Examining predictors of treatment effect in digital Acceptance and Commitment Therapy for chronic pain.

Digitally delivered behavioral interventions for chronic pain have been encouraging with effects similar to face-to-face treatment. Although many chronic pain patients benefit from behavioral treatment, a substantial proportion do not improve. To contribute to more knowledge about factors that predict treatment effects in digitally delivered behavioral interventions for chronic pain, the present study analyzed pooled data (N = 130) from three different studies on digitally delivered Acceptance and Commitment Therapy (ACT) for chronic pain. Longitudinal linear mixed-effects models for repeated measures were used to identify variables with significant influence on the rate of improvement in the main treatment outcome pain interference from pre- to post-treatment. The variables were sorted into six domains (demographics, pain variables, psychological flexibility, baseline severity, comorbid symptoms and early adherence) and analysed in a stepwise manner. The study found that shorter pain duration and higher degree of insomnia symptoms at baseline predicted larger treatment effects. The original trials from which data was pooled are registered at clinicaltrials.gov (registration number: NCT03105908 and NCT03344926).

ACTsmart: Guided Smartphone-Delivered Acceptance and Commitment Therapy for Chronic Pain-A Pilot Trial.

BACKGROUND: Acceptance and commitment therapy (ACT) is a behavioral health intervention with strong empirical support for chronic pain but, to date, widespread dissemination is limited. Digital solutions improve access to care and can be integrated into patients' everyday lives. OBJECTIVE: ACTsmart, a guided smartphone-delivered ACT intervention, was developed to improve the accessibility of an evidence-based behavioral treatment for chronic pain. In the present study, we evaluated the preliminary efficacy of ACTsmart in adults with chronic pain. METHODS: The study was an open-label pilot trial. The treatment lasted for 8 weeks, and participants completed all outcome measures at pretreatment and posttreatment and at 3-, 6-, and 12-month follow-ups, with weekly assessments of selected measures during treatment. The primary outcome was pain interference. The secondary outcomes were psychological flexibility, values, insomnia, anxiety, depressive symptoms, health-related quality of life, and pain intensity. All outcomes were analyzed using linear mixed-effects models. RESULTS: The sample consisted of 34 adults (88% women) with long-standing chronic pain (M=20.4 years, SD=11.7). Compliance to treatment was high, and at the end of treatment, we observed a significant improvement in the primary outcome of pain interference (d = -1.01). All secondary outcomes significantly improved from pretreatment to posttreatment with small to large effect sizes. Improvements were maintained throughout 12 months of follow-up. CONCLUSION: The results of this pilot study provide preliminary support for ACTsmart as an accessible and effective behavioral health treatment for adults with chronic pain and warrant a randomized controlled trial to further evaluate the efficacy of the intervention.

Efficacy of the small step program in a randomised controlled trial for infants below age 12 months with clinical signs of CP; a study protocol.

BACKGROUND: Children with cerebral palsy (CP) have life-long motor disorders, and they are typically subjected to extensive treatment throughout their childhood. Despite this, there is a lack of evidence supporting the effectiveness of early interventions aiming at improving motor function, activity, and participation in daily life. The study will evaluate the effectiveness of the newly developed Small Step Program, which is introduced to children at risk of developing CP during their first year of life. The intervention is based upon theories of early learning-induced brain plasticity and comprises important components of evidence-based intervention approaches used with older children with CP. METHOD AND DESIGN: A two-group randomised control trial will be conducted. Invited infants at risk of developing CP due to a neonatal event affecting the brain will be randomised to either the Small Step Program or to usual care. They will be recruited from Astrid Lindgren Children's Hospital at regular check-up and included at age 3-8 months. The Small Step Program was designed to provide individualized, goal directed, and intensive intervention focusing on hand use, mobility, and communication in the child's own home environment and carried out by their parents who have been trained and coached by therapists. The primary endpoint will be approximately 35 weeks after the start of the intervention, and the secondary endpoint will be at 2 years of age. The primary outcome measure will be the Peabody Developmental Motor Scale (second edition). Secondary assessments will measure and describe the children's general and specific development and brain pathology. In addition, the parents' perspective of the program will be evaluated. General linear models will be used to compare outcomes between groups. DISCUSSION: This paper presents the background and rationale for developing the Small-Step Program and the design and protocol of a randomized controlled trial. The aim of the Small Step Program is to influence development by enabling children to function on a higher level than if not treated by the program and to evaluate whether the program will affect parent's ability to cope with stress and anxiety related to having a child at risk of developing CP. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02166801 . Registered June 12, 2014.

Is outcome of constraint-induced movement therapy in unilateral cerebral palsy dependent on corticomotor projection pattern and brain lesion characteristics?

AIM: The aim of the study was to explore individual variations in outcome of hand function after constraint-induced movement therapy (CIMT) in relation to the organization of corticomotor projection and brain lesion characteristics in participants with unilateral cerebral palsy (CP). METHOD: Sixteen participants (eight males, eight females; mean age 13 y, [SD 2 y] range 10-16 y) with unilateral CP (nine right-sided; Manual Ability Classification System [MACS] level I, n=1; level II, n=15) who participated in a 2-week CIMT day camp (63 h) were included in the study. Various aspects of hand function were measured by the Jebsen-Taylor Hand Function Test (JTHFT), the Assisting Hand Assessment (AHA), and the Melbourne Assessment, both before and after the day camp. Transcranial magnetic stimulation was used to explore the corticomotor organization, and brain lesion characteristics were described by visual assessment of conventional structural magnetic resonance images. RESULTS: At a group level, the training was associated with significant improvements in JTHFT (p=0.003) and AHA (p=0.046), but not in Melbourne Assessment scores. Improvements were found in all types of corticomotor projection patterns, i.e. contralateral, mixed, and ipsilateral. There was no relationship between functional improvement and brain lesion characteristics. INTERPRETATION: Individuals with CP experience improved motor outcomes after CIMT, independent of corticomotor projection pattern and lesion characteristics.

Associations between sickness behavior, but not inflammatory cytokines, and psychiatric comorbidity in chronic pain.

OBJECTIVES: Approximately one in five adults experiences chronic pain, often in co-occurrence with depression, insomnia, anxiety, and lower self-rated health. Elevated levels of cytokines, e.g. tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 8 (IL-8), and interleukin 10 (IL-10), have been identified in patients with chronic pain. Depression, insufficient sleep, poor self-rated health, and pain intensity have also been associated with inflammatory biomarkers. This study aimed to investigate the interrelationships between inflammatory biomarkers and depression, insomnia, anxiety, self-rated health, sickness behavior, and pain intensity in patients with chronic pain. METHODS: Self-report questionnaires and blood samples analyzed for plasma levels of inflammatory biomarkers were collected from 80 adult patients with chronic pain. Associations between inflammatory biomarkers (TNF-α, IL-6, IL-8, IL-10, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)) and depression, insomnia, anxiety, self-rated health, sickness behavior, and pain intensity, were analyzed using bivariate Spearman rank correlation coefficients and regression analyses. RESULTS: Participants were mainly women (72.5 %), with a mean age of 50.8 years, and a reported mean pain duration of 16.7 years. There were significant correlations between insomnia and CRP (rs =.26, p <.05); sex and ESR (rs =.29, p <.05); age and IL-6 (rs =.29, p <.05) and IL-8 (rs =.30, p <.05); BMI and IL-6 (rs =.50, p <.001), CRP (rs =.63, p <.001) and ESR (rs =.42, p <.001). Ratings of depression were positively and significantly related to ratings of sickness behavior and anxiety (ß =.32 and ß =.40, respectively), explaining 49 % of the total variance in depression ratings. Insomnia was positively and significantly related to sickness behavior (ß =.37) explaining 31 % of the total variance in insomnia ratings. Inflammatory biomarkers, however, did not contribute significantly to the models. CONCLUSIONS: Participants reported high levels of symptoms, yet the associations between these ratings and the inflammatory biomarkers were either absent or weak. Also, despite high levels of self-reported sickness behavior, overall the inflammatory status remained within the normal range. Ratings of sickness behavior contributed more than inflammatory markers in explaining ratings of depression and insomnia. The present results point to the complexity of chronic pain, and the challenges of identifying biomarkers that explain symptomatology.

Individually tailored exercise in patients with postural orthostatic tachycardia syndrome related to post-COVID-19 condition - a feasibility study.

Postural orthostatic tachycardia syndrome (POTS) occurs in approximately 30% of people with highly symptomatic post-COVID-19 condition (PCC). It involves several symptoms that limit physical and psychological functions and cause reduced quality of life. Evidence for different treatments of POTS and PCC is limited, and this study aimed to evaluate the feasibility of individually tailored physical exercise. The secondary aim of the study was to evaluate the preliminary effectiveness of this intervention. Twenty-six participants (81% female, median age 41 years) were enrolled and performed individually tailored endurance and strength training, with progression, for twelve weeks. During the intervention period, the participants had weekly support from a physiotherapist. Feasibility was evaluated with good compliance, with 76% adherence to exercise prescription and 96% completing the study protocol. The treatment was safe, and the evaluation methods (questionnaires, physical assessments, and accelerometer monitoring) were judged to be feasible. After the intervention, improvements in symptom burden as well as in psychological and physical functions were observed. In conclusion, future randomized controlled trials can be performed with only minor adjustments and could include questionnaires, physical assessment and accelerometer monitoring, which were demonstrated as feasible by this study.

Inflammatory Blood Signature Related to Common Psychological Comorbidity in Chronic Pain.

Chronic pain is characterized by high psychological comorbidity, and diagnoses are symptom-based due to a lack of clear pathophysiological factors and valid biomarkers. We investigate if inflammatory blood biomarker signatures are associated with pain intensity and psychological comorbidity in a mixed chronic pain population. Eighty-one patients (72% women) with chronic pain (>6 months) were included. Patient reported outcomes were collected, and blood was analyzed with the Proseek Multiplex Olink Inflammation Panel (Bioscience Uppsala, Uppsala, Sweden), resulting in 77 inflammatory markers included for multivariate data analysis. Three subgroups of chronic pain patients were identified using an unsupervised principal component analysis. No difference between the subgroups was seen in pain intensity, but differences were seen in mental health and inflammatory profiles. Ten inflammatory proteins were significantly associated with anxiety and depression (using the Generalized Anxiety Disorder 7-item scale (GAD-7) and the Patient Health Questionnaire (PHQ-9): STAMBP, SIRT2, AXIN1, CASP-8, ADA, IL-7, CD40, CXCL1, CXCL5, and CD244. No markers were related to pain intensity. Fifteen proteins could differentiate between patients with moderate/high (GAD-7/PHQ-9 > 10) or mild/no (GAD-7/PHQ-9 < 10) psychological comorbidity. This study further contributes to the increasing knowledge of the importance of inflammation in chronic pain conditions and indicates that specific inflammatory proteins may be related to psychological comorbidity.

Evaluating the construct validity and internal consistency of the Sickness Questionnaire in a Swedish sample of adults with longstanding pain.

OBJECTIVES: Low-grade inflammation is a possible contributing factor in the development and persistence of chronic primary pain syndromes. Related to inflammatory activity is sickness behavior, a set of behavioral responses including increased pain sensitivity, fatigue, malaise, fever, loss of appetite, as well as depressive behavior and anhedonia. To capture these behavioral responses and their relation to longstanding pain, psychometrically sound self-report questionnaires are needed. The Sickness Questionnaire (SicknessQ) was developed to assess self-reported sickness behavior based on studies on acute immune activation while maintaining relevance for persistent conditions. The aim of the current study was to evaluate aspects of the validity and reliability of the SicknessQ in a Swedish sample of persons with longstanding pain. METHODS: Aspects of construct validity were evaluated by means of performing a confirmatory factor analysis (CFA) (testing structural validity) and by relevant hypothesis testing i.e., that ratings of sickness behavior in combination with other related factors (e.g., depression and anxiety) would be significantly related to ratings of avoidance. Reliability was evaluated by means of analyzing the internal consistency of items. RESULTS: Following the CFA, a non-significant Chi-Square test (χ2 [32, N=190] = 42.95, p=0.094) indicated perfect model fit. Also, the relative fit indices supported adequate model fit (CFI = 0.978; TLI = 0.969; RMSEA = 0.0430). Sickness behavior (p<0.0001), depression (p<0.05) and pain duration (p<0.05) significantly contributed to the regression model, explaining 45% of the total variance in avoidance. Internal consistency was adequate, as indicated by a Cronbach's α value of 0.82 for the entire questionnaire. CONCLUSIONS: Results indicate that the SicknessQ has adequate structural validity as well as adequate internal consistency, and is significantly associated with avoidance. The SicknessQ appears to have utility as a self-report questionnaire to assess symptoms of sickness behavior for adults with longstanding pain.

Baseline Pro-Inflammatory Cytokine Levels Moderate Psychological Inflexibility in Behavioral Treatment for Chronic Pain.

Background: The medical and scientific communities struggle to understand chronic pain and find effective treatments. Multimodal approaches are encouraging but show significant individual differences. Methods: Seventy-eight persons (56 women) with chronic pain received Acceptance and Commitment Therapy and provided blood samples before and after treatment. The participants completed surveys with the blood sampling. Blood plasma was analyzed for IL-6 and TNF-α levels with the Olink Inflammation Panel (Olink Bioscience Uppsala, Sweden). The treatment effects and moderating effects of low-grade inflammation on changes in outcomes were analyzed using linear mixed models. Results: Pain interference (p < 0.001) and psychological inflexibility (p < 0.001) improved significantly during treatment, but pain intensity did not (p = 0.078). Cytokine levels did not change over the course of the treatment (IL-6/TNF-α p = 0.086/0.672). Mean baseline levels of IL-6 and TNF-α moderated improvement in psychological inflexibility during the course of treatment (p = 0.044), but cytokine levels did not moderate changes in pain interference (p = 0.205) or pain intensity (p = 0.536). Conclusions: Higher baseline inflammation levels were related to less improvement in psychological inflexibility. Low-grade inflammation may be one factor underlying the variability in behavioral treatment in chronic pain.

Dissociation of brain areas associated with force production and stabilization during manipulation of unstable objects.

Multifinger dexterous manipulation of unstable or deformable objects requires control of both direction and magnitude of fingertip force vectors. Our aim was to study the neuroanatomical correlates of these two distinct control functions. Brain activity was measured using functional magnetic resonance imaging while 16 male subjects (age: 26-42, M = 32, SD ± 4 years) compressed four springs representing a 2 × 2 factorial design with two levels of force and instability requirements. Significant activations associated with higher instability were located bilaterally in the precentral gyri, the postcentral gyrus, and the cerebellum. In the main effect for high force, activity was found in areas located in the primary motor regions contralateral to the active hand and bilaterally in the cerebellum. An overlap in activation between the two main effects was found bilaterally in the cerebellum (lobule VI). This study not only confirms a recently described bilateral fronto-parieto-cerebellar network for manipulation of increasingly unstable objects, but critically extends our understanding by describing its differentiated modulation with both force magnitude and instability requirements. Our results, therefore, expose a previously unrecognized and context-sensitive system of brain regions that enable dexterous manipulation for different force magnitude and instability requirements of the task.

Autistic Traits and Attention-Deficit Hyperactivity Disorder Symptoms Associated With Greater Pain Interference and Depression, and Reduced Health-Related Quality of Life in Children With Chronic Pain.

Previous research indicates elevated levels of clinically significant traits and symptoms of autism spectrum disorder and attention-deficit hyperactivity disorder (ADHD) in children with chronic pain, but associations with functioning and depression are yet unclear. The current study examined the relationships of autistic traits and ADHD symptoms with pain interference, depression, and health-related quality of life, as well as the mediating roles of insomnia and psychological inflexibility, in children with chronic pain (n = 146, 8-17 years, 102 girls) presenting at a tertiary pain clinic. Children completed measures of pain intensity, depression, pain interference, health-related quality of life, insomnia, and psychological inflexibility. Parents (n = 146, 111 mothers) completed measures to assess autistic traits and ADHD symptoms in their children. Children with clinically significant autistic traits and ADHD symptoms presented with significantly higher levels of depressive symptoms and pain interference, and significantly lower health-related quality of life, than did the other children. Autistic traits and ADHD symptoms contributed significantly to the prediction of pain interference and depressive symptoms, as well as health-related quality of life. Psychological inflexibility mediated the relationships between ADHD symptoms and autistic traits on the one hand and depression, pain interference, and health-related quality of life on the other, while insomnia mediated the relationships between ADHD symptoms and depression, pain interference, and health-related quality of life. All analyses were adjusted for demographics and pain intensity. Results suggest the utility of screening for neurodevelopmental disorders in children with chronic pain. Furthermore, the findings may indicate insomnia and skills related to psychological flexibility as potential treatment targets in interventions aiming at improving functioning and health-related quality of life in children with chronic pain and co-occurring symptoms of neurodevelopmental disorders.

Internet-delivered acceptance and commitment therapy as microlearning for chronic pain: A randomized controlled trial with 1-year follow-up.

BACKGROUND: Studies of Internet-delivered acceptance and commitment therapy (ACT) for chronic pain have shown small to moderate positive effects for pain interference and pain acceptance. Effects on pain intensity, depression, anxiety and quality of life (QoL) have been less favourable, and improvements for values and sleep are lacking. In this randomized controlled trial iACT - a novel format of Internet-ACT using daily microlearning exercises - was examined for efficacy compared to a waitlist condition. METHODS: Adult participants (mean age 49.5 years, pain duration 18.1 years) with diverse chronic pain conditions were recruited via self-referral, and randomized to iACT (n = 57) or waitlist (n = 56). The primary outcome was pain interference. The secondary outcomes were QoL, depression, anxiety, insomnia and pain intensity. The process variables included psychological inflexibility and values. Post-assessments were completed by 88% (n = 100) of participants. Twelve-month follow-up assessments were completed by 65% (iACT only, n = 37). Treatment efficacy was analysed using linear mixed models and an intention-to-treat-approach. RESULTS: Significant improvements in favour of iACT were seen for pain interference, depression, anxiety, pain intensity and insomnia, as well as process variables psychological inflexibility and values. Between-group effect sizes were large for pain interference (d = 0.99) and pain intensity (d = 1.2), moderate for anxiety and depressive symptoms and small for QoL and insomnia. For the process variables, the between-group effect size was large for psychological inflexibility (d = 1.0) and moderate for values. All improvements were maintained at 1-year follow-up. CONCLUSIONS: Internet-ACT as microlearning may improve a broad range of outcomes in chronic pain. SIGNIFICANCE: The study evaluates a novel behavioral treatment with positive results on pain interference, mood as well as pain intensity for longtime chronic pain sufferers. The innovative format of a digital ACT intervention delivered in short and experiential daily learnings may be a promising way forward.

Hand function in relation to brain lesions and corticomotor-projection pattern in children with unilateral cerebral palsy.

AIM: To investigate relationships between hand function, brain lesions, and corticomotor projections in children with unilateral cerebral palsy (CP). METHOD: The study included 17 children (nine males, eight females; mean age 11.4 [SD 2.4] range 7-16 y), with unilateral CP at Gross Motor Function Classification System level I and Manual Ability Classification System level I or II. Hand function was assessed with the Box and Blocks test and Assisting Hand Assessment (AHA). Conventional structural magnetic resonance images were assessed visually for type, location, and extent of brain lesions. Single-pulse transcranial magnetic stimulation (TMS) provided information on organization of corticomotor projections. RESULTS: The most favourable hand function was seen in children who had white-matter damage of immaturity with mild white-matter loss and contralateral motor projections. Children with ipsilateral projections had the most impaired function. Nevertheless, in this subgroup a range of ability was seen (AHA 29-59%). Motor-projection patterns appeared to be influenced by lesion extent and location, but not by lesion type. INTERPRETATION: Combining information from structural magnetic resonance images and TMS can improve prediction of hand function. A wide variation in hand function was seen within all motor-projection patterns. Although the most impaired hand function was seen in the ipsilateral motor-projection group, some children in this group had fairly good ability. Such information is important for treatment planning.

Evidence of validity in a new method for measurement of dexterity in children and adolescents.

AIM: many everyday activities involve manipulation of objects with the fingertips. Impaired performance in manipulative tasks is common in neurodevelopmental disorders. Thus accurate assessment of an individual's ability to coordinate fingertip forces is important for planning treatment. We evaluated a recently developed assessment tool (the Strength-Dexterity Test), which is based on manipulation of unstable objects, in a paediatric population. METHOD: a Rasch model was used to examine the validity and reliability of the Strength-Dexterity Test in a sample of 56 typically developing children and adolescents (30 males, 26 females; age range 4y 10mo-17y 3mo; mean age 9y 8mo, SD 3y 8mo). In addition, we examined how performance on this test relates to widely used tests for assessment of gross manual dexterity (assessed with the Box and Blocks Test) and finger strength measured with a pinch meter. RESULTS: the constructs measured with the 78-item Strength-Dexterity Test include dexterity and strength, and form a unique unidimensional latent trait, named fingertip force coordination, that improves with age. The test has internal scale validity when applied to a typical paediatric population. Positive correlations (significant at p<0.001) were found among all three tests. INTERPRETATION: we provide preliminary evidence of construct validity in the Strength-Dexterity Test. Our findings suggest that this test has the potential to be developed into a promising tool for assessing dexterity in children.

Do Infants at Risk of Developing Cerebral Palsy or Other Neurodevelopmental Disorders Learn What They Practice?

Through secondary analyses of the Small Step. Randomized Control Trial, we tested the hypothesis that children at risk of developing cerebral palsy (CP) or other neurodevelopmental disorders would learn what they practice, i.e., that they would have a more rapid development within the specifically trained foci (hand use or mobility) of each time period compared to the development rate within the foci not trained at that time. Nineteen infants (6.3 (1.62) months corrected age) included in the Small Step program were assessed at six time points during the intervention. For statistical analysis, general and mixed linear models were used, and the independent variables were the Peabody Developmental Motor scale (stationary, locomotion, grasping and visuomotor sub scales), the Gross Motor Function Measure-66 and the Hand Assessment for Infants. Outcomes related to gross motor function improved significantly more after mobility training than after hand use training, while fine motor function was improved to the same extent following both training types. Significantly higher improvements after the first training period were seen in one out of three outcome measures in both gross and fine motor assessments. The improvements observed were all independent of diagnosis at two years. The concept "you learn what you practice" was most clearly confirmed in the case of gross motor development.

ACTsmart - development and feasibility of digital Acceptance and Commitment Therapy for adults with chronic pain.

Accessibility of evidence-based behavioral health interventions is one of the main challenges in health care and effective treatment approaches are not always available for patients that would benefit from them. Digitization has dramatically changed the health care landscape. Although mHealth has shown promise in addressing issues of accessibility and reach, there is vast room for improvements. The integration of technical innovations and theory driven development is a key concern. Digital solutions developed by industry alone often lack a clear theoretical framework and the solutions are not properly evaluated to meet the standards of scientifically proven efficacy. On the other hand, mHealth interventions developed in academia may be theory driven but lack user friendliness and are commonly technically outdated by the time they are implemented in regular care, if they ever are. In an ongoing project aimed at scientific innovation, the mHealth Agile Development and Evaluation Lifecycle was used to combine strengths from both industry and academia in the development of ACTsmart - a smartphone-based Acceptance and Commitment Therapy treatment for adult chronic pain patients. The present study describes the early development of ACTsmart, in the process of moving the product from alpha testing to a clinical trial ready solution.

Psychological Flexibility and Its Relationship to Distress and Work Engagement Among Intensive Care Medical Staff.

Intensive care settings place specific work-related demands on health care professionals that may elicit stress and negatively influence occupational health and work engagement. Psychological flexibility has emerged as a promising construct that could help explain variation in reported health. Understanding the role of psychological flexibility in occupational psychological health among intensive care medical staff may potentially guide the development of effective interventions. Thus, the present study evaluated the relationships between psychological flexibility (Work-related Acceptance and Action Questionnaire), distress (Perceived Stress Scale, General Health Questionnaire) and work engagement (Utrecht Work Engagement Scale) in a sample of 144 health care professionals from one adult (ICU, N = 98) and one pediatric (PICU, N = 46) intensive care unit. In addition to cross-sectional analyses, a subset of data (PICU, N = 46) was analyzed using a longitudinal design. Results illustrated that higher levels of distress were associated with lower levels of work engagement. Furthermore, psychological flexibility was related to greater work engagement, and psychological flexibility had a significant indirect effect on the relationship between distress and work engagement. Lastly, increased psychological flexibility over time corresponded with increased work engagement. Although tentative, the results suggest the importance of psychological flexibility for work engagement in health care professionals within intensive care settings.

Corrigendum: Motor Abilities in Adolescents Born Preterm Are Associated With Microstructure of the Corpus Callosum.

[This corrects the article DOI: 10.3389/fneur.2019.00367.].

The role of low-grade inflammation in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) - associations with symptoms.

BACKGROUND: Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) often present with a range of flu-like symptoms resembling sickness behavior as well as widespread pain and concentration deficits. The aim of this study was to explore the association between inflammatory markers previously shown to be related to fatigue severity in ME/CFS and common ME/CFS symptoms post-exertional fatigue, impaired cognitive processing, musculoskeletal pain and recurrent flu-like symptoms, and the moderating effect of sex on these associations. METHODS: 53 adult patients diagnosed with ME/CFS at a specialist clinic were included in the study. Fasting blood plasma was analyzed using the Olink Proseek Multiplex Inflammation panel (ß-NGF, CCL11, CXCL1, CXCL10, IL-6, IL-7, IL-8, IL-10, IL-18, TGF-α, TGF-ß-1 and SCF) and BioRad Human Cytokine Type 1 assay (TNF-α). Participants rated the average severity of symptoms (0-10) based on the 2011 International Consensus Criteria of ME/CFS during a structured clinical interview. Associations between inflammatory markers and symptom severity were analyzed using bivariate correlations and moderated regression analyses bootstrapped with 5000 repetitions. RESULTS AND CONCLUSIONS: Only ß-NGF was associated with the fatigue severity measure. However, higher levels of CCL11, CXCL10, IL-7, TNF-α and TGF-ß-1 were significantly associated with higher levels of impaired cognitive processing and musculoskeletal pain, and sex was a significant moderator for CXCL10, IL-7 and TGF-ß-1. Future studies should investigate the relationship between inflammatory markers and key symptoms in ME/CFS in a longitudinal design in order to explore if and for whom low-grade inflammation may contribute to illness development.

Internet-delivered acceptance and commitment therapy (iACT) for chronic pain-feasibility and preliminary effects in clinical and self-referred patients.

BACKGROUND: Acceptance and commitment therapy (ACT) is an evidence-based treatment to improve functioning and quality of life (QoL) for chronic pain patients, but outreach of this treatment is unsatisfactory. Internet-delivery has been shown to increase treatment access but there is limited evidence regarding feasibility and effectiveness of web-based ACT for chronic pain. The aim of the study was to evaluate and iterate a novel internet-delivered ACT program, iACT, in a clinical and a self-referred sample of chronic pain patients. The intervention was developed in close collaboration with patients. To enhance learning, content was organized in short episodes to promote daily engagement in treatment. In both the clinical and self-referred samples, three critical domains were evaluated: (I) feasibility (acceptability, practicality and usage); (II) preliminary efficacy on pain interference, psychological inflexibility, value orientation, QoL, pain intensity, anxiety, insomnia and depressive symptoms; and (III) potential treatment mechanisms. METHODS: This was an open pilot study with two samples: 15 patients from a tertiary pain clinic and 24 self-referred chronic pain participants, recruited from October 2015 until January 2017. Data were collected via an online platform in free text and self-report measures, as well as through individual oral feedback. Group differences were analyzed with Chi square-, Mann-Whitney U- or t-test. Preliminary efficacy and treatment mechanism data were collected via self-report and analyzed with multilevel linear modeling for repeated measures. RESULTS: Feasibility: patient feedback guided modifications to refine the intervention and indicated that iACT was acceptable in both samples. User insights provided input for both immediate and future actions to improve feasibility. Comprehensiveness, workability and treatment credibility were adequate in both samples. Psychologists spent on average 13.5 minutes per week per clinical patient, and 8 minutes per self-referred patient (P=0.004). Recruitment rate was 24 times faster in the self-referred sample (24 patients in 1 month, compared to 15 patients in 15 months, P<0.001) and the median distance to the clinic was 40 km in the clinical sample, and 426 km in the self-referred sample (P<0.001). Preliminary effects: post-assessments were completed by 26 participants (67%). Significant effects of time were seen from pre- to post-treatment across all outcome variables. Within group effect sizes (Cohen's d) at post-treatment ranged from small to large: pain interference (d=0.64, P<0.001), psychological inflexibility (d=1.43, P<0.001), value progress (d=0.72, P<0.001), value obstruction (d=0.42, P<0.001), physical QoL (d=0.41, P=0.005), mental QoL (d=0.67, P=0.005), insomnia (d=0.31, P<0.001), depressive symptoms (d=0.47, P<0.001), pain intensity (d=0.78, P=0.001) and anxiety (d=0.46, P<0.001). Improvements were sustained at 1-year follow-up. Psychological inflexibility and value progress were found to be potential treatment mechanisms. CONCLUSIONS: The results from the present study suggests that iACT was feasible in both the clinical and the self-referred sample. Together with the positive preliminary results on all outcomes, the findings from this feasibility study pave the way for a subsequent large randomized efficacy trial.