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Neuroscience and Biobehavioral Reviews 75 (2017) 314330

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews


journal homepage: www.elsevier.com/locate/neubiorev

New developments in brain research of internet and gaming disorder


Aviv Weinstein a, , Abigail Livny b , Abraham Weizman c
a
Dept. of Behavioral Science and the Integrative Cognition and Brain Center, University of Ariel, Science Park, Ariel 40700, Israel
b
The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel-Hashomer, Israel
c
Research Unit, Geha Mental Health Center, Beilinson Campus, P.O. Box 102, Petah Tiqva 49 100. Israel

a r t i c l e i n f o a b s t r a c t

Article history: There is evidence that the neural mechanisms underlying Internet Gaming Disorder (IGD) resemble those
Received 11 May 2016 of drug addiction. Functional Magnetic Resonance Imaging (fMRI) studies of the resting state and mea-
Received in revised form 22 January 2017 sures of gray matter volume have shown that Internet game playing was associated with changes to
Accepted 29 January 2017
brain regions responsible for attention and control, impulse control, motor function, emotional regula-
Available online 11 February 2017
tion, sensory-motor coordination. Furthermore, Internet game playing was associated with lower white
matter density in brain regions that are involved in decision-making, behavioral inhibition and emo-
Keywords:
tional regulation. Videogame playing involved changes in reward inhibitory mechanisms and loss of
Internet gaming disorder
Brain imaging
control. Structural brain imaging studies showed alterations in the volume of the ventral striatum that
fMRI is an important part of the brains reward mechanisms. Finally, videogame playing was associated with
Dopamine dopamine release similar in magnitude to those of drugs of abuse and lower dopamine transporter and
Reward dopamine receptor D2 occupancy indicating sub-sensitivity of dopamine reward mechanisms.
2017 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314
1.1. Background- the neural mechanisms underlying reward and the effects of drugs of abuse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315
1.2. Brain imaging studies of the resting state in IGD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316
1.3. Studies on the brains gray matter volume and white matter density . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316
1.4. Cortical thickness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319
2. Functional connectivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320
2.1. Functional connectivity at a resting state . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320
2.2. Functional connectivity, reward and the striatum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320
3. Brain activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320
3.1. Cue-exposure activation studies of videogame urges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320
3.2. Inhibitory control mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
3.3. Reward . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
4. Brain imaging studies on dopamine, 5-HT and other neurotransmitters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
5. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
Declaration of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328

1. Introduction

Internet Gaming Disorder (IGD) involves excessive or poorly


controlled preoccupations, urges or behaviors regarding computer
Corresponding author. and videogame play that lead to impairment or distress. There are
E-mail addresses: avivwe@ariel.ac.il, avivweinstein@yahoo.com (A. Weinstein). three different models proposed for IGD: an impulse-control disor-

http://dx.doi.org/10.1016/j.neubiorev.2017.01.040
0149-7634/ 2017 Elsevier Ltd. All rights reserved.
A. Weinstein et al. / Neuroscience and Biobehavioral Reviews 75 (2017) 314330 315

der, an obsessive-compulsive disorder, and a behavioral addiction Table 1


Internet gaming disorder criteria in the Diagnostic and Statistical Manual of Mental
model (Grant et al., 2010). The behavioral addiction model argues
Disorders. (DSM-5) Internet Gaming Disorder Proposed Criteria.
that IGD shows the features of excessive use despite adverse conse-
quences, withdrawal phenomena, and tolerance that characterize Persistent and recurrent use of the Internet to engage in games, often with
other players, leading to clinically significant
substance use disorders. In the fifth edition of the Diagnostic
Impairment or distress as indicated by five (or more) of the following in a
and Statistical Manual of Mental Disorders (DSM-5) (American month period:
Psychiatric Association, 2013), IGD is identified in Section III as a
Preoccupation with Internet games. (The individual thinks about previous
condition warranting more clinical research and experience before
gaming activity or anticipates playing the next game;
it might be considered for inclusion as a formal disorder (see Internet gaming becomes a dominant activity in daily life).
(Weinstein et al., 2014; Weinstein and Aboujaoude, 2015) for Note: This disorder is distinct from Internet gambling, which is included under
review). The work group moved from a broad conceptualization gambling disorder.
2. Withdrawal symptoms when Internet gaming is taken away. (These
(along the lines of problematic internet use) to a narrower one,
symptoms are typically described as irritability, anxiety, or
focusing primarily on pathological online gaming and avoiding use Sadness, but there are no physical signs of pharmacological withdrawal).
of the term addiction. Noteworthy, the DSM-5 does not offer suf- 3. Tolerancethe need to spend increasing amounts of time engaged in
ficient guidance on how to approach individuals with suspected Internet games.
Internet-related psychopathology or how to design or interpret 4. Unsuccessful attempts to control the participation in Internet games.
5. Loss of interests in previous hobbies and entertainment as a result of, and
research studies into this topic. Instead, clinicians and researchers
with the exception of, Internet games.
have to rely on proposed definitions, along with several screening 6. Continued excessive use of Internet games despite knowledge of
and assessment instruments developed for problematic internet psychosocial problems.
use and problematic video game use (Weinstein and Aboujaoude, 7. Has deceived family members, therapists, or others regarding the amount of
Internet gaming.
2015).
8. Use of Internet games to escape or relieve a negative mood (e.g., feelings of
There is a debate whether IGD is the best clinical term for helplessness, guilt, anxiety).
diagnosing Internet addiction. For example, Young (Young, 1998) 9. Has jeopardized or lost a significant relationship, job, or educational or
considers online games a specific subtype of Internet activities, and career opportunity because of participation in Internet games.
she developed her Internet addiction criteria that were based on Note: Only non-gambling Internet games are included in this disorder. Use of
the Internet for required activities in a business or
the Diagnostic and Statistical Manual of Mental Disorders, Fourth
profession is not included; nor is the disorder intended to include other
Edition (DSM-IV) criteria for pathological gambling (American recreational or social Internet use. Similarly, sexual Internet sites are excluded.
Psychiatric Association, 1994). Her theory states that online game
Specify current severity:
addicts gradually lose control over their game play; that is, they are Internet gaming disorder can be mild, moderate, or severe depending on the
unable to decrease the amount of time spent playing while immers- degree of disruption of normal activities. Individuals
ing themselves increasingly in this particular recreational activity with less severe Internet gaming disorder may exhibit fewer symptoms and
and eventually develop problems in their real life (Young, 2009). less disruption of their lives. Those with severe
Internet gaming disorder will have more hours spent on the computer and
Table 1 describes the proposed inclusion criteria for IGD
more severe loss of relationships or career or school opportunities.
Surveys in the US and Europe have indicated prevalence rates
In Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5). 2013,
of between 1.5% and 8.2%, of the countrys population with vary-
American Psychiatric Association. pp. 795796.
ing diagnosis methods between countries (Durkee et al., 2012).
Cross-sectional studies on samples of patients reported high co-
morbidity of IGD with psychiatric disorders, especially affective reported differences between IGD group and control groups but
disorders, anxiety disorders and attention deficit hyperactivity dis- these differences do not imply a causal role of IGD. Group differ-
order (ADHD) (Weinstein et al., 2014; Weinstein and Aboujaoude, ences may reflect predisposing factors rather than decreases due
2015). Previous reviews have described brain-imaging studies in to IGD.
IGD until 2013 (Weinstein and Lejoyeux, 2015; Zhu et al., 2015;
Kuss and Griffiths, 2012). In view of the rapid developments in 1.1. Background- the neural mechanisms underlying reward and
brain research in IGD, this review will update these studies with the effects of drugs of abuse
new developments in brain imaging of IGD between 2013 and now.
Secondly, it will analyze these findings in relation to the three mod- There is a vast body of pre-clinical evidence that the dopaminer-
els proposed for IGD namely behavioral addiction, impulse control gic system mediates reward in general and the rewarding effects of
disorder and obsessive-compulsive disorder in order to improve drugs (Koob, 1992; Di Chiara and North, 1992; Wise, 1996; Di Chiara
our clinical definition and diagnosis of this disorder. Finally, we and Bassareo, 2007). The mesolimbic dopamine (DA) pathway that
will bring parallel evidence from brain imaging studies in patho- includes DA cells in ventral tegmental area projecting into nucleus
logical gambling which is now recognized as a behavioral addiction accumbens seems to be crucial for drug reward (Wise, 2009). Other
(American Psychiatric Association, 2013) and with compulsive sex- DA pathways such as the meso-striatal pathway includes DA cells in
ual disorder. substantia nigra projecting into dorsal striatum and meso-cortical
A PubMed search was conducted using the search terms Inter- pathway includes DA cells in the ventral tegmental area project-
net addiction Internet Gaming Disorder and Pathological Internet ing into frontal cortex are now also recognized as contributing to
use, each of which was combined with each of the terms brain drug reward and addiction (Wise, 2009). The mode of DA cell firing
imaging, or fMRI or PET or resting state using the conjunction also differently modulates the rewarding and conditioning effects,
AND. Each term was required to be present in the Title/Abstract of drugs (predominantly phasic DA cell firing) compared with the
of the paper. The search was further restricted by English as the changes in executive function that occur in addiction (predomi-
publication language and Publication Date from 2008 to May 2016. nantly tonic DA cell firing) (Wanat et al., 2009).
The only studies that were selected for the review were original Brain imaging studies using Positron Emission Tomography
research papers that were published in peer-reviewed journals. (PET) in humans showed that the stimulant drugs cocaine and
The search has yielded eligible 52 studies including 16 studies of methylphenidate released dopamine in the striatum (Volkow et al.,
the resting state, 13 studies of functional connectivity, 18 activa- 1996a) and there is further evidence that the dopaminergic striatal-
tion studies and 5 studies of pharmacology. As a general caution, thalamic-orbitofrontal circuit mediates the rewarding effects of
throughout this review, in making group comparisons, there are cocaine (Volkow et al., 1997a; Volkow et al., 1997b). Similarly,
316 A. Weinstein et al. / Neuroscience and Biobehavioral Reviews 75 (2017) 314330

cocaine administration in fMRI activated the ventral tegmental presumably enhanced the brain synchronization in sensory-motor
area, pons, basal forebrain, caudate, cingulate, and the lateral pre- coordination and decreased the excitability in visual and auditory
frontal cortex (Breiter et al., 1997). These studies support the related brain regions. This evidence is further supported by find-
theory that the dopaminergic striatal-thalamic-orbitofrontal cir- ings of enhanced ReHo measures in brainstem, cerebellum, limbic
cuit underlies compulsive drug use. lobe and frontal lobe in IGD college students (Liu et al., 2010).
Similarly to drug use disorders, the connections or synchroniza-
1.2. Brain imaging studies of the resting state in IGD tion among these regions shown by ReHo enhancement and the
frontal lobe corroborates the evidence for enhancement of reward
Resting state is a method of functional brain imaging that pathways. Finally, both IGD and alcohol use disorder participants
evaluates regional interactions that occur when a subject is not had increased ReHo in the posterior cingulate cortex whereas IGD
performing an explicit task. The resting state approach is use- patients had decreased ReHo in the superior temporal gyrus com-
ful to explore the brains functional organization and to examine pared with alcohol use disorder and healthy control participants
if it alters in neurological or psychiatric diseases (De Luca et al., (Kim et al., 2015). The increase in posterior cingulate cortex has
2006). Excessive Internet game use was associated with abnor- been associated with reward at uncertainty or reflecting risk pref-
mal resting state activity in the orbito-frontal cortex, striatum, erences in addiction. Reduced ReHo in the superior temporal gyrus
and sensory regions, which are responsible for impulse control, relates presumably to impairments in higher audio-visual infor-
reward processing, and somatic representation of previous expe- mation processing as well as response inhibition, although both
riences (Park et al., 2010). The study measured regional cerebral findings need to be replicated. In conclusion, there are brain regions
metabolic rates of glucose (rCMRglu) in PET in IGD and control par- that are only indirectly involved in drug addiction such as the
ticipants. The orbito-frontal cortex, striatum, and sensory regions parietal and occipital cortex. Furthermore, brain regions that are
are also associated with other types of impulse control disorders involved in memory (amygdala and hippocampus) and conscious
and substance/non-substance use disorder. The resting brain activ- urges to use drugs (insula) are involved in many other processes.
ity can be observed through changes in blood flow in the brain that However, these regions serve also for the function and maintenance
creates a blood-oxygen-level dependent (BOLD) signal that can be of drug addiction.
measured using fMRI (De Luca et al., 2006). Using the arterial spin-
labeling perfusion technique(footnote 1) in fMRI, adolescents with 1.3. Studies on the brains gray matter volume and white matter
IGD showed higher global Cerebral Blood Flow (CBF) in areas that density
are important for learning and memory (amygdala/hippocampus),1
conscious urges to use drugs (insula) executive function and inhibi- The brains gray matter is a major component of the central ner-
tion (pre-frontal cortex, anterior cingulate cortex and parietal lobe) vous system made up of neuronal cell bodies and it is involved in
(Feng et al., 2013). There were lower CBF measures in the middle motor control, perception, memory, emotions, and speech. A study
temporal gyrus, middle occipital gyrus, and cingulate gyrus. The that measured gray matter volume in fMRI together with perfor-
results so far indicate that IGD seems to share psychological and mance on the Monetary Incentive Delay task and the Cambridge
neural mechanisms with other types of impulse control disorders Gambling Task showed higher left striatal grey matter volume in
and substance use disorder (Volkow et al., 2010). Since there are frequent video game players that also negatively correlated with
only few publications that present structural changes in IGD, these deliberation time on the Cambridge Gambling Task (Kuhn et al.,
findings need to be replicated in the future. See Table 2 for structural 2011). Furthermore, there was enhanced activity in the left stria-
studies on the resting state in IGD. tum during feedback of loss compared with no loss on the Monetary
Another measure of brain connectivity in the resting state is Incentive Delay task in frequent video game players that negatively
regional homogeneity (ReHo) (footnote 2) in fMRI.2 ReHo rep- correlated with deliberation time on the task. An association of
resents the temporal homogeneity of the regional BOLD signal video game playing with higher left ventral striatum volume could
of fMRI, which may reflect neural activity. Therefore, abnormal reflect altered reward processing and represent adaptive neural
ReHo in certain regions of the brain may be associated with the plasticity in frequent videogame players. Other studies showed that
neurobiological impairments underpinning various neuropsychi- IGD participants had lower gray matter density in areas responsi-
atric disorders that involve temporal changes in disruption to local ble for behavioral and emotional problems (cingulate gyrus) urges
function. IGD individuals showed enhanced regional homogeneity (insula), and regulation of emotional behavior (lingual gyrus) which
(ReHo) in the brainstem, inferior parietal lobule, cerebellum, and are major concern in IGD (Zhou et al., 2011). Patients with IGD
middle frontal gyrus that relate with sensory-motor coordination showed increased gray matter volumes of the thalamus whereas
(Dong et al., 2012a). IGD individuals also had decreased ReHo in pro-gamers showed such increase in the cingulate gyrus and these
temporal, occipital and parietal brain regions that are responsible changes may be associated with the effects of gaming on attention
for visual and auditory functions. Long-time online game playing and sensory-motor coordination (Han et al., 2012). Furthermore,
lower diffusional kurtosis imaging (DKI footnote 3) was reported in
adolescents with IGD (Sun et al., 2014).3 These areas are associated
1
Arterial Spin labeling (ASL) The goal of Arterial Spin Labeling (ASL) methods is
with attention and control (anterior cingulate cortex), impulse con-
to image tissue perfusion. Perfusion is defined as the amount of blood delivered trol (orbito-frontal cortex), motor function (supplementary motor
to capillary beds in a given tissue per unit time. Because the microvasculature is area, primary motor cortex), emotional regulation (lingual gyrus),
too small to be spatially resolved using current MRI techniques, perfusion cannot and are compatible with models of drug addiction (Volkow et al.,
be measured by directly imaging blood flow using angiographic methods, and it is
2010). Finally, IGD adolescents showed reduced gray matter vol-
necessary to measure the net delivery of blood to each imaging voxel instead. The
general approach taken by ASL is to modify the magnetization of arterial blood, use ume of the anterior cingulate cortex, pre-cuneus, supplementary
this magnetically tagged blood as an endogenous tracer, and measure the delivery motor area, superior parietal lobule, dorsal lateral prefrontal cortex,
of the tracer to target tissues (Wolf and Detre, 2007).
2
Regional Homogeneity (ReHo) is a voxel-based measure of brain activity that
evaluates the similarity or synchronization between the time series of a given voxel
3
and its nearest neighbors (Zang et al., 2004). This measure is based on the hypothesis Diffusional kurtosis imaging (DKI) extends conventional diffusion tensor imag-
that intrinsic brain activity is manifested by clusters of voxels rather than single ing (DTI) by estimating the kurtosis of the water diffusion probability distribution
voxels. ReHo requires no a priori definition of ROIs and can provide information function. Qualitatively, a large diffusional kurtosis suggests a high degree of diffu-
about the local/regional activity of regions throughout the brain. sional heterogeneity and microstructural complexity (Jensen et al., 2005).
Table 2
Resting state and structural studies of internet and gaming disordera .

Citation Methods Participants Main Findings

Park et al. (2010) Regional cerebral metabolic rates of Eleven Internet and gaming overusers Increased activity in the OFC, striatum, and sensory regions.
glucose (rCMRglu) in Positron and nine control participants
Emission Tomography (PET)
Liu et al. (2010) Regional homogeneity (ReHo) measure Nineteen IGD college students (11 Enhanced ReHo in the cerebellum, brainstem, right cingulate gyrus, bilateral para-hippocampus,
in MRI males 8 females) and nineteen control right frontal lobe (rectal gyrus, inferior frontal gyrus and middle frontal gyrus), left superior
partcipants. frontal gyrus, left pre-cuneus, right post-central gyrus, right middle occipital gyrus, right inferior
temporal gyrus, left superior temporal gyrus and middle temporal gyrus
Kuhn et al. (2011) Gray matter volume measure in MRI Seventy six frequent compared with Higher left striatal gray matter volume
seventy eight infrequent adolescent Left striatal grey matter volume negatively correlated with deliberation time on Cambridge
video game players (14 years old). Gambling Task
Activity on the Monetary Incentive Delay task was enhanced during feedback of loss compared
with no loss.
Zhou et al. (2011) Gray matter volume measure in MRI Eighteen Internet addicted adolescents Lower gray matter density in the left ACC, left PCC, left insula, and left lingual gyrus
(16 males 2 females) and fifteen
control participants (13 males)
Yuan et al. (2011) White matter fractional anisotropy Eighteen adolescents with IGD (12 Decreased gray matter volume in the bilateral DLPFC, the SMA, the OFC, the cerebellum and the
(FA) changes using the diffusion tensor males) and eighteen control left rostral ACC
imaging (DTI) in MRI participants. Enhanced FA value of the left PLIC and reduced FA value in the white matter within the right PHG.
Gray matter volumes of the DLPFC, rACC, SMA, and white matter FA changes of the PLIC correlated
with the duration of internet addiction.
Dong et al. Regional homogeneity (ReHo) measure Fifteen Internet and gaming disorder Enhanced regional homogeneity (ReHo) in the brainstem, inferior parietal lobule, left posterior
(2012a,b,c,d) in MRI and fourteen control paritcipants cerebellum, and left middle frontal gyrus, decreased ReHo in temporal, occipital and parietal
cortex.
Han et al. (2012) Gray matter volume measure in MRI Twenty IGD participants, eighteen Increased impulsiveness and perseverative errors, and volume in left thalamus gray matter, but
male control participants and decreased gray matter volume in inferior temporal gyri, right middle occipital gyrus, and left
seventeen pro-gamers. inferior occipital gyrus.
Lin et al. (2012) Brain white matter integrity measured Seventeen Internet Addiction Disorder Lower FA in the OFC, corpus callosum, cingulate, inferior frontal-occipital fasciculus, and corona
by Diffusion Tensor Imaging (DTI) in (14 males) and sixteen control radiation, internal and external capsules,
MRI. Whole brain voxel-wise analysis adolescents. FA values in the left genu of the corpus callosum negatively correlated with scores on the Screen
of fractional anisotropy (FA) was for Child Anxiety Related Emotional Disorders, and between FA values in the left external capsule
performed by tract-based spatial and Youngs Internet addiction scale.
A. Weinstein et al. / Neuroscience and Biobehavioral Reviews 75 (2017) 314330

statistics (TBSS)
Dong et al. (2012a,b,c,d) White matter integrity using diffusion Sixteen Internet Gaming Addicted Higher fractional anisotropy (FA), in the thalamus and left PCC. Higher FA in the thalamus was
tensor imaging (DTI) in MRI participants and fifteen control associated with greater severity of internet addiction.
participants.
Weng et al. (2013) Gray matter density and white matter Seventeen IGD participants (13 females Gray matter atrophy in the right OFC, bilateral insula, and right supplementary motor area.
density changes using Voxel-based and 4 males) and seventeen control Reduced FA in the right genu of corpus callosum, bilateral frontal lobe white matter, and right
morphometry (VBM) analysis and participants (15 females 2 males). external capsule.
tract-based spatial statistics (TBSS) Gray matter volumes of the right OFC, bilateral insula and FA values of the right external capsule
was reported by positively correlated with Young Internet Addiction scores.
317
318

Table 2 (Continued)

Citation Methods Participants Main Findings

Hong et al. (2013a,b) Cortical thickness in MRI Fifteen male adolescents diagnosed Decreased cortical thickness in the right lateral OFC.
with internet addiction and fifteen
male control participants.
Yuan et al. (2013) Cortical thickness in MRI. Eighteen adolescents with internet Increased cortical thickness in the left precentral cortex, precuneus, inferior middle frontal cortex
gaming disorder and eighteen control temporal and middle temporal cortices.
participants. Decreased cortical thicknesses of the left lateral OFC, insula, lingual gyrus, the right postcentral
gyrus,entorhinal cortex and inferior parietal cortex.
cortical thicknesses of the left precentral cortex, pre-cuneus and lingual gyrus correlated with
duration of online gaming addiction and the cortical thickness of the orbito-frontal cortex
correlated with the impaired task performance during the color-word Stroop task.
Sun et al. (2014) Diffusional kurtosis imaging (DKI) in Eighteen participants with Internet Lower gray matter diffusion in the right anterolateral cerebellum, right inferior and superior
the detection of gray matter diffusion Gaming Disorder and twenty one temporal gyri, right SMA, middle occipital gyrus, right pre-cuneus, postcentral gyrus, right inferior
control participants. frontal gyrus, left lateral lingual gyrus, left paracentral lobule, left ACC, and median cingulate
cortex, bilateral fusiform gyrus, insula, PCC, and thalamus.
Higher GM volume in the right inferior and middle temporal gyri, and right PHG, and lower
volume in the left precentral gyrus.
Wang et al. (2015a,b) Gray matter volume measure in MRI Twenty-eight internet participants Gray matter volume of the bilateral ACC, pre-cuneus, SMA, SPL, left DLPFC, left insula, and bilateral
with Internet Gaming Disorder and cerebellum decreased in IGD participants compared with healthy control participants.
twenty-eight control participants Gray matter volume of the ACC negatively correlated with the incongruent response errors on the
Stroop
Kim et al. (2015) Regional homogeneity (ReHo) measure Sixteen patients with Internet gaming IGD and AUD participants had increased ReHo in the PCC. IGD participants showed decreased
in MRI addiction (IGD), fourteen alcohol use ReHo in the right superior temporal gyrus compared with AUD and control participants. Patients
disorder (AUD) and fifteen control with AUD showed decreased ReHo in the ACC.
participants.
Lin et al. (2015a,b) Gray matter density and white matter Thirty five participants with Internet Higher FA in the thalamus and left PCC
density changes using voxel-based Gaming Disorder and thirty six control Higher FA in the thalamus was associated with greater severity of internet addiction
morphometric analysis in MRI. participants.
Takeuchi et al. (2016) Diffusion tensor imaging mean A hundred and fourteen boys and a The amount of videogame play was associated with increased MD in the left middle, inferior, and
diffusivity (MD) hundred and twenty six girls orbital frontal cortex; left pallidum; left putamen; left hippocampus; left caudate; right putamen;
right insula; and thalamus in both cross-sectional and longitudinal analyses.
A. Weinstein et al. / Neuroscience and Biobehavioral Reviews 75 (2017) 314330

Higher MD in the areas of the left thalamus, left hippocampus, left putamen, left insula, and left
Heschl gyrus was associated with lower intelligence.

Abbreviations;: dorsolateral prefrontal cortex (DLPFC) Supplementary Motor Area (SMA) Orbito-Frontal Cortex (OFC), Anterior Cingulate Cortex (ACC) Posterior Limb of the Internal Capsule (PLIC), Para-Hippocampal Gyrus (PHG),
Posterior Cingulate Cortex (PCC), Superior Temporal gyrus (STG), Medial Prefrontal Cortex (MPFC), Angular Gyrus (AG), Superior Parietal Lobule (SPL).
a
Studies arranged chronologically.
A. Weinstein et al. / Neuroscience and Biobehavioral Reviews 75 (2017) 314330 319

Fig. 1. Regions that showed reduced gray matter volume in IGD participants in more than two studies- anterior cingulate (Zhou et al., 2011; Yuan et al., 2011; Wang et al.,
2015a,b) supplementary motor area (Wang et al., 2015a,b; Weng et al., 2013; Sun et al., 2014) Cerebellum (Yuan et al., 2011; Wang et al., 2015a,b) Insula (Zhou et al., 2011;
Weng et al., 2013; Sun et al., 2014; Wang et al., 2015a,b) Inferior Temporal gyrus (Han et al., 2012; Sun et al., 2014).

insula, and bilateral cerebellum (Wang et al., 2015a). These findings optimized voxel-based morphometry (VBM) technique (footnote
are compatible with previous studies on gray matter volume in IGD 7) in adolescents with IGD.7 Decreased gray matter volume
(Zhou et al., 2011; Yuan et al., 2011; Ko et al., 2013a; Weng et al., in areas responsible for attention, motor and cognitive control
2013). Moreover, gray matter volume of the anterior cingulate cor- (dorso-lateral prefrontal cortex, anterior cingulate cortex and
tex negatively correlated with the incongruent response errors of supplementary motor area and reduced white matter in areas
Stroop task that is a measure of cognitive control mechanism (Wang responsible for memory encoding and retrieval (para-hippocampal
et al., 2015a). Since few studies present structural changes in gray gyrus) and relaying sensory and motor information (limb of the
matter in IGD, these findings need further replication. internal capsule) were reported by Yuan et al. (2011). There was
Fig. 1 shows brain regions with reduced gray matter volume in further evidence for gray matter atrophy in the right orbito-frontal
frequent IGD players. cortex, bilateral insula, and right supplementary motor area in IGD
The brains white matter is another component of the central (Weng et al., 2013). They also had reduced FA in the right genu of
nervous system that consists mostly of glial cells and myelinated the corpus callosum, bilateral frontal lobe white matter, and right
axons that transmit signals from cerebellum to other brain cen- external capsule. Lower gray matter density in areas responsible
ters. Diffusion Tensor Imaging (DTI) (footnote 4) evaluated brain for cognitive and motor control (orbito-frontal cortex and supple-
white matter integrity by measuring Fractional anisotropy (FA) mentary motor area) and reduced white matter in areas responsible
(footnote 5) in adolescents with IGD and control participants (Lin for cognitive planning and control (frontal lobe and external cap-
et al., 2012).4 High FA indicates greater white matter integrity.5 sule) were reported (Lin et al., 2015a). IGD participants also showed
The analysis of FA by tract-based spatial statistics (TBSS) (footnote lower white matter density in the inferior frontal gyrus, insula,
6) demonstrated lower FA in the orbito-frontal cortex, corpus cal- amygdala, and anterior cingulate cortex brain regions that are
losum, cingulate, inferior frontal-occipital fasciculus,6 and corona involved in decision-making, behavioral inhibition and emotional
radiation, internal and external capsules in IGD participants and FA regulation. IGD participants showed reduced FA the anterior cingu-
values in the left external capsule correlated with Youngs Inter- late cortex and right dorsolateral-prefrontal cortex pathways and
net addiction scale. Both findings possibly reflect negative changes they were associated with executive function measured on the
in white matter density as result of game play. IGD participants Stroop task (Yuan et al., 2016). Finally, a study on a large sample
also showed higher FA in the thalamus and left posterior cingulate of school children in Japan used diffusion tensor imaging mean
cortex relative to healthy control participants presumably indicat- diffusivity (MD) measurement (Takeuchi et al., 2016). Increased
ing greater white matter integrity (Dong et al., 2012d). Secondly, videogame play was associated with delayed development of the
higher FA in the thalamus was associated with greater severity of microstructure in extensive brain regions such as the orbito-frontal
IGD but it unclear whether this is a pre-existing vulnerability fac- cortex, pallidum, putamen, hippocampus, caudate/putamen insula
tor, or may arise secondary to IGD, perhaps as a direct result of and the thalamus. Furthermore, higher MD in the areas of the tha-
excessive Internet game playing. lamus, hippocampus, putamen and the insula was associated with
Further studies combined measurement of white matter FA lower intelligence.
changes and gray matter volume using DTI analysis and an Since there are few studies that present structural changes in
IGD, replication of these findings is required. Furthermore, these
are cross-sectional studies precluding any inference on causality.
4
Diffusion tensor imaging (DTI) is be used to map and characterize the three-
dimensional diffusion of water as a function of spatial location (Alexander et al.,
2007). The diffusion tensor describes the magnitude, the degree of anisotropy, and
the orientation of diffusion anisotropy. Estimates of white matter connectivity pat-
terns in the brain can be obtained using diffusion anisotropy.
5
Fractional anisotropy (FA) reflects the directionality of water diffusion and
coherence of white matter fiber tracts. FA is a measure often used in diffusion imag-
7
ing where it is thought to reflect fiber density, axonal diameter, and myelination in Volume Based Morphometry (VBM) aims to identify differences in the local com-
white matter (Smith et al., 2006). position of brain tissue, while discounting large scale differences in gross anatomy
6
Track Based Spatial Statistics (TBSS) analyses are fully automated, simple to and position. This is achieved by spatially normalizing all the structural images to
apply and investigate the whole brain. It does not require pre-specifying and pre- the same stereotactic space, segmenting the normalized images into gray and white
localizing regions or features of interest. Limitations include problems caused by matter, smoothing the gray and white matter images and finally performing a statis-
alignment inaccuracies, and the lack of a principled way for choosing smoothing tical analysis to localize significant differences between two or more experimental
extent (Smith et al., 2006). groups (Mechelli et al., 2005).
320 A. Weinstein et al. / Neuroscience and Biobehavioral Reviews 75 (2017) 314330

1.4. Cortical thickness nitive control and craving in the addictive brain is unique to drug
addiction.
A study that measured cortical thickness in fMRI together with The activity in the anterior and middle cingulate and thala-
the color-word Stroop task revealed increased cortical thickness mus correlated with the IGD severity and impulsivity. Disruption
in the left precentral cortex, pre-cuneus, and middle frontal cor- in functional connectivity may also affect motivation and reward.
tex, inferior temporal and middle temporal cortices in adolescents Smokers with IGD exhibited decreased functional connectivity with
with IGD (Yuan et al., 2013). The cortical thicknesses of the left posterior cingulate cortex in the right rectus gyrus compared with
lateral orbito-frontal cortex, insula, lingual gyrus, the right postcen- non-smokers IGD (Chen et al., 2014). The rectus gyrus is part of the
tral gyrus, entorhinal cortex and inferior parietal cortex decreased. orbito-frontal cortex, which is involved in the evaluation of reward
The cortical thickness of the orbito-frontal cortex correlated with of stimuli and the explicit representation of reward expectancy for
impaired performance on the color-word Stroop task. Male ado- substances.
lescents with IGD had also shown decreased cortical thickness in
the right lateral orbito-frontal cortex compared with control par- 2.2. Functional connectivity, reward and the striatum
ticipants (Hong et al., 2013a). The apparent contradiction between
the two studies showing increased and decreased cortical thickness Lower functional connectivity in IGD affected executive control
seems to suggest that the changes are not robust and merit further networks and it negatively correlated with the Stroop effect (Dong
investigation. et al., 2015). Impulsivity also correlated negatively with functional
connectivity in the amygdala, dorso-lateral prefrontal cortex and
the orbito-frontal cortex (Ko et al., 2015) and it was associated with
2. Functional connectivity
alterations over the frontal-limbic connections (Park et al., 2015).
Consistent with the evidence of the role of motivation and reward in
Functional connectivity is the temporal dependency of neuronal
drug addiction, there is evidence that the striatum plays an impor-
activation patterns of anatomically separated brain regions. In the
tant role in the underlying pathophysiology of IGD. Adolescents
past years, an increasing body of neuroimaging studies has started
with IGD showed significantly reduced dorsal putamen functional
to explore functional connectivity by measuring the level of co-
connectivity with the posterior insula-parietal operculum (Hong
activation of resting-state fMRI time-series between brain regions
et al., 2015). IGD participants also showed increased volumes of
(van den Heuvel and Hulshoff Pol, 2010). See Table 3 for studies of
dorsal striatum (caudate) and ventral striatum (nucleus accum-
Functional connectivity in IGD.
bens) (Cai et al., 2015). In addition, caudate volume correlated with
Stroop task performance and NA volume was associated with the
2.1. Functional connectivity at a resting state Internet addiction test (IAT) score in the IGD group. The insula
that plays a key role in the manifestation of urges for drugs is also
Participants with IGD exhibited increased functional connectiv- associated with the core symptoms of IGD. IGD participants exhib-
ity between the cerebellum, posterior lobe and middle temporal ited enhanced resting state functional connectivity between the
gyrus and decreased connectivity between the inferior parietal anterior insula and the anterior cingulate cortex, putamen, angular
lobule and right inferior temporal gyrus compared with partic- gyrus, and pre-cuneous, areas that are involved in salience, crav-
ipants without IGD (Ding et al., 2013). The increased functional ing, self-monitoring, and attention (Zhang et al., 2015). Finally, IGD
connectivity in the bilateral posterior cerebellum may be associ- participants had decreased connectivity measures between the left
ated with cognitive regulation, signal processing, and storage of and right superior, inferior and middle frontal gyrus (Wang et al.,
relevant auditory-verbal memory processes. The decreased con- 2015b).
nectivity in the inferior temporal gyrus may be the result of a In conclusion, participants with IGD showed reduced con-
long duration of game playing (Dong et al., 2012c). These alter- nectivity in several areas including the cerebellum, amygdala,
ations are consistent with those in patients with substance use orbito-frontal cortex and dorso-lateral prefrontal cortex, striatum,
disorder, thus suggesting that IGD may share similar neurobiolog- anterior cingulate cortex, thalamus and the insula. These functional
ical abnormalities with substance use disorder (Ma et al., 2010). brain networks are responsible for executive function, cognitive
Chronic heroin users showed increased functional connectivity control, sensory processing motivation and reward and they are
between nucleus accumbens and ventral/rostral anterior cingulate common to IGD and substance use disorders. As mentioned earlier,
cortex, between nucleus accumbens and orbital frontal cortex, and in making group comparisons, group differences between IGD users
between amygdala and orbito-frontal cortex and reduced func- and control participants may reflect predisposing factors rather
tional connectivity between prefrontal cortex and orbito-frontal than decreases due to IGD. Furthermore, there are only few stud-
cortex and between prefrontal cortex and anterior cingulate cortex ies with several regions that have been replicated so the evidence
(Ma et al., 2010). Consistent with current models emphasizing the needs to be interpreted with caution.
role of cortico-subcortical pathology in addiction (Sutherland et al.,
2012), adolescents with IGD also showed reduced functional con- 3. Brain activation
nectivity in cortical-subcortical circuits (pre-frontal and parietal
cortex), the putamen and the insula (Hong et al., 2013b). IGD ado- Many studies of brain function with PET or fMRI involve
lescents also had disruption in the functional connectivity in areas the interpretation of a subtracted PET/fMRI image, usually the
responsible for learning memory and executive function (ante- difference between two images under baseline and stimulation
rior cingulate cortex and middle cingulate), processing of auditory, conditions. The purpose of these studies is to see which areas of
visual, and somato-sensory stimuli (inferior parietal lobe) and relay the brain activated the stimulation condition (Worsley et al., 1996).
of sensory and motor signals (thalamus) (Wee et al., 2014). Other See Table 4 for activation studies of IGD in fMRI
disorders such as impulse control disorders and attention disor-
ders also show impaired functional connectivity of brain networks 3.1. Cue-exposure activation studies of videogame urges
responsible for executive function and sensory processing. How-
ever, the enhanced resting-state functional connectivity within the The first brain activation study in IGD participants has used
regions associated with reward, memory, craving and motivation, an fMRI procedure to measure contrasts between a space-
and reduced connections within the regions associated with cog- infringement game and a control task (Hoeft et al., 2008). Males
Table 3
Studies of Functional connectivity in fMRIa .

Citation Method Participants Main findings

Ding et al. (2013) Functional connectivity in fMRI Seventeen adolescents with Internet Increased functional connectivity in the bilateral cerebellum posterior lobe and middle temporal gyrus.
Gaming Disorder and twenty four Decreased connectivity in the bilateral inferior parietal lobule and right inferior temporal gyrus
control adolescents. Connectivity with the PCC positively correlated with Internet Addiction Scores in the right pre-cuneus, PCC, thalamus,
caudate, nucleus accumbens, SMA, and lingual gyrus. It negatively correlated with the right cerebellum, anterior lobe
and left SPL.
Hong et al. (2013a,b) Functional connectivity in fMRI Twelve adolescents with internet Reduced functional connectivity in cortico-subcortical circuits (24% with Pre-frontal and 27% with parietal cortex).
addiction and eleven control Bilateral putamen was the most extensively involved subcortical brain region.
participants.
Feng et al. (2013) Arterial spin-labeling (ASL) Fifteen adolescents with IGA and Higher global Cerebral Blood Flow (CBF) in the left inferior temporal lobe/Fusiform gyrus, left PHG/amygdala, right
perfusion in fMRI eighteen control adolescents. medial frontal lobe/ACC, left and right insula, right middle temporal gyrus, right pre-central gyrus, left SMA, left
cingulate gyrus, and right inferior parietal lobe.
Lower CBF in the left middle temporal gyrus, left middle occipital gyrus, and right cingulate gyrus.
Wee et al. (2014) Functional connectivity in fMRI Seventeen adolescents with IGD and Disruption in the functional connectivity with the frontal, occipital, and parietal lobes.
sixteen control participants. Functional connectivity with the frontal, occipital, and parietal lobes correlated with the IAD severity.
Chen et al. (2014) Functional connectivity in fMRI Twenty-nine smokers with IGD, Decreased resting state functional connectivity with posterior cingulate cortex in the right rectus gyrus. Increased
twenty two nonsmokers with IGD, and resting state functional connectivity with the left middle frontal gyrus in smokers with IGA compared with
thirty control participants. nonsmokers with IGA.
Dong et al. (2015) Functional connectivity in fMRI Thirty-five IGD and thirty six control Lower functional connectivity in executive control networks
participants. functional-connectivity measures in executive control networks were negatively correlated with Stroop effect and
positively correlated with brain activations in executive-control regions across groups.
Ko et al. (2015) Gray matter density (GMD) and Thirty males with IGD and thirty Lower GMD in the bilateral amygdala and higher impulsivity. Lower functional connectivity with the left amygdala
Functional connectivity in fMRI control participants. over the left DLPFC and with the right amygdala over the left DLPFC and OFC.
Higher functional connectivity with the bilateral amygdala over the contralateral insula.
The functional connectivity between the left amygdala and DLPFC negatively correlated with impulsivity. The
functional connectivity of the right amygdala to the left DLPFC and OFC also negatively correlated with impulsivity.
Hong et al. (2015) Functional connectivity in fMRI Twelve male adolescents with internet Reduced dorsal putamen functional connectivity with the posterior insula-parietal operculum.
in subdivisions of striataum gaming disorder and eleven male Time spent playing online games predicted significantly greater functional connectivity between the dorsal putamen
control participants. and bilateral primary somatosensory cortices
Lower functional connectivity between the dorsal putamen and bilateral sensorimotor cortices in healthy control
participants.
Cai et al. (2015) Functional connectivity in fMRI Twenty-seven adolescents with IGD Increased volumes of dorsal striatum (caudate) and ventral striatum (nucleus accumbens) and more errors on the
in striatal nuclei (caudate, and thirty control participants. Stroop task. Caudate volume correlated with Stroop task performance and nucleus accumbens (NAc) volume was
putamen, and nucleus associated with the internet addiction test (IAT) score in the IGD group.
accumbens) volumes
Wang et al. (2015a,b) Functional connectivity and Seventeen participants with IGD and Decreased VMHC between the left and right superior frontal gyrus (orbital part), inferior frontal gyrus (orbital part),
voxel-mirrored homotopic twenty four healthy control middle frontal gyrus and superior frontal gyrus.
connectivity (VMHC) method participants.
Zhang et al. (2015) Functional connectivity of the Seventy four young adults with Enhanced functional connectivity between the anterior insula and a network of regions including ACC, putamen,
A. Weinstein et al. / Neuroscience and Biobehavioral Reviews 75 (2017) 314330

insula in fMRI Internet gaming disorder (IGD) and angular gyrus, and pre-cuneous.
forty one control participants. Stronger functional connectivity between the posterior insula and postcentral gyrus, pre-central gyrus, SMA, STG. IGD
severity was positively associated with connectivity between the anterior insula and AG, and STG, and with
connectivity between the posterior insula and STG.
Duration of Internet gaming was positively associated with connectivity between the anterior insula and ACC.
Park et al. (2015) Functional connectivity in fMRI Nineteen Internet gaming disorder Higher impulsiveness and higher global efficiency and lower local efficiency pathological states
adolescents and twenty age-matched Topological alterations were specifically attributable to inter-regional connections incident on the frontal region, and
control participants. the degree of impulsiveness was associated with the topological alterations over the frontal-limbic connections.
Yuan et al. (2016) Functional connectivity in fMRI Twenty-eight IGD adolescents and Reduced FA in salience network, right central executive network tracts, and between-network (the ACC-right DLPFC
twenty-five control participants tracts).
Correlation between the effective and structural connection from salience network to central executive network and
the number of errors during incongruent condition in Stroop task in both IGD and control participants.

Abbreviations: dorsolateral prefrontal cortex (DLPFC) Supplementary Motor Area (SMA) Orbito-Frontal Cortex (OFC), Anterior Cingulate Cortex (ACC) Posterior Limb of the Internal Capsule (PLIC), Para-Hippocampal Gyrus (PHG),
Posterior Cingulate Cortex (PCC), Superior Temporal gyrus (STG), Medial Prefrontal Cortex (MPFC), Angular Gyrus (AG), Superior Parietal Lobule (SPL).
a
Studies arranged chronologically.
321
322

Table 4
Activation studiesa .

Citation Methods Participants Main findings

Hoeft et al. (2008) Brain activation contrasting a Eleven males and eleven female Males showed greater activation and functional connectivity compared to females in the meso-cortico-limbic system.
space-infringement game with healthy students.
a control task in fMRI
Ko et al. (2009) Brain activation using gaming Ten participants with IGD and ten The right orbitofrontal cortex, right nucleus accumbens, bilateral ACC and medial frontal cortex,
pictures and neutral pictures control participants. right DLPFC, and right caudate nucleus were activated in the addicted group.
together with fMRI scanning. The activation of the region-of-interest (ROI) defined by the above brain areas was positively
correlated with self-reported gaming urges and recalling of gaming experience.
Han et al. (2010a,b) Responses to Internet Eleven male participants with online Activation of ACC and OFC in response to video-game cues.
video-game cues in the gaming addiction and eight control The change of craving for Internet video games positively correlated with the change in activity of
Orbito-frontal and cingulate participants. the ACC.
cortices in fMRI
Dong and Huang (2011) A guessing task measuring Fourteen male Internet addicts and Increased activation in OFC cortex in gain trials and decreased anterior cingulate activation in loss
monetary gain and loss in fMRI thirteen male control participants. trials.
Sun et al. (2012) The World of Warcraft (WoW) Ten participants with internet and DLPFC, bilateral temporal cortex, cerebellum, right inferior parietal lobule, right cuneus, right
game figures with fMRI gaming disorder and ten control hippocampus, para-hippocampal gyrus and the left caudate nucleus were activated.
participants. Craving measures were positively associated with activity in the bilateral pre-frontal cortex, ACC
and right inferior parietal lobe.
Kim et al. (2012) A ball-throwing animation task Seventeen adolescent internet and Activation in the thalamus, bilateral precentral area, bilateral middle frontal area, and the right
in fMRI gaming disorder participants and temporal-parietal junction.
seventeen control adolescents. Higher activation in the left temporal-parietal-occipital junction, right para-hippocampal area.
The duration of internet use correlated with the activity of posterior area of left middle temporal
gyrus.
Dong et al. (2012a,b,c,d) The Stroop task and an Twelve male Internet gaming disorder Higher activations in the left AG during avatar-perception.
event-related fMRI participants and twelve control A positive correlation between gender identity and brain activation in the left AG during
participants. self-perception.
Ko et al. (2013a) Gaming pictures and neutral Fifteen participants with internet and Brain activity in bilateral DLPFC, pre-cuneus, left PHG, PCC and right ACC were activated in
pictures in fMRI scanning. gaming disorder and fifteen remitted response to gaming cues.
IGD participants and fifteen control Higher activation over right DLPFC and left PHG than the remission group.
participants.
Ko et al. (2013b) Images associated with online Sixteen participants with both IGD and The ACC and the PHG were activated in both cue-induced gaming urge and smoking craving
A. Weinstein et al. / Neuroscience and Biobehavioral Reviews 75 (2017) 314330

games, smoking, and neutral nicotine dependence and sixteen among the comorbid group in comparison to the control group.
images in fMRI. control participants.
Lorenz et al. (2013) A dot probe paradigm with Eight male Internet gaming disorder Greater brain responses in short-presentation trials in MPFC and ACC and in long-presentation
short-presentation (attentional participants and nine control trials in lingual gyrus.
bias) and long-presentation participants.
(cue reactivity) trials in fMRI
Stroop effect-related activity in the ACC PCC Diminished efficiency of response-inhibition
processes
Dong et al. (2013) A continuous wins-and-losses Sixteen male IGD participants and Longer response time, lower repeat rate and greater Stroop effect.
task to monitor fifteen control participants. Increased brain activities in the inferior frontal cortex, insula, ACC.
decision-making in fMRI Decreased activation in the caudate and PCC after continuous wins.
Increased brain activities in the inferior frontal gyrus and decreased brain activation in the PCC
after continuous losses.
Lemnager et al. (2014) Images of Massively Sixteen Internet gaming disorder Decreased bilateral brain activations in the AG and the Middle Occipital gyrus during
Multiplayer Online participants and seventeen control self-perception.
Role-Playing Games participants.
(MMORPGs) during fMRI.
Liu et al. (2014) Go/NoGo tasks with/without Eleven Internet gaming disorder and The control group increased brain activations in the right DLPFC and SPL under gaming cue
gaming distraction in the fMRI. eleven control participants. distraction in comparison with the IGD group.
Brain activation of the right DLPFC and SPL were negatively associated with performance of
response inhibition among the IGD group.
Ko et al. (2014) Response inhibition using fMRI Twenty six subjects with Internet Higher score for impulsivity and higher brain activation in the left OFC and bilateral caudate
gaming disorder and twenty three nucleus. Both groups exhibited activation of the insula and ACC during error processing.
control participants.
Ding et al. (2014) A response-inhibition using Go/No-Go task in fMRI. Seventeen adolescents with IGD and Increased activity during No-Go trials in the left superior medial frontal gyrus, right ACC, right
seventeen control participants superior/middle frontal gyrus, left inferior parietal lobule, left precentral gyrus, and left
pre-cuneus and cuneus.
The bilateral middle temporal gyrus, bilateral inferior temporal gyrus, and right SPL showed
decreased activity.
Activation of the left superior medial frontal gyrus was positively associated with Barratt
Impulsivity Scale and Chen Internet Addiction Scale (CIAS)
Lin et al. (2014) A probability-discounting task with fMRI. Nineteen IGD participants and 21 Decreased activation in the inferior frontal gyrus and the precentral gyrus when choosing the
control participants. probabilistic options.
Chen et al. (2015) Response inhibition using Go/No go task in fMRI. Fifteen men with IGD for at least 1 Higher impulsivity and lower activity of the right SMA/pre-SMA activation of the right SMA,
year, and 15 control participants. DLPFC, and caudate for response inhibition in control group.
Liu et al. (2016) Task-state in fMRI. 19 Internet gaming disorder . Increased activation in the right SPL, right insular lobe, right pre-cuneus, right cingulate gyrus,
individuals and 19 control participants. right STG, and left brainstem.
A. Weinstein et al. / Neuroscience and Biobehavioral Reviews 75 (2017) 314330

Abbreviations;: dorsolateral prefrontal cortex (DLPFC) Supplementary Motor Area (SMA) Orbito-Frontal Cortex (OFC), Anterior Cingulate Cortex (ACC) Posterior Limb of the Internal Capsule (PLIC), Para-Hippocampal Gyrus (PHG),
Posterior Cingulate Cortex (PCC), Superior Temporal gyrus (STG), Medial Prefrontal Cortex (MPFC), Angular Gyrus (AG), Superior Parietal Lobule (SPL).
a
Studies arranged chronologically.
323
324 A. Weinstein et al. / Neuroscience and Biobehavioral Reviews 75 (2017) 314330

showed greater activation and functional connectivity compared to inhibition processing, and left orbito-frontal cortex and ventral
females in the meso-cortico-limbic system. These findings may be striatum that are associated with cue reactivity in IGD participants
attributable to higher motivational states in males, as well as gen- (Lorenz et al., 2013).
der differences in reward prediction, learning reward values, and Finally, IGD adolescents showed activation of thalamus, bilateral
cognitive state during computer video game playing. These gen- precentral area, bilateral middle frontal area, the right temporal-
der differences may help explain why males are more attracted parietal junction and the right para-hippocampal gyrus during
to, and more likely to become hooked on video games. The fol- ball-throwing animations simulating the experience of disembod-
lowing study has shown gaming pictures and neutral pictures in ied state in cyberspace (Kim et al., 2012). Massively multi player
fMRI to IGD and control participants (Ko et al., 2009). The IGD online role players showed decreased activation of the angular
group showed activation of the right hemispheric orbito-frontal gyrus and the middle occipital gyrus during evaluating of their own
cortex, nucleus accumbens, bilateral anterior cingulate cortex and body image, areas that have been associated with visual-spatial
medial frontal cortex, right dorso-lateral prefrontal cortex, and attention and body self-awareness (Lemnager et al., 2014). In con-
right caudate nucleus. The activation of these regions positively clusion, several studies have shown a consistent pattern of brain
correlated with self-reported gaming urges and recalling of gaming regions that were activated in response to video playing stim-
experience provoked by the gaming pictures. The neural substrate uli. Fig. 2 shows brain regions that were activated in response to
of cue-induced gaming urge/craving in online gaming disorder is videogame cues in frequent IGD players.
therefore similar to that of the cue-induced craving in substance
use disorder. 3.2. Inhibitory control mechanisms
Since then, several studies have followed changes in gaming
cue-induced brain activity in IGD. They have followed changes in Similarly to substance and alcohol use disorder, individuals
brain activity between baseline and following 6 weeks of Internet with IGD may display faulty inhibitory control mechanism. IGD
video-game play using fMRI (Han et al., 2010a). During a standard- participants showed diminished efficiency of response-inhibition
ized 6-week video-game play period, brain activity in the anterior processes indicated by greater Stroop effect-related activity in the
cingulate cortex and orbito-frontal cortex of the IGD group but not anterior and posterior cingulate cortex (Dong et al., 2012b). IGD
in the control group, increased in response to Internet video-game participants also committed more commission errors on Go/No Go
cues. In addition, the change of craving for Internet video games tasks when a gaming picture presented at the background (Liu et al.,
positively correlated with the change in activity of the anterior 2014). The results indicate an impaired function of response inhi-
cingulate cortex in all participants. These changes in Frontal-lobe bition in IGD under gaming distraction and a lack of activation of
activity with extended video-game play may be similar to those the dorso-lateral prefrontal cortex and superior parietal lobule that
observed during the early stages of addiction. A following study help keeping cognitive control and attention allocation for response
showed that gaming cues activated bilateral dorso-lateral pre- inhibition under gaming cue distraction. There is further evidence
frontal cortex, pre-cuneus, left para-hippocampus gyrus, posterior for impulsivity and response inhibition and impaired function in
cingulate cortex and right anterior cingulate cortex in the IGD group the insula during error processing and greater activation of the
(Ko et al., 2013b). These regions also positively correlated with frontal-striatal network in order to maintain response inhibition
subjective gaming urge during cue exposure. The IGD group had performance in IGD (Ko et al., 2014). IGD participants perform-
also stronger activation over right dorso-lateral prefrontal cortex ing the Go/No Go task in fMRI also showed greater impulsivity
and left para-hippocampal gyrus than a group of remitted former and lower activity of the right supplementary motor area/pre-
IGD players. The two areas could be candidate markers for cur- supplementary motor area (Chen et al., 2015). In adolescents with
rent IGD. Furthermore, the brain correlates of cue-induced gaming IGD, during No-Go trials there was increased activity in the left
urge and smoking craving in participants with both Internet gam- superior medial frontal gyrus, right anterior cingulate cortex, right
ing disorder and nicotine dependence were compared (Ko et al., superior/middle frontal gyrus, left inferior parietal lobe, left pre-
2013a). Cue-induced gaming urge and smoking craving activated central gyrus, and left pre-cuneus and cuneus (Ding et al., 2014).
the anterior cingulate cortex and the para-hippocampal gyrus in IGD participants failed to recruit frontal-basal ganglia pathway
the comorbid group in comparison with the control group. Both and inhibit unwanted actions on the Go-Stop paradigm (Li et al.,
IGD and nicotine dependence share therefore similar mechanisms 2014). Impaired function of the pre-frontal cortex may relate to
of cue-induced reactivity of the frontal-limbic network in particular high impulsivity that in turn may contribute to impaired cognitive
the para-hippocampal gyrus and the anterior cingulate cortex. control and the development of IGD.
World of Warcraft (WoW) game figures activated the dorso- The impairment in performance of response inhibition tasks is a
lateral prefrontal cortex, bilateral temporal cortex, cerebellum, consistent finding that is followed by failure to recruit frontal-basal
right inferior parietal lobule, right cuneus, right hippocampus, ganglia pathways and use of other brain areas during inhibition in
para-hippocampal gyrus and the left caudate nucleus in fMRI in IGD both adolescents and adults with IGD.
participants (Sun et al., 2012). Craving measures were positively
associated with activity in the bilateral pre-frontal cortex, anterior 3.3. Reward
cingulate cortex and right inferior parietal lobe. These regions were
associated with cognitive, emotion and motivation-related func- Behavioral addictions such as IGD similarly to drug abusers
tion in drug addiction. Furthermore, a prospective study of IGD and are associated with faulty decision-making and preference for
control participants in which they all received Internet videogame immediate reward to long-term gains. IGD individuals subjectively
stimuli in fMRI showed that IGD participants had increased activa- experienced monetary gain and loss during the performance of a
tion in regions that are associated with visuo-spatial orientation, guessing task while reward and punishment processing were mea-
space, attention, mental imagery and executive function (right sured (Dong et al., 2011). IGD participants also showed increased
superior parietal lobule, insular lobe, pre-cuneus, cingulate gyrus, activation in orbito-frontal cortex in gain trials and decreased ante-
superior temporal gyrus, and left brainstem) (Liu et al., 2016). IGD rior cingulate cortex activation in loss trials implicating enhanced
participants also showed attention bias to short presentations of reward sensitivity and decreased loss sensitivity. Consistent with
game pictures and enhanced brain responses in medial pre-frontal this finding, IGD participants who performed on a continuous wins-
cortex and anterior cingulate cortex. There was high connectivity and-losses task which measures decision making in fMRI showed
between the right inferior frontal gyrus, which is associated with increased brain activity in the inferior frontal cortex, insula, ante-
A. Weinstein et al. / Neuroscience and Biobehavioral Reviews 75 (2017) 314330 325

Fig. 2. Regions that showed activation in response to internet and videogame cues in IGD participants Caudate Nucleus (Ko et al., 2009; Sun et al., 2012; Dong et al., 2013;
Ko et al., 2014) orbito-frontal cortex (Ko et al., 2009; Han et al., 2010a,b; Dong and Huang, 2011; Ko et al., 2014) anterior cingulate (Ko et al., 2009; Han et al., 2010a,b; Dong
and Huang, 2011; Ko et al., 2013a,b; Lorenz et al., 2013; Dong et al., 2013; Ding et al., 2014), Dorsolateral Prefrontal Cortex (Ko et al., 2009; Sun et al., 2012; Ko et al., 2013a;
Liu et al., 2014) Para-hippocampus (Sun et al., 2012; Ko et al., 2013a,b) Precuneus (Ko et al., 2013a; Ding et al., 2014; Liu et al., 2016) Posterior cingulate cortex (Ko et al.,
2013a,b; Lorenz et al., 2013; Dong et al., 2013) Inferior Frontal Cortex (Dong et al., 2013; Lin et al., 2015b).

rior cingulate cortex and decreased activation in the caudate and tor availability in the striatum. Dopamine D2 receptor binding
posterior cingulate cortex after continuous wins (Dong et al., 2013). potential was measured using the radiolabeled ligand [11 C] raclo-
In addition, IGD participants showed increased brain activities in pride and positron emission tomography in men with and without
the inferior frontal gyrus and decreased brain activation in the pos- IGD (Kim et al., 2011). IGD participants showed reduced levels
terior cingulate cortex after continuous losses. IGD participants of dopamine D2 receptor availability in subdivisions of the stria-
engaged more brain resources in order to perform on the decision- tum including the bilateral dorsal caudate and right Putamen thus
making task and they showed impaired executive function. They contributing to the hypothesis of deficient dopamine reward mech-
also did not pay adequate attention to considering previous selec- anisms in IGD. To test whether there is dopamine deficiency at
tions and relevant outcomes during decision-making. This finding the pre-synaptic level striatal dopamine transporter (DAT) levels
implies impaired decision making together with enhanced com- were measured using (99 m) Tc-TRODAT-1 in single photon emis-
pensatory brain-mechanisms. Consistent with the mechanism of sion computed tomography (SPECT) in individuals with IGD (Hou
impulsive decision-making, IGD participants who performed on et al., 2012). Analysis of DAT availability showed that the volume
a probability-discounting task in fMRI preferred the probabilistic of the striatum and the striatum/whole brain ratio were reduced
options to fixed ones and were faster to respond compared with in individuals with IGD compared with control participants. Taken
control participants (Lin et al., 2015b). They also showed decreased together, these results suggest that IGD is associated with dysfunc-
activation in the inferior frontal gyrus and the precentral gyrus tion in the dopaminergic brain systems. These findings also support
when choosing the probabilistic options than control participants. the claim that IGD may share similar neurobiological abnormalities
Both of the behavioral performance and fMRI results so far indi- with other addictive disorders. Finally, PET radio ligands [11 ] C-N-
cated impaired risk evaluation, which might be the reason why methylspiperone ([11 ] C-NMSP) was used to assess the availability
IGD participants continue playing online games despite the risks of D2 and 5-HT2A receptors and [18 ] F-fluoro-d-glucose ([18 ] F-FDG)
of widely known negative consequence a mechanism that is also was used to assess regional brain glucose metabolism in male IGD
typical of individuals with substance use and pathological gam- and control participants (Tian et al., 2014). The same individuals
bling disorder. However, with IGD the negative consequences of underwent PET imaging under both resting and Internet gaming
ongoing activity are much more subtle compared with substance task conditions. IGD participants showed a significant decrease in
use and pathological gambling hence despite of the commonali- rCMRglu metabolism in the Prefrontal, Temporal, and Limbic sys-
ties on a neurobiological level there is not enough evidence for tems. Lower levels of D2 receptor availability were observed in the
pathophysiology in IGD. striatum, and they were correlated with years of use. A low level of
Finally, IGD adolescents had decreased reward sensitivity D2 receptors in the Striatum was associated with decreased rCM-
irrespective of the type of reward and feedback (Kim et al., Rglu metabolism in the orbito-frontal cortex. The results seem to
2014). Adolescent IGD may be only sensitive to error monitor- indicate that D2 and 5-HT2A receptor-mediated dysregulation of
ing regardless of positive feelings, such as sense of satisfaction or the orbito-frontal cortex could underlie a mechanism for loss of
achievement. Further studies are required to investigate decision control and compulsive behavior in IGD.
making in adolescents and concomitant brain regions. Previous studies showed dopamine-release in the ventral stria-
tum while playing computer games in a similar magnitude to
4. Brain imaging studies on dopamine, 5-HT and other amphetamine-induced dopamine release in healthy participants
neurotransmitters (Koepp et al., 1998; Weinstein, 2010) and in Parkinsons patients
with addiction, obsession and gambling compared with Parkin-
Neurotransmitters such as DA, serotonin (5-HT) play an impor- sons patients without these symptoms (Steeves et al., 2009). These
tant role in drug and alcohol dependence, mainly by mediating findings identify striatal function driven by dopamine as a core can-
dopamine reward and withdrawal mechanisms (Goldstein and didate promoting addictive behavior. Consistent with the evidence
Volkow, 2002; Fowler et al., 2007). It is therefore useful to investi- for the role of dopamine in addiction, pathological gamblers have
gate the function of these neurotransmitters in IGD. See Table 5 for an increased striatal dopamine release while losing money, a bio-
Studies measuring dopamine receptor and transporter deficiency logical signal that may hinder the termination of gambling and
in IGD. excessive gambling in Parkinsons patients due to dopaminergic
Consistent with previous evidence that drug and alcohol use medication (Linnet et al., 2010).
disorders (Volkow et al., 1993; Volkow et al., 1996b; Volkow et al., Finally, Magnetic Resonance Spectroscopy (MRS) was utilized
2001; Wang et al., 1997) are associated with deficient dopamine to measure pre-frontal and temporal cortical function in patients
reward activity, it is important to investigate whether IGD would with IGD (Han et al., 2014). MRS studies of human brain disorders
also be associated with reduced levels of dopaminergic recep- have detected decreases in brain N-acetyl aspartate (NAA) concen-
326 A. Weinstein et al. / Neuroscience and Biobehavioral Reviews 75 (2017) 314330

Table 5
Studies measuring dopamine receptor and transporter deficiency in videogame playersa .

Citation Methods Participants Main findings


123
Weinstein (2010) The radiolabeled ligand [ IBZM] and Eight healthy control participants. Motorbike riding videogame released
Single Photon Computerized 10.5% dopamine in the striatum in
Tomography (SPECT) to assess control participants
dopamine D2 receptor binding
potential in the ventral striatum before
and after playing a motorbike riding
videogame
Kim et al. (2011) The radiolabeled ligand [11 C]raclopride Five male internet addicts and seven Reduced levels of dopamine D2
and positron emission tomography to male control participants. receptor availability in subdivisions of
assess dopamine D2 receptor binding the striatum including the bilateral
potential dorsal caudate and right putamen.
Hou et al. (2012) Striatal dopamine transporter (DAT) Five male internet addicts and nine DAT expression level of the striatum
levels measured by male control participants. was decreased.
(99m)Tc-TRODAT-1 single photon The volume, weight and whole brain
emission computed tomography were greatly reduced.
(SPECT)
Tian et al. (2014) Methylspiperone [11 ]C-NMSP) to Twelve adult male IGD and fourteen Decrease in glucose metabolism in the
assess the availability of D2 /5-HT2A control participants. prefrontal, temporal, limbic regions
receptors and [18]F-fluoro-d-glucose Dysregulation of D2 receptors in the
([18 ]F-FDG) to assess regional brain striatum correlated with years of use.
glucose metabolism in positron Low level of D2 receptors in the
emission tomography (PET) striatum was associated with
decreased glucose metabolism in the
OFC.
Han et al. (2014) Magnetic Resonance Spectroscopy Seventy three young IGD participants Lower levels of NAA in the right frontal
(MRS) and thirty eight control participants. cortex.
Lower levels of choline in the medial
temporal cortex.
The Young Internet Addiction Scale
(YIAS) scores and perseverative
responses negatively correlated with
the level of NAA in the right frontal
cortex. The Beck Depressive Inventory
(BDI) scores negatively correlated with
choline levels in the right temporal
Lobe.
a
Studies arranged chronologically Abbreviations: Orbito-Frontal Cortex (OFC).

trations when neuronal loss or dysfunction is involved. Increased on structural and functional changes as result of IGD little can be
choline which is a precursor of acetylcholine indicates increase inferred about the effects of these changes on the development and
in cell production or membrane breakdown, which can suggest maintenance of IGD.
demyelination. Levels of NAA in the right frontal cortex and the The neuroimaging findings are also compatible with recent
levels of choline in the medial temporal cortex were lower in theoretical models which try to explain the development and
IGD participants compared with control participants. Furthermore, maintenance of IGD (Dong and Potenza (Dong and Potenza, 2014)
Young Internet Addiction Scale (YIAS) scores and perseverative and Brand et al. (Brand et al., 2016a). Dong and Potenza (Dong
responses in IGD participants negatively correlated with the level and Potenza, 2014) proposed a cognitive-behavioral model for
of NAA in the right frontal cortex. Beck Depression Inventory scores IGD which focuses on three domains- motivational drives related
in IGD participants negatively correlated with Choline levels in the to reward-seeking and stress-reduction, behavioral control relat-
right temporal lobe. Although, participants with IGD in this study ing to executive inhibition, and decision-making that involves
were free from psychiatric co-morbidity, they appear to share char- weighing the pros and cons of engaging in motivated behaviors.
acteristics with Attention Deficit Hyperactivity Disorder (ADHD) According to this model, neural processes underlying attention,
and major depressive disorder in terms of neurochemical changes response inhibition and behavioral flexibility in individuals with
in frontal and temporal cortices. IGD relate importantly to IGD severity, although the extent to which
these findings reflect predisposing factors or neural functions that
arise during phases of IGD development is not yet understood.
5. Discussion
Brand et al. (Brand et al., 2016a) proposed a model describing
the processes underlying the development and maintenance of
The studies reviewed so far show consistent findings demon-
Internet-use disorders. Internet-use disorders are considered to be
strating the resemblance between the neural mechanisms
the consequence of interactions between neurobiological and psy-
underlying substance use disorder and IGD. The evidence reviewed
chological predisposing factors, moderating factors, such as coping
so far supports the behavioral addiction model of IGD since it shows
styles and cognitive biases, affective and cognitive responses to
structural changes and altered functional mechanisms of reward
situational triggers in combination with reduced executive func-
and craving in IGD that are similar to substance use disorders. The
tion. The neural correlates of Internet-gaming disorder and other
behavioral addiction model argues that IGD shows the features
Internet-use disorders may reflect a maladaptive interaction of
of excessive use despite adverse consequences, withdrawal phe-
cue-reactivity/craving and reduced prefrontal/executive function,
nomena, and tolerance that characterize substance use disorders.
as suggested for substance addiction (Brand et al., 2016a). Both
Although there is clinical evidence for withdrawal and tolerance
models argue that an interaction of limbic and prefrontal brain
as result of IGD (Young, 2009) there is no brain imaging evidence
areas reflect the behavioral aspects of cue-reactivity and craving
to support it. Furthermore, since there are no longitudinal studies
A. Weinstein et al. / Neuroscience and Biobehavioral Reviews 75 (2017) 314330 327

together with diminished executive and inhibitory control result- nection of IGD with serotonergic vulnerability and harm-avoidance
ing in the excessive/addictive use of games or other applications. there is little brain imaging evidence to support the model of inter-
There is supporting evidence that IGD is associated with dys- net addiction as an obsessive-compulsive disorder.
functional frontal-lobe mechanisms responsible for reward and The evidence reviewed so far on changes in the reward circuitry
self-regulation. A recent meta-analysis of fMRI in individuals with in IGD is parallel to other behavioral addictions like pathological
IGD found a significant activation in the bilateral medial frontal gambling (PG) and compulsive sexual disorder (CSD). Pathological
gyrus and the left cingulate gyrus, as well as the left medial tem- gambling is associated with changes in the reward circuitry in the
poral gyrus and fusiform gyrus (Meng et al., 2015). Furthermore, brain, with craving and with reduced activity of the meso-limbic
the on-line time of IGD participants positively correlated with acti- reward system that may be related to impaired impulse control
vations in the left medial frontal gyrus and the right cingulate (Reuter et al., 2005). Brain imaging studies have shown that gam-
gyrus. These findings implicate the important role of dysfunctional bling cues have evoked gambling urges in pathological gamblers
prefrontal lobe in the neuropathological mechanism of IGD. Con- which were associated with deactivation in areas that were nor-
sidering the overlapped role of prefrontal lobe in the reward and mally associated with craving (frontal para-limbic and limbic brain
self-regulatory system, this is supportive evidence for the classifica- structures) in fMRI (Potenza et al., 2003a). Particularly when view-
tion of IGD as a behavioral addiction. The association between IGD ing gambling cues, pathological gamblers demonstrated relatively
and impaired self-regulation is compatible with the model of IGD decreased activity in brain regions that are associated with impulse
as an impulse-control disorder, although the main evidence is for regulation. The deactivation of regions associated with impulse
reward deficiency. Furthermore, due to its association with reward regulation is supported by evidence for decreased activity in the
deficiency, IGD, similarly to ADHD, may be classified as a reward ventral-medial pre-frontal cortex during performance of the Stroop
deficiency syndrome (Blum et al., 2008; Weinstein and Weizman, task in pathological gamblers. This region is implicated in disor-
2012). ders characterized by poor impulse control (Potenza et al., 2003b).
Studies of the resting state, functional and structural studies The latter finding is consistent with a recent brain imaging study
all support the notion that the brains reward system and other showing that pathological gamblers had lower cerebral glucose
related systems mediating loss of control and inhibition are under- metabolic rates (rCMRglu) in the ventral parts of the striatum and
going changes as result of IGD. Furthermore, studies on gaming thalamus, and higher rates of rCMRglu in the dorsal parts as com-
cue-induced reactivity have shown an activation pattern that is pared with the control participants (Pallanti et al., 2010). Because of
similar to drug-dependent patients who were exposed to drug cues. their extensive connectivity to the frontal cortex, striatal and thala-
There is also some evidence that pharmacological treatment with mic functional alteration may contribute to faulty decision-making
medication such as bupropion can alter this activity and attenu- processes in PG patients.
ate cue-induced brain activity in excessive video-game users (Han Compulsive sexual behavior has also been conceptualized as
et al., 2007), similar to the attenuation that occurs in nicotine- a behavioral addiction with common neural circuits that are
dependent users (Weinstein et al., 2010). Furthermore, regular responsible for processing of natural and drug reward. A study
or chronic IGD resulted in reduced brains dopamine indicated investigating the responses to sexually explicit materials in individ-
by lower dopamine transporter density and lower dopamine D2 uals with and without compulsive sexual behavior in fMRI (Voon
receptor occupancy in the brains of videogame players. This evi- et al., 2014) showed that exposure to sexually explicit cues in
dence is compatible with previous evidence for reduced dopamine compulsive sexual disorder was associated with activation of the
D2 receptor occupancy in cocaine, methamphetamine, heroin and dorsal anterior cingulate, ventral striatum and amygdala, areas that
alcohol abusers (Volkow et al., 1993; Volkow et al., 1996b; Volkow were previously activated in response to drug cues. The greater
et al., 2001; Wang et al., 1997). It seems that excessive use of the engagement of cortico-striatal limbic circuitry in compulsive sexual
brains dopamine reward system as result of videogame playing behavior following exposure to sexual cues suggests that the neural
resembles the down-regulation seen in case of drug and alco- mechanisms underlying compulsive sexual disorder are similar to
hol abuse. Finally, videogame playing induced striatal dopamine IGD and pathological gambling. Finally, Brand (Brand et al., 2016b)
release indicating that this is a major force promoting addictive showed enhanced response of the ventral striatum in heterosex-
behavior. Although videogame playing released dopamine to a sim- ual male participants to pornographic materials and that Ventral
ilar extent as drugs such as cocaine and amphetamines the two striatum activity was correlated with the self-reported symptoms
processes are entirely different pharmacologically, one is endoge- of Internet pornography addiction. Mechanisms for reward antici-
nous dopamine whereas the other is exogenous dopamine. pation in ventral striatum may contribute to a neural explanation
A single pharmaco-genetic study supports the hypothesis that of why individuals with certain preferences and sexual fantasies
IGD is similar to substance use disorder (Han et al., 2010b). It are at-risk for losing their control over Internet pornography con-
found that IGD participants in Korea may have high reward depen- sumption. This evidence is compatible to previous evidence of the
dence on Cloningers Personality Questionnaire TPQ (Cloninger involvement of the ventral striatum in reward in pathological gam-
et al., 1991), and higher prevalence of associated dopamine bling and IGD.
genes (Taq1A1 variation of dopamine D2 receptor and low activ- One of the major limitations in brain imaging studies of IGD
ity Val158Met in the Catecholamine-O-Methyltransferase COMT is they are mainly cross-sectional studies without baseline mea-
alleles) than control participants (Han et al., 2010b). A second sures that rely on associations between structural and functional
Korean study has shown that IGD users IGD participants may brain changes in the brain and Internet and videogame character-
have genetic and personality traits similar to depressed patients. istics. These associations do not provide any proof that IGD activity
They had higher frequencies of the long-arm allele (SS-5HTTLPR), plays a causal role in the development of the adolescent or adult
greater harm avoidance on Cloningers Personality Questionnaire brain. There are factors that may mediate such associations such
TPQ (Cloninger et al., 1991), and higher Beck Depression Inven- as educational, cognitive, emotional and social factors. The use of
tory scores than control participants. SS-5HTTLPR frequency was tasks that measure specific executive functions such as cognitive
associated with harm avoidance in IGD users (Lee et al., 2009). control, decision-making and reward together with structural and
The pharmaco-genetic evidence of serotonergic vulnerability and functional brain imaging strengthen the conclusions drawn from
harm-avoidance together with MRS imaging evidence for neuro- these studies in IGD. There are also methodological considerations
chemical changes support the clinical evidence for comorbidity of of age (use of adolescents and students), culture (most studies were
IGD with mood disorders and ADHD. Despite the evidence for con- done in the Far East) and lack of comparison groups with sub-
328 A. Weinstein et al. / Neuroscience and Biobehavioral Reviews 75 (2017) 314330

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Prof. Weinstein is supported by grant from the National Institute
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