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.

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.

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.

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.

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.

A checklist for assessing the methodological quality of concurrent tES-fMRI studies (ContES checklist): a consensus study and statement.

Low-intensity transcranial electrical stimulation (tES), including alternating or direct current stimulation, applies weak electrical stimulation to modulate the activity of brain circuits. Integration of tES with concurrent functional MRI (fMRI) allows for the mapping of neural activity during neuromodulation, supporting causal studies of both brain function and tES effects. Methodological aspects of tES-fMRI studies underpin the results, and reporting them in appropriate detail is required for reproducibility and interpretability. Despite the growing number of published reports, there are no consensus-based checklists for disclosing methodological details of concurrent tES-fMRI studies. The objective of this work was to develop a consensus-based checklist of reporting standards for concurrent tES-fMRI studies to support methodological rigor, transparency and reproducibility (ContES checklist). A two-phase Delphi consensus process was conducted by a steering committee (SC) of 13 members and 49 expert panelists through the International Network of the tES-fMRI Consortium. The process began with a circulation of a preliminary checklist of essential items and additional recommendations, developed by the SC on the basis of a systematic review of 57 concurrent tES-fMRI studies. Contributors were then invited to suggest revisions or additions to the initial checklist. After the revision phase, contributors rated the importance of the 17 essential items and 42 additional recommendations in the final checklist. The state of methodological transparency within the 57 reviewed concurrent tES-fMRI studies was then assessed by using the checklist. Experts refined the checklist through the revision and rating phases, leading to a checklist with three categories of essential items and additional recommendations: (i) technological factors, (ii) safety and noise tests and (iii) methodological factors. The level of reporting of checklist items varied among the 57 concurrent tES-fMRI papers, ranging from 24% to 76%. On average, 53% of checklist items were reported in a given article. In conclusion, use of the ContES checklist is expected to enhance the methodological reporting quality of future concurrent tES-fMRI studies and increase methodological transparency and reproducibility.

fMRI and transcranial electrical stimulation (tES): A systematic review of parameter space and outcomes.

The combination of non-invasive brain stimulation interventions with human brain mapping methods have supported research beyond correlational associations between brain activity and behavior. Functional MRI (fMRI) partnered with transcranial electrical stimulation (tES) methods, i.e., transcranial direct current (tDCS), transcranial alternating current (tACS), and transcranial random noise (tRNS) stimulation, explore the neuromodulatory effects of tES in the targeted brain regions and their interconnected networks and provide opportunities for individualized interventions. Advances in the field of tES-fMRI can be hampered by the methodological variability between studies that confounds comparability/replicability. In order to explore variability in the tES-fMRI methodological parameter space (MPS), we conducted a systematic review of 222 tES-fMRI experiments (181 tDCS, 39 tACS and 2 tRNS) published before February 1, 2019, and suggested a framework to systematically report main elements of MPS across studies. Publications dedicated to tRNS-fMRI were not considered in this systematic review. We have organized main findings in terms of fMRI modulation by tES. tES modulates activation and connectivity beyond the stimulated areas particularly with prefrontal stimulation. There were no two studies with the same MPS to replicate findings. We discuss how to harmonize the MPS to promote replication in future studies.

Guidelines for TMS/tES clinical services and research through the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has broadly disrupted biomedical treatment and research including non-invasive brain stimulation (NIBS). Moreover, the rapid onset of societal disruption and evolving regulatory restrictions may not have allowed for systematic planning of how clinical and research work may continue throughout the pandemic or be restarted as restrictions are abated. The urgency to provide and develop NIBS as an intervention for diverse neurological and mental health indications, and as a catalyst of fundamental brain research, is not dampened by the parallel efforts to address the most life-threatening aspects of COVID-19; rather in many cases the need for NIBS is heightened including the potential to mitigate mental health consequences related to COVID-19. OBJECTIVE: To facilitate the re-establishment of access to NIBS clinical services and research operations during the current COVID-19 pandemic and possible future outbreaks, we develop and discuss a framework for balancing the importance of NIBS operations with safety considerations, while addressing the needs of all stakeholders. We focus on Transcranial Magnetic Stimulation (TMS) and low intensity transcranial Electrical Stimulation (tES) - including transcranial Direct Current Stimulation (tDCS) and transcranial Alternating Current Stimulation (tACS). METHODS: The present consensus paper provides guidelines and good practices for managing and reopening NIBS clinics and laboratories through the immediate and ongoing stages of COVID-19. The document reflects the analysis of experts with domain-relevant expertise spanning NIBS technology, clinical services, and basic and clinical research - with an international perspective. We outline regulatory aspects, human resources, NIBS optimization, as well as accommodations for specific demographics. RESULTS: A model based on three phases (early COVID-19 impact, current practices, and future preparation) with an 11-step checklist (spanning removing or streamlining in-person protocols, incorporating telemedicine, and addressing COVID-19-associated adverse events) is proposed. Recommendations on implementing social distancing and sterilization of NIBS related equipment, specific considerations of COVID-19 positive populations including mental health comorbidities, as well as considerations regarding regulatory and human resource in the era of COVID-19 are outlined. We discuss COVID-19 considerations specifically for clinical (sub-)populations including pediatric, stroke, addiction, and the elderly. Numerous case-examples across the world are described. CONCLUSION: There is an evident, and in cases urgent, need to maintain NIBS operations through the COVID-19 pandemic, including anticipating future pandemic waves and addressing effects of COVID-19 on brain and mind. The proposed robust and structured strategy aims to address the current and anticipated future challenges while maintaining scientific rigor and managing risk.

Methodology for tDCS integration with fMRI.

Understanding and reducing variability of response to transcranial direct current stimulation (tDCS) requires measuring what factors predetermine sensitivity to tDCS and tracking individual response to tDCS. Human trials, animal models, and computational models suggest structural traits and functional states of neural systems are the major sources of this variance. There are 118 published tDCS studies (up to October 1, 2018) that used fMRI as a proxy measure of neural activation to answer mechanistic, predictive, and localization questions about how brain activity is modulated by tDCS. FMRI can potentially contribute as: a measure of cognitive state-level variance in baseline brain activation before tDCS; inform the design of stimulation montages that aim to target functional networks during specific tasks; and act as an outcome measure of functional response to tDCS. In this systematic review, we explore methodological parameter space of tDCS integration with fMRI spanning: (a) fMRI timing relative to tDCS (pre, post, concurrent); (b) study design (parallel, crossover); (c) control condition (sham, active control); (d) number of tDCS sessions; (e) number of follow up scans; (f) stimulation dose and combination with task; (g) functional imaging sequence (BOLD, ASL, resting); and (h) additional behavioral (cognitive, clinical) or quantitative (neurophysiological, biomarker) measurements. Existing tDCS-fMRI literature shows little replication across these permutations; few studies used comparable study designs. Here, we use a representative sample study with both task and resting state fMRI before and after tDCS in a crossover design to discuss methodological confounds. We further outline how computational models of current flow should be combined with imaging data to understand sources of variability. Through the representative sample study, we demonstrate how modeling and imaging methodology can be integrated for individualized analysis. Finally, we discuss the importance of conducting tDCS-fMRI with stimulation equipment certified as safe to use inside the MR scanner, and of correcting for image artifacts caused by tDCS. tDCS-fMRI can address important questions on the functional mechanisms of tDCS action (e.g., target engagement) and has the potential to support enhancement of behavioral interventions, provided studies are designed rationally.

A novel approach to the extraction of fetal electrocardiogram based on empirical mode decomposition and correlation analysis.

Fetal heart rate monitoring is the process of checking the condition of the fetus during pregnancy and it would allow doctors and nurses to detect early signs of trouble during labor and delivery. The fetal ECG (FECG) signal is so weak and also is corrupted by other signals and noises, mainly by maternal ECG signal. It is so hard to acquire a noise-free, precise and reliable FECG using the conventional methods. In this study, a combination of empirical mode decomposition (EMD) algorithms, correlation and match filtering is used for extracting FECG from maternal abdominal ECG signals. The proposed method benefits from match filtering ability to detect fetal signal and QRS complex to detect weak QRS peaks. The combined method, has been applied successfully on different signal qualities, even for signals that their analysis was hard and complicated for other methods. This method is able to detect R-R intervals with high accuracy. It was proved that the complete ensemble empirical mode decomposition method provides a better frequency resolution of modes and also requires less iterations that leads to a considerably less computational cost than EMD and ensemble empirical mode decomposition and can reconstruct the FECG completely from the calculated modes. We believe that this method opens a new field in non-invasive maternal abdominal signal processing so the FECG signal could be extracted with high speed and accuracy.

Introducing a combined approach of empirical mode decomposition and PCA methods for maternal and fetal ECG signal processing.

OBJECTIVES: The purpose of this study was to evaluate the effectiveness of the non-linear adaptive combined approach on the analysis of maternal and fetal signals corrupted by noise. METHODS: Empirical mode decomposition (EMD) is a non-linear adaptive technic for data analysis and has been widely used in biomedical data. When we apply EMD on ECG signals, the number of modes that contain cardiac information may vary regarding the subject, type of the signal and recording conditions. This fact can cause some difficulties in signal reconstruction and noise removal using the derived modes. For overcoming this issue, we designed a method to combine principal component analysis (PCA) method with EMD to remove the correlation between the calculated modes and provide a smaller set of uncorrelated orthogonal. RESULTS: We have developed a combined method that proves the power of using PCA on the output of EMD method. The combined method reduces the power of oscillatory artifacts of the baseline. Thus, the PCA-EMD combination provides a noise-free signal. CONCLUSIONS: The combination of EMD and PCA methods worked well in being adaptive (from of EMD) and reconstruction (from PCA). It has been proved that this combined method is helpful in separating the signal components, especially in extracting the pure data from the baseline fluctuations.