Simulation of CMT1A, CIDP, CIDP Subtypes, GBS, MMN and ALS
Recently, nerve excitability properties (such as threshold
electrotonus, strength-duration time constants, rheobasic currents,
recovery cycles) have been measured in healthy subjects and patients
with demyelinating neuropathies (CMT1A, CIDP, GBS, MMN) and
neuronopathies such as ALS (Bostock et al. 1995, Mogyoros et al.
1998, Cappelen-Smith et al. 2001, Kuwagara et al. 2002, 2003, Nodera
et al. 2004, Sung et al. 2004), using the noninvasive technique of
threshold tracking. Similarly, in the last ten years, we have simulated
progressively greater degrees of mild systematic (ISDs, PSDs, PISDs
– 20, 50, 70, 80%), mild focal (IFD, PFD, PIFD – 70%), severe systematic
(ISD – 93%, PSD – 90%, PISD – 82%) and severe focal (IFD, PFD,
PIFD – 96%) demyelinations for human motor nerve fi bres. We
have also investigated and discussed their multiple excitability
properties (such as action, electrotonic and extracellular potentials,
strength-duration time constants, rheobasic currents, and recovery
cycles) (Stephanova and Daskalova 2005a,b, 2008, Stephanova and
Alexandrov 2006, Stephanova et al. 2005, 2006a,b, 2007a,b, 2011a,b,
Krustev et al. 2010, Stephanova 2010). These studies confi rm that
the transition from conduction slowing (mild demyelinations) to
conduction block (severe demyelinations) of action potential leads
Chapter III
Simulated Demyelinating
Neuropathies and
Neuronopathies
34 Computational Neuroscience: Simulated Demyelinating Neuropathies and Neuronopathies
to amplifi cation of the degree of excitability property changes,
as the direction of these changes is maintained. The studies also
confi rm that the mild ISDs, PSDs and PISDs are specifi c indicators
for CMT1A, CIDP and CIDP subtypes, respectively, whereas the
severe IFD and PFD, PIFD are specifi c indicators for GBS and
MMN, respectively.
Three progressively greater degrees of ALS motor neuron
disease were observed by Bostock et al. (1995), comparing threshold
electrotonus responses to 100 ms polarizing current stimuli,
recorded from patients and normal controls. Following the above
authors’ axonal ion channel dysfunction suggestions, we have
mathematically simulated, investigated and discussed these three
ALS subtypes (Daskalova and Stephanova 2001, Stephanova and
Daskalova 2002, Stephanova 2006, 2010).
Using our multi-layered model of human motor nerve fi bre,
without taking into account the myelin sheath aqueous layers,
simulations of normal case, mild systematic and severe focal
demyelinations each of them internodal, paranodal and paranodal
internodal are given below. Demyelinations that were investigated
are associated with a corresponding loss of myelin end bulbs and
myelin lamellae away from the axolemma (Fig. 4). The characteristic
parameter values defi ning the simulated cases are given in Table
1. A 70% reduction value is not suffi cient to develop a conduction
block of action potential in the systematically demyelinated cases.
Such demyelinations are regarded as mild. A 96% reduction value is
the fi rst degree of the focally demyelinated subtypes for achieving
the conduction block in a single internode. Such demyelinations are
regarded as severe.
Table 1. Membrane parameter values characteristic for human motor nerve fi bres
in the normal and demyelinated cases, when demyelinations are mild (70%) and
severe (96%), respectively. N (number of myelin lamellae); R
my
(myelin resistance);
C
my
(myelin capacitance); R
pn
(paranodal seal resistance).
NR
my
[MΩ]C
my
[pF] R
pn
[MΩ]
Normal 150 250 1.5 125
ISD 70% 45 75 5 125
PSD 70% 150 250 1.5 37.5
PISD 70% 45 75 5 37.5
IFD 96% 6 10 37.5 125
PFD 96% 150 250 1.5 5
PIFD 96% 6 10 37.5 5
We have also simulated cases of uniform nodal and internodal
axonal dysfunctions termed ALS1, ALS2 and ALS3. Their
characteristic parameter values are given in Table 2.
The mild systematic and severe focal demyelinations presented
here are regarded as simulated hereditary (CMT1A), chronic
(CIDP, CIDP subtypes) and acquired (GBS, MMN) demyelinating
neuropathies, whereas the ALS subtypes presented here are
regarded as simulated ALS motor neuron disease. The results
Fig. 4. Schematic diagram of human motor nerve fi bres from the 7th to the 14th
nodes in the normal, systematically and focally demyelinated cases. The reduction
of the myelin lamellae (defi ning internodal systematic demyelination, ISD), or
of the paranodal seal resistance (defi ning paranodal systematic demyelination,
PSD), or simultaneously both of them (defi ning paranodal internodal systematic
demyelination, PISD) is uniform along the fi bre length. Reduction of the same
myelin parameters is restricted to only three (8th, 9th and 10th) consecutive
internodes for the internodal focal demyelination (IFD), paranodal focal
demyelination (PFD) and paranodal internodal focal demyelination (PIFD),
respectively (from Stephanova and Daskalova 2008).
Simulated Demyelinating Neuropathies and Neuronopathies 35

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