A New Paradigm of Neuromuscular Electrical Stimulation in Attenuating Muscle Atrophy: a Randomised Controlled Trial

Introduction:

Skeletal muscle responds to the stimulus of mechanical load for growth and maintenance. Prolonged reductions in muscle activity and mechanical loading such as spaceflight, limb immobilization, bedrest, and/or inactivity alter the balance between protein synthesis and degradation, resulting in skeletal muscle atrophy (1-3). This is characterized by a decrease in muscle mass, myofiber cross-sectional area, contractile strength and speed, as well as slow-to-fast fiber type transformation (4,5). Many countermeasures have been reported to attenuate the loss of muscle atrophy and neuromuscular electrical stimulation (NMES) has been frequently used in conditions such as spinal cord injury, immobilization, and muscle disuse post-surgery (6,7). Indeed, a recent Cochrane review on the effectiveness of NMES for muscle weakness in adults with progressive diseases such as COPD, chronic heart failure and cancer indicated that NMES is an effective means of improving muscle weakness (8). The meta-analyses included eleven randomized controlled trial (RCT) studies involving a total of 218 participants. NMES significantly improved quadriceps strength by a Standardised Mean Difference (SMD) of 0.9 (95% confidence interval (CI) 0.33 to 1.46). This is approximately equals to 25 Newton metres (Nm) and should be regarded as clinically significant. Similarly, another recent systematic review also showed NMES is effective in preventing skeletal-muscle weakness in critically ill patients. Eight eligible studies involving 172 patients were included in the analysis. Out of the eight studies, five studies reported an increase in strength or better preservation of strength with NMES, with one study having a large effect size (1.44). Two studies found better preservation of muscle mass with NMES, with small to moderate effect sizes (0.11-0.39) while no significant benefits were found in two other studies (9).

The effectiveness of NMES is dependent upon the clinical condition and is influenced by different stimulation parameters, particularly the stimulation frequency and duration. Traditionally, NMES has been viewed as the application of a transcutaneous electrical current to the neuromuscular junction, aimed to depolarise the motor unit action potential and inducing muscle contraction (10). This electrically induced muscle contraction simulates active muscle strengthening and is based on the principle of muscle training that by appropriate loading, muscle strength will be increased. To achieve this training effect, the stimulation parameters employed normally aimed to produce tetanic contraction with a current density that the subject can maximally tolerated (8,9). However, this currently adopted stimulation protocol (ie. high frequency at or above 50Hz, amplitude at subjects' maximum tolerated limit and short duration (30 min to 1 hr) to counteract muscle atrophy has two main drawbacks. First, it has been well established that mechanical unloading is associated with detrimental changes to the structure and function of skeletal muscles, characterized by reduction in muscle mass, myofiber cross-sectional area, contractile strength and speed, as well as slow-to-fast fiber type transformation (for review, see 11). Thus, the slow twitch muscle fibers are more susceptible to unloading or disuse effect rather than fast twitch muscle fibers. The traditional high frequency stimulation protocol (50 Hz) does not match the motor unit firing pattern of a slow-twitch muscle. Moreover, the high current density would inevitably caused discomfort if not pain to the subjects during the electrical stimulation. The subjects cannot tolerate the electrical stimulation for hours. This is particularly the case if the application is to the subjects with disuse muscle atrophy or subjects with muscle weakness caused by progressive diseases. Very often, the pain tolerance of this group of subjects is generally lower than the normal healthy subjects. Thus, the currently adopted protocol might not necessary render the best possible outcome of NMES for the enhancement of muscle function. The beneficial effects of NMES to counteract muscle atrophy had not been fully utilized. A recent systematic review that examines metabolic and structural changes in lower limb skeletal muscle following neuromuscular electrical stimulation identified only 18 studies. Eight of these studies investigated enzymatic activities, seven studies on muscle fibre composition, and 14 on muscle fibre size. Among these 18 studies, only 9 are RCT studies, and the methodological quality generally was poor. The authors concluded that NMES seems to be able to produce favourable changes in oxidative enzyme activity, skeletal muscle fibre type and skeletal muscle fibre size. In view of the large heterogeneity in NMES protocols, the authors concluded that there was no definite consensus regarding the stimulation frequencies for optimal muscular changes (12), For instance, Theriault et al. (13) had conducted prolonged electrical stimulation to the knee extensor of 8 healthy adults. The electrical stimulation protocol was of 8-week duration for 8 hour per day and 6 days per week. The stimulation parameter was of low frequency (8 Hz) with intensity just being able to produce visible vibration. The results suggested significant improvement in knee extensor performance after 4 week of stimulation. However, the study is not a RCT study and there is control group in the study. On the other hand, one of the RCT studies that investigated the effects of NMES and incorporated high frequency (50Hz) but very low amplitude (without muscle contraction) as the placebo group had incidentally revealed that the placebo produced better effect than the intervention group. The NMES group vs placebo group by a SMD of -0.12 (95% CI: -0.63, 0.39) (8,14). Banerjee and his group has also shown an electrical stimulation protocol with low frequency (4 Hz) yet high amplitude (300mA), 1 hr/day for 6 week can significantly increase the quadriceps strength of healthy sedentary adults and patients with stable chronic heart failure (15, 16). Thus, the findings from basic science and these clinical studies suggested the need for further exploration of more effective NMES stimulation protocol to attenuate muscle atrophy.

Aims and Hypotheses to be Tested:

To address these, the investigators of this proposal have challenged the traditional thought that NMES should be with high frequency and high amplitude. The investigators had tested the hypothesis that low frequency and low amplitude is effective in attenuating muscle atrophy, and investigated the cellular mechanisms associated with muscle unloading. Using the hindlimb suspension animal model, the investigators have previously demonstrated that, during hindlimb suspension, application of low-frequency electrical stimulation at 20 Hz on the soleus muscles with defined timing and pulse parameters partially rescued the loss of satellite cells and improved fiber cross-sectional areas (17). The investigators have further demonstrated that using an electrical stimulation paradigm of frequency: 20 Hz; duration: 3 h, twice daily to eight-week-old male BALB/c mice that were subjected to a 14-day hindlimb unloading (HU). This stimulation paradigm can enhance satellite cell proliferative potential as well as suppress apoptotic cell death in disuse induced muscle atrophy. Morphologically, the hindlimb with electrical stimulation showed significant improvement in muscle mass, cross-sectional area, and peak tetanic force relative to the HU limb (18). Recently, the investigators further investigated the optimum stimulation protocol and demonstrated that among three low frequency protocol, 2, 10 and 20 Hz, stimulation at 2 Hz for 2 × 3 h/day achieved the best effect in attenuating the loss of muscle fiber cross-sectional area and force. This stimulation parameter led to a 1.2-fold increase in satellite cell proliferation, and was effective in rescuing cells from apoptosis (19). With all these encouraging findings from the basic science research, the investigators believe the proposed new paradigm of NMES can be tested on subjects with progressive muscle atrophy. The investigators hypothesis that NMES at 2 Hz for 2 × 3 h/day is effective in attenuating/improving lower limb postural muscle atrophy, namely quadriceps and gastrocnemius and soleus muscle complex.