Neuromuscular model for MND: Quantifying the effect of motor neuron disease on neural and non-neural properties of the lower limbs

Motor Neuron Disease (MND) is a group of terminal neurodegenerative disease,
leading to progressive loss of motor function. Treatment of MNDs such as
Amyotrophic Lateral Sclerosis (ALS), progressive muscular atrophy (PMA) and
primary lateral sclerosis (PLS), remains an unresolved challenge despite
intensive research into diagnosis, prognosis and therapy. New therapeutics, and
the quality of care after diagnosis can be enhanced by early, more personalized
diagnosis at individual patient level, enabling tailored care and
individualized treatment.
To personalize the diagnosis, there is a need for reliable quantitative
biomarkers, for early detection of disease onset and to distinguish the
different sub-types of the disease with different symptoms and progression
rates. Several quantitative biomarkers have been investigated for use in MND,
including Motor Unit Number Estimation (MUNE), Motor Unit Number Index (MUNIX),
Cortical Excitability in Transcranial Magnetic Stimulation (TMS),
electromyography (EMG) Inter-muscular Coherence, Magnetic Resonance (MR) and
other imaging techniques, and EEG signatures. However, these biomarkers cannot
appropriately identify the complex interplay of neuromuscular factors
contributing to motor dysfunction in individuals. To examine these factors, a
proper quantification of motor and sensory factors and their behavior during
systematic manipulation of task conditions is required. This study will apply
parameter estimation paradigms to a non-linear neuromuscular model of the human
wrist from measurements of EMG, force and motion. The estimated parameters are
expected to function as a set of novel neuromuscular biomarkers, beyond what is
currently attainable from clinical neurological examination and other
quantitative measurement techniques in MND.

The proposed study is significant from several neurological perspectives:
- it aims to enhance the qualitative measures of disease progression with
quantitative measures
- it recognises the heterogeneity of the disease by assessing a set of
neuromuscular biomarkers to quantify the different dimensions of the disease;
- and it is based on neuro-electric activity measures that are non-invasive and
can be employed inexpensively with patients participating in clinical
trials.

The key objective of the study is to assess the validity of a quantitative
uniform examination technique for estimating physiological properties in MND
patients, to better examine the neuromuscular properties from which defective
motor behavior originates, both at a group level and at the individual level.
Therefore, we would like to measure the neuromuscular properties of patients,
controls and asymptomatic carriers with the use of a wrist manipulator. In
doing so, our aim is to advance understanding of MND pathology and identify
novel, inexpensively measured biomarkers that can distinguish MND patients
based on neural and non-neural properties. Such biomarkers have applications in
disease prognostics and measurements of therapeutic activity of
neurotherapeutic candidates. Successful discrimination between neuromuscular
properties can be used to diagnose MND, which may also be useful for better
patient care and for the development of novel neuro-motor rehabilitation.

Prospective observational study, cross-sectional design.

The MND community is in great need of a technique that allows patient wide
uniform assessment of high resolution quantitative biomarkers of factors
contributing to MND symptoms. This protocol will align with current clinical
practice and therefore will not interfere in clinical decision making.
The protocol uses additional measurements of motor function, through the use of
a single-axis haptic robot (Wristalyzer; MOOG FCS, Nieuw Vennep, the
Netherlands) for very accurate assessment of wrist movements. The measurements
will be performed during visiting days of the *Imaging in MND* study (METC
protocol number 11-552). No follow-up visits are required for any of the
subjects.
Measurements are non-invasive and bear minimal risks. Active participation of
the subjects is required, though tasks will mostly involve submaximal efforts
and small movements. The measurement protocol takes around 45 minutes, but
patients are offered extra rest periods if necessary.
The Wristalyzer is safeguarded by hard- and software bounds, which are adapted
to each individual. In addition, task intensities are adapted to strength level
of each patient to ensure that the range of movement does not exceed 3 degrees
from the neutral wrist position.