Evidence of decreased brain functional connectivity was found in adolescents with internet addiction. Consistent with current models emphasizing the role of cortico-subcortical pathology in addiction 
, 24% of the connections in the altered network differentiating addicted individuals and healthy controls involved links between frontal and subcortical regions. An additional 27% linked subcortical and parietal areas, with more limited evidence for involvement of the insula, again consistent with recent evidence of an involvement of these regions in addiction. Note that our analysis provides a stringent test of cortico-subcortical models of addiction, as it included measures of pair-wise functional connectivity between 90 different regions distributed throughout the brain. The fact that cortico-subcortical systems emerged as a prominent pathology using this completely data-driven analysis provides strong support for the involvement of these systems in internet addiction. Moreover, our findings indicate that internet addiction shares neurobiological characteristics in common with other addictive disorders, and that subcortical regions in particular may represent core sites of brain network pathology. An important note is the view from the National Institute on Drug Abuse that behavioral addictions might be relatively pure models of addiction, taking into account that these conditions are not contaminated by the effects of substances 
. Whereas the study of many other addiction disorders is invariably confounded by secondary toxicity effects of substance abuse, internet addiction is diagnosed behaviorally and thus provides a more targeted model for studying addiction that is free from long-term drug effects.
In this study, the NBS was used with network size measured based on its extent; that is, the total number of connections comprising the network. This size measure is not suited to detecting focal effects involving single, isolated connections that do not collectively form a network. To test for these kinds of focal between-group differences, the NBS analysis was repeated testing for differences in component mass rather than size. The mass statistic provides greater sensitivity to focal, intense effects than testing for differences in component size. In addition, we also thresholded edge-wise comparisons using the FDR, which will be very sensitive to high-intensity, focal effects. No significant between-group differences were apparent with either the FDR or mass statistics, suggesting that aberrant connectivity in internet addiction encompasses a distributed network involving several cortical and subcortical regions.
Given that brain network properties are known to be sensitive to the choice of parcellation template, we investigated several alternative parcellation schemes in order to assess the reproducibility of any findings to changes in nodal definitions 
. This enabled us to rule out the possibility that certain findings were merely due to a statistically favorable positioning of nodes, but not reproducible with other well-known parcellations.
In contrast to the decreased strength of functional connectivity, topological parameters revealed no significant group differences. Even when we conducted further exploratory analyses based on less stringent control against type I error, the results indicated possible topological difference mainly involving the occipital lobe, which was unaffected in the NBS analysis. Thus, while internet addiction was associated with a widespread and significant decrease of functional connectivity in cortico-subcortical circuits, this decrease was not associated with a global disruption in brain functional network topology. This study demonstrates that widespread differences in functional connectivity can exist in the absence of alterations in basic topological measures. It may seem remarkable that differences in connectivity strength were so widespread in the absence of any significant topological differences. However, it is important to remark that topology and connectivity strength are distinct properties of the connectome and abnormalities in one need not imply abnormalities in the other. Similar findings have been observed in other disorders 
. We note however, that group differences in some topological properties trended towards statistical significance. Analysis of a larger sample may afford the necessary power to declare these effects significant. Our results suggest that topological changes may be more subtle than those observed for functional connectivity measures.
Among the 59 connections included in the altered network, 25 were interhemispheric connections and 34 were intrahemispheric, pointing to involvement of long-range as well as short-range connections throughout the brain. Given that internet addiction is a newly recognized mental health condition, with its concept and diagnostic criteria still elusive and undetermined, perhaps it might be surprising to find such an extensively affected network in the brain of these subjects. Recently, Lin et al. (2012) investigated brain white matter integrity in adolescents with internet addiction using diffusion-tensor imaging, and found a widespread decrease in fractional anisotropy (FA) throughout the brain with no area of higher FA in internet addiction group 
. Such results implicate a possible anatomical basis for the functional disturbances observed in our sample, a hypothesis that could be tested using combined fMRI and diffusion-weighted imaging in the same participants 
Regarding the large number of interhemispheric connections found in the altered network, efficient interhemispheric communication has long been thought to be important in brain functions 
. However, relatively few neuroimaging studies of addiction have addressed the functional integration between bilateral hemispheres. Recently, Kelly et al. (2011) observed reduced interhemispheric functional connectivity in cocaine-dependent adults 
. They showed primary involvement of a fronto-parietal network, with a relative sparing of temporal regions, results that parallel our findings. Although the authors discussed the finding mainly as reflecting the long-term effects of chronic cocaine exposure, they also mentioned the possibility that reduced interhemispheric functional connectivity may have preceded the exposure to cocaine as a vulnerability to addiction disorders. Our results suggest that these interhemispheric changes reflect either a vulnerability for addiction disorders or a neural correlate of generic addictive behavior, rather than being secondary to prolonged drug use, given that addiction in our sample was defined in purely behavioral terms. These possibilities could be evaluated by testing for phenotypic similarities between unaffected relatives of individuals with either drug or behavioral addiction disorders.
Interestingly, a similar pattern of decreased resting-state functional connectivity between frontal and parietal regions was reported both in cocaine- and heroin-dependent individuals 
. In a recent review, Sutherland et al. (2012) suggested that decreased connectivity in the fronto-parietal circuits might be a central component in the impaired cognitive control network of drug-addicted populations 
. Our finding in internet addiction also supports the notion that decreased functional connectivity between frontal and parietal regions might be a common characteristic across different types of addiction, suggesting the presence of a shared phenotype that is not a secondary consequence of drug use. In addition, a recent investigation of whole-brain functional connectivity in schizophrenia showed prominent fronto-temporal rather than fronto-parietal or fronto-striatal changes 
, consistent with classical pathophysiological models of the disorder 
. Of course, the most remarkable finding of the present study is that internet addiction was associated with pathology of striatal circuits in particular, a system commonly implicated in other addictive disorders, suggesting a shared neurobiological phenotype. Identifying altered striatal circuits overlapping with those of well-established addictive disorders might be useful for testing whether the addiction model is an appropriate theoretical framework for understanding the disorder 
. However, whether a relatively stronger impairment of fronto-parietal and fronto-striatal functional connectivity could be largely specific to addiction disorders still remains in question. Future studies directly comparing different disorders are needed in order to establish specificity.
One of the most interesting findings in the current study was the strong involvement of the putamen. This brain structure is known to modulate several neurotransmitters including dopamine, and blunted striatal dopaminergic function has been strongly implicated as one of the key biological mechanisms of addiction disorders 
. Dopamine is a key modulator of putamen function and may play an important role in the functional connectivity disturbances observed in this study. This is consistent with recent evidence that striatal dopamine transporter and D2 receptor availability is altered in people with internet addiction 
and that genetic and pharmacologic modulation of brain dopamine levels can exert a profound impact on functional connectivity patterns 
. Taking into account these former reports and the proposed neurobiological mechanism of addiction involving blunted striatal dopaminergic function 
, understanding the effects of dopamine on the network identified as showing altered functional connectivity in the present study will represent an important way forward in understanding the neurobiological correlates of internet addiction.
Our finding that the putamen was the most extensively involved subcortical region in the decreased functional network, sparing the caudate nucleus, is also interesting. Both structures are part of the striatum, which in turn is part of the subcortical structures. The putamen is typically considered a brain region associated with motor activity, and has less often been implicated in substance addition than the caudate. Among motor activities, a well-learned sequence of repetitive finger movements has been shown to be associated with activation in the putamen 
. People suffering from internet addiction may undergo a far higher frequency of certain behaviors over a long period of time, which include repetitive manipulation of the mouse and keyboard, and these experiences can affect their brain. Therefore, aberrant connectivity stemming from the putamen perhaps indicates a specific characteristic of internet addiction. However, as we did not measure the degree of finger manipulation in our participants, the implication of decreased rather than increased functional connectivity involving the putamen in relation to mouse/keyboard manipulation remains open to future research. Alternatively, the involvement of the putamen in our findings may reflect its role in cognitive processes that are shared with the caudate and which are impaired in addiction, such as reward processing 
Another point worthy of discussion is the absence of any increased functional connectivity in the internet addiction group. Although we mainly expected to find decreased functional connectivity in the addiction group, in fact, we did not exclude the possibility of observing increased functional connectivity as well, particularly given the hypothesis that adolescents with internet addiction might show a practice effect due to excessive online activities 
. One possible explanation for the negative finding could be that our small sample size lacked the power to detect this practice-related increase in functional connectivity. However, it is not yet fully established whether cognitive performance in certain tasks or severity of certain psychopathologies manifest as decreased or increased functional connectivity 
. Another consideration should be that the effect of long-term excessive internet use might differentially influence the brain according to subpopulation. For example, a subpopulation called professional online game players engages in intensive internet activities, spends similarly long amounts of time practicing online games and probably performs better in those games than people with internet addiction, and yet seems not to be addicted as evidenced by significantly lower YIAS score 
. Hence, it could be hypothesized that practice effects in internet activities perhaps manifest differently depending on the individual.
The present study has some important limitations. First, the sample size was quite small, which likely limited our power to detect significant correlations between functional connectivity and YIAS scores. Thus, the current finding needs to be replicated in a larger sample of participants with internet addiction and controls. It is, however, noteworthy that our sample size was on the whole comparable to that of former functional neuroimaging studies of internet addiction. Our sample was unique, as most former studies were based on adults 
. Second, the diagnostic criteria for internet addiction are not solidly established yet, though our findings do point to a potential neurobiological basis for this putative disorder. Third, although we excluded comorbid mental disorders using K-SADS-PL, subthreshold-level symptoms of comorbid mental conditions might have still been present. Fourth, collection of a broader range of clinical information such as sleeping habits may have enriched our data and improved our contribution to the literature 
. Finally, the cross-sectional study design limits the interpretation of a causal relationship between decreased functional connectivity and the development of internet addiction. It should be noted that head motion has emerged as an important confound in functional neuroimaging 
. Head motion was comprehensively assessed in this study using a range of recently proposed rotational and displacement measures 
. No significant difference between groups was found for any of the head motion measures considered.
In summary, the results of this study suggest that adolescents with internet addiction display altered brain functional connectivity in the absence of gross disturbances of network topology. The altered network showed an extensive involvement of long-range interhemispheric connections as well as short-range intrahemispheric links throughout the brain. Subcortical brain regions may play an important role in this altered network, particularly the putamen, which showed decreased connections with all three major cerebral lobes involved.