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Critical illness-associated weakness (CIAW) is an umbrella term used to describe a group of neuromuscular disorders caused by severe illness. It can be subdivided into three major classifications based on the component of the neuromuscular system (i.e. peripheral nerves or skeletal muscle or both) that are affected. This includes critical illness polyneuropathy (CIP), critical illness myopathy (CIM), and an overlap syndrome, critical illness polyneuromyopathy (CIPNM). It is a common complication observed in people with critical illness requiring intensive care unit (ICU) admission. Given CIAW is found in individuals experiencing grave illness, it can be challenging to study from a practical standpoint. However, over the past 2 decades, many insights into the pathophysiology of this condition have been made. Results from studies in both humans and animal models have found that a profound systemic inflammatory response and factors related to bioenergetic failure as well as microvascular, metabolic, and electrophysiological alterations underlie the development of CIAW. Current management strategies focus on early mobilization, achieving euglycemia, and nutritional optimization. Other interventions lack sufficient evidence, mainly due to a dearth of large trials. The goal of this Physiology in Medicine article is to highlight important aspects of the pathophysiology of these enigmatic conditions. It is hoped that improved understanding of the mechanisms underlying these disorders will lead to further study and new investigations for novel pharmacologic, nutritional, and exercise-based interventions to optimize patient outcomes.

In skeletal muscle, postactivation potentiation (PAP) is observed following a conditioning contraction (CC) as a large (two- to three-fold) increase in evoked twitch force and rate of force development (RFD). However, this enhancement has not been observed to occur during potentiated voluntary contractions. The purpose of this study was to determine whether the lack of voluntary potentiation may be related to the development of central (corticospinal) inhibition. Participants (n = 10, all males) completed voluntary and evoked index finger abduction contractions and transcranial magnetic stimulated motor-evoked potentials (MEP) of the motor cortex were recorded from the first dorsal interosseous (FDI). Central inhibition was assessed by measuring the silent period following the MEP. The FDI was potentiated via 10-s conditioning contractions at 60% of maximal index finger abduction strength, using both voluntary and evoked tetanic contractions. Immediately following CC and transcutaneous electrical twitches. Following both voluntary and tetanic CC, force and RFD of the twitch were similarly increased (~200% and ~160%, respectively). The silent period was elongated by ~10% following both forms of CC. These results indicate that corticospinal inhibition does occur following CC, but that it is unrelated to the voluntary activation during the CC. These results also show that following CC, the positive contractile effects at the muscle are concurrently accompanied by inhibitory effects at the corticospinal level. NEW & NOTEWORTHY We demonstrate that postactivation potentiation in human skeletal muscle is accompanied by central inhibition at the corticospinal level. However, the magnitude of central inhibition does not differ between peripherally evoked or voluntary conditioning contractions. Therefore, it is possible this central inhibition is related to muscle sensory feedback.

Ventricular arrhythmias are associated with neurological impairment and could represent a source of cerebral hypoperfusion. In the present study, data from healthy individuals (n = 11), patients with ischaemic heart disease (IHD; ejection fraction40%; n = 9) and patients with heart failure with reduced ejection fraction (HFrEF; EF = 31 (5)%, n = 11), as well as data from swine surgeries, where spontaneous ventricular arrhythmias were observed during cerebrovascular examination (transcranial Doppler ultrasound in humans and laser Doppler in swine) were analysed retrospectively to investigate the effect of arrhythmia on cerebral microvascular haemodynamics. A subset of participants also completed the Montreal Cognitive Assessment (MoCA). Middle cerebral artery mean blood velocity (MCA

Guillain-Barre syndrome (GBS) is the most common cause of acute paralytic neuropathy worldwide. GBS manifests as rapidly progressive, symmetrical numbness, paresthesia, and weakness secondary to either peripheral nerve demyelination or axonal loss. Despite effective disease modifying therapies (e.g., intravenous immunoglobulin) and individualized rehabilitation programs, many individuals recovering from GBS experience substantial muscle atrophy and incomplete recovery of strength with resultant long-term functional impairment. This narrative review explores the therapeutic potential of omega-3 fatty acid supplementation on enhancing recovery of people with GBS. This purported benefit may occur through several potential mechanisms, supported indirectly through studies using both experimental animal and clinical human models. These mechanisms include: (i) Anti-atrophic effects on skeletal muscle undergoing disuse and systemic inflammation; (ii) the use of omega-3s as a key building block comprising myelin; (iii) immune modulating effects optimizing conditions for remyelination; and (iv) preventing excitotoxic-like neuron death. The physiological mechanisms are explored in detail with examination of relevant clinical trials conducted to date. Through this exploration, there is sufficient support to justify future investigations directly examining the role omega-3 fatty acid supplementation may play as an adjunctive intervention that could have significant benefit at low cost and minimal risk of adverse events.

Exercise-induced alterations in adipose tissue insulin and/or β-adrenergic signaling may contribute to increases in whole-body fat oxidation following acute exercise. Thus, we examined changes in insulin (Akt, AS160) and β-adrenergic (PKA) signaling proteins in subcutaneous adipose tissue and whole-body fat oxidation in overweight women following acute high-intensity interval exercise (HIIE). Overweight females completed two experimental sessions in a randomized order: 1) control (bed rest) and 2) HIIE (10 × 4 min running intervals at 90% HR(max), 2-min recovery). Subcutaneous abdominal adipose tissue biopsies were obtained from 10 participants before (pre−), immediately (0hr) after (post−), 2hr post−, and 4hr post-exercise. Plasma glucose and insulin levels were assessed in venous blood samples obtained at each biopsy time-point from a different group of 5 participants (BMI-matched to biopsy group). Fat oxidation rates were estimated using the respiratory exchange ratio (RER) in all participants using indirect calorimetry pre−, 2hr post−, and 4hr post-exercise. RER was decreased (p < 0.05) at 2hr post-exercise after HIIE (0.77 ± 0.04) compared to control (0.84 ± 0.04). Despite higher plasma glucose (p < 0.01) and insulin (p < 0.05) levels at 0hr post-exercise versus control, no significant interaction effects were observed for Akt or AS160 phosphorylation (p > 0.05). Phosphorylation of PKA substrates was unaltered in both conditions (p > 0.05). Collectively, altered β-adrenergic and insulin signaling in subcutaneous adnominal adipose tissue does not appear to explain increased whole-body fat oxidation following acute HIIE.

The purpose of this study was to determine if differences in functional connectivity strength (FCS) with age were confounded by vascular parameters including resting cerebral blood flow (CBF

Human biological aging from maturity to senescence is associated with a gradual loss of muscle mass and neuromuscular function. It is not until very old age (>80 years) however, that these changes often manifest into functional impairments. A driving factor underlying the age-related loss of muscle mass and function is the reduction in the number and quality of motor units (MUs). A MU consists of a single motoneuron, located either in the spinal cord or the brain stem, and all of the muscle fibres it innervates via its peripheral axon. Throughout the adult lifespan, MUs are slowly, but progressively lost. The compensatory process of collateral reinnervation attempts to recapture orphaned muscle fibres following the death of a motoneuron. Whereas this process helps mitigate loss of muscle mass during the latter decades of adult aging, the neuromuscular system has fewer and larger MUs, which have lower quality connections between the axon terminal and innervated muscle fibres. Whether this process of MU death and degradation can be attenuated with habitual physical activity has been a challenging question of great interest. This review focuses on age-related alterations of the human neuromuscular system, with an emphasis on the MU, and presents findings on the potential protective effects of lifelong physical activity. Although there is some discrepancy across studies of masters athletes, if one considers all experimental limitations as well as the available literature in animals, there is compelling evidence of a protective effect of chronic physical training on human MUs. Our tenet is that high-levels of physical activity can mitigate the natural trajectory of loss of quantity and quality of MUs in old age.

Introduction We assessed motor unit (MU) properties and neuromuscular stability in the tibialis anterior (TA) of chronic inflammatory demyelinating polyneuropathy (CIDP) patients using decomposition-based quantitative electromyography. Methods Dorsiflexion strength was assessed, and surface and concentric needle electromyography were sampled from the TA. Estimates of MU numbers were derived using decomposition-based quantitative electromyography and spike-triggered averaging. Neuromuscular transmission stability was assessed from concentric needle-detected MU potentials. Results CIDP patients had 43% lower compound muscle action potential amplitude than controls, and despite near-maximum voluntary activation, were 37% weaker. CIDP had 27% fewer functioning MUs in the TA, and had 90% and 44% higher jiggle and jitter values, respectively compared with controls. Conclusions CIDP had lower strength and compound muscle action potential values, moderately fewer numbers of MUs, and significant neuromuscular instability compared with controls. Thus, in addition to muscle atrophy, voluntary weakness is also due to limitations of peripheral neural transmission consistent with demyelination. Muscle Nerve 56: 413–420, 2017

Diabetic polyneuropathy (DPN) refers to peripheral nerve dysfunction as a complication of diabetes mellitus. This condition is relatively common and is likely a result of vascular and/or metabolic disturbances related to diabetes. In the early or less severe stages of DPN it typically results in sensory impairments but can eventually lead to major dysfunction of the neuromuscular system. Some of these impairments may include muscle atrophy and weakness, slowing of muscle contraction, and loss of power and endurance. Combined with sensory deficits these changes in the motor system can contribute to decreased functional capacity, impaired mobility, altered gait, and increased fall risk. There is no pharmacological disease-modifying therapy available for DPN and the mainstay of treatment is linked to treating the diabetes itself and revolves around strict glycemic control. Exercise therapy (including aerobic, strength, or balance training-based exercise) appears to be a promising preventative and treatment strategy for patients with DPN and those at risk. The goal of this Physiology in Medicine article is to highlight important and overlooked dysfunction of the neuromuscular system as a result of DPN with an emphasis on the physiologic basis for that dysfunction. Additionally, we sought to provide information that clinicians can use when following patients with diabetes or DPN including support for the inclusion of exercise-based therapy as an effective, accessible, and inexpensive form of treatment.

Introduction The aim of this study was to determine whether diabetic polyneuropathy (DPN) is associated with reduced muscle quality using MRI. Methods MRIs of the tibialis anterior (TA) muscle were recorded from 9 individuals (5 men) with DPN (∼65 years) and 8 (4 men) age- and gender-matched controls. A magnetization transfer ratio (MTR) and T2 relaxation times of the TA were calculated. Results Despite equal voluntary activation, the DPN group was ∼37% weaker than controls, with a significantly lower proportion (∼8%) of contractile tissue and lower MTR (0.28 ± 0.03 vs. 0.32 ± 0.02 percent units). T2 relaxation time was significantly longer in the DPN group (77 ± 16 ms) compared with controls (63 ± 6 ms). Conclusions These findings indicate a reduction in the structural integrity and myocellular protein density in the TA of those with DPN. Thus, muscle weakness in DPN is likely due to both a loss of muscle mass and a reduction in contractile quality.

Blood flow and muscle oxygenation during low, moderate, and maximal sustained isometric contractions. Am J Physiol Regul Integr Comp Physiol 309: R475–R481, 2015. First published June 17, 2015; doi:10.1152/ajpregu.00387.2014.—A reduction of blood flow to active muscle will precipitate fatigue, and sustained isometric contractions produce intramuscular and compartmental pressures that can limit flow. The present study explored how blood flow and muscle oxygenation respond to isometric contractions at low, moderate, and maximal intensities. Over two visits, 10 males (26 2 yr; means SD) performed 1-min dorsiflexion contractions at 30, 60, and 100% of maximal voluntary contraction (MVC) torque. Doppler ultrasound of the anterior tibial artery was used to record arterial diameter and mean blood velocity and to calculate absolute blood flow. The tissue oxygenation index (TOI) of tibialis anterior was acquired with nearinfrared spectroscopy (NIRS). There was a progressive increase in blood flow at 30% MVC (peak of 289 139% resting value), no change from rest until an increase in the final 10 s of exercise at 60% MVC (peak of 197 102% rest), and an initial decrease (59 30% resting value) followed by a progressive increase at 100% MVC (peak of 355 133% rest). Blood flow was greater at 30 and 100% than 60% MVC during the last 30 s of exercise. TOI was 63% at rest and, within 30 s of exercise, reached steady-state values of 42%, 22%, and 22% for 30, 60, and 100% MVC, respectively. Even maximal contraction of the dorsiflexors is unable to cause more than a transient decrease of flow in the anterior tibial artery. Unlike dynamic or intermittent isometric exercise, our results indicate blood flow is not linearly graded with intensity or directly coupled with oxygenation during sustained isometric contractions.

Introduction: Both voluntary and evoked conditioning contractions will potentiate muscle twitch contractile properties. The response of a voluntary contraction to each condition type is not well understood but it may be a more functional model than evoked twitch potentiation. Methods: Baseline measurements from tibialis anterior included: maximal isometric twitch torque and rate of torque development (RTD); maximal evoked 50-HZ tor- que; and maximal voluntary ballistic RTD. Potentiation was induced by a 10-s voluntary or tetanic contraction ( 78% MVC), followed by 2 twitches and 2 ballistic contractions. Results: Twitch properties (torque and RTD) were potentiated equally after each conditioning contraction. Ballistic RTD was greater post-tetanus (390.2 659.3 Nm/s) than post-voluntary (356.4 669.1 Nm/s), but both were reduced from baseline (422.0 688.9 Nm/s). Conclusions: Twitch potentiation was similar between conditioning contraction types, but ballistic RTD was lower after post-tetanus than post-voluntary. The results indicate central inhibition or fatigue concurrent with peripheral potentiation.

We assessed motor unit (MU) properties and neuromuscular stability in the tibialis anterior (TA) of chronic inflammatory demyelinating polyneuropathy (CIDP) patients using decomposition-based quantitative electromyography.Dorsiflexion strength was assessed, and surface and concentric needle electromyography were sampled from the TA. Estimates of MU numbers were derived using decomposition-based quantitative electromyography and spike-triggered averaging. Neuromuscular transmission stability was assessed from concentric needle-detected MU potentials.CIDP patients had 43% lower compound muscle action potential amplitude than controls, and despite near-maximum voluntary activation, were 37% weaker. CIDP had 27% fewer functioning MUs in the TA, and had 90% and 44% higher jiggle and jitter values, respectively compared with controls.CIDP had lower strength and compound muscle action potential values, moderately fewer numbers of MUs, and significant neuromuscular instability compared with controls. Thus, in addition to muscle atrophy, voluntary weakness is also due to limitations of peripheral neural transmission consistent with demyelination. Muscle Nerve 56: 413-420, 2017.

to the editor: We thank Senefeld and Hunter ([1][1]) for their interest and for providing a thoughtful discussion of the distinction between neuron cell body and axonal cellular processes implicated in diabetic polyneuropathy (DPN). They succinctly highlight several of the key underlying

Triceps surae function can be modified by changes in knee joint angle through altering the effective contribution of the bi-articular gastrocnemeii. However, the impact on plantar flexor power from altering knee angle has not been studied systematically across a range of loads. Here, in 11 young men (25.7 ± 2.2 years), we determine the effect of knee angle on torque, velocity and power at loads ranging from 15 to 75 % maximal voluntary isometric contraction (MVC). Contractile properties were recorded with either the knee extended (170º) or flexed (90º). Despite similar voluntary activation (~97 %), peak twitch and MVC torques were 25 and 16 % lower in the flexed than extended knee (P0.05), respectively. Across all loads, subjects were 15-24 % less powerful with the knee flexed than extended (P0.05). In the flexed knee at relative loads ≤30 % MVC, impaired power was accompanied by 6-9 % slower shortening velocities than the extended knee. However, for the higher loads, limited torque production in the flexed knee was the key factor contributing to the generation of maximal power than for the extended position. This was supported by no change in velocity at higher loads (30 % MVC) and a 15-22 % lower maximal rate of torque development across all loads. Hence, in a flexed knee position, which disadvantages the contribution of the gastrocnemeii, results in a left-downward shift in the torque-power relationship impairing maximal power production. Thus, the gastrocnemeii are not only a major contributor to plantar flexion torque, but also critical for modifying loaded shortening velocity and ultimately power production.

Bone geometry is an important measure of bone strength and is known to be affected by weight-bearing and adult ageing. Engagement in weight-bearing activity decreases with age, thus in this study we compared bone geometry changes between weight-bearing (tibia) and non-weight-bearing (fibula) leg bones in three different age groups of women. Magnetic resonance images of the right leg were acquired in 9 young (20-27 years), 7 old (61-69 years) and 7 very old (71-80 years) women. Total and cortical bone volumes and medullary cavity volumes (mm(3)) were calculated at proximal and distal sites for both bones. Tibial cortical bone volume was significantly less at the proximal site in old (17%) and very old (24%) groups versus young subjects. Cortical bone volume in the proximal fibula was also significantly reduced in the older groups (7 and 12%), but to a substantially lesser extent than in the tibia. In contrast, distal bone geometry appeared largely to be conserved in both tibia and fibula. Proximally, medullary cavity volume was greater in the older groups in the tibia but not the fibula. Distally, the only difference found in either bone was a significantly greater fibular medullary cavity in the very old group. These findings suggest weight-bearing bones in women are more susceptible than non-weight-bearing bones to age-related changes in bone geometry likely due to decreases in weight-bearing activities. Also, weight-bearing activity appears to provide a greater osteogenic stimulus at the distal portions of the leg bones.

Our group has shown a greater number of functioning motor units (MU) in a cohort of highly active older (∼65 yr) masters runners relative to age-matched controls. Because of the precipitous loss in the number of functioning MUs in the eighth and ninth decades of life it is unknown whether older world class octogenarian masters athletes (MA) would also have greater numbers of functioning MUs compared with age-matched controls. We measured MU numbers and neuromuscular transmission stability in the tibialis anterior of world champion MAs (∼80 yr) and compared the values with healthy age-matched controls (∼80 yr). Decomposition-enhanced spike-triggered averaging was used to collect surface and intramuscular electromyography signals during dorsiflexion at ∼25% of maximum voluntary isometric contraction. Near fiber (NF) MU potential analysis was used to assess neuromuscular transmission stability. For the MAs compared with age-matched controls, the amount of excitable muscle mass (compound muscle action potential) was 14% greater ( P < 0.05), there was a trend ( P = 0.07) toward a 27% smaller surface-detected MU potential representative of less collateral reinnervation, and 28% more functioning MUs ( P < 0.05). Additionally, the MAs had greater MU neuromuscular stability than the controls, as indicated by lower NF jitter and jiggle values ( P < 0.05). These results demonstrate that high-performing octogenarians better maintain neuromuscular stability of the MU and mitigate the loss of MUs associated with aging well into the later decades of life during which time the loss of muscle mass and strength becomes functionally relevant. Future studies may identify the concomitant roles genetics and exercise play in neuroprotection.

Introduction: Diabetes mellitus can be associated with peripheral neuropathy which may affect numbers of function- ing motor units (MUs) of limb muscles. Direct quantitative assess- ment of MU numbers and muscle strength have not been performed in humans. We compared the estimated number of MUs of individuals with diabetic polyneuropathy (DPN) versus controls. Methods: Patients with signs/symptoms of DPN were studied using decomposition-enhanced quantitative electromy- ography of the tibialis anterior (TA). Motor unit number estimates were derived from this analysis. Results: Dorsiflexion strength was 60% less in DPN than controls (P

The aim of this study was to determine whether diabetic polyneuropathy (DPN) is associated with reduced muscle quality using MRI.MRIs of the tibialis anterior (TA) muscle were recorded from 9 individuals (5 men) with DPN (∼65 years) and 8 (4 men) age- and gender-matched controls. A magnetization transfer ratio (MTR) and T2 relaxation times of the TA were calculated.Despite equal voluntary activation, the DPN group was ∼37% weaker than controls, with a significantly lower proportion (∼8%) of contractile tissue and lower MTR (0.28 ± 0.03 vs. 0.32 ± 0.02 percent units). T2 relaxation time was significantly longer in the DPN group (77 ± 16 ms) compared with controls (63 ± 6 ms).These findings indicate a reduction in the structural integrity and myocellular protein density in the TA of those with DPN. Thus, muscle weakness in DPN is likely due to both a loss of muscle mass and a reduction in contractile quality.

to the editor: We read with interest the comments from Sacco et al. ([4][1]) on our manuscript. We feel clarification on their points is necessary to reflect the entirety of the literature on the subject. Although there may be some early effects on motor-related issues in diabetes (DM), based on

Objective The aim of this study was to describe the characteristics of patients referred with complex regional pain syndrome (CRPS) diagnosis to a tertiary care pain center. Method Descriptive chart review study of all patients referred by family physicians or community specialists as having CRPS (2006–2010). Data extraction included demographics, pain ratings, and diagnosis utilizing the Budapest CRPS criteria. Results The study population consisted of 54 subjects (male [M] = 7, female [F] = 47). Only 27.7% were classified as CRPS by the clinical expert. Four additional subjects carrying other diagnoses but found to have CRPS were added to the analysis. The non-CRPS group consisted of 39 subjects (M = 8, F = 31) and the CRPS group of 19 (M = 2, F = 17). CRPS patients were statistically significantly more likely to 1) have suffered a fracture; 2) report symptoms in each of the four symptom categories, as well as signs in three or four categories collectively; and 3) have allodynia/hyperalgesia alone or in combination (85/90%) as compared with the non-CRPS group (23/25%, respectively). The non-CRPS group was much more likely to report no symptoms or signs at all in the different symptom and sign categories. Of the 39 non-CRPS patients, 74% had other diagnosable entities (1/3 suffering from specific neuropathic pain conditions, e.g., radiculopathy, diabetic neuropathy, etc. and 2/3 from discreet musculoskeletal entities), while 18% were diagnosed with psychogenic pain disorders including conversion reaction associated with immobility or paralysis. Discussion Besides fulfilling the Budapest CRPS diagnostic criteria, the most important other factor for diagnosing CRPS is the exclusion of a neuropathic, musculoskeletal, or non-biomedical condition accounting for the presentation.

Diabetic polyneuropathy (DPN) can cause muscle atrophy, weakness, contractile slowing, and neuromuscular transmission instability. Our objective was to assess the response of the impaired neuromuscular system of DPN in humans when stressed with a sustained maximal voluntary contraction (MVC). Baseline MVC and evoked dorsiflexor contractile properties were assessed in DPN patients ( n = 10) and controls ( n = 10). Surface electromyography was used to record tibialis anterior evoked maximal compound muscle action potentials (CMAPs) and neuromuscular activity during MVCs. Participants performed a sustained isometric dorsiflexion MVC for which task termination was determined by the inability to sustain ≥60% MVC torque. The fatigue protocol was immediately followed by a maximal twitch, with additional maximal twitches and MVCs assessed at 30 s and 2 min postfatigue. DPN patients fatigued ∼21% more quickly than controls ( P < 0.05) and featured less relative electromyographic activity during the first one-third of the fatigue protocol compared with controls ( P < 0.05). Immediately following fatigue, maximal twitch torque was reduced similarly (∼20%) in both groups, and concurrently CMAPs were reduced (∼12%) in DPN patients, whereas they were unaffected in controls ( P > 0.05). Twitch torque and CMAP amplitude recovered to baseline 30 s postfatigue. Additionally, at 30 s postfatigue, both groups had similar (∼10%) reductions in MVC torque relative to baseline, and MVC strength recovered by 2 min postfatigue. We conclude DPN patients possess less endurance than controls, and neuromuscular transmission failure may contribute to this greater fatigability.

Peripheral nerve blood flow (NBF) does not autoregulate but, instead, responds passively to changes in mean arterial pressure (MAP). How this relationship is impacted by insulin-treated experimental diabetes (ITED) is unknown. We tested the hypothesis that ITED will reduce NBF across a range of MAP in Sprague Dawley rats. Following 10 weeks of control or ITED conditions, conscious MAP (tail-cuff) was measured, and under anaesthesia, the MAP (carotid artery catheter, pressure transducer) and NBF (Doppler ultrasound, 40 MHz) responses to sodium nitroprusside (60 µg/kg) and phenylephrine (12 µg/kg) infusion were recorded (regression equations for MAP vs NBF were created for each rodent). Thereafter, motor nerve conduction velocity (MNCV) and nerve vascularization (haematoxylin and eosin stain) were determined. Conscious MAP was higher and MNCV was lower in the ITED group ( p < 0.01). In response to drug infusions, the ΔMAP and ΔNBF were similar between groups ( p ≥ 0.18). Estimated conscious NBF (based on substituting conscious MAP values into each individual regression equation) was greater in the ITED group ( p < 0.01). Sciatic nerve vascularization was similar between groups ( p ≥ 0.50). In contrast to the hypothesis, NBF was not reduced across a range of MAP. In spite of increased estimated conscious NBF values, MNCV was reduced in rats with ITED.

Insulin stimulates nerve arterial vasodilation through a nitric oxide (NO) synthase (NOS) mechanism. Experimental diabetes reduces vasa nervorum NO reactivity. Studies investigating hyperglycemia and nerve arterial vasodilation typically omit insulin treatment and use sedentary rats resulting in severe hyperglycemia. We tested the hypotheses that 1) insulin-treated experimental diabetes and inactivity (DS rats) will attenuate insulin-mediated nerve arterial vasodilation, and 2) deficits in vasodilation in DS rats will be overcome by concurrent exercise training (DX rats; 75–85% V̇o2 max, 1 h/day, 5 days/wk, for 10 wk). The baseline index of vascular conductance values (VCi = nerve blood flow velocity/mean arterial blood pressure) were similar ( P ≥ 0.68), but peak VCi and the area under the curve (AUCi) for the VCi during a euglycemic hyperinsulinemic clamp (EHC; 10 mU·kg−1·min−1) were lower in DS rats versus control sedentary (CS) rats and DX rats ( P ≤ 0.01). Motor nerve conduction velocity (MNCV) was lower in DS rats versus CS rats and DX rats ( P ≤ 0.01). When compared with DS rats, DX rats expressed greater nerve endothelial NOS (eNOS) protein content ( P = 0.04). In a separate analysis, we examined the impact of diabetes in exercise-trained rats alone. When compared with exercise-trained control rats (CX), DX rats had a lower AUCi during the EHC, lower MNCV values, and lower sciatic nerve eNOS protein content ( P ≤ 0.03). Therefore, vasa nervorum and motor nerve function are impaired in DS rats. Such deficits in rats with diabetes can be overcome by concurrent exercise training. However, in exercise-trained rats (CX and DX groups), moderate hyperglycemia lowers vasa nervorum and nerve function.

Age-related decrements within the sensorimotor system may lead to alterations and impairments in postural control, but a link to a vestibular mechanism is unclear. The purpose of the present study was to determine whether vestibular control of standing balance is altered with adult aging. Eight old (~77 years) and eight young (~26 years) men stood without aids on a commercially available force plate with their head turned to the right, arms relaxed at their sides and eyes closed while receiving stochastic vestibular stimuli (0-25 Hz, root mean square amplitude=0.85 mA). Surface electromyography signals were sampled from the left soleus, medial gastrocnemius and tibialis anterior. Whole-body balance, as measured by the anteroposterior forces and muscle responses, was quantified using frequency (coherence and gain functions) and time (cumulant density function) domain correlations with the vestibular stimuli. Old men exhibited a compressed frequency response of the vestibular reflex with a greater relative gain at lower frequencies for the plantar flexors and anteroposterior forces than young. In the time domain, the peak amplitude of the short latency response was 45-64% lower for the plantar flexors and anteroposterior forces (p≤0.05) in the old than young, but not for the tibialis anterior (p=0.21). The old men had a 190% and 31% larger medium latency response for only the tibialis anterior and anteroposterior forces, respectively, than young (p≤0.01). A strong correlation between the tibialis anterior and the force response was also detected (r=0.80, p

Diabetic polyneuropathy (DPN) is a progressive axonopathy marked by loss of motor fibers, compensatory collateral reinnervation and reduced stability of neuromuscular transmission. Our objective wa...

The relative contributions of intrinsic and extrinsic neuromuscular factors on sarcopenia are poorly understood. The associations among age-related declines of strength, muscle mass, and muscle quality in response to motor unit (MU) loss have not been systematically investigated in the same groups of subjects. The purpose was to assess MU loss, MRI-derived muscle cross-sectional area (CSA), muscle protein quantity (MPQ), and normalized strength of the dorsiflexors in one group of young (∼25 years) adult males compared with two groups of healthy men aged 60-85 years. Muscle strength was assessed on a dynamometer and was ∼25 % lower in both older groups, but CSA was less only in the older (>75 years) men, with no differences between the young and old (60-73 years). Normalized strength tended to be lower in both groups of aged men compared to young. For MPQ, only the older men showed ∼8 % lower values than the young and old men. Older men had fewer functioning MUs than old, and both groups of aged men had fewer MUs than young men. Muscle quality appears to be maintained in the old likely due to compensatory MU remodeling, but in the older group (>75 years), MU loss was higher and MPQ was lower. © 2014 American Aging Association.

The objective of the study was to assess the effects of diabetic polyneuropathy (DPN) on muscle contractile properties in humans, and how these changes are related to alterations in muscle morphology and denervation. Patients with DPN ( n = 12) were compared with age- and sex-matched controls ( n = 12). Evoked and voluntary contractile properties, including stimulated twitch responses and maximal voluntary contractions, of the dorsiflexor muscles were assessed using an isometric ankle dynamometer. Motor unit number estimates (MUNE) of the tibialis anterior (TA) were performed via quantitative electromyography and decomposition-enhanced spike-triggered averaging. Peak tibialis anterior (TA) cross-sectional area (CSA; cm2), and relative proportion of contractile to noncontractile tissue (%) was determined from magnetic resonance images. Patients with DPN demonstrated decreased strength (−35%) and slower (−45%) dorsiflexion contractile properties for both evoked and voluntary contractions ( P < 0.05). These findings were not accounted for by differences in voluntary activation ( P > 0.05) or antagonist coactivation ( P > 0.05). Additionally, patients with DPN were weaker when strength was normalized to TA total CSA (−30%; P < 0.05) or contractile tissue CSA (−26%; P < 0.05). In the DPN patient group, TA MUNEs were negatively related to both % noncontractile tissue ( P < 0.05; r = 0.72) and twitch half-relaxation time ( P < 0.05; r = 0.60), whereas no relationships were found between these variables in controls ( P > 0.05). We conclude that patients with DPN demonstrated reduced strength and muscle quality as well as contractile slowing. This process may contribute to muscle power loss and functional impairments reported in patients with DPN, beyond the loss of strength commonly observed.

Human adult aging is associated with a loss of strength, contractile velocity and hence, power. The principal plantar flexors, consisting of the bi-articular gastrocnemeii and the mono-articular soleus, appear to be affected differently by the aging process. However, the age-related effect of knee joint angle on the torque-angular velocity relationship and power production of this functionally important muscle group is unknown. The purpose was to determine whether flexing the knee, thereby reducing the gastrocnemius contribution to plantar flexion, would exacerbate the age-related decrements in plantar flexion power, or shift the torque-angular velocity relationship differently in older compared with young men. Neuromuscular properties were recorded from 10 young (~25 y) and 10 old (~78 y) men with the knee extended (170°) and flexed (90°), in a randomized order. Participants performed maximal voluntary isometric contractions (MVCs), followed by maximal velocity-dependent shortening contractions at pre-set loads, ranging from 15 to 75% MVC. The young men were ~20-25% stronger, ~12% faster and ~30% more powerful than the old for both knee angles (P0.05). In both age groups, isometric MVC torque was ~17% greater in the extended than flexed knee position, with no differences in voluntary activation (95%). The young men produced 7-12% faster angular velocities in the extended knee position for loads ≤30% MVC, but no differences at higher loads; whereas there were no detectable differences in angular velocity between knee positions in the old across all relative loads. For both knee angles, young men produced peak power at 43.3±9.0% MVC, whereas the old men produced peak power at 54.8±7.9% MVC. These data indicate that the young, who have faster contracting muscles compared with the old, can rely more on velocity than torque for generating maximal power.

To assess the number and properties of motor units in an upper and lower limb muscle (tibialis anterior [TA] and first dorsal interosseous [FDI]) in human diabetic polyneuropathy (DPN) using decomposition-based quantitative electromyography (DQEMG).DQEMG protocols were performed in the TA and FDI of 12 patients with confirmed diabetes mellitus and associated DPN, as well as 12 age-matched control participants. Maximal dorsiflexion strength was also assessed using a dynamometer.In both muscles, patients with DPN had significantly reduced motor unit number estimates (MUNEs) (ΔTA ∼45%; ΔFDI ∼30%), compound muscle action potentials (CMAPs) (ΔTA ∼30%; ΔFDI ∼20%), and mean firing rates were reduced (ΔTA ∼15%; ΔFDI ∼15%) compared to controls (p0.05). For the TA, patients with DPN had larger mean surface motor unit potentials (SMUPs) (ΔTA ∼40%; p0.05), whereas in the FDI no differences were found (p0.05).DPN may result in motor unit loss, remodeling, and altered firing rate patterns. The magnitude of changes in the neuromuscular properties of DPN patients are muscle dependent and reflect a length-dependent disease progression.DQEMG may be a clinically useful technique in identifying the presence and severity of neuromuscular pathophysiology and tracking disease progression in DPN.

Both voluntary and evoked conditioning contractions will potentiate muscle twitch contractile properties. The response of a voluntary contraction to each condition type is not well understood but it may be a more functional model than evoked twitch potentiation.Baseline measurements from tibialis anterior included: maximal isometric twitch torque and rate of torque development (RTD); maximal evoked 50-Hz torque; and maximal voluntary ballistic RTD. Potentiation was induced by a 10-s voluntary or tetanic contraction (∽78% MVC), followed by 2 twitches and 2 ballistic contractions.Twitch properties (torque and RTD) were potentiated equally after each conditioning contraction. Ballistic RTD was greater post-tetanus (390.2 ± 59.3 Nm/s) than post-voluntary (356.4 ± 69.1 Nm/s), but both were reduced from baseline (422.0 ± 88.9 Nm/s).Twitch potentiation was similar between conditioning contraction types, but ballistic RTD was lower after post-tetanus than post-voluntary. The results indicate central inhibition or fatigue concurrent with peripheral potentiation.

Objectives:Conduction block (CB) from focal neuropathyis often associated with weakness and fatigue inaffected muscles. Ulnar neuropathy at the elbow(UNE) provides an excellent model to examine therelationships between electrophysiologically de-fined CB and quantitative measurement of weak-ness and fatigue.Methods:Eight healthy control subjects (47 6 14 years) andnine patients (53 6 3 years) with clinical andelectrophysiological features of UNE with CB werestudied. All underwentbilateral, ulnar motor nerveconduction studies recording from the first dorsalinterosseous muscle as well as quantitative mea-surement of strength and fatigue of the first dorsalinterosseous with a custom dynamometer.Results:Strength and fatigue were similar in the dominantand nondominant hands of control subjects andunaffected limb in patients. Varying degrees ofconduction block (14–62%, mean 36%) and con-duction slowing (31 m/s 6 7) were observed inthose with UNE. CB was associated with significantreductions in strength (42%) and fatigue (23%) ona timed fatiguetask. The reductions in strength(r =0.74)andfatigue(r=0.60)were stronglycorrelatedwith the degree of CB.Conclusions:CB in UNE defined by electrophysiological criteriawasstronglycorrelatedwithweaknessandfatigueinthe first dorsal interosseous. Fatigue may be simplyrelated to the reduction in strength, but activity orfrequency dependent CB may also contribute.Key Words: peripheral neuropathy, conductionblock, demyelination, weakness, fatigue

Objective The aim of this study was to compare the use of a custom intrinsic hand dynamometer (HD) with that of a standard pinch dynamometer (PD) in assessing strength in patients with ulnar neuropathy at the elbow. Design Nine patients (age, 53 ± 3 yrs) with clinical and electrophysiological features of ulnar neuropathy at the elbow with conduction block (CB) were studied. All underwent bilateral ulnar motor nerve conduction studies recording from the first dorsal interosseous and a quantitative measurement of strength of the first dorsal interosseous using a custom-made HD and a standard PD. Results The maximal strength of the ulnar neuropathy at the elbow-affected side (16.2 ± 8.0 N) was found to be significantly lower than that of the unaffected side (27.9 ± 11.2 N), as measured by HD. Strength differences were not significant between the affected (62.7 ± 26.4 N) and unaffected sides (48.0 ± 20.5 N) using PD. HD force decrement (in comparison with the unaffected limb) correlated strongly with CB percentage (r = 0.74). No relationship was found between PD and CB (r = 0.05). Conclusions HD was better able to measure the weakness of affected muscles than did PD, and its results correlated well with the extent of electrophysiological CB. Therefore, a custom HD would provide a better indication of disease severity, progression, or improvement in strength in studies of ulnar neuropathy at the elbow with CB.

Fatigue, defined as any exercise-induced reduction in the ability to generate muscle force or power, is task dependent and multifaceted in that both central and peripheral contributing factors to fatigue vary depending on the activity performed (Taylor & Gandevia, 2008). Therefore, identifying the potential site(s) of fatigue is of substantial importance in understanding the underlying mechanisms. The pioneering work of Merton (1954) concluded that the primary site of fatigue was peripheral, and central mechanisms do not contribute. Percutaneous electrical stimulation was applied to the ulnar nerve during a fatiguing maximal voluntary effort of the adductor pollicis resulting in no additional force output. In other words, the mechanical response to the electrical stimulus, the twitch, was ‘occluded’ or blocked indicating complete voluntary activation in a fatigued state. However, this technique does not permit assessment of the descending drive reaching the motoneurones and thus may not accurately reflect fatigue-induced alterations in voluntary drive. More recently, fatigue-associated changes to several supraspinal and spinal factors have been proposed as contributors to the development and recovery from, fatigue. Supraspinal factors include: inhibitory inputs within and between the motor cortices, and among other brain regions (Taylor & Gandevia, 2008). Spinal factors consist of excitatory and inhibitory inputs that converge onto the spinal cord above, and at the level of the motoneurone innervating the muscle group(s) of interest. Group I, II, III and IV afferents can provide excitatory and inhibitory inputs to the homonymous α and γ motoneurone pool. Increases of metabolic by-products, temperature and tension that occur with high-intensity fatigue may attenuate excitatory input from muscle afferents, or alternatively, contribute an inhibitory input to the motoneurones (Taylor & Gandevia, 2008). Furthermore, intrinsic motoneurone adaptation during sustained maximal voluntary isometric contraction (MVC) reduces motor output (Taylor & Gandevia, 2008). Despite the emergence of new techniques and methodologies, the site(s) responsible for central nervous system impairments during fatigue are unclear; however, the study we reviewed (McNeil et al. 2011) may provide new insight regarding influential factors of motoneurone responsiveness during high-intensity fatigue. Transcranial magnetic stimulation (TMS) of the motor cortex evokes a short latency electromyographic (EMG) response known as a motor evoked potential (MEP), followed by a silent period (SP) in the EMG recording when delivered during a MVC. By electrically stimulating the corticospinal pathway at the level of the mastoid processes, a cervicomedullary motor evoked potential (CMEP) is recorded at the muscle level. The relative contribution of supraspinal and spinal factors to fatigue can be inferred from a comparison of these two (MEP and CMEP) evoked potentials. During exercise, an increase in the area of the MEP response relative to the CMEP suggests an increase in motor cortex excitability, whereas a lengthening of the SP following delivery of TMS indicates intracortical inhibition. In a recent study, McNeil et al. (2009) observed similar increases in MEP and CMEP area in the biceps brachii early during a sustained 2 min MVC followed by a decrease in CMEP area (∼20%) and no decrease in MEP area in the final 30 s. The maintained MEP and decreased CMEP suggest a spinal mechanism is responsible for the reduction in motoneurone excitability during a maximal sustained fatiguing contraction (McNeil et al. 2009). However, this study also demonstrated the masking effect of descending drive on CMEP area by eliciting MEPs and CMEPs during unconditioned and conditioned states (McNeil et al. 2009). An unconditioned response is elicited while descending drive is intact, whereas a conditioned response is elicited during the SP following a conditioning stimulus (an initial TMS used to generate a SP) in which very little activity in background EMG is observed. McNeil et al. (2009) reported a near obliteration of the MEP and CMEP during a sustained MVC within 30 s when recorded during the SP implying a reduction in motoneurone excitability as the principal contributor to reduced motor output in the absence of voluntary drive. However, the origin of a reduction in motoneurone excitability was less certain. The two leading hypotheses explaining fatigue at the motoneurone level in the SP during sustained MVC are the dysfacilitation of Ia and II afferent input from the muscle spindle, and intrinsic motoneurone adaptation (McNeil et al. 2009). Repetitive discharge of the motoneurone is believed to cause increased cation-activated potassium leak conductance (Button et al. 2007) reducing the responsiveness of motoneurones: termed motoneurone adaptation. Intrinsic motoneurone adaptation has been demonstrated directly in animals (Button et al. 2007) and indirectly in humans (Carpentier et al. 2001). Muscle spindle dysfacilitation and motoneurone adaptation served as the impetus for a recent study inThe Journal of Physiologyby McNeil et al. (2011). The study used TMS of the motor cortex and subcortical transmastoid electrical stimulation of the corticospinal tract in the presence and absence of tendon vibration to determine whether increased afferent input to the motoneurone pool postpones the reduction, and preserves the size, of conditioned CMEPs. The study consisted of two protocols, one investigating MEPs and the other investigating CMEPs. Both protocols used a conditioning stimulus (TMS) preceding a second stimulus (either TMS or transmastoid electrical stimulation) to elicit conditioned responses (conditioned MEPs or CMEPs, respectively). Each protocol began with participants performing 12 brief MVCs with either paired motor cortical–corticospinal or motor cortical–motor cortical stimuli with and without vibration. These MVCs provided control values for the normalization of subsequent conditioned MEPs and CMEPs. Tendon vibration was applied to the skin over the distal biceps tendon at ∼80 Hz using a handheld pneumatic vibrator to increase the level of Ia excitatory input from muscle spindles. Following the initial control MVCs, participants began a sustained MVC of the elbow flexors for 2 min. During the fatigue protocol, single (motor cortical or corticospinal) and paired (motor cortical-corticospinal or motor cortical-motor cortical) stimuli were delivered in an alternating fashion every 5 s beginning at 5 s in the presence and absence of tendon vibration. McNeil et al. (2011) used an experimentally tested “optimal frequency” range of vibration to elicit reflexes in the relaxed muscle and to increase torque during a sustained MVC. Tendon vibration, however, did not affect the size of conditioned MEPs or CMEPs during brief MVCs prior to the fatigue task. The inability to generate a facilitation of the conditioned MEPs and CMEPs using a 10 s, 80 Hz mechanical vibration of the muscle tendon during non-fatiguing contractions is surprising and questions the efficacy of the vibratory stimulus in this protocol. The sustained (fatiguing) 2 min MVC resulted in large, equivalent reductions of the conditioned MEPs and CMEPs independent of whether tendon vibration was applied. Similar reductions in conditioned MEPs and CMEPs were reported by the same authors in the absence of tendon vibration (McNeil et al. 2009). Despite the potential concerns associated with the vibratory stimulus, McNeil et al. (2011) suggested that the reduction in motoneurone excitability was a consequence of motoneurone adaptation, and not the result of reduced afferent input as a result of muscle spindle dysfacilitation. Motoneurone adaptation is closely related to many common characteristics of large motoneurones innervating fast motor units including high rheobase and low input resistance (Button et al. 2007). An increased cation concentration in the motoneurone is also the impetus for the opening of channels responsible for the activation of the persistent inward current, which greatly increases the gain of the current–frequency relationship of motoneurones. Thus, the same stimulus responsible for facilitation of motor output may also be responsible for the fatigue-associated declines in motoneurone excitability during sustained MVCs. Considering the task in the present study was performed maximally, one may assume all motoneurones in the motoneurone pool were active. With this in mind, the rapid, sizeable decline in motoneurone excitability is likely to be partially related to the changes in large motoneurone excitability. The biceps brachii is composed of near equal distribution of slow and fast motoneurones. Considering slow motoneurones are more sensitive to Ia afferent input, it is possible that a muscle with a slower motor unit composition may exhibit a heightened response to tendon vibration. To test this hypothesis, a muscle composed primarily of slow motoneurones, such as the soleus, could be investigated.