Muscle fatigue has been defined as “the failure to maintain a required or expected force”  and it is a complex phenomenon experienced in everyday life that has reached great interest in the areas of sports, medicine and ergonomics . Muscle fatigue can affect task performance, posture-movement coordination , position sense  and it can be a highly debilitating symptom in several pathologies . For many patients with neuromuscular impairments, taking into account muscle fatigue is of crucial importance in the design of correct rehabilitation protocols  and fatigue assessment can provide crucial information about skeletal muscle function. Specifically, several neuromuscular diseases (e.g. Duchenne, Becker Muscular Dystrophies, and spinal muscular atrophy) present muscle fatigue as a typical symptom , and fatigue itself accounts for a significant portion of the disease burden. A systematic approach to assess muscle fatigue might provide important cues on the disability itself, on its progression and on the efficacy of adopted therapies. In particular, therapeutic strategies are now under deep investigation and a lot of effort has been devoted to accelerate the development of drugs targeting these disorders . Therefore, the need for an objective tool to measure muscle fatigue is impelling and of great relevance.
Currently, in clinical practice muscle fatigue is evaluated by means of qualitative rating scales like the 6-min walk test (6MWT)  or through subjective questionnaires administered to the patient (e.g. the Multidimensional Fatigue Inventory (MFI), the Fatigue Severity Scale (FSS), and the Visual Analog Scale (VAS)) . During the 6MWT patients have to walk, as fast as possible, along a 25 meters linear course and repeat it as often as they can for 6 min: ‘fatigue’ is then defined as the difference between the distance covered in the sixth minute compared to the first. Obviously, such a measure is only applicable to ambulant patients and this is a strong limitation to clinical investigation because a patient may lose ambulatory ability during a clinical trial, resulting in lost ability to perform the primary clinical endpoint . It should also be considered that neuromuscular patients, e.g. subjects with Duchenne Muscular Dystrophy, generally lose ambulation before 15 years of age , excluding a large part of the population from the measurement of fatigue through the 6MWT. Since neuromuscular patients often experience a progressive weakness also in the upper limb, reporting of muscle fatigue in this region is common. A fatigue assessment for upper limb muscles could be used to monitor patients across different stages of the disease. As for the questionnaires, the MFI is a 20 items scale designed to evaluate five dimensions of fatigue (general fatigue, physical fatigue, reduced motivation, reduced activity, and mental fatigue) . Similarly, the FSS questionnaire contains nine statements that rate the severity of fatigue symptoms and the patient has to agree or disagree with them . The VAS is even more general: the patient has to indicate on a 10 cm line ranging from “no fatigue” to “severe fatigue” the point that best describes his/her level of fatigue . Despite the ease to administer, such subjective assessments of fatigue may not correlate with the actual severity or characteristics of fatigue, and may provide just qualitative information with low resolution, reliability and objectivity. Considering various levels of efficacy among the methods currently used in clinical practice, research should focus on the development of an assessment tool for muscle fatigue, that is easy and fast to administer, even to patients with a high level of impairment. Such a tool, should provide clear results, be easy to read and understand by a clinician, be reliable and objectively correlated with the physiology of the phenomenon.
In general, muscle fatigue can manifest from either central and/or peripheral mechanisms. Under controlled conditions, surface electromyography (sEMG) is a non-invasive and widely used technique to evaluate muscle fatigue . Certain characteristics of the sEMG signal can be indicators of muscle fatigue. For example during sub-maximal tasks, muscle fatigue will present with decreases in muscle fiber conduction velocity and frequency and increases in amplitude of the sEMG signal . The trend and rate of change will depend on the intensity of the task: generally, sEMG amplitude has been observed to increase during sub-maximal efforts and decrease during maximal efforts; further it has been reported that there is a significantly greater decline in the frequency content of the signal during maximal efforts compared to sub-maximal . Accordingly, spectral (i.e. mean frequency) and amplitude parameters (i.e. Root Mean Square (RMS)) of the signals, can be used to measure muscle fatigue as extensively discussed in many widely acknowledged studies [16, 18, 19], however, context of contraction type and intensity must be specified for proper interpretation. A significant problem with the majority of existing protocols is that they rely on quantifying maximal voluntary force loss, maximum voluntary muscle contraction (MVC) [18, 20, 21] or high fatiguing dynamic tasks [19, 22] that cannot be reliably performed in clinical practice, especially in the case of pediatric subjects. Actually, previous works pointed out that not only the capacity to maintain MVC can be limited by a lack of cooperation [23, 24], but also, that sustaining a maximal force in isometric conditions longer than 30 s reduces subject’s motivation leading to unreliable results . Besides, neuromuscular patients might have a high level of impairment and low residual muscular function thus making even more difficult, as well as dangerous for their muscles, sustaining high levels of effort or the execution of a true MVC. In order to overcome this issue, maximal muscle contractions can be elicited by magnetic  or electrical stimulation . Although such procedures allow to bypass the problem mentioned above, these involve involuntary muscle activation and not physiological recruitment of motor units ; moreover, they can be uncomfortable for patients and can require advanced training, which makes them difficult to be included in clinical fatigue assessment protocols. As for the above mentioned problem with children motivation, work by Naughton et al.  showed that the test-retest coefficient of variation of fatigue index during a Wing-Gate test, significantly decreased when using a computerized feedback game linked to pedal cadence, suggesting that game-based procedures may ensure more consistent results in children assessment.
In recent years, the assessment of sensorimotor function has been deepened thanks to the introduction of innovative protocols administered through robotic devices [28, 29, 30, 31]. These methods have the ambition to add meaningful information to the existing clinical scales and can be exploited as a basis for the implementation of a muscle fatigue assessment protocol. In order to fill the gap between the need of a quantitative clinical measurement protocol of muscle fatigue and the lack of an objective method which does not demand a high level of muscle activity, we propose a new method based on a robotic test, which is fast and easy to administer. Further, we decided to address the analysis of muscle fatigue on the upper limb as to provide a test suitable to assess patients from the beginning to the late stages of the disease, regardless of walking ability. Moreover, we focused on an isolated wrist flexion/extension tasks to assess wrist muscle fatigue. This ensured repeatability of the tests and prevented the adoption of compensatory movements or poor postures that may occur in multi-segmental tasks, involving the shoulder-elbow complex. In the present work, we tested the method on healthy subjects with the specific goal to evaluate when during the test the first meaningful symptoms of fatigue appaered and not how much subjects are fatigued at the end of the test. The most relevant and novel features of the proposed test include the ability to perform the test regardless of the subjects’ capability and strength, the objectivity and repeatability of the data it provides, and the simplicity and minimal time required to administer.[…]