Neurobiological Link between Stress and Gaming: A Scoping Review

Research on video gaming has been challenged by the way to properly measure individual play experience as a continuum, and current research primarily focuses on persons with gaming disorder based on the diagnostic criteria established in relation to substance use and gambling. To better capture the complexity and dynamic experience of gaming, an understanding of brain functional changes related to gaming is necessary. Based on the proinflammatory hypothesis of addiction, this scoping review was aiming to (1) survey the literature published since 2012 to determine how data pertinent to the measurement of stress response had been reported in video gaming studies and (2) clarify the link between gaming and stress response. Eleven studies were included in this review, and the results suggest that gaming could stimulate a stress-like physiological response, and the direction of this response is influenced by an individual’s biological profile, history of gaming, and gaming content. Our findings highlight the need for future investigation of the stress-behaviour correlation in the context of gaming, and this will assist in understanding the biological mechanisms underlying game addiction and inform the potential targets for addiction-related proinflammatory research.


Introduction
Video games have progressed significantly since the release of Pong, the first arcade game, in 1972 [1]. Since then, video games have evolved from black and white, two-dimensional graphics into the current state of games with amazing 3D graphics and hooking storylines, which can be addicting. Recent advancements in technology have made games extremely accessible on devices such as tablets, smartphones, computers, smart televisions, virtual reality, and gaming consoles [2].
Currently, it is difficult to estimate the prevalence of problematic gamers worldwide due to the lack of a clear definition and internationally agreed-upon psychometric measures in problematic gaming [3]. Research on a United States and Singaporean national representative sample of adolescents found problematic game use at approximately 9% [4], 0.4% in Poland, and 4.7% in Indonesia [5]. In a Norwegian sample of 3389 [6] and a Dutch sample of 902 [7], it was found that only 1.4% were addicted gamers in both studies. However, the low prevalence rates in both studies could be a result of the age characteristics of the sample, as they included seniors aged up to 81 years old who may be less interested in gaming. Moreover, 67% of New Zealand's population are gamers, with 9% being problematic gamers [8]. It was also found that 53% of New Zealand gamers are men, and 73% are adults aged 18 years or older [8].
The reasons for game playing are fluid and vary between individuals, as some games serve as a method to cope with stress, while others are played for entertainment, out of boredom, in search of challenges, or as a way to pass the time [9]. The consequence of poor coping methods and the advancement of technology has resulted in a constantly growing number of gamers who are addicted to having the ability to play games portably, which allows them to spend time gaming at any time and place [9,10]. This is an issue because there is no restriction on the location of gaming, which allows individuals to game at work, school, while driving, or in public places. As a result, areas such as work and school performances are affected, putting oneself and others in danger.
At present, research on video gaming has been challenged by the lack of ways to properly measure individual play experiences. Attention has largely been addressed to those who are defined as problem gamers or persons with gaming disorder based on the diagnostic criteria established in relation to substance use and gambling [11]. However, the reality is that "problem" gaming and healthy engagement with gaming as a leisure activity can be challenging to differentiate. Positive and negative effects of gaming could appear simultaneously and be shaped by sociocultural factors such as social isolation and loneliness [12,13]. Thus, there is a need to shift from the traditional way of assessing gaming in binary forms of "disease" or "health" to a new approach that defines gaming as a continuum; this would help to capture the complexity and dynamic experience of gaming, leading to great potential to avert disease before onset [12].
A framework linking the adverse effects of gaming with compromised molecular physiological conditions has been proposed [12] and is in line with the proinflammatory hypothesis of addiction, suggesting modulating pro-inflammatory molecules could lead to brain functional and behavioural changes contributing to addiction [14,15]. One of the main routes to locate the innate immune system implicated in addiction is through the nuclear factor kappa-light-chain-enhancer of the activated B cell (NF-kB) signalling pathway [16]. This pathway increases the release of proinflammatory cytokines such as Interleukin-1 beta (IL-1β) and tumour necrosis factor-alpha (TNF-α), influencing the neurobiological processes involved in the development of addiction [17]. Furthermore, involvements of other cells, such as IL-6, IL-1β, IL-2 IFN-γ, and C-reactive protein (CRP), in addition, have also been reported [16]. Importantly, the increased release of proinflammatory cytokines frequently follows the chronic stress response, stimulating the Hypothalamic-Pituitary-Adrenal (HPA) axis [18]. Stress leads to an increase in HPA axis activity to a stressor by initiating the release of corticotrophin-releasing factor (CRF) at the hypothalamus [19]. CRF secretion initiates the release of adrenocorticotropic hormone (ACTH) from the pituitary and glucocorticoids (GC), such as cortisol, from the adrenal gland [19]. GCs not only mediate the stress response but also have widespread homeostatic control over the body, including the immune system with potent immune-suppressive and anti-inflammatory effects [20]. Acute and chronic stress differ at HPA axis activation, with chronic stress leading to the hypersecretion of CRF and GCs and hyposensitivity to feedback inhibition regulated by cortisol [18]. It has been shown that reduced glucocorticoid responsiveness leads to increased concentrations of proinflammatory cytokines, plays a role in major depression [21], and is involved in the development of addiction [22].
Although a recent review suggests an association between video game playing time and physical health deterioration indicators, including BMI and general health status [23], the implication of this association for the immune system is unclear. The degree of psychological and immune reactivity in response to acute stress has been shown to predict depression symptoms and susceptibility to addiction, suggesting the potential of using these measures for assessing individual vulnerability to mental disorders [24]. Given that stress relief has been reported by game players as one of the main motivations for gaming, the aim of this scoping review was to survey the literature to determine how data pertinent to the measurement of stress response had been reported in video gaming studies and clarify the link between gaming and stress response. We believe that investigating the stress-behaviour correlation will assist in understanding the biological mechanisms underlying video game addiction and inform the potential targets for addiction-related proinflammatory research. To achieve the goals of the present review, three research questions were proposed for guidance, including: (1) Who are the research participants examined in the gaming-related stress research? (2) What measurements are used to measure gaming-related stress? (3) What is the neurobiological evidence in stress-related gaming research?

Methods
A scoping review methodology defined by Arskey and O'Malle [25] was used. Relevant articles were sought from PubMed, Scopus, and EBSCO (databases at EBSCOhost comprised of APA PsycArticles, APA PsycInfo, MEDLINE, and MEDLINE Ultimate) between 2002 and 15 October 2022, using the following search terms to search the databases (all in titles and abstracts): (gaming OR game) AND (stress OR immun*). As the literature search was not conducted on a systematic basis, the evidence reviewed may not be exhaustive.

Study Selection
The criteria for article inclusion in the review was the employment of neurobiological methods such as electroencephalography, electrocardiography, and other cardiovascular function parameters, cortisol, and/or other hormones/metabolites measures to investigate stress or immune function, used to investigate the gaming behaviour of adolescents and adult participants. Only articles in English published in the last 10 years (between 2012 and 2022) were selected. Articles not available in the full text or published in a peer-reviewed format, as well as reviews, meta-analyses, opinions, and editorials, were excluded. Although the criteria for inclusion was the investigation of gaming behaviour, studies investigating e-sports or watching the games played by others were excluded, as the competition level of e-sports made it unique from general gaming.
The databases were scanned based on the search terms, and the search results were imported to a systematic review web tool, Rayyan [26]. Duplicates were deleted, and the remaining articles were screened by titles and abstracts. Eleven articles met the criteria and were included in this review. The illustration of the study selection process is presented in Figure 1 using the PRISMA flow diagram [27]. diction-related proinflammatory research. To achieve the goals of the present review three research questions were proposed for guidance, including: (1) Who are the re search participants examined in the gaming-related stress research? (2) What measure ments are used to measure gaming-related stress? (3) What is the neurobiological evi dence in stress-related gaming research?

Methods
A scoping review methodology defined by Arskey and O'Malle [25] was used. Rel evant articles were sought from PubMed, Scopus, and EBSCO (databases at EBSCOhos comprised of APA PsycArticles, APA PsycInfo, MEDLINE, and MEDLINE Ultimate between 2002 and 15 October 2022, using the following search terms to search the data bases (all in titles and abstracts): (gaming OR game) AND (stress OR immun*). As th literature search was not conducted on a systematic basis, the evidence reviewed may no be exhaustive.

Study Selection
The criteria for article inclusion in the review was the employment of neurobiolog ical methods such as electroencephalography, electrocardiography, and other cardio vascular function parameters, cortisol, and/or other hormones/metabolites measures to investigate stress or immune function, used to investigate the gaming behaviour of ado lescents and adult participants. Only articles in English published in the last 10 year (between 2012 and 2022) were selected. Articles not available in the full text or published in a peer-reviewed format, as well as reviews, meta-analyses, opinions, and editorials were excluded. Although the criteria for inclusion was the investigation of gaming be haviour, studies investigating e-sports or watching the games played by others were ex cluded, as the competition level of e-sports made it unique from general gaming.
The databases were scanned based on the search terms, and the search results wer imported to a systematic review web tool, Rayyan [26]. Duplicates were deleted, and th remaining articles were screened by titles and abstracts. Eleven articles met the criteri and were included in this review. The illustration of the study selection process is pre sented in Figure 1 using the PRISMA flow diagram [27].

Synthesis of Results
The articles were subsequently discussed through consensus between authors (Table 1).

Research Participants and Study Design
Study sample sizes ranged from 23 to 148 participants, while group sizes varied from 11 to 50 individuals per group. Only male participants were enrolled in seven out of 11 studies [28][29][30][31][32][33][34]. While three studies enrolled adolescents as well-two with a defined age range from 15 to 25 years [31,33] and one from 16 to 29 years [32], the rest involved adult participants only.
Three studies included IGD groups and healthy participants as controls [31,33,34], and one study additionally included individuals with alcohol use disorder [35]. Different types or modes of video games for participants' allocation into different groups were used in three studies [29,36,37]. One study compared high vs. low gaming involvement groups [38], two studies compared experimental groups vs. control groups [30,32], and only one study investigated the experimental group solely [29].
No significant differences on cortisol, cortisone, testosterone, progesterone, DHEA or corticosterone between groups. Greater self-reported anxiety associated with increased cortisol and cortisone. IGD: greater cortisone associated with greater self-reported chronic stress (TICS total).

(Porter and Goolkasian, 2019) [36]
To determine if playing video games can induce stress by manipulating video game instructions to evoke threat or challenge appraisals.

Neurobiological Evidence on Stress-Related Gaming Research
Some of the research specifically assessed the acute effect of gaming on stress response activity, while others measured the long-term gaming-related effect on stress. The findings of the research included in this review were grouped by their specific primary measurements.

Blood Pressure (BP) and Heart Rate (HR)
BP and HR are sensitive to changes in autonomic balance, and stress could lead to excess sympathoadrenal activation, influencing BP and HR [39]. The findings of gaming research on BP and HR have been inconsistent. In a study assessing the effect of gaming on acute stress, a lab-based stressor was introduced to the participants prior to gaming. In line with reduced self-reported stress, both heart rate and blood pressure were lower after game play [37]. The authors argued that game play not only provides a break to players who can escape from stressful events in real life, but also that a sense of control and autonomy gained through gaming could contribute to stress relief. Similarly, a study that examined the cardiovascular stress response to gaming failed to identify any significant game-related change in BP and HR, suggesting that video games do not act as mental stressors and are unable to induce stress [36]. Nevertheless, specific instructions for game playing and type of game could lead to differences in cardiovascular stress responses; for example, when participants were told that they would be evaluated based on their performance of gaming, increased negative emotion ratings and decreased heart rate variability were observed. Compared to the puzzle game players, fighting game players showed increased blood pressure and decreased heart rate variability and also reported higher positive emotion ratings [36]. In contrast, a modest stress response associated with video gaming has also been reported: playing a video game for 1 h resulted in greater systolic blood pressure (SBP), heart rate, and feelings of stress [40].

EEG and Saliva Samples
EEG signals containing information about mental states might be a helpful tool to measure changes in brain activity patterns caused by stress [41,42]. EEG asymmetry index, power, coherence, and other features were widely investigated in stress studies, with the alpha asymmetry index and greater frontal right alpha activity being a consistent and robust stress-related feature reflecting emotional arousal [42,43].
Salivary cortisol is routinely used as a standard to measure stress response and is appreciated as a marker of HPA axis activity [44], with increased cortisol secretion in response to stress. Cortisol can interact with the brain's reward system and might be involved in addictions by contributing to the reinforcing effects of substances such as alcohol [45]. Such results led to the investigation of dysregulated HPA axis responses to a stressor in non-substance addictive disorders as well; however, considering IGD findings are mixed [26].
Only several studies addressed the EEG in relation to gaming in conjunction with saliva sample analysis. EEG was recorded during the play of a football match using a 14-channel EMOTIV system, and saliva samples were collected before and after the game. The results show that salivary cortisol concentration was significantly decreased after gaming, and the power of the EEG signal was increased in most of the electrodes in lower bands (3 Hz) and higher frequency bands (15 Hz), but decreased in the occipital lobe (in 6 and 10 Hz) and in the frontal lobe (in 15 and 18 Hz) [28]. Unfortunately, the authors did not elaborate on the implication of brain wave change in stress relief. In contrast, opposite results were also reported-the stress marker (salivary cortisol) and the fear marker (α-amylase) levels increased after playing the brain teaser game [30].
Furthermore, the specific content-related effect of video games was also evaluated [29]. EEG and the concentrations of cortisol and α-amylase were measured prior to and following playing four different types of games, respectively, including the Runner game, Excitement game, Fear game, and Puzzle game. It has been found that the concentration of α-amylase and cortisol increased significantly after playing the Fear game, Runner game, and Excitement game but decreased after playing the Puzzle game. The secretion of the salivary enzyme (α-amylase) is a reliable measure of the activity of the sympathetic nervous system, and its increase is often associated with stress-induced fear, which can happen quickly within a few seconds [46]. On the other hand, cortisol is considered the most important stress hormone secreted by the adrenal cortex of humans, and its effect on mental function could be modulated by the duration and intensity of stress. Acute stress enhances mental abilities, while chronic stress leads to dysfunction. Thus, reduction in α-amylase and cortisol in puzzle games may indicate the deactivation of the stress system due to the mental demand required for problem solving in puzzle games. In contrast, the Runner game, Excitement game, and Fear game increase the stress response, which may lead to impairment in cognitive function in the long run [29]. In line with this, impaired memory after a violent game was also reported by others; however, cortisol levels were decreased in this case [32].

Hair Sample
In contrast, a study using hair samples for the analysis of cortisol, cortisone, testosterone, progesterone, dehydroepiandrosterone (DHEA), and corticosterone reported negative results, showing no significant difference in basal HPA axis functioning between individuals with IGD and healthy controls [33]. However, a lack of change in measures of hair cortisol does not exclude the possibility of altered neurobiological stress reactivity to acute stress in IGD. Research shows that although patients with IGD show no higher basal HPA axis activity than health controls, they exhibit increased levels of subjective stress, negative affect, and heart rate, as well as transiently decreased levels of cortisol during a standardised laboratory stress task, and this greater negative stress response was strongly correlated with IGD severity [31].

Blood Sample
The close link between stress and the pathophysiology of addictive disorders is well established. Thus, some researchers have compared the stress-related biological profile of individuals with Internet gaming disorder (IGD) with that of those with substance use disorder. For example, a study examined the differences in stress level and serum levels of tryptophan (TRP), 5-hydroxytryptamine or serotonin (5-HT), kynurenine (KYN), and kynurenine acid (KYNA) between young adults with IGD, those with alcohol use disorder (AUD), and health control [35]. The KYN pathway is one of the TRP metabolism pathways, which is initiated by the enzyme indoleamine 2,3-dioxygenase (IDO) and the 5-HT, and alterations of TRP level metabolism could be caused by either stress and/or immune system activation. The results demonstrated that the KYN levels and KYNA/KYN ratios for the IGD group were intermediate between those of the AUD group and healthy controls, showing increased KYN levels and KYN/TRP ratios and decreased KYNA levels and KYNA/KYN ratios relative to the healthy controls; nevertheless, the level of TRP was not different between groups [35]. Furthermore, higher levels of stress, lower resilience, and impaired executive functions were found in both addictive disorder groups compared to the health controls. These findings were considered to be an indication of vulnerable neuronal networks associated with addictive disorders, which could be caused by great exposure to stress.
In line with this, an association between increased social wellbeing and reduced expression of a stress-induced gene profile, so-called "conserved transcriptional response to adversity" (CTRA), has been found in individuals experiencing positive psychosocial effects from gaming, such as motivation for achievement, socialisation, and immersion via gaming, but this association has become weaker and non-significant in those with a low level of positive involvement in gaming. It appears that the effects of gaming could be different from one person to another due to individual differences. The authors have proposed the "rich-get-richer" and "poor-get-poorer" effects in the context of gaming and argued that videogaming could be considered a therapeutic device primarily for psychosocially healthy individuals [38].

What Are Implications of Gaming-Related Stress Research?
There is dynamism and complexity in the immune system and addiction, such as large interindividual variations of inflammation, a history of addiction, medical or psychiatric symptoms associated with addiction, etc. Video game addiction, conceptualised as a non-chemical addiction, not only shares many key addiction symptoms, such as loss of control, craving, and mood regulation, but also affects the brain, activating the brain's reward system in a similar way as substance use disorder. Without the confounding problems of polydrug use and drug effects, it may provide a competing way to investigate addiction itself.
Based on the research evidence included in this review, it appears that it remains unclear whether gaming helps to reduce stress or not. Even in the case when the authors acknowledged that a reduction in stress after gaming has been observed, a function of time on stress reduction could not be ruled out, and it is unclear how gaming compares to other stress-reducing activities [37]. Nevertheless, gaming could induce a physiological stress response, such as increased blood pressure paired with a decreased heart rate [36], reduced cardiac coherence [47], and increased salivary cortisol [29]. The extent of the altered physiological response might be related to either the actual content and type of game or the intensity of game playing. In some cases, the content and type of game could be considered stressors of varying degrees, while the intensity of gaming may reflect the severity of problematic gaming.
Furthermore, some of the physiological stress response induced by gaming might be related to biological correlates, as evidence showed differences in gene expression profiles between functional gamers and individuals with IGD. The association between problematic internet use and reduced self-reported immune function that is independent of the impact of comorbidities such as depression, isolation, and anxiety has been reported [48]. For example, the conserved transcriptional response to adversity (CTRA), a leukocyte gene expression profile activated by chronic stress. It has been found that persons with more frequent positive gaming experiences are less likely to manifest the elevated CTRA genomic profile compared to those with IGD [49]. In line with this, abnormal neurobiology in the brain regions related to impulse control, reward processing, and somatic memory, such as the orbitofrontal cortex (OFC), striatum, and sensory regions, has been found in people who are excessive internet game users. Compared to normal game users, those excessive internet game users show greater impulsiveness, and the intensity of game play is positively correlated to impulsiveness [50]. It has been suggested that the psychological and neural mechanisms underlying other types of impulse control disorders and substance/nonsubstance-related addiction may be shared by game overuse [50].
This scoping review comes with limitations that need to be acknowledged. The majority of the study samples included in this review were male, and this would compromise the generalizability of our results to the general population. Furthermore, video game types are also quite heterogeneous (e.g., competitive action game vs. puzzle game), and the results presented in this review primarily focused on gaming in general rather than the specific type of game-related effect. We only included the research published in English in the last ten years, and given the relatively high prevalence of gaming in Asian countries, we might miss out on some invaluable evidence published in other languages.
In conclusion, gaming could stimulate a stress-like physiological response, and the direction of this response might be modulated by an individual's biological profile, history of gaming, and content of gaming. To date, understanding the health impact of gaming is still in its infancy. By acknowledging the positive effect of gaming on cognition and a person's life, its potential harm should not be ignored, and this should call for more biologically-based research to reveal what factors lead to individual differences in the development and maintenance of problematic behaviours.