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0<D O O
Neurobiological findings related to Internet use disorders
Neurobiology of Internet use disorders
Byeongsu Park, MD1, Doug Hyun Han, MD, PhD2, and Sungwon Roh, MD, PhD3
department of Neurology, Seoul National University Hospital; 2Department of Psychiatry, Chung-Ang University Medical Center; and 3Department of Psychiatry, Hanyang University College of Medicine, Seoul, Korea
Correspondence: Sungwon Roh, MD, PhD, Department of Psychiatry, Hanyang University College of Medicine, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, Korea. Email: swroh@hanyang.ac.kr Tel: +82-2-2290-8422 Fax: +82-2-2298-2055 ABSTRACT
In the last ten years, numerous neurobiological studies have been conducted on Internet addiction or Internet use disorder. Various neurobiological research methods—such as magnetic resonance imaging; nuclear imaging modalities, including positron emission tomography and single photon emission computed tomography; molecular genetics; and neurophysiology methods—have made it possible to discover structural or functional impairments in the brains of individuals with Internet use disorder. Specifically, Internet use disorder is associated with structural or functional impairment in the orbitofrontal cortex, dorsolateral prefrontal cortex, anterior cingulate cortex, and posterior cingulate cortex. These regions are associated with the processing of reward, motivation, memory, and cognitive control. Early neurobiological research results in this area indicated that Internet use disorder shares many similarities with substance use disorders, including, to a certain extent, a shared pathophysiology. However, recent studies suggest that
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differences in biological and psychological markers exist between Internet use disorder and ^^^^ substance use disorders. Further research is required for a better understanding of the pathophysiology of Internet use disorder.
q Key words: Internet use disorder, Internet addiction, Internet gaming disorder, neurobiology,
neuroimaging INTRODUCTION
In the past decade, an increasing number of studies have investigated excessive Internet use, which leads to behavioral addiction. Various activities that the Internet offers, such as gaming, ^^^^^^ shopping, and social networking, have hedonic qualities. Vulnerable individuals come to use the Internet obsessively and excessively, and their social and occupational functions are impaired. This pathological phenomenon, which has recently shown a dramatic increase, is called Internet addiction (IA) or Internet use disorder (IUD). Internet gaming disorder (IGD), which has a rticularly high prevalence among male adolescents, is a specific form of IUD and has been the most extensively investigated form thus far.1-6 Behavioral addictions, such as gambling disorder ^^^^ and IUD, share certain clinical characteristics with substance addiction, including the development of tolerance, psychological and/or physical withdrawal symptoms, excessive behavior, loss of control, and cravings.5 Furthermore, changes in the brains of individuals with
adi pai
IUD and gambling disorder demonstrate similarities to those observed in substance use disorders (SUDs). This implies that IUD and SUDs are likely to share at least a subset of similar underlying neurobiological mechanisms.7
The purpose of this review is to summarize the major studies that have implemented neurobiological methods to investigate structural and functional changes that occur in the brains
of individuals with IUD or IGD. Typical neurobiological methods used in these studies are ^^^^ neuroimaging and neurophysiologic techniques, as these enable the identification of the involved brain areas. The various neuroimaging techniques used include structural magnetic resonance
^^^^ imaging (sMRI), such as voxel-based morphometry (VBM) and diffusion tensor imaging (DTI); 9 ^^^ functional magnetic resonance imaging (fMRI); and nuclear imaging, such as positron emission tomography (PET) and single photon emission computed tomography (SPECT).
Neurophysiologic studies using electroencephalogram (EEG) to study IUD are also discussed in this review. This review covers the studies on IA, IUD, and IGD together, without distinction, and uses these terms as they were presented in the original works.
SEARCH STRATEGIES AND CRITERIA
Literature from December 2005 to December 2015 was searched in the Web of Science and Google Scholar databases using the keywords 'Internet addict*', 'compulsive Internet', 'video gam*', 'Internet gam*', and 'excessive Internet use'. Review articles were included if associated with our topic.
^^^^ Study inclusion criteria were as follows: 1) studies were peer-reviewed, in English, and ^^^^ published from December 2005 to December 2015; 2) studies used imaging techniques such as magnetic resonance spectroscopy (MRS), PET, SPECT, and structural and functional MRI (such as DTI, VBM, arterial spin labeling [ASL], and regional homogeneity [ReHo]); and/or 3) studies used neurophysiologic techniques (such as EEG and event-related potential); pharmacogenetic techniques (such as PET with a radioactive dye); or molecular genetic testing (such as acetylcholine receptor polymorphisms).
Eighty-four studies satisfied the inclusion criteria. Excluding duplicative studies that used
similar research methods, sMRI was used in 13 studies, and fMRI, in 38. Ten studies employed ^^^^ PET, and one study employed SPECT. Fourteen studies used EEG. If two or more neurobiological techniques were implemented within the same study, studies are discussed below ^^^^ inall relevant sections. Due to the large number of studies, only pioneering studies are discussed, such as those that discovered neurobiological changes before and after treatments or utilized specific neurobiological techniques for the first time. We found some inconsistency between similar studies, which might be explained by newer methods and larger sample sizes of follow-up studies. The main studies discussed in this review are summarized in Table 1. Brief information about the remaining studies can be found in the supplemental tables (Tables s1-s6).
FINDINGS FROM MRI STUDIES sMRI studies show that decreased gray matter density is associated with IUD
sMRI offers superior spatial resolution and is useful for determining changes in anatomic structures. Studies employing MRI on IGD patients revealed structural damage to specific brain regions. Various sMRI techniques have been used in order to study the characteristics of brain ^^^^ structure, discussed in turn below.
^^^^ VBM is a neuroimaging technique which involves voxel-wise comparisons of gray and white matter in different groups of subjects. Using VBM, Zhou et al. showed that IA adolescents have low gray matter density in the left anterior cingulate cortex (ACC), left posterior cingulate cortex (PCC), left insula, and left lingual gyrus.8 Yuan et al, also used VBM to study IA adolescents but found a decrease in gray matter density in the bilateral dorsolateral prefrontal cortex, supplementary motor area, orbitofrontal cortex (OFC), cerebellum, and left rostral ACC.9 Furthermore, Weng et al. showed reduced gray matter density in IGD individuals localized to the
right OFC, bilateral insula, and right supplementary motor area.10 Although all three studies ^^^^ similarly found reduced gray matter density in the brains of subjects with IA or IGD, the regions exhibiting gray matter atrophy did not correspond fully between studies. This discrepancy may ^^^^ bedue to technical differences between the three studies.
Many of the brain regions found to be altered in the IA brain by VBM have been linked
previously to functions contributing to the development of addictive or compulsive behaviors. For example, damage to the prefrontal cortex (PFC) occurs in other addictive disorders. Gray matter atrophy of the PFC is associated with a loss of control of behavior, which is an important characteristic of IA. Furthermore, the OFC regulates impulse control and decision-making, and the dorsolateral PFC and rostral ACC are responsible for cognitive control.11 Functional neuroimaging studies suggest that activity in the insula triggers the explicit motivation to use addictive drugs.12 The VBM study results also correspond to those of previous studies showing
Pthat the PFC and insula contribute to the underlying mechanism of SUDs.13
Yuan et al. combined sMRI with a behavioral test, confirming that during late adolescence, individuals with IGD had impaired cognitive control in a Stroop color-word test compared to a ^^^^ control group. In these individuals, cortical thickness was decreased in left lateral OFC, insula, lingual gyrus, right postcentral gyrus, entorhinal cortex, and inferior parietal cortex.14 The reduced cortical thickness of the left lateral OFC in IGD subjects was correlated with the degree of cognitive impairment in the color-word Stroop task. Similarly, the degree of reduction in cortical thickness in the left precentral gyrus, precuneus, and lingual gyrus of IGD adolescents was associated with the duration of addiction.15 In other studies using the same method, a
reduction in OFC thickness was found in male adolescents with IA.16 As a decrease of OFC thickness has previously been shown in the brains of subjects with drug and behavioral
addictions, this implies that IGD development may involve brain regions similar to those involved in these conditions.16, 17
In contrast to their findings in the OFC, Yuan et al. also reported an increase in cortical thickness in the left precentral cortex, precuneus, middle frontal cortex, and inferior and middle temporal cortices in IGD subjects.14 The precuneus is responsible for processing visual imagery,
attention, and memory retrieval and is well known as a region involved in cue-induced craving.18 attention, and memory retrieval and is well known as a region involved in cue-induced craving.
The inferior and middle temporal cortices also participate in gaming cue-induced craving. Thus, the increase in cortical thickness in these areas is likely to be related to gaming cue-induced craving.19
DTI is another sMRI method used to quantify the status of white matter tracts via fractional anisotropy (FA), which measures the diffusivity of water molecules in the brain. This method is also used for visualizing white matter tracts.20 Dong et al. reported that the FA increased in the
thalamus and left PCC of IGD patients compared to that of healthy controls.21 Lin et al.
nfirmed these findings, showing that the FA of IA subjects was low in a broad range of brain regions, including the orbitofrontal white matter and corpus callosum, and that no brain region exhibited a higher FA level than controls.22 Another DTI study reported that the FA of white matter in the right parahippocampal gyrus decreased and the FA increased in the left posterior limb of the internal capsule in adolescents with IA compared to the control group.9 Collectively, these studies indicate that IA may cause impairments in both white matter and gray matter or, alternatively, that the changes to these brain structures can predispose individuals to IA. However, the brain regions where the alteration of FA occurs vary from study to study. Thus, further research into this matter is required.
Finally, in studies using proton MRS, individuals with IA showed a decrease in the ratio of N-
acetylaspartate (NAA) to creatine (Cr) in the bilateral frontal lobe white matter and an increase in the ratio of choline-containing compounds to Cr.23 NAA is considered a marker of neurons, and Cr is a metabolite that maintains a regular density despite neuronal loss. Therefore, a decrease of NAA/Cr ratio in certain brain regions may imply the loss or malfunction of corresponding neurons.24 These research findings imply a decline in frontal lobe functioning in IApatients.
fMRI studies identify IA brain activity associated with reward and addiction
fMRI studies measure changes in blood oxygen in the brain to localize brain regions where neuronal activity is occurring The increase of blood flow provides the active brain regions with more glucose and oxygen. Thus, an index of brain activity can be obtained by determining the oxyhemoglobin to deoxyhemoglobin ratio (distinguished on the basis that deoxygenated
Phemoglobin is paramagnetic and oxygenated hemoglobin is diamagnetic). Regional brain function can be studied indirectly by measuring the contrast of blood-oxygen level-dependent (BOLD) signal while performing cognitive tasks or before and after providing cues. ASL ^^^^ perfusion MRI can measure the absolute quantification of cerebral blood flow (CBF), and the increase of CBF is related to regional neuronal activity.25
Feng et al. investigated changes in resting CBF in adolescent IGD patients using ASL
perfusion fMRI. The CBF of IGD patients in a resting state was measured and compared to that of healthy controls. In the brains of IGD patients, an increase in CBF was observed in multiple regions, including the left inferior temporal lobe, fusiform gyrus, left parahippocampal gyrus, amygdala, right medial frontal lobe, ACC, left insula, right insula, right middle temporal gyrus, right precentral gyrus, left supplementary motor area, left cingulate gyrus, and right inferior
parietal lobe. A decrease was observed in the left middle temporal gyrus, left middle occipital ^^^^ gyrus, and right cingulate gyrus. Of these brain regions, the amygdala and hippocampus belong to a circuit involved in learning and memory that is related to cue-induced craving.27 The insula isassociated with an impairment in self-awareness,28 and the prefrontal cortex is associated with executive functions.13 All of these brain regions have been associated previously with addiction. However, it is yet unclear whether the increased CBF is a primary consequence due to addiction itself or a secondary reaction to compensate for addiction-induced brain damage.
Functional connectivity impairments also were observed in IUD patients. Ding et al. showed that, in comparison to healthy controls, IGD patients' functional connectivity increased in the ^^^^^^ bilateral cerebellum posterior lobe and middle temporal gyrus and decreased in the bilateral inferior parietal lobe and right inferior temporal gyrus.29 In another study that researched resting-state functional connectivity in IA adolescents, functional connectivity decreased mainly in _ „„ « « w№ prefrontal and ^ cortices.30 — brain regions, the bilateral putamen was largely invaded. Similar to these results, a decrease in resting-state functional connectivity has been observed in the frontoparietal network in patients with cocaine and heroin use disorders, with a relative sparing of temporal regions.31, 32
ReHo is a voxel-based measurement of brain activity in a resting-state. It assesses the similarity or synchronization of the time series of certain voxels and their adjacent voxels.33 Liu et al. implemented the ReHo method to study the cerebral functioning characteristics of IA undergraduates in a resting state. In comparison to healthy controls, ReHo in the brains of IA undergraduates increased significantly in the inferior parietal lobe, left posterior cerebellum, and left middle frontal gyrus and decreased in temporal, occipital, and parietal brain regions.34 The differences in brain regions showing increased vs decreased regional homogeneity are
informative. The temporal lobe region is responsible for processing auditory information, ^^^^ comprehension, and linguistic memory, and the occipital lobe is responsible for processing visual information. The cerebellum has various functions, including the regulation of cognitive activity, ^^^^ whereas the cingulate gyrus incorporates sensory information and is associated with monitoring conflicts. Hippocampi are part of the mesocorticolimbic system related to reward pathways.
These results imply that in IA patients the synchronization of sensory-motor coordination
increases but the synchronization of visual and auditory brain activity decreases.
fMRI studies show increased activity in IA brain areas involved in impulsivity and craving
Impulsivity often is exhibited by IA patients.35 Response inhibition (the ability to suppress a pre-
planned motor action) is known to decline when impulsivity occurs. Impulsivity is generally assessed through stop-signal tasks or go/no-go tasks.36 Ko et al. assessed the changes in brain activation during response inhibition and error processing in IGD patients and healthy controls using fMRI. All participants answered questionnaires on IA and impulsivity and performed event-related go/no-go tasks while undergoing fMRI scans. IGD patients scored higher on impulsivity than healthy controls and showed higher brain activity in the left OFC and bilateral ^^^^ caudate nucleus when processing response inhibition. The insula and ACC were activated in both
IGD patients and healthy controls during error processing. Right insular activity was lower in the
IGD group than in the control group. OFC has previously been associated with response inhibition.38 These studies show that the frontostriatal network takes part in response inhibition and that both the ACC and insula, which are part of salience network, are involved in error processing.39 Collectively, changes in the activation of these brain regions may explain the loss of control during online gaming in IGD patients.
Dong et al. studied the neural correlations of response inhibition in male subjects with IA using an event-related fMRI and Stroop color-word task.40 The Stroop color-word task is an assessment tool for inhibitory control, which is one of the aspects of cognitive control. In ^^^^ incongruent Stroop trials, the IA group showed stronger BOLD signaling in the ACC and dorsal PCC in comparison to the control group. The ACC is a brain region known to be involved in conflict monitoring and cognitive control.41 Therefore, higher ACC activity in incongruent Stroop trials may imply a decline in cognitive efficiency. The PCC is part of the default mode network and performs attentional processes.42 Increased dorsal PCC activity implies incomplete disengagement of the default mode network and an impairment in optimizing the tasks related to ^^^^^^ attentional resources in the IA subjects.
In an attempt to define the neural substrates of cue-induced gaming urge in IGD patients, Ko etal. showed participants gaming pictures while fMRI scans were taken. The IA group showed
Phigher activity in the right OFC, right nucleus accumbens, bilateral anterior cingulate, medial frontal cortex, right dorsolateral prefrontal cortex (DLPFC), and right caudate nucleus in comparison to the control group. These activated brain regions were positively correlated with self-reported gaming urges43 and resembled activated regions in the brains of drug addicts who reported cravings.44
Similarly, Dong et al. compared reward and punishment processing in IA male subjects and healthy controls. All participants had fMRI scans while performing a reality-simulated task of imagining the situation of gaining or losing money in a card game. The IA group showed an increase of OFC activity in the gain trial and a decrease of ACC activity in the loss trial.45 The OFC is known to be activated by reward;46 the ACC, by losses.47 Therefore, these results indicate a relative increase of reward sensitivity and a decrease of loss sensitivity in the IA group in
comparison to the control group. ^^^^ Another study by Ko et al. made a comparison of cue-induced craving in IGD subjects, IGD subjects in remission, and healthy controls.19 These researchers found that the bilateral DLPFC, ^^^^ precuneus, left parahippocampus, posterior cingulate, and right anterior cingulate were more active in response to gaming cues in the IGD group than the control group. The remission group showed lower activity in the right DLPFC and left parahippocampal gyrus than the IGD group. Thus, activity levels in these regions may be used as indicators of the current level of addiction to internet gaming.
fMRI also may be useful in determining the effects of certain treatments on IUD. Han et al. studied whether 6-week treatment with bupropion reduces the craving for Internet game play and video game cue-induced brain activity in individuals with IGD.48 In response to video game cues, theIGD group showed higher activity in the left occipital lobe, left dorsolateral PFC, and left
Pparahippocampal gyrus than the control group. After the bupropion treatment, the IGD group exhibited decreases in the degree of craving, total time spent on gaming, and cue-induced brain activity in the DLPFC. The clinical improvement and the changes in brain activity were similar tothose when smokers with tobacco use disorder were treated with bupropion.49
Finally, a study by Han et al. compared the brain activity of university students before and after playing video games for 7 weeks.50 When Internet video-game cues were suggested, the excessive Internet gaming group (playing more than 2,520 minutes) showed an increase of brain activity in the ACC and OFC in comparison to the general player group (playing less than 2,520 minutes). These results resemble the brain activity exhibited by individuals with SUDs after a small dose of a substance is injected and substance cues are suggested.51,52 This indicates that brain activation may not cause excessive playing of Internet video games but instead may be a
consequence.
FINDINGS FROM NUCLEAR IMAGING STUDIES
^^ Inthe field of neuroscience, studies on brain neuron activity and disease processes are conducted using nuclear imaging. PET and SPECT are nuclear imaging methods that are characterized by high sensitivity and show clinical utility with a variety of nuclear imaging agents.53 Glucose consumption, CBF, and oxygen consumption can be quantified as indices of brain energy metabolism using SPECT and PET. In addition, the binding site density for specific neurotransmitters can be measured by PET and SPECT using specific neuroreceptor radiotracers.
^^^^^^ In a study using 18F-fluoro-deoxyglucose (18F-FDG) PET imaging, males with IGD showed an increase in glucose metabolism in the right middle OFC, left caudate nucleus, and right insula, and a decrease in the bilateral postcentral gyrus, left precentral gyrus, and bilateral occipital
Pregions in comparison to the control group.54 This finding indicates that the neurobiological mechanism of IGD is related to the OFC, striatum, and sensory regions, which are responsible for impulse control, reward processing, and somatic representation of previous experiences, respectively.13
PET has shown that impairments in dopaminergic systems can occur in the brains of IA or IGD patients. Koepp et al. performed pioneering work using PET to demonstrate striatal dopamine release levels when playing a video game.55 As the binding potential of 11C-raclopride to dopamine D2 receptors decreases when the endogenous dopamine density becomes higher, it is possible to estimate the density of endogenous dopamine by measuring the changes in the binding potential of the radioligand. In the results of this study, the binding capacity of 11C-raclopride to dopamine receptors in the striatum decreased during video game play in
comparison to baseline levels, indicating an increase in dopamine release and binding. The ^^^^ changes in binding potential while playing a video game were similar to those following the injection of amphetamines or methylphenidate, suggesting that gaming activity induces changes ^^^^ indopaminergic activity comparable to psychoactive substances. Kim et al. measured the D2 dopamine receptor availability in the brains of IA patients using PET and the radioligand 11C-raclopride.56 Consistent with the previous findings by Koepp et al, Individuals with IA showed
decreased dopamine D2 receptor availability in the bilateral caudate and left putamen compared to the control group, which indicated a decrease of dopamine activity.
The dopamine transporter is a plasma membrane protein which actively transports dopamine from the extracellular space into presynaptic neurons.57 Hou et al. measured dopamine transporter levels in IA patients using 99mTc-TRODAT-1 SPECT and found that the striatal dopamine transporter levels of the IA group decreased compared to the control group.58 Similar
Presults have been reported in patients with SUDs.59, 60
Tian et al. used PET with 1 lC-N-methylspiperone (11C-NMSP) and 18F-FDG to study dopamine D2 receptor levels and glucose metabolism in the brains of male subjects with IGD during a break and after playing an internet game.61 A decrease of glucose metabolism was ^^^^ observed in the prefrontal, temporal, and limbic systems of the IGD group. The binding of 11C-NMSP decreased in the right inferior temporal gyrus during a break in the IGD group in comparison to the control group. Striatal 11C-NMSP binding in the IGD group significantly increased after playing an Internet game, indicating a decrease in dopamine D2 receptors. Furthermore, a significant positive correlation was observed between striatal 11C-NMSP binding and orbitofrontal 18F-FDG activity, showing that the striatal-prefrontal pathways take part in the dysregulation of striatal D2 receptors. The mechanisms of loss of control and compulsive
behavior found in IGD patients may be associated with this dysregulation of striatal D2 receptors. Collectively, several lines of evidence support that IA is associated with impairments in the
dopaminergic systems of the brain. dopaminergic systems of the brain.
FINDINGS FROM NEUROPHYSIOLOGIC STUDIES
EEG measures the neuronal activity of cerebral cortex by placing multiple electrodes on certain areas of the scalp of participants.62 Event-related potentials are a method to study the brain-behavior relationships by measuring time-locked EEG activities.63 According to the research by Yu et al., a decrease of P300 amplitudes and longer P300 latencies were observed in IA patients compared to healthy controls.64 Similarly, a decrease of P300 amplitudes was also observed in patients with SUDs.65 IAD patients receiving cognitive behavioral therapy for three months exhibited significantly decreased P300 latencies, indicating that cognitive function
Pimpairment in IA patients can be improved through psychological treatment.
According to the study of Dong et al., compared to healthy controls, IA patients showed lower NoGo-N2 amplitude, higher NoGo-P3 amplitude, and longer NoGo-P3 peak latency in event-related brain potentials while performing the Go/NoGo tasks.66 This suggests that the activation is decreased in the conflict detection stage of IA patients and that more cognitive control is required in the next step of inhibiting tasks. The same research team conducted a study on
cognitive control using the color-word Stroop task.67 In the study on event-related potentials, the IAD group demonstrated longer reaction time and more response errors in incongruent conditions in comparison to the control group, reflecting a possible impairment in executive control.
FINDINGS FROM MOLECULAR GENETIC STUDIES
^^^^ Attempts have been made to find genetic changes that convey a predisposition for IUD.
Researchers investigated dopamine D2 receptors and genetic polymorphisms in the genes ^^^^ encoding enzymes that break down dopamine. It was discovered that the Taq1A1 allele of the DRD2 gene and the low-activity allele of catechol-O-methyltransferase (COMT) appeared more
frequently in the excessive Internet video game play group relative to the control group. The DRD2 Taq1A1 allele was associated with the high reward dependence.68, 69
Previous studies also suggest that excessive Internet use shares a phenotype with depression to some extent. Adolescents with problematic Internet use showed a higher frequency for a ^^^^^^ homozygous short allelic variant of the serotonin transporter gene (SS-5HTTLPR), greater harm avoidance, and higher Beck Depression Inventory scores.70 Montag et al. investigated the genetic polymorphisms of nicotinic acetylcholine receptor subunit alpha 4 (CHRNA4) in IA patients. The T-variant (CC genotype) of the rs1044396 polymorphism on the CHRNA4 gene was more frequent in the IA group than in the control group.71 Evidence for molecular genetic variants in the serotonergic, dopaminergic, and acetylcholinergic neurotransmitter pathways have been C ^ described for both IUD and SUDs.71-73
DIFFERENCES BETWEEN IUD AND SUD PATIENTS
Although the above literature indicates that IUD and SUDs share at least some common underlying neurobiological mechanisms, recently, several studies have suggested that differences exist in brain activities between IUD and SUD patients. Han et al. reported that patients with alcohol dependence had positive functional connectivity from the DLPFC to striatal areas whereas patients with IGD had negative connectivity from the DLPFC to striatal areas.74
Furthermore, Kim et al. declared that patients with IGD had decreased regional homogeneity from the PCC to inferior temporal cortex, compared to patients with alcohol dependence.75 Finally, using quantitative EEG, Son et al. showed that lower absolute beta power could be used as a potential trait marker of IGD whereas higher absolute power in the delta band may be a potential marker for alcohol dependence.76
CONCLUSIONS
Recently, research into the neurobiology of IUD has increased remarkably. The majority of studies have examined the similarities and differences between SUDs and behavioral addictions ^^^^^^ using various neuroimaging techniques. Based on the past research on IUD, we conclude that IUD is associated with structural or functional impairments in the OFC, dorsolateral PFC, ACC, and PCC regions, which are involved in the processing of reward, motivation, memory, and cognitive control. IUD also is associated with impairment of dopamine D2 receptor function, which is associated with dysregulation in the OFC. These results correspond to those of SUD studies and, thus, IUD and SUDs may share certain underlying neurobiological mechanisms. ^^^^ However, there are many differences in neurobiological mechanisms between different addictive ^^^^ drugs. For example, opiate addiction and psychostimulant addiction are behaviorally and neurobiologically distinct from each other. Similar findings also can be observed in behavioral addictions. Moreover, recent studies directly comparing IGD and SUDs report differences between the two disorders.
Research on the treatment of IUD is in its initial phase, and much work remains to be done. In order to develop IUD-specific treatments, the neurobiological mechanisms underlying IUD must first be elucidated. Randomized controlled clinical trials of the effectiveness of
pharmacotherapies for IUD are yet to be conducted. Furthermore, PET studies using new ^^^^ radiotracers should be used to determine the efficacy of pharmacotherapy and to predict treatment results. Further study should include both male and female subjects, as female ^^^^ participants have rarely been included in IA and IGD studies. In addition, longitudinal studies are needed to fully understand the dynamics of these conditions, as IA and IGD patients are often
adolescents or young adults.
The majority of studies were conducted in East Asia. To generalize the findings, further studies should involve subjects with various ethnic or cultural backgrounds. Additional studies using a larger number of participants should be conducted in order to reduce inconsistencies ^^^^^^ resulting from multiple small studies using relatively fewer participants. Despite the fact that our knowledge of IUD has significantly increased recently, a consensus on the operational definition and diagnosis of IUD has still not been achieved. This is due in part to inconsistencies in the selection of study participants. Therefore, future research should more precisely define the selection criteria for participants.
ACKNOWLEDGMENTS
^^^^ This work was supported by the research fund of the Hanyang University (HY-2016), Seoul, Republic of Korea.
CONFLICTS OF INTEREST
The authors declare that they have no conflicts of interest.
AUTHOR CONTRIBUTIONS
^^^^ conception and design of the study: SR; acquisition and analysis of data: BP, DHH, SR; drafting the manuscript and tables, BP, DHH, SR.
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Accepted Article
cr> On to 00
Table 1. Summary of neurobiological findings related to Internet use disorders
^ Study Subjects Neurobiological changes compared to controls
Yuan et 18 male addicts and Gray matter density al., 18 male controls IGD group showed decreased gray matter density in left
anterior cingulate cortex, left posterior cingulate cortex, left insula, and left lingual gyrus
Lin et al, 201222
<D O O
17 addicts (2 females and 14 males) and 16 controls (2 females and 15 males)
Diffusion tensor image
Subjects with IA showed significantly lower FA in orbitofrontal white matter, corpus callosum, cingulum, inferior frontooccipital fasciculus, corona radiation, and internal and external capsules.
Zhou et 18 addicts (2 al., females and 16
20119 males) and 15 controls (2 females and 13 males)
Voxel-based morphometry
IA adolescents had lower gray matter density in the left anterior cingulate cortex, left posterior cingulate cortex, left insula, and left lingual gyrus.
Feng et al,
Liu et al,
Hong et
15 addicts (2 females and 13 males) and 18 control (4 females and 14 males)
Arterial spin-labeling perfusion fMRI
Adolescents with IGA showed significantly higher global cerebral blood flow in the left inferior temporal lobe/fusiform gyrus, left parahippocampal gyrus/amygdala, right medial frontal lobe/anterior cingulate cortex, left insula, right insula, right middle temporal gyrus, right precentral gyrus, left supplementary motor area, left cingulate gyrus, and right inferior parietal lobe. Lower cerebral blood flow was found in the left middle temporal gyrus, left middle occipital gyrus, and right cingulate gyrus.
19 addicts (8 Resting fMRI; regional homogeneity
females and 11 Adults with IGD showed increased ReHo in cerebellum,
males) and 19 controls (8 females and 11 males)
brainstem, right cingulate gyrus, bilateral parahippocampus, right frontal lobe (rectal gyrus, inferior frontal gyrus, and middle frontal gyrus), left superior frontal gyrus, left precuneus, right postcentral gyrus, right middle occipital gyrus, right inferior temporal gyrus, left superior temporal gyrus, and middle temporal gyrus.
12 male addicts and Resting fMRI; inter-regional connectivity
11 male controls Adolescents with IA showed more impaired connections involving cortico-subcortical circuits.
Ko et al., 200943
<D O O
10 male addicts and Block design, gaming cue induced reactivity
10 male controls Adults with IGD showed activated brain regions in right orbitofrontal cortex, right nucleus accumbens, bilateral anterior cingulate and medial frontal cortex, right dorsolateral prefrontal cortex, and right caudate nucleus.
Dong et 12 male addicts and Event related, Stroop task
al., 12 male controls Adults with IGD showed increased activation in the
201145 orbitofrontal cortex in gain trials and decreased anterior
cingulate activation in loss trials.
Dong et 14 male addicts and Reality-simulated guessing task
al., 13 male controls Adults with IGD showed greater BOLD signal in the anterior
201240 and posterior cingulate cortices during incongruent Stroop
p trials.
Han et al, 11 male addicts and Treatment response, fMRI with StarCraft cue
201048 8 male controls IGD subjects showed decreased craving for Internet video
game play, total game play time, and cue-induced brain
1 activity in dorsolateral prefrontal cortex after a 6-week
period of bupropion.
Liu et al, 14 addicts and 14 Magnetic resonance spectroscopy
201323 controls Subjects with IAD showed decreased N-acetylaspartate to
creatine ratio and choline containing compounds to creatine
ratio in the bilateral frontal lobe white matter.
Hou et al., 5 male addicts and Single photon emission computed tomography
9 controls
Individuals with IAD showed decreased dopamine transporter expression level of striatum, and the volume and weight of bilateral corpus striatum as well as the (99m)Tc-TRODAT-1 uptake ratio of corpus striatum/the whole brain were greatly reduced in individuals with IAD.
Kim et al., 5 male addicts and 11C-raclopride PET
7 male controls
Individuals with IA showed reduced levels of dopamine D2 receptor availability in subdivisions of the striatum, including the bilateral dorsal caudate and right putamen.
Park et al, 11 male addicts and 18F-fluorodeoxyglucose PET
9 male controls Over-users had increased glucose metabolism in the right middle orbitofrontal gyrus, left caudate nucleus, and right insula, and decreased metabolism in the bilateral postcentral gyrus, left precentral gyrus, and bilateral occipital regions.
Tian et al, 12 male addicts and 11C-N-methylspiperone PET
14 male controls A significant decrease in glucose metabolism was observed in the prefrontal, temporal, and limbic systems. Dysregulation of D2 receptors was observed in the striatum, which was correlated to years of overuse. A low level of D2 receptors in the striatum was significantly associated with decreased glucose metabolism in the orbitofrontal cortex
Neurophy siology
Yu et al.,
10 IUD subjects and 10 controls
EEG/Event-related potentials
Excessive Internet use resulted in a significant decrease in the P300 amplitudes and a significant increase in the P300 latency in all electrodes.
Molecular
genetics
Han et al, 79 addicts and 75
controls
Taq1A1 allele of the dopamine D2 receptor
The Taq1A1 and low activity (COMT) alleles were significantly more prevalent in the excessive internet game play group relative to the comparison group.
Lee et al., 91 IA subjects and Allelic variant of the serotonin transporter gene
200870 75 controls The homozygous short allelic variant of the serotonin
transporter gene (SS-5HTTLPR) is more frequent in the excessive internet use group.
Montag et 131 IA subjects and Nicotinic acetylcholine receptor subunit alpha 4
al, 132 controls (CHRNA4)
201271 The T-variant (CC genotype) of the rs1044396
polymorphism on the CHRNA4 gene occurred significantly more frequently in the IA group.
^^^^^^ Abbreviations: BOLD, blood-oxygen level-dependent signal; COMT, catechol-O-^^^^ methyltransferase; EEG, electroencephalogram; FA, fractional anisotropy; fMRI, functional magnetic resonance imaging; IA, Internet addition; IAD, Internet addiction disorder; IGA, Internet gaming addiction; IGD, Internet gaming disorder; PET, positron emission tomography; ReHo, regional homogeneity; sMRI, structural magnetic resonance imaging.
