Targeting inflammation to influence mood following spinal cord injury: a randomized clinical trial

Background: The purpose of the present study was to examine the efficacy of targeting inflammation as a means of improving mood following spinal cord injury (SCI) and explore the potential mechanisms of action. Methods: The study was a randomized, parallel-group, controlled, clinical trial (NCT02099890) whereby 20 participants with varying levels and severities of SCI were randomized (3:2) to either the treatment group, consisting of a 12-week anti-inflammatory diet, or control group. Outcome measures were assessed at baseline, 1 and 3 months, and consisted of CES-D scores of depression, markers of inflammation as assessed by various pro- and anti-inflammatory cytokines and several amino acids related to depression. Results: A significant group × time interaction was found for CES-D (Center for Epidemiologic studies Depression Scale) score ( p = 0.01), the TRP/LNAA (tryptophan/large neutral amino acid) ratio ( p = 0.04), the composite score of pro-inflammatory cytokines ( p = 0.04), IL-1 β (interleukin-1 beta) ( p = 0.04), and IFN- γ (interferon gamma) ( p = 0.03). Pearson ’ s r correlation showed significance between the Δ IL-1 β and both the Δ CES-D score ( r = 0.740, p < 0.01) and the Δ KYN/TRP (kynurenine/tryptophan) ratio ( r = 0.536, p = 0.02). The Δ KYN/TRP ratio was also significantly correlated with the Δ CES-D score ( r = 0.586, p = 0.01). Mediation analysis showed that the relationship between the Δ KYN/TRP ratio and the Δ CES-D score was mediated by the Δ IL-1 β . Subgroup analysis showed that participants with high CES-D scores had significantly higher concentrations of IL-1 β , and all correlations were maintained or strengthened within this subgroup. Conclusions: Overall, the results demonstrated the effectiveness of targeting inflammation as a means of improving mood in SCI, with potential mechanisms relating to the reduction in IL-1 β and improvements in levels of neuroactive compounds related to the kynurenine pathway. Due to the limited sample size, results should be interpreted with caution; however, they are worthy of further examination due to the potential impact of inflammation on depressio

The Effect of Age and Gender on the Relative Fatigability of the Human Adductor Pollicis Muscle

The purpose of this study was to examine the relationships between age, gender and fatigue resistance, and further, to determine the relative influence that estrogen status, membrane excitability, absolute force and muscle length have over the development of fatigue. A total of 48 subjects, classified by age and gender participated in this study; 12 young males (25.3 ± 2.1 yrs.), 12 young females (23.5 ± 2.1 yrs.), 12 elderly males (71.7 ± 5.6 yrs.) and 12 elderly females (69.5 ± 4.6 yrs.). The young females were all eumenorrheic, not taking oral contraceptives and tested in the mid-follicular phase of the menstral cycle. None of the elderly females were on hormone replacement therapy. A 3 minute paradigm of intermittent maximal voluntary contractions (MVC) was used to fatigue the adductor pollicis muscle, in which 5s MVC's were alternated with 2s rest periods. In addition, maximal twitches were evoked in each 2s rest period. No gender difference in fatigability was evident between young males and young females when considering the fatigue index of the evoked twitch (FI-PT) (young males: 39.8 ± 26.7%, young females: 36.6 ± 19.0%). There was also no gender difference in fatigability found between elderly males and elderly females when considering the FI-PT (elderly males: 24.9 ± 26.6%, elderly females: 16.4 ± 48.9%). However, potentiation of the evoked twitches during fatigue may have confounded these measures. When considering the changes in voluntary force during fatigue, there was a strong trend for a gender by time interaction between young males and young females.(p=0.06), which suggests that the former were more fatigable. The trend for this gender difference was also apparent in the voluntary fatigue index (FI-MVC) (young males: 44.7 ± 10.5%, young females: 37.8 ± 14.1 %; p=0.12). Similarly, young males had a significant decrease in M-wave amplitude during the fatigue protocol and a trend for a decrease in M-wave area (p=0.08), while young females showed no significant decreases in either M-wave measure during the fatigue protocol. There was no gender difference found between the elderly males and elderly females when considering the FI-MVC (elderly males: 24.2 ± 10.7%, elderly females: 26.3 ± 14.5%). Both groups also showed small but significant reductions in theM-wave amplitude during the fatigue protocol, although M-wave area was well maintained. The fact that a strong trend for a gender difference in fatigability was found in the young subjects but not the elderly subjects, suggests that estrogen may possess fatigue resisting properties, even during short duration exercise in which glycogen depletion is not a concern. With respect to the age-related differences in fatigue, elderly males were found to be significantly more fatigue resistant than young males as indicated by the FI-MVC (p<0.01), and the significant age by time interaction during the fatigue protocol (p<0.01). In contrast, only a trend was found for an age by time interaction between the young and elderly females during the fatigue protocol (p=0.06). This trend for an age-related difference in fatigue amongst women was also reflected in the FI- MVC (p=0.13).ThesisMaster of Science (MSc

Syndromics: A Bioinformatics Approach for Neurotrauma Research

Substantial scientific progress has been made in the past 50 years in delineating many of the biological mechanisms involved in the primary and secondary injuries following trauma to the spinal cord and brain. These advances have highlighted numerous potential therapeutic approaches that may help restore function after injury. Despite these advances, bench-to-bedside translation has remained elusive. Translational testing of novel therapies requires standardized measures of function for comparison across different laboratories, paradigms, and species. Although numerous functional assessments have been developed in animal models, it remains unclear how to best integrate this information to describe the complete translational “syndrome” produced by neurotrauma. The present paper describes a multivariate statistical framework for integrating diverse neurotrauma data and reviews the few papers to date that have taken an information-intensive approach for basic neurotrauma research. We argue that these papers can be described as the seminal works of a new field that we call “syndromics”, which aim to apply informatics tools to disease models to characterize the full set of mechanistic inter-relationships from multi-scale data. In the future, centralized databases of raw neurotrauma data will enable better syndromic approaches and aid future translational research, leading to more efficient testing regimens and more clinically relevant findings

THE EFFECTS OF EXERCISE TRAINING ON CARDIOVASCULAR REGULATION IN INDIVIUALS WITH SPINAL CORD INJURY

Introduction. Individuals with spinal cord injury (SCI) are prone to severe cardiovascular dysfunction and an increased risk of mortality from various cardiovascular diseases. The underlying mechanisms responsible for the increased cardiovascular risk are not precisely understood, however, the reduced activity levels that accompany SCI certainly contribute. Unfortunately, muscular paralysis (partial or complete) limits the exercise options for individuals with SCI and the role of exercise rehabilitation as a means of reversing cardiovascular risk is not fully understood in this population. Recently developed methods may be particularly useful in evaluating the effects of exervise on the cardiovascular health and function in individuals with SCI. Specifically, power spectral analysis of heart rate variability (HRV) and blood pressure variability (BPV) have become commonly used, non-invasive methods used to quantify the autonomic control of the cardiovascular system. Clinically, measures of HRV and BPV have particular value as relatively decreased cardiac vagal predominance has been associated with an increased risk of cardiovascular mortality, and increased BPV is associated with end organ damage. In addition, Doppler ultrasound imaging techniques allow for the determination of arterial dimension and function. As such, these imaging techniques may be used to determine arterial blood flow and vascular compliance; the latter referring to the ability of the vessel to expand and recoil during changes in intravascular pressure. Clinically, these measures are also of value as reductions in blood flow contribute to thrombus formation, in addition to delayed wound healing and an increased risk of pressure sore formation, while reductions in arterial compliance are a contributing factor to vascular damage, and the associated risks of thrombosis, myocardial infarction and stroke. The primary purpose of this thesis was to examine the effects of exercise training on resting measures of HRV, BPV and arterial dimension and function in individuals with SCI. A secondary purpose, was to determine the effects of exervise training on the ability to tolerate orthostatic stress in individuals with SCI. Although the first training study in this thesis used arm ergometry and resistance training as the exercise stimulus, the principle mode of exercise training that was used was body-weight supported treadmill training (BWSTT) as it may be particularly well suited as a cardiovascular stimulus in the SCI population. Specifically, BWSTT is an upright exercise that involves the legs, and may be performed without the risks that are commonly associated with functional electrically stimulated (FES) exercise such as burns to the skin, stimulation-induced pain and autonomic dysreflexia. It was hypothesized that BWSTT would result in i)positive changes in the autonomic regulation of the cardiovascular system, as indicated by measures of HRV and BPC, AND II) positive changes in arterial dimension and function, as indicated by Doppler ultrasound measures. Regarding the effects of exercise training on orthostatic tolerance, previous work has provided some evidence that exercise training confers an enhanced ability for individuals with SCI to respond to cardiovascular stress. On the other hand, it was also reasonable to hypothesize that potential training-induced reductions in sympathetic outflow and arterial resistance would decrease the ability to tolerate postural stress in individuals with SCI. Methods. Short-term, continuous ECG and blood pressure (Finapres) recordings were taken before and after exercise training in individuals with SCI and used to determine measures of HRV and BPV, respectively. In addition, Doppler ultrasound imaging was performed on the femoral and carotid arteries, before and after exercise training, in order to determine vascular dimension and function. All testing was conducted in the resting supine position and during an orthostatic stress (60∘head-up tilt). Results. 1. Measures of heart rate variability (HRV) and blood pressure variability (BPV) were found to be reproducible in individuals with SCI, regardless of the level of injury. As such, clinicians and researchers may be encouraged to use these measures to determine the effectiveness of various interventions on the cardiovacular health in the SCI population. 2. Individuals with incomplete tetraplegia were found to retain the ability to make positive changes in cardiac sympathovagal balance following 3 months of combined arm ergometry and resistance exercise training. No exercise-induced changes were noted in orthostatic tolerance. 3. The results of the third study demonstrated that individuals with incomplete tetraplegia can make positive adaptation to the autonomic regulation of the cardiovascular system following 6 months of BWSTT as indicated by measures of HRV and BPV. In addition, these adaptations occurred without an accompanying tendency to become less tolerant of orthostatic stress. 4. The results of the fourth study showed that individuals with motor-complete SCI may experience favourable vascular changes following 4 months of BWSTT. Although there were no significant exercise-induced changes in measures of HRV and BPV, the results suggested that favourable changes in both these measures may occur in individuals who rexperience a substantial heart rate (HR) response to this type of training. Greater HR responses were elicited in those who were more orthostatically intolerant and had greater muscle spasticity. Finally, BWSTT was found to women worsen orthostatic intolerance in individuals with tetraplegia, but not in those with paraplegia. Conclusions. Individuals with SCI retain the ability to make positive changes in cardiovascular regulation with exercise training, as indicated by measures of HRV and BPC, as well as by Doppler ultrasound measures of arterial function. Individuals with less severe SCI (ASIA C and D injuries) may be particularly well suited for BWSTT as a means to promote cardiovascular improvement. Specifically, individuals with spared motor function (ASIA C injuries) made positive adaptations in meaures of HRV and BPC after 6 months of BWSTT, and further, due to the spared sensory ability, these individuals may not be able to tolerant FES exercise. Individuals with motor-complete SCI may experience positive vascular changes with BWSTT, regardless of the HR elicited during this form of exercise. In addition, those with high muscle spasticity and a susceptibility to orthostatic intolerance may experience positive adaptations in measures of HRV and BPV.Doctor of Philosophy (PhD

The Optimal Joint Angle for Adductor Pollicis Force Production in Men and Women

The purpose of this study was to determine the joint angle that allows for the greatest MVC and evoked twitch forces from the adductor pollicis (AP), and also whether there is a gender difference in either the above forces or the optimum thumb angle. Ten men (25.2 yrs) and 10 women (27.6 yrs) participated. The nondominant hand was placed palm-down with the thumb fixed at four angles of abduction (55, 70, 85, 100°). Male MVC forces were significantly greater than female, and there was no significant effect of joint angle on MVC force in either gender. For the evoked twitch, men were significantly stronger than women when tested at the 100 and 85° angles, and a significant effect was found for joint angle such that the lowest twitch force occurred at 55°. Men also tended to have a greater rate of force development than women (p = 0.07). These data suggest that studies using the AP muscle in stimulated and voluntary paradigms should use a thumb angle between 70 and 100° of abduction, or approximately 85°, and that the same angle can be used for both men and women. Key words: evoked twitch, MVC, gender, EMG, rate of force development </jats:p