Introduction

Internet gaming disorder is reported as an increasing problem worldwide, shown to result in critical academic, social, and occupational impairment of individuals [1, 2]. More than one-eighth of adults in the United States show signs of being addicted to the internet [3] and a national weighted sample of 1,178 US youths found that 8.5% of gamers were classified as pathological gamers [4]. A similar or higher proportion has been reported in Europe and Asia [5], particularly, as many as 14.1% of adolescents (roughly 20 million people) in China [6]. Although cognitive and psychological dysfunctions associated with internet gaming disorder have been observed clinically, neurobiological alterations related to this disorder remain unclear [4, 7].

Recently, computer-assisted neuroimaging has helped us greatly to understand brain function and neuropsychiatric disorders [8–10]. Imaging evidence suggests that internet game overuse is a clinical disorder with brain microstructure and functional changes similar to those accompanying substance addiction [11]. For instance, structural magnetic resonance imaging (MRI) analysis has found regional gray matter density and volume abnormalities in internet game disorder subjects [12, 13]. Significantly lower fractional anisotropy has been identified throughout the brain in internet game disorder subjects but not in controls, which purport that internet game overuse may damage both gray matter and white matter fibers connecting emotional processing, attention, and decision making [11]. In the past decade, noninvasive functional examination by positron emission tomography (PET) has been used to monitor cerebral blood flow and glucose/oxygen metabolism, and provide further information on specific molecules (transporters and receptors) and cellular processes (neurotransmitter synthesis and release). The advantage of PET technology is that it can be used to trace the biologic changes in cognitive and behavioral brain function during real-time tasks without the interference of ambient noise generated by the MRI scanner [14]. A previous PET study using 11C-raclopride, a reversible dopamine receptor ligand, found that striatal dopamine release was reduced in the internet addiction subjects under the resting state [15]. And another separate 18F-fluoro-D-glucose (18F-FDG) PET study observed altered glucose metabolism in the frontal lobe in internet addiction patients at resting state [5]. Those two studies, although groundbreaking, used only one PET tracer under resting state and did not compare resting and task conditions; therefore, could not provide an in-depth investigation of the connection between level of dopamine D2 (D2) receptor and glucose metabolism in internet disorder subjects under internet game playing condition.

In the present study, we assessed brain D2 receptor function and glucose metabolism in the same subjects by PET imaging, and investigated whether the correlation exists between D2 receptor function and glucose metabolism. To address these questions, PET imaging [with 11C-N-methylspiperone (11C-NMSP), as an irreversible D2 receptor antagonist, and 2-deoxy-2-18F-fluoro-D-glucose (18F-FDG), a marker of brain function] was used to compare test and control subjects in both resting and internet gaming task states. To the best of our knowledge, this is the first PET study to examine the postsynaptic D2 receptors and regional brain glucose metabolism in the same subjects with internet gaming disorder.

Methods and materials

Subjects

Study participants were recruited via advertisements posted on the Bulletin Board System (BBS) and campus of the university or invitees from a local cyber bar in Hangzhou, China. All participants met the following criteria: age 18 years or above; Chinese-speaking; right-handed; college-level educated; capable of internet game playing; no history of substance use (including cigarettes and alcohol). They were required to complete a medical screening and thorough psychiatric interview to confirm the diagnosis of internet gaming disorder according the MINI-International Neuropsychiatric Interview [16] and the proposed diagnostic criteria for internet addiction [17, 18]. Exclusion criteria included significant medical condition including current or past chronic heart, renal, liver, endocrine, metabolic, neurological illness or injury; current or past mood disorder, anxiety disorder, psychotic disorder, or mental retardation based on DSM-IV criteria; current or past use of psychiatric medication; current use of over-the-counter medication or nutrition supplements; current or planned pregnancy; history of allergies and intolerability of PET scan; lack of capacity to provide informed consent. To exclude the possible influence on dopamine receptors and brain activity [19], subjects with current body mass index (BMI) below 18 or above 24 were excluded.

The internet disorder subjects were addicted to World of Warcraft, the most popular multiplayer, online strategy simulation game in China. The severity of internet game use was evaluated by the Young’s Internet Addiction Test [20, 21]. This scale consists of a 20-item questionnaire regarding online internet use including psychological dependence, compulsive use, and withdrawal, as well as related problems with school, sleep, family, and time management. For each item, a graded response is selected from 1 (“rarely”) to 5 (“always”). The possible total score ranged from 20 to 100 with the following cut-off points defining mild, moderate and severe stages of internet addiction: 20–49 points (mild), 50–79 points (moderate), and 80–100 points (severe). This approach has exhibited good psychometric properties, with the split-half reliability 0⋅859 and the Cronbach’s alpha 0⋅902 [22, 23]. Participants were then divided into two groups: internet gaming disorder (scored > 50) and the control (scored ≤ 49). Finally, we recruited 12 male internet gaming disorder subjects addicted to specific internet games and 14 male controls, since the prevalence of internet game overuse is highest among 18–23-year-old men [6, 24, 25].

Table 1 lists the demographic information of each group. The mean age of the internet gaming disorder group and the healthy control group was 23.5 ± 2.6 years and 22.7 ± 1.3 years, respectively. The mean educational background was 13.1 ± 0.7 educational years for the internet gaming disorder group, and 13.3 ± 0.7 years for the healthy control group. There was no significant difference in either age (P = 0.351) or educational level (P = 0.470) between these two groups. The total Young’s Internet Addiction Test score of the internet gaming disorder group and control group were 77.6 ± 6.8 and 28.7 ± 3.7, respectively (P < 0.001). The internet gaming disorder subjects were asked to provide a best estimate of the duration of years they spent on the internet game rather than academic or employment-related pursuits.

Table 1 Demographic information of participants in each group
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After the procedures and possible consequences of the study were explained to the participants, written informed consent according to the Declaration of Helsinki were obtained. This study protocol was approved by the Ethics Committee of the Second Affiliated Hospital of Zhejiang University School of Medicine. This study is registered in the Chinese Clinical Trial Registry with number ChiCTR-OCC-09000358.

Procedures

The PET study was conducted at the PET Center of the Second Affiliated Hospital of Zhejiang University School of Medicine. Subjects were scanned on a PET scanner (SHR-22000; Hamamatsu Photonics) in two-dimensional imaging mode. Each of the participants received four PET scans using both radiotracers, two with 11C-NMSP and two with 18F-FDG PET, under resting and internet gaming task states, and on separate days. The time interval between PET scans performed under each of the two conditions did not exceed 2 weeks. A randomized crossover study using a computer-assisted random number generator was performed to compare the resting and task states. Before starting the PET scan, all subjects were familiarized with the process and acclimated to the PET facility. They were not allowed to play any internet games 24 h prior to each scan. An intravenous catheter was placed in one side of the antecubital vein and infused with normal saline to keep it open. Subjects were placed in the scanner with the head oriented approximately parallel to the canthomeatal line to include imaging from vertex to cerebellum. A head holder was used for comfort and to minimize subject motion.

For the PET scan under the internet game task state, each participant was instructed to play World of Warcraft attentively in a separate room. This game is a massive multiplayer online role-playing game. The players control a character avatar within a game world in third- or first-person view, exploring the landscape, fighting various monsters, completing quests, and interacting with non-player characters (NPCs) or other players. They began playing 30 min before radiotracer injection and continued until immediately before the initiation of PET acquisition. The participants received remuneration and reimbursement for travel expenses upon completion of the study.

For 18F-FDG PET imaging, subjects were required to fast for more than 6 h. 18F was synthesized on an automated synthesis system (F100; Sumitomo Heavy Industries) according to classical methods [26]. The 10-min transmission and 3-min emission scans were taken 60 min after a bolus intravenous (i.v.) injection of 4−6 mCi [18F]FDG.

For 11C-NMSP PET imaging, the synthesis of 11C-NMSP was performed by a simple modification based on the previous study [27] using an automated synthesis system (C-11-B II 11C-methyl iodide; Sumitomo Heavy Industries). 11C-NMSP PET studies were taken 40 min after a bolus i.v. injection of approximately 20 mCi 11C-NMSP. To create the normal 11C-NMSP SPM image template, additional dynamic scans were obtained at 0–60 min after injection of 11C-NMSP under the resting state in healthy controls. Subjects were kept awake with eyes opened lying in the PET scanner throughout the PET study; the room was dimly light and noise was kept at a minimum. All PET scans were conducted between 9 a.m. and 12 p.m.

Data acquisition and analysis

All images from the PET scanner system were converted into statistical parametric mapping (SPM) format using MRIcro [28]. Subsequent image preprocessing and statistical analyses were performed using SPM8 package (Wellcome Department of Cognitive Neurology, London, UK) run on MATLAB 7.1 (MathWorks Inc., Natick, MA, USA). The PET images were normalized to Montreal Neurological Institute (MNI) space as described previously [29], by using the PET template in SPM for FDG and homemade template for NMSP. Other parameters for normalization were set with the default parameters of SPM8: no weighting; 25mm cutoff; 16 non-linear iterations; one non-linear regularization; bounding box [(-78:78) (-112:76) (-50:85)]; voxel size 3 * 3 * 2; tri-linear interpolation; no wrap. An 8-mm full-width-half-maximum Gaussian kernel was used to smooth the data for statistical analysis. As in the Wang, et al. study [30], templates of regions of interest (ROIs) including caudate, putamen, amygdala, occipital cortex, anterior cingulate, hippocampus, dorsolateral prefrontal cortex and cerebellum were defined by voxels in 5–7 mm best-fitted spheres centered at the corresponding MNI coordinations, and the difference in uptake intensity were calculated by REST 1.6 software [31].

Comparisons between internet gaming disorder and control groups were performed using a two-sample t test with SPM8 for imaging data and SPSS10.0 for demographics. Comparisons between resting and task states were performed using paired t tests with SPM8. The cerebellum was used as a reference region in NMSP binding analysis as the low density of 5-HT2A and D2 receptors in this brain region allow for minimal levels of specific binding [32]. The correlations between the internet gaming disorder subjects’ binding ratios for selected brain regions divided by cerebellar binding ratios, and severity or duration of addiction were calculated by Pearson linear correlation analysis. The significance of group differences was estimated by the theory of random Gaussian fields, significant levels for glucose metabolism were set at P < 0.01 (uncorrected), and significant levels for NMSP binding were set at P < 0.001 (uncorrected). Data analysts were blinded to subject identity and diagnostic grouping.

The striatum to cerebellum (S/C) ratio on 11C-NMSP PET images and the regional cortex to cerebellum (R/C) ratio on FDG PET images under internet gaming task were calculated according to the previously established method [33]. The correlation between changes of D2 receptor availability and glucose metabolism was calculated by comparing S/C and R/C ratios using Pearson's correlation analysis.

Results

Glucose metabolic changes: between-group differences (internet gaming disorder vs. normal volunteer)

Internet gaming disorder subjects had significantly decreased glucose metabolism in the bilateral superior temporal poles and right orbitofrontal gyrus, but significantly increased in the right supplementary motor area, right middle cingulum and left superior medial frontal cortex, compared to the normal controls (Fig. 1a and Table 2).

Fig. 1
figure 1

a Whole brain SPM showing the results of 18F-FDG PET study in internet gaming disorder subjects. In the resting state, there are areas of increased glucose metabolism in the right supplementary motor area, middle cingulum and thalamus (red color); decreased glucose metabolism in the right orbitofrontal gyrus and bilateral temporal poles, especially on the right (blue color) (P < 0.01 uncorrected, k = 100); and (b) in the gaming task state, areas of glucose metabolism decreased significantly in the insula, orbitofrontal gyrus, temporal pole bilaterally and the rectus gyrus, putamen, supramarginal gyrus, and anterior cingulum on the right side (yellow color) (P < 0.01 uncorrected, k = 100). c–d Whole brain SPM demonstrating the comparison results of 18F-FDG PET study after game task compared with resting state. In the normal volunteers (c), glucose metabolism was significantly increased in the midbrain, right thalamus and bilateral occipital lobes especially in the right side (red color), while decreased in the right temporal pole, middle frontal gyrus, rectal gyrus and left side of medial temporal gyrus, superior temporal gyrus and medial frontal gyrus (blue color) (P < 0.01 uncorrected, k = 100). However, in the internet gaming disorder subjects (d), glucose metabolism was increased in the occipital lobe bilaterally (red color) but decreased in the left superior frontal gyrus and rectal gyrus (blue color) (P < 0.01 uncorrected, k = 100)

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Table 2 Comparison of FDG uptakes in internet gaming disorder and control groups
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The immediate effect of the internet game task on glucose metabolic changes was compared between internet disorder subjects and controls. It is interesting that for the internet gaming task, significantly decreased regional glucose metabolism was found in the right rectus, the right orbital part of the inferior frontal cortex, and the left orbital part of the superior frontal cortex in the internet gaming disorder group (Fig. 1b and Table 2). However, no significant increased regional glucose metabolism was observed in comparison to normal controls.

Glucose metabolic changes: within-group differences (internet gaming task vs. resting state)

In healthy control volunteers, glucose metabolism was increased significantly in the right cuneus and right calcarine, but decreased significantly in the left medial and temporal cortex, left medial frontal cortex after the internet gaming task (Fig. 1c and Table 2).

In the internet gaming disorder subjects, glucose metabolism was increased significantly in the right lingual gyrus, left cerebellum and calcarine, but decreased significantly in the left medial part of the superior frontal cortex, left rectus and left superior frontal cortex during the internet gaming task in comparison with the rest state (Fig. 1d and Table 2).

Monoamine receptor changes: between-group differences

Between-group comparison indicated that 11C-NMSP binding levels were lower in the right inferior temporal gyrus in internet disorder subjects than in normal controls in the resting state (cluster level: KE = 117, PFWE-corrected = 0.002) (Fig. 2a).

Fig. 2
figure 2

a Whole brain SPM results of 11C-NMSP PET study in the resting state. A lower level of 11C-NMSP binding was found in the right inferior temporal gyrus in the resting state in the internet gaming disorder subjects than that in normal controls (yellow color) (P < 0.001 uncorrected, k = 100), while in the game task state (b), 11C-NMSP binding in the putamen was significantly lower in the internet overuse group than the normal control group, especially in the right side (yellow color) (P < 0.001 uncorrected, k = 100). c Correlation of the putamen to the cerebellum ratio of 11C-NMSP binding and Young score. Both right (P = 0.024, r = −0.775) and left P/T ratio (P = 0.034, r = −0.744) correlated negatively with the Young score in the internet disorder subjects. d Correlation of the left orbitofrontal cortex (OFC) to the cerebellum ratio of 11C-NMSP binding and the years of internet overuse history. The L/C ratio of 11C-NMSP correlated negatively with the duration of internet overuse (P = 0.034, r = −0.745)

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The immediate effect of the internet game task on monoamine receptor activation was compared between internet disorder subjects and controls. After the internet gaming task, 11C-NMSP binding in the putamen was significantly lower in internet gaming disorder subjects than in normal controls, especially on the right side (cluster level: KE = 136, PFWE-corrected = 0.020) (Fig. 2b).

Monoamine receptor changes: self-controlled comparison

When within-participant regional 11C-NMSP binding was calculated in response to the internet gaming task in each group, no significant 11C-NMSP binding changes were found in either the healthy or the internet gaming disorder group comparing internet gaming task and resting states.

Correlation between monoamine receptor changes and history of internet gaming disorder

11C-NMSP binding in both right and left putamen negatively correlated with Young scores in internet gaming disorder subjects (Fig. 2c). We found that, under the internet gaming state, the ratio of regional 11C-NMSP binding of left orbitofrontal cortex to the cerebellum correlated negatively to the years of internet overuse (Fig. 2d).

Correlation between monoamine receptor and glucose metabolism

Under the internet gaming task, the right and left striatum/cerebellum (S/C) ratios of D2 receptors correlated positively to the regional orbitofrontal cortex to cerebellum (R/C) ratio of glucose metabolism (right: P = 0.036; left: P = 0.016, respectively) (Fig. 3).

Fig. 3
figure 3

Correlation between D2 receptors in striatum and glucose metabolism in regional orbitofrontal cortex under internet gaming task. Significant positive correlation was found between either right or left striatum/cerebellum (S/C) ratio and orbitofrontal cortex/cerebellum (R/C) ratio. (Right S/C ratio vs. R/C ratio: R = 0.664, P = 0.036; Left S/C ratio vs. R/C ratio: R = 0.731, P = 0.016, respectively)

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Discussion

In this study, we investigated the D2 receptor activation and glucose metabolism in internet gaming disorder subjects in comparison to normal controls. Our results demonstrated that internet gaming disorder altered brain activity. Decreased glucose metabolism in the prefrontal, temporal, limbic system and dysregulation of dopamine D2 receptors in striatum were correlated to years of overuse. To the best of our knowledge, this is the first PET study in the level of D2 receptors associated with glucose metabolism in internet gaming disorder subjects.

Interestingly, after the internet gaming task, both overuse and control groups showed increased glucose metabolism in the occipital region, but decreased glucose metabolism in the prefrontal and temporal regions. This finding suggests that these regions are predominantly involved in internet gaming task processing. Considering the role of the occipital region as the visual center, closely associated with vision stimulation, increased glucose metabolism after the gaming task indicated that internet games may modify visual selective attention [34] and cortical networks for complex visual motor transformations [35].

Prefrontal glucose metabolism in the internet gaming disorder subjects was lower than that of normal controls, supporting the hypothesis that internet disorder subjects have prefrontal dysfunction similar to drug addiction [36]. On the other hand, compared with the normal controls, internet gaming disorder subjects had fewer regions of increased glucose metabolism. This suggested that internet gaming disorder subjects concentrated more attentively during the internet gaming task than the normal controls.

By the further between-group comparison of 11C-NMSP binding in the resting and internet gaming task states, we found that after the internet gaming task, 11C-NMSP binding in the putamen, especially on the right side, was significantly lower in internet gaming disorder subjects than in normal controls. 11C-NMSP bindings in both the right and left putamen negatively correlated with Young scores in internet gaming disorder subjects in this study. The putamen is located in the rostral division as part of the striatum, which is known to regulate movement and influence various types of learning. The striatum dopamine pathway attracts the most attention for addiction studies as it has been strongly implicated in addiction and reward processing [37]. A previous PET study using 11C-raclopride finds that striatal dopamine release is reduced in the internet addiction subjects [15]. However, 11C-raclopride competes with the endogenous dopamine for binding to the receptor; higher or lower synaptic concentration of dopamine results in less or more radioligand binding, respectively [29]. Thus, 11C-raclopride binding is often used to reflect the presynaptic dopamine release level, which is prone to be affected by human behavior [38, 39]. In contrast, the radiotracer 11C-NMSP, which we used in this study, binds the D2 receptors substantially irreversibly in the time frame of a PET scan and represents the D2 receptors more accurately [29, 40]. Therefore, our results imply that internet gaming disorder subjects could acquire dopaminergic pathway dysfunction in the striatal region as a result of their chronic gaming behavior.

We also found that the regional 11C-NMSP binding ratio of the left orbitofrontal cortex correlated negatively to the years of internet gaming disorder, which indicates that dopaminergic dysfunction is more significant in chronic internet gaming disorder. Although we found that there is no relevant with exclusion of that 8 years addiction subject, we consider that this is very important for us to understand the long-term internet gaming effect. Furthermore, D2 receptor availability in the striatum during the internet gaming task correlated positively to glucose metabolism in the orbitofrontal cortex. The orbitofrontal cortex is involved in decision-making, especially in signaling expected rewards or punishments associated with an action given the particular details of a situation [41]. Significantly reduced glucose metabolism in the orbitofrontal cortex is found in individuals with borderline personality disorder who have high levels of impulsivity [42]. A significant connection was found between dopamine D2 receptors in the putamen and glucose metabolism in the orbitofrontal cortex, a brain region involved with compulsive behaviors, suggested that dysregulation of the orbitofrontal cortex may be one of the mechanisms by which disruption of dopamine activity in methamphetamine abusers could lead to compulsive drug-taking behavior [43, 44]. In our study, the correlation between 11C-NMSP binding and 18F-FDG activity suggested that dysregulation of striatal D2 receptors maybe via striatal prefrontal pathways. This is consistent with the previous study using 11C-raclopride to assess D2 receptors and 18F-FDG to assess regional brain glucose metabolism in obese subjects [45]. Some other studies using fMRI also found that the prefrontal cortex strongly correlated with the striatum in self-control and the regulation of different kinds of appetitive desires [46, 47].

Additionally, we found that low levels of dopamine D2 receptors in the striatum significantly correlated with decreased serotonin 5-HT2A receptors in both the right and left temporal cortices in internet gaming disorder subjects (R = 0.904, P = 0.002 and R = 0.950, P = 0.001, respectively). These data suggest the likelihood of an interaction between bindings at dopamine D2 and serotonin 5-HT2A receptors. Thus, internet gaming disorder, resulting from a complex interaction of multiple receptor and neurotransmitter systems, does not lend itself ideally to an analysis of isolated receptor systems.

This study presented several important findings, deepening our understanding of the pathological mechanism of internet overuse. However, there were several limitations. Firstly, the monoamine binding potential was estimated using region-to-cerebellum ratios. Since test and control subjects declined arterial blood withdrawal, we could not obtain data for arterial input function. Therefore, we could not exclude the possibility that reduced monoamine binding potential was a result of change in KD (radioligand equilibrium dissociation constant) and not a result of change in Bmax (receptor density). BPND (the ratio at equilibrium of specifically bound radioligand to that of nondisplaceable radioligand in tissue) for the simplified reference tissue model (SRTM) is the only possible binding outcome measure, as total and free arterial plasma concentrations are necessary for calculation of BPP (the ratio at equilibrium of the concentration of specifically bound radioligand in tissue to the concentration of free radioligand in tissue) and BPF (the ratio at equilibrium of specifically bound radioligand to that of total parent radioligand in plasma) [45]. Secondly, there was no control group for those with a history of prolonged internet use for purposes other than gaming, such as work or study. It is unclear whether prolonged internet use can impair brain function. Thirdly, potential effects of the motor task should also be considered between the internet disorder and control groups. For instance, after long-term internet game playing, internet disorder subjects’ arm, hand or body motor movements may have potential effect on their 18F-FDG-brain scan. In addition, although the measures of pleasure or reward have been done at the subjects' screening stage, in future studies, these measures should be acquired immediately after internet gaming tasks to compare the level of pleasure or reward. Fourthly, some clusters appear to be outside the orbitofrontal cortex, since the mask was defined manually based on the standard SPM template. Theoretically, only cortical regions should be included in the mask. While for the SPM result of PET images, clusters outside the cortex were inevitable sometimes [48]. Lastly, since diagnostic criteria for internet game disorder and exclusion criteria for the participants are still under investigation, the criteria used in this study may have some limitations. In addition, the sample size was relatively small due to the difficulties of enrolling research subjects for sequential PET scans. Therefore, the cross-sectional comparison cannot determine if changes in brain function were due to chronic game play or if those brain dysfunctions caused internet overuse. Further longitudinal study should be performed to confirm whether the findings of our study represent either the cause or the effect of internet overuse.

In summary, for the first time, we found a significant association between D2 receptor level and glucose metabolism in the same subjects with internet gaming disorder, which indicates that D2 receptor-mediated dysregulation of the orbitofrontal cortex could underlie a mechanism for loss of control and compulsive behavior in internet gaming disorder subjects.