The Mechanisms of Stress in Epileptogenesis
Article information
Abstract
Epileptogenesis is a gradual, multifaceted pathological process in which the brain undergoes structural and/or functional changes that ultimately culminate in the onset of spontaneous seizures. This process is driven by a range of biological and environmental influences. Growing evidence indicates that stress is a major risk factor for epileptogenesis, amplifying neural hyperexcitability and seizure susceptibility through multiple neurobiological pathways, including hyperactivation of the hypothalamic-pituitary-adrenal axis, disruption of neurogenesis and circuit remodeling, excitatory–inhibitory imbalance, and neuroinflammatory responses. The pediatric period represents a uniquely vulnerable stage of development in which the brain is particularly sensitive to such stress-induced changes. Early exposure to stress during this critical window may produce enduring alterations that heighten the risk of chronic epilepsy. This review consolidates current knowledge on the principal pathophysiological mechanisms through which stress influences epileptogenesis, emphasizing childhood vulnerability and the resulting implications for clinical intervention. These insights may guide the development of novel therapeutic and preventive strategies tailored to early-life susceptibility.
Introduction
Epilepsy is a chronic neurological disorder characterized by recurrent unprovoked or reflex seizures, affecting over 50 million individuals worldwide [1]. Approximately 1 in 150 children are diagnosed with epilepsy within the first decade of life, with its incidence peaking during infancy and early childhood [2]. Epilepsy arising during this critical neurodevelopmental period is a substantial clinical concern, as it is associated with long-term adverse effects on brain maturation, including impairments in cognitive and emotional functioning [3].
A central concept in understanding epilepsy’s pathogenesis is epileptogenesis, which refers to a series of pathological processes by which the brain undergoes structural and/or functional alterations that eventually give rise to spontaneous seizures [4]. These changes may be initiated by diverse etiological factors such as traumatic brain injury, infection, metabolic disturbances, or genetic predisposition, and they typically progress through three stages: an initial insult, a latent period, and the eventual onset of spontaneous seizures [5].
Stress is a physiological and psychological response to internal or external demands that challenge homeostasis, functioning as a protective mechanism to maintain stability [6]. Recent research underscores that, beyond traditional physical and biological triggers, stress is a potent environmental contributor to epileptogenesis. It exerts widespread effects on the central nervous system and can enhance epileptogenic susceptibility by modulating key neurobiological mechanisms, including the hypothalamic-pituitary-adrenal (HPA) axis hyperactivation, impaired neurogenesis and circuit remodeling, excitatory–inhibitory imbalance, and neuroinflammatory cascades [7-11].
Because the pediatric brain is still undergoing dynamic structural and functional development, it is especially sensitive to external stressors. Early-life stress can provoke long-lasting alterations in brain regions such as the hippocampus and amygdala, which in turn may promote the formation of seizure-prone networks [12]. Understanding how stress interacts with epileptogenesis during childhood is therefore a crucial step toward designing effective early intervention and prevention strategies.
In this review, we examine the major biological pathways through which stress influences epileptogenesis, with a particular focus on the neurological vulnerability of the developing pediatric brain. We also consider the clinical implications of these mechanisms and outline future research directions.
Stress and Epileptogenesis
1. Biological mechanisms of epileptogenesis
Epileptogenesis describes the progressive transformation of the brain into a state capable of generating spontaneous seizures, driven by both structural and functional alterations. Fig. 1 provides a schematic overview of the sequential biological processes that underlie this transition. The process is typically triggered by an initiating event—such as trauma, infection, or ischemia—followed by a latent period that may span weeks to years before recurrent seizures appear clinically [4,5,13].
Major biological mechanisms of epileptogenesis. The process typically begins with an initial insult, followed by a latent period during which various structural and functional brain changes occur. These include stress-induced hypothalamic-pituitary-adrenal (HPA) axis activation, structural remodeling, neurotransmitter imbalance (excitatory–inhibitory imbalance), neuroinflammation, and oxidative stress, ultimately leading to the development of spontaneous seizures.
From a pathophysiological standpoint, epileptogenesis encompasses a range of cellular and network-level changes. First, heightened structural plasticity, including axonal sprouting and synaptic reorganization of dentate granule cells, leads to aberrant neural connections. Under normal conditions, the dentate gyrus functions as a gatekeeper, regulating activity from seizure-generating regions in the hippocampus and entorhinal cortex to prevent propagation. However, the formation of novel excitatory feedback loops among granule cells undermines this gating function, enabling seizure spread within the hippocampus and to other limbic structures [14-16]. Alterations in neurogenesis and apoptosis also contribute: reduced proliferation of neural stem cells or abnormal differentiation following stress or injury may integrate aberrant neurons into existing circuits, reinforcing epileptogenic networks [17].
Second, epileptogenesis involves altered neurotransmitter receptor expression. Inhibitory signaling mediated by γ-aminobutyric acid (GABA) receptors is central to the brain’s response to injury and the subsequent development of epilepsy. N-methyl-D-aspartate (NMDA) receptors regulate the number, distribution, and subtypes of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and GABA receptors on both excitatory and inhibitory neurons, influencing the formation of GABAergic and glutamatergic synapses. Reduced GABA receptor expression weakens inhibitory synaptic transmission, whereas upregulation of NMDA and AMPA receptors enhances excitatory drive. These shifts disrupt inhibitory–excitatory balance, heighten neuronal hyperexcitability, and promote epileptogenesis [18-20].
Third, neuroinflammation is a key factor in increasing seizure susceptibility. Following injury, activated glial cells, particularly microglia and astrocytes, release pro-inflammatory cytokines that impair neuronal function and survival. These mediators also compromise the integrity of the blood–brain barrier (BBB), facilitating the entry of peripheral inflammatory molecules into the brain [9,21,22].
In summary, epileptogenesis is a complex, multifactorial process driven by the interplay of diverse pathological mechanisms rather than any single cause. These alterations accumulate over time, progressively increasing both seizure frequency and severity.
2. The stress response and the central nervous system
Stress is a physiological and psychological reaction to internal or external threats, functioning as a defensive mechanism to maintain homeostasis within the brain. Central to this response is the HPA axis. When exposed to a stressor, the hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the anterior pituitary to secrete adrenocorticotropic hormone (ACTH). ACTH then triggers cortisol release from the adrenal cortex, orchestrating a wide array of peripheral and central stress responses [23,24].
In the short term, cortisol supports adaptive survival responses, including increased energy mobilization, immune suppression, and elevated blood glucose levels. However, chronic exposure to elevated cortisol can damage the central nervous system, leading to neuronal injury in the hippocampus, synaptic loss, and dendritic atrophy. The hippocampus and amygdala are key regulators of HPA axis feedback; damage to these regions can impair this feedback loop, resulting in dysregulated stress responses [25].
Importantly, CRH enhances excitatory synaptic transmission, thereby increasing seizure susceptibility. Cortisol also suppresses GABAergic inhibition while facilitating glutamatergic excitation, collectively heightening overall neuronal excitability [26].
In children, the stress response system is still maturing, and the HPA axis exhibits heightened sensitivity to environmental stimuli. Early-life stress can induce long-term hyperresponsiveness of the HPA axis, potentially increasing vulnerability to epileptogenesis. Consequently, stress-related alterations in the central nervous system represent a key pathological link between early-life adversity and epilepsy development [27].
Stress is a multidimensional phenomenon that can be classified according to both source and severity. Preclinical and clinical studies commonly group stressors into three categories. Psychological stressors include experiences such as social isolation, bullying, interpersonal conflict, parental separation, and other adverse life events. Physical stressors encompass repeated corporal punishment, physical abuse, and chronic illness. Environmental stressors include persistent poverty, housing instability, exposure to natural disasters, experiences of war, and living as a refugee [28,29]. The intensity and duration of stress critically influence its neurobiological impact: while mild, acute stress may provoke transient adaptive changes, moderate to severe chronic stress has been shown to dysregulate the HPA axis, elevate glucocorticoid levels, and suppress hippocampal neurogenesis. Such effects are especially harmful during adolescence—a sensitive developmental stage—where they may increase seizure susceptibility and contribute to lasting cognitive and emotional impairments [9].
3. Mechanisms linking stress to epileptogenesis
1) HPA axis
The HPA axis is the central regulator of the stress response. Repeated or chronic stress leads to sustained activation of this system, producing wide-ranging effects on the central nervous system. In particular, elevated levels of CRH and cortisol under stress conditions have been shown to increase seizure susceptibility [8,26].
CRH, secreted by the hypothalamus, enhances excitatory synaptic transmission by acting on both presynaptic and postsynaptic membranes, primarily via activation of NMDA receptors. This effect is especially pronounced in the developing brain, where excessive CRH activity in regions such as the hippocampus and amygdala can induce long-term synaptic remodeling and the formation of hyperexcitable circuits [30]. Elevated CRH and its receptor CRHR1 have been identified in epileptogenic tissue from patients with infantile spasms, and their expression has been linked to increased seizure frequency [31].
Although cortisol typically exerts anti-inflammatory effects, chronic elevation can become neurotoxic. In the hippocampus, prolonged glucocorticoid receptor activation has been associated with neuronal apoptosis, synaptic loss, and suppressed neurogenesis. These changes destabilize neural circuits, creating a permissive environment for epileptogenic network formation [25].
These effects are particularly significant during neurodevelopment, when HPA axis negative feedback mechanisms are functionally immature. As a result, stress-induced HPA activation can be exaggerated and prolonged, leading to chronic hypercortisolemia. Persistently elevated cortisol has been implicated in hippocampal dysfunction and reduced neuroplasticity, both of which heighten vulnerability to epileptogenesis [27].
Furthermore, seizures themselves can disrupt HPA axis regulation, establishing a vicious cycle in which dysregulation further increases seizure susceptibility. In this way, stress and seizures act through mutually reinforcing mechanisms that may accelerate epileptogenesis. This bidirectional relationship is especially evident in children exposed to early-life stress, highlighting the importance of early clinical intervention [8,27,32].
Fig. 2 illustrates the bidirectional relationship between stress and seizure susceptibility through the activation of the HPA axis. Chronic stress leads to sustained cortisol release, which contributes to neurobiological changes promoting epileptogenesis, while recurrent seizures further dysregulate the HPA axis, forming a vicious cycle.
The role of the hypothalamic-pituitary-adrenal (HPA) axis in stress-driven epileptogenesis. Exposure to stress activates the hypothalamus, which releases corticotropin-releasing hormone (CRH). This stimulates the anterior pituitary to secrete adrenocorticotropic hormone (ACTH), leading to cortisol release from the adrenal glands. Elevated cortisol levels promote neural hyperexcitability and increase seizure susceptibility. In turn, seizure activity further activates the HPA axis, establishing a pathological feedback loop.
2) Impaired neurogenesis and circuit remodeling
Neurogenesis, which predominantly occurs in the dentate gyrus of the hippocampus, plays a central role in learning, memory, emotional regulation, and the maintenance of neuronal excitability homeostasis. Stress suppresses neurogenesis, thereby promoting maladaptive circuit remodeling that contributes to epileptogenesis [17,33].
Stress hormones, particularly cortisol, inhibit neural stem cell proliferation and survival, disrupt neuronal maturation, and impair the integration of newly generated neurons into functional networks. Under such conditions, immature or aberrantly connected neurons may become incorporated into hyperexcitable circuits, strengthening epileptogenic pathways. These changes are especially pronounced in the hippocampus under chronic stress [7,33].
Stress also reduces dendritic complexity and synaptic density, decreasing overall network connectivity and neuronal plasticity [7]. Conversely, pathological axonal sprouting and synaptic reorganization can reinforce hyperexcitable networks, providing a structural foundation for spontaneous seizures [14-16].
During early brain development, the rapid formation of neural connections makes the brain particularly sensitive to stress-induced disruptions. Impaired neurogenesis and circuit abnormalities during this period can produce long-lasting increases in seizure susceptibility, facilitating the transition to epilepsy. Notably, early-life stress often consolidates these changes, contributing to both later epilepsy onset and cognitive or emotional dysfunction [12,33].
3) Excitation–inhibition imbalance
The balance between excitatory (glutamatergic) and inhibitory (GABAergic) neurotransmission is fundamental for normal brain function. Stress disrupts this equilibrium, leading to increased network hyperexcitability and a predisposition to epileptogenesis [26].
Chronic stress impairs GABAergic inhibitory circuits by reducing GABA receptor expression and suppressing glutamic acid decarboxylase, the key enzyme for GABA synthesis. These changes weaken inhibitory control, increasing neuronal excitability and lowering the seizure threshold [18-20,32,34].
Stress also promotes the activation of the glutamatergic system. Glutamate is a key excitatory neurotransmitter involved in synaptic signaling throughout the brain. Cortisol alters glutamate transporter function, increasing glutamate accumulation in the synaptic cleft. This results in excessive NMDA and AMPA receptor activation, leading to neuronal depolarization, calcium overload, and excitotoxicity. These effects drive structural remodeling and the formation of hyperexcitable networks in the hippocampus and cortex [19].
During early cortical development, GABA can act as a depolarizing neurotransmitter prior to its maturation into an inhibitory signal. Thus, stress-induced excitation–inhibition imbalance may have particularly severe effects in the immature brain. Early exposure to stress can permanently alter the organization of excitatory and inhibitory circuits, constituting a key mechanism underlying increased susceptibility to epileptogenesis [35].
4) Neuroinflammation
Stress is a potent environmental factor capable of initiating or exacerbating neuroinflammatory responses, which play a significant role in epileptogenesis. Within the central nervous system, microglia and astrocytes respond to stress by releasing pro-inflammatory cytokines, leading to neurotransmitter imbalances, synaptic dysfunction, and increased BBB permeability. These changes collectively create conditions that heighten seizure susceptibility [9,21].
Pro-inflammatory cytokines such as interleukin (IL)-1β, tumor necrosis factor-alpha (TNF-α), and IL-6 promote hippocampal hyperexcitability and facilitate seizure circuit formation. IL-1β enhances glutamatergic signaling through NMDA receptor modulation, while TNF-α increases AMPA receptor surface expression, amplifying excitatory synaptic transmission [36,37].
Stress-induced inflammatory activity also increases BBB permeability, enabling peripheral immune cells and inflammatory mediators to infiltrate brain tissue. This facilitates sustained neuroinflammation, further destabilizing seizure-related circuits. Chronic stress may therefore act as a key modulator of epileptogenesis through persistent inflammatory pathways [9,21,36].
In early childhood, the concurrent maturation of the immune and nervous systems renders the brain especially vulnerable to inflammation-driven circuit remodeling. Early-life stress or infection can prime microglia, making them hyperresponsive to subsequent stimuli. Later stress exposure can then provoke exaggerated neuroinflammatory responses, intensifying the risk of epileptogenic changes [38].
Thus, stress-induced neuroinflammation plays a pivotal role in both the structural and functional remodeling of the hippocampus and cortex, serving as a major mechanism in the pathogenesis of epilepsy.
5) Oxidative stress and its interaction with neuroinflammation
Recent studies have underscored the close interplay between oxidative stress and neuroinflammation, both of which play central roles in the pathophysiology of epileptogenesis. Among the key mediators, NADPH oxidase (NOX) enzymes—particularly NOX2—are activated during early immune responses following brain injury, leading to the generation of reactive oxygen species (ROS). These ROS subsequently activate the nuclear factor κB signaling pathway, which promotes the expression and release of pro-inflammatory cytokines, thereby establishing a self-perpetuating cycle between oxidative stress and inflammation [39].
NOX2-driven production of superoxide (O₂⁻) and hydrogen peroxide (H₂O₂) induces the expression of inflammatory mediators such as IL-1β, TNF-α, and high mobility group box 1 (HMGB1). These cytokines, in turn, further upregulate NOX expression, resulting in sustained ROS production. This amplified oxidative burden depletes glutathione (GSH), disrupts mitochondrial function, and causes neuronal injury, all of which contribute to the progression of epileptogenesis [40,41].
Cortisol—released as part of the stress response—can worsen mitochondrial ROS production while suppressing GSH synthesis, thereby increasing neuronal vulnerability to oxidative damage. Parvalbumin-positive inhibitory neurons (PVINs), which are essential for maintaining inhibitory tone in cortical circuits, are especially sensitive to oxidative stress due to their high metabolic demands. Disruption of the perineuronal net surrounding PVINs has been shown to increase seizure susceptibility, likely through destabilization of local inhibitory networks [42].
Oxidative stress also activates the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, a key component of innate immunity, leading to further IL-1β production and exacerbating seizure risk. Notably, interventions such as ketogenic diets and nuclear factor erythroid 2-related factor 2 (Nrf2)-activating compounds, including sulforaphane and N-acetylcysteine, have demonstrated the capacity to boost GSH synthesis and suppress ROS production. These strategies confer both anti-inflammatory and anti-epileptic effects, highlighting the therapeutic potential of targeting oxidative stress pathways [43,44].
In summary, stress-induced inflammatory responses and secondary oxidative stress form a pathological feedback loop that accelerates epileptogenesis. Targeting both pathways simultaneously may represent a promising therapeutic approach. This relationship is particularly relevant in the pediatric brain, where immature antioxidant defenses render neurons more susceptible to oxidative injury.
6) Preclinical evidence from stress-based animal models
Beyond molecular and cellular mechanisms, evidence from animal studies provides direct experimental validation of stress-induced epileptogenic changes. Preclinical models demonstrate that stress exposure during early life or adolescence can enhance seizure susceptibility through multiple neurochemical pathways.
For example, Amini-Khoei et al. [45] employed a maternal separation (MS) paradigm—180 minutes per day from postnatal day 2 to 14—and found that adult animals subjected to this stressor exhibited increased seizure susceptibility, modulated by the endogenous opioid system. MS animals displayed altered responses to both convulsant and anticonvulsant doses of morphine, and restraint stress revealed reduced pain thresholds, suggesting hyporesponsiveness of the opioid system. These findings suggest that early-life stress-induced disruption of endogenous opioidergic function may contribute to long-term seizure vulnerability.
In another study, juvenile mice exposed to four weeks of social isolation stress beginning on postnatal day 21–23 exhibited heightened susceptibility to pentylenetetrazole-induced seizures, accompanied by anxiety- and depressive-like behaviors. This proconvulsant effect was reversed by NMDA receptor antagonists (MK-801 and ketamine) and attenuated by nitric oxide (NO) synthase inhibitors, implicating dysregulation of the NMDA/NO signaling pathway. Furthermore, upregulation of the N-methyl-D-aspartate receptor subunit 2B subunit of the NMDA receptor in the hippocampus was identified as a molecular contributor. Collectively, these findings demonstrate that both MS and social isolation paradigms sensitize the developing brain to seizures through distinct but converging molecular mechanisms, reinforcing the link between early-life stress and epileptogenic vulnerability [46].
4. Neurodevelopmental sensitivity to early-life stress
Childhood is a period of rapid central nervous system development, during which biological responses to external stimuli differ substantially from those in adulthood. Notably, the HPA axis undergoes gradual maturation during the first years of life. In this critical window, stress exposure can result in excessive and prolonged cortisol secretion due to heightened HPA reactivity and immature negative feedback regulation. These physiological characteristics magnify the impact of stress on brain function and development [12,25].
Compared to adults, children possess a range of neurobiological features that increase the effect of stress on brain development and seizure susceptibility. These distinctions are particularly relevant in the context of epileptogenesis and are summarized in Table 1.
Neurodevelopmental distinctions in the stress response relevant to seizure susceptibility
Adverse childhood experiences (ACEs) exert long-term effects on the structure and function of brain regions central to emotion regulation and memory, including the hippocampus, amygdala, and prefrontal cortex, which are also critically involved in epileptogenesis. The hippocampus is especially sensitive to cortisol, and chronic stress has been shown to cause neuronal loss and impair neurogenesis within this region, thereby facilitating the formation of epileptogenic circuits [12,32].
The pediatric brain’s heightened synaptic plasticity and active circuit formation further increase its sensitivity to stress. Overexpression of CRH, elevated release of pro-inflammatory cytokines, and the immaturity of GABAergic inhibitory circuits have all been linked to greater early seizure susceptibility, potentially promoting the transition to spontaneous seizures later in life [8,38].
In addition, the immature antioxidant defense systems of the developing brain make it more vulnerable to oxidative stress, which may exacerbate inflammation-induced neuronal injury. This vulnerability can contribute to the self-reinforcing cycle between oxidative stress and neuroinflammation, thereby accelerating epileptogenic processes [39].
Clinical evidence aligns with these findings. Epidemiological studies show that children exposed to ACEs—such as abuse, neglect, or family instability—are at significantly higher risk of developing epilepsy later in life compared to non-exposed peers [47]. Furthermore, pediatric epilepsy patients with a history of stress have a higher prevalence of behavioral and emotional comorbidities (e.g., anxiety, depression, attention-deficit/hyperactivity disorder), which are associated with poorer seizure control and reduced quality of life [40-42].
Taken together, these data suggest that childhood stress functions not merely as a seizure trigger but as a neurobiological modulator of epileptogenesis. Accordingly, early identification and intervention following stress exposure in childhood may represent a crucial strategy for preventing epilepsy and improving long-term neurological and psychosocial outcomes.
5. Clinical implications and preventive strategies
The recognition of stress as a contributing factor to epileptogenesis has important clinical implications, suggesting that stress management should be integrated into the prevention, early detection, and treatment of epilepsy. Given the profound and lasting effects of childhood stress on brain development, early intervention may be critical for delaying or potentially preventing the onset of epilepsy.
Emerging preclinical data also indicate that antioxidant-based strategies, such as ketogenic diets and Nrf2-activating compounds, can confer both anti-inflammatory and anti-epileptic benefits by disrupting the oxidative stress–neuroinflammation cycle.
First, pharmacological interventions targeting the biological underpinnings of stress-induced epileptogenesis are under investigation. CRH receptor antagonists may help regulate HPA axis hyperactivity and lower seizure susceptibility. Anti-inflammatory agents, including IL-1β and TNF-α inhibitors, could attenuate stress-induced neuroinflammatory responses. Additionally, GABAergic agents aimed at restoring inhibitory circuitry may disrupt the pathophysiological link between stress and epilepsy [8,36].
Second, psychosocial interventions play a critical role. Parental education, stress-reduction strategies (e.g., mindfulness, relaxation training), and early mental health support can help mitigate HPA axis hyperactivity and foster a healthier neurodevelopmental environment. Family-based interventions, in particular, have shown efficacy in stabilizing the child’s stress response system [8,48].
Third, developing strategies for risk stratification and early intervention is essential. In children with a history of early-life stress, neurophysiological monitoring, HPA axis reactivity testing, and neuroimaging may detect early signs of epileptogenesis, enabling timely preventive measures before seizure onset. This approach requires the identification of reliable biomarkers and the creation of predictive models based on these markers [33].
Finally, implementing these approaches effectively will require a multidisciplinary framework involving pediatricians, neurologists, psychiatrists, and social workers. A coordinated, biopsychosocial model of care is critical—not only for early intervention but also for preventing secondary complications of epilepsy, such as learning difficulties and psychiatric disorders.
In conclusion, early assessment and intervention for stress may prove pivotal in improving quality of life and reducing the risk or severity of epilepsy. Future research should focus on validating these preventive strategies and facilitating their translation into standard clinical practice.
Conclusion
This review has explored, from multiple perspectives, the biological mechanisms by which stress influences epileptogenesis. Epileptogenesis cannot be accounted for solely by structural injury or genetic predisposition; growing evidence highlights the pivotal role of environmental factors—particularly stress—in shaping central nervous system function and driving maladaptive circuit reorganization. Stress contributes to the formation of epileptogenic networks through diverse mechanisms, including hyperactivation of the HPA axis, suppression of neurogenesis, excitation–inhibition imbalance, and neuroinflammation—effects that are especially pronounced during brain development.
Children display heightened biological reactivity to stress and undergo a developmental period characterized by increased structural plasticity, making the effects of stress on epileptogenesis potentially more profound than in adults. Early-life stress is associated not only with elevated epilepsy risk but also with cognitive and emotional impairments, which may complicate treatment and reduce quality of life.
Accordingly, stress should be recognized as a significant, modifiable risk factor for epileptogenesis, underscoring the importance of early identification and timely intervention. An integrated management strategy—combining pharmacological therapies, psychosocial interventions, risk screening, and multidisciplinary collaboration—is essential for effective prevention and long-term care.
Future research should aim to elucidate the mechanistic links between stress and epileptogenesis, validating preventive strategies, and translating these findings into clinical practice. Ultimately, advancing our understanding of stress regulation holds the potential to inform a new therapeutic paradigm for the prevention and mitigation of epilepsy.
Notes
Conflicts of interest
Sang Ook Nam is an editorial board member of the journal, but he was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.
Author contribution
Conceptualization: SON. Data curation: HYJ. Formal analysis: HYJ. Funding acquisition: SON. Methodology: HYJ. Project administration: HYJ, SON. Writing - original draft: HYJ. Writing - review & editing: SON.
Acknowledgments
This work was supported by a 2-year research grant from Pusan National University.