A genetically encoded fluorescent sensor for manganese(II), engineered from lanmodulin.

The design of selective metal-binding sites is a challenge in both small-molecule and macromolecular chemistry. Selective recognition of manganese (II)-the first-row transition metal ion that tends to bind with the lowest affinity to ligands, as described by the Irving-Williams series-is particularly difficult. As a result, there is a dearth of chemical biology tools with which to study manganese physiology in live cells, which would advance understanding of photosynthesis, host-pathogen interactions, and neurobiology. Here we report the rational re-engineering of the lanthanide-binding protein, lanmodulin, into genetically encoded fluorescent sensors for MnII, MnLaMP1 and MnLaMP2. These sensors with effective Kd(MnII) of 29 and 7 µM, respectively, defy the Irving-Williams series to selectively detect MnII in vitro and in vivo. We apply both sensors to visualize kinetics of bacterial labile manganese pools. Biophysical studies indicate the importance of coordinated solvent and hydrophobic interactions in the sensors' selectivity. Our results establish lanmodulin as a versatile scaffold for design of selective protein-based biosensors and chelators for metals beyond the f-block.

Reconsidering the czcD (NiCo) Riboswitch as an Iron Riboswitch.

Recent work has proposed a new mechanism of bacterial iron regulation: riboswitches that undergo a conformational change in response to FeII. The czcD (NiCo) riboswitch was initially proposed to be specific for NiII and CoII, but we recently showed via a czcD-based fluorescent sensor that FeII is also a plausible physiological ligand for this riboswitch class. Here, we provide direct evidence that this riboswitch class responds to FeII. Isothermal titration calorimetry studies of the native czcD riboswitches from three organisms show no response to MnII, a weak response to ZnII, and similar dissociation constants (∼1 µM) and conformational responses for FeII, CoII, and NiII. Only the iron response is in the physiological concentration regime; the riboswitches' responses to CoII, NiII, and ZnII require 103-, 105-, and 106-fold higher "free" metal ion concentrations, respectively, than the typical availability of those metal ions in cells. By contrast, the "Sensei" RNA, recently claimed to be an iron-specific riboswitch, exhibits no response to FeII. Our results demonstrate that iron responsiveness is a conserved property of czcD riboswitches and clarify that this is the only family of iron-responsive riboswitch identified to date, setting the stage for characterization of their physiological function.

Iron-responsive riboswitches.

All cells must manage deficiency, sufficiency, and excess of essential metal ions. Although iron has been one of most important metals in biology for billions of years, the mechanisms by which bacteria cope with high intracellular iron concentrations are only recently coming into focus. Recent work has suggested that an RNA riboswitch (czcD or "NiCo"), originally thought to respond specifically to CoII and NiII excess, is more likely a selective regulator of FeII levels in important human gut bacteria and pathogens. We discuss the challenges and controversies encountered in the characterization of iron-responsive riboswitches, and we suggest a physiological role in responding to iron overload, perhaps during anaerobiosis. Finally, we place these riboswitches in the context of the better understood mechanisms of protein-based metal ion regulation, proposing that riboswitch-mediated mechanisms may be particularly important in regulating transport of the weakest-binding biological divalent metal ions, MgII, MnII, and FeII.

The czcD (NiCo) Riboswitch Responds to Iron(II).

Iron is essential for nearly every organism, and mismanagement of its intracellular concentrations (either deficiency or excess) contributes to diminished virulence in human pathogens, necessitating intricate metalloregulatory mechanisms. To date, although several metal-responsive riboswitches have been identified in bacteria, none has been shown to respond to FeII. The czcD riboswitch, present in numerous human gut microbiota and pathogens, was recently shown to respond to NiII and CoII but thought not to respond to FeII, on the basis of aerobic, in vitro assays; its function in vivo is not well understood. We constructed a fluorescent sensor using this riboswitch fused to the RNA aptamer, Spinach2. When assayed anaerobically, the resulting sensor responds in vitro to FeII, as well as to MnII, CoII, NiII, and ZnII, but only in the cases of FeII and MnII do the apparent Kd values (0.4 and 11 µM, respectively) fall within the range of labile metal concentrations maintained by known metalloregulators. We also show that the sensor-which is, to the best of our knowledge, the first reversible genetically encoded fluorescent sensor for FeII-responds to iron in Escherichia coli cells. Finally, we demonstrate that the putative metal exporters directly downstream of two czcD riboswitches efficiently rescue iron toxicity in a heterologous expression system. Together, our results indicate that iron merits consideration as a plausible physiological ligand for czcD riboswitches, although a response to general metal stress cannot be ruled out at present.

Alterations in functional networks during cue-reactivity in Internet gaming disorder.

BACKGROUND: Cue-induced brain reactivity has been suggested to be a fundamental and important mechanism explaining the development, maintenance, and relapse of addiction, including Internet gaming disorder (IGD). Altered activity in addiction-related brain regions has been found during cue-reactivity in IGD using functional magnetic resonance imaging (fMRI), but less is known regarding the alterations of coordinated whole brain activity patterns in IGD. METHODS: To investigate the activity of temporally coherent, large-scale functional brain networks (FNs) during cue-reactivity in IGD, independent component analysis was applied to fMRI data from 29 male subjects with IGD and 23 matched healthy controls (HC) performing a cue-reactivity task involving Internet gaming stimuli (i.e., game cues) and general Internet surfing-related stimuli (i.e., control cues). RESULTS: Four FNs were identified that were related to the response to game cues relative to control cues and that showed altered engagement/disengagement in IGD compared with HC. These FNs included temporo-occipital and temporo-insula networks associated with sensory processing, a frontoparietal network involved in memory and executive functioning, and a dorsal-limbic network implicated in reward and motivation processing. Within IGD, game versus control engagement of the temporo-occipital and frontoparietal networks were positively correlated with IGD severity. Similarly, disengagement of temporo-insula network was negatively correlated with higher game-craving. DISCUSSION: These findings are consistent with altered cue-reactivity brain regions reported in substance-related addictions, providing evidence that IGD may represent a type of addiction. The identification of the networks might shed light on the mechanisms of the cue-induced craving and addictive Internet gaming behaviors.

Neural Correlates of Personalized Spiritual Experiences.

Across cultures and throughout history, human beings have reported a variety of spiritual experiences and the concomitant perceived sense of union that transcends one's ordinary sense of self. Nevertheless, little is known about the underlying neural mechanisms of spiritual experiences, particularly when examined across different traditions and practices. By adapting an individualized guided-imagery task, we investigated neural correlates of personally meaningful spiritual experiences as compared with stressful and neutral-relaxing experiences. We observed in the spiritual condition, as compared with the neutral-relaxing condition, reduced activity in the left inferior parietal lobule (IPL), a result that suggests the IPL may contribute importantly to perceptual processing and self-other representations during spiritual experiences. Compared with stress cues, responses to spiritual cues showed reduced activity in the medial thalamus and caudate, regions associated with sensory and emotional processing. Overall, the study introduces a novel method for investigating brain correlates of personally meaningful spiritual experiences and suggests neural mechanisms associated with broadly defined and personally experienced spirituality.

Gradient theories of brain activation: A novel application to studying the parental brain.

PURPOSE OF REVIEW: Parental brain research primarily employs general-linear-model-based (GLM-based) analyses to assess blood-oxygenation-level-dependent responses to infant auditory and visual cues, reporting common responses in shared cortical and subcortical structures. However, this approach does not reveal intermixed neural substrates related to different sensory modalities. We consider this notion in studying the parental brain. RECENT FINDINGS: Spatial independent component analysis (sICA) has been used to separate mixed source signals from overlapping functional networks. We explore relative differences between GLM-based analysis and sICA as applied to an fMRI dataset acquired from women while they listened to infant cries or viewed infant sad faces. SUMMARY: There is growing appreciation for the value of moving beyond GLM-based analyses to consider brain functional organization as continuous, distributive, and overlapping gradients of neural substrates related to different sensory modalities. Preliminary findings suggest sICA can be applied to the study of the parental brain.

Spiritual experiences are related to engagement of a ventral frontotemporal functional brain network: Implications for prevention and treatment of behavioral and substance addictions.

BACKGROUND AND AIMS: Spirituality is an important component of 12-step programs for behavioral and substance addictions and has been linked to recovery processes. Understanding the neural correlates of spiritual experiences may help to promote efforts to enhance recovery processes in behavioral addictions. We recently used general linear model (GLM) analyses of functional magnetic resonance imaging data to examine neural correlates of spiritual experiences, with findings implicating cortical and subcortical brain regions. Although informative, the GLM-based approach does not provide insight into brain circuits that may underlie spiritual experiences. METHODS: Spatial independent component analysis (sICA) was used to identify functional brain networks specifically linked to spiritual (vs. stressful or neutral-relaxing) conditions using a previously validated guided imagery task in 27 young adults. RESULTS: Using sICA, engagement of a ventral frontotemporal network was identified that was engaged at the onset and conclusion of the spiritual condition in a manner distinct from engagement during the stress or neutral-relaxing conditions. Degree of engagement correlated with subjective reports of spirituality in the scanner (r = .71, p < .001) and an out-of-the-magnet measure of spirituality (r = .48, p < .018). DISCUSSION AND CONCLUSION: The current findings suggest a distributed functional neural network associated with spiritual experiences and provide a foundation for investigating brain mechanisms underlying the role of spirituality in recovery from behavioral addictions.

Shared facial emotion processing functional network findings in medication-naïve major depressive disorder and healthy individuals: detection by sICA.

BACKGROUND: The fundamental mechanism underlying emotional processing in major depressive disorder (MDD) remains unclear. To better understand the neural correlates of emotional processing in MDD, we investigated the role of multiple functional networks (FNs) during emotional stimuli processing. METHODS: Thirty-two medication-naïve subjects with MDD and 36 healthy controls (HCs) underwent an emotional faces fMRI task that included neutral, happy and fearful expressions. Spatial independent component analysis (sICA) and general linear model (GLM) were conducted to examine the main effect of task condition and group, and two-way interactions of group and task conditions. RESULTS: In sICA analysis, MDD patients and HCs together showed significant differences in task-related modulations in five FNs across task conditions. One FN mainly involving the ventral medial prefrontal cortex showed lower activation during fearful relative to happy condition. Two FNs mainly involving the bilateral inferior frontal gyrus and temporal cortex, showed opposing modulation relative to the ventral medial prefrontal cortex FN, i.e., greater activation during fearful relative to happy condition. Two remaining FNs involving the fronto-parietal and occipital cortices, showed reduced activation during both fearful and happy conditions relative to the neutral condition. However, MDD and HCs did not show significant differences in expression-related modulations in any FNs in this sample. CONCLUSIONS: SICA revealed differing functional activation patterns than typical GLM-based analyses. The sICA findings demonstrated unique FNs involved in processing happy and fearful facial expressions. Potential differences between MDD and HCs in expression-related FN modulation should be investigated further.

Openness to Changing Religious Views Is Related to Radial Diffusivity in the Genu of the Corpus Callosum in an Initial Study of Healthy Young Adults.

A quest orientation to religion is characterized by a search for answers to complex existential questions, a perception of religious doubt as positive, and an openness to change one's religious views as one grows and changes. This orientation is inversely related to fundamentalism, authoritarianism, and prejudice and directly related to cognitive complexity, openness to experience, and prosociality. To date, the neural correlates of religious quest have not been investigated. This study assessed the relationships between measures linked to white-matter integrity and quest religious orientation among 24 healthy participants using diffusion tensor imaging (DTI) and the quest scale. A tract-based spatial statistical analysis whole-brain-corrected initially employing an accepted threshold (pTFCE < 0.05) and then applying a Bonferroni correction (pTFCE < 0.0042) identified a region of the genu of the corpus callosum as showing radial diffusivity measures being related to openness to change religious beliefs. When not employing a Bonferroni correction (pTFCE < 0.05), the openness-to-change subscale of the quest scale negatively correlated with radial diffusivity and mean diffusivity measures in extensive white-matter regions in both hemispheres that include the corpus callosum body, genu, and splenium, superior longitudinal fasciculus, forceps minor, external capsule, and inferior fronto-occipital fasciculus. No relationships were found with the other subscales. These findings suggest that a greater openness to change one's religious views is associated with better white-matter integrity specifically in the genu of the corpus callosum and likely in a more extensive set of white-matter structures interconnecting widespread cortical and subcortical regions in the brain across hemispheres. They, furthermore, suggest structural similarities that may link this tendency to associated positive psychological traits, including creative cognition and post-traumatic growth.

Gray-matter relationships to diagnostic and transdiagnostic features of drug and behavioral addictions.

Alterations in neural structure have been reported in both cocaine-use disorder and gambling disorder, separately, suggesting similarities across addiction diagnoses. Individual variation in neural structure has also been associated with impulsivity, a dimensional construct implicated in addictions. This study combines categorical (diagnosis-based) and dimensional (transdiagnostic) approaches to identify neural structural alterations linked to addiction subtypes and trait impulsivity, respectively, across individuals with gambling disorder (n = 35), individuals with cocaine-use disorder (n = 37) and healthy comparison individuals (n = 37). High-resolution T1-weighted data were analyzed using modulated voxel-based morphometry (VBM). Statistical analyses were conducted using whole-brain general-linear models, corrected for family-wise error (pFWE < .05). Categorical analyses indicated a main effect of diagnostic group on prefrontal (dorsal anterior cingulate and ventromedial prefrontal cortex) gray matter volumes (GMVs), involving decreased GMVs among cocaine-use disorder participants only. Dimensional analyses indicated a negative association between trait impulsivity and cortical (insula) and subcortical (amygdala and hippocampus) GMVs across all participants. Conjunction analysis indicated little anatomical overlap between regions identified as differentiating diagnostic groups and regions covarying with impulsivity. These data provide first evidence of neural structural differences between gambling disorder and an illicit substance-use disorder. They further indicate dissociable effects of diagnostic groupings and trait impulsivity on neural structure among individuals with behavioral and drug addictions. Study findings highlight the importance of considering both categorical and dimensional (e.g. Research Domain Criteria; RDoC) analysis approaches within the context of addictions research.

Functional neural changes following behavioral therapies and disulfiram for cocaine dependence.

A growing literature exists on neural correlates of treatment outcome. However, different types-or components of-treatment have distinct theorized mechanisms of action. And it is not yet known how changes in neural activity across treatment relate to engagement in different treatment components. Participants with cocaine use disorders in a randomized clinical trial received cognitive-behavioral therapy (CBT) plus, in a 2 × 2 design, contingency management (CM) or no CM, and disulfiram or placebo. Participants performed a functional MRI Stroop task, a measure of cognitive control, at the beginning of and after the 12-week treatment. Analyses assessed changes in Stroop-related neural activity within the sample overall and assessed how changes in Stroop-related activity correlated with measures of treatment process specific to each form of treatment (i.e., participation in CBT sessions, receipt of CM prizes, administration of disulfiram pills). Within the sample overall, compared with beginning of treatment, posttreatment Stroop-related neural activity was diminished in the hippocampus, thalamus, cingulate, precentral, post- and precentral gyrus, and precuneus and culmen regions (pFWE < .05). In separate whole-brain correlation analyses, greater reductions in Stroop-related activity were associated with more treatment engagement-"CBT sessions" with the precentral gyrus, inferior parietal lobule, and middle and medial frontal gyrus; "CM prizes" with the postcentral frontal gyrus. Disulfiram "medication days" were not associated with changes in Stroop-related activity. Findings suggest that key process indicators of CBT and CM may be associated with functional changes in cognitive-control-related neurocircuitry. (PsycINFO Database Record

Shared microstructural features of behavioral and substance addictions revealed in areas of crossing fibers.

BACKGROUND: Similarities between behavioral and substance addictions exist. However, direct neurobiological comparison between addictive disorders is rare. Determination of disorder-specificity (or lack thereof) of alterations within white-matter microstructures will advance understanding of the pathophysiology of addictions. METHODS: We compared white-matter microstructural features between individuals with gambling disorder (GD; n=38), cocaine-use disorder (CUD; n=38) and healthy comparison (HC; n=38) participants, as assessed using diffusion-weighted magnetic resonance imaging (dMRI). To provide a more precise estimate of diffusion within regions of complex architecture (e.g., cortico-limbic tracts), analyses were conducted using a crossing-fiber model incorporating local-orientation modeling (tbss_x). Anisotropy estimates for primary and secondary fiber orientations were compared using ANOVAs corrected for multiple comparisons across space using threshold-free cluster enhancement (pFWE<.05). RESULTS: A main effect of group on anisotropy of secondary fiber orientations within the left internal capsule, corona radiata, forceps major and posterior thalamic radiation, involving reduced anisotropy among GD and CUD participants in comparison to HC participants. No differences in anisotropy measures were found between GD and CUD individuals. CONCLUSIONS: This is the first study to compare diffusion indices directly between behavioral and substance addictions and the largest dMRI study of GD. Our findings indicate similar white-matter microstructural alterations across addictions that cannot be attributed solely to exposure to drugs or alcohol and thus may be a vulnerability mechanism for addictive disorders.

White-matter crossing-fiber microstructure in adolescents prenatally exposed to cocaine.

BACKGROUND: Prenatal cocaine exposure (PCE) is associated with risk-taking behaviors, including increased initiation of substance use in adolescence. The neurobiological underpinnings of these behaviors in adolescents with PCE are not well understood. The goal of this study was to compare diffusion-weighted imaging data between adolescents with and without PCE using crossing-fiber models, which may provide more comprehensive estimates of white-matter microstructure within regions of multiple (e.g., primary and secondary) fiber orientations. METHODS: Thirty-nine PCE individuals and 17 comparably aged prenatally non-drug-exposed (NDE) youths were recruited from a longitudinal cohort followed since birth. White matter was examined using tensor-derived and crossing-fiber models. Whole-brain investigations were performed, as were analyses on seven white-matter regions, which included the splenium, body and genu of the corpus callosum, bilateral cingulum, and the right and left superior longitudinal fasciculus (SLF). RESULTS: Whole-brain analyses revealed no group differences. However, ROI analyses for anisotropy estimates derived from the crossing-fiber model revealed significant group differences for secondary fibers, with reduced anisotropy among PCE adolescents compared to prenatally non-exposed youth in the right cingulum and the left SLF, and increased anisotropy in the genu. CONCLUSIONS: Our findings suggest that white-matter differences in PCE adolescents are subtle and localized primarily within secondary fiber orientations, perhaps arising from altered white-matter development.

Assessing the effects of cocaine dependence and pathological gambling using group-wise sparse representation of natural stimulus FMRI data.

Assessing functional brain activation patterns in neuropsychiatric disorders such as cocaine dependence (CD) or pathological gambling (PG) under naturalistic stimuli has received rising interest in recent years. In this paper, we propose and apply a novel group-wise sparse representation framework to assess differences in neural responses to naturalistic stimuli across multiple groups of participants (healthy control, cocaine dependence, pathological gambling). Specifically, natural stimulus fMRI (N-fMRI) signals from all three groups of subjects are aggregated into a big data matrix, which is then decomposed into a common signal basis dictionary and associated weight coefficient matrices via an effective online dictionary learning and sparse coding method. The coefficient matrices associated with each common dictionary atom are statistically assessed for each group separately. With the inter-group comparisons based on the group-wise correspondence established by the common dictionary, our experimental results demonstrated that the group-wise sparse coding and representation strategy can effectively and specifically detect brain networks/regions affected by different pathological conditions of the brain under naturalistic stimuli.

Large-scale functional network overlap is a general property of brain functional organization: Reconciling inconsistent fMRI findings from general-linear-model-based analyses.

Functional magnetic resonance imaging (fMRI) studies regularly use univariate general-linear-model-based analyses (GLM). Their findings are often inconsistent across different studies, perhaps because of several fundamental brain properties including functional heterogeneity, balanced excitation and inhibition (E/I), and sparseness of neuronal activities. These properties stipulate heterogeneous neuronal activities in the same voxels and likely limit the sensitivity and specificity of GLM. This paper selectively reviews findings of histological and electrophysiological studies and fMRI spatial independent component analysis (sICA) and reports new findings by applying sICA to two existing datasets. The extant and new findings consistently demonstrate several novel features of brain functional organization not revealed by GLM. They include overlap of large-scale functional networks (FNs) and their concurrent opposite modulations, and no significant modulations in activity of most FNs across the whole brain during any task conditions. These novel features of brain functional organization are highly consistent with the brain's properties of functional heterogeneity, balanced E/I, and sparseness of neuronal activity, and may help reconcile inconsistent GLM findings.

A Preliminary Study of DBH (Encoding Dopamine Beta-Hydroxylase) Genetic Variation and Neural Correlates of Emotional and Motivational Processing in Individuals With and Without Pathological Gambling.

Background and aims Corticostriatal-limbic neurocircuitry, emotional and motivational processing, dopaminergic and noradrenergic systems and genetic factors have all been implicated in pathological gambling (PG). However, allelic variants of genes influencing dopaminergic and noradrenergic neurotransmitters have not been investigated with respect to the neural correlates of emotional and motivational states in PG. Dopamine beta-hydroxylase (DBH) converts dopamine to norepinephrine; the T allele of a functional single-nucleotide polymorphism rs1611115 (C-1021T) in the DBH gene is associated with less DBH activity and has been linked to emotional processes and addiction. Here, we investigate the influence of rs1611115 on the neural correlates of emotional and motivational processing in PG and healthy comparison (HC) participants. Methods While undergoing functional magnetic resonance imaging, 18 PG and 25 HC participants, all European Americans, viewed gambling-, sad-, and cocaine-related videotapes. Analyses focused on brain activation differences related to DBH genotype (CC/T-carrier [i.e., CT and TT]) and condition (sad/gambling/cocaine). Results CC participants demonstrated greater recruitment of corticostriatal-limbic regions, relative to T-carriers. DBH variants were also associated with altered corticostriatal-limbic activations across the different videotape conditions, and this association appeared to be driven by greater activation in CC participants relative to T-carriers during the sad condition. CC relative to T-carrier subjects also reported greater subjective sadness to the sad videotapes. Conclusions Individual differences in genetic composition linked to aminergic function contribute significantly to emotional regulation across diagnostic groups and warrant further investigation in PG.

Implications of cortical balanced excitation and inhibition, functional heterogeneity, and sparseness of neuronal activity in fMRI.

Blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) studies often report inconsistent findings, probably due to brain properties such as balanced excitation and inhibition and functional heterogeneity. These properties indicate that different neurons in the same voxels may show variable activities including concurrent activation and deactivation, that the relationships between BOLD signal and neural activity (i.e., neurovascular coupling) are complex, and that increased BOLD signal may reflect reduced deactivation, increased activation, or both. The traditional general-linear-model-based-analysis (GLM-BA) is a univariate approach, cannot separate different components of BOLD signal mixtures from the same voxels, and may contribute to inconsistent findings of fMRI. Spatial independent component analysis (sICA) is a multivariate approach, can separate the BOLD signal mixture from each voxel into different source signals and measure each separately, and thus may reconcile previous conflicting findings generated by GLM-BA. We propose that methods capable of separating mixed signals such as sICA should be regularly used for more accurately and completely extracting information embedded in fMRI datasets.

A Feasibility Study of Bilateral Anodal Stimulation of the Prefrontal Cortex Using High-Definition Electrodes in Healthy Participants.

Transcranial direct current stimulation (tDCS) studies often use one anode to increase cortical excitability in one hemisphere. However, mental processes may involve cortical regions in both hemispheres. This study's aim was to assess the safety and possible effects on affect and working memory of tDCS using two anodes for bifrontal stimulation. A group of healthy subjects participated in two bifrontal tDCS sessions on two different days, one for real and the other for sham stimulation. They performed a working memory task and reported their affect immediately before and after each tDCS session. Relative to sham, real bifrontal stimulation did not induce significant adverse effects, reduced decrement in vigor-activity during the study session, and did not improve working memory. These preliminary findings suggest that bifrontal anodal stimulation is feasible and safe and may reduce task-related fatigue in healthy participants. Its effects on neuropsychiatric patients deserve further study.

Impaired decision-making under risk is associated with gaming-specific inhibition deficits among college students with Internet gaming disorder.

A growing body of evidence indicates that both inhibition and decision-making deficits play essential roles in the development and maintenance of Internet gaming disorder (IGD). Clarifying whether impaired decision-making among individuals with IGD is related to poor inhibition will advance our understanding of IGD and contribute to intervention development. However, the relationship between these two functions remains unclear. In this study, we sought to systemically examine inhibitory processes, decision-making and the relationship between the two among individuals with IGD. Thirty-four individuals with IGD and 32 matched healthy controls (HCs) were recruited. In comparison to HCs, IGD subjects demonstrated inhibition deficits during performance of the gaming-related Go/No-Go task and impaired decision-making under risk. In addition, errors on No-Go trials during the gaming-related Go/No-Go task were positively associated with decision-making impairments under risk but not under ambiguity among IGD subjects. These results suggest individuals with IGD are impaired in some aspects of inhibition and decision-making functions, and that decision-making deficits under risk are linked to poor inhibition specifically related to gaming cues, which has implications for the development of novel intervention.