Chronic oxytocin administration stimulates the oxytocinergic system in children with autism.

Clinical efficacy of intranasal administration of oxytocin is increasingly explored in autism spectrum disorder, but to date, the biological effects of chronic administration regimes on endogenous oxytocinergic function are largely unknown. Here exploratory biological assessments from a completed randomized, placebo-controlled trial showed that children with autism (n = 79, 16 females) receiving intranasal oxytocin for four weeks (12 IU, twice daily) displayed significantly higher salivary oxytocin levels 24 hours after the last oxytocin nasal spray administration, but no longer at a four-week follow up session. Regarding salivary oxytocin receptor gene (OXTR) epigenetics (DNA-methylation), oxytocin-induced reductions in OXTR DNA-methylation were observed, suggesting a facilitation of oxytocin receptor expression in the oxytocin compared to the placebo group. Notably, heightened oxytocin levels post-treatment were significantly associated with reduced OXTR DNA-methylation and improved feelings of secure attachment. These findings indicate that four weeks of chronic oxytocin administration stimulated the endogenous oxytocinergic system in children with autism.

At the Head and Heart of Oxytocin's Stress-Regulatory Neural and Cardiac Effects: A Chronic Administration RCT in Children with Autism.

INTRODUCTION: Intranasal administration of oxytocin presents a promising new approach to reduce disability associated with an autism spectrum disorder diagnosis. Previous investigations have emphasized the amygdala as the neural foundation for oxytocin's acute effects. However, to fully understand oxytocin's therapeutic potential, it is crucial to gain insight into the neuroplastic changes in amygdala circuitry induced from chronic oxytocin administrations, particularly in pediatric populations. OBJECTIVE: We aimed to examine the impact of a 4-week course of intranasal oxytocin on amygdala functional connectivity in children with autism, compared to placebo. Additionally, we investigated whether oxytocin improves cardiac autonomic arousal, as indexed by high-frequency heart rate variability. METHODS: Fifty-seven children with autism aged 8-12 years (45 boys, 12 girls) participated in a double-blind, randomized pharmaco-neuroimaging trial involving twice-daily administrations of intranasal oxytocin or placebo. Resting-state fMRI scans and simultaneous, in-scanner heart rate recordings were obtained before, immediately after, and 4 weeks after the nasal spray administration period. RESULTS: Significant reductions in intrinsic amygdala-orbitofrontal connectivity were observed, particularly at the 4-week follow-up session. These reductions were correlated with improved social symptoms and lower cardiac autonomic arousal. Further, oxytocin's neural and cardiac autonomic effects were modulated by epigenetic modifications of the oxytocin receptor gene. The effects were more pronounced in children with reduced epigenetic methylation, signifying heightened expression of the oxytocin receptor. CONCLUSION: These findings underscore that a 4-week oxytocin administration course decreases amygdala connectivity and improves cardiac autonomic balance. Epigenetic modulators may explain inter-individual variation in responses to oxytocin.

Endogenous oxytocin levels in children with autism: Associations with cortisol levels and oxytocin receptor gene methylation.

Alterations in the brain's oxytocinergic system have been suggested to play an important role in the pathophysiology of autism spectrum disorder (ASD), but insights from pediatric populations are sparse. Here, salivary oxytocin was examined in the morning (AM) and afternoon (PM) in school-aged children with (n = 80) and without (n = 40) ASD (boys/girls 4/1), and also characterizations of DNA methylation (DNAm) of the oxytocin receptor gene (OXTR) were obtained. Further, cortisol levels were assessed to examine links between the oxytocinergic system and hypothalamic-pituitary-adrenal (HPA) axis signaling. Children with ASD displayed altered (diminished) oxytocin levels in the morning, but not in the afternoon, after a mildly stress-inducing social interaction session. Notably, in the control group, higher oxytocin levels at AM were associated with lower stress-induced cortisol at PM, likely reflective of a protective stress-regulatory mechanism for buffering HPA stress activity. In children with ASD, on the other hand, a significant rise in oxytocin levels from the morning to the afternoon was associated with a higher stress-induced cortisol release in the afternoon, likely reflective of a more reactive stress regulatory release of oxytocin for reactively coping with heightened HPA activity. Regarding epigenetic modifications, no overall pattern of OXTR hypo- or hypermethylation was evident in ASD. In control children, a notable association between OXTR methylation and levels of cortisol at PM was evident, likely indicative of a compensatory downregulation of OXTR methylation (higher oxytocin receptor expression) in children with heightened HPA axis activity. Together, these observations bear important insights into altered oxytocinergic signaling in ASD, which may aid in establishing relevant biomarkers for diagnostic and/or treatment evaluation purposes targeting the oxytocinergic system in ASD.

Comparison of the effectiveness of eHealth self-management interventions for pain between oncological and musculoskeletal populations: a systematic review with narrative synthesis.

OBJECTIVES: The aim of this systematic review is to compare the effectiveness of eHealth self-management interventions on pain intensity between oncological and musculoskeletal populations and to examine barriers and facilitators of the use of eHealth self-management tools. CONTENT: In March 2021, a systematic search of the literature was conducted using the databases PubMed and Web of Science. Studies that investigated the effect of eHealth self-management interventions on pain intensity in an oncological and/or a musculoskeletal population were included. SUMMARY: No study was found with a direct comparison of the two populations. Of the ten included studies, only one (musculoskeletal) found a significant interaction effect in favor of the eHealth program and three (musculoskeletal and breast cancer) showed a significant time-effect of the eHealth intervention. In both populations user-friendliness of the tool was considered as a facilitator, the length of the program and the lack of an in-person session as barrier. Due to the absence of a direct comparison, no conclusion can be made on how the effectiveness differs between both populations. OUTLOOK: Further research should incorporate patient-experienced barriers and facilitators and there is a high need of studies making the direct comparison of the effect of an eHealth self-management intervention on pain intensity in an oncological vs. a MSK population.

Feasibility and pilot testing of a personalized eHealth intervention for pain science education and self-management for breast cancer survivors with persistent pain: a mixed-method study.

PURPOSE: Here, we describe the development and pilot study of a personalized eHealth intervention containing a pain science education program and self-management support strategies regarding pain and pain-related functioning in female survivors of breast cancer. First, we aimed to evaluate the eHealth intervention's acceptability, comprehensibility, and satisfaction; second, we aimed to assess its preliminary efficacy. METHODS: A mixed-method study design was used. Breast cancer survivors with persistent pain were recruited. After 6 weeks of engagement with the eHealth intervention, acceptability, comprehensibility, and satisfaction were measured quantitatively with a self-constructed questionnaire and described qualitatively using focus groups. A joint display was used to present the meta-interferences between data. Efficacy was assessed via mixed effects models with repeated measures (outcomes assessed at baseline, 6 weeks, and 12 weeks). RESULTS: Twenty-nine women with persistent pain after breast cancer surgery participated. Overall, the eHealth program was well received and experienced as easy to use and helpful. The eHealth intervention seems useful as an adjunct to comprehensive cancer aftercare. Efficacy estimates suggested a significant improvement in pain-related functioning, physical functioning, and quality of life. CONCLUSION: A personalized eHealth intervention appears valuable for persistent pain management after breast cancer surgery. A large controlled clinical trial to determine effectiveness, and a full process evaluation, seems warranted.

Pain prevalence and characteristics in survivors of solid cancers: a systematic review and meta-analysis.

PURPOSE: The latest systematic review on the prevalence of pain in cancer survivors was published 5 years ago. The current review aims to provide an extended overview on the prevalence of pain, pain mechanisms, pain characteristics, and assessment methods in cancer survivors. METHODS: A systematic research was conducted on 17th of April 2020 using MEDLINE, Embase, Scopus, Web of Science, and Cochrane looking at studies from 2014 to 2020. Studies had to report pain prevalence rates in cancer survivors with a solid tumor who finished curative treatment at least 3 months ago. Methodological quality was assessed by two independent reviewers using the Joanna Briggs Institute quality appraisal tool. Characteristics of the included studies, participants and reported pain prevalence rates were extracted. The reported prevalence rates of the individual studies were pooled within a meta-analysis. Meta-regressions were performed to identify possible determinants of the pooled pain prevalence. RESULTS: After deduplication, 7300 articles were screened, after which 38 were included in the meta-analysis. Risk of bias was rated low in 26 articles and moderate in 12 articles. The pooled pain prevalence was 47% (95%CI 39-55), with a heterogeneity of 98.99%. CONCLUSION: This meta-analysis suggests that nearly half of cancer survivors report pain after completing curative treatment at least 3 months ago. However, substantial unexplained heterogeneity warrants cautious interpretation of these results. Meta-regression using cancer type, treatment location, pain measurement, and follow-up time as a covariate could not explain influencing factors explaining the high heterogeneity.

Physical Activity Levels of Breast Cancer Patients Before Diagnosis Compared to a Reference Population: A Cross-Sectional Comparative Study.

PURPOSE: We hypothesize that prediagnosis physical activity (PA) levels of breast cancer patients are below those of a reference population without breast cancer. Therefore, the aim of the present study was to compare prediagnosis PA levels (including total-, occupational-, sport- and household activity levels) of breast cancer patients with activity levels of a reference population. METHODS: Female patients with primary breast cancer (n = 265) filled in the Flemish Physical Activity Computerized Questionnaire (FPACQ) the day before surgery recalling the year before diagnosis. PA levels were expressed as Metabolic Equivalent Task (MET) values. Smooth reference curves of PA levels were estimated in a representative sample of 3466 women without breast cancer with the LMS method, which allowed comparison of prediagnosis PA data of the breast cancer sample with this reference. RESULTS: Compared to women without breast cancer, total PA levels were significantly lower in the year prior to breast cancer diagnosis over all age groups (Mean ± SD z-scores (95% CI) = -1.51 ± 1.86 (-1.74 to -1.29)). More specifically, household PA levels of breast cancer patients were significantly lower between ages 40-60, while occupational PA levels were significantly higher in this age group. No differences were found between sports PA levels. CONCLUSIONS: Patients with breast cancer show significantly lower total PA levels during the year prior to surgery compared to a reference population. Especially household activity levels are lower in patients between ages 40 and 60. Given this, a return to prediagnosis PA levels may not be sufficient for protection from disease in the future.

The association between upper limb function and variables at the different domains of the international classification of functioning, disability and health in women after breast cancer surgery: a systematic review.

PURPOSE: To investigate the variables per International Classification of Functioning, Disability and Health (ICF)-domain that are associated with upper limb (UL) function in women after breast cancer surgery. MATERIALS AND METHODS: PubMed and Web of Science were searched until 7 January 2020. Eligibility criteria were: prospective investigation of an association between one or more variables of the ICF model and UL function in women after breast cancer surgery. PRISMA guidelines were used to conduct and report the systematic review. The Quality In Prognosis Studies tool (QUIPS) was used to evaluate risk of bias. RESULTS: Twelve studies were included (2244 participants). Risk of bias of the included studies was low to moderate. Variables at the ICF-function level that were systematically associated with decreased UL function across multiple included papers were: increased UL pain, decreased shoulder range of motion, decreased handgrip strength and a higher number of comorbidities. Results on the association between UL function and variables at other ICF-domains were conflicting. CONCLUSION: UL function was associated with certain variables at the ICF-function level. Variability in disease stages, treatment and measurement methods might explain inconsistent associations with other variables. Only limited studies investigated associations between UL function and psychosocial factors.IMPLICATIONS FOR REHABILITATIONThis paper gives an overview of associations between different variables of the ICF model and UL dysfunctions in women after breast cancer surgery.Identified associated factors are situated at the ICF function level, i.e., UL pain, decreased handgrip strength and shoulder (abduction) ROM.These factors are modifiable and should be monitored, prevented and treated in physical therapy practice.UL dysfunction is not consistently associated with treatment-related variables.The role of psychosocial personal factors in UL dysfunctions should be considered and further explored.

Pain Prevalence During Cancer Treatment: A Systematic Review and Meta-Analysis.

CONTEXT: Pain is one of the most complex and prevalent symptoms in the cancer population. Despite the protective role of acute cancer-related pain, it is also an important predictor for the likelihood of developing chronic pain after cancer treatment. OBJECTIVES: Since the last systematic review on pain prevalence rates during cancer treatment dates already from 2016, the aim of the present systematic review was to provide an overview of pain prevalence rates during cancer treatment since this previous review. METHODS: A systematic search of the literature, including studies between 2014 and 2020, was conducted using the databases Pubmed, Embase, Scopus, Web of Science and Cochrane. Studies reporting pain prevalence rates during or within three months after curative cancer treatment was included. Title/abstract and full-text was screened double-blinded, followed by independent evaluation of the risk of bias. All prevalence rates were pooled within meta-analyses and a meta-regression was performed to clarify the amount of heterogeneity. RESULTS: Of the 9052 studies, 12 studies were included in the meta-analysis of which 10 included breast cancer and two lung cancer patients. The pooled pain prevalence rate was 40% (95%CI 0.29-0.51), with a heterogeneity of 96%. Out of the meta-regression, only the covariate "method of pain measurement" significantly clarified the heterogeneity (P < 0.05), resulting in a residual heterogeneity of 94.88%. CONCLUSION: Five years after the last systematic review published on this topic, pain is still very prevalent during cancer treatment. However, the pain prevalence rates were also very heterogeneous. These two findings emphasize the need for further research on the development of adequate pain assessment and pain management approaches during cancer treatment.

Cognitions and physical impairments in relation to upper limb function in women with pain and myofascial dysfunctions in the late stage after breast cancer surgery: an exploratory cross-sectional study.

PURPOSE: Upper limb (UL) function is one of the health outcomes that matters the most for women with breast cancer. However, a better understanding of the factors contributing to UL dysfunctions in the late stage after breast cancer surgery is needed. This study explores associations between impairment-related and cognition-related factors and UL function in women with pain and myofascial dysfunctions at the affected UL region in this late stage after breast cancer surgery. METHODS: In forty-one women, UL function (dependent variable) was evaluated by the Disabilities of Arm, Shoulder and Hand questionnaire. As independent impairment-related factors, relative excessive arm volume (perimetry), pain intensity (maximum score on the visual analogue scale past week) and humerothoracic elevation and scapular lateral rotation (kinematic analysis) were assessed. As independent cognition-related factors, pain catastrophizing (Pain Catastrophizing Scale) and pain hypervigilance (Pain Vigilance and Awareness Questionnaire) were evaluated. Bi-variable analyses and a stepwise regression analysis were used to explore associations. RESULTS: A higher pain intensity (r = 0.52; p < 0.001), more pain catastrophizing (r = 0.49; p < 0.001) and more pain hypervigilance (r = 0.40; p = 0.01) were related to more UL dysfunction. Pain intensity (p = 0.029) and pain catastrophizing (p = 0.027) explained furthermore 29.9% of variance in UL function. CONCLUSIONS: Pain intensity and cognition-related factors are significantly associated with UL function in women with pain and myofascial dysfunctions, indicating the need of assessing pain beliefs in women in the late stage after breast cancer surgery.IMPLICATIONS FOR REHABILITATIONPain intensity and pain-related beliefs, including pain attention and catastrophizing, are related to the severity of upper limb dysfunctions in the late stage after breast cancer surgery.Impairments such as lymphedema and movement restrictions seem not related to upper limb function in the assessed sample.To understand upper limb dysfunctions in the late stage after breast cancer, assessing pain beliefs is needed.

Effectiveness of perioperative pain science education on pain, psychological factors and physical functioning: A systematic review.

OBJECTIVE: To synthesize the evidence on the effectiveness of pain science education on pain, psychological factors and physical functioning in adults who underwent surgery. DATA SOURCES: A systematic literature search of English articles using PubMed/Medline, Embase, Web of Science Core Collection, and Cochrane Library. REVIEW METHODS: The search strategy was constructed as follows: (((pain) AND (education)) OR (pain education)) AND (surgery). Only controlled quantitative studies in adults reporting outcome(s) on pain, psychological factors and/or physical functioning were included. Risk of bias was assessed using the Cochrane risk of bias tools. P-values and corresponding effect sizes for interaction-effect (time × group) portrayed the difference in change over time between groups were of interest. The last search was conducted on February 28, 2021. RESULTS: Nine papers (n = 1078) were deemed eligible for this review. Two randomized controlled trials showed significant interaction effects. Breast cancer patients who had received one preoperative pain science education session showed a significant increase in postoperative pain compared to controls (P-value = 0.0394). Furthermore, psychological factors (pain catastrophizing and kinesiophobia) decreased in participants who had received pain science education before total knee arthroplasty, while this was not the case in the control group (P-value < 0.001, ƞ2p:0.11). CONCLUSIONS: Overall, pain science education did not result in any significant postoperative effects on pain, psychological factors and/or physical functioning compared to controls. There is currently no strong evidence for the implementation of pain science education in the perioperative period.Registration number: PROSPERO: ID 161267, registration number CRD42020161267.