World addiction medicine reports: formation of the International Society of Addiction Medicine Global Expert Network (ISAM-GEN) and its global surveys.

Addiction medicine is a dynamic field that encompasses clinical practice and research in the context of societal, economic, and cultural factors at the local, national, regional, and global levels. This field has evolved profoundly during the past decades in terms of scopes and activities with the contribution of addiction medicine scientists and professionals globally. The dynamic nature of drug addiction at the global level has resulted in a crucial need for developing an international collaborative network of addiction societies, treatment programs and experts to monitor emerging national, regional, and global concerns. This protocol paper presents methodological details of running longitudinal surveys at national, regional, and global levels through the Global Expert Network of the International Society of Addiction Medicine (ISAM-GEN). The initial formation of the network with a recruitment phase and a round of snowball sampling provided 354 experts from 78 countries across the globe. In addition, 43 national/regional addiction societies/associations are also included in the database. The surveys will be developed by global experts in addiction medicine on treatment services, service coverage, co-occurring disorders, treatment standards and barriers, emerging addictions and/or dynamic changes in treatment needs worldwide. Survey participants in categories of (1) addiction societies/associations, (2) addiction treatment programs, (3) addiction experts/clinicians and (4) related stakeholders will respond to these global longitudinal surveys. The results will be analyzed and cross-examined with available data and peer-reviewed for publication.

Neuroscience-informed classification of prevention interventions in substance use disorders: An RDoC-based approach.

Neuroscience has contributed to uncover the mechanisms underpinning substance use disorders (SUD). The next frontier is to leverage these mechanisms as active targets to create more effective interventions for SUD treatment and prevention. Recent large-scale cohort studies from early childhood are generating multiple levels of neuroscience-based information with the potential to inform the development and refinement of future preventive strategies. However, there are still no available well-recognized frameworks to guide the integration of these multi-level datasets into prevention interventions. The Research Domain Criteria (RDoC) provides a neuroscience-based multi-system framework that is well suited to facilitate translation of neurobiological mechanisms into behavioral domains amenable to preventative interventions. We propose a novel RDoC-based framework for prevention science and adapted the framework for the existing preventive interventions. From a systematic review of randomized controlled trials using a person-centered drug/alcohol preventive approach for adolescents, we identified 22 unique preventive interventions. By teasing apart these 22 interventions into the RDoC domains, we proposed distinct neurocognitive trajectories which have been recognized as precursors or risk factors for SUDs, to be targeted, engaged and modified for effective addiction prevention.

Converging Evidence for Frontopolar Cortex as a Target for Neuromodulation in Addiction Treatment.

Noninvasive brain stimulation technologies such as transcranial electrical and magnetic stimulation (tES and TMS) are emerging neuromodulation therapies that are being used to target the neural substrates of substance use disorders. By the end of 2022, 205 trials of tES or TMS in the treatment of substance use disorders had been published, with heterogeneous results, and there is still no consensus on the optimal target brain region. Recent work may help clarify where and how to apply stimulation, owing to expanding databases of neuroimaging studies, new systematic reviews, and improved methods for causal brain mapping. Whereas most previous clinical trials targeted the dorsolateral prefrontal cortex, accumulating data highlight the frontopolar cortex as a promising therapeutic target for transcranial brain stimulation in substance use disorders. This approach is supported by converging multimodal evidence, including lesion-based maps, functional MRI-based maps, tES studies, TMS studies, and dose-response relationships. This review highlights the importance of targeting the frontopolar area and tailoring the treatment according to interindividual variations in brain state and trait and electric field distribution patterns. This converging evidence supports the potential for treatment optimization through context, target, dose, and timing dimensions to improve clinical outcomes of transcranial brain stimulation in people with substance use disorders in future clinical trials.

An online global survey and follow-up expert groups on the scope and needs related to training, research, and mentorship among early-career addiction medicine professionals.

Addiction medicine is a rapidly growing field with many young professionals seeking careers in this field. However, early-career professionals (ECPs) face challenges such as a lack of competency-based training due to a shortage of trainers, limited resources, limited mentorship opportunities, and establishment of suitable research areas. The International Society of Addiction Medicine (ISAM) New Professionals Exploration, Training & Education (NExT) committee, a global platform for early-career addiction medicine professionals (ECAMPs), conducted a two-phase online survey using a modified Delphi-based approach among ECAMPs across 56 countries to assess the need for standardized training, research opportunities, and mentorship. A total of 110 respondents participated in Phase I (online key informant survey), and 28 respondents participated in Phase II (online expert group discussions on three themes identified in Phase I). The survey found that there is a lack of standardized training, structured mentorship programs, research funding, and research opportunities in addiction medicine for ECAMPs. There is a need for standardized training programs, improving research opportunities, and effective mentorship programs to promote the next generation of addiction medicine professionals and further development in the entire field. The efforts of ISAM NExT are well-received and give a template of how this gap can be addressed.

Dose-response in modulating brain function with transcranial direct current stimulation: From local to network levels.

Understanding the dose-response relationship is crucial in studying the effects of brain stimulation techniques, such as transcranial direct current stimulation (tDCS). The dose-response relationship refers to the relationship between the received stimulation dose and the resulting response, which can be described as a function of the dose at various levels, including single/multiple neurons, clusters, regions, or networks. Here, we are focused on the received stimulation dose obtained from computational head models and brain responses which are quantified by functional magnetic resonance imaging (fMRI) data. In this randomized, triple-blind, sham-controlled clinical trial, we recruited sixty participants with methamphetamine use disorders (MUDs) as a sample clinical population who were randomly assigned to receive either sham or active tDCS. Structural and functional MRI data, including high-resolution T1 and T2-weighted MRI, resting-state functional MRI, and a methamphetamine cue-reactivity task fMRI, were acquired before and after tDCS. Individual head models were generated using the T1 and T2-weighted MRI data to simulate electric fields. In a linear approach, we investigated the associations between electric fields (received dose) and changes in brain function (response) at four different levels: voxel level, regional level (using atlas-based parcellation), cluster level (identifying active clusters), and network level (task-based functional connectivity). At the voxel level, regional level, and cluster level, no FDR-corrected significant correlation was observed between changes in functional activity and electric fields. However, at the network level, a significant positive correlation was found between frontoparietal connectivity and the electric field at the frontopolar stimulation site (r = 0.42, p corrected = 0.02; medium effect size). Our proposed pipeline offers a methodological framework for analyzing tDCS effects by exploring dose-response relationships at different levels, enabling a direct link between electric field variability and the neural response to tDCS. The results indicate that network-based analysis provides valuable insights into the dependency of tDCS neuromodulatory effects on the individual's regional current dose. Integration of dose-response relationships can inform dose optimization, customization, or the extraction of predictive/treatment-response biomarkers in future brain stimulation studies.

Are we really targeting and stimulating DLPFC by placing transcranial electrical stimulation (tES) electrodes over F3/F4?

In many clinical trials involving transcranial electrical stimulation (tES), target electrodes are typically placed over DLPFC with the assumption that this will primarily stimulate the underlying brain region. However, our study aimed to evaluate the electric fields (EF) that are actually delivered and identify prefrontal regions that may be inadvertently targeted in DLPFC tES. Head models were generated from the Human Connectome Project database's T1 + T2-weighted MRIs of 80 healthy adults. Two common DLPFC montages were simulated; symmetric-F4/F3, and asymmetric-F4/Fp1. Averaged EF was extracted from (1) the center of the target electrode (F4), and (2) the top 1% of voxels showing the strongest EF in individualized EF maps. Interindividual variabilities were quantified with the standard deviation of EF peak location/value. Similar steps were repeated with 66 participants with methamphetamine use disorder (MUDs) as an independent clinical population. In healthy adults, the group-level location of EF peaks was situated in the medial-frontopolar, and the individualized EF peaks were positioned in a cube with a volume of 29 cm3 /46 cm3 (symmetric/asymmetric montages). EFs in the frontopolar area were significantly higher than EF "under" the target electrode in both symmetric (peak: 0.41 ± 0.06, F4:0.22 ± 0.04) and asymmetric (peak: 0.38 ± 0.04, F4:0.2 ± 0.04) montages (Heges'g > 0.7). Similar results with slight between-group differences were found in MUDs. We highlighted that in common DLPFC tES montages, in addition to interindividual/intergroup variability, the frontopolar received the highest EFs rather than DLPFC as the main target. We specifically recommended considering the potential involvement of the frontopolar area as a mechanism underlying the effectiveness of DLPFC tES protocols.

Closing the loop between brain and electrical stimulation: towards precision neuromodulation treatments.

One of the most critical challenges in using noninvasive brain stimulation (NIBS) techniques for the treatment of psychiatric and neurologic disorders is inter- and intra-individual variability in response to NIBS. Response variations in previous findings suggest that the one-size-fits-all approach does not seem the most appropriate option for enhancing stimulation outcomes. While there is a growing body of evidence for the feasibility and effectiveness of individualized NIBS approaches, the optimal way to achieve this is yet to be determined. Transcranial electrical stimulation (tES) is one of the NIBS techniques showing promising results in modulating treatment outcomes in several psychiatric and neurologic disorders, but it faces the same challenge for individual optimization. With new computational and methodological advances, tES can be integrated with real-time functional magnetic resonance imaging (rtfMRI) to establish closed-loop tES-fMRI for individually optimized neuromodulation. Closed-loop tES-fMRI systems aim to optimize stimulation parameters based on minimizing differences between the model of the current brain state and the desired value to maximize the expected clinical outcome. The methodological space to optimize closed-loop tES fMRI for clinical applications includes (1) stimulation vs. data acquisition timing, (2) fMRI context (task-based or resting-state), (3) inherent brain oscillations, (4) dose-response function, (5) brain target trait and state and (6) optimization algorithm. Closed-loop tES-fMRI technology has several advantages over non-individualized or open-loop systems to reshape the future of neuromodulation with objective optimization in a clinically relevant context such as drug cue reactivity for substance use disorder considering both inter and intra-individual variations. Using multi-level brain and behavior measures as input and desired outcomes to individualize stimulation parameters provides a framework for designing personalized tES protocols in precision psychiatry.

Optimizing Individual Targeting of Fronto-Amygdala Network with Transcranial Magnetic Stimulation (TMS): Biophysical, Physiological and Behavioral Variations in People with Methamphetamine Use Disorder.

Background: Previous studies in people with substance use disorders (SUDs) have implicated both the frontopolar cortex and amygdala in drug cue reactivity and craving, and amygdala-frontopolar coupling is considered a marker of early relapse risk. Accumulating data highlight that the frontopolar cortex can be considered a promising therapeutic target for transcranial magnetic stimulation (TMS) in SUDs. However, one-size-fits-all approaches to TMS targets resulted in substantial variation in both physiological and behavioral outcomes. Individualized TMS approaches to target cortico-subcortical circuits like amygdala-frontopolar have not yet been investigated in SUDs. Objective: Here, we (1) defined individualized TMS target location based on functional connectivity of the amygdala-frontopolar circuit while people were exposed to drug-related cues, (2) optimized coil orientation based on maximizing electric field (EF) perpendicular to the individualized target, and (3) harmonized EF strength in targeted brain regions across a population. Method: MRI data including structural, resting-state, and task-based fMRI data were collected from 60 participants with methamphetamine use disorders (MUDs). Craving scores based on a visual analog scale were collected immediately before and after the MRI session. We analyzed inter-subject variability in the location of TMS targets based on the maximum task-based connectivity between the left medial amygdala (with the highest functional activity among subcortical areas during drug cue exposure) and frontopolar cortex using psychophysiological interaction (PPI) analysis. Computational head models were generated for all participants and EF simulations were calculated for fixed vs. optimized coil location (Fp1/Fp2 vs. individualized maximal PPI location), orientation (AF7/AF8 vs. orientation optimization algorithm), and stimulation intensity (constant vs. adjusted intensity across the population). Results: Left medial amygdala with the highest (mean ± SD: 0.31±0.29) functional activity during drug cue exposure was selected as the subcortical seed region. Amygdala-to-whole brain PPI analysis showed a significant cluster in the prefrontal cortex (cluster size: 2462 voxels, cluster peak in MNI space: [25 39 35]) that confirms cortico-subcortical connections. The location of the voxel with the most positive amygdala-frontopolar PPI connectivity in each participant was considered as the individualized TMS target (mean ± SD of the MNI coordinates: [12.6 64.23 -0.8] ± [13.64 3.50 11.01]). Individual amygdala-frontopolar PPI connectivity in each participant showed a significant correlation with VAS scores after cue exposure (R=0.27, p=0.03). Averaged EF strength in a sphere with r = 5mm around the individualized target location was significantly higher in the optimized (mean ± SD: 0.99 ± 0.21) compared to the fixed approach (Fp1: 0.56 ± 0.22, Fp2: 0.78 ± 0.25) with large effect sizes (Fp1: p = 1.1e-13, Hedges'g = 1.5, Fp2: p = 1.7e-5, Hedges'g = 1.26). Adjustment factor to have identical 1 V/m EF strength in a 5mm sphere around the individualized targets ranged from 0.72 to 2.3 (mean ± SD: 1.07 ± 0.29). Conclusion: Our results show that optimizing coil orientation and stimulation intensity based on individualized TMS targets led to stronger electric fields in the targeted brain regions compared to a one-size-fits-all approach. These findings provide valuable insights for refining TMS therapy for SUDs by optimizing the modulation of cortico-subcortical circuits.

Habituation or sensitization of brain response to food cues: Temporal dynamic analysis in an functional magnetic resonance imaging study.

Introduction: In the modern obesogenic environment, heightened reactivity to food-associated cues plays a major role in overconsumption by evoking appetitive responses. Accordingly, functional magnetic resonance imaging (fMRI) studies have implicated regions of the salience and rewards processing in this dysfunctional food cue-reactivity, but the temporal dynamics of brain activation (sensitization or habituation over time) remain poorly understood. Methods: Forty-nine obese or overweight adults were scanned in a single fMRI session to examine brain activation during the performance of a food cue-reactivity task. A general linear model (GLM) was used to validate the activation pattern of food cue reactivity in food > neutral contrast. The linear mixed effect models were used to examine the effect of time on the neuronal response during the paradigm of food cue reactivity. Neuro-behavioral relationships were investigated with Pearson's correlation tests and group factor analysis (GFA). Results: A linear mixed-effect model revealed a trend for the time-by-condition interactions in the left medial amygdala [t(289) = 2.21, ß = 0.1, P = 0.028], right lateral amygdala [t(289) = 2.01, ß = 0.26, P = 0.045], right nucleus accumbens (NAc) [t(289) = 2.81, ß = 0.13, P = 0.005] and left dorsolateral prefrontal cortex (DLPFC) [t(289) = 2.58, ß = 0.14, P = 0.01], as well as in the left superior temporal cortex [42 Area: t(289) = 2.53, ß = 0.15, P = 0.012; TE1.0_TE1.2 Area: t(289) = 3.13, ß = 0.27, P = 0.002]. Habituation of blood-oxygenation-level-dependent (BOLD) signal during exposure to food vs. neutral stimuli was evident in these regions. We have not found any area in the brain with significant increased response to food-related cues over time (sensitization). Our results elucidate the temporal dynamics of cue-reactivity in overweight and obese individuals with food-induced craving. Both subcortical areas involved in reward processing and cortical areas involved in inhibitory processing are getting habituated over time in response to food vs. neutral cues. There were significant bivariate correlations between self-report behavioral/psychological measures with individual habituation slopes for the regions with dynamic activity, but no robust cross-unit latent factors were identified between the behavioral, demographic, and self-report psychological groups. Discussion: This work provides novel insights into dynamic neural circuit mechanisms supporting food cue reactivity, thereby suggesting pathways in biomarker development and cue-desensitization interventions.

Effects of opium use on one-year major adverse cardiovascular events (MACE) in the patients with ST-segment elevation MI undergoing primary PCI: a propensity score matched - machine learning based study.

BACKGROUND: Considerable number of people still use opium worldwide and many believe in opium's health benefits. However, several studies proved the detrimental effects of opium on the body, especially the cardiovascular system. Herein, we aimed to provide the first evidence regarding the effects of opium use on one-year major adverse cardiovascular events (MACE) in the patients with ST-elevation MI (STEMI) who underwent primary PCI. METHODS: We performed a propensity score matching of 2:1 (controls: opium users) that yielded 518 opium users and 1036 controls. Then, we performed conventional statistical and machine learning analyses on these matched cohorts. Regarding the conventional analysis, we performed multivariate analysis for hazard ratio (HR) of different variables and MACE and plotted Kaplan Meier curves. In the machine learning section, we used two tree-based ensemble algorithms, Survival Random Forest and XGboost for survival analysis. Variable importance (VIMP), tree minimal depth, and variable hunting were used to identify the importance of opium among other variables. RESULTS: Opium users experienced more one-year MACE than their counterparts, although it did not reach statistical significance (Opium: 72/518 (13.9%), Control: 112/1036 (10.8%), HR: 1.27 (95% CI: 0.94-1.71), adjusted p-value = 0.136). Survival random forest algorithm ranked opium use as 13th, 13th, and 12th among 26 variables, in variable importance, minimal depth, and variable hunting, respectively. XGboost revealed opium use as the 12th important variable. Partial dependence plot demonstrated that opium users had more one-year MACE compared to non-opium-users. CONCLUSIONS: Opium had no protective effects on one-year MACE after primary PCI on patients with STEMI. Machine learning and one-year MACE analysis revealed some evidence of its possible detrimental effects, although the evidence was not strong and significant. As we observed no strong evidence on protective or detrimental effects of opium, future STEMI guidelines may provide similar strategies for opium and non-opium users, pending the results of forthcoming studies. Governments should increase the public awareness regarding the evidence for non-beneficial or detrimental effects of opium on various diseases, including the outcomes of primary PCI, to dissuade many users from relying on false beliefs about opium's benefits to continue its consumption.

Key implementation factors in telemedicine-delivered medications for opioid use disorder: a scoping review informed by normalisation process theory.

Telemedicine could improve access to medications for opioid use disorder (MOUD). Telemedicine-delivered MOUD (TMOUD) has expanded substantially in response to the restrictions imposed by the COVID-19 pandemic on in-person clinical contact, yet this expansion has not happened consistently across all health systems and countries. This Review aims to understand key factors in TMOUD implementation that might explain variations in uptake. We did a scoping review using three English language databases for articles reporting on the implementation of TMOUD services. 57 peer-reviewed articles were identified, subjected to open coding and thematic analysis, and further interpreted through normalisation process theory (NPT). NPT was originally used to evaluate telehealth innovations and has been applied extensively to describe, assess, and develop the implementation potential of a broad range of complex health-care interventions. By categorising our findings according to the four core NPT constructs of coherence, cognitive participation, collective action, and reflexive monitoring, we aim to rationalise the current evidence base to show the workability of TMOUD in practice. We find that variations in TMOUD models in practice depend on organisations' attitudes towards risk, clinicians' tensions around giving up control over standard practices, organisation-level support in overcoming operational and technological challenges, and evaluation methods that might neglect a potential widening of the digital divide.

Cortical Morphology in Cannabis Use Disorder: Implications for Transcranial Direct Current Stimulation Treatment.

Introduction: Transcranial direct current stimulation (tDCS) has been studied as an adjunctive treatment option for substance use disorders (SUDs). Alterations in brain structure following SUD may change tDCS-induced electric field (EF) and subsequent responses; however, group-level differences between healthy controls (HC) and participants with SUDs in terms of EF and its association with cortical architecture have not yet been modeled quantitatively. This study provides a methodology for group-level analysis of computational head models to investigate the influence of cortical morphology metrics on EFs. Methods: Whole-brain surface-based morphology was conducted, and cortical thickness, volume, and surface area were compared between participants with cannabis use disorders (CUD) (n=20) and age-matched HC (n=22). Meanwhile, EFs were simulated for bilateral tDCS over the dorsolateral prefrontal cortex. The effects of structural alterations on EF distribution were investigated based on individualized computational head models. Results: Regarding EF, no significant difference was found within the prefrontal cortex; however, EFs were significantly different in left-postcentral and right-superior temporal gyrus (P<0.05) with higher levels of variance in CUD compared to HC [F(39, 43)=5.31, P<0.0001, C=0.95]. Significant differences were observed in cortical area (caudal anterior cingulate and rostral middle frontal), thickness (lateral orbitofrontal), and volume (paracentral and fusiform) between the two groups. Conclusion: Brain morphology and tDCS-induced EFs may be changed following CUD; however, differences between CUD and HCs in EFs do not always overlap with brain areas that show structural alterations. To sufficiently modulate stimulation targets, whether individuals with CUD need different stimulation doses based on tDCS target location should be checked.

DLPFC stimulation alters large-scale brain networks connectivity during a drug cue reactivity task: A tDCS-fMRI study.

Transcranial direct current stimulation (tDCS) is a promising intervention for reducing craving/consumption in individuals with substance use disorders. However, its exact mechanism of action has not yet been well explored. We aimed to examine the network-based effects of tDCS while people with methamphetamine use disorders (MUDs) were exposed to drug cues. In a randomized, double-blind sham-controlled trial with a crossover design, 15 participants with MUDs were recruited to receive 20 min of active/sham tDCS with an anode/cathode over F4/F3. MRI data, including structural and task-based functional MRI during a standard drug cue-reactivity task, were collected immediately before and after stimulation sessions. Craving scores were also recorded before and after MRI scans. Individualized head models were generated to determine brain regions with strong electric fields (EFs). Using atlas-based parcellation of head models, averaged EFs were extracted from the main nodes of three large-scale networks that showed abnormalities in MUDs; executive control (ECN), default mode (DMN), and ventral attention (VAN) networks. Main nodes with high EF intensity were used as seed regions for task-based functional connectivity (FC) [using generalized psychophysiological interaction (gPPI)] and activity [using a general linear model (GLM)] calculations. Subjective craving showed a significant reduction in immediate craving after active (-15.42 ± 5.42) compared to sham (-1 ± 2.63). In seed-to-whole brain results, the PFC node in ECN showed an enhanced PPI connectivity with precuneus and visual cortex; the cluster center in MNI (6, -84, -12); the PFC node in DMN showed a decreased PPI connectivity with contralateral parietal cortex;(-48, -60, 46). ROI-to-ROI results showed increased PPI connectivity within/between ECN-VAN while connectivity between ECN-DMN decreased. In line with connectivity, functional activity in the right PFC node in DMN decreased after tDCS while activity in PFC nodes of ECN/VAN increased. EF calculations in PFC nodes revealed that EF in DMN was outward, while the direction of EFs was inward in ECN/VAN. This study provides new insight into neural circuitry underlying MUDs that can be modulated by tDCS at the network level and specifically suggests that bilateral tDCS increases cortical excitability in ECN and VAN, while it has opposite effects on DMN that may be related to the direction of EFs.

Online closed-loop real-time tES-fMRI for brain modulation: A technical report.

Recent studies suggest that transcranial electrical stimulation (tES) can be performed during functional magnetic resonance imaging (fMRI). The novel approach of using concurrent tES-fMRI to modulate and measure targeted brain activity/connectivity may provide unique insights into the causal interactions between the brain neural responses and psychiatric/neurologic signs and symptoms, and importantly, guide the development of new treatments. However, tES stimulation parameters to optimally influence the underlying brain activity may vary with respect to phase difference, frequency, intensity, and electrode's montage among individuals. Here, we propose a protocol for closed-loop tES-fMRI to optimize the frequency and phase difference of alternating current stimulation (tACS) for two nodes (frontal and parietal regions) in individual participants. We carefully considered the challenges in an online optimization of tES parameters with concurrent fMRI, specifically in its safety, artifact in fMRI image quality, online evaluation of the tES effect, and parameter optimization method, and we designed the protocol to run an effective study to enhance frontoparietal connectivity and working memory performance with the optimized tACS using closed-loop tES-fMRI. We provide technical details of the protocol, including electrode types, electrolytes, electrode montages, concurrent tES-fMRI hardware, online fMRI processing pipelines, and the optimization algorithm. We confirmed the implementation of this protocol worked successfully with a pilot experiment.

Digitalized transcranial electrical stimulation: A consensus statement.

OBJECTIVE: Although relatively costly and non-scalable, non-invasive neuromodulation interventions are treatment alternatives for neuropsychiatric disorders. The recent developments of highly-deployable transcranial electric stimulation (tES) systems, combined with mobile-Health technologies, could be incorporated in digital trials to overcome methodological barriers and increase equity of access. The study aims are to discuss the implementation of tES digital trials by performing a systematic scoping review and strategic process mapping, evaluate methodological aspects of tES digital trial designs, and provide Delphi-based recommendations for implementing digital trials using tES. METHODS: We convened 61 highly-productive specialists and contacted 8 tES companies to assess 71 issues related to tES digitalization readiness, and processes, barriers, advantages, and opportunities for implementing tES digital trials. Delphi-based recommendations (>60% agreement) were provided. RESULTS: The main strengths/opportunities of tES were: (i) non-pharmacological nature (92% of agreement), safety of these techniques (80%), affordability (88%), and potential scalability (78%). As for weaknesses/threats, we listed insufficient supervision (76%) and unclear regulatory status (69%). Many issues related to methodological biases did not reach consensus. Device appraisal showed moderate digitalization readiness, with high safety and potential for trial implementation, but low connectivity. CONCLUSIONS: Panelists recognized the potential of tES for scalability, generalizability, and leverage of digital trials processes; with no consensus about aspects regarding methodological biases. SIGNIFICANCE: We further propose and discuss a conceptual framework for exploiting shared aspects between mobile-Health tES technologies with digital trials methodology to drive future efforts for digitizing tES trials.

Transcranial direct current stimulation to modulate fMRI drug cue reactivity in methamphetamine users: A randomized clinical trial.

Transcranial direct current stimulation (tDCS) has been studied as a therapeutic option to alter maladaptive brain functions associated with chronic substance use. We present a randomized, triple-blind, sham-controlled, clinical trial to determine the neural substrates of tDCS effects on drug craving. Sixty participants with methamphetamine use disorder were assigned to two groups: active tDCS (5 x 7 cm2 , 2 mA, 20 min, anode/cathode over the F4/Fp1) and sham stimulation. Neuroimaging data of a methamphetamine cue reactivity task were collected immediately before and after stimulation. There was a significant reduction in self-reported craving after stimulation without any significant effect of time-by-group interaction. Our whole-brain analysis demonstrated that there was a global decrease in brain reactivity to cues following sham but not active tDCS. There were significant time-by-group interactions in five main clusters in middle and inferior frontal gyri, anterior insula, inferior parietal lobule, and precuneus with higher activations after active stimulation. There was a significant effect of stimulation type in the relationship between electrical current at the individual level and changes in task-modulated activation. Brain regions with the highest electric current in the prefrontal cortex showed a significant time-by-group interaction in task-modulated connectivity in the frontoparietal network. In this trial, there was no significant effect of the one session of active-F4/Fp1 tDCS on drug craving self-report compared to sham stimulation. However, activation and connectivity differences induced by active compared to sham stimulation suggested some potential mechanisms of tDCS to modulate neural response to drug cues.

Task-Dependent Effective Connectivity of the Reward Network During Food Cue-Reactivity: A Dynamic Causal Modeling Investigation.

Neural reactivity to food cues may play a central role in overeating and excess weight gain. Functional magnetic resonance imaging (fMRI) studies have implicated regions of the reward network in dysfunctional food cue-reactivity, but neural interactions underlying observed patterns of signal change remain poorly understood. Fifty overweight and obese participants with self-reported cue-induced food craving viewed food and neutral cues during fMRI scanning. Regions of the reward network with significantly greater food versus neutral cue-reactivity were used to specify plausible models of task-related neural interactions underlying the observed blood oxygenation level-dependent (BOLD) signal, and a bi-hemispheric winning model was identified in a dynamic causal modeling (DCM) framework. Neuro-behavioral correlations are investigated with group factor analysis (GFA) and Pearson's correlation tests. The ventral tegmental area (VTA), amygdalae, and orbitofrontal cortices (OFC) showed significant food cue-reactivity. DCM suggests these activations are produced by largely reciprocal dynamic signaling between these regions, with food cues causing regional disinhibition and an apparent shifting of activity to the right amygdala. Intrinsic self-inhibition in the VTA and right amygdala is negatively correlated with measures of food craving and hunger and right-amygdalar disinhibition by food cues is associated with the intensity of cue-induced food craving, but no robust cross-unit latent factors were identified between the neural group and behavioral or demographic variable groups. Our results suggest a rich array of dynamic signals drive reward network cue-reactivity, with the amygdalae mediating much of the dynamic signaling between the VTA and OFCs. Neuro-behavioral correlations suggest particularly crucial roles for the VTA, right amygdala, and the right OFC-amygdala connection but the more robust GFA identified no cross-unit factors, so these correlations should be interpreted with caution. This investigation provides novel insights into dynamic circuit mechanisms with etiologic relevance to obesity, suggesting pathways in biomarker development and intervention.

Effects of Transcranial Direct Current Stimulation on Attentional Bias to Methamphetamine Cues and Its Association With EEG-Derived Functional Brain Network Topology.

BACKGROUND: Although transcranial direct current stimulation (tDCS) has shown to potentially mitigate drug craving and attentional bias to drug-related stimuli, individual differences in such modulatory effects of tDCS are less understood. In this study, we aimed to investigate a source of the inter-subject variability in the tDCS effects that can be useful for tDCS-based treatments of individuals with methamphetamine (MA) use disorder (IMUD). METHODS: Forty-two IMUD (all male) were randomly assigned to receive a single-session of either sham or real bilateral tDCS (anodal right/cathodal left) over the dorsolateral prefrontal cortex. The tDCS effect on MA craving and biased attention to drug stimuli were investigated by quantifying EEG-derived P3 (a measure of initial attentional bias) and late positive potential (LPP; a measure of sustained motivated attention) elicited by these stimuli. To assess the association of changes in P3 and LPP with brain connectivity network (BCN) topology, the correlation between topology metrics, specifically those related to the efficiency of information processing, and the tDCS effect was investigated. RESULTS: The P3 amplitude significantly decreased following the tDCS session, whereas the amplitudes increased in the sham group. The changes in P3 amplitudes were significantly correlated with communication efficiency measured by BCN topology metrics (r = -0.47, P = .03; r = -0.49, P = .02). There was no significant change in LPP amplitude due to the tDCS application. CONCLUSIONS: These findings validate that tDCS mitigates initial attentional bias, but not the sustained motivated attention, to MA stimuli. Importantly, however, results also show that the individual differences in the effects of tDCS may be underpinned by communication efficiency of the BCN topology, and therefore, these BCN topology metrics may have the potential to robustly predict the effectiveness of tDCS-based interventions on MA craving and attentional bias to MA stimuli among IMUD.

Transcranial direct current stimulation to modulate brain reactivity to food cues in overweight and obese adults: study protocol for a randomized controlled trial with fMRI (NeuroStim-Obesity).

BACKGROUND: With increasing obese populations worldwide, developing interventions to modulate food-related brain processes and functions is particularly important. Evidence suggests that transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) may modulate the reward-control balance towards facilitation of cognitive control and possible suppression of reward-related mechanisms that drive food cue-induced craving. This protocol describes a clinical trial that investigates the neurocognitive mechanisms of action for tDCS to modulate food cue-reactivity and cravings in people with obesity. METHOD: The NeuroStim-Obesity trial is a prospective, randomized, sham-controlled, double-blind single-session tDCS trial targeting food craving in those with obesity or overweighed. Once randomized, 64 adults with obesity or overweighed complete one session in which they receive either active or sham tDCS over the DLPFC (anode F4 and cathode F3, 2 mA intensity for 20 min). The primary outcome is change in neural response to the food cue-reactivity task in the ventral striatum after a single-session bilateral tDCS compared to sham stimulation. Secondary outcomes include changes in food craving evaluated by the Food Craving Questionnaire-State (FCQ-S). We will also explore the predictive role of brain structure and functional networks assessed by structural and functional magnetic resonance imaging (MRI) during both task performance and the resting-state that are acquired pre- and post-intervention to predict response to tDCS. DISCUSSION: The results will provide novel insight into neuroscience for the efficacy of tDCS and will advance the field towards precision medicine for obesity. Exploratory results will examine the potential predictive biomarkers for tDCS response and eventually provide personalized intervention for the treatment of obesity. TRIAL REGISTRATION: Iranian Registry of Clinical Trials (IRCT) IRCT20121020011172N4 . Retrospectively registered on 4 June 2020.