We would like to thank Lars Hintermann for taking part in the demonstration of the motor function measure and timed function tests.

Before recruitment, the study was approved by the local ethics committee [Ethics Committee of the two Basel Cantons (EKBB 63/13)] and the Swiss Drug Agency (Swissmedic 2013DR3151) and registered under ClinicalTrials.gov (NCT01995032).
1. Clinical Assessment of Muscle Function
<ol>
	<li>Motor function measure (MFM)
	<ol>
		<li>Have the patient perform each of the following tasks and score them as shown in Table 1. 
		Note: The MFM contains 32 independent items that must be performed in the given order to avoid unnecessarily repositioning and exhaustion of the patient5. See Table 1 for a detailed description of each task and scoring.
		<ol>
			<li>Ask the patient to lie down on his back. Ask him to hold his head in midline position and turn it from one side to the other. In this and all subsequent steps, score the patient on a scale of 0 to 3 (see Table 1) based on performance of the task.</li>
			<li>Ask the patient to lie down on his back with the head in midline position. Ask him to raise the head and maintain the position.</li>
			<li>Ask the patient to lie down on his back. Ask him to bring one knee to the chest.</li>
			<li>Ask the patient to lie down on his back with one leg flexed both at the hip and knee at approximately 90&#176;. Ask him to place the lower leg parallel to the mat with the foot in plantar flexion. Ask him to perform a maximal dorsiflexion of the foot.</li>
			<li>Ask the patient to lie down on his back. Ask him to place one upper limb beside his body and to bring the hand to the opposite shoulder.</li>
			<li>Ask the patient to lie down on his back with the lower limbs half-flexed and the feet resting on the mat slightly apart. Ask him to maintain this position and raise the pelvis.</li>
			<li>Ask the patient to lie down on his back. Ask him to turn over onto the stomach and free both upper limbs.</li>
			<li>Ask the patient to lie down on his back. Ask him to sit up.</li>
			<li>Ask the patient to sit on the mat. Ask him to maintain the seated position and keep the hands in contact in front of the trunk.</li>
			<li>Ask the patient to sit on the mat and place a tennis ball in front of him. Ask him to touch the ball and sit back again. 
			Note: The tennis ball should be at a distance so that the patient must lean his trunk forward about 30&#176; away from the starting position in order to touch it.</li>
			<li>Ask the patient to sit on the mat with the lower limbs in front of him. Ask him to stand up.</li>
			<li>Ask the patient to stand in front of the chair. Ask him to sit down on the chair.</li>
			<li>Ask the patient to sit on the chair. Ask him to maintain the seated position as straight as possible.</li>
			<li>Ask the patient to sit on the chair with the head in complete flexion. Ask him to raise the head and maintain this position.</li>
			<li>Ask the patient to sit on the chair in front of a table with the forearms (except for the elbows) on the table. Ask him to place both hands on top of the head.</li>
			<li>Ask the patient to sit on the chair in front of a table with the forearms on the table. Place a pencil on the table and ask him to touch the pencil. 
			Note: The pencil should be placed at a distance equal to the length of the patient&#39;s upper limb.</li>
			<li>Ask the patient to sit on the chair in front of a table with the forearms on the table. Ask him to pick up the coins next to his hand and to hold them in the same hand. 
			Note: All coins should be placed next to the patient&#39;s hand and picked up successively with one hand.</li>
			<li>Ask the patient to sit on the chair in front of a table with the forearms on the table. Place a CD glued to a piece of cardboard on the table. Ask him to place one finger in the center of the CD and to trace around the edge of the disc with the finger.</li>
			<li>Ask the patient to sit on the chair in front of a table with the forearms on the table. Hold a pencil and a paper on the table. Ask him to pick up the pencil and draw inside the frame.</li>
			<li>Ask the patient to sit on the chair in front of a table with the forearms on the table. Put a sheet of paper in his hands and ask him to tear the paper at least 4 cm.</li>
			<li>Ask the patient to sit on the chair in front of a table with the forearms on the table. Place a tennis ball next to his hand. Ask him to pick up the ball, raise it, and turn the hand.</li>
			<li>Ask the patient to sit on the chair in front of a table with the forearms on the table. Place a diagram with pictures on the table. Ask him to place the finger at the center of the diagram on the word &#8220;start&#8221;, then place the finger on the drawings.</li>
			<li>Ask the patient to sit on the chair with the arms next to his body and the table at a distance equivalent to the length of his forearm. Ask him to place both hands on the table.</li>
			<li>Ask the patient to sit on the chair with both feet on the ground. Ask him to stand up.</li>
			<li>Ask the patient to stand with the upper limbs resting on a piece of equipment for support. Ask him to release the support and stand straight.</li>
			<li>Ask the patient to stand with the upper limbs resting on a piece of equipment for support. Ask him to release the support and raise one foot.</li>
			<li>Ask the patient to stand without support. Ask him to touch the floor with one hand and stand up again.</li>
			<li>Ask the patient to stand and walk 10 steps on his heels.</li>
			<li>Ask the patient to stand without support. Draw a straight line (about 6 m long and 2 cm wide) on the floor, and ask him to walk on the line.</li>
			<li>Ask the patient to stand without support. Ask him to run.</li>
			<li>Ask the patient to stand on one foot without support with the other foot off the ground. Ask him to hop in place.</li>
			<li>Ask the patient to stand without support. Ask him to squat and stand up again.</li>
		</ol>
		</li>
		<li>Calculate the scores.
		<ol>
			<li>Add the scores of all 32 items, divide the sum by 96, and multiply it by 100 to calculate the final score.</li>
			<li>To calculate scores of the subdomains, add the score of all items in that domain and divide it by the maximum score for the domain, then multiply it by 100. 
			Note: All scores must be calculated as percentages.</li>
		</ol>
		</li>
	</ol>
	</li>
	<li>6-minute walk test (6MWT) 
	<ol>
		<li>Task performance
		<ol>
			<li>Let the patient rest for 10 min prior to testing. Demonstrate the walking process.</li>
			<li>Ask the patient to stand at the starting line on the right side of the 0 cone. Give the instructions, &#8220;Ready, set, go&#8221;.</li>
			<li>When saying &#8220;go&#8221;, let the patient start walking around the cones without crossing the middle and, if possible, without slowing down or stopping.</li>
			<li>At 6 min, stop the timer and let the patient stop walking. Count down the final seconds of the test and mark the point at which the patient stopped.</li>
		</ol>
		</li>
		<li>Calculation of the scores
		<ol>
			<li>Record each timepoint at which the patient passes a cone.</li>
			<li>Calculate the total distance by adding a and b, where a is defined as the distance of the final lap (between the last cone rounded until the finishing point at 6 min), and b is defined as the distance in meters prior to the last cone (distance at the time of the last cone rounded).</li>
		</ol>
		</li>
	</ol>
	</li>
	<li>Timed 10-meter walk/run test (10MWT) 
	<ol>
		<li>Task performance
		<ol>
			<li>Ask the patient to stand at the starting line. Stand at the 12-meter mark and give the instructions, &#8220;Ready, set, go&#8221;.</li>
			<li>When saying &#8220;go&#8221;, let the patient start walking/running.</li>
			<li>Measure the time and observe the quality of the walk/run. Stop the timer when the second foot of the patient passes the finish line at 10 m.</li>
			<li>Repeat the test three times, and use the fastest performance to calculate the score.</li>
		</ol>
		</li>
		<li>Calculation of the scores
		<ol>
			<li>Score the patient on a 6-point scale (1-6) based on the quality of the walk/run during the fastest trial. Score 1 if he is not able to walk by himself, and score 2 if he is not able to walk by himself but is able to walk when supported by a knee-ankle-foot orthosis or another person.</li>
			<li>Score 3 if he is not able to increase the walking speed and his gait remains highly adapted and lordotic. Score 4 if he is able to increase the walking speed but not able to run while the gait remains moderately adapted.</li>
			<li>Score 5 if he is almost running but cannot raise his feet from the ground. Score 6 if he is able to run and raise both feet from the ground.</li>
		</ol>
		</li>
	</ol>
	</li>
	<li>Supine-up time
	<ol>
		<li>Task performance
		<ol>
			<li>Ask the patient to lie down on the examination table in supine position. 
			Note: In the case where a mat is necessary, be sure that it is fixed and not slippery.</li>
			<li>Give the instructions, &#8220;Ready, set, go&#8221;. When saying &#8220;go&#8221;, let the patient start standing up as fast as he can.</li>
			<li>Measure the time and observe the quality of the task. Stop the timer when the patient has assumed an upright position with arms by his side. Provide a chair after the patient has attempted to stand from the floor for 30 seconds.</li>
			<li>Repeat the test three times, and use the fastest performance to calculate the score.</li>
		</ol>
		</li>
		<li>Calculation of the scores
		<ol>
			<li>Score the patient on a 6-point scale (1-6). Score 1 if he is not able to stand up from supine position. Score 2 if he is able to stand up from supine position when using a furniture for support.</li>
			<li>Score 3 if he turns over in supine position and needs both hands &#8220;climbing up&#8221; on the legs to reach the standing position. Score 4 if he turns over in supine position and needs one hand on the leg to reach the standing position.</li>
			<li>Score 5 if he turns to the side and uses one or both hands on the ground but not on the leg to reach the standing position. Score 6 if he is able to stand up without turning over or using the hands on the legs.</li>
		</ol>
		</li>
	</ol>
	</li>
</ol>
2. Quantitative Muscle MRI
<ol>
	<li>Perform axial MRI of the thighs including all muscles (flexors, extensor, and adductors) on a 3 Tesla scanner using a 36-channel peripheral angio and spine coil. Perform localizers and slice positioning as previously described11,17.</li>
	<li>Use a three-dimensional (3D) gradient echo sequence with two different echo times for in-phase and opposed-phase imaging [30 slices, repetition time (TR) = 20 ms, echo time 1 (TE1) = 2.45 ms, echo time (TE2) = 3.68 ms, flip angle = 15, acquisition time = 2 min 49 s] and a multi-contrast spin echo with 14 echo times to quantify the transverse relaxation times. Use a field of view of 400 x 400 mm and 384 x 384 matrix to achieve 1 mm in-plane resolution and 3 mm slice thickness.</li>
	<li>Manually draw regions of interest (ROI) on the MR images containing the whole muscle area of flexors, extensors, and adductors of each leg.</li>
	<li>Use the two-point Dixon method and generate relative fat content maps using the pixelwise fat fraction, given f/(f + w), where f = fat images, w = water images17.</li>
	<li>Calculate the T2-relaxation time and mean fat fraction for each muscle group.</li>
</ol>

<ol>
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The authors have nothing to disclose.

Several promising outcome measures have been used in clinical trials in patients with Duchenne muscular dystrophy (DMD). The MFM is a validated and reproducible functional test that involves a detailed examination of crucial motor functions in 32 steps4, while the 6MWT can provide useful information about the patient&#39;s endurance.
All currently validated tests have limitations due to inter- and intra-rater variabilities and all require cooperation of the patient and ...

Outcome measures that reliably reflect treatment response are an essential requirement of successful clinical trials. Due to the rapid development of new therapeutic strategies, stronger effort has been made to define reproducible as well as sensitive methods that monitor clinical outcomes.
Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder and the most common type of muscular dystrophy in children. It is characterized by severe involvement of predominantly the skeletal and heart muscle and a progressive disease course, with loss of ambulation around 8-12 years old and premature death mainly before 30 years old1. Validated tests such as motor function measure and timed function tests are widely accepted as clinical tools for monitoring disease progression, as they assess many aspects of daily life functions. Furthermore, in ambulatory cases, they seem to be more sensitive than quantitative muscle strength measures, which cannot be appropriately performed in weak and non-cooperative patients2,3.
The motor function measure (MFM) assesses functions of the neck, trunk, arm, and leg muscles and abilities such as standing, transferring, and walking. It can even be performed in patients who have lost ambulation, as it reflects three dimensions of motor performance4. The MFM (validated for patients aged 6-60 years with DMD) was evaluated based on the MFM User&#39;s Manual5. It includes 32 items and is divided into three subdomains: D1 (assessment of standing and transfer), D2 (assessment of axial and proximal motor function), and D3 (assessment of distal motor function). All items are scored on a 4-point scale (0-3). The test is validated in neuromuscular disorders and can sufficiently monitor changes in muscle function and predict loss of ambulation. Moreover, it agrees with clinical changes perceived by the treating physicians and patients with DMD6,7. Timed function tests are also commonly used as outcome measures, though they are mainly performed in ambulatory patients. Among these, the 6-minute walk test (6MWT) has received special attention since it shows the highest test-retest reliability, predicts clinical decline and loss of ambulation, and correlates more accurately with muscle function measures compared to quantitative muscle strength measures8,9. The test measures the maximal walking distance of a patient in 6 minutes10. It is guided by two trained professionals, a &#34;follower&#34; who walks 1-2 meters behind the patient, and an &#34;evaluator&#34; who records the time. Other timed function tests have lower test-retest reliability and do not reflect endurance, an important marker of ambulatory function8,9,10,11. These tests include the timed 10-meter run/walk test (10MWT), which measures the best performance of walking/running for a 10-meter distance, and the supine-up time, which measures the ability to stand up from supine position2. The use of the motor function measure and timed function tests as primary and secondary endpoints in clinical trials is justified; however, a major limitation is that none are independent of patient collaboration and the skills of the evaluator.
Quantitative MRI (QMRI) is an objective method to visualize well-described morphological abnormalities of the musculature including edema, muscle degeneration, and increased content of adipose and connective tissue12. The use of MRI as a diagnostic tool in neuromuscular disorders has already been established, but its role in monitoring disease progression and treatment response is still limited to clinical trials. T2-relaxation time is known to be increased in muscle dystrophies due to muscle damage, edema, fatty replacement, and inflammation, and further information about muscle fat content can be extracted through calculation of the mean fat fraction (FF). QMRI has been shown to be a promising biomarker, as measurements have correlated with clinical outcome and disease progression, while a mean fat fraction of 50% predicted loss of ambulation13,14. Moreover, QMRI has been able to detect subclinical changes in patients with stable or even improved outcome measures15,16. QMRI data of extensors muscles has also shown to be meaningful regarding its correlation with clinical outcomes17. QMRI is a non-invasive and sensitive method; nevertheless, its cost and the possibility of reduced compliance in younger children may limit its use.
The reliability of functional tests and QMRI has been previously shown in Becker&#39;s muscular dystrophy18. The aim of this cross-sectional study was to highlight sensitive clinical and radiological outcome measures in ambulant children with DMD, as the need for standardized and disease-specific assessments is increasing in the era of clinical trials in neuromuscular disorders.

<table><tbody><tr><td>Physiotherapy mat</td><td>&amp;nbsp;-&amp;nbsp;</td><td>&amp;nbsp;-&amp;nbsp;</td><td>should not be slippery; alternatively use a wide examination table</td></tr><tr><td>Cushions</td><td>&amp;nbsp;-&amp;nbsp;</td><td>&amp;nbsp;-&amp;nbsp;</td><td>&amp;nbsp;-&amp;nbsp;</td></tr><tr><td>Table&amp;nbsp;</td><td>&amp;nbsp;-&amp;nbsp;</td><td>&amp;nbsp;-&amp;nbsp;</td><td>with adjustable height; it should allow the patient to rest forearms while seated and elbows flexed at 90&amp;deg;</td></tr><tr><td>Chair</td><td>&amp;nbsp;-&amp;nbsp;</td><td>&amp;nbsp;-&amp;nbsp;</td><td>with adjustable height if possible; it should allow the patient to touch the floor with the feet while seated with the hips and knees flexed at 90&amp;deg;</td></tr><tr><td>Stopwatch</td><td>&amp;nbsp;-&amp;nbsp;</td><td>&amp;nbsp;-&amp;nbsp;</td><td>&amp;nbsp;-&amp;nbsp;</td></tr><tr><td>CD or CD-ROM glued onto a piece of cardboard</td><td>&amp;nbsp;-&amp;nbsp;</td><td>&amp;nbsp;-&amp;nbsp;</td><td>&amp;nbsp;-&amp;nbsp;</td></tr><tr><td>10 coins&amp;nbsp;</td><td>&amp;nbsp;-&amp;nbsp;</td><td>&amp;nbsp;-&amp;nbsp;</td><td>dimensions: 20 mm wide and 2 mm thick (10 euro cents or equivalent)</td></tr><tr><td>Lead pencil</td><td>&amp;nbsp;-&amp;nbsp;</td><td>&amp;nbsp;-&amp;nbsp;</td><td>&amp;nbsp;-&amp;nbsp;</td></tr><tr><td>Tennis ball</td><td>&amp;nbsp;-&amp;nbsp;</td><td>&amp;nbsp;-&amp;nbsp;</td><td>&amp;nbsp;-&amp;nbsp;</td></tr><tr><td>Sheets of A4 paper or equivalent&amp;nbsp;</td><td>&amp;nbsp;-&amp;nbsp;</td><td>&amp;nbsp;-&amp;nbsp;</td><td>weight: 70-80g</td></tr><tr><td>Clipboard</td><td>&amp;nbsp;-&amp;nbsp;</td><td>&amp;nbsp;-&amp;nbsp;</td><td>&amp;nbsp;-&amp;nbsp;</td></tr><tr><td>Two small traffic cones&amp;nbsp;</td><td>&amp;nbsp;-&amp;nbsp;</td><td>&amp;nbsp;-&amp;nbsp;</td><td>&amp;nbsp;-&amp;nbsp;</td></tr><tr><td>Tape&amp;nbsp;</td><td>&amp;nbsp;-&amp;nbsp;</td><td>&amp;nbsp;-&amp;nbsp;</td><td>for marking arrows and stop&amp;nbsp;&amp;nbsp;</td></tr><tr><td>Line traced on the floor</td><td>&amp;nbsp;-&amp;nbsp;</td><td>&amp;nbsp;-&amp;nbsp;</td><td>2 centimeters wide and 6 meters long</td></tr><tr><td>Corridor</td><td>&amp;nbsp;-&amp;nbsp;</td><td>&amp;nbsp;-&amp;nbsp;</td><td>indoor, straight, up to 30 meters long&amp;nbsp;</td></tr></tbody></table>

measurements of motor function and other clinical outcome parameters in ambulant children with duchenne muscular dystrophy

While the number of new treatment options tested in patients with Duchenne muscular dystrophy (DMD) is increasing, there is still no defining of the most reliable assessments regarding therapeutic efficacy. We present clinical and radiological outcome measures used in ambulatory patients participating in our trial &#34;Treatment with L-citrulline and metformin in Duchenne muscular dystrophy&#34;. The motor function measure is a validated test in patients with neuromuscular disorders that consists of 32 items and assesses all three dimensions of motor performance including standing and transfer (D1 subscore), axial and proximal motor function (D2 subscore), and distal motor function (D3 subscore). The test shows high intra- and inter-rater variability but only when strictly following guidelines of the materials, examination steps, and calculation of scores. The 6-minute walk test, timed 10-meter walk/run test, and supine-up time are commonly used timed functional tests that also sufficiently monitor changes in muscle function; however, they strongly depend on patient collaboration. Quantitative MRI is an objective and sensitive biomarker to detect subclinical changes, though the examination costs may be a reason for its limited use. In this study, a high correlation between all clinical assessments and quantitative MRI scans was found. The combinational use of these methods provides a better understanding about disease progression; however, longitudinal studies are needed to validate their reliability.

Baseline data of 47 ambulatory male patients (aged 6.5 to 10.8 years) with DMD were analyzed. All patients participated previously in the &#34;Treatment with L-citrulline and metformin in Duchenne muscular dystrophy&#34; study. Patients were enrolled from the University Children&#39;s Hospital Basel and from the patient registries of Switzerland, Germany, and Austria. Except for one patient, who refused to take part in the scanning, MRI of all thigh muscles was performed...

Watch this Scientific Journal Video about Measurements of Motor Function and Other Clinical Outcome Parameters in Ambulant Children with Duchenne Muscular Dystrophy at JoVE.com

Measurements of Motor Function and Other Clinical Outcome Parameters in Ambulant Children with Duchenne Muscular Dystrophy

The aim of this study is to present the most reliable clinical outcome measures and their correlations with quantitative muscle MRI in ambulant patients with Duchenne muscular dystrophy.

While the number of new treatment options tested in patients with Duchenne muscular dystrophy (DMD) is increasing, there is still no defining of the most ...

measurements-motor-function-other-clinical-outcome-parameters

Research

JoVE Journal

Medicine

10.3K Views.  University of Basel. Deze methode kan helpen bij het beantwoorden van belangrijke vragen met betrekking tot behandelingsrespons en klinische daling overuren in klinische studies voor patiënten met Duchenne Spierdystrofie. De belangrijkste voordelen van deze techniek zijn de lagere afhankelijkheid van de naleving van de patiënt, en geschiktheid voor zowel ambulante als nonambulante patiënten. Het aantonen van de procedure zal Christine Seppi, een opgeleide fysiotherapeut voor motorische functie maatregel van de...

Video: Measurements of Motor Function and Other Clinical Outcome Parameters in Ambulant Children with Duchenne Muscular Dystrophy

Methods to Quantify Pharmacologically Induced Alterations in Motor Function in Human Incomplete SCI

Spinal cord injury (SCI) is a debilitating disorder, which produces profound deficits in volitional motor control. Following medical stabilization, recovery from SCI typically involves long term rehabilitation. While recovery of walking ability is a primary goal in many patients early after injury, those with a motor incomplete SCI, indicating partial preservation of volitional control, may have the sufficient residual descending pathways necessary to attain this goal. However, despite physical interventions, motor impairments including weakness, and the manifestation of abnormal involuntary reflex activity, called spasticity or spasms, are thought to contribute to reduced walking recovery. Doctrinaire thought suggests that remediation of this abnormal motor reflexes associated with SCI will produce functional benefits to the patient. For example, physicians and therapists will provide specific pharmacological or physical interventions directed towards reducing spasticity or spasms, although there continues to be little empirical data suggesting that these strategies improve walking ability.
In the past few decades, accumulating data has suggested that specific neuromodulatory agents, including agents which mimic or facilitate the actions of the monoamines, including serotonin (5HT) and norepinephrine (NE), can initiate or augment walking behaviors in animal models of SCI. Interestingly, many of these agents, particularly 5HTergic agonists, can markedly increase spinal excitability, which in turn also increases reflex activity in these animals. Counterintuitive to traditional theories of recovery following human SCI, the empirical evidence from basic science experiments suggest that this reflex hyper excitability and generation of locomotor behaviors are driven in parallel by neuromodulatory inputs (5HT) and may be necessary for functional recovery following SCI. 
The application of this novel concept derived from basic scientific studies to promote recovery following human SCI would appear to be seamless, although the direct translation of the findings can be extremely challenging. Specifically, in the animal models, an implanted catheter facilitates delivery of very specific 5HT agonist compounds directly onto the spinal circuitry. The translation of this technique to humans is hindered by the lack of specific surgical techniques or available pharmacological agents directed towards 5HT receptor subtypes that are safe and effective for human clinical trials. However, oral administration of commonly available 5HTergic agents, such as selective serotonin reuptake inhibitors (SSRIs), may be a viable option to increase central 5HT concentrations in order to facilitate walking recovery in humans. Systematic quantification of how these SSRIs modulate human motor behaviors following SCI, with a specific focus on strength, reflexes, and the recovery of walking ability, are missing.
This video demonstration is a progressive attempt to systematically and quantitatively assess the modulation of reflex activity, volitional strength and ambulation following the acute oral administration of an SSRI in human SCI. Agents are applied on single days to assess the immediate effects on motor function in this patient population, with long-term studies involving repeated drug administration combined with intensive physical interventions.

This video demonstrates modulation of reflex activity, volitional strength and ambulation through clinical and quantitative assessments in individuals with motor incomplete SCI as a result of acute oral administration of a serotonin reuptake inhibitor (SSRI).

Spinal cord injury (SCI) is a debilitating disorder, which produces profound deficits in volitional motor control. Following medical stabilization, ...

Assessing Functional Performance in the Mdx Mouse Model

Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder for which no cure is available. Nevertheless, several potential pharmaceutical compounds and gene therapy approaches have progressed into clinical trials. With improvement in muscle function being the most important end point in these trials, a lot of emphasis has been placed on setting up reliable, reproducible, and easy to perform functional tests to pre clinically assess muscle function, strength, condition, and coordination in the mdx mouse model for DMD. Both invasive and noninvasive tests are available. Tests that do not exacerbate the disease can be used to determine the natural history of the disease and the effects of therapeutic interventions (e.g. forelimb grip strength test, two different hanging tests using either a wire or a grid and rotarod running). Alternatively, forced treadmill running can be used to enhance disease progression and/or assess protective effects of therapeutic interventions on disease pathology. We here describe how to perform these most commonly used functional tests in a reliable and reproducible manner. Using these protocols based on standard operating procedures enables comparison of data between different laboratories.

Assessing Functional Performance in the Mdx Mouse Model

The primary outcome measure in clinical trials for neuromuscular disorders is generally improved muscle function. Therefore, assessing the effect of potential therapeutic compounds on muscle performance pre clinically in mouse models is of great importance. We here describe several functional tests to address this.

Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder for which no cure is available. Nevertheless, several potential ...

Behavior

Behavioral and Locomotor Measurements Using an Open Field Activity Monitoring System for Skeletal Muscle Diseases

The open field activity monitoring system comprehensively assesses locomotor and behavioral activity levels of mice. It is a useful tool for assessing locomotive impairment in animal models of neuromuscular disease and efficacy of therapeutic drugs that may improve locomotion and/or muscle function. The open field activity measurement provides a different measure than muscle strength, which is commonly assessed by grip strength measurements. It can also show how drugs may affect other body systems as well when used with additional outcome measures. In addition, measures such as total distance traveled mirror the 6 min walk test, a clinical trial outcome measure. However, open field activity monitoring is also associated with significant challenges: Open field activity measurements vary according to animal strain, age, sex, and circadian rhythm. In addition, room temperature, humidity, lighting, noise, and even odor can affect assessment outcomes. Overall, this manuscript provides a well-tested and standardized open field activity SOP for preclinical trials in animal models of neuromuscular diseases. We provide a discussion of important considerations, typical results, data analysis, and detail the strengths and weaknesses of open field testing. In addition, we provide recommendations for optimal study design when using open field activity in a preclinical trial.

Open field activity levels are used to assess locomotive and behavioral activity levels. This protocol provides a well-designed, standardized protocol to use in preclinical trials for neuromuscular disorders.

The open field activity monitoring system comprehensively assesses locomotor and behavioral activity levels of mice. It is a useful tool for assessing ...

A Simple and Low-cost Assay for Measuring Ambulation in Mouse Models of Muscular Dystrophy

Measuring functional outcomes in the treatment of muscular dystrophy is an essential aspect of preclinical testing. The assessment of voluntary ambulation in mouse models is a non-invasive and reproducible activity assay that is directly analogous to measures of patient ambulation such as the 6-minute walk test and related mobility scores. Many common methods for testing mouse ambulation speed and distance are based on the open field test, where an animal&#39;s free movement within an arena is measured over time. One major downside to this approach is that commercial software and equipment for high-resolution motion tracking is expensive and may require transferring mice to specialized facilities for testing. Here, we describe a low-cost, video-based system for measuring mouse ambulation that utilizes free and open-source software. Using this protocol, we demonstrate that voluntary ambulation in the dystrophin-null mdx mouse model for Duchenne muscular dystrophy (DMD) is decreased relative to wild-type mouse activity. In mdx mice expressing the utrophin transgene, these activity deficits are not observed and the total distance traveled is indistinguishable from wild-type mice. This method is effective for measuring changes in voluntary ambulation associated with dystrophic pathology, and provides a versatile platform that can be readily adapted to diverse research settings.

This protocol describes a flexible, low-cost system for measuring mouse ambulation in an open field activity assay. We show that a 6-minute ambulation assay based on this system detects a decrease in voluntary movement in mdx mice, and accurately distinguishes improvement in a muscle-specific rescue of these animals.

Measuring functional outcomes in the treatment of muscular dystrophy is an essential aspect of preclinical testing. The assessment of voluntary ambulation ...

An Objective and Child-friendly Assessment of Arm Function by Using a 3-D Sensor

Progressive and irreversible muscle atrophy characterizes Spinal Muscular Atrophy (SMA) and other similar muscle disorder diseases. Objective assessment of muscle functions is an essential and important, although challenging, prerequisite for successful clinical trials. Current clinical rating scales restrain the movement abnormalities to certain predefined coarse-grained individual items. The Kinect 3-D sensor has emerged as a low-cost and portable motion sensing technology used to capture and track people&#39;s movement in many medical and research fields. A novel approach using this 3-D sensor was developed and a game-like test was designed to objectively measure the upper limb function of patients with SMA. The prototype test targeted joint movement capability. While sitting in a virtual scene, the patient was instructed to extend, flex, and lift the whole arm in order to reach and place some objects. Both kinematic and spatiotemporal characteristics of upper limb movement were extracted and analyzed, e.g., elbow extension and flexion angles, hand velocity, and acceleration. The first study included a small cohort of 18 ambulant SMA patients and 19 age- and gender-matched healthy controls. A comprehensive analysis of arm movement was achieved; however, no significant difference between the groups were found due to the mismatch of patient&#39;s capability and the test difficulty. Based on this experience, a second version of the test consisting of a modified version of the first game with increased difficulties and a second game targeting muscle endurance were designed and implemented. The new test has not been conducted in any patient groups yet. Our work has demonstrated the potential capability of the 3-D sensor in assessing such muscle function and suggested an objective approach to complement the clinical rating scales.

An objective measure of muscle functions is challenging especially in children. Based on a commercially available digital 3-D sensor, a child-friendly gaming test was developed to assess upper limb function for clinical trials.

Progressive and irreversible muscle atrophy characterizes Spinal Muscular Atrophy (SMA) and other similar muscle disorder diseases. Objective assessment ...

Integrating VR and Biosensors for Quantitative Motion-Muscle Activity Assessment

Setup for the Quantitative Assessment of Motion and Muscle Activity During a Virtual Modified Box and Block Test

The ability to move allows us to interact with the world. When this ability is impaired, it can significantly reduce one's quality of life and independence and may lead to complications. The importance of remote patient evaluation and rehabilitation has recently grown due to limited access to in-person services. For example, the COVID-19 pandemic unexpectedly resulted in strict regulations, reducing access to non-emergent healthcare services. Additionally, remote care offers an opportunity to address healthcare disparities in rural, underserved, and low-income areas where access to services remains limited. 
Improving accessibility through remote care options would limit the number of hospital or specialist visits and render routine care more affordable. Finally, the use of readily available commercial consumer electronics for at-home care can enhance patient outcomes due to improved quantitative observation of symptoms, treatment efficacy, and therapy dosage. While remote care is a promising means to address these issues, there is a crucial need to quantitatively characterize motor impairment for such applications. The following protocol seeks to address this knowledge gap to enable clinicians and researchers to obtain high-resolution data on complex movement and underlying muscle activity. The ultimate goal is to develop a protocol for remote administration of functional clinical tests. 
Here, participants were instructed to perform a medically-inspired Box and Block task (BBT), which is frequently used to assess hand function. This task requires subjects to transport standardized cubes between two compartments separated by a barrier. We implemented a modified BBT in virtual reality to demonstrate the potential of developing remote assessment protocols. Muscle activation was captured for each subject using surface electromyography. This protocol allowed for the acquisition of high-quality data to better characterize movement impairment in a detailed and quantitative manner. Ultimately, these data have the potential to be used to develop protocols for virtual rehabilitation and remote patient monitoring.

Author Spotlight: Enhancing Remote Rehabilitation with Virtual Reality and Electromyography

The protocol described here aims to enhance the quantitative evaluation of upper limb deficits, with the goal of developing additional technology for remote assessment both in the clinic and at home. Virtual reality and biosensor technologies are combined with standard clinical techniques to provide insights into the functioning of the neuromuscular system.

The ability to move allows us to interact with the world. When this ability is impaired, it can significantly reduce one's quality of life and ...

Engineering

A Battery of Motor Tests in a Neonatal Mouse Model of Cerebral Palsy

As the sheer number of transgenic mice strains grow and rodent models of pediatric disease increase, there is an expanding need for a comprehensive, standardized battery of neonatal mouse motor tests. These tests can validate injury or disease models, determine treatment efficacy and/or assess motor behaviors in new transgenic strains. This paper presents a series of neonatal motor tests to evaluate general motor function, including ambulation, hindlimb foot angle, surface righting, negative geotaxis, front- and hindlimb suspension, grasping reflex, four limb grip strength and cliff aversion. Mice between the ages of post-natal day 2 to 14 can be used. In addition, these tests can be used for a wide range of neurological and neuromuscular pathologies, including cerebral palsy, hypoxic-ischemic encephalopathy, traumatic brain injury, spinal cord injury, neurodegenerative diseases, and neuromuscular disorders. These tests can also be used to determine the effects of pharmacological agents, as well as other types of therapeutic interventions. In this paper, motor deficits were evaluated in a novel neonatal mouse model of cerebral palsy that combines hypoxia, ischemia and inflammation. Forty-eight hours after injury, five tests out of the nine showed significant motor deficits: ambulation, hindlimb angle, hindlimb suspension, four limb grip strength, and grasping reflex. These tests revealed weakness in the hindlimbs, as well as fine motor skills such as grasping, which are similar to the motor deficits seen in human cerebral palsy patients.

Presented is a concise battery of mouse neonatal motor tests. Using these tests, neonatal motor deficits can be demonstrated in a variety of neonatal motor disorders. By having a standardized set of tests, results from different studies can be compared, allowing for better and accurate reporting between groups.

As the sheer number of transgenic mice strains grow and rodent models of pediatric disease increase, there is an expanding need for a comprehensive, ...

Home-Based Monitor for Gait and Activity Analysis

Current outcomes in neuromuscular disorder clinical trials include motor function scales, timed tests, and strength measures performed by trained clinical evaluators. These measures are slightly subjective and are performed during a visit to a clinic or hospital and constitute therefore a point assessment. Point assessments can be influenced by daily patient condition or factors such as fatigue, motivation, and intercurrent illness. To enable home-based monitoring of gait and activity, a wearable magneto-inertial sensor (WMIS) has been developed. This device is a movement monitor composed of two very light watch-like sensors and a docking station. Each sensor contains a tri-axial accelerometer, gyroscope, magnetometer, and a barometer that record linear acceleration, angular velocity, the magnetic field of the movement in all directions, and barometric altitude, respectively. The sensors can be worn on the wrist, ankle, or wheelchair to record the subject&#8217;s movements during the day. The docking station enables data uploading and recharging of sensor batteries during the night. Data are analyzed using proprietary algorithms to compute parameters representative of the type and intensity of the performed movement. This WMIS can record a set of digital biomarkers, including cumulative variables, such as total number of meters walked, and descriptive gait variables, such as the percentage of the most rapid or longest stride that represents the top performance of patient over a predefined period of time.

This innovative device uses magneto-inertial sensors to permit gait and activity analysis in uncontrolled environments. Currently in the qualification process as an outcome measure in the European Medical Agency, one of the applications will be to serve as a clinical endpoint in clinical trials in neuromuscular diseases.

Current outcomes in neuromuscular disorder clinical trials include motor function scales, timed tests, and strength measures performed by trained clinical ...

Bioengineering

Isometric and Eccentric Force Generation Assessment of Skeletal Muscles Isolated from Murine Models of Muscular Dystrophies

Critical to the evaluation of potential therapeutics for muscular disease are sensitive and reproducible physiological assessments of muscle function. Because many pre-clinical trials rely on mouse models for these diseases, isolated muscle function has become one of the standards for Go/NoGo decisions in moving drug candidates forward into patients. We will demonstrate the preparation of the extensor digitorum longus (EDL) and diaphragm muscles for functional testing, which are the predominant muscles utilized for these studies. The EDL muscle geometry is ideal for isolated muscle preparations, with two easily accessible tendons, and a small size that can be supported by superfusion in a bath. The diaphragm exhibits profound progressive pathology in dystrophic animals, and can serve as a platform for evaluating many potential therapies countering fibrosis, and promoting myofiber stability. Protocols for routine testing, including isometric and eccentric contractions, will be shown. Isometric force provides assessment of strength, and eccentric contractions help to evaluate sarcolemma stability, which is disrupted in many types of muscular dystrophies. Comparisons of the expected results between muscles from wildtype and dystrophic muscles will also be provided. These measures can complement morphological and biochemical measurements of tissue homeostasis, as well as whole animal assessments of muscle function.

Muscle function measurements contribute to the evaluation of potential therapeutics for muscle pathology, as well as to the determination of mechanisms underlying physiology of this tissue. We will demonstrate the preparation of the extensor digitorum longus and diaphragm muscles for functional testing. Protocols for isometric and eccentric contractions will be shown, as well as differences in results between dystrophic muscles, representing a pathological state, and wildtype muscles.

Critical to the evaluation of potential  therapeutics for muscular disease are sensitive and reproducible physiological  assessments of muscle function. ...

Biology

Quantified Assessment of Infant's Gross Motor Abilities Using a Multisensor Wearable

Developing objective and quantitative methods of early gross motor assessment is essential to better understand neurodevelopment and to support early therapeutic interventions. Here, we&#160;present&#160;a method to quantify gross motor performance using a multisensor wearable, MAIJU (Motility Assessment of Infants with a JUmpsuit), which offers an automated, scalable,&#160;quantitative, and objective assessment using&#160;a fully automated cloud-based pipeline. This wearable suit is equipped with four movement sensors that record synchronized data to a mobile phone utilizing a low-energy Bluetooth connection. An offline analysis in the cloud server generates fully analyzed results within minutes for each recording. These results include a graphical report of the recording session and a detailed result matrix that gives second-by-second classifications for posture, movement, infant carrying, and free playtime. Our recent results show the virtue of such&#160;quantified motor assessment&#160;providing&#160;a potentially&#160;effective method for distinguishing variations in the infant&#39;s gross motor development.

This paper outlines the assessment of infants' gross motor performance with a multisensor wearable and its fully automated deep learning-based analysis pipeline. The method quantifies the posture and movement patterns of infants from lying supine until they master walking independently.

Developing objective and quantitative methods of early gross motor assessment is essential to better understand neurodevelopment and to support early ...

Measurements of Motor Function and Other Clinical Outcome Parameters in Ambulant Children with Duchenne Muscular Dystrophy

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