Gabrielle Todd

Measurement of voluntary activation of fresh and fatigued human muscles using transcranial magnetic stimulation

Recently, transcranial magnetic stimulation of the motor cortex (TMS) revealed impaired voluntary activation of muscles during maximal efforts. Hence, we evaluated its use as a measure of voluntary activation over a range of contraction strengths in both fresh and fatigued muscles, and compared it with standard twitch interpolation using nerve stimulation. Subjects contracted the elbow flexors isometrically while force and EMG from biceps and triceps were recorded. In one study, eight subjects made submaximal and maximal test contractions with rests to minimise fatigue. In the second study, eight subjects made sustained maximal contractions to reduce force to 60 % of the initial value, followed by brief test contractions. Force responses were recorded following TMS or electrical stimulation of the biceps motor nerve. In other contractions, EMG responses to TMS (motor evoked potentials, MEPs) or to stimulation at the brachial plexus (maximal M waves, Mmax) were recorded. During contractions of 50 % maximum, TMS elicited large MEPs in biceps (> 90 % Mmax) which decreased in size (to ≈70 % Mmax) with maximal efforts. This suggests that faster firing rates made some motor units effectively refractory. With fatigue, MEPs were also smaller but remained > 70 % Mmax for contractions of 50–100 % maximum. For fresh and fatigued muscle, the superimposed twitch evoked by motor nerve and motor cortex stimulation decreased with increasing contraction strength. For nerve stimulation the relation was curvilinear, and for TMS it was linear for contractions of 50‐100 % maximum (r2= 1.00). Voluntary activation was derived using the expression: (1 – superimposed twitch/resting twitch) × 100. The resting twitch was measured directly for nerve stimulation and for TMS, it was estimated by extrapolation of the linear regression between the twitch and voluntary force. For cortical stimulation, this resulted in a highly linear relation between voluntary activation and force. Furthermore, the estimated activation corresponded well with contraction strength. Using TMS or nerve stimulation, voluntary activation was high during maximal efforts of fresh muscle. With fatigue, both measures revealed reduced voluntary activation (i.e. central fatigue) during maximal efforts. Measured with TMS, this central fatigue accounted for one‐quarter of the fall in maximal voluntary force. We conclude that TMS can quantify voluntary activation for fresh or fatigued muscles at forces of 50–100 % maximum. Unlike standard twitch interpolation of the elbow flexors, voluntary activation measured with TMS varies in proportion to voluntary force, it reveals when extra output is available from the motor cortex to increase force, and it elicits force from all relevant synergist muscles.

Evidence for a supraspinal contribution to human muscle fatigue

1 Muscle fatigue can be defined as any exercise‐induced loss of ability to produce force with a muscle or muscle group. It involves processes at all levels of the motor pathway between the brain and the muscle. Central fatigue represents the failure of the nervous system to drive the muscle maximally. It is defined as a progressive exercise‐induced reduction in voluntary activation or neural drive to the muscle. Supraspinal fatigue is a component of central fatigue. It can be defined as an exercise‐induced decline in force caused by suboptimal output from the motor cortex. 2 When stimulus intensity is set appropriately, transcranial magnetic stimulation (TMS) over the motor cortex during an isometric maximal voluntary contraction (MVC) of the elbow flexors commonly evokes a small twitch‐like increment in flexion force. This increment indicates that, despite the subjects maximal effort, motor cortical output at the moment of stimulation was not maximal and was not sufficient to drive the motoneurons to produce maximal force from the muscle. An exercise‐induced increase in this increment demonstrates supraspinal fatigue. 3 Supraspinal fatigue has been demonstrated during fatiguing sustained and intermittent maximal and submaximal contractions of the elbow flexors where it accounts for about one‐quarter of the loss of force of fatigue. It is linked to activity and the development of fatigue in the tested muscles and is little influenced by exercise performed by other muscles. 4 The mechanisms of supraspinal fatigue are unclear. Although changes in the behaviour of cortical neurons and spinal motoneurons occur during fatigue, they can be dissociated from supraspinal fatigue. One factor that may contribute to supraspinal fatigue is the firing of fatigue‐sensitive muscle afferents that may act to impair voluntary descending drive.

Hyperthermia: a failure of the motor cortex and the muscle

Fatigue is increased during hyperthermia, and torque declines more rapidly in sustained maximal voluntary contractions (MVCs). This can be caused by a greater decline in voluntary activation of muscle (i.e. ‘central fatigue’). The present study aimed to localize the site of failure of voluntary drive during hyperthermia. Seven subjects made brief (2–3 s) and sustained (2 min) MVCs of elbow flexor muscles in two experiments. Core temperature was normal (∼37°C) in the first experiment, and elevated (∼38.5°C) by passive heating in the second. During some MVCs, transcranial magnetic stimulation of the motor cortex (TMS) was delivered, and the evoked torque (superimposed twitch) and EMG responses were measured. During hyperthermia, voluntary torque was reduced by ∼2.4% during brief MVCs (P= 0.03), and decreased further (∼12%) during sustained MVCs (P= 0.01). The superimposed twitch amplitude in the sustained MVC was ∼50% larger (P= 0.01). Thus, the ability to drive the muscle maximally in a sustained fashion was decreased, and some motor cortical output, which could have increased torque, remained untapped by voluntary drive. The additional central fatigue was not associated with altered motor cortical ‘excitability’, as EMG responses produced by TMS were similar at the two temperatures. However, the peak relaxation rate of muscle increased by ∼20% (P= 0.005) during hyperthermia. Hence, faster motor unit firing rates would be required to produce fusion of force. The increased central fatigue during hyperthermia may represent a failure of descending voluntary drive to compensate for changed muscle properties, despite the availability of additional cortical output.

Measurement and reproducibility of strength and voluntary activation of lower-limb muscles

Accurate measurement of muscle strength and voluntary muscle activation is important in the assessment of disorders that affect the motor pathways or muscle. We designed a multipurpose system to assess the variability and reproducibility of isometric torque measurements obtained during maximal voluntary efforts of the knee flexor, knee extensor, ankle dorsiflexor, and ankle plantarflexor muscles on each side. It used two isometric myographs mounted on an adjustable frame. Measurements of maximal voluntary torque (range, 25–188 Nm) displayed low variability within a testing session and over five testing sessions (coefficient of variation range, 5–11%). We used the same equipment to measure voluntary activation of the triceps surae muscles. Voluntary activation, measured with a sensitive twitch interpolation method, increased with increasing voluntary contraction torque (P < 0.001) and was very high during maximal efforts (mean, 97.8 ± 2.1%; median, 98.5%). Furthermore, measurements of voluntary activation during maximal efforts were reproducible across testing sessions with very little variability (coefficient of variation, <2%). The myograph system and the testing procedures should allow accurate measurement of strength and voluntary drive in longitudinal patient studies. Muscle Nerve 29: 834–842, 2004

Recovery from supraspinal fatigue is slowed in old adults after fatiguing maximal isometric contractions

This study compared the contribution of supraspinal fatigue to muscle fatigue in old and young adults. Transcranial magnetic stimulation (TMS) of motor cortex was used to assess voluntary activation during maximal voluntary contractions (MVCs) of elbow flexor muscles in 17 young adults (25.5 +/- 3.6 yr; mean +/- SD) and 7 old adults (73.0 +/- 3.3 yr). Subjects performed a fatigue task involving six sustained MVCs (22-s duration, separated by 10 s). Young adults exhibited greater reductions in maximal voluntary torque (67 +/- 15% of baseline) than the old (37 +/- 6%; P < 0.001). Increments in torque (superimposed twitch) generated by TMS during sustained MVCs increased for the young and old (P < 0.001) but were larger for the old adults at the start of the sustained contractions and during recovery (P < 0.05). Voluntary activation was less for the old adults at the start of some sustained contractions and during recovery (P = 0.02). Motor-evoked potential area increased similarly with age during the fatiguing task but was greater for the old adults than young during recovery. Silent period duration lengthened less for the old adults during the fatigue task. At the end of the fatiguing task, peak relaxation rate of muscle fibers had declined more in the young than the old adults. The greater endurance with age is largely due to a difference in mechanisms located within the muscle. However, recovery from the fatiguing exercise is impaired for old adults because of greater supraspinal fatigue than in the young.

Passive mechanical properties of human gastrocnemius muscle-tendon units, muscle fascicles and tendons in vivo

SUMMARY This study provides the first in vivo measures of the passive length–tension properties of relaxed human muscle fascicles and their tendons. A new method was used to derive passive length–tension properties of human gastrocnemius muscle–tendon units from measures of ankle stiffness obtained at a range of knee angles. Passive length–tension curves of the muscle–tendon unit were then combined with ultrasonographic measures of muscle fascicle length and pennation to determine passive length–tension curves of the muscle fascicles and tendons. Mean slack lengths of the fascicles, tendons and whole muscle–tendon units were 3.3±0.5 cm, 39.5±1.6 cm and 42.3±1.5 cm, respectively (means ± s.d., N=6). On average, the muscle–tendon units were slack (i.e. their passive tension was zero) over the shortest 2.3±1.2 cm of their range. With combined changes of knee and ankle angles, the maximal increase in length of the gastrocnemius muscle–tendon unit above slack length was 6.7±1.9 cm, of which 52.4±11.7% was due to elongation of the tendon. Muscle fascicles and tendons underwent strains of 86.4±26.8% and 9.2±4.1%, respectively, across the physiological range of lengths. We conclude that the relaxed human gastrocnemius muscle–tendon unit falls slack over about one-quarter of its in vivo length and that muscle fascicle strains are much greater than tendon strains. Nonetheless, because the tendons are much longer than the muscle fascicles, tendons contribute more than half of the total compliance of the muscle–tendon unit.

Corticomotor excitability and plasticity following complex visuomotor training in young and old adults.

Previous studies with transcranial magnetic stimulation (TMS) have shown that advancing age may influence plasticity induction in human motor cortex (M1), but these changes have been assessed with TMS‐induced paradigms or simple motor tasks. The aim of this study was to examine changes in corticospinal excitability and intracortical inhibition as markers of corticomotor plasticity following complex motor training in young and old adults. Electromyographic recordings were obtained from the right first dorsal interosseous (FDI) muscle of 16 young (20–35 years) and 16 older (aged 60–75 years) adults before and after motor skill training. Motor training consisted of three 6‐minute blocks of a complex visuomotor task that required matching the metacarpophalangeal (MCP) joint angle of the index finger using abduction–adduction movements. Single‐ and paired‐pulse TMS over the left M1 was used to assess changes in right FDI motor‐evoked potentials (MEPs) and short‐interval intracortical inhibition (SICI) before and after each training block. Visuomotor tracking performance was diminished in old compared with young adults throughout training. However, improvement in tracking error was similar for young and old adults (7–24% increase in each training block). For young and old adults, motor training increased FDI MEP amplitude (≥ 20%) and reduced the magnitude of SICI (≥ 19%) after each visuomotor training block, reflecting use‐dependent plasticity. However, no difference in corticomotor plasticity (change in MEP or SICI) was observed between young and old adults. Further studies are needed to identify the experimental or behavioral factors that might contribute to the maintenance of corticomotor plasticity in older adults.

Reduced motor cortex plasticity following inhibitory rTMS in older adults

OBJECTIVE Ageing is accompanied by diminished practice-dependent plasticity. We investigated the effect of age on another plasticity inducing paradigm, repetitive transcranial magnetic stimulation (rTMS). METHODS Healthy young (n=15; 25+/-4 years) and old (n=15; 67+/-5 years) adults participated in two experiments. Motor evoked potentials (MEPs) were measured in the target muscle (first dorsal interosseus, FDI) and a remote muscle (abductor digiti minimi) during a set of single stimuli. Subjects then received real or sham inhibitory rTMS (intermittent subthreshold trains of 6Hz stimulation for 10min). MEPs were measured for 30min after rTMS. RESULTS In young adults, MEPs in the target FDI muscle were approximately 15% smaller in the real rTMS experiment than in the sham rTMS experiment (P<0.026). In old adults, FDI MEP size did not differ between experiments. CONCLUSIONS Advancing age is associated with reduced efficacy of inhibitory rTMS. SIGNIFICANCE This work has important implications for the potential therapeutic use of rTMS in stroke and neurological disease.

Voluntary movement and repetitive transcranial magnetic stimulation over human motor cortex

Repetitive transcranial magnetic stimulation (rTMS) can induce short-term reorganization of human motor cortex. Here, we investigated the effect of rTMS during relaxation and weak voluntary muscle contraction on motor cortex excitability and hand function. Subjects (n = 60) participated in one of four studies. Single transcranial magnetic stimuli were delivered over the motor area of the first dorsal interosseus for measurement of motor evoked potential (MEP) size before and after real or sham rTMS delivered at an intensity of 80% of active motor threshold. rTMS involved trains of stimuli applied at 6 Hz for 5 s and repeated every 30 s for 10 min. Resting MEP size was suppressed for 15 min after rTMS during relaxation. However, MEP suppression was abolished when additional brief voluntary contractions were performed before and after rTMS (study 1). Resting MEP size was suppressed for 30 min after rTMS during weak voluntary contraction. MEP suppression was present even though voluntary contractions were performed before and after rTMS (study 2). The MEP suppression most likely reflects a decrease in motor cortical excitability. Surprisingly, rTMS during voluntary contraction did not alter maximal finger tapping speed or performance on a grooved pegboard test, object grip and lift task (study 3), and visuomotor tracking task (study 4). These studies document the complex relationship between voluntary movement and rTMS-induced plasticity in motor cortex. This work has implications for the optimization of rTMS parameters for improved efficacy and potential therapeutic applications.

Illicit stimulant use is associated with abnormal substantia nigra morphology in humans.

Use of illicit stimulants such as methamphetamine, cocaine, and ecstasy is an increasing health problem. Chronic use can cause neurotoxicity in animals and humans but the long-term consequences are not well understood. The aim of the current study was to investigate the long-term effect of stimulant use on the morphology of the human substantia nigra. We hypothesised that history of illicit stimulant use is associated with an abnormally bright and enlarged substantia nigra (termed ‘hyperechogenicity’) when viewed with transcranial sonography. Substantia nigra morphology was assessed in abstinent stimulant users (n = 36; 31±9 yrs) and in two groups of control subjects: non-drug users (n = 29; 24±5 yrs) and cannabis users (n = 12; 25±7 yrs). Substantia nigra morphology was viewed with transcranial sonography and the area of echogenicity at the anatomical site of the substantia nigra was measured at its greatest extent. The area of substantia nigra echogenicity was significantly larger in the stimulant group (0.273±0.078 cm2) than in the control (0.201±0.054 cm2; P<0.001) and cannabis (0.202±0.045 cm2; P<0.007) groups. 53% of stimulant users exhibited echogenicity that exceeded the 90th percentile for the control group. The results of the current study suggest that individuals with a history of illicit stimulant use exhibit abnormal substantia nigra morphology. Substantia nigra hyperechogenicity is a strong risk factor for developing Parkinsons disease later in life and further research is required to determine if the observed abnormality in stimulant users is associated with a functional deficit of the nigro-striatal system.