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Mathematical models of muscle force are modified with a Riccati-Bass equation to yield better predictive results in paralyzed human soleus. Fresh and fatigued muscle forces are compared to ascertain the predictive power of such a modification.

Mathematical models of muscle force are modified with a Riccati-Bass equation to yield better predictive results in paralyzed human soleus. Fresh and fatigued muscle forces are compared to ascertain the predictive power of such a modification.

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MUSCLE

M.J. Conaway, Ph.D.

Introduction

Spinal cord injury (SCI) causes many adverse health consequences including paralysis

and muscle atrophy. Rehabilitative limb integrity maintenance strategies are designed to

facilitate optimal care while a cure for paralysis is found. These electrotherapeutic limb

stimulation strategies are based in part on mathematical models of muscle force development.

The models of Ding and colleagues (4-12) succeeded in predicting force responses to

electrical stimulus inputs with frequencies up to 5 pulses per second (pps) in intact and paralyzed

quadriceps muscles. However, the models failed to predict force responses to inputs with

frequencies greater than 5 pps. This is clinically important since most standard

electrotherapeutic protocols prescribe inputs with stimulation frequencies greater than 5 pps. (15)

The Ding model assumed a constant nonlinear summation of divalent calcium (Ca2+)

currents in single muscle fibers in response to extrinsic electrical stimulation. We hypothesize

that the summation of divalent calcium currents from individual muscle fibers is nonlinear and

time-varying throughout a contraction, which in turn leads to time-varying force generated by a

paralyzed muscle in response to an extrinsic input stimulus. The hypothesis was tested by

modifying the Ding model by making the nonlinear summation a function of the frequency of the

input stimulus. Our model describes the hypothesized nonlinear dynamics of calcium recruitment

with a variant of the time-varying Riccati-Bass function. Using unconstrained optimization, the

augmented model was validated and tested by comparing the force of contraction predicted by

the model to the force of contraction measured by stimulating trained and untrained soleus

muscle in paralyzed subjects.

Methods

Human subjects

We collected force profiles in the Clinical Measurement Laboratory at The University of Iowa

Hospitals and Clinics (UIHC). Subjects with spinal cord injury (SCI) and paralysis qualified for

the study if they have had complete paralysis at the level of T12 or above for at least 1.5 years.

Two of the investigators (RKS, LFL) work extensively with SCI subjects and have assisted in the

identification of the subjects from the laboratory. Subjects of either sex and any race were

considered for enrollment; however four Caucasian male subjects were used. Only subjects

greater than 18 years of age were enrolled. These subjects had no other known medical

conditions.

The subjects were recruited by personal contact, telephone, or mail by physical therapy staff after

a review of records to determine their time after injury. Each subject was asked to fill out a

questionnaire that identifies demographics and injury history. Informed consent was obtained

from each subject. The risks of the study were outlined in the consent form.

The Institutional Review Board of The University of Iowa approved the experimental protocol.

Subject confidentiality was strictly honored. The subjects have not been identified by name in

publications or presentations at scientific sessions.

Subject

17

18

27

28

Age (yr)

33.5

23.8

25.1

23.0

Gender

M

M

M

M

Height (cm)

180

185

188

188

Weight (kg)

111

68

77

68

American Spinal Cord Injury Association

Force Measurement

SCI* Level

T9

T10

T4

T4

ASIA Scale

A

A

A

A

Years Injured

4.24

1.51

2.73

1.68

We measured the plantar flexion torque with a subject in the seated position with the knee and

ankle at 90o. Adjustability of a heel cup, force transducer, and axis of rotation allowed the force

transducer (AWU-250, Genisco Technology) to be positioned under the first metatarsal head. The

foot plate axis of rotation was aligned with the anatomic axis of the ankle. Stabilization of the

heel to the foot plate during torque production was provided by a rigid ankle cuff directing three

vectors of force through the calcaneus via turnbuckles. A double strap secured over the femur

provided additional stabilization of the heel in the foot plate assembly during plantar flexion. A

schematic of the torque measurement system has been previously shown in the literature (14).

Calibration of the torque measurement system was done with known loads. The calibration

yielded a linear regression equation with an r2correlation value of 0.99. The force transducer was

electronically coupled to a multichannel recorder.

Stimulus Instrumentation

Two silver-silver chloride electrodes (8 mm in diameter, with an inter-electrode distance of

20mm) recorded soleus compound muscle action potential activity to verify supramaximal

activation. Each electrode contained an on-site pre-amplifier with a gain of 36. The signal was

further amplified by a GCS 67 amplifier (Therapeutics Unlimited, Iowa City, IA, USA) with

adjustable gain from 500 to 10,000. The amplifier utilized a high impedance circuit (greater than

15 M at 100 Hz), with a common mode rejection ratio of 87 dB at 60 Hz and a bandwidth of

40-4000 pulses per second.

A custom-designed constant current stimulator and isolation unit was used to provide the

stimulus. The stimulator had a current range from 0 to 200 mA with current variations of less

than 5%, and a maximum voltage capability of 400 V. The stimulator was triggered by digital

pulses from a data-acquisition board (Metrabyte DAS 16F, Keithley Instruments Inc., Cleveland,

OH, USA) housed in a microcomputer under custom software control. The stimulation intensity

was supramaximal, which is approximately 50% greater than the intensity required to produce a

maximum compound muscle action potential. Stimulation inputs were delivered via a doublepronged stimulation electrode secured over the tibia nerve with the use of a gel pad that adhered

to the back of the leg.

Data collection procedures

The skin over the soleus muscle was scrubbed with alcohol, and an electrode was applied 2 cm

lateral to the muscle midline at one-third the distance from the lateral malleolus to the fibular

head. After visual inspection of the M-waves, the electrode was slightly repositioned as needed

in order to accentuate the biphasic waveform. Each subject had the right foot placed in the torque

measuring device and secured as previously described. The test position minimized the

contribution of the gastrocnemius to the plantar flexor torque.

The stimulus electrode was driven with pulse sequences generated by the custom-made constantcurrent stimulator using 250 sec pulse widths. The placement of the electrode was optimized to

produce the largest soleus M-wave peak-to-peak amplitude. Stimulation intensities were then

increased to approximately 1.5 times greater than required for a maximum M-wave to ensure

supramaximal stimulation throughout the protocol.

The force generated by the stimuli, the EMG, and the stimulation trigger signals were

simultaneously recorded and later analyzed using MATLAB 7.0 software (The Mathworks,

Natick, MA). All data were digitized at 1000 samples per second.

Following the work of Frey-Law and Shields (14), we began the stimulation protocol with a

series of 1 pps twitches to determine the optimal electrode placement and ensure supramaximal

levels of activation. We then gave five warm-up contractions, 7-pulse trains (20 pps trains, 330

msec on: 670 msec off) applied at 1 train/sec, to ensure the soleus muscle was in a more

potentiated state, but without inducing fatigue. Following the warm-up, we then administered a

pre-programmed number of stimulation trains with four inputs of each different input waveform.

The set of input waveforms consisted of the following: a twitch, a 5 pps input with no doublet (5

CT), 5 pps inputs with beginning (5 DT) and center doublets (5 DDT), a 10 pps input (10 CT),

followed by another 10 pps input with a beginning doublet (10 DT),an additional 10 pps input

with a dual doublet (10 DDT),a doublet ramp of 15 pulses (DR),and a 20 pps input (20

CT).Some of these pulse trains are shown in Figure 1.

only the 10 pps series and the doublet ramp used for parameter

determination for each model.

The doublet ramp was comprised of a range of frequencies (5, 7.5, 10, 15, and 20 pps,

with 167 pps doublets) over a duration of less than 1500 milliseconds. This unique waveform

provides on average equal time at all stimulation frequencies to ameliorate the bias from any

specific frequency (14).

Because there was a full data set available exclusively for Subject 18, that data set was used for

the first part of this study. However, doublet ramp data were available for Subjects 17, 18, 27,

28. Those data were used in the second part of this study.

Mathematical Model Formulation

The model developed by Ding et al. (4-12) proposed that thedynamicisometricforcesare

governedbyEqs.13.Thismodeldescribesthetransientbehaviorofthetwostatevariables,

musclestimulation.Thestatevariable

theisometricforceproducedby

behavesasaMichaelisMentenprocess.(23)

Thevariablesaregovernedbythefreeparametersc,A,

timeconstantthatmodulatesCN.Theparameter

,1,and2.Theparametercisthe

due to the absence of strongly bound cross-bridges,and2isthetime constant of decline in force

due to the extra friction between actin and myosin resulting from the presence of cross-bridges.

TheparameterAisthescaledgain.

22\* MERGEFORMAT ()

33\* MERGEFORMAT ()

44\* MERGEFORMAT ()

Equation 1 represents the time-varying change in developed force as a function of the

time-varying calcium-troponin binding throughout a contraction. Equation 2 represents the

global summation of nonlinear activation of individual muscle fibers in response to an input

train. Equation 3 represents the dynamics of calcium-troponin binding, captured in the unitless

variable

and modulated by the time constant c, which qualitatively describes the rate-

limiting step before the actin and myosin mechanically translate across each other and generate

force. (12)

Ding and colleagues (5) decomposed the contractile response to account for the distinct

physiological step of cross-bridge activation. To model cross-bridge activation, it was shown that

the force-prediction ability of the model is relatively insensitive to the specic curvature and

amplitude of the calcium and calcium-troponin complex transient. This implied that the first two

steps in the 1997 model (4) could be combined into one by the unitless variable CN. From the

following differential equation, the dynamics of CN are modulated by the time constant, c, which

describes qualitative the rate-limiting step before the actin and myosin mechanically translate

across each other and generate force. (5)

To account for the nonlinear summation of calcium transients in single muscle bers

stimulated with doublets, Ding et al (6) proposed the R-model in Eq. 3, which was based on the

earlier work of Duchateau and Hainaut (13) who investigated the force summation from human

adductor pollicis muscles triggered by paired stimuli at different interpulse intervals (IPIs)

ranging from 5 ms to 200 ms. The results showed that the forces generated by the doublet trains

were greater than the sum of two individual twitches. Furthermore, the force enhancement from

the second pulse was highest when the IPI was 5 ms and declined exponentially with increases of

the IPI. The enhanced force of the paired stimuli was suggested to be due to the enhanced release

of divalent calcium by the second pulse (13). In the R-model, a factor Ri was introduced to

account for the nonlinear summation. (6) Ding et al. modied the two-step model by adding a

factor where

is a scaling term that accounts for the differences in the degree of activation by

each pulse relative to the rst pulse of the train (6). The magnitude of the enhancement is

characterized by a scalar

Although the Ding model accurately predicted isometric force for gastrocnemius and

soleus muscles during brief trains of stimulation, it failed to predict force from long-train

stimulations. When the muscle was stimulated with long trains, the model overestimated the

higher frequency force output for both fast-contracting gastrocnemius and slow-contracting

soleus and underestimated the lower frequency force response for soleus muscle (5). One of the

limitations of this model is that it does not account for parameters that vary with time. It was

suggested that better curve tting and predictions of the data from long trains may require the

model to vary several parameters during the contraction (5), Modeling the forces from the long

train stimulation patterns was beyond the scope of this particular study Thus, however, the

changes to the model that are necessary to predict the force generated under long train

stimulation were not quantitatively explored. Furthermore, the original model cannot predict

forces during non-isometric contractions because the force-velocity and length-tension

relationships were not factored into the formulation. Finally, Ding and colleagues suggest that

the model be modied if it is to predict the response of any muscle during fatigue-inducing

repetitive activations. (5) However, they demonstrated that the parameter relationships found for

intact muscle did not apply to paralyzed muscle. (6)

Dingandcolleagues(5,6)hypothesizedthatthemodelwouldaccuratelypredictforce

responsetolongtrainstimulationforpatientswithspinalcordinjury.Thehypothesiswastested

overawiderangeofinputfrequenciesandstimulationpatternsinthenonfatiguedstateusing

datacollectedfromparalyzedhumanquadricepsfemorismuscles.Itwasfoundthatthe

predictionsfromtheforcemodelexplainedmorethan90%andofthevarianceofthecollected

forceprofiles.Hence,themodelwasshowntohavesuccessfullycalculatedrelationships

betweenforceandfrequencyfornonfatiguedmusclestothreevarietiesofinputtrains.

In the Ding models (5, 6), the parameter R0 is treated as a scalar parameter. Yet, it is

defined as a quantitative measure of the nonlinear summation of the Ca2+ from preceding pulses.

In addition to the empirical derivation, the construct of the definition is in itself mathematically

inconsistent. Hence, to transform the parameter to make it congruent with the physiological

reality of equilibrating chemical reactions that occur within a contacting muscle, we extended the

model by modeling R0 with a form of the Riccati-Bass differential equation dF/dt=(p-qF)(1-F).

(2). By including Eq. 5 in our augmented model, we were able to correct this inconsistency and

extend the model, thereby allowing for nonlinearity in the calcium concentration during extrinsic

stimulation.

55\* MERGEFORMAT ()

The time-dependent Riccati-Bass type differential equation (2) describes the manner in which

extra calcium in the sarcomere, elicited from extrinsic stimulation, behaves between pulses. The

differential equation must be negative to model the change in calcium-troponin binding from

subsequent pulses in a stimulus train as a decaying process.

Therefore, using Eq. 5, nonlinearity to the second order may be examined for the

autocatalytic process of periodic calcium release in fresh muscle contraction, especially when

there is no force decay from fatigue. A more accurate estimate of the initial

to calculate Ri and, ultimately, rate-limiting CN during later stages of force generation at higher

stimulate on frequencies and in response to special pulse forms such as doublets. The numerical

values of the model coefficients were determined by parameter estimation. For our study, initial

parameter values were taken from Frey Law and Shields (14) as well as from Bass (2).

Model Validation

Table 2 contains the parameter sets for the Ding and Experimental muscle force models.

For each model, the subset of free parameters, as well as the subset of fixed parameters with

initial values, is given.

Our model of muscle force was validated using an input of 5 pulses per second with a

beginning doublet (5 DT). In addition, the model is shown to be robust using various inputs in

untrained and trained muscles in different subjects. The various inputs are:

Twitch

Doublet ramp

10 pps with beginning doublet (10 DT)

20 pps with no doublet (20 CT)

Table 2 Initial values of parameter sets for force models under unconstrained optimization. Free

parameters were estimated by Levenburg-Marquardt unconstrained optimization.

Model

Ding

Experimental

Fixed parameters

with initial values

c=20 ms

R0=6.9

c=20 ms

Free parameters

A, km, 1, 2

km, 1, 2, 1, 2

A is scaled

Differences in mean squared error and correlation between experimental data and

predictions from the original Ding model and our modified model were determined for various

inputs and training states. We used the Levenburg-Marquardt unconstrained optimization

algorithm to estimate model parameters. Model agreement with the data was calculated by

minimizing the residual difference between the force predicted from the results of the nonlinear

ordinary differential equation grey-box model and the force measured from test subjects (with

unknown parameters (idnlgrey). In this study, agreement is defined as how well a particular

model traces a force plot taken from a paralyzed human muscle. To estimate agreement, we used

a third-order estimator with three initial states and, for unconstrained optimization, six free

parameters.

In addition To quantify the difference, we used paired t-tests and two-way analysis of variance

without replication in this study. We used paired t-tests to compare average mean square error and

average correlation coefficient in Ding and Experimental model structures. Two-way We used the

two-way ANOVA without replication investigated sources of error between training status and differences

between subjects as well as differences in model predictive ability across different inputs. All statistics

have been done in Excel 2007 (Microsoft, Redmond, WA). The level of significance was set at 0.05.

Results

Validation and testing of our model

Our model of muscle force was validated using an input of 5 pulses per second with a beginning

doublet (5 DT). In addition, the model is shown to be robust using various inputs in untrained

and trained muscles in different subjects. Unconstrained optimization on the six free parameters

is used throughout this study to calculate agreement between model and data.

Human Data

3

2.5

Model/Subject/Trainin

2

g

1.5

Experimental 18

trained

1

Mean

Squared

Error

0.02486

4

Mean

Absolute

Error

0.00984

4

Correlatio

n

Coefficient

0.764018

95% CI

r2

p-value

(0.6612320.866804

)

0.58372

4

<0.000

1

0.5

0

Figure

2.Validation

of

Experimental

force

model

with

5 pps

train with

0

100

200

300

400

500

600

700

800

900

Time (ms)

beginning doublet in trained

muscle in Subject 18.The model had

To investigate

robustness

using

realistic

initial parameter values (c=20, 1=28.3, 2=62.7,

76.4%

agreement

with

the data.

km=0.06, 1=0.38, 2=0.5), our force model was run with various inputs.

The model was run first with a twitch input in the trained muscle of Subject 18.

Human Data

Model/Subject/Trainin

g

Experimental 18

trained

Mean

Squared

Error

0.02101

9

Mean

Absolute

Error

0.00556

3

Correlatio

n

Coefficient

0.923751

95% CI

r2

p-value

(0.9195780.927925

)

0.85331

6

<0.000

1

model had 92.4% agreement with the data.

The model was then run with a doublet ramp input in the trained limb of Subject 17.

Human Data

Model fit: 66.3%

4

3.5

3

Force

response

(N)

2.5

2

1.5

1

0.5

0

0

Model/Subject/Training

Experimental 17

trained

1.8

200

400

600

Time (ms)

800

Mean

Mean

Correlatio

Squared

Absolute

n

Error

Error

Coefficient

0.2627 0.071286 0.66334

83

53response. (sim)

7

Force

95% CI

r2

p-value

(0.64215

3

0.70022

1)

0.4400

29

<0.0001

1.6

e response (N)

Figure

4.Doublet ramp in trained muscle in Subject 17. The model had

1.4

66.3% agreement with the data.

1.2

1

0.6

0.4

0.2

0

0

20

40

60

80

100 120

Time (ms)

140

160

180

200

The model was then run with a 10 DT input in the untrained limb of Subject 18.

Force response. (sim)

Human Data

Model fit: 49.28%

5

4.5

4

3.5

3

2.5

2

1.5

1

0.5

0

200

Model/Training/Input

Experimental

untrained 10 DT

400

Mean

Squared

Error

0.21256

9

600

800

Time (ms)

Mean

Absolute

Error

0.103256

1000

Correlatio

n

Coefficient

0.49276

1200

95% CI

r2

p-value

(0.39156

0.59781)

0.24281

<0.000

1

unconstrained model had 49.28% agreement with the data.

The model was then run with a 20 CT input in the untrained muscle of Subject 18.

Force response. (sim)

Human Data

Model fit: 84.38%

4

Force

3

response

(N)

0

0

100

200

300

400

500

Time (ms)

600

700

Model/Training/Inpu

t

Mean Squared

Error

Mean Absolute

Error

Correlation

Coefficient

95% CI

r2

p-value

Experimental

untrained 20 DT

0.101846

0.0502358

0.843761

(0.7523

8

0.93714

)

0.71193

3

<0.000

1

It is thus shown

force model

is robust

inputs across training states.

modelthat

hadour

84.38%

agreement

with for

the different

data.

Using unconstrained optimization on the six free parameters shows that the agreements between

data and model range approximately from 49.3 to 92.4 percent.

Using unconstrained optimization parameter values, various statistics have been

calculated. Differences in mean squared error and correlation with respect to the experimental

data have been compared between the two force models for various inputs.

Table 3. Average prediction measures across inputs with frequencies greater than 5 pulses per

second and training status from both models in unconstrained optimization in Subject 18.

95% CI

r2

p-value

(0.8068250.889838

)

0.71966

5

<0.000

1

0.868417

(0.814411

0.922424)

0.75414

9

<0.000

1

0.239113

0.370379

(0.320528

0.418183)

0.13718

<0.000

1

0.34596

6

0.208889

0.531295

(0.489438

0.570709)

0.28227

4

<0.000

1

Ding

untrained 10 DT

Experimental

untrained 10 DT

Ding

untrained 10 DDT

0.28267

0.138498

0.715163

0.511458

0.21256

9

0.441139

0.103256

0.849276

(0.675599

0.750619)

(0.826456 0.86931)

0.305584

0.450897

(0.408164

0.491659)

0.72126

9

0.20330

8

<0.000

1

<0.000

1

<0.000

1

Experimental

untrained 10 DDT

0.36855

9

0.202462

0.498218

(0.457791

0.536589)

0.24822

1

<0.000

1

Ding

untrained 20 CT

0.28267

0.138498

0.715163

(0.675599

0.750619)

0.511458

<0.000

1

Experimental

untrained 20 CT

0.21267

3

0.103256

0.849276

(0.826456 0.86931)

0.72226

1

<0.000

1

Ding

untrained 20 DT

0.18044

6

0.0880614

0.867647

(0.848684

0.884382)

0.752811

<0.000

1

Experimental

0.10184

0.0502358

0.96142

(0.955573

0.92432

<0.000

Model/Training/Input

Ding

trained 10 CT

Mean

Squared

Error

0.01687

2

Mean

Absolute

Error

0.01583

Correlatio

n

Coefficient

0.848331

Experimental

trained 10 CT

0.12140

5

0.015871

Ding

untrained 10 CT

0.38907

2

Experimental

untrained 10 CT

untrained 20 DT

Ding

trained 20 DDT

0.27153

9

0.155377

Experimental

trained 20 DDT

0.20427

2

0.120135

0.966511)

0.757612

(0.722992

0.788436)

0.57397

6

<0.000

1

0.874776

(0.855515

0.891619)

0.76522

2

<0.000

1

10 DT=10 pps with beginning doublet

10 DDT=10 pps with dual doublet

20 CT=20 pps continuous train

20 DT=20 pps with beginning doublet

20 DDT=20 pps with dual doublet

Table 4. Comparison of average mean square error and average correlation coefficient in Ding

and Experimental model structures under unconstrained optimization with input frequencies

greater than 5 pulses per second.

Model

Structure

Average Mean

Squared Error

(95% CI)

Ding

0.266344

0.27228

0.223899

0.199028

Experimental

Average

Correlation

Coefficient

(95% CI)

0.556248

0.579553

0.776097

0.358257

From the 95% confidence intervals of the means for both metrics from each model, it is

seen that our model structure has less average mean squared error and greater correlation than

the Ding model structure of muscle force across different inputs and subjects. Furthermore, a

two-sided paired t-test with six degrees of freedom for the average mean squared error at =0.05

yields t=-5,19888. That is significantly less than the critical value t=2.446912. For the

correlation coefficient, a two-sided paired t-test with six degrees of freedom at =0.05 yields t=2.67107. That is considerably less than the critical value t=2.446912.

Table 5.Average prediction measures for doublet ramp inputs across training states from both

models in unconstrained optimization in all Subjects.

Model/Subject/Training

Ding 17

trained

Mean

Squared

Error

0.2594

69

Mean

Absolute

Error

0.071415

1

Correlatio

n

Coefficient

0.70922

3

Experimental 17

trained

0.2627

83

0.071286

53

0.66334

7

Ding 18

trained

0.5029

97

0.123568

0.83168

6

Experimental18

trained

0.1608

62

0.051936

3

0.84793

2

Ding 18

untrained

0.3180

82

0.198839

0.56072

9

Experimental 18

untrained

0.1920

51

0.066694

1

0.78784

9

Ding 27

trained (w/ noise)

0.5137

29

0.280128

0.03512

27

Experimental 27

trained (w/ noise)

0.5097

8

0.280446

0.02879

45

95% CI

r2

p-value

(0.68190

5

0.73456

5)

(0.64215

3

0.70022

1)

(0.81462

5

0.84730

9)

(0.83234

4

0.86218)

0.5029

97

<0.0001

0.4400

29

<0.0001

0.6917

02

<0.0001

0.7189

89

<0.0001

(0.52335

1

0.59595

4)

(0.76691

1

0.80711

2)

(0.01781

3

0.08786

27)

(0.02414

0.3144

17

<0.0001

0.6207

07

<0.0001

0.0012

33

0.1933

77

0.0008

29

0.2863

33

Ding 28

trained

0.2367

06

0.161284

0.82262

2

Experimental 28

trained

0.2441

11

0.160966

0.79552

8

Ding 28

untrained

0.1351

37

0.048723

8

0.90484

5

Experimental 28

untrained

0.1332

02

0.047086

1

0.91725

9

5

0.08157

34)

(0.80474

0.83901

2)

(0.77525

2

0.81416

6)

(0.89498

4

0.91382

3)

(0.90862

2

0.92511

2)

0.6767

06

<0.0001

0.76522

2

<0.0001

0.8187

45

<0.0001

0.8413

65

<0.0001

Table 6. Comparison of average mean square error and average correlation coefficient in Ding

and Experimental model structures under unconstrained optimization for doublet ramp inputs.

Model

Structure

Average Mean

Squared Error

(95% CI)

Ding

0.327687

0.15195

0.250465

0.136109

Experimental

Average

Correlation

Coefficient

(95% CI)

0.644038

0.321587

0.673452

0.326668

From the 95% confidence intervals of the means for both metrics from each model, it is

seen that our model structure has less average mean squared error and greater correlation than

the Ding model structure of muscle force across different subjects as well as training status when

using the doublet ramp input stimulus. Furthermore, a two-sided paired t-test with five degrees

of freedom for the average mean squared error at =0.05 yields t=-2.24589. That is significantly

less than the critical value t=2.57082. For the correlation coefficient, a two-sided paired t-test

with five degrees of freedom at =0.05 yields t=-1.79335. That is considerably less than the

critical value t=2.57082. Hence, the hypothesis that the summation of force from individual

muscle fibers is nonlinear and time-varying throughout a contraction could not be rejected.

Table 7. Two factor analysis of variance without replication for mean squared error between

Ding and Experimental force models for inputs greater than 5 pulses per second using

unconstrained optimization.

Source

of

Variatio

n

Model

SS

Error

0.16468

0.00630

6

0.01297

9

Total

0.18396

4

Training

df

6

1

6

MS

0.02744

7

0.00630

6

0.00216

3

F

12.6879

7

2.91496

7

P-value

0.00348

4

0.13863

F crit

4.28386

6

5.98737

8

13

Table 8.Two factor analysis of variance without replication for mean squared error between Ding

and Experimental force models for doublet ramp inputs using unconstrained optimization.

Source

of

Variatio

n

Subject

Training

SS

0.15944

9

Error

0.01789

0.04862

3

Total

0.22596

2

df

MS

5

0.03189

0.01789

0.00972

5

F

3.27929

1

1.83962

6

P-value

0.10918

9

0.23302

5

F crit

5.05032

9

6.60789

1

11

Conclusion

This study provides the first systematic evaluation of a model that includes calcium

dynamics for predicting force in electrically stimulated, chronically paralyzed human muscle.

The major finding of this study is that, by including a Riccati-Bass diffusion function (2) for R0in

modeling force, the structure of our model predicts force with greater agreement and with less

mean squared error than the Ding model using unconstrained optimization. This is highly

significant significantly. Hence, the specific aim of this study has been successfully answered.

Our force model structure is the first to incorporate Riccati-Bass diffusion functions (2) to

characterize the calcium dynamics in force summation from individual muscle fibers. These

functions are used for making predictions of the continuation of ongoing diffusion processes. In

this study, the problem is one of parameter estimation for specific diffusion function coefficients

at the beginning of actual physiologic processes and then making predictions about the future

behavior of the processes by optimizing the estimated functions at different points in time. (16)

Furthermore, the two influences on the calcium diffusion process are distinguished as probability

of binding and probability of dissociation. (15) These phenomena are reflected by 1 and 2 in

our model. The external influence comes from the extrinsic stimulation, which releases more

free calcium, applied to the muscle that causes calcium to move. Internal influence is a function

of the relevant structures and ions in the sarcoplasmic reticulum, namely calcium channels and

free calcium, which are thought to behave according to specific aggregate probabilities in

different states.

However, upon model optimization, the respective strengths of these two influences are

unequal, with the second parameter always being greater than the first. In fresh muscle, the

affinity for calcium and troponin to dissociate after the first pulse during a stimulated contraction

was always greater than the affinity for calcium and troponin to bind after the first pulse during a

stimulated contraction. It has been shown that the quality of a functional state is a vital factor

that underlies such differences. (16) In fact, an implicit assumption of many muscle farce-

fatigue models is the assumption that diffusion occurs homogeneously, or that the tendency

towards binding or activation remains constant throughout a contraction. (15) The diffusion

processes are functions of time-varying inputs, and hence, the models are exponentially

modulated. However, the processes must also be considered with respect to structural

heterogeneity of a muscle membrane. Hence, the question of whether the assumed mathematical

distribution of free divalent calcium actually modulates the modeled force must be posed.

ThevariableR0hasthefollowingphysiologicalrationale.Repetitivestimulationof

muscleselicitscontractionsthatsummatenonlinearly,especiallywhentensionsaturatesatthe

highfrequencytetaniclevel.Theforcefrequencycurveunderisometricconditionsisgenerally

sigmoidal.Thisindicatesanadditionalnonlinearityatlowfrequencies.Ithasalsobeenfound

thattheforcefromtwocloselyspacedstimulicouldbesignificantlylargerandmoreprolonged

comparedtoatwitch.Atlowfrequenciesthatgeneratetwitcheswithoutfusion,staircase

phenomenainbothmathematicaldirectionshavebeenobserved.Thisimpliesafacilitationor

depressionoftheforceprofilesfromsuccessiveinputs,aswellasposttetanicpotentiationof

twitches.Thelengthtensionandforcevelocitycurvesofmuscleshowotherwellknown

nonlinearities.Finally,smallmagnitudenonlinearitieshavebeenrecordedthatareassociated

withthebendingofmyofilamentbondsuntilfracture.(22)

SteinandParmiggiani(22)foundtwophasesofnonlinearsummationunderawiderange

ofconditionsinfastandslowtwitchmammalianmuscles.Earlydepressionorlessthanlinear

summationoccurswhenasecondcontractionissuperimposedontherisingphaseofatwitch,

andaphaseoffacilitationormorethanlinearsummationisseenlaterinthetimecourseofthe

twitch.Thetwophasescouldbedifferentaspectsofthesamebasicphenomenonsincetheearly

depressionbecomesmoreprominentwithrepetitivestimulationasthelaterfacilitationbecomes

lesspronounced.Yet,theybelievedthatthetwotypesofnonlinearitiesarisefromdistinct

mechanismsforseveralreasons.First,laterfacilitationwasstillpresentwithtimeintervals

greaterthanthecontractiontimeofthemusclesthatwerestudied.Meanwhile,earlydepression

wastotallyeliminated.

Withrespecttowholemuscleactivation(Ri),SteinandParmaggiani(22)additionally

foundthattheincreasingdepressionwithadditionalpulsesandvariationofthedepressionwith

thetwitchtotetanusratiounderavarietyoftestconditionsweretotallyconsistentwiththe

initialdepressionduetoasaturatingprocessinamuscle.Fromexperimentsonamphibian

muscleatlowtemperatures,itwashypothesizedthatamuscleismaximallyactivatedfora

prolongedtimeperiod.Thisisdenotedastheplateauoftheactivestate.Thisplateauoccludes

forcegenerationsincealaterinputcouldnotgenerateanyextraforceunlesstheactivestate

decreasedbelowitsplateaulevel.Nevertheless,itisgenerallyacceptedthatmammalianmuscles

atnormaltemperaturesarenotatmaximalactivationfromasingleinput.However,ifasecond

pulseissuperimposedontheriseofatwitch,alessthanlinearsummationofgeneratedforce

initiallyoccurs.Thisisknownasdepression.(22)Asthetwitchpeaks,thisearlydepression

transitionstoasubsequentmorethanlinearsummation.Thisisknownasfacilitation.Several

possiblemechanismshavebeenproposedforthefacilitationofforcegenerationfromsubsequent

inputs.(21)

ParmaggianiandStein(21)foundthatthefacilitationofthetensionproducedbya

subsequentpulsedecayedinexponentiallyasafunctionoftheinterpulseinterval,regardlessof

howfacilitationwasmeasured.Incomparingfastandslowtwitchmuscles,thetimecourseof

thefacilitationdependedonmusclecontractiontime.Thus,itwasconcludedthatthesame

processesthatmodulatetwitchcontractiontimealsolikelymodulatetensionfacilitationduetoa

subsequentpulse.However,tensionfacilitationisremarkablydifferentforlaterpulsesinatrain.

Whilethefacilitationduetoasecondpulsedecreasesexponentiallywiththeinterpulseinterval,

theoptimalintervalforthirdpulsefacilitationisgreaterthan100msinslowtwitchmuscles.

Comparingfastandslowmuscles,theoptimalinterpulseintervalwasfoundtobecloselyrelated

tothedurationofcontraction,andwasshowntorangefrom1.26to1.5timesthedurationofthe

twitchinthefastandslowmusclesinvestigated.Hence,thissuggestedagainarelationship

betweenthemechanismsthatmodulatedurationofcontractionandthosethatgoverntension

facilitation.Nevertheless,ParmiggianiandStein(21)envisionedaprogressivesaturation,instead

ofsuddenocclusion,asadditionaldivalentcalciumreleasedbysuccessivestimulioccupymore

andmoreofthesitesontroponin.

The biophysical interpretation of the mathematics of calcium diffusion

in muscle (

there will be a specific instant in time when the state converges to a limit of

stability. The amount transformed from the aggregate CaTr in a specific

time unit depends on the characteristic of the species-specific limit, and on

the number of perturbations in the state of the aggregate. (17, 19, 23) It is

known that in a system in which consecutive reactions occur in the presence

of a product of autocatalysis, essential conditions exist that allow oscillating

processes with damping, especially in the case of two consecutive reaction of

global system. (18-20) In the case of extrinsic contraction of a paralyzed

muscle, the autocatalytic calcium-troponin formation and dissociation

reactions are thought to lag each other hysteretically in a bistable state. (23)

Therefore, by the Principle of Le Chatelier (1, 19, 20, 23), it is assumed that

CaTr formation or dissociation is a function of the free calcium available in

the sarcoplasm during a contraction.

We hypothesized that the structure of our force model yields a more robust model of

muscle force generation, with respect to different inputs, than does the structure of the Ding force

model. Using the 95% confidence intervals of the means for mean squared error and correlation

coefficients from each model, our model structure performs markedly better than the Ding model

structure at force prediction such that the confidence intervals do not overlap. Furthermore,

Table 7 shows that two-factor analysis of variance for Ding and Experimental force models

shows that the difference in model structure accounts for over 89% of the variation in the mean

squared error. Additionally, Table 8 shows that two factor analysis of variance without replication

for mean squared error between Ding and Experimental force models for doublet ramp inputs

accounts for about 71% of the variation. Hence, these statistics imply that that including a

variant of the Riccati-Bass equation in models of muscle force, even under unconstrained

optimization, makes a vast improvement in the predictive ability of the Hill-Huxley nonlinear

muscle model, for a group of inputs used on one subject as well as for a single input used on a

group of subjects, because specific biochemical processes that occur during a contraction are

accounted for in a manner that is more realistic physiologically.

greater correlation and less mean squared error with respect to the paralyzed human soleus data

than does the Ding model, then that suggests that the structure of our model is a more accurate

predictor of force than is the structure of the Ding model. Specifically, such findings imply that

the structure of our model is more physiologically plausible in predicting muscle force in

electrically stimulated paralyzed human soleus. (3)

We conclude, therefore, that including a variant of the Riccati-Bass differential equation

in models of muscle force makes a vast improvement in the predictive ability of the Hill-Huxley

nonlinear muscle model of Ding because the summation of force generated from individual

muscle fibers are assumed to be nonlinear and time-varying throughout a contraction. Such an

addition improves the predictive ability of the original Ding model. More generally, the

fundamental question to be considered is whether expansion-contraction can approximate

curvilinear motion when the former is far more rapid in one direction or a small angle than in

others. Since the expansion-contraction equations and their solutions are analytic and closedform, finding theorems for these approximations could simplify the study of physiologic

processes. (3)

Because the Riccati-Bass equation generates sigmoidal diffusion functions (2), we argue

from the literature that many clinically germane physiological processes exhibit similar

behavior. Furthermore, it is at best inappropriate to assume that physiologic processes behave as

scalar elements since biochemical reactions occur in all directions in a volume. Thus, including

the fundamental construct of the diffusion function in physiological systems theory by extending

this powerful equation to different clinical problems and associated models is of great societal

importance and urgency. Better assessments will lead to optimal therapeutics. Therapeutics that

better enable function will decrease health care costs and increase the societal contributions

made by these individuals. In the modern economy, every bit of savings is exponentially helpful.

ACKNOWLEDGEMENT

The project described was supported by Award Number R01NR010285 from the National

Institute of Nursing Research. The content is solely the responsibility of the authors and does not

necessarily represent the official views of the National Institute of Nursing Research or the

National Institutes of Health.

APPENDIX: List of parameters for muscle force models.

Symbol

Unit

CN

Definition

Value

Varies

Mechanical force

Varies

ti

ms

Varies

Varies

N

tp

ms

Varies

tq

ms

Varies

ms

20

N/ms

Scaling factor

Varies

ms

strongly bound cross-bridges

28.3

ms

friction between actin and myosin resulting from

the presence of cross-bridges

62.7

to the change in calcium current

0.06

after the first pulse during a stimulated

contraction

0.38

km

ms-1

ms-1

dissociate after the first pulse during

a stimulated contraction

0.5

REFERENCES

1.

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Bass FM.A new product growth model for consumer durables.MgmtSci, 1969;15(5):215227.

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fatigue in paralyzed human soleus. [dissertation]. Iowa City (IA): The University of

Iowa; 2010.

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Ding J, Wexler AS, Binder-Macleod SA. A mathematical model that predicts skeletal

muscle force. IEEE Trans Biomed Eng, 1997; 44(5): 337-48.

6.

Ding J, Binder-Macleod SA, and Wexler AS. Two-step, predictive, isometric force model

tested on data from human and rat muscles. J ApplPhysiol, 1998; 85: 2176-89.

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Ding J, Wexler AS, and Binder-Macleod SA. Development of a mathematical model that

predicts optimal muscle activation patterns by using brief trains. J ApplPhysiol, 2000; 88:

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Ding J, Wexler AS, Binder-Macleod SA. A predictive fatigue model--I: Predicting the

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Ding J, Wexler AS, Binder-Macleod SA. A mathematical model that predicts the forcefrequency relationship of human skeletal muscle. Muscle Nerve. 2002 Oct;26(4):477-85.

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Ding J, Wexler AS, Binder-Macleod SA. Mathematical models for fatigue minimization

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