non-SCI Subjects Research Articles

CCR7-mediated T follicular helper cell differentiation is associated with the pathogenesis and immune microenvironment of spinal cord injury-induced immune deficiency syndrome.

Spinal cord injury-induced immune deficiency syndrome (SCI-IDS) is a disorder characterized by systemic immunosuppression secondary to SCI that dramatically increases the likelihood of infection and is difficult to treat. T follicular helper (Tfh) cells regulated by chemokine receptor CCR7 are associated with SCI-IDS after acute SCI. The present study explored the roles of CCR7 in SCI-IDS occurrence and immune microenvironment composition. Gene expression profile data of peripheral blood leukocytes from SCI and non-SCI subjects were collected from the Gene Expression Omnibus database. According to differential gene expression analysis, a protein-protein interaction (PPI) network, and risk model construction, the CCR7 expression level was prominently related to acute SCI and CCR7 expression was significantly downregulated after acute SCI. Next, we constructed a clinical prediction model and used it to identify patients with acute SCI. Using Gene Ontology (GO) analysis and gene set enrichment analysis (GSEA), we discovered that immune-related biological processes, such as T cell receptor signaling pathway, were suppressed, whereas chemokine-related signaling pathways were activated after acute SCI. Immune infiltration analysis performed using single sample GSEA and CIBERSORT suggested that Tfh cell function was significantly correlated with the CCR7 expression levels and was considerably reduced after acute SCI. Acute SCI was divided into two subtypes, and we integrated multiple classifiers to analyze and elucidate the immunomodulatory relationships in both subtypes jointly. The results suggested that CCR7 suppresses the immunodeficiency phenotype by activating the chemokine signaling pathway in Tfh cells. In conclusion, CCR7 exhibits potential as a diagnostic marker for acute SCI.

Spinal motor mapping by epidural stimulation of lumbosacral posterior roots in humans.

SummaryEpidural electrical stimulation of the spinal cord is an emergent strategy for the neurological recovery of lower-extremity motor function. Motoneuron pools are thought to be recruited by stimulation of posterior roots. Here, we linked electromyographic data of epidurally evoked lower-extremity responses of 34 individuals with upper motoneuron disorders to a population model of the spinal cord constructed using anatomical parameters of thousands of individuals. We identified a relationship between segmental stimulation sites and activated spinal cord segments, which made spinal motor mapping from epidural space possible despite the complex anatomical interface imposed by the posterior roots. Our statistical approach provided evidence for low-threshold sites of posterior roots and effects of monopolar and bipolar stimulation previously predicted by computer modeling and allowed us to test the impact of different upper motoneuron disorders on the evoked responses. Finally, we revealed a statistical association between intraoperative and postoperative mapping of the spinal cord.

3T MR-defecography—A feasibility study in sensorimotor complete spinal cord injured patients with neurogenic bowel dysfunction

IntroductionTo investigate whether MR-defecography can be employed in sensorimotor complete spinal cord injury (SCI) subjects as a potential diagnostic tool to detect defecational disorders associated with neurogenic bowel dysfunction (NBD) using standard parameters for obstructed defecation. Material and methodsIn a prospective single centre clinical trial, we developed MR-defecography in traumatic sensorimotor complete paraplegic SCI patients with upper motoneuron type injury (neurological level of injury T1 to T10) using a conventional 3T scanner. Defecation was successfully induced by eliciting the defecational reflex after rectal filling with ultrasonic gel, application of two lecicarbon suppositories and digital rectal stimulation. Examination was performed with patients in left lateral decubitus position using T2-weighted turbo spin echo sequence in the sagittal plane at rest (TE 89ms, TR 3220ms, FOV 300mm, matrix 512×512, ST 4mm) and ultrafast-T2-weighted-sequence in the sagittal plane with repeating measurements (TE 1.54ms, TR 3.51ms, FOV 400mm, matrix 256×256, ST 6mm). Changes of anorectal angle (ARA), anorectal descent (ARJ) and pelvic floor weakness were documented and measured data was compared to reference values of asymptomatic non-SCI subjects in the literature to assess feasibility. ResultsMR-defecography provides evaluable imaging sequences of the induced evacuation phase in SCI patients. Measurement results for ARA, ARJ, hiatal width (H-line) and hiatal descent (M-line) deviate significantly from reference values in the literature in asymptomatic subjects without SCI. The overall mean values in our study for SCI patients were: ARA (rest) 127.3°, ARA (evacuation) 137.6°, ARJ (rest) 2.4cm, ARJ (evacuation) 4.0cm, H-line (rest) 7.6cm, H-line (evacuation) 8.1cm, M-line (rest) 2.6cm, M-line (evacuation) 4.2cm. ConclusionsMR-defecography is feasible in sensorimotor complete SCI patients. Individual MR-defecography findings may help to determine specific therapeutical options for respective patients suffering from severe NBD.

Resting-state synchrony between the retrosplenial cortex and anterior medial cortical structures relates to memory complaints in subjective cognitive impairment

Subjective cognitive impairment (SCI) is a clinical state characterized by subjective cognitive deficits without cognitive impairment. To test the hypothesis that this state might involve dysfunction of self-referential processing mediated by cortical midline structures, we investigated abnormalities of functional connectivity in these structures in individuals with SCI using resting-state functional magnetic resonance imaging. We performed functional connectivity analysis for 23 individuals with SCI and 30 individuals without SCI. To reveal the pathophysiological basis of the functional connectivity change, we performed magnetic resonance-diffusion tensor imaging. Positron emission tomography-amyloid imaging was conducted in 13 SCI and 15 nonSCI subjects. Individuals with SCI showed reduced functional connectivity in cortical midline structures. Reduction in white matter connections was related to reduced functional connectivity, but we found no amyloid deposition in individuals with SCI. The results do not necessarily contradict the possibility that SCI indicates initial cognitive decrements, but imply that reduced functional connectivity in cortical midline structures contributes to overestimation of the experience of forgetfulness.

Low force contractions induce fatigue consistent with muscle mRNA expression in people with spinal cord injury.

Spinal cord injury (SCI) is associated with muscle atrophy, transformation of muscle fibers to a fast fatigable phenotype, metabolic inflexibility (diabetes), and neurogenic osteoporosis. Electrical stimulation of paralyzed muscle may mitigate muscle metabolic abnormalities after SCI, but there is a risk for a fracture to the osteoporotic skeletal system. The goal of this study was to determine if low force stimulation (3 Hz) causes fatigue of chronically paralyzed muscle consistent with selected muscle gene expression profiles. We tested 29 subjects, nine with a SCI and 20 without and SCI, during low force fatigue protocol. Three SCI and three non‐SCI subjects were muscle biopsied for gene and protein expression analysis. The fatigue index (FI) was 0.21 ± 0.27 and 0.91 ± 0.01 for the SCI and non‐SCI groups, respectively, supporting that the low force protocol physiologically fatigued the chronically paralyzed muscle. The post fatigue potentiation index (PI) for the SCI group was increased to 1.60 ± 0.06 (P <0.001), while the non‐SCI group was 1.26 ± 0.02 supporting that calcium handling was compromised with the low force stimulation. The mRNA expression from genes that regulate atrophy and fast properties (MSTN, ANKRD1, MYH8, and MYCBP2) was up regulated, while genes that regulate oxidative and slow muscle properties (MYL3, SDHB, PDK2, and RyR1) were repressed in the chronic SCI muscle. MSTN, ANKRD1, MYH8, MYCBP2 gene expression was also repressed 3 h after the low force stimulation protocol. Taken together, these findings support that a low force single twitch activation protocol induces paralyzed muscle fatigue and subsequent gene regulation. These findings suggest that training with a low force protocol may elicit skeletal muscle adaptations in people with SCI.

Subjective Experiences of Men With and Without Spinal Cord Injury: Tolerability of the Juvent and WAVE Whole Body Vibration Plates

Device tolerability is an important determinant of subject adherence and intervention effectiveness. Although popular in rehabilitation settings, the tolerability of whole-body vibration (WBV) among patients with spinal cord injury (SCI) is unknown. To assess feedback from SCI and non-SCI subjects on the usability of passive standing and WBV devices (Juvent [Juvent Medical, Somerset, NJ] and WAVE [WAVE Manufacturing, Windsor, Ontario, Canada]) using a priori specified knee postures, plate amplitudes, and frequencies. A matched groups design with repeated measures. A tertiary SCI rehabilitation center. Eight men with chronic SCI (C4-L2, American Spinal Injury Association Impairment Scale A-D) and 10 men without SCI of similar height, weight, and body mass index. Subjects (N = 18; 8 with SCI) underwent intermittent WBV during passive standing (EasyStand 5000 [Altimate Medical, Morton, MN]) for 45 minutes using the optimized WAVE and Juvent plates. WBV parameters were sequentially altered every 2 minutes and included parameter combinations of (1) postures of 140°, 160°, and 180° knee extension (180° with Juvent only); (2) amplitudes of 0.7 mm and 1.1 mm (WAVE only); and (3) frequencies of 25 Hz, 35 Hz, and 45 Hz. Outcome assessments were completed at 4-minute intervals throughout WBV exposure. Qualitative, semistructured interviews were used to generate neutral, positive, and negative descriptors of the subjects' overall experience and device preference. SCI subjects reported a greater frequency of positive descriptors than non-SCI subjects during WBV, regardless of plate, posture, amplitude, or frequency, with the exception of 1 combination of parameters (WAVE plate at 140°, 1.1 mm, and 25 Hz). Non-SCI subjects reported the highest frequency of negative effects with the WAVE plate at 160°, 1.1 mm, 25 Hz, and 35 Hz. Non-SCI subjects preferred the Juvent, whereas SCI subjects preferred the WAVE plate. SCI and non-SCI subjects reported differing frequencies of positive and negative descriptors and indicated divergent device preferences. SCI subjects preferred the WAVE plate and vibration at high frequency. Future research will determine the therapeutic potential and adverse events associated with the device and WBV parameters tolerable for persons with SCI.

Gravitational force modulates muscle activity during mechanical oscillation of the tibia in humans

Mechanical oscillation (vibration) is an osteogenic stimulus for bone in animal models and may hold promise as an anti-osteoporosis measure in humans with spinal cord injury (SCI). However, the level of reflex induced muscle contractions associated with various loads ( g force) during limb segment oscillation is uncertain. The purpose of this study was to determine whether certain gravitational loads ( g forces) at a fixed oscillation frequency (30 Hz) increases muscle reflex activity in individuals with and without SCI. Nine healthy subjects and two individuals with SCI sat with their hip and knee joints at 90° and the foot secured on an oscillation platform. Vertical mechanical oscillations were introduced at 0.3, 0.6, 1.2, 3 and 5 g force for 20 s at 30 Hz. Non-SCI subjects received the oscillation with and without a 5% MVC background contraction. Peak soleus and tibialis anterior (TA) EMG were normalized to M-max. Soleus and TA EMG were <2.5% of M-max in both SCI and non-SCI subjects. The greatest EMG occurred at the highest acceleration (5 g). Low magnitude mechanical oscillation, shown to enhance bone anabolism in animal models, did not elicit high levels of reflex muscle activity in individuals with and without SCI. These findings support the g force modulated background muscle activity during fixed frequency vibration. The magnitude of muscle activity was low and likely does not influence the load during fixed frequency oscillation of the tibia.

Arterial Stiffness in Persons with SCI: A Pilot Study

Low cardiovascular fitness and abdominal obesity are risk factors for increasing arterial stiffness, and cardiovascular disease (CVD) in the able-body population. These risk factors are also common among people with spinal cord injury (SCI) whom also have an elevated risk of CVD. PURPOSE: To test the hypothesis that SCI subjects have higher arterial stiffness and CVD risk than age-gender matched non-SCI subjects, assessed by pulse wave velocity (PWV) in cm/sec. METHODS: Subjects included 12 men with motor complete SCI (Age: 51+−11 yrs, Height: 179+−6.6cm; Body weight: 84.0+−20.2 kg, Injury Level: C3-L3, Time post injury: 25+−10.7 yrs) and eight Non-SCI controls (Age: 45+−10 yrs; Height: 175.1+− cm; Body weight: 75.6+−10.9 kg). PWV of the aorta was measured between the carotid and femoral artery as an index of arterial stiffness using the echo doppler method. Trunk adiposity was assessed using Dual-energy X-ray Absorptiometry. Peak oxygen uptake (Vo2peak: mL/kg/min) was assessed via arm ergometry. RESULTS: There were no statistically significant differences between SCI subjects and Non-SCI peers in age, height and body weight, despite what appears to be important baseline clinical differences between the groups. PWV in SCI subjects (1331+−327 cm/sec) were significantly higher (P<0.05) than that of Non-SCI peers (951+−335 cm/sec). Trunk fat mass in SCI subjects (14.7+−7.0 kg) was larger (P<0.05) than that of Non-SCI peers (7.0+−3.4 kg). Vo2peak in SCI subjects (15.9+−4.7 mL/kg/ min) was lower than that of Non-SCI peers (18.3+−8.4 mL/kg/min). CONCLUSIONS: The higher PWV in SCI subjects compared to Non-SCI subjects may suggest a higher risk of CVD among SCI subjects. Although further data collection is required, PWV has the potential to become a good diagnostic test for CVD among people with SCI.

Doublet stimulation protocol to minimize musculoskeletal stress during paralyzed quadriceps muscle testing

With long-term electrical stimulation training, paralyzed muscle can serve as an effective load delivery agent for the skeletal system. Muscle adaptations to training, however, will almost certainly outstrip bone adaptations, exposing participants in training protocols to an elevated risk for fracture. Assessing the physiological properties of the chronically paralyzed quadriceps may transmit unacceptably high shear forces to the osteoporotic distal femur. We devised a two-pulse doublet strategy to measure quadriceps physiological properties while minimizing the peak muscle force. The purposes of the study were 1) to determine the repeatability of the doublet stimulation protocol, and 2) to compare this protocol among individuals with and without spinal cord injury (SCI). Eight individuals with SCI and four individuals without SCI underwent testing. The doublet force-frequency relationship shifted to the left after SCI, likely reflecting enhancements in the twitch-to-tetanus ratio known to exist in paralyzed muscle. Posttetanic potentiation occurred to a greater degree in subjects with SCI (20%) than in non-SCI subjects (7%). Potentiation of contractile rate occurred in both subject groups (14% and 23% for SCI and non-SCI, respectively). Normalized contractile speed (rate of force rise, rate of force fall) reflected well-known adaptations of paralyzed muscle toward a fast fatigable muscle. The doublet stimulation strategy provided repeatable and sensitive measurements of muscle force and speed properties that revealed meaningful differences between subjects with and without SCI. Doublet stimulation may offer a unique way to test muscle physiological parameters of the quadriceps in subjects with uncertain musculoskeletal integrity.

Glucose Intolerance, Insulin Resistance, and C Peptide Levels in Patients With Spinal Cord Injury

Background Diabetes mellitus, glucose intolerance, hyperinsulinemia, and insulin resistance are more common among spinal cord injury (SCI) survivors. Objective To investigate the presence and rate of diabetes, glucose intolerance, insulin resistance, and C peptide levels in patients with SCI and to evaluate possible relationships between these parameters and age, sex, completeness and duration of injury, lesion level, and body mass index. Methods Patients with SCI living in the community and subjects who were seen and recruited in an outpatient unit of a Physical Medicine and Rehabilitation Department with different complaints, but with no history of diabetes were included. The results were evaluated on the basis of the “1997 The American Diabetic Association Criteria.” The completeness of injury was based on ASIA 2000 revised criteria. After a 12-hour period of starvation, fasting blood glucose levels, capillary blood samples, and for insulin and C peptide levels, venous blood samples were taken, both from patients with SCI and in the control group. Results In the SCI group, 2.33% (n=1) of patients was diagnosed as diabetes and 13.95% (n=6) were diagnosed with glucose intolerance. In the non-SCI group, 10.0% (n=2) were diagnosed with glucose intolerance. Conclusions The diabetes and glucose intolerance were observed in 16.28% of SCI subjects as compared with 10.00% of non-SCI subjects.

Motor preparation in postural control in seated spinal cord injured people

Spinal cord injured (SCI) people try to compensate for the loss of postural muscle function by increased use of non-postural muscles. Such alternative muscle use, however, may necessitate important modifications in motor control. In this study motor programming processes were investigated in three groups, i.e. in high thoracic SCI, low thoracic SCI and non-SCI subjects. A bimanual forward-reaching task, in which graded sitting balance perturbation was systematically invoked, was presented to the subjects as a visual precue choice reaction time (RT) task. Effects of movement preparation were examined by precuing reaching distance information. RT and movement times were recorded. Centre of pressure (CP) displacement was used as an indicator for sitting balance perturbation. Results indicated that high thoracic SCI subjects programmed balance-perturbing reaching movements as fast as did non-SCI subjects. Low thoracic SCI subjects, on the other hand, showed substantially longer programming times. This latter outcome is consistent with the hypothesis that the low thoracic SCI subjects adopted a more complex postural control strategy involving residual motor functions in an attempt to actively compensate for loss of postural muscle function. High thoracic SCI subjects, on the other hand, appeared to adopt a less complex and thus easier to programme postural control strategy.

Impaired balance control in paraplegic subjects

Postural muscle use during sitting balance control was studied in persons with a complete thoracic spinal cord injury (SCI). It was hypothesized that these subjects use non-postural muscles such as the latissimus dorsi (LD) and trapezius pars ascendens (TPA) to restore sitting balance, whereas non-SCI subjects primarily use their erector spinae (ES). This adaptive postural strategy in SCI subjects presupposes stabilizing effects of the scapular protractors, such as the pectoralis major (PM) and the serratus anterior (SA), on the shoulder girdle. Sitting balance was perturbed systematically in three groups of either low thoracic SCI, high thoracic SCI or non-SCI participants. Centre of pressure changes and activity of the LD, TPA, PM, SA, ES and oblique abdominal (OA) muscles were measured during task execution. Because non-SCI subjects differ from SCI subjects in their ability to tilt their pelvis during sitting, the correlation between pelvic movement and postural changes during task execution was also investigated. Results indicate that high thoracic SCI subjects use their LD, TPA, PM, SA and high thoracic part of the ES more in situations of similarly perturbed sitting balance than non-SCI subjects. Differences are smaller in the low thoracic SCI group. A kinematic concept combining alternative postural muscle activity and altered movement in thoracic SCI subjects is discussed.

Chronic baclofen therapy improves the blunted growth hormone response to intravenous arginine in subjects with spinal cord injury.

Human GH (hGH) secretion is stimulated by vigorous physical activity, whereas immobilization reduces its release. In paralyzed subjects with spinal cord injury (SCI), it has recently been shown that the release of hGH to provocative stimulation and plasma insulin-like growth factor-I (IGF-I) levels are reduced. The acute administration of baclofen, a gamma-aminobutyric acid derivative, has been shown to stimulate hGH release. The present study investigated the effect of chronic administration of baclofen on the provocative testing of hGH secretion and plasma IGF-I levels. Sixteen subjects with SCI were studied; eight subjects were treated (40-80 mg/day; > 6 months) with baclofen (Bac+), and eight were not (Bac-). Additionally, 8 non-SCI subjects were studied as controls. The groups were matched for gender and age. The subjects were not receiving any medications known to influence hGH secretion. After an overnight fast, arginine hydrochloride (30 g/subject) was infused iv over 30 min, with blood drawn for hormone determinations at baseline and 30, 60, 90, and 120 min. In the Bac- group compared with the Bac+ group, the arginine-stimulated mean plasma hGH levels at 30 and 60 min (P < 0.05) and peak and sum plasma hGH levels (P < 0.01) were reduced. There were no significant differences in the plasma hGH response between the Bac+ group and the control group. Plasma IGF-I levels may reflect the integrated tissue response to hGH. A significant inverse relationship was present between age and plasma IGF-I levels for the control and Bac+ groups, but not for the Bac- group. The mean plasma IGF-I level was significantly reduced in the Bac- compared with the Bac+ group. No significant differences in mean plasma IGF-I levels were noted between the Bac+ and control groups. SCI is associated with body composition changes and metabolic alterations that may be exacerbated by reduced activity of the hGH-IGF-I axis. Oral chronic baclofen therapy appears to reverse the deleterious effects of paralysis and immobilization on hGH physiology.

Blunted Growth Hormone Response to Intravenous Arginine in Subjects with a Spinal Cord Injury

The influence of the activities of daily living on human growth hormone (hGH) release and plasma insulin-like growth factor (IGF-I) levels is not known. Individuals with spinal cord injury (SCI) and paralysis generally have reduced levels of activity compared with ambulatory subjects. We studied sixteen subjects with SCI and sixteen nonSCI subjects matched for age, gender and body mass index (BMI) as controls. After an intravenous infusion of arginine hydrochloride (30 g/subject over 30 minutes), mean plasma hGH values at 30 and 60 minutes were significantly lower in the group with SCI compared with the control group (3.4 +/- 0.7 versus 10.7 +/- 2.5 ng/ml, p < 0.01; and 5.2 +/- 1.5 versus 12.5 +/- 2.7 ng/ml, p < 0.05). Also, peak and sum hGH responses were significantly lower in the group with SCI than in the control group (5.8 +/- 1.5 versus 14.1 +/- 2.8 ng/ml, p < 0.01; and 15.2 +/- 3.1 versus 34.8 +/- 7.2 ng/ml, p < 0.02). Controlling for age and BMI, the results remained significant. However, the mean plasma IGF-I level was significantly lower in SCI subjects younger than 45 years old than in the similar subgroup of age-restricted controls (202 +/- 19 versus 324 +/- 27 ng/ml, p < 0.05), whereas, a comparison of subgroups of subjects 45 years or older did not reveal a significant difference. These findings support the hypothesis that decreased daily physical activity results in depression of the hGH/IGF-I axis in younger individuals with SCI and may be considered to be a state of premature aging.(ABSTRACT TRUNCATED AT 250 WORDS)

Constipation associated with chronic spinal cord injury: the effect of pelvic parasympathetic stimulation by the Brindley stimulator

Ten subjects with severe constipation due to complete spinal cord injury (SCI) had prolonged oro-anal transit time (p less than 0.01), diminished faecal water content (p less than 0.05) and a reduced frequency of defaecation (p less than 0.01) compared to 10 non-SCI subjects. Paraplegics with an implanted Brindley S234 anterior sacral nerve root stimulator had a significant increase in frequency of defaecation (p less than 0.01), compared to the SCI group while the faecal water content was less although not significantly so. The Brindley stimulator group also showed a more rapid colonic transit than the SCI group but this did not reach statistical significance. SCI is associated with constipation which therefore appears to be favourably influenced by the Brindley S234 anterior nerve root stimulator. The effects produced are compatible with stimulation of left colonic motility, which facilitates the emptying of the distal colon, but also suggest that part of the response restricts transit in some areas of the colon or rectum. Since the motility changes induced by the Brindley stimulator do not affect the right colon a relatively greater residence time of the faecal bolus in this part of the large bowel would enhance water absorption.