Elucidating the relationship between white matter structure, demographic, and clinical variables in schizophrenia-a multicenter harmonized diffusion tensor imaging study.

White matter (WM) abnormalities are repeatedly demonstrated across the schizophrenia time-course. However, our understanding of how demographic and clinical variables interact, influence, or are dependent on WM pathologies is limited. The most well-known barriers to progress are heterogeneous findings due to small sample sizes and the confounding influence of age on WM. The present study leverages access to the harmonized diffusion magnetic-resonance-imaging data and standardized clinical data from 13 international sites (597 schizophrenia patients (SCZ)). Fractional anisotropy (FA) values for all major WM structures in patients were predicted based on FA models estimated from a healthy population (n = 492). We utilized the deviations between predicted and real FA values to answer three essential questions. (1) "Which clinical variables explain WM abnormalities?". (2) "Does the degree of WM abnormalities predict symptom severity?". (3) "Does sex influence any of those relationships?". Regression and mediator analyses revealed that a longer duration-of-illness is associated with more severe WM abnormalities in several tracts. In addition, they demonstrated that a higher antipsychotic medication dose is related to more severe corpus callosum abnormalities. A structural equation model revealed that patients with more WM abnormalities display higher symptom severity. Last, the results exhibited sex-specificity. Males showed a stronger association between duration-of-illness and WM abnormalities. Females presented a stronger association between WM abnormalities and symptom severity, with IQ impacting this relationship. Our findings provide clear evidence for the interaction of demographic, clinical, and behavioral variables with WM pathology in SCZ. Our results also point to the need for longitudinal studies, directly investigating the casualty and sex-specificity of these relationships, as well as the impact of cognitive resiliency on structure-function relationships.

Time-Resolved Fluorescence Anisotropy of a Molecular Rotor Resolves Microscopic Viscosity Parameters in Complex Environments.

Understanding viscosity in complex environments remains a largely unanswered question despite its importance in determining reaction rates in vivo. Here, time-resolved fluorescence anisotropy imaging (TR-FAIM) is combined with fluorescent molecular rotors (FMRs) to simultaneously determine two non-equivalent viscosity-related parameters in complex heterogeneous environments. The parameters, FMR rotational correlation time and lifetime, are extracted from fluorescence anisotropy decays, which in heterogeneous environments show dip-and-rise behavior due to multiple dye populations. Decays of this kind are found both in artificially constructed adiposomes and in live cell lipid droplet organelles. Molecular dynamics simulations are used to assign each population to nano-environments within the lipid systems. The less viscous population corresponds to the state showing an average 25° tilt to the lipid membrane normal, and the more viscous population to the state showing an average 55° tilt. This combined experimental and simulation approach enables a comprehensive description of the FMR probe behavior within viscous nano-environments in complex, biological systems.

Functional dysconnectivity of the limbic loop of frontostriatal circuits in first-episode, treatment-naive schizophrenia.

Frontostriatal circuits dysfunction has been implicated in the etiology and psychopathology of patients with schizophrenia (SZ). However, few studies have investigated SZ-related functional connectivity (FC) alterations in discrete frontostriatal circuits and their relationship with pathopsychology in first-episode schizophrenia (FESZ). The goal of this study was to identify dysfunctions in discrete frontostriatal circuits that are associated with key features of FESZ. To this end, a case-control, cross-sectional study was conducted, wherein resting-state (RS) functional magnetic resonance (fMRI) data were collected from 37 treatment-naïve FESZ patients and 29 healthy control (HC) subjects. Seed-based FC analyses were performed by placing six bilateral pairs of seeds within a priori defined subdivisions of the striatum. We observed significantly decreased FC for the FESZ group relative to the HC group [p < .05, family-wise error (FWE)-corrected] in the limbic loop, but not in the sensorimotor or associative loops, of frontostriatal circuitry. Moreover, bilaterally decreased inferior ventral striatum/nucleus accumbens (VSi)-dorsal anterior cingulate cortex (dACC) FC within the limbic loop correlated inversely with overall FESZ symptom severity and the disorganization factor score of PANSS. These findings provide new insight into the role of frontostriatal limbic loop hypoconnectivity in early-stage schizophrenia pathology and suggest potential novel therapeutic targets.

Multifocal multiphoton volumetric imaging approach for high-speed time-resolved Förster resonance energy transfer imaging in vivo.

In this Letter, we will discuss the development of a multifocal multiphoton fluorescent lifetime imaging system where four individual fluorescent intensity and lifetime planes are acquired simultaneously, allowing us to obtain volumetric data without the need for sequential scanning at different axial depths. Using a phase-only spatial light modulator (SLM) with an appropriate algorithm to generate a holographic pattern, we project a beamlet array within a sample volume of a size, which can be preprogrammed by the user. We demonstrate the capabilities of the system to image live-cell interactions. While only four planes are shown, this technique can be rescaled to a large number of focal planes, enabling full 3D acquisition and reconstruction.

New high-speed centre of mass method incorporating background subtraction for accurate determination of fluorescence lifetime.

We demonstrate an implementation of a centre-of-mass method (CMM) incorporating background subtraction for use in multifocal fluorescence lifetime imaging microscopy to accurately determine fluorescence lifetime in live cell imaging using the Megaframe camera. The inclusion of background subtraction solves one of the major issues associated with centre-of-mass approaches, namely the sensitivity of the algorithm to background signal. The algorithm, which is predominantly implemented in hardware, provides real-time lifetime output and allows the user to effectively condense large amounts of photon data. Instead of requiring the transfer of thousands of photon arrival times, the lifetime is simply represented by one value which allows the system to collect data up to limit of pulse pile-up without any limitations on data transfer rates. In order to evaluate the performance of this new CMM algorithm with existing techniques (i.e. rapid lifetime determination and Levenburg-Marquardt), we imaged live MCF-7 human breast carcinoma cells transiently transfected with FRET standards. We show that, it offers significant advantages in terms of lifetime accuracy and insensitivity to variability in dark count rate (DCR) between Megaframe camera pixels. Unlike other algorithms no prior knowledge of the expected lifetime is required to perform lifetime determination. The ability of this technique to provide real-time lifetime readout makes it extremely useful for a number of applications.

256 × 2 SPAD line sensor for time resolved fluorescence spectroscopy.

We present a CMOS chip 256 × 2 single photon avalanche diode (SPAD) line sensor, 23.78 µm pitch, 43.7% fill factor, custom designed for time resolved emission spectroscopy (TRES). Integrating time-to-digital converters (TDCs) implement on-chip mono-exponential fluorescence lifetime pre-calculation allowing timing of 65k photons/pixel at 200 Hz line rate at 40 ps resolution using centre-of-mass method (CMM). Per pixel time-correlated single-photon counting (TCSPC) histograms can also be generated with 320 ps bin resolution. We characterize performance in terms of dark count rate, instrument response function and lifetime uniformity for a set of fluorophores with lifetimes ranging from 4 ns to 6 ns. Lastly, we present fluorescence lifetime spectra of multicolor microspheres and skin autofluorescence acquired using a custom built spectrometer. In TCSPC mode, time-resolved spectra are acquired within 5 minutes whilst in CMM mode spectral lifetime signatures are acquired within 2 ms for fluorophore in cuvette and 200 ms for skin autofluorescence. We demonstrate CMOS line sensors to be a versatile tool for time-resolved fluorescence spectroscopy by providing parallelized and flexible spectral detection of fluorescence decay.

0.5 billion events per second time correlated single photon counting using CMOS SPAD arrays.

We present a digital architecture for fast acquisition of time correlated single photon counting (TCSPC) events from a 32×32 complementary metal oxide semiconductor (CMOS) single photon avalanche detector (SPAD) array (Megaframe) to the computer memory. Custom firmware was written to transmit event codes from 1024-TCSPC-enabled pixels for fast transfer of TCSPC events. Our 1024-channel TCSPC system is capable of acquiring up to 0.5×10(9) TCSPC events per second with 16 histogram bins spanning a 14 ns width. Other options include 320×10(6) TCSPC events per second with 256 histogram bins spanning either a 14 or 56 ns time window. We present a wide-field fluorescence microscopy setup demonstrating fast fluorescence lifetime data acquisition. To the best of our knowledge, this is the fastest direct TCSPC transfer from a single photon counting device to the computer to date.

A fluorescent biosensor reveals conformational changes in human immunoglobulin E Fc: implications for mechanisms of receptor binding, inhibition, and allergen recognition.

IgE binding to its high affinity receptor FcεRI on mast cells and basophils is a key step in the mechanism of allergic disease and a target for therapeutic intervention. Early indications that IgE adopts a bent structure in solution have been confirmed by recent x-ray crystallographic studies of IgEFc, which further showed that the bend, contrary to expectation, is enhanced in the crystal structure of the complex with receptor. To investigate the structure of IgEFc and its conformational changes that accompany receptor binding in solution, we created a Förster resonance energy transfer (FRET) biosensor using biologically encoded fluorescent proteins fused to the N- and C-terminal IgEFc domains (Cε2 and Cε4, respectively) together with the theoretical basis for quantitating its behavior. This revealed not only that the IgEFc exists in a bent conformation in solution but also that the bend is indeed enhanced upon FcεRI binding. No change in the degree of bending was seen upon binding to the B cell receptor for IgE, CD23 (FcεRII), but in contrast, binding of the anti-IgE therapeutic antibody omalizumab decreases the extent of the bend, implying a conformational change that opposes FcεRI engagement. HomoFRET measurements further revealed that the (Cε2)(2) and (Cε4)(2) domain pairs behave as rigid units flanking the conformational change in the Cε3 domains. Finally, modeling of the accessible conformations of the two Fab arms in FcεRI-bound IgE revealed a mutual exclusion not seen in IgG and Fab orientations relative to the membrane that may predispose receptor-bound IgE to cross-linking by allergens.

Influence of molecular shape, conformability, net surface charge, and tissue interaction on transscleral macromolecular diffusion.

The purpose of this study was to investigate the influence of molecular shape, conformability, net surface charge and tissue interaction on transscleral diffusion. Unfixed, porcine sclera was clamped in an Ussing chamber. Fluorophore-labelled neutral albumin, neutral dextran, or neutral ficoll were placed in one hemi-chamber and the rate of transscleral diffusion was measured over 24 h using a spectrophotometer. Experiments were repeated using dextrans and ficoll with positive or negative net surface charges. Fluorescence recovery after photobleaching (FRAP) was undertaken to compare transscleral diffusion with diffusion through a solution. All molecules were 70 kDa. With FRAP, the diffusion coefficient (D) of neutral molecules was highest for albumin, followed by ficoll, then dextran (p < 0.0001). Positive dextrans diffused fastest, followed by negative, then neutral dextrans (p = 0.0004). Neutral ficoll diffused the fastest, followed by positive then negative ficoll (p = 0.5865). For the neutral molecules, transscleral D was highest for albumin, followed by dextran, then ficoll (p < 0.0001). D was highest for negative ficoll, followed by neutral, then positive ficoll (p < 0.0001). By contrast, D was highest for positive dextran, followed by neutral, then negative dextran (p = 0.0021). In conclusion, diffusion in free solution does not predict transscleral diffusion and the molecular-tissue interaction is important. Molecular size, shape, and charge may all markedly influence transscleral diffusion, as may conformability to a lesser degree, but their effects may be diametrically opposed in different molecules, and their influence on diffusion is more complex than previously thought. Each variable cannot be considered in isolation, and the interplay of all these variables needs to be tested, when selecting or designing drugs for transscleral delivery.

The relationship between reward-based learning and nicotine dependence in smokers with schizophrenia.

Cigarette smoking rates remain remarkably high in schizophrenia relative to smoking in other psychiatric groups. Impairments in the reward system may be related to elevated rates of nicotine dependence and lower cessation rates in this psychiatric group. Smokers with schizophrenia and schizoaffective disorder (SWS; n=15; M(age)=54.87, S.D.=6.51, 100% male) and a non-psychiatric control group of smokers (NCL; n=16; M(age)=50.38, S.D.=11.52; 93.8% male) were administered a computerized signal detection task to measure reward-based learning. Performance on the signal detection task was assessed by response bias, discriminability, reaction time, and hit rate. Clinician-assessed and self-reported measures of smoking and psychiatric symptoms were completed. SWS exhibited similar patterns of reward-based learning compared to control smokers. However, decreased reward-based learning was associated with increased levels of nicotine dependence in SWS, but not among control smokers. Nicotine withdrawal and urge to smoke were correlated with anhedonia within the SWS group. Among SWS, reduced reward responsiveness and increased anhedonia were associated with and may contribute to greater co-occurring nicotine dependence. These findings emphasize the importance of targeting reward system functioning in smoking cessation treatment for individuals with schizophrenia.

Loosening of Associations in Chronic Schizophrenia: Intersectionality of Verbal Learning, Negative Symptoms, and Brain Structure.

In 1908, Bleuler proposed a unitary theory of schizophrenia, hypothesizing a "loosening of associations" as the central mechanism underlying disturbances in thinking, motivation, and affective expression. Here, we test Bleuler's model in an archival sample of 79 healthy controls and 76 patients with chronic schizophrenia who had completed neuropsychological tests, including a measure of learning of novel word pairs, which was specifically selected to probe the structure and formation of new verbal associations. The patients also had positive and negative symptoms ratings, including measures of flat affect, anhedonia, and thought disorder. A subset of patients and controls (n = 39) had available prior archival 3-T magnetic resonance imaging (MRI) measures of prefrontal cortex (PFC) gray matter volumes. In relation to controls, patients showed evidence of a selective impairment in associative learning, independent of their overall reduced neuropsychological functioning. This neuropsychological impairment, in turn, correlated significantly with overall levels of negative but not positive symptoms, with the data showing an especially strong contribution of flattened emotional expression to verbal associate learning deficits in this patient sample. Moreover, the archival MRI data were consistent with prior research pointing to an important role of the PFC in supporting verbal associate learning and memory in patients and controls. Taken together, the current results provided evidence of a selective impairment in schizophrenia on a PFC-supported verbal associate learning and memory task, which was accompanied by negative symptoms in general, and flattened emotional expression, in particular.

Brain structural abnormalities of the associative striatum in adolescents and young adults at genetic high-risk of schizophrenia: Implications for illness endophenotypes.

OBJECTIVE: Dysfunction in cortico-striatal circuitry represents a core component of the pathophysiology in schizophrenia (SZ) but its potential as a candidate endophenotype of the illness is often confounded by neuroleptic medication. METHODS: Accordingly, 26 adolescent and young adult participants at genetic high-risk for schizophrenia, but who were asymptomatic and neuroleptic naïve, and 28 age-matched controls underwent 1.5T structural magnetic resonance imaging of the striatum, manually parcellated into limbic (LST), associative (AST), and sensorimotor (SMST) functional subregions. RESULTS: In relation to their age peers, participants at genetic high-risk for schizophrenia showed overall lower striatal gray matter volume with their most pronounced loss, bilaterally in the AST, but not the LST or SMST. Neuropsychological testing revealed reduced executive functioning for genetically at-risk participants, although the groups did not differ significantly in overall intelligence or oral reading. For controls but not for at-genetic high-risk participants, stronger executive functioning correlated with increased bilateral AST volume. CONCLUSIONS: Reduced bilateral AST volume in genetic high-risk adolescents and young adults, accompanied by heritable loss of higher cognitive brain-behavior relationships, might serve as a useful endophenotype of SZ.

Social barriers influence inflammatory bowel disease (IBD) outcomes and disproportionally affect Hispanics and non-Hispanic Blacks with IBD.

Background: The impact of social determinants of health in inflammatory bowel disease (IBD) remains understudied. We evaluated the impact of social barriers on IBD outcomes within a diverse cohort of patients. Methods: We performed a cross-sectional study on adult IBD patients and assessed known social determinants of health. We calculated the total prevalence of these barriers in the sample as a whole and within each ethnic group. We summed the number of barriers present for each individual to create a cumulative social barrier score (SBS), and we evaluated the relationship of each barrier and of the cumulative SBS with IBD outcomes, including disease activity and depressive symptoms. Results: A total of 316 patients were included in the study. Disparities in the prevalence of social barriers emerged by ethnicity: non-Hispanic Blacks reported the greatest number of social barriers, followed by Hispanic patients. Prevalent social barriers included financial strains (38.4%), such as food insecurity, medical care delays (~30%), and low educational attainment (26.8%). Social barriers associated with poor IBD outcomes included low educational attainment, poor health literacy, and financial insecurity. High SBS was associated with greater depressive symptoms [odds ratio (OR) 1.94, 95% confidence interval (CI) 1.21-2.9, p = 0.001] and lower reported use of medications. Greater ulcerative colitis (UC) disease activity was observed in patients with greater SBS. No associations were identified between SBS and IBD surgeries, hospitalizations, or disease location. Conclusion: Our study identifies social barriers that may impact IBD care and are disproportionately higher in non-Hispanic Blacks and Hispanics in the United States. Future studies should focus on implementing interventions to reduce these barriers and improve delivery of care.

Fluorescence anisotropy of molecular rotors.

We present polarization-resolved fluorescence measurements of fluorescent molecular rotors 9-(2-carboxy-2-cyanovinyl)julolidine (CCVJ), 9-(2,2-dicyanovinyl)julolidine (DCVJ), and a meso-substituted boron dipyrromethene (BODIPY-C(12)). The photophysical properties of these molecules are highly dependent on the viscosity of the surrounding solvent. The relationship between their quantum yields and the viscosity of the surrounding medium is given by an equation first described and presented by Förster and Hoffmann and can be used to determine the microviscosity of the environment around a fluorophore. Herein we evaluate the applicability of molecular rotors as probes of apparent viscosity on a microscopic scale based on their viscosity dependent fluorescence depolarization. We develop a theoretical framework, combining the Förster-Hoffmann equation with the Perrin equation and compare the dynamic ranges and usable working regimes for these dyes in terms of utilising fluorescence anisotropy as a measure of viscosity. We present polarization-resolved fluorescence spectra and steady-state fluorescence anisotropy imaging data for measurements of intracellular viscosity. We find that the dynamic range for fluorescence anisotropy for CCVJ and DCVJ is significantly lower than that of BODIPY-C(12) in the viscosity range 0.6<η<600 cP. Moreover, using steady-state anisotropy measurements to probe microviscosity in the low (<3 cP) viscosity regime, the molecular rotors can offer a better dynamic range in anisotropy compared with a rigid dye as a probe of microviscosity, and a higher total working dynamic range in terms of viscosity.

Microstructural Changes in the Left Mesocorticolimbic Pathway are Associated with the Comorbid Development of Fatigue and Depression in Multiple Sclerosis.

BACKGROUND AND PURPOSE: Lower reward responsiveness has been associated with fatigue in multiple sclerosis (MS). However, association of MS-related fatigue with damage to the mesocorticolimbic reward pathway (superolateral medial forebrain bundle [slMFB]) has not been assessed. We investigated the association of fatigue and depression with slMFB damage in MS patients stratified based on longitudinal fatigue patterns. METHODS: Patient stratification: 1. Sustained Fatigue (SF): latest two Modified Fatigue Impact Scale (MFIS) ≥ 38 (n = 26); 2. Reversible Fatigue (RF): latest MFIS < 38, and at least one previous MFIS ≥ 38 (n = 25); 3. Never Fatigued (NF): ≥ 5 consecutive MFIS < 38 (n = 42); 4. Healthy Controls (n = 6). Diffusion MRI-derived measures of fractional anisotropy (FA), axial (AD), mean (MD), and radial diffusivity (RD) of the slMFB were compared between the groups. Depression was assessed using the Center for Epidemiologic Studies-Depression Scale (CES-D). RESULTS: Depressed (CES-D ≥ 16) SF patients showed significantly higher MD and RD than nondepressed SF and RF, and depressed RF patients, and significantly lower FA than nondepressed SF and depressed RF patients in their left slMFB. Depressed SF patients showed significantly higher left slMFB MD and AD than healthy controls. CONCLUSION: Microstructural changes to the left slMFB may play a role in the comorbid development of fatigue and depression in MS.

Nance-Horan Syndrome-like 1 protein negatively regulates Scar/WAVE-Arp2/3 activity and inhibits lamellipodia stability and cell migration.

Cell migration is important for development and its aberrant regulation contributes to many diseases. The Scar/WAVE complex is essential for Arp2/3 mediated lamellipodia formation during mesenchymal cell migration and several coinciding signals activate it. However, so far, no direct negative regulators are known. Here we identify Nance-Horan Syndrome-like 1 protein (NHSL1) as a direct binding partner of the Scar/WAVE complex, which co-localise at protruding lamellipodia. This interaction is mediated by the Abi SH3 domain and two binding sites in NHSL1. Furthermore, active Rac binds to NHSL1 at two regions that mediate leading edge targeting of NHSL1. Surprisingly, NHSL1 inhibits cell migration through its interaction with the Scar/WAVE complex. Mechanistically, NHSL1 may reduce cell migration efficiency by impeding Arp2/3 activity, as measured in cells using a Arp2/3 FRET-FLIM biosensor, resulting in reduced F-actin density of lamellipodia, and consequently impairing the stability of lamellipodia protrusions.

Phospholipid encapsulated semiconducting polymer nanoparticles: their use in cell imaging and protein attachment.

Semiconducting polymer nanospheres (SPNs) have been synthesized and encapsulated in phospholipid micelles by a solvent evaporation technique. Four different conjugated polymers were used, yielding aqueous dispersions of nanoparticles which emit across the visible spectrum. The synthesis was simple and easily reproducible, and the resultant nanoparticle solutions exhibited high colloidal stability. As these encapsulated SPNs do not contain any toxic materials and show favorable optical properties, they appear to be a promising imaging agent in biomedical and imaging applications. The SPNs were used in simple fluorescence imaging experiments and showed uptake in SH-SY5Y neuroblastoma and live HeLa cells. Carboxylic acid functionalized SPNs were also synthesized and conjugated to bovine serum albumin (BSA) by carbodiimide-mediated chemistry, a key step in the realization of targeted imaging using conjugated polymers.

Rapid wide-field photon counting imaging with microsecond time resolution.

We report a novel wide-field imaging method capable of time-correlated single photon counting. It is based on a photon counting image intensifier coupled to an ultra-fast CMOS camera running at 40 kHz frame rate. Using a pulsed excitation source and decaying luminescent sample, the arrival times of hundreds of photons can be determined simultaneously in many pixels with microsecond resolution and reduced photon pile-up. The detection system is mounted on an inverted microscope and applied to time-resolved imaging of Europium-containing polyoxometalate nanoparticles.

A diffusion tensor imaging study of the anterior limb of the internal capsule in schizophrenia.

Frontal-subcortical cognitive and limbic feedback loops modulate higher cognitive functioning. The final step in these feedback loops is the thalamo-cortical projection through the anterior limb of the internal capsule (AL-IC). Using diffusion tensor imaging (DTI), we evaluated abnormalities in the AL-IC fiber tract in schizophrenia. Participants comprised 16 chronic schizophrenia patients and 19 male, normal controls, who were group matched for handedness, age, and parental socioeconomic status, and underwent DTI on a 1.5 Tesla GE system. We measured the diffusion indices, fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD), and manually segmented, based on FA maps, AL-IC volume, normalized for intracranial contents (ICC). The results showed a significant reduction in the ICC-corrected volume of the AL-IC in schizophrenia, but did not show diffusion measure group differences in the AL-IC in FA, MD, RD or AD. In addition, in the schizophrenia patients, AL-IC FA correlated positively with performance on measures of spatial and verbal declarative/episodic memory, and right AL-IC ICC-corrected volume correlated positively with more perseverative responses on the Wisconsin Card Sort Test (WCST). We found a reduction in AL-IC ICC-corrected volume in schizophrenia, without FA, MD, RD or AD group differences, implicating the presence of a structural abnormality in schizophrenia in this subcortical white matter region which contains important cognitive, and limbic feedback pathways that modulate prefrontal cortical function. Despite not demonstrating a group difference in FA, we found that AL-IC FA was a good predictor of spatial and verbal declarative/episodic memory performance in schizophrenia.

What We Know About Massively Multiplayer Online Role-Playing Games.

The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders defines internet gaming disorder without differentiating games from their respective genres, such as first-person shooter versus real-time strategy versus online gaming. Our review of the literature on massively multiplayer online role-playing games (MMORPGs) suggests that MMORPGs are different from other games because they are the most addictive, and therefore deserve to be looked at separately. MMORPGs are internet platforms for online users to interact with each other in a virtual story line. The overview of the existing literature delineates the positive and negative aspects of MMORPGs and also the available evidence on neuroscientific and neuroanatomical correlates between internet gaming disorder and other addictions. Evidence shows that a player's characteristics and motivations can determine his or her risk of developing problematic play. Problematic MMORPG use may lead to mental disorders such as depression and addiction, and can negatively affect quality of life, and vice versa. Conversely, some players may benefit from being part of a social community and from using it as a learning platform or as a safe space to explore gender-identity issues. Brain circuitry and metabolism are changed through problematic MMORPG use, with the affected areas including the ventral striatum and left angular gyrus.