programs by enabling patients to set realistic goals and monitor their progress [46]. Tailored exercise programs improve physical functioning and foster a sense of agency and empowerment, both of which are crucial for psychological well-being and motivation during recovery.

Moreover, the importance of ongoing support and monitoring during exercise interventions cannot be overstated. Health professionals play a pivotal role in guiding patients through exercise routines, ensuring safety, and providing encouragement. Supervised exercise sessions, whether conducted in clinical settings or via telehealth platforms, have demonstrated higher adherence rates than unsupervised programs [47]. These findings underscore the need for healthcare systems to incorporate structured support mechanisms that promote consistent participation in exercise therapy.

In conclusion, exercise therapy, encompassing both aerobic and resistance training, represents a vital component of rehabilitation for PSF. Evidence supporting its effectiveness is compelling, such that personalized exercise regimens improve outcomes and enhance adherence. Future research should continue to investigate the optimal combinations of exercise types, durations, and intensities, as well as the mechanisms by which these interventions mitigate fatigue and improve quality of life for stroke survivors. As the neuroimmune mechanisms underlying PSF become better understood, the integration of exercise therapy into comprehensive rehabilitation strategies will be essential for improving recovery trajectories in this population [48].

COGNITIVE BEHAVIORAL THERAPY: CBT has emerged as a pivotal intervention for PSF, primarily by targeting cognitive and behavioral patterns that contribute to the psychological burden of fatigue. CBT utilizes a structured approach to help patients identify and modify negative thought processes that exacerbate fatigue and emotional distress. By emphasizing the interplay among thoughts, feelings, and behaviors, CBT empowers patients to develop coping strategies that strengthen resilience against fatigue. Research indicates that CBT can reduce fatigue levels by fostering a more positive mindset and encouraging engagement in activities that support physical and mental well-being [49]. Moreover, the integration of relaxation training and stress management techniques within CBT frameworks has shown promising results with respect to PSF. These complementary strategies reduce anxiety and stress – factors that often intensify fatigue – while promoting a sense of control and self-efficacy. For instance, studies have demonstrated that patients who receive CBT combined with relaxation techniques report improved fatigue levels and enhanced quality of life relative to those who receive standard care [50]. This multifaceted approach is particularly beneficial for individuals who experience the debilitating effects of PSF because it addresses both psychological and physiological contributors to fatigue. Furthermore, CBT’s adaptability allows customization to individual patient needs, supporting its effectiveness across diverse patient populations. The positive outcomes associated with CBT underscore the importance of integrating psychological therapies into holistic care for stroke survivors. As research progresses, further exploration is crucial to clarify the neurobiological mechanisms underlying CBT’s effects in PSF and its potential to mitigate the neuroimmune dysregulation observed after stroke. Ultimately, the integration of CBT into rehabilitation programs enhances psychological well-being and contributes to improved overall recovery, highlighting the need for comprehensive strategies to manage PSF [51].

NUTRITION AND SLEEP-RELATED INTERVENTIONS: Nutrition and sleep are practical, modifiable targets that may influence PSF through immune, neuroendocrine, and circadian pathways. Nutritional status is correlated with stroke rehabilitation outcomes, supporting routine assessment and optimization during recovery [52]. Small pilot interventions suggest that multi-nutrient supplementation can improve fatigue and functional measures in post-stroke cohorts, although PSF-specific evidence remains preliminary and heterogeneous [53]. Immune–nutrition markers – such as the neutrophil-to-lymphocyte ratio [NLR] and prognostic nutritional index [PNI] – measured at admission have been associated with PSF at 6 months, indicating biologically coherent links among inflammation, nutritional status, and later fatigue [54]. Disrupted sleep is common after stroke; recent intensive longitudinal data indicate bidirectional, day-to-day coupling between sleep and fatigue or mood in stroke survivors [55]. More broadly, sleep and inflammation are bidirectionally linked, reinforcing the rationale for sleep-focused approaches to PSF [56]. Although trials of sleep-promoting strategies with PSF as a primary endpoint are scarce, early post-stroke studies – such as blue-light therapy – have examined sleepiness and fatigue as secondary outcomes; CBT-based sleep interventions in acquired brain injury populations have demonstrated feasibility and potential benefit [57]. Given the high prevalence of obstructive sleep apnea after stroke and existing guidance on screening and management, symptom-guided care – including obstructive sleep apnea screening and treatment, circadian hygiene interventions, and CBT for insomnia when appropriate – should be incorporated while PSF-specific trials are developed.

From a feasibility perspective, nutrition and sleep strategies are low-cost and scalable within rehabilitation workflows. They should serve as adjuncts to mechanism-targeted pharmacological or neuromodulatory approaches and be prioritized for pragmatic, phenotype-stratified trials that incorporate standardized fatigue outcomes and biomarker panels.

MULTIDISCIPLINARY TEAM COLLABORATION:

The integration of multidisciplinary collaboration among neurology, rehabilitation, and psychology is essential for formulating personalized, comprehensive intervention strategies for patients with PSF. This collaborative approach recognizes the multifaceted nature of PSF, which is influenced by neurological, psychological, and functional factors. Neurologists contribute expertise regarding the neurobiological mechanisms of stroke and its sequelae, whereas rehabilitation specialists address functional independence and quality of life through tailored physical and occupational therapies. Psychologists manage the emotional and cognitive aspects of recovery, helping patients cope with the psychological burden of stroke and fatigue. By combining these diverse perspectives, healthcare providers can develop individualized treatment plans that address each patient’s unique needs. For instance, a patient experiencing severe fatigue may benefit from a rehabilitation program that includes CBT to reduce anxiety and depression, along with physical therapy to improve endurance and strength. This holistic framework enhances intervention effectiveness and fosters a supportive environment in which patients feel understood and cared for, ultimately improving treatment adherence and outcomes.

Compelling evidence supports the efficacy of multidisciplinary collaboration in improving quality of life and rehabilitation outcomes for patients with PSF. Studies have shown that patients receiving integrated care from multiple specialists report higher satisfaction and exhibit greater functional gains compared with patients receiving conventional care. This is particularly relevant given the complex interplay among physical, cognitive, and emotional factors in stroke recovery. A recent review highlighted the role of immune responses in stroke recovery and emphasized how interventions targeting these responses can be optimized through coordinated efforts among various specialties [21]. Furthermore, the psychological impacts of stroke – especially the high prevalence of depression and anxiety – require the involvement of mental health professionals. By addressing these psychological components, multidisciplinary teams can mitigate the risk of prolonged fatigue and enhance overall recovery.

Moreover, the implementation of personalized comprehensive intervention strategies through multidisciplinary collaboration aligns with contemporary patient-centered care, which emphasizes tailoring treatments to individual profiles. This approach considers not only the medical aspects of stroke recovery but also patients’ preferences, values, and social contexts, thereby promoting a more holistic recovery experience. As healthcare systems increasingly recognize the importance of integrated care models, collaborations among neurology, rehabilitation, and psychology will likely become standard practice in managing PSF. This shift is essential to address the complex needs of stroke survivors and ensure delivery of the most effective and comprehensive care. In conclusion, multidisciplinary collaboration in developing personalized intervention strategies represents a substantial advancement in PSF management, with the potential to greatly improve quality of life and rehabilitation outcomes.

INTEGRATION OF EMERGING TECHNOLOGIES: The integration of emerging technologies – particularly virtual reality (VR) and augmented reality (AR) – into post-stroke fatigue rehabilitation is an area of increasing interest. These technologies offer innovative approaches to enhance patient engagement and motivation during rehabilitation. VR provides immersive environments that simulate real-world scenarios, allowing patients to practice motor skills and cognitive tasks in a controlled yet dynamic setting. This immersive experience can increase willingness to participate in rehabilitation exercises, transforming repetitive or challenging tasks into engaging activities. Studies have shown that VR can improve motor recovery and cognitive rehabilitation by encouraging patients to extend their functional limits in a safe environment, a crucial component of post-stroke recovery [58].

In contrast, AR overlays digital information onto the real world and provides real-time feedback and guidance during rehabilitation exercises. This capability can be particularly beneficial for patients with PSF because it allows movement visualization and immediate corrective feedback, enhancing motor learning. The interactive nature of AR can also foster a sense of accomplishment and progress, which is vital for maintaining motivation throughout the rehabilitation journey. Both VR and AR can be tailored to individual needs, enabling personalized rehabilitation experiences that align with each patient’s specific deficits and preferences, thus maximizing therapeutic effectiveness [59].

Moreover, the use of these technologies has been shown to positively influence the psychological aspects of rehabilitation. By creating more engaging and enjoyable experiences, VR and AR can help reduce anxiety and depression – common conditions among stroke survivors with fatigue and cognitive impairments. Gamification elements often incorporated into VR and AR applications further motivate patients to participate in rehabilitation, promoting adherence to therapy regimens that might otherwise be perceived as tedious or overwhelming. The social components of these technologies, including opportunities to interact with other patients or healthcare providers in virtual environments, can also foster a sense of community and support that is essential for emotional well-being during recovery [58].

As research continues to explore the efficacy and applications of VR and AR in PSF rehabilitation, it is essential to address challenges associated with their implementation. Factors such as accessibility, cost, and the need for technical training for both patients and healthcare providers must be considered to ensure effective integration into standard rehabilitation practice. Ongoing studies are needed to determine the long-term benefits of these interventions and identify best practices for their use across diverse patient populations. Overall, the incorporation of VR and AR into rehabilitation for PSF represents a promising frontier in neurorehabilitation, with the potential to transform recovery by enhancing engagement, motivation, and functional outcomes [59] (Table 2).

Future Research Directions

EXPLORATION OF BIOMARKERS:

The search for specific biomarkers associated with PSF is crucial for early diagnosis and tailored treatment strategies. Recent studies have highlighted the importance of immune indicators such as the NLR and PNI in characterizing the inflammatory and nutritional status of patients with stroke. These biomarkers show promise as prognostic tools, particularly in the context of PSF. In a study of 333 patients with first-ever ischemic stroke, 39% experienced PSF at 6 months after stroke. Those in the PSF group had higher NLR and lower PNI values at admission, indicating a strong correlation between these biomarkers and fatigue. Correlation coefficients were significant, such that NLR showed a positive correlation (r=0.750) with PSF, whereas PNI exhibited a negative correlation (r=−0.685). In multivariate analyses, both NLR and PNI emerged as independent predictors of PSF; odds ratios indicated substantial risk associated with elevated NLR and reduced PNI. These findings suggest that NLR and PNI could serve as valuable tools for early identification of individuals with high PSF risk, enabling timely interventions to mitigate the effect of fatigue on rehabilitation outcomes [54].

The application of genomics and proteomics offers innovative avenues for biomarker discovery in PSF. These technologies allow deeper investigation into the molecular mechanisms underlying fatigue and its relationship with post-stroke inflammatory processes. Genomic studies can identify genetic variations that predispose individuals to PSF, whereas proteomic analyses can reveal specific protein expression patterns associated with fatigue. High-throughput sequencing and mass spectrometry can facilitate the identification of novel biomarkers that reflect the complex interplay between immune responses and neurochemical changes in the post-stroke period. By leveraging these technologies, researchers can enhance understanding of the biological mechanisms that drive PSF and identify potential therapeutic targets. The discovery of specific inflammatory cytokines or neurotransmitter metabolites as biomarkers could support the development of targeted therapies to alleviate PSF. Thus, the integration of conventional clinical assessments with advanced genomic and proteomic approaches holds great promise for improving the precision of PSF diagnosis and treatment. This multifaceted strategy may ultimately contribute to better outcomes and improved quality of life for stroke survivors affected by fatigue [54].

In summary, the exploration of biomarkers related to PSF is a vital component of ongoing research aimed at improving stroke management. The identification of immune indicators such as NLR and PNI has shown considerable potential for early screening and risk stratification. Moreover, the application of genomic and proteomic technologies could pave the way for discovery of novel biomarkers that may further clarify the pathophysiology of PSF and support targeted interventions. As research in this area progresses, these advancements are expected to lead to more effective diagnostic and therapeutic strategies, ultimately enhancing rehabilitation outcomes and improving overall quality of life for stroke survivors.

DEVELOPMENT OF PERSONALIZED TREATMENT STRATEGIES:

The development of personalized treatment strategies for PSF is essential, given the heterogeneous nature of the condition and its multifaceted impact on patients’ lives. A tailored approach that incorporates individual characteristics – such as genotype, phenotype, and clinical features – can substantially enhance treatment efficacy. For instance, research indicates that personality traits such as extraversion and optimism influence the experience of fatigue in stroke survivors, suggesting that psychological profiles should inform treatment planning [60]. By understanding how these traits impact fatigue severity, healthcare providers can design interventions that align with patients’ psychological characteristics, thereby improving engagement and outcomes. Prospective, stratified randomized controlled trials should enrich or stratify by the dominant fatigue subtype and predefine subtype-specific endpoints, reflecting distinct predictors observed across physical and cognitive fatigue [61]. Furthermore, the integration of artificial intelligence and big data analytics holds considerable promise for personalizing treatment. These technologies can analyze large volumes of patient data to identify patterns and predict responses to various interventions. For example, artificial intelligence algorithms can process data from wearable devices that track physical activity, sleep patterns, and fatigue symptoms in real time, allowing dynamic adjustments to treatment plans based on individual responses [62]. This real-time feedback loop enables clinicians to tailor interventions more precisely, ensuring that they address each patient’s unique needs.

Moreover, incorporating machine learning techniques can facilitate the identification of subgroups of stroke survivors who may respond differently to specific interventions. For instance, a study using experience sampling methods indicated that fatigue levels significantly varied according to activity type and perceived effort [63]. By leveraging such insights, personalized rehabilitation programs can be designed with activity types and intensities optimized for each patient, thereby minimizing fatigue and enhancing recovery. Psychosocial factors, such as motivation, also play crucial roles in managing PSF. Research has shown that autonomous motivation can buffer the negative effects of fatigue on mood, highlighting the importance of addressing motivational factors in treatment strategies [64]. Personalized interventions that foster motivation through goal setting, self-monitoring, and positive reinforcement can empower patients to take an active role in their recovery and improve fatigue management.

The need for personalized treatment strategies is further underscored by findings from studies that explored the experiences of stroke survivors and their caregivers. Many survivors report that current clinical practices do not adequately address their individual needs regarding fatigue management [63]. This gap highlights the importance of shared decision-making, ensuring that treatment plans are not only evidence-based but also aligned with patients’ lived experiences and preferences. A collaborative approach enables clinicians to develop tailored interventions that are more likely to be accepted and followed.

Overall, the development of personalized treatment strategies for PSF is a promising direction for better patient outcomes. By integrating insights from personality assessments, leveraging artificial intelligence and big data analytics, and fostering patient engagement through motivational strategies, healthcare providers can create individualized interventions that address the unique challenges faced by stroke survivors. As research in this area continues to advance, clinicians must remain adaptable and responsive to diverse patient needs, ultimately enhancing the quality of care and support provided to individuals with PSF.

Conclusions

PSF is a multifaceted and complex condition that significantly affects quality of life among stroke survivors. As outlined in this review, the pathophysiology of PSF involves interconnected neuroimmune mechanisms, including inflammatory responses, neurotransmitter imbalances, neuroendocrine dysregulation, and alterations in neuroplasticity. Each factor contributes to the onset and progression of fatigue after stroke, highlighting the need for a comprehensive understanding of their interplay.

Emerging intervention strategies – including immunomodulatory therapies, neuromodulation techniques, and both pharmacological and non-pharmacological approaches – offer promising avenues for alleviating PSF by targeting the biological processes that drive fatigue. However, current research limitations must be acknowledged. From a feasibility perspective, the repurposing of anti-inflammatory or immune-modulating agents is generally more scalable than device-based neuromodulation, which involves greater demands related to training, equipment, and cost. Pragmatic, phenotype-stratified drug trials should be prioritized; tDCS and rTMS are best pursued within research protocols or specialized centers. Many existing studies rely on small sample sizes, inconsistent designs, and non-standardized outcome measures, limiting generalizability and hindering practical application.

From an expert perspective, it is crucial to balance the diverse research findings and clinical presentations associated with PSF. Although the array of contributing factors must be identified, it is equally important to consider individual variability among patients. Factors such as age, stroke severity, comorbidities, and psychosocial components can greatly influence the experience of fatigue and the effectiveness of interventions. Therefore, a one-size-fits-all approach may be insufficient. Personalized treatment plans that incorporate each patient’s unique characteristics and needs are more likely to yield sustained improvements.

Looking ahead, the field of PSF research must prioritize the development of high-quality clinical and basic studies to clarify the underlying mechanisms of fatigue. Large-scale, multicenter investigations with rigorous methodologies will be essential to validate existing findings and identify new therapeutic avenues. Interdisciplinary collaboration among neurologists, psychologists, rehabilitation specialists, and immunologists will be critical for advancing a holistic approach to PSF management.

The integration of comprehensive interventions that combine pharmacological treatments with lifestyle modifications, cognitive-behavioral strategies, and neurorehabilitation techniques may represent a substantial advancement in PSF care. By addressing the multifactorial nature of PSF, such integrated approaches can enhance treatment effectiveness and improve quality of life for stroke survivors.

In summary, although great progress has been made in elucidating the mechanisms of PSF and identifying potential interventions, considerable work remains. Future studies should aim to address current research limitations and focus on personalized, integrated treatment strategies that reflect the diverse experiences of stroke survivors. Through these efforts, more effective interventions may be developed that not only alleviate fatigue but also promote recovery and enhance the overall well-being of individuals affected by stroke.