Effect of high-definition transcranial direct current stimulation among late-subacute and chronic stroke survivors with fatigue: A randomized-controlled crossover trial protocol.

Post-stroke fatigue (PSF) is a commonly overlooked symptom that impacts daily functioning and quality of life. It is caused by altered functional connectivity within the brain networks, which can potentially be influenced by neuromodulation. Multiple cortical regions have been targeted to reduce PSF, but the most efficient ones remain uncertain. Therefore, we aim to identify the most appropriate cortical stimulation site to reduce PSF. Twenty participants with PSF will be included in this cross-over trial. Each participant will receive one session of active anodal high definition- transcranial direct current stimulation (HD-tDCS) over three different cortical areas and one session of sham tDCS in a cross-over manner, with a two-week of washout period in between. Pre- and post- fatigue will be assessed using Fatigue Severity Scale and fatigability using electromyography by determining the time to task failure. Resting-state electroencephalography will be performed before and after each stimulation session to determine the functional connectivity of the cortical areas stimulated.

EEG-Based Cortical Alterations in Individuals With Chronic Knee Pain Secondary to Osteoarthritis: A Cross-sectional Investigation.

Chronic painful knee osteoarthritis (OA) is a disabling physical health condition. Alterations in brain responses to arthritic changes in the knee may explain persistent pain. This study investigated source localized, resting-state electroencephalography activity and functional connectivity in people with knee OA, compared to healthy controls. Adults aged 44 to 85 years with knee OA (n = 37) and healthy control (n = 39) were recruited. Resting-state electroencephalography was collected for 10 minutes and decomposed into infraslow frequency (ISF) to gamma frequency bands. Standard low-resolution electromagnetic brain tomography statistical nonparametric maps were conducted, current densities of regions of interest were compared between groups and correlation analyses were performed between electroencephalography (EEG) measures and clinical pain and functional outcomes in the knee OA group. Standard low-resolution electromagnetic brain tomography nonparametric maps revealed higher (P = .006) gamma band activity over the right insula (RIns) in the knee OA group. A significant (P < .0001) reduction in ISF band activity at the pregenual anterior cingulate cortex, whereas higher theta, alpha, beta, and gamma band activity at the dorsal anterior cingulate cortex, pregenual anterior cingulate cortex, the somatosensory cortex, and RIns in the knee OA group were identified. ISF activity of the dorsal anterior cingulate cortex was positively correlated with pain measures and psychological distress scores. Theta and alpha activity of RIns were negatively correlated with pain interference. In conclusion, aberrations in infraslow and faster frequency EEG oscillations at sensory discriminative, motivational-affective, and descending inhibitory cortical regions were demonstrated in people with chronic painful knee OA. Moreover, EEG oscillations were correlated with pain and functional outcome measures. PERSPECTIVE: This study confirms alterations in the rsEEG oscillations and its relationship with pain experience in people with knee OA. The study provides potential cortical targets and the EEG frequency bands for neuromodulatory interventions for managing chronic pain experience in knee OA.

Exploring electroencephalographic infraslow neurofeedback treatment for chronic low back pain: a double-blinded safety and feasibility randomized placebo-controlled trial.

Chronic low back pain (CLBP) is a disabling condition worldwide. In CLBP, neuroimaging studies demonstrate abnormal activities in cortical areas responsible for pain modulation, emotional, and sensory components of pain experience [i.e., pregenual and dorsal anterior cingulate cortex (pgACC, dACC), and somatosensory cortex (SSC), respectively]. This pilot study, conducted in a university setting, evaluated the feasibility, safety, and acceptability of a novel electroencephalography-based infraslow-neurofeedback (EEG ISF-NF) technique for retraining activities in pgACC, dACC and SSC and explored its effects on pain and disability. Participants with CLBP (n = 60), recruited between July'20 to March'21, received 12 sessions of either: ISF-NF targeting pgACC, dACC + SSC, a ratio of pgACC*2/dACC + SSC, or Placebo-NF. Descriptive statistics demonstrated that ISF-NF training is feasible [recruitment rate (7 participants/month), dropouts (25%; 20-27%), and adherence (80%; 73-88%)], safe (no adverse events reported), and was moderate to highly acceptable [Mean ± SD: 7.8 ± 2.0 (pgACC), 7.5 ± 2.7 (dACC + SCC), 8.2 ± 1.9 (Ratio), and 7.7 ± 1.5 (Placebo)]. ISF-NF targeting pgACC demonstrated the most favourable clinical outcomes, with a higher proportion of participants exhibiting a clinically meaningful reduction in pain severity [53%; MD (95% CI): - 1.9 (- 2.7, - 1.0)], interference [80%; MD (95% CI): - 2.3 (- 3.5, - 1.2)], and disability [73%; MD (95% CI): - 4.5 (- 6.1, - 2.9)] at 1-month follow-up. ISF-NF training is a feasible, safe, and an acceptable treatment approach for CLBP.

Feasibility and Safety of High-Definition Infraslow Pink Noise Stimulation for Treating Chronic Tinnitus-A Randomized Placebo-Controlled Trial.

INTRODUCTION: Tinnitus has been linked to activity and connectivity changes in the auditory cortex (AC), parahippocampus (PHC), and posterior cingulate cortex (PCC). Although previous studies have targeted these areas individually, no study has yet modulated them simultaneously. Furthermore, novel stimulation designs may be superior to traditional alternating or direct current stimulation. This pilot study investigated the feasibility and safety of a novel brain stimulation technique (high-definition transcranial infraslow pink noise stimulation [HD-tIPNS]) for treating chronic tinnitus targeting the AC, PHC, and PCC. MATERIALS AND METHODS: A pilot, double-blind, randomized two-arm placebo-controlled parallel trial was conducted, with clinical outcomes collected at baseline, three days, and ten days after treatment. Participants with chronic tinnitus (n = 20) received 12 sessions (three per week for four weeks) of either HD-tIPNS or acti-sham stimulation. Primary outcomes included feasibility, safety, and resting-state electroencephalography (rsEEG) measures, and secondary outcomes included tinnitus and quality of life questionnaires. Feasibility, safety, and secondary measures were assessed using descriptive statistics. rsEEG was analyzed using standard low-resolution electromagnetic brain tomography. RESULTS: No long-term adverse events were reported. Mild side effects included headache and dizziness, indicating the safety of this stimulation. Participants were rapidly recruited and adhered to the study protocol with minimal difficulty. Drop-out rate was 13%, and the treatment approach was acceptable to participants, supporting the feasibility of the protocol. Tinnitus measures were similar between HD-tIPNS and acti-sham stimulation. rsEEG analyses revealed decreased beta-1 activity in PCC ten days after treatment for acti-sham. The HD-tIPNS group showed decreased beta-1 activity in inferior parietal lobule three days after treatment. Increased functional connectivity in the beta-1 frequency between left and right PHC was found in the HD-tIPNS group compared with the acti-sham group, three days after treatment. CONCLUSIONS: In conclusion, the novel approach is safe and feasible and revealed EEG changes unsupported by clinical benefit. Further research is essential to evaluate the potential of this multifocal network stimulation approach. CLINICAL TRIAL REGISTRATION: This study was registered with the Australia New Zealand Clinical Trial Registry (Registry number: ACTRN12621000151831; Universal Trial Number: U1111-1261-6945).

High-Definition Transcranial Infraslow Pink-Noise Stimulation Can Influence Functional and Effective Cortical Connectivity in Individuals With Chronic Low Back Pain: A Pilot Randomized Placebo-Controlled Study.

INTRODUCTION: Pain can be regarded as an emergent property of multiple interacting, dynamically changing brain networks and thus needs a targeted treatment approach. A novel high-definition transcranial infraslow pink-noise stimulation (HD-tIPNS) technique was developed to modulate the key hubs of the three main nociceptive pathways simultaneously, ie, the pregenual anterior cingulate cortex (pgACC) (descending inhibitory pathway), the dorsal anterior cingulate cortex (dACC) (medial nociceptive pathway), and both somatosensory cortices (S1) (lateral nociceptive pathway). This study aimed to evaluate safety and verify whether a single session of HD-tIPNS may disrupt functional and effective connectivity between targeted cortical regions. MATERIALS AND METHODS: A pilot double-blind randomized two-arm placebo-controlled parallel trial was conducted. Participants (N = 30) with chronic low back pain were equally randomized to receive a single session of either sham stimulation or HD-tIPNS (targeting the pgACC, dACC, and bilateral S1). Primary outcomes included safety and electroencephalographic measures, and secondary outcomes included pain measures, collected after treatment. A Mann-Whitney U test was used to compare between-group differences in percentage changes with baseline for each outcome measures. A Wilcoxon signed-rank test was used to identify difference in effective connectivity measure before and after HD-tIPNS. RESULTS: No serious adverse events were reported. A significant decrease in instantaneous functional connectivity was noted between the pgACC and dACC (U = 47.0, Z = -2.72, p = 0.007) and the pgACC and left S1 (U = 41.0, Z = -2.97, p = 0.003) in the infraslow band after HD-tIPNS when compared with sham stimulation. A significant decrease in instantaneous effective connectivity was noted in the direction of the dACC to the pgACC (Z = -2.10, p = 0.035), in the infraslow band after HD-tIPNS when compared with baseline. No changes in clinical pain measures were detected. CONCLUSIONS: HD-tIPNS can safely modulate the functional and effective connectivity between targeted pain-related cortical hubs. Further studies are warranted to evaluate whether repeated exposures to HD-tIPNS can incur clinical benefits through inducing changes in functional and effective connectivity at targeted cortical regions. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is ACTRN12621001438842.

Self-regulation training for people with knee osteoarthritis: a protocol for a feasibility randomised control trial (MiNT trial).

Introduction: Knee osteoarthritis (OA) is a chronic secondary musculoskeletal pain condition resulting in disability, reduced quality of life, and high societal costs. Pain associated with knee OA is linked to increased sensitivity in sensory, cognitive, and emotional areas of the brain. Self-regulation training targeting brain functioning related to pain experience could reduce pain and its associated disability. Self-regulatory treatments such as mindfulness meditation (MM) and electroencephalography neurofeedback (EEG-NF) training improve clinical outcomes in people with knee OA. A feasibility clinical trial can address factors that could inform the design of the full trial investigating the effectiveness of self-regulation training programmes in people with knee OA. This clinical trial will evaluate the feasibility, safety, acceptability, experience and perceptions of the self-regulatory training programmes. Methods: The proposed feasibility trial is based on a double-blind (outcome assessor and investigators), three-arm (MM usual care, EEG-NF + usual care and usual care control group) randomised controlled parallel clinical trial. Participants with knee OA will be recruited from the community and healthcare practices. A research assistant (RA) will administer both interventions (20-min sessions, four sessions each week, and 12 sessions over three successive weeks). Feasibility measures (participant recruitment rate, adherence to interventions, retention rate), safety, and acceptability of interventions will be recorded. An RA blinded to the group allocation will record secondary outcomes at baseline, immediately post-intervention (4th week), and 3 months post-intervention. The quantitative outcome measures will be descriptively summarised. The qualitative interviews will evaluate the participants' experiences and perceptions regarding various aspects of the trial, which includes identifying the barriers and facilitators in participating in the trial, evaluating their opinions on the research procedures, such as their preferences for the study site, and determining the level of acceptability of the interventions as potential clinical treatments for managing knee OA. Maori participant perceptions of how assessment and training practices could be acceptable to a Maori worldview will be explored. The interviews will be audio-recorded and analysed thematically. Discussion: This trial will provide evidence on the feasibility, safety, and acceptability of the MM and EEG-NF training in people with knee OA, thus informing the design of a full randomised clinical control trial.

Infraslow closed-loop brain training for anxiety and depression (ISAD): a protocol for a randomized, double-blind, sham-controlled pilot trial in adult females with internalizing disorders.

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.

Infraslow Neurofeedback Training Alters Effective Connectivity in Individuals with Chronic Low Back Pain: A Secondary Analysis of a Pilot Randomized Placebo-Controlled Study.

This study explored the effect of electroencephalographic infraslow neurofeedback (EEG ISF-NF) training on effective connectivity and tested whether such effective connectivity changes are correlated with changes in pain and disability in people with chronic low back pain. This involved secondary analysis of a pilot double-blinded randomised placebo-controlled study. Participants (n = 60) were randomised to receive ISF-NF targeting either the pregenual anterior cingulate cortex (pgACC), dorsal anterior cingulate and somatosensory cortex (dACC + S1), ratio of pgACC*2/dACC + S1, or Sham-NF. Resting-state EEG and clinical outcomes were assessed at baseline, immediately after intervention, and at one-week and one-month follow-up. Kruskal-Wallis tests demonstrated significant between-group differences in effective connectivity from pgACC to S1L at one-month follow up and marginal significant changes from S1L to pgACC at one-week and one-month follow up. Mann-Whitney U tests demonstrated significant increases in effective connectivity in the ISF-NF up-training pgACC group when compared to the Sham-NF group (pgACC to S1L at one-month (p = 0.013), and S1L to pgACC at one-week (p = 0.008) and one-month follow up (p = 0.016)). Correlational analyses demonstrated a significant negative correlation (ρ = -0.630, p = 0.038) between effective connectivity changes from pgACC to S1L and changes in pain severity at one-month follow-up. The ISF-NF training pgACC can reduce pain via influencing effective connectivity between pgACC and S1L.

Source localized infraslow neurofeedback training in people with chronic painful knee osteoarthritis: A randomized, double-blind, sham-controlled feasibility clinical trial.

Persistent pain is a key symptom in people living with knee osteoarthritis (KOA). Infra-slow Neurofeedback (ISF-NF) training is a recent development focusing on modulating cortical slow-wave activity to improve pain outcomes. A parallel, two-armed double-blinded, randomized sham-controlled, feasibility clinical trial aimed to determine the feasibility and safety of a novel electroencephalography-based infraslow fluctuation neurofeedback (EEG ISF-NF) training in people with KOA and determine the variability of clinical outcomes and EEG changes following NF training. Eligible participants attended nine 30-min ISF-NF training sessions involving three cortical regions linked to pain. Feasibility measures were monitored during the trial period. Pain and functional outcomes were measured at baseline, post-intervention, and follow-up after 2 weeks. Resting-state EEG was recorded at baseline and immediate post-intervention. Participants were middle-aged (61.7 ± 7.6 years), New Zealand European (90.5%), and mostly females (62%) with an average knee pain duration of 4 ± 3.4 years. The study achieved a retention rate of 91%, with 20/22 participants completing all the sessions. Participants rated high levels of acceptance and "moderate to high levels of perceived effectiveness of the training." No serious adverse events were reported during the trial. Mean difference (95% CI) for clinical pain and function measures are as follows for pain severity [active: 0.89 ± 1.7 (-0.27 to 2.0); sham: 0.98 ± 1.1 (0.22-1.7)], pain interference [active: 0.75 ± 2.3 (-0.82 to 2.3); Sham: 0.89 ± 2.1 (-0.60 to 2.4)], pain unpleasantness [active: 2.6 ± 3.7 (0.17-5.1); sham: 2.8 ± 3 (0.62-5.0)] and physical function [active: 6.2 ± 13 (-2.6 to 15); sham: 1.6 ± 12 (-6.8 to 10)]. EEG sources demonstrated frequency-specific neuronal activity, functional connectivity, and ISF ratio changes following NF training. The findings of the study indicated that the ISF-NF training is a feasible, safe, and acceptable intervention for pain management in people with KOA, with high levels of perceived effectiveness. The study also reports the variability in clinical, brain activity, and connectivity changes following training.

Tinnitus and the Triple Network Model: A Perspective.

Tinnitus is defined as the conscious awareness of a sound without an identifiable external sound source, and tinnitus disorder as tinnitus with associated suffering. Chronic tinnitus has been anatomically and phenomenologically separated into three pathways: a lateral "sound" pathway, a medial "suffering" pathway, and a descending noise-canceling pathway. Here, the triple network model is proposed as a unifying framework common to neuropsychiatric disorders. It proposes that abnormal interactions among three cardinal networks-the self-representational default mode network, the behavioral relevance-encoding salience network and the goal-oriented central executive network-underlie brain disorders. Tinnitus commonly leads to negative cognitive, emotional, and autonomic responses, phenomenologically expressed as tinnitus-related suffering, processed by the medial pathway. This anatomically overlaps with the salience network, encoding the behavioral relevance of the sound stimulus. Chronic tinnitus can also become associated with the self-representing default mode network and becomes an intrinsic part of the self-percept. This is likely an energy-saving evolutionary adaptation, by detaching tinnitus from sympathetic energy-consuming activity. Eventually, this can lead to functional disability by interfering with the central executive network. In conclusion, these three pathways can be extended to a triple network model explaining all tinnitus-associated comorbidities. This model paves the way for the development of individualized treatment modalities.

High-definition transcranial infraslow pink noise stimulation for chronic low back pain: protocol for a pilot, safety and feasibility randomised placebo-controlled trial.

INTRODUCTION: Chronic low back pain (CLBP) is a common disabling health condition. Current treatments demonstrate modest effects, warranting newer therapies. Brain imaging demonstrates altered electrical activities in cortical areas responsible for pain modulation, emotional and sensory components of pain experience. Treatments targeting to change electrical activities of these key brain regions may produce clinical benefits. This pilot study aims to (1) evaluate feasibility, safety and acceptability of a novel neuromodulation technique, high-definition transcranial infraslow pink noise stimulation (HD-tIPNS), in people with CLBP, (2) explore the trend of effect of HD-tIPNS on pain and function, and (3) derive treatment estimates to support sample size calculation for a fully powered trial should trends of effectiveness be present. METHODS AND ANALYSIS: A pilot, triple-blinded randomised two-arm placebo-controlled parallel trial. Participants (n=40) with CLBP will be randomised to either sham stimulation or HD-tIPNS (targeting somatosensory cortex and dorsal and pregenual anterior cingulate cortex). Primary outcomes include feasibility and safety measures, and clinical outcomes of pain (Brief Pain Inventory) and disability (Roland-Morris disability questionnaire). Secondary measures include clinical, psychological, quantitative sensory testing and electroencephalography collected at baseline, immediately postintervention, and at 1-week, 1-month and 3 months postintervention. All data will be analysed descriptively. A nested qualitative study will assess participants perceptions about acceptability of intervention and analysed thematically. ETHICS AND DISSEMINATION: Ethical approval has been obtained from Health and Disability Ethics Committee (Ref:20/NTB/67). Findings will be reported to regulatory and funding bodies, presented at conferences, and published in a scientific journal. TRIAL REGISTRATION NUMBER: ACTRN12620000505909p.

Is There Evidence for the Specificity of Closed-Loop Brain Training in the Treatment of Internalizing Disorders? A Systematic Review.

Introduction: Internalizing 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. Methods: We considered only randomized, double-blind, sham-controlled trials. Outcomes of interest included self/parent/teacher reports and clinician ratings of ID-related symptomatology. Results: Of 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. Discussion: The 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].

Pain and the Triple Network Model.

Acute pain is a physiological response that causes an unpleasant sensory and emotional experience in the presence of actual or potential tissue injury. Anatomically and symptomatically, chronic pathological pain can be divided into three distinct but interconnected pathways, a lateral "painfulness" pathway, a medial "suffering" pathway and a descending pain inhibitory circuit. Pain (fullness) can exist without suffering and suffering can exist without pain (fullness). The triple network model is offering a generic unifying framework that may be used to understand a variety of neuropsychiatric illnesses. It claims that brain disorders are caused by aberrant interactions within and between three cardinal brain networks: the self-representational default mode network, the behavioral relevance encoding salience network and the goal oriented central executive network. A painful stimulus usually leads to a negative cognitive, emotional, and autonomic response, phenomenologically expressed as pain related suffering, processed by the medial pathway. This anatomically overlaps with the salience network, which encodes behavioral relevance of the painful stimuli and the central sympathetic control network. When pain lasts longer than the healing time and becomes chronic, the pain- associated somatosensory cortex activity may become functionally connected to the self-representational default mode network, i.e., it becomes an intrinsic part of the self-percept. This is most likely an evolutionary adaptation to save energy, by separating pain from sympathetic energy-consuming action. By interacting with the frontoparietal central executive network, this can eventually lead to functional impairment. In conclusion, the three well-known pain pathways can be combined into the triple network model explaining the whole range of pain related co-morbidities. This paves the path for the creation of new customized and personalized treatment methods.

The anatomy of pain and suffering in the brain and its clinical implications.

Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Chronic pain, with a prevalence of 20-30 % is the major cause of human suffering worldwide, because effective, specific and safe therapies have yet to be developed. It is unevenly distributed among sexes, with women experiencing more pain and suffering. Chronic pain can be anatomically and phenomenologically dissected into three separable but interacting pathways, a lateral 'painfulness' pathway, a medial 'suffering' pathway and a descending pain inhibitory pathway. One may have pain(fullness) without suffering and suffering without pain(fullness). Pain sensation leads to suffering via a cognitive, emotional and autonomic processing, and is expressed as anger, fear, frustration, anxiety and depression. The medial pathway overlaps with the salience and stress networks, explaining that behavioural relevance or meaning determines the suffering associated with painfulness. Genetic and epigenetic influences trigger chronic neuroinflammatory changes which are involved in transitioning from acute to chronic pain. Based on the concept of the Bayesian brain, pain (and suffering) can be regarded as the consequence of an imbalance between the two ascending and the descending pain inhibitory pathways under control of the reward system. The therapeutic clinical implications of this simple pain model are obvious. After categorizing the working mechanisms of each of the available treatments (pain killers, psychopharmacology, psychotherapy, neuromodulation, psychosurgery, spinal cord stimulation) to 1 or more of the 3 pathways, a rational combination can be proposed of activating the descending pain inhibitory pathway in combination with inhibition of the medial and lateral pathway, so as to rebalance the pain (and suffering) pathways.

Tinnitus and Brain Stimulation.

The pathophysiological mechanisms that underlie the generation and maintenance of tinnitus are being unraveled progressively. Based on this knowledge, a large variety of different neuromodulatory interventions have been developed and are still being designed, adapting to the progressive mechanistic insights in the pathophysiology of tinnitus. rTMS targeting the temporal, temporoparietal, and the frontal cortex has been the mainstay of non-invasive neuromodulation. Yet, the evidence is still unclear, and therefore systematic meta-analyses are needed for drawing conclusions on the effectiveness of rTMS in chronic tinnitus. Different forms of transcranial electrical stimulation (tDCS, tACS, tRNS), applied over the frontal and temporal cortex, have been investigated in tinnitus patients, also without robust evidence for universal efficacy. Cortex and deep brain stimulation with implanted electrodes have shown benefit, yet there is insufficient data to support their routine clinical use. Recently, bimodal stimulation approaches have revealed promising results and it appears that targeting different sensory modalities in temporally combined manners may be more promising than single target approaches.While most neuromodulatory approaches seem promising, further research is required to help translating the scientific outcomes into routine clinical practice.

Tinnitus and tinnitus disorder: Theoretical and operational definitions (an international multidisciplinary proposal).

As for hypertension, chronic pain, epilepsy and other disorders with particular symptoms, a commonly accepted and unambiguous definition provides a common ground for researchers and clinicians to study and treat the problem. The WHO's ICD11 definition only mentions tinnitus as a nonspecific symptom of a hearing disorder, but not as a clinical entity in its own right, and the American Psychiatric Association's DSM-V doesn't mention tinnitus at all. Here we propose that the tinnitus without and with associated suffering should be differentiated by distinct terms: "Tinnitus" for the former and "Tinnitus Disorder" for the latter. The proposed definition then becomes "Tinnitus is the conscious awareness of a tonal or composite noise for which there is no identifiable corresponding external acoustic source, which becomes Tinnitus Disorder "when associated with emotional distress, cognitive dysfunction, and/or autonomic arousal, leading to behavioural changes and functional disability.". In other words "Tinnitus" describes the auditory or sensory component, whereas "Tinnitus Disorder" reflects the auditory component and the associated suffering. Whereas acute tinnitus may be a symptom secondary to a trauma or disease, chronic tinnitus may be considered a primary disorder in its own right. If adopted, this will advance the recognition of tinnitus disorder as a primary health condition in its own right. The capacity to measure the incidence, prevalence, and impact will help in identification of human, financial, and educational needs required to address acute tinnitus as a symptom but chronic tinnitus as a disorder.

Sedentary behaviour facilitates conditioned pain modulation in middle-aged and older adults with persistent musculoskeletal pain: a cross-sectional investigation.

INTRODUCTION: Higher physical activity (PA) and lower sedentary behaviour (SB) levels have demonstrated beneficial effects on temporal summation (TS) and conditioned pain modulation (CPM) in healthy adults. This cross-sectional study investigated the relationships between PA and SB and TS/CPM responses in individuals with chronic musculoskeletal pain. METHODS: Sixty-seven middle-aged and older adults with chronic musculoskeletal pain were recruited from the community. Questionnaires measuring demographics, pain, and psychological measures were completed. Physical activity/SB levels were measured using the International Physical Activity Questionnaire-short form and Sedentary Behaviour Questionnaire, respectively. Semmes monofilament was used to assess mechanical TS (MTS) at the most symptomatic (MTS-S) and a reference region (MTS-R); change in the pain scores (baseline-10th application) was used for analysis. Conditioned pain modulation procedure involved suprathreshold pressure pain threshold (PPT-pain4) administered before and after (CPM30sec, CPM60sec, and CPM90sec) conditioning stimulus (2 minutes; ∼12°C cold bath immersion). For analysis, PPT-pain4 (%) change scores were used. RESULTS: PPT-pain4 (%) change scores at CPM30sec and CPM60sec demonstrated significant weak positive correlations with SB levels and weak negative correlations with PA measures. After adjusting for confounding variables, a significant positive association was found between SB (h/d) and PPT-pain4 (%) change scores at CPM30sec and CPM60sec. No significant associations between MTS and PA/SB measures. CONCLUSION: Sedentariness is associated with higher pain inhibitory capacity in people with chronic musculoskeletal pain. The observed relationship may be characteristic of a protective (sedentary) behaviour to enhance pain modulatory mechanism. Prospective longitudinal studies using objective PA/SB measures are required to validate the observed relationship in a larger sample size.

Gait quality and velocity influences activity tracker accuracy in individuals post-stroke.

Objective: Fitbit Zip™ (FBZ) is a low-cost user-friendly device that could help motivate individuals post-stroke to increase their physical activity. However, inaccuracy in step counts from altered gait variables could cause dissatisfaction and reduce compliance. The aim of this study was to determine the influence of gait variables on the concurrent validity of the FBZ. Method: In a cross-sectional study, 19 community-dwelling stroke survivors (mean 66 (SD 8) years)  wore a FBZ at the non-paretic hip, and were videoed completing a six minute walk test (6MWT). Steps recorded by the FBZ were compared against the criterion standard of manually counted steps from video-recordings. Spatio-temporal gait parameters were calculated, and gait quality was assessed using the Wisconsin Gait Analysis (WGA) tool. Concurrent validity of FBZ was determined using Kendall's Tau correlation coefficient. Linear regression analysis determined the association between gait parameters, quality, and FBZ accuracy. Results: A very strong correlation was observed between the FBZ steps and manual counting (τ = 0.80, p < .001). Step difference demonstrated significant negative association with gait velocity (R2 = 0.35, B = -59.94, p = .007), and positive association with WGA score (R2 = 0.69, B = 4.59, p < .001), indicating poor FBZ accuracy in participants with lower speed (≤0.8m/s) and poor gait quality (WGA score>16). Conclusions: FBZ is an accurate measure of step activity in independent ambulators with stroke walking at speeds > 0.8m/s, but accuracy can be compromised with lower speed and poor gait quality. Clinicians should consider gait velocity and quality before advising FBZ as a motivational tool to increase physical activity in individuals post-stroke.

Thermal profiles over the Achilles tendon in a cohort of non-injured collegiate athletes over the course of a cross country season.

OBJECTIVES: To determine normal temperatures over the Achilles tendon over nine weeks. DESIGN: A prospective cohort study with nine weeks of observation. SETTING: University's Human Biomechanics and Physiology Laboratory. PARTICIPANTS: Male or female competitive runners running at least 25 miles per week who did not report pain in the region of the Achilles over 9 weeks of data collection. MAIN OUTCOME MEASURE: Thermal images taken at the same time and day of the week, were used to measure the temperature of the skin over the Achilles tendon. RESULTS: Seventeen athletes were eligible for analysis. The Achilles tendon temperatures were right 28.7 °C ±â€¯1.3 °C, left 28.8 °C ±â€¯1.3 °C. ICC demonstrated a very high consistency and minimal variations in temperatures (right 0.86 (95% CI = 0.58, 0.98), left 0.79 (95% CI = 0.38, 0.97). The mean difference between sides over the season was 0.50 °C ±â€¯0.43 °C (p = 0.681). A decreasing trend in the Achilles tendon temperatures as the season progressed was observed. CONCLUSION: This is the first report of normal thermal profiles over an extended period. Variations in Achilles temperatures left to right, and over time were not significant. The decreasing temperature trend over the season warrants further investigation.

Reliability of surface electromyography activity of gluteal and hamstring muscles during sub-maximal and maximal voluntary isometric contractions.

BACKGROUND: Normalizing to a reference signal is essential when analysing and comparing electromyography signals across or within individuals. However, studies have shown that MVC testing may not be as reliable in persons with acute and chronic pain. OBJECTIVES: The purpose of this study was to compare the test-retest reliability of the muscle activity in the biceps femoris and gluteus maximus between a novel sub-MVC and standard MVC protocols. METHODS: This study utilized a single individual repeated measures design with 12 participants performing multiple trials of both the sub-MVC and MVC tasks on two separate days. The participant position in the prone leg raise task was standardised with an ultrasonic sensor to improve task precession between trials/days. Day-to-day and trial-to-trial reliability of the maximal muscle activity was examined using ICC and SEM. FINDINGS: Day-to-day and trial-to-trial reliability of the EMG activity in the BF and GM were high (0.70-0.89) to very high (≥0.90) for both test procedures. %SEM was <5-10% for both tests on a given day but higher in the day-to-day comparisons. The lower amplitude of the sub-MVC is a likely contributor to increased %SEM (8-13%) in the day-to-day comparison. CONCLUSIONS: The findings show that the sub-MVC modified prone double leg raise results in GM and BF EMG measures similar in reliability and precision to the standard MVC tasks. Therefore, the modified prone double leg raise may be a useful substitute for traditional MVC testing for normalizing EMG signals of the BF and GM.