Neuromuscular electrical stimulation to combat cognitive aging in people with spinal cord injury: protocol for a single case experimental design study.

INTRODUCTION: Individuals with spinal cord injury (SCI) can experience accelerated cognitive aging. Myokines (factors released from muscle cells during contractions), such as brain-derived neurotrophic factor (BDNF), are thought to have beneficial effects on cognition. Neuromuscular electrical stimulation (NMES) was shown to elicit a large release of myokines. However, the effects of NMES on cognitive function have not been studied. OBJECTIVE: To present the study protocol for a clinical trial evaluating the effects of NMES aimed at improving cognition and BDNF. METHODS: A replicated randomized three-phases single-case experimental design (SCED) with sequential multiple baseline time series and a single-armed prospective trial will be conducted with 15 adults with chronic SCI (> 12 months after injury) above L1 neurological level undergoing 30-min quadriceps NMES, 3 days per week for 12 weeks. MAIN STUDY ENDPOINTS: Primary endpoint is cognitive performance (assessed by a smartphone test) conducted three times per week during the baseline phase with random duration of 3 to 8 weeks, the intervention phase of 12 weeks, and the follow-up phase of 3 weeks after a no measurement rest period of 12 weeks. Secondary endpoints are changes in BDNF levels and cognitive performance measured before the baseline period, before and after intervention and after a 12 weeks follow-up. CONCLUSION: This will be the first study investigating the effects of 12 weeks NMES on both cognition and BDNF levels in individuals with SCI. The SCED results provide information on individual treatment effect courses which may direct future research. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05822297, 12/01/2023).

Relationships between type of pain and work participation in people with long-standing spinal cord injury: results from a cross-sectional study.

STUDY DESIGN: Multicentre, cross-sectional study. OBJECTIVES: To describe the relationships between the presence of (different types of) pain and participation in paid work in people with long-standing spinal cord injury (SCI). Furthermore, the associations of pain-related work limitations, age, gender, relationship, education, lesion level, and time since injury (TSI) with work participation (WP) were investigated. SETTING: The Netherlands. METHODS: Individuals (n = 265) with SCI for ≥ 10 years were included. Data were collected through a structured consultation with a rehabilitation physician and self-report questionnaire. Descriptive statistics and logistic regression analysis were performed. RESULTS: Median age of participants was 47.9 years, median time since injury was 22 years, 73% were male, 69% had complete SCI and 59% had paraplegia, 50% had paid work, 63% reported musculoskeletal pain, 49% reported neuropathic pain, and 31% reported other pain. Self-reported pain-related work limitations were significantly (V = 0.26 and V = 0.27) related to WP. In bivariable logistic regression analyses, no statistically significant relationships between type of pain and WP were observed. Younger age (OR=0.96), male gender (OR=0.52), a stable relationship (OR = 1.70), and shorter time since SCI (OR = 0.97) were significantly associated with a higher chance of being employed. Multivariable analysis confirmed these findings and in addition showed a higher level of education to be positively related with WP. CONCLUSION: Age, gender, relationship, education, TSI and self-reported work limitations showed a relationship with WP. Different types of pain were unrelated to WP. SPONSORSHIP: Fonds NutsOHRA through the Dutch Organization for Health Research and Development (ZonMw), Project number 89000006.

Perceived Physical Activity Decline as a Mediator in the Relationship Between Pain Catastrophizing, Disability, and Quality of Life in Patients with Painful Diabetic Neuropathy.

BACKGROUND: To fully understand the burden of painful diabetic neuropathy (PDN), we investigated the relationship of pain catastrophizing with disability and quality of life in patients with PDN. Furthermore, we studied the mediating roles of physical activity and/or decline in physical activity. METHODS: This questionnaire-based cross-sectional study included 154 patients with PDN. Linear regression analyses, adjusted for age, gender, pain intensity, and insulin treatment, were performed to assess the association of pain catastrophizing (Pain Catastrophizing Scale [PCS]) with the outcome variables disability (Pain Disability Index [PDI]) and quality of life (Norfolk Quality of Life Questionnaire Diabetic Neuropathy Version [QOL-DN]). The mediating roles of actual physical activity (Physical Activity Rating Scale [PARS]) and perceived Physical Activity Decline (PAD) were assessed using mediation analyses according to Baron and Kenny. RESULTS: This study included 154 patients (62% male). Mean age was 65.7 years (SD = 6.6). PCS (M = 20.3, SD = 13.1) was significantly associated with PDI (M = 32.4, SD = 17.0; R2 = 0.356, P < 0.001), QOL-DN (M = 52.6, SD = 26.1; R2 = 0.437, P < 0.001), and PAD (M = 7.4, SD = 5.7; R2 = 0.087, P = 0.045). PAD acted as a partial mediator in the associations of PCS with PDI and QOL-DN, respectively. There was no association of PCS with PARS. CONCLUSIONS: Pain catastrophizing was associated with increased disability and decreased quality of life in patients with PDN. Also, it was associated with a perceived decline in physical activity, which had a mediating role in the association between catastrophizing and disability and quality of life, respectively. This study emphasizes the role of catastrophic thinking about pain and the experienced loss in daily activities due to PDN.

Painful Diabetic Neuropathy Anxiety Rasch-Transformed Questionnaire (PART-Q30(©) ).

The association between painful diabetic neuropathy (PDN) and anxiety has been acknowledged using various anxiety scales capturing various fear entities. It has never been examined whether these generally applied anxiety questionnaires could be pooled to construct one overall anxiety metric. After completion by a cohort of 151 patients with PDN, data obtained from seven generally applied fear scales were stacked (n = 88 items) and subjected to Rasch analyses (pre-PART-Q88) to create the PDN overall Anxiety Questionnaire (PART-Q30(©) ). We subsequently examined the impact of the final constructed PART-Q30(©) on disability and Quality of Life (QoL) using the Rasch-Transformed Pain Disability Index (RT-PDI) and the Norfolk Quality of Life Questionnaire, Diabetic Neuropathy version (RT-Norfolk). The pre-PART-Q88 data did not meet Rasch model's expectations. Through stepwise examination for model fit, disordered thresholds, local dependency and item bias, we succeeded in reducing the data and constructing a 30 items overall anxiety scale (PART-Q30(©) ) that fulfilled all model's expectations, including unidimensionality. An acceptable internal reliability was found (person-separation-index: 0.90). PART-Q30(©) explained 36% of disability and combined with RT-PDI 63% of QoL (assessed with RT-Norfolk).

Myokines may target accelerated cognitive aging in people with spinal cord injury: A systematic and topical review.

Persons with spinal cord injury (SCI) can suffer accelerated cognitive aging, even when correcting for mood and concomitant traumatic brain injury. Studies in healthy older adults have shown that myokines (i.e. factors released from muscle tissue during exercise) may improve brain health and cognitive function. Myokines may target chronic neuroinflammation, which is considered part of the mechanism of cognitive decline both in healthy older adults and SCI. An empty systematic review, registered in PROSPERO (CRD42022335873), was conducted as proof of the lack of current research on this topic in people with SCI. Pubmed, Embase, Cochrane and Web of Science were searched, resulting in 387 articles. None were considered eligible for full text screening. Hence, the effect of myokines on cognitive function following SCI warrants further investigation. An in-depth narrative review on the mechanism of SCI-related cognitive aging and the myokine-cognition link was added to substantiate our hypothetical framework. Readers are fully updated on the potential role of exercise as a treatment strategy against cognitive aging in persons with SCI.

Altered Circulating Immune Cell Distribution in Traumatic Spinal Cord Injury Patients in Relation to Clinical Parameters.

Following a spinal cord injury (SCI), an inflammatory immune reaction is triggered which results in advanced secondary tissue damage. The systemic post-SCI immune response is poorly understood. This study aimed to extensively analyse the circulating immune cell composition in traumatic SCI patients in relation to clinical parameters. High-dimensional flow cytometry was performed on peripheral blood mononuclear cells of 18 traumatic SCI patients and 18 healthy controls to determine immune cell subsets. SCI blood samples were collected at multiple time points in the (sub)acute (0 days to 3 weeks post-SCI, (s)aSCI) and chronic (6 to >18 weeks post-SCI, cSCI) disease phase. Total and CD4+ T cell frequencies were increased in cSCI patients. Both CD4+ T cells and B cells were shifted towards memory phenotypes in (s)aSCI patients and cSCI patients, respectively. Most profound changes were observed in the B cell compartment. Decreased immunoglobulin (Ig)G+ and increased IgM+ B cell frequencies reflected disease severity, as these correlated with American Spinal Injury Association (ASIA) impairment scale (AIS) scores. Post-SCI B cell responses consisted of an increased frequency of CD74+ cells and CD74 expression level within total B cells and B cell subsets. Findings from this study suggest that post-SCI inflammation is driven by memory immune cell subsets. The increased CD74 expression on post-SCI B cells could suggest the involvement of CD74-related pathways in neuroinflammation following SCI. In addition, the clinical and prognostic value of monitoring circulating IgM+ and IgG+ B cell levels in SCI patients should be further evaluated.

Exposure in Vivo as a Treatment Approach to Target Pain-Related Fear: Theory and New Insights From Research and Clinical Practice.

Pain-related fear (PRF) can be a significant factor contributing to the development and maintenance of pain-related disability in individuals with persistent pain. One treatment approach to target PRF and related avoidance behavior is exposure in vivo (EXP). EXP has a long history in the field of anxiety, a field that is constantly evolving. This Perspective outlines recent theoretical advancements and how they apply to EXP for PRF, including suggestions for how to optimize inhibitory learning during EXP; reviews mechanistic work from neuroimaging supporting the targeting of PRF in people with chronic pain; and focuses on clinical applications of EXP for PRF, as EXP is moving into new directions regarding who is receiving EXP (eg, EXP in chronic secondary pain) and how treatment is provided (EXP in primary care with a crucial role for physical therapists). Considerations are provided regarding challenges, remaining questions, and promising future perspectives. IMPACT: For patients with chronic pain who have elevated pain-related fear (PRF), exposure is the treatment of choice. This Perspective highlights the inhibitory learning approach, summarizes mechanistic work from experimental psychology and neuroimaging regarding PRF in chronic pain, and describes possible clinical applications of EXP in chronic secondary pain as well as in primary care.

Effectiveness of Exposure in Vivo for Patients with Painful Diabetic Neuropathy: a Pilot Study of Effects on Physical Activity and Quality of Life.

OBJECTIVE: To evaluate the effects of personalized exposure in vivo on level of physical activity and quality of life in patients with painful diabetic neuropathy. DESIGN: Randomized, single-case, ABC design. SUBJECTS: Twelve patients with painful diabetic neuropathy, age > 18 years, diabetes mellitus type II, Clinical Neurological Examination score > 5, Diabetic Neuropathy Symptom Score ≥ 1 and Douleur Neuropathique 4 Questions score ≥ 3. METHODS: The treatment consists of an Intensive screening, followed by an 8-week exposure in vivo intervention specifically adapted to the needs/risks of patients with painful diabetic neuropathy, and 6-months follow-up. Outcome measures included daily and non-daily measures of physical activity, quality of life, metabolic parameters, disability, depression, general and painful diabetic neuropathy-related anxiety, pain intensity and pain catastrophizing. RESULTS: Due to high drop-out rates (n = 6 during screening, n = 2 during treatment, n = 1 after treatment), only 3 participants completed the study. Slight, but non-significant, changes in physical activity and disability were observed. In quality of life, no changes were observed. CONCLUSION: Analysis of the reasons for the high drop-out rate indicate that exposure in vivo may have added value in patients with painful diabetic neuropathy only for those patients: (i) whose daily life functioning is impaired mainly by the painful diabetic neuropathy; (ii) in whom painful diabetic neuropathy-related fears are exaggerated and irrational; (iii) in whom specific activities evoke the painful diabetic neuropathy-related fears; (iv) whose spouse and healthcare providers are involved in the treatment; and (v) who are willing to change their daily behaviour. Further research is needed into this subject.

Learning self-care skills after spinal cord injury: a qualitative study.

BACKGROUND: People with a recent spinal cord injury (SCI) often follow intensive rehabilitation. Learning appropriate self-care, deal with their impairments and prevent secondary health conditions (SHCs), is highly important during rehabilitation. To date it is not clear how self-care skills are taught to people with SCI. The objective of this study was to understand how people with SCI experienced the learning of appropriate self-care skills during inpatient rehabilitation, including the role of the rehabilitation team. METHODS: Individual semi-structured interviews were conducted with 15 people with SCI, recently discharged from initial inpatient rehabilitation. Interviews were audio-taped, transcribed and analyzed thematically. RESULTS: Two main themes and seven sub-themes were identified. Participants stated that the contribution of the rehabilitation team to learning self-care, including prevention of SHCs, was mostly made by optimizing opportunities to learn through experience. For preventing SHCs, education and lessons learned from the professionals during therapy and the formal educational program, was experienced as especially important. Further, the motivational attitude of the professionals which participants found stimulating and was based on respect, combined with their positive contribution as one team, were seen as essentials elements for learning appropriate self-care. However participants did not recognize the contribution of the nursing staff as part of their rehabilitation, although it was seen as very important. An important aspect of the participants' own contribution was challenging oneself to learn self-care. This was done in different ways by the participants. Further, their own mental adjustment was considered important in the learning process. The gaining of confidence was by most participants seen as personal characteristic, although they also recognized the importance of the team effort and the experiences they underwent. CONCLUSIONS: Learning appropriate self-care was mostly done through experience, by challenging themselves, and making use of the opportunities given by the members of the rehabilitation team. The same strategies used by the rehabilitation team to teach people with SCI to perform appropriate self-care, were also helpful for the participants to gain confidence. Explicit attention for self-care training as an important goal in SCI rehabilitation may strengthen the nursing staff's role and stimulate interdisciplinary working.

The effect of exercise therapy combined with psychological therapy on physical activity and quality of life in patients with painful diabetic neuropathy: a systematic review.

Background and aims Approximately 25% of patients with diabetes mellitus type 2 (DMII) develop painful diabetic neuropathy (PDN). PDN is known to affect both mental and physical wellbeing, resulting in anxiety, depression, low quality of life and physical disability. Pharmacological treatment of PDN aims at pain relief and is often ineffective and/or has many side effects. Rehabilitation treatment modalities that are designed to help the patient deal with PDN related complaints, are mostly focussed on either physical (e.g. exercise therapy) or psychological aspects (e.g. cognitive behavioural therapy, CBT). There is emerging evidence that PDN can be approached from a biopsychosocial perspective, in which physical and psychosocial aspects are integrated. From this biopsychosocial approach it is plausible that integrated treatment modalities such as acceptance commitment therapy (ACT) or exposure in vivo (EXP) could be effective in patients with PDN. The objective of this review was to provide an overview of the current evidence on the effects of rehabilitation treatments that combine exercise therapies with psychological therapies in order to improve physical activity (PA) and quality of life (QoL) in patients with PDN. Methods Systematic review of the current literature. EMBASE, MEDLINE, Medline In-Process citations and e-Pubs ahead-of-print, Pedro, Web of Science, PsycINFO, CENTRAL, PubMed and Google Scholar were searched. All studies on interventions combining exercise therapy with psychological interventions in patients with PDN, aged >18 years, were included. Outcome measures were PA, QoL. Results The search resulted in 1603 records after removing duplicates. After screening on titles and abstracts, 100 records remained. From these, not one study reported on interventions that combined exercise therapy with psychological interventions. Through a secondary hand search, a total of three reviews were identified that described a total of five studies regarding either physical or psychological interventions in patients with PDN. These studies reported moderate effects of (1) mindfulness meditation on QoL, (2) CBT on pain severity, (3) mindfulness-based stress reduction intervention on function, health-related QoL, pain catastrophizing and depression, (4) aerobic exercise on QoL and (5) Tai Chi on glucose control, balance, neuropathic symptoms, and some dimensions of QoL in patients with PDN. All studies were of a moderate quality, and results should be interpreted with caution. Conclusions Based on increasing knowledge in the domain of chronic pain, it could be assumed that integrated rehabilitation treatments for patients with PDN are beneficial. There is no literature to support this and more research should be done on integrated biopsychosocial interventions in patients with PDN. Implications This empty review highlights the importance that more research should be done on integrated biopsychosocial interventions in patients with PDN. Currently, our research group is performing a study on the effects of EXP treatment in patients with PDN.

Biopsychosocial Rehabilitation Treatment "Exposure In Vivo" for Patients with Painful Diabetic Neuropathy: Development of a Treatment Protocol.

OBJECTIVE: Painful diabetic neuropathy is associated with low quality of life, depression and anxiety. Patients are limited in their performance of activities of daily living due to fears related to their condition. Treatment modalities are needed to help patients cope with their pain and pain-related disability. Exposure in vivo is an effective treatment in other chronic pain syndromes, increasing patients' functional ability and quality of life. This paper presents an Exposure in vivo treatment protocol for patients with painful diabetic neuropathy. PROTOCOL: An 8-week Exposure in vivo treatment protocol was specifically adapted to the needs and risks of patients with painful diabetic neuropathy. New screening tools were developed for patients with PDN; the Painful Diabetic Neuropathy Anxiety Rasch-Transformed Questionnaire (PART-Q30) identifies specific fears related to painful diabetic neuropathy (e.g. fear of hypoglycaemia); and a customized version of the Photograph-series Of Daily Activities (PHODA-PDN) detects fear-eliciting activities related to the condition in individual patients. During Exposure in vivo, catastrophic interpretations regarding painful stimuli are challenged and corrected, thereby diminishing pain-related fear and enabling the patient to re-engage in activities of daily living. An interdisciplinary team provides Exposure in vivo in 1-h sessions twice a week. DISCUSSION: To the best of our knowledge, this treatment protocol is the first intervention using Exposure in vivo specifically adapted to the needs and risks of patients with painful diabetic neuropathy.

Living with painful diabetic neuropathy: insights from focus groups into fears and coping strategies.

OBJECTIVE: Painful diabetic neuropathy (PDN) is known to negatively affect quality of life. Being physically active is a crucial part of successful diabetes self-management, but regimen adherence is often low. Coping strategies and fears have shown to be related to less physical activity (PA). The aim of the present study was to obtain more in-depth information on psychological risk factors leading to less PA in persons with PDN. DESIGN: Three semi-structured focus group interviews were conducted with a representative sample of persons with PDN (N = 12). Data were transcribed verbatim and analysed using a hybrid method of thematic analyses and a grounded theory approach. MAIN OUTCOME MEASURES: Fears and coping strategies related to PA in persons with PDN. RESULTS: Several specific fears were identified; fear of hypoglycaemia, fear of pain increase, fear of total exhaustion, fear of physical injury, fear of falling, fear of loss of identity, and fear of negative evaluation by others. To cope with these fears, avoidance, remaining active, cognitive distraction, and acceptance strategies were described. CONCLUSION: In persons with PDN, diabetes-related fears and pain-related fears play a role in less engagement in PA, indicating the need for new methods for improving self-management in persons with PDN.

BclI glucocorticoid receptor polymorphism in relation to cardiovascular variables: the Hoorn and CODAM studies.

OBJECTIVE: Excess glucocorticoids are known to cause hypertension and cardiovascular disease (CVD). The BclI glucocorticoid receptor (GR) polymorphism increases glucocorticoid sensitivity and is associated with adverse metabolic effects. Previous studies investigating cardiovascular implications have shown inconsistent results. Therefore, the aim of the present study was to investigate the association of the BclI polymorphism with blood pressure, atherosclerosis, low-grade inflammation, endothelial dysfunction, and prevalent CVD. DESIGN: Observational cohort study, combining two cohort studies designed to investigate genetic and metabolic determinants of CVD. METHODS: We genotyped 1228 individuals (aged 64.7 years±8.5) from the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study and Hoorn study for the BclI polymorphism. We measured blood pressure, ankle-brachial index (ABI), and carotid intima-media thickness (cIMT). Low-grade inflammation and endothelial dysfunction scores were computed by averaging Z-scores of six low-grade inflammation markers and four endothelial dysfunction markers respectively. Prevalent CVD was assessed with questionnaires, hospital records, ECG, and ABI. RESULTS: Homozygous carriers (GG) had higher mean arterial pressure (103.8±12.4  mmHg vs 101.6±12.2  mmHg (mean±S.D.); P<0.05) compared with non-carriers (CC). Homozygous carriers had lower ABI compared with heterozygous carriers (CG) (1.08±0.13 vs 1.11±0.14; P<0.05). After adjustment for all covariates in the full model, the association with ABI was no longer significant. BclI was not associated with systolic blood pressure, cIMT, low-grade inflammation, endothelial dysfunction, and prevalent CVD. CONCLUSIONS: The BclI polymorphism of the GR gene may contribute to an unfavorable cardiovascular profile; however, the effects on cardiovascular variables appear to be limited and partly mediated by the metabolic phenotype exerted by BclI.