Normative Modeling Reveals Functional Connectivity Heterogeneity and Subtypes in Internet Gaming Disorder

doi:10.21203/rs.3.rs-6938965/v1

Background

Internet gaming disorder (IGD) is associated with abnormal functional connectivity (FC) in brain networks. However, findings from resting-state fMRI (RS-fMRI) studies are highly inconsistent, likely due to individual heterogeneity in IGD-related neural alterations—a feature commonly observed in other psychiatric disorders but understudied in IGD.

Methods

We applied normative modeling to RS-fMRI data to characterize individualized FC deviations between the nucleus accumbens (NAcc) and the rest of the brain in 173 IGD participants. Using a large sample of healthy controls (N = 232) to establish age- and sex-adjusted normative ranges, we quantified the abnormality of each IGD individual’s FC profile. Further, we performed k-means clustering on deviation values within the frontoparietal network (FPN) and basal ganglia network (BGN) to identify neurobiological subtypes.

Results

Our findings revealed considerable heterogeneity in FC abnormalities among IGD participants. Only a minority showed strong and widespread deviations, while most exhibited mild but diverse patterns. Clustering analysis identified five distinct IGD subtypes with varying hyper- and hypoconnectivity profiles in FPN and BGN.

Conclusions

These results highlight the heterogeneous neural basis of IGD and underscore the limitations of group-level comparisons. Normative modeling and FC-based subtyping offer a promising direction for individualized assessment and may inform personalized interventions, such as connectivity- and frequency-specific TMS targeting cognitive control and reward circuits.

Internet gaming disorder

functional connectivity

heterogeneity

normative modeling

subtypes

Internet gaming disorder (IGD) refers to the problematic and excessive use of internet games, which can be detrimental to various aspects of one's education and life (1, 2). American psychiatric association (APA) has included IGD in Section III of fifth edition of diagnostic and statistical manual of mental disorders (DSM-5) as warranting more clinical research in 2013 (3). Using resting-state functional magnetic resonance imaging (RS-fMRI), researchers have conducted numerous studies on the characteristics and underlying neural basis of IGD, demonstrating some core neural variation of IGD, such as abnormal brain functional networks related to cognitive control, reward processing (4–7).

However, after summarizing previous RS-fMRI studies on IGD, we found that it is hard to draw a uniform conclusion about the underlying neural mechanism of IGD. For example, some researchers found that compared to healthy control (HC) group, IGD group displayed decreased functional connectivity (FC) between the dorsolateral prefrontal cortex (DLPFC) and nucleus accumbens (NAcc) (8), decreased FC between the orbitofrontal cortex (OFC) and putamen (9), and decreased FC between the anterior cingulate cortex (ACC) and caudate (10). On the other hand, some researchers identified increased FC between the OFC and putamen (11), increased FC between the DLPFC and posterior cingulate cortex (PCC) (12), and increased FC between the middle frontal gyrus (MFG) and caudate (13) in IGD group in comparison with HC group. Both the direction and the focal area of abnormalities of IGD group exhibited different across different RS-fMRI studies. We inferred that the heterogeneity of IGD in the abnormalities of resting-state FC patterns is the main reason for these inconsistent results. Heterogeneity is one of core features of many disorders, including schizophrenia, autism, bipolar disorder and substance addiction (14–18). However, the heterogeneity of IGD is barely understood. The heterogeneity of IGD emphasizes the importance of identifying individualized abnormality of IGD, thus contributing to prompt the individualized treatment for IGD. In contrast, group-level differences from comparisons between IGD and healthy groups in previous studies might not necessarily be representative of any IGD gamer. They only represent a small part of the neural abnormalities that characterize IGD and the bulk of the small part of abnormalities are comprised of individual IGD who are highly deviated from the norm (19).

Accordingly, the present study was set to map the individualized abnormalities of brain FC in IGD using a recent methodology named normative modeling. Normative modeling has been well documented and applied in studies of heterogeneity in other psychiatric disorders, such as autism, schizophrenia, depressive and bipolar disorder (14, 16, 20, 21). A normative model can be understood as a statistical model that maps demographic or behavioral variables to a quantitative brain readout. Using brain data from a large number of typically developed individuals (i.e., HC individuals), a Bayesian process regression model was used to calculate the normative range within which brain metrics could be varied up or down for HC individuals at specific ages and sexes (22). Then, each IGD individual brain metric is compared to the normative model of same age and sex to compute their individualized abnormalities/deviations relative to HC individuals. This is the first goal of the present study. We assumed that different IGD individual would exhibit different abnormalities/deviations from normative model, i.e., heterogeneity, in resting-state brain FC, as we summarized from previous RS-fMRI studies.

Additionally, the bilateral NAcc was selected as the region of interest (ROI) for the resting-state ROI-based brain FC analysis to compute the FC between the NAcc and the whole remaining brain regions in the current study. The NAcc, the main projection region of the mesolimbic pathway, has been confirmed to be involved in driving craving and development and maintain of addiction in many addicted types, including IGD (23–25). Moreover, many studies have revealed abnormal activation/FC of the NAcc in individuals with IGD (8, 26–28).

The second goal of the present study is to distinguish different subtypes of IGD using clustering algorithm. Clustering algorithm is also a common approach to biological heterogeneity. This approach is successful to some extent and is appropriate if the clinical cohort can be cleanly divided into a relatively small number of homogeneous subgroups based on the measures chosen (20, 29). Accordingly, by using clustering algorithm, we expect to identify some homogeneous subtypes of IGD individuals based on their direction and magnitude of deviations from normative models regarding FC. Particularly, according to previous studies on IGD, the cognitive control and reward networks were most related to IGD (4, 26, 28, 30, 31). Thus, we aimed to identify the subtypes of IGD participants based on their abnormalities/deviations from normative model in the cognitive control and reward networks. In the current study, we used the frontoparietal network (FPN) and the basal ganglia network (BGN) from Shen’s brain functional atlas (32), which were implicated in the cognitive control and reward networks separately (33–35).

Participants

The present study included 173 university students with IGD (males/females: 98/75) and 232 HCs (males/females: 139/93). The numbers of males and females were matched between the two groups (χ²=0.436, p =0.509). All the participants were free of any psychiatric/neurological disorders confirmed by structured psychiatric interviews (Mini International Neuropsychiatric Interview). No participant reported any illegal drug use and gambling, and excessive nicotine and alcohol uses. The diagnosis of IGD was based on the Young's Internet Addiction Test (IAT) (36) and DSM-5 criteria for IGD (37). Consistent with previous studies of IGD (4, 38-40), the diagnostic criteria for the IGD group included: 1) an IAT score >50; 2) a DSM-5 criteria score >5; and 3) spending most of their internet time in playing games. Participants with DSM-5 criteria scores <5 and IAT scores <50 were classified as the HC group. As shown in Table 1, the IGD group reported significant greater IAT scores and DSM-5 scores than the HC group.

Table 1. Demographic information and group differences

Items	IGD (M=98, F=75)	HC (M=139, F=93)	t	p
Age (years)	21.13±2.33	21.53±2.43	-1.663	0.097
IAT score	66.15±9.13	40.32±10.92	25.223	<0.001
DSM-5 score	6.08±1.13	2.51±1.37	26.447	<0.001

Table values: mean ± standard deviation

Abbreviations: IGD, internet gaming disorder; HC, healthy control; M, male; F, female; IAT, internet addiction test; DSM-5, the fifth edition of diagnostic and statistical manual of mental disorders.

RS-fMRI data acquisition

All participants underwent a RS-fMRI scan for 7 min using a 3 T scanner (Siemens Trio, Malvern, PA, USA) equipped for echo-planar imaging (EPI). During the scan, they were asked to open eyes and stay still and relaxed. The scan parameters were as follows: repetition time (TR) = 2000 ms, echo time (TE) = 30 ms, slice number = 33, interleaved sequence, slice thickness = 3 mm, voxel size = 3 × 3 × 3 mm³, field of view (FOV) = 220 × 220 mm², flip angle = 90^◦ and matrix of 64 × 64.

Preprocessing of RS-fMRI data

Data preprocessing was performed using DPABI V8.2 (http://rfmri.org/dpabi). The preprocessing steps included: 1) discarding the first 10 time points; 2) slice-timing; 3) realign for head-motion correction; 4) spatial normalization to Montreal Neurological Institute (MNI) standard space; 5) spatial smoothing (FWHM = 6 mm); 6) linear trend removal; 7) nuisance covariates regression, including head-motion covariates using the Friston 24-parameter model as well as signals from white matter, cerebrospinal fluid and global signals; 8) band-pass filtering with a range of 0.01-0.1 Hz.

Constructing normative models of FC

An overview of the normative modeling approach is provided in Figure 1; this approach has been described previously (22). First, ROI (bilateral NAcc)-based FC values were generated for each participant using DPABI v8.2. Second, warped Bayesian linear regression (41) was used to generate the normative models of FC at each specific voxel of the whole brain on the HC group (N=232), using age and gender as independent variables to predict FC, i.e., dependent variable, which was performed using the PCNtoolkit (Predictive Clinical Neuroscience toolkit) (42). The normative model of each voxel contains both the predicted FC and related predictive confidence at this voxel. The predictive confidence could be interpreted as centiles of variation within the norm population. Third, the normative model helps us place each participant within the normative range and then quantify their deviations (i.e., Z scores) of FC from the healthy range at each specific brain voxel. One participant-specific (i) Z score at each voxel (j) is calculated using the equation below:

This equation combines three sources of information: 1) the difference between true response () and predicted response (); 2) the predicted variance of the specific voxel (); 3) the variance of the normative data of the specific voxel (). Using this equation, a normative probability map (NPM) with all the Z scores of all the brain voxel for each participant is generated. Thus, the NPM of one participant provides a statistical estimate of how much the FC of the participant differs from the FC of healthy normative pattern at each voxel, i.e., Z scores. Lastly, to identify brain voxels with significant deviations from healthy normative pattern across the whole brain of each participant, the NPM of each participant was thresholded using FDR (false discovery rate) at p<0.01 (22). To examine the spatial spread of the significant deviations among the IGD group, an overlap map by counting all the participant-level FDR-corrected NPMs was generated. This can be used to identify which brain regions had positive deviation (increased FC) or negative deviation (decreased FC) among the IGD group compared to the HC group.

Estimating regional deviations for each participant

To better depict the important deviations of each participant’s FC, we calculated one summary index for each participant, i.e., regional deviation to capture the maximum deviation across specific brain regions or functional networks. To calculate regional deviations, we first parcellated the whole brain into 10 functional networks (the FPN, BGN, limbic network, default mode network, medial frontal network, motor network, visual association network, visual network I and II, and cerebellum network) from Shen’s brain functional atlas (32) (https://bioimagesuiteweb.github.io/ webapp/connviewer.html?species5human). Then, the trimmed mean of 1% of top positive/negative deviations across each functional network was taken as the regional deviation for each region of each participant. In the end, the greater trimmed mean deviation between positive and negative deviations was taken as the representative deviation for each participant in one functional network.

Cluster analysis

Cluster analysis was applied to identify subtypes of IGD participants. In the current study, the data-driven K-means cluster analysis (43) was conducted using the “kmeans” function in MATLAB to classify the IGD participants based on their regional deviations of the cognitive control and reward networks, i.e., FPN and BGN. The optimal number of clusters was determined by two methods: 1) the average Silhouette score for each value of cluster numbers, and the solution with the highest Silhouette score was considered as the optimal clustering configuration (44); 2) the within-cluster sum of squares (WCSS) and the elbow method, where the point of inflection indicated a suitable number of clusters (45).

Individual deviation from normative models

Figure 2 presents the summary maps of intra-individual FDR-corrected NPMs for the IGD and HC groups, highlighting voxels that showed significant positive or negative deviations from the normative models. As expected, the HC group showed few significant deviations, indicating that the normative model provided a good fit for this group. This fit was achieved under 10-fold cross-validation and was therefore unbiased. In contrast, the voxels with significant deviations in the IGD group were noticeably more than the HC group and were widespread across the brain.

Figure 3 presents the top ten IGD participants with significant deviated voxels. The IGD participants with a large range of deviated voxels represented only a very small fraction of the IGD group, and their deviations were different from each other. This result emphasized that individual differences exist within the IGD group and cannot be ignored.

Comparison between normative modeling and case-control

Using traditional case-control method, we performed an independent sample t test on the FC of the IGD group and the HC group. FWE correction with voxel p=0.01 and cluster p=0.05 was applied to obtain significant group difference on FC. The results (Figure 4A) showed that the IGD group had significant stronger FC between NAcc and limbic lobe (i.e., the putamen, pallidum, thalamus, amygdala, and hippocampus than the HC group.

Then, we removed the top 20 IGD participants with extreme deviations from the IGD group, and performed an independent sample t test on the FC of the remaining IGD participants (N=153) and the HC group. FWE correction with voxel p=0.01 and cluster p=0.05 was also applied. As shown in Figure 4B, no significant difference was found. This result further revealed the existence of individual differences, i.e., heterogeneity, within the IGD group. Moreover, the abnormalities of IGD found in previous studies using case-control method may only be caused by a small proportion of IGD individuals.

The IGD subtypes based on K-means cluster analyses

By using the custom code in MATLAB, we computed the average Silhouette score and the WCSS of cluster number for a range of cluster numbers from 2 to 10. Based on the results from both the Silhouette analysis (Figure 5A) and the elbow method applied to the WCSS curve (Figure 5B), the optimal number of clusters was determined to be 5. The k-means algorithm then iteratively assigned cases to clusters to minimize within-cluster variance. The final cluster solution demonstrated good validity, stability and interpretability.

As shown in Figure 5C and Table 2, based on the regional deviations of the FPN and BGN, the IGD group was clustered into 5 subgroups: 1) the first subtype occupied 30.06% and showed negative deviations both in the FPN and in the BGN, and the average IAT score of this subgroup was 64.23, the average DSM-5 score was 5.98; 2) the second subtype occupied 17.92, showing positive deviations both in the FPN and in the BGN, and the average IAT score was 68.00, the average DSM-5 score was 6.23; 3) the third subtype occupied 25.43%, showing negative deviations in the FPN and positive deviations in the BGN, and the average IAT score was 67.07, the DSM-5 score was 6.13; 4) the fourth subtype occupied 26.01%, showing positive deviations in the FPN and negative deviations in the BGN, and the average IAT score was 65.80, the DSM-5 score was 6.09; 5) the fifth subtype p only have one IGD participant, showing extreme positive deviations in the FPN and extreme negative deviations in the BGN, and the IAT score was 84.00, the DSM-5 score was 7.

Table 2. The results of k-means cluster analysis.

	Cluster 1 N=52	Cluster 2 N=31	Cluster 3 N=44	Cluster 4 N=45	Cluster 5 N=1
Proportion (%)	30.06	17.92	25.43	26.01	0.58
Mean regional deviations of the FPN	-3.02	3.34	-2.95	3.10	11.52
Mean regional deviations of the BGN	-2.90	3.44	3.04	-3.12	-10.68
Mean IAT scores	64.23	68.00	67.07	65.80	84.00
Mean DSM-5 scores	5.98	6.23	6.13	6.09	7.00

Abbreviations: N, Number; FPN, frontoparietal network; BGN, basal ganglia network; IAT, internet addiction test; DSM-5, the fifth edition of diagnostic and statistical manual of mental disorders.

The heterogeneity in abnormal FC of IGD participants

Our results provide compelling evidence that IGD is characterized by substantial heterogeneity in resting-state FC. The normative modeling approach revealed that a minority of IGD individuals exhibited widespread and diverse deviations in FC between NAcc and the remaining brain, the majority exhibited less and also diverse deviations. The ‘diverse’ could be seen from the overlap of all the IGD participants’ FDR-corrected deviation maps (Figure 2). Only 5/4 participants had significant positive/ negative deviation on a certain voxel. This is consistent with prior findings in psychiatric disorders such as autism spectrum disorder, major depression disorder and bipolar disorder, where patients show various deviations across brain in neural features, i.e., grey matter, cortical thickness), and only a small portion of patients show large deviations (14, 16, 20, 21). Such heterogeneity suggests that case-control studies, which average across individuals, likely highlight abnormalities present in only a subset—potentially explaining inconsistent findings among IGD RS-fMRI studies as we reviewed in Background. Indeed, when the top 20 most deviant IGD participants were removed, typical group-level FC differences (e.g., increased NAcc–limbic connectivity in IGD) vanished in our analysis. This underscores that normative modeling is vital for uncovering individual FC aberrations masked by averaged group contrasts, and aligns with findings in other psychiatric domains advocating for precision medicine approaches (46, 47).

Beyond overall variability, heterogeneity of IGD manifested in distinct patterns of FC deviations across core functional networks related to IGD, i.e., the FPN responsible for cognitive control and the BGN responsible for reward processing (34, 35). By clustering the representative deviations of the two networks (regional deviation) in all the IGD participants, we identified five subtypes of IGD. Such an approach revealed that some IGD participants had negative deviations—a potential indicator of hypoconnectivity affecting cognitive control/reward processing, whereas others showed positive deviations, suggesting hyperconnectivity in cognitive control/reward circuits. This clustering results further explain why some researchers identified hyperconnectivity between the inferior frontal gyrus responsible for cognitive control and NAcc in IGD (48) whereas some researchers identified hypoconnectivity between the DLPFC responsible for cognitive control and NAcc in IGD (8, 31). Our findings suggest that deviations vary qualitatively across individuals with IGD, instead of one uniform pattern. Clinically, this implies that interventions such as cognitive training or reward-modulating therapies should be tailored—some IGD individuals may benefit from enhancing frontoparietal control, others from regulating striatal hyperactivity.

Identification of IGD Subtypes and Clinical Implications

The k‑means clustering on individualized FC deviations of the FPN and BGN yielded five distinct IGD subtypes. These were: (1) both hypoconnectivity between FPN and NAcc, as well as between BGN and NAcc; (2) both hyperconnectivity between FPN and NAcc, as well as between BGN and NAcc; (3) hypoconnectivity between FPN and NAcc–hyperconnectivity between BGN and NAcc; (4) hyperconnectivity between FPN and NAcc–hypoconnectivity between BGN and NAcc; and (5) extreme mode of subtype 4 (one IGD participant), the addiction severity of this participant was the highest (the highest IAT score and DSM-5 score). Interestingly, average addiction severity scores (IAT/DSM-5) were comparable across subtypes 1-4, suggesting that addiction severity does not align directly with FC deviation profiles. This resonates with normative modeling studies in autism and obsessive-compulsive disorder that identified cross-diagnostic subtypes not predicted by traditional symptom scales (20, 49). Our findings highlight the possible existence of meaningful neurobiological subtypes that conventional clinical assessments fail to detect.

These findings point toward a precision psychiatry framework for IGD: mapping FC deviation patterns enables subtype-specific interventions, especially transcranial magnetic stimulation (TMS) intervention (50). For example, individuals in subtype 3 (reduced control, heightened reward connectivity) may benefit from a dual intervention approach: high-frequency TMS (≥10 Hz) targeting control-related areas such as the DLPFC to strengthen executive function, and low-frequency TMS (≤1 Hz) to reward-related areas (e.g., striatum, ventromedial PFC) to reduce hyperactive reward processing (51, 52). Conversely, subtype 4 (enhanced control but diminished reward responsiveness) may benefit from high-frequency TMS stimulation of reward-related circuits to restore motivational salience, while avoiding further stimulation of already over-engaged control networks. Our single-participant outlier (subtype 5), showing extreme FC deviation, underscores the need for individualized TMS protocols—tailored not only in anatomical targets but also in frequency—to address unique neurofunctional profiles. These insights support a frequency- and connectivity-informed TMS framework for personalized IGD treatment. Future research should validate these subtypes in longitudinal cohorts, link them with task-related fMRI and behavioral profiles, and assess response to tailored interventions. Expanding normative models to incorporate dynamic FC and multimodal imaging—such as cortical thickness and molecular connectivity—could refine subtype definitions. Ultimately, embracing normative modeling and data-driven subtyping may enable meaningful stratification of IGD and pave the way for mechanism-based, personalized treatments (46).

The current study reveals two key findings related to IGD. First, using a normative modeling framework, we uncovered substantial individual heterogeneity in resting-state FC abnormalities among IGD participants. While some individuals showed pronounced FC deviations between the NAcc and widespread brain regions, most exhibited less extensive and highly variable patterns, suggesting that group-level analyses may obscure meaningful individual differences. Second, by clustering individualized deviations within the FPN and BGN, we identified five distinct FC-based IGD subtypes. These subtypes demonstrated divergent patterns of hyper- or hypoconnectivity in cognitive control and reward circuits, which were not aligned with clinical severity scores. These findings support a precision psychiatry approach for IGD, emphasizing the need for individualized neurobiological characterization and targeted interventions such as connectivity- and frequency-informed TMS.

Abbreviation	Full Term
IGD	Internet Gaming Disorder
APA	American Psychiatric Association
DSM-5	Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
HC	Healthy Control
RS-fMRI	Resting-State Functional Magnetic Resonance Imaging
FC	Functional Connectivity
DLPFC	Dorsolateral Prefrontal Cortex
NAcc	Nucleus Accumbens
OFC	Orbitofrontal Cortex
ACC	Anterior Cingulate Cortex
PCC	Posterior Cingulate Cortex
MFG	Middle Frontal Gyrus
ROI	Region of Interest
FPN	Frontoparietal Network
BGN	Basal Ganglia Network
NPM	Normative Probability Map
FDR	False Discovery rate
FWE	Family-Wise Error
WCSS	Within-Cluster Sum of Squares
TR	Repetition Time
TE	Echo Time
FOV	Field of View
MNI	Montreal Neurological Institute
FWHM	Full Width at Half Maximum
TMS	Transcranial Magnetic Stimulation

Ethics approval and consent to participate

The Institutional Review Board of Hangzhou Normal University approved the present study. All procedures involving human participants were conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants, and all of them completed the MRI safety screening questionnaire before the scan.

Clinical trial number: not appliable.

Consent for publication

Not applicable.

Availability of data and materials

The datasets generated and analyzed during the current study are not publicly available due to restrictions related to participant privacy and institutional ethical regulations, but are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

This work was supported by the National Natural Science Foundation of China (NSFC) [number 32300925], Youth Fund for Humanities and Social Sciences Research of the Ministry of Education of China [number 23YJC190023], and the Construction Fund of Key Medical Disciplines of HangZhou [number 2025HZGF02]. The funding sources had no involvement in any of the manuscript.

Authors’ contributions

Z.W. and L.W. conducted the statistical analysis and wrote the manuscript. L.W. and G.D. collected the research data and modified the manuscript. Y.X. and Y.W. contributed to the data analysis. All authors read and approved the final manuscript.

Acknowledgements

Not applicable.

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No competing interests reported.

Normative Modeling Reveals Functional Connectivity Heterogeneity and Subtypes in Internet Gaming Disorder

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Abstract

Background

Methods

Results

Conclusions

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Background

Methods

Results

Discussion

Conclusions

List of abbreviations

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References

Additional Declarations

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Version 1