Background The core intrinsic connectivity networks (core-ICNs), encompassing the default-mode network (DMN), salience network (SN) and central executive network (CEN), have been shown to be dysfunctional in individuals with internalizing disorders (IDs, e.g. major depressive disorder, MDD; generalized anxiety disorder, GAD; social anxiety disorder, SOC). As such, source-localized, closed-loop brain training of electrophysiological signals, also known as standardized low-resolution electromagnetic tomography (sLORETA) neurofeedback (NFB), targeting key cortical nodes within these networks has the potential to reduce symptoms associated with IDs and restore normal core ICN function. We intend to conduct a randomized, double-blind (participant and assessor), sham-controlled, parallel-group (3-arm) trial of sLORETA infraslow (<0.1 Hz) fluctuation neurofeedback (sLORETA ISF-NFB) 3 times per week over 4 weeks in participants (n=60) with IDs. Our primary objectives will be to examine patient-reported outcomes (PROs) and neurophysiological measures to (1) compare the potential effects of sham ISF-NFB to either genuine 1-region ISF-NFB or genuine 2-region ISF-NFB, and (2) assess for potential associations between changes in PRO scores and modifications of electroencephalographic (EEG) activity/connectivity within/between the trained regions of interest (ROIs). As part of an exploratory analysis, we will investigate the effects of additional training sessions and the potential for the potentiation of the effects over time. Methods We will randomly assign participants who meet the criteria for MDD, GAD, and/or SOC per the MINI (Mini International Neuropsychiatric Interview for DSM-5) to one of three groups: (1) 12 sessions of posterior cingulate cortex (PCC) ISF-NFB up-training (n=15), (2) 12 sessions of concurrent PCC ISF up-training and dorsal anterior cingulate cortex (dACC) ISF-NFB down-training (n=15), or (3) 6 sessions of yoked-sham training followed by 6 sessions genuine ISF-NFB (n=30). Transdiagnostic PROs (Hospital Anxiety and Depression Scale, HADS; Inventory of Depression and Anxiety Symptoms – Second Version, IDAS-II; Multidimensional Emotional Disorder Inventory, MEDI; Intolerance of Uncertainty Scale – Short Form, IUS-12; Repetitive Thinking Questionnaire, RTQ-10) as well as resting-state neurophysiological measures (full-band EEG and ECG) will be collected from all subjects during two baseline sessions (approximately 1 week apart) then at post 6 sessions, post 12 sessions, and follow-up (1 month later). We will employ Bayesian methods in R and advanced source-localisation software (i.e. exact low-resolution brain electromagnetic tomography; eLORETA) in our analysis. Discussion This protocol will outline the rationale and research methodology for a clinical pilot trial of sLORETA ISF-NFB targeting key nodes within the core-ICNs in a female ID population with the primary aims being to assess its potential efficacy via transdiagnostic PROs and relevant neurophysiological measures. Trial registration Our study was prospectively registered with the Australia New Zealand Clinical Trials Registry (ANZCTR; Trial ID: ACTRN12619001428156). Registered on October 15, 2019.

Background: Mental illnesses are increasing worldwide with the internalizing disorders (IDs; e.g., anxiety disorders, depressive disorders) being the most prevalent. Current first-line therapies (e.g., pharmacotherapy) offer high failure rates and substantial side effects. Electroencephalographic neurofeedback (EEG-NFB) has been shown to be an effective and safe treatment for these conditions; however, there remains much doubt regarding the existence of specificity (i.e., clinical effects specific to the modulation of the EEG variables of interest). This is a protocol for a quantitative review that will attempt to determine if there is evidence for EEG-NFB specificity in the treatment of IDs. Methods: We will consider all published and unpublished randomized, double-blind (i.e., trainees and raters), sham/placebo-controlled (i.e., feedback contingent on a random signal, the activity from a different person's brain, or an unrelated signal from the trainee's own brain) trials involving humans with at least one ID diagnosis without exclusion by language, locality, ethnicity, age, or sex. Effect sizes will be calculated for individual studies and combined in a meta-analysis. Discussion: This protocol outlines the research methodology for a quantitative review undertaken to assess for evidence of EEG-NFB specificity in the treatment of IDs. Registration: This review was registered with the International Prospective Register of Systematic Reviews (PROSPERO; registration number: CRD42020159702).

Electroencephalographic (EEG) alterations have been demonstrated in acute, chronic, and experimentally induced musculoskeletal (MSK) pain conditions. However, there is no cumulative evidence on the associated EEG characteristics differentiating acute, chronic, and experimentally induced musculoskeletal pain states, especially compared to healthy controls. The present systematic review was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines (PRISMA) to review and summarize available evidence for cortical brain activity and connectivity alterations in acute, chronic, and experimentally induced MSK pain states. Five electronic databases were systematically searched from their inception to 2022. A total of 3471 articles were screened, and 26 full articles (five studies on chronic pain and 21 studies on experimentally induced pain) were included for the final synthesis. Using the Downs and Black risk of assessment tool, 92% of the studies were assessed as low to moderate quality. The review identified a ‘very low’ level of evidence for the changes in EEG and subjective outcome measures for both chronic and experimentally induced MSK pain based on the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) criteria. Overall, the findings of this review indicate a trend toward decreased alpha and beta EEG power in evoked chronic clinical pain conditions and increased theta and alpha power in resting-state EEG recorded from chronic MSK pain conditions. EEG characteristics are unclear under experimentally induced pain conditions.

Background: The core intrinsic connectivity networks (ICNs), encompassing the default-mode network (DMN), salience network (SN) and central executive network (CEN), have been shown to be dysfunctional in individual’s with internalizing disorders (IDs; e.g. major depressive disorder, MDD; generalized anxiety disorder, GAD; social anxiety disorder, SOC). As such, source-localised electroencephalogram neurofeedback (EEG-NFB) therapy targeting key cortical nodes within these networks has the potential to reduce symptoms associated with IDs and restore normal core ICN function. We intend to conduct a transdiagnostic, randomized, double-blind, sham-controlled, dose-response, parallel-group trial of standardized low-resolution electromagnetic tomography electrophysiological infraslow (<0.1 Hz) fluctuation neurofeedback (sLORETA eISF-NFB) 3 times per week over 4 weeks in participants (n=60) with IDs. Our primary aim will be to assess the clinical efficacy of sLORETA eISF-NFB via relevant patient-reported outcomes (PROs). Methods: We will randomly assign participants with a current diagnosis of MDD, GAD, and/or SOC to one of four groups: 1) 12 sessions of posterior cingulate cortex (PCC) up-training (n=15), 2) 6 sessions of yoked-sham training followed by 6 sessions of PCC up-training (n=15), 3) 12 sessions of concurrent mid-cingulate (MCC) down-training and PCC up-training (n=15), or 4) 6 sessions of yoked-sham training followed by 6 sessions of concurrent MCC down-training and PCC up-training. Transdiagnostic PROs, as well as resting-state neuro-physiological measures (EEG; electrocardiography, ECG; electrodermal activity, EDA), will be collected from all subjects at baseline, mid-training, 1 week post-training, and 1 month post-training. We will further compare baseline PROs and neuro-physiological measures to age- and sex-matched non-ID (i.e. no ID diagnosis) controls. Discussion: This protocol will outline the rationale and research methodology for a clinical trial of sLORETA eISF-NFB targeting key nodes within the core ICNs in a population with IDs with the primary aim being to assess its specific (e.g. non-placebo induced) efficacy via PROs. Trial Registration: Our study was prospectively registered with the Australia New Zealand Clinical Trials Registry (ANZCTR; Trial Id: ACTRN12619001428156)

IntroductionInternalizing disorders (IDs), e.g., major depressive disorder (MDD), posttraumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD) are the most prevalent psychopathologies experienced worldwide. Current first-line therapies (i.e., pharmacotherapy and/or psychotherapy) offer high failure rates, limited accessibility, and substantial side-effects. Electroencephalography (EEG) guided closed-loop brain training, also known as EEG-neurofeedback (EEG-NFB), is believed to be a safe and effective alternative, however, there is much debate in the field regarding the existence of specificity [i.e., clinical effects specific to the modulation of the targeted EEG variable(s)]. This review was undertaken to determine if there is evidence for EEG-NFB specificity in the treatment of IDs.MethodsWe considered only randomized, double-blind, sham-controlled trials. Outcomes of interest included self/parent/teacher reports and clinician ratings of ID-related symptomatology.ResultsOf the four reports (total participant number = 152) meeting our eligibility criteria, three had point estimates suggesting small to moderate effect sizes favoring genuine therapy over sham, however, due to small sample sizes, all 95% confidence intervals (CIs) were wide and spanned the null. The fourth trial had yet to post results as of the submission date of this review. The limited overall number of eligible reports (and participants), large degree of inter-trial heterogeneity, and restricted span of ID populations with published/posted outcome data (i.e., PTSD and OCD) precluded a quantitative synthesis.DiscussionThe current literature suggests that EEG-NFB may induce specific effects in the treatment of some forms of IDs, however, the evidence is very limited. Ultimately, more randomized, double-blind, sham-controlled trials encompassing a wider array of ID populations are needed to determine the existence and, if present, degree of EEG-NFB specificity in the treatment of IDs.Systematic Review Registration[https://www.crd.york.ac.uk/prospero], identifier [CRD42020159702].