New developments in brain research of internet and gaming disorder

Highlights

• The neural mechanisms underlying Internet Gaming Disorder (IGD) resemble those of drug addiction.

• Brain imaging studies showed changes in regions responsible for control of attention, impulses , motor, sensory-motor and emotional regulation.

• Videogame playing was associated with lower white matter density in regions involved in decision-making, behavioral inhibition and emotional regulation.

• Videogame playing involved changes in reward inhibitory mechanisms and loss of control.

• Videogame playing was associated with dopamine release similar in magnitude to those of drugs of abuse.

Abstract

There is evidence that the neural mechanisms underlying Internet Gaming Disorder (IGD) resemble those of drug addiction. Functional Magnetic Resonance Imaging (fMRI) studies of the resting state and measures of gray matter volume have shown that Internet game playing was associated with changes to brain regions responsible for attention and control, impulse control, motor function, emotional regulation, sensory-motor coordination. Furthermore, Internet game playing was associated with lower white matter density in brain regions that are involved in decision-making, behavioral inhibition and emotional regulation. Videogame playing involved changes in reward inhibitory mechanisms and loss of control. Structural brain imaging studies showed alterations in the volume of the ventral striatum that is an important part of the brain's reward mechanisms. Finally, videogame playing was associated with dopamine release similar in magnitude to those of drugs of abuse and lower dopamine transporter and dopamine receptor D₂ occupancy indicating sub-sensitivity of dopamine reward mechanisms.

Introduction

Internet Gaming Disorder (IGD) involves excessive or poorly controlled preoccupations, urges or behaviors regarding computer and videogame play that lead to impairment or distress. There are three different models proposed for IGD: an impulse-control disorder, an obsessive-compulsive disorder, and a behavioral addiction model (Grant et al., 2010). The behavioral addiction model argues that IGD shows the features of excessive use despite adverse consequences, withdrawal phenomena, and tolerance that characterize substance use disorders. In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (American Psychiatric Association, 2013), IGD is identified in Section III as a condition warranting more clinical research and experience before it might be considered for inclusion as a formal disorder (see (Weinstein et al., 2014, Weinstein and Aboujaoude, 2015) for review). The work group moved from a broad conceptualization (along the lines of problematic internet use) to a narrower one, focusing primarily on pathological online gaming and avoiding use of the term “addiction”. Noteworthy, the DSM-5 does not offer sufficient guidance on how to approach individuals with suspected Internet-related psychopathology or how to design or interpret research studies into this topic. Instead, clinicians and researchers have to rely on proposed definitions, along with several screening and assessment instruments developed for problematic internet use and problematic video game use (Weinstein and Aboujaoude, 2015).

There is a debate whether IGD is the best clinical term for diagnosing Internet addiction. For example, Young (Young, 1998) considers online games a specific subtype of Internet activities, and she developed her Internet addiction criteria that were based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for pathological gambling (American Psychiatric Association, 1994). Her theory states that online game addicts gradually lose control over their game play; that is, they are unable to decrease the amount of time spent playing while immersing themselves increasingly in this particular recreational activity and eventually develop problems in their real life (Young, 2009). Table 1 describes the proposed inclusion criteria for IGD

Surveys in the US and Europe have indicated prevalence rates of between 1.5% and 8.2%, of the country's population with varying diagnosis methods between countries (Durkee et al., 2012). Cross-sectional studies on samples of patients reported high co-morbidity of IGD with psychiatric disorders, especially affective disorders, anxiety disorders and attention deficit hyperactivity disorder (ADHD) (Weinstein et al., 2014, Weinstein and Aboujaoude, 2015). Previous reviews have described brain-imaging studies in IGD until 2013 (Weinstein and Lejoyeux, 2015, Zhu et al., 2015, Kuss and Griffiths, 2012). In view of the rapid developments in brain research in IGD, this review will update these studies with new developments in brain imaging of IGD between 2013 and now. Secondly, it will analyze these findings in relation to the three models proposed for IGD namely behavioral addiction, impulse control disorder and obsessive-compulsive disorder in order to improve our clinical definition and diagnosis of this disorder. Finally, we will bring parallel evidence from brain imaging studies in pathological gambling which is now recognized as a behavioral addiction (American Psychiatric Association, 2013) and with compulsive sexual disorder.

A PubMed search was conducted using the search terms ‘Internet addiction’ ‘Internet Gaming Disorder’ and ‘Pathological Internet use,’ each of which was combined with each of the terms ‘brain imaging,’ or ‘fMRI’ or ‘PET’ or ‘resting state’ using the conjunction ‘AND.’ Each term was required to be present in the ‘Title/Abstract’ of the paper. The search was further restricted by ‘English’ as the publication language and Publication Date from 2008 to May 2016. The only studies that were selected for the review were original research papers that were published in peer-reviewed journals. The search has yielded eligible 52 studies including 16 studies of the resting state, 13 studies of functional connectivity, 18 activation studies and 5 studies of pharmacology. As a general caution, throughout this review, in making group comparisons, there are reported differences between IGD group and control groups but these differences do not imply a causal role of IGD. Group differences may reflect predisposing factors rather than decreases due to IGD.

There is a vast body of pre-clinical evidence that the dopaminergic system mediates reward in general and the rewarding effects of drugs (Koob, 1992, Di Chiara and North, 1992, Wise, 1996, Di Chiara and Bassareo, 2007). The mesolimbic dopamine (DA) pathway that includes DA cells in ventral tegmental area projecting into nucleus accumbens seems to be crucial for drug reward (Wise, 2009). Other DA pathways such as the meso-striatal pathway includes DA cells in substantia nigra projecting into dorsal striatum and meso-cortical pathway includes DA cells in the ventral tegmental area projecting into frontal cortex are now also recognized as contributing to drug reward and addiction (Wise, 2009). The mode of DA cell firing also differently modulates the rewarding and conditioning effects, of drugs (predominantly phasic DA cell firing) compared with the changes in executive function that occur in addiction (predominantly tonic DA cell firing) (Wanat et al., 2009).

Brain imaging studies using Positron Emission Tomography (PET) in humans showed that the stimulant drugs cocaine and methylphenidate released dopamine in the striatum (Volkow et al., 1996a) and there is further evidence that the dopaminergic striatal-thalamic-orbitofrontal circuit mediates the rewarding effects of cocaine (Volkow et al., 1997a, Volkow et al., 1997b). Similarly, cocaine administration in fMRI activated the ventral tegmental area, pons, basal forebrain, caudate, cingulate, and the lateral prefrontal cortex (Breiter et al., 1997). These studies support the theory that the dopaminergic striatal-thalamic-orbitofrontal circuit underlies compulsive drug use.

Resting state is a method of functional brain imaging that evaluates regional interactions that occur when a subject is not performing an explicit task. The resting state approach is useful to explore the brain’s functional organization and to examine if it alters in neurological or psychiatric diseases (De Luca et al., 2006). Excessive Internet game use was associated with abnormal resting state activity in the orbito-frontal cortex, striatum, and sensory regions, which are responsible for impulse control, reward processing, and somatic representation of previous experiences (Park et al., 2010). The study measured regional cerebral metabolic rates of glucose (rCMRglu) in PET in IGD and control participants. The orbito-frontal cortex, striatum, and sensory regions are also associated with other types of impulse control disorders and substance/non-substance use disorder. The resting brain activity can be observed through changes in blood flow in the brain that creates a blood-oxygen-level dependent (BOLD) signal that can be measured using fMRI (De Luca et al., 2006). Using the arterial spin-labeling perfusion technique(footnote 1) in fMRI, adolescents with IGD showed higher global Cerebral Blood Flow (CBF) in areas that are important for learning and memory (amygdala/hippocampus),¹ conscious urges to use drugs (insula) executive function and inhibition (pre-frontal cortex, anterior cingulate cortex and parietal lobe) (Feng et al., 2013). There were lower CBF measures in the middle temporal gyrus, middle occipital gyrus, and cingulate gyrus. The results so far indicate that IGD seems to share psychological and neural mechanisms with other types of impulse control disorders and substance use disorder (Volkow et al., 2010). Since there are only few publications that present structural changes in IGD, these findings need to be replicated in the future. See Table 2 for structural studies on the resting state in IGD.

Another measure of brain connectivity in the resting state is regional homogeneity (ReHo) (footnote 2) in fMRI.² ReHo represents the temporal homogeneity of the regional BOLD signal of fMRI, which may reflect neural activity. Therefore, abnormal ReHo in certain regions of the brain may be associated with the neurobiological impairments underpinning various neuropsychiatric disorders that involve temporal changes in disruption to local function. IGD individuals showed enhanced regional homogeneity (ReHo) in the brainstem, inferior parietal lobule, cerebellum, and middle frontal gyrus that relate with sensory-motor coordination (Dong et al., 2012a). IGD individuals also had decreased ReHo in temporal, occipital and parietal brain regions that are responsible for visual and auditory functions. Long-time online game playing presumably enhanced the brain synchronization in sensory-motor coordination and decreased the excitability in visual and auditory related brain regions. This evidence is further supported by findings of enhanced ReHo measures in brainstem, cerebellum, limbic lobe and frontal lobe in IGD college students (Liu et al., 2010). Similarly to drug use disorders, the connections or synchronization among these regions shown by ReHo enhancement and the frontal lobe corroborates the evidence for enhancement of reward pathways. Finally, both IGD and alcohol use disorder participants had increased ReHo in the posterior cingulate cortex whereas IGD patients had decreased ReHo in the superior temporal gyrus compared with alcohol use disorder and healthy control participants (Kim et al., 2015). The increase in posterior cingulate cortex has been associated with reward at uncertainty or reflecting risk preferences in addiction. Reduced ReHo in the superior temporal gyrus relates presumably to impairments in higher audio-visual information processing as well as response inhibition, although both findings need to be replicated. In conclusion, there are brain regions that are only indirectly involved in drug addiction such as the parietal and occipital cortex. Furthermore, brain regions that are involved in memory (amygdala and hippocampus) and conscious urges to use drugs (insula) are involved in many other processes. However, these regions serve also for the function and maintenance of drug addiction.

The brain’s gray matter is a major component of the central nervous system made up of neuronal cell bodies and it is involved in motor control, perception, memory, emotions, and speech. A study that measured gray matter volume in fMRI together with performance on the Monetary Incentive Delay task and the Cambridge Gambling Task showed higher left striatal grey matter volume in frequent video game players that also negatively correlated with deliberation time on the Cambridge Gambling Task (Kuhn et al., 2011). Furthermore, there was enhanced activity in the left striatum during feedback of loss compared with no loss on the Monetary Incentive Delay task in frequent video game players that negatively correlated with deliberation time on the task. An association of video game playing with higher left ventral striatum volume could reflect altered reward processing and represent adaptive neural plasticity in frequent videogame players. Other studies showed that IGD participants had lower gray matter density in areas responsible for behavioral and emotional problems (cingulate gyrus) urges (insula), and regulation of emotional behavior (lingual gyrus) which are major concern in IGD (Zhou et al., 2011). Patients with IGD showed increased gray matter volumes of the thalamus whereas pro-gamers showed such increase in the cingulate gyrus and these changes may be associated with the effects of gaming on attention and sensory-motor coordination (Han et al., 2012). Furthermore, lower diffusional kurtosis imaging (DKI footnote 3) was reported in adolescents with IGD (Sun et al., 2014).³ These areas are associated with attention and control (anterior cingulate cortex), impulse control (orbito-frontal cortex), motor function (supplementary motor area, primary motor cortex), emotional regulation (lingual gyrus), and are compatible with models of drug addiction (Volkow et al., 2010). Finally, IGD adolescents showed reduced gray matter volume of the anterior cingulate cortex, pre-cuneus, supplementary motor area, superior parietal lobule, dorsal lateral prefrontal cortex, insula, and bilateral cerebellum (Wang et al., 2015a). These findings are compatible with previous studies on gray matter volume in IGD (Zhou et al., 2011, Yuan et al., 2011, Ko et al., 2013a, Weng et al., 2013). Moreover, gray matter volume of the anterior cingulate cortex negatively correlated with the incongruent response errors of Stroop task that is a measure of cognitive control mechanism (Wang et al., 2015a). Since few studies present structural changes in gray matter in IGD, these findings need further replication.

Fig. 1 shows brain regions with reduced gray matter volume in frequent IGD players.

The brain’s white matter is another component of the central nervous system that consists mostly of glial cells and myelinated axons that transmit signals from cerebellum to other brain centers. Diffusion Tensor Imaging (DTI) (footnote 4) evaluated brain white matter integrity by measuring Fractional anisotropy (FA) (footnote 5) in adolescents with IGD and control participants (Lin et al., 2012).⁴ High FA indicates greater white matter integrity.⁵ The analysis of FA by tract-based spatial statistics (TBSS) (footnote 6) demonstrated lower FA in the orbito-frontal cortex, corpus callosum, cingulate, inferior frontal-occipital fasciculus,⁶ and corona radiation, internal and external capsules in IGD participants and FA values in the left external capsule correlated with Young's Internet addiction scale. Both findings possibly reflect negative changes in white matter density as result of game play. IGD participants also showed higher FA in the thalamus and left posterior cingulate cortex relative to healthy control participants presumably indicating greater white matter integrity (Dong et al., 2012d). Secondly, higher FA in the thalamus was associated with greater severity of IGD but it unclear whether this is a pre-existing vulnerability factor, or may arise secondary to IGD, perhaps as a direct result of excessive Internet game playing.

Further studies combined measurement of white matter FA changes and gray matter volume using DTI analysis and an optimized voxel-based morphometry (VBM) technique (footnote 7) in adolescents with IGD.⁷ Decreased gray matter volume in areas responsible for attention, motor and cognitive control (dorso-lateral prefrontal cortex, anterior cingulate cortex and supplementary motor area and reduced white matter in areas responsible for memory encoding and retrieval (para-hippocampal gyrus) and relaying sensory and motor information (limb of the internal capsule) were reported by Yuan et al. (2011). There was further evidence for gray matter atrophy in the right orbito-frontal cortex, bilateral insula, and right supplementary motor area in IGD (Weng et al., 2013). They also had reduced FA in the right genu of the corpus callosum, bilateral frontal lobe white matter, and right external capsule. Lower gray matter density in areas responsible for cognitive and motor control (orbito-frontal cortex and supplementary motor area) and reduced white matter in areas responsible for cognitive planning and control (frontal lobe and external capsule) were reported (Lin et al., 2015a). IGD participants also showed lower white matter density in the inferior frontal gyrus, insula, amygdala, and anterior cingulate cortex brain regions that are involved in decision-making, behavioral inhibition and emotional regulation. IGD participants showed reduced FA the anterior cingulate cortex and right dorsolateral-prefrontal cortex pathways and they were associated with executive function measured on the Stroop task (Yuan et al., 2016). Finally, a study on a large sample of school children in Japan used diffusion tensor imaging mean diffusivity (MD) measurement (Takeuchi et al., 2016). Increased videogame play was associated with delayed development of the microstructure in extensive brain regions such as the orbito-frontal cortex, pallidum, putamen, hippocampus, caudate/putamen insula and the thalamus. Furthermore, higher MD in the areas of the thalamus, hippocampus, putamen and the insula was associated with lower intelligence.

Since there are few studies that present structural changes in IGD, replication of these findings is required. Furthermore, these are cross-sectional studies precluding any inference on causality.

A study that measured cortical thickness in fMRI together with the color-word Stroop task revealed increased cortical thickness in the left precentral cortex, pre-cuneus, and middle frontal cortex, inferior temporal and middle temporal cortices in adolescents with IGD (Yuan et al., 2013). The cortical thicknesses of the left lateral orbito-frontal cortex, insula, lingual gyrus, the right postcentral gyrus, entorhinal cortex and inferior parietal cortex decreased. The cortical thickness of the orbito-frontal cortex correlated with impaired performance on the color-word Stroop task. Male adolescents with IGD had also shown decreased cortical thickness in the right lateral orbito-frontal cortex compared with control participants (Hong et al., 2013a). The apparent contradiction between the two studies showing increased and decreased cortical thickness seems to suggest that the changes are not robust and merit further investigation.