Determining the Refraction
the model to better implement medical devices.
Time Constant from a Neural
Membrane
James Ingram
Introduction
Nerve stimulation is critical to the role of many
medical devices used to sustain or improve
quality of life. These electronics such as
pacemakers, cochlear implants, Transcutaneous
Electrical Nerve Stimulation (TENS), operate
using a small stimulus applied to a target area. In
a pacemaker, electrode leads are placed in the
atrial and ventricular channels for determining
the timing of cardiac depolarization. If the
depolarization does not match expected
parameters, the pacemaker can inhibit, trigger,
or pace in a neighboring chamber. Nerve
stimulation of the cardiac muscle begins in the
sinoatrial (SA) node, which proceeds to a rapid
potential across the His-Purkinje System (HPS).
While devices such as pacemakers have received
thorough research for optimization, there are
emerging medical devices which have yet to
undergo such scrutiny. The original pacemakers
would undergo replacements quite often due to
the power output being used to stimulate the
heart. Having run more tests, engineers and
researchers found longer duration between
stimulus pulses requires less output to generate
an action potential [1]. Implantable pacemakers
begin production and testing in 1958, while
external pacemakers date 1950; both before the
Hodgkin-Huxley (HH) model of neuron
propagation.
The HH model has become a standard
consideration for modern medical devices which
rely on nerve stimulation [2]. The model
produces information on lipid bilayer current in
addition to ion channels. Through Ohm’s law, it
is possible to derive the potentials of tissue
given their known impedance values as well.
Further relationships have been developed from
Knowing that a neuron enters a refractory
period, a larger stimulus is required to induce an
action potential. This relation described in Fig. 3
[1], showing the threshold voltage exponentially
decreasing with pulse width. Creating a new
stimulus medical device requires the derivation
of a model that best fits the biological interest.
Using measured data points, the creation of a
model to represent and predict neuron
stimulation should be feasible.
Methods
Initial Parameters
A simulation of the HH model (HH Sim) was
imported into MATLAB R2019a software,
compiled, and used to collect datapoints for
analysis, no neuron properties were changed
from initial loading. The equation;
𝑅𝑇 = 𝐴/ 𝐵 − 𝑒 /
where RT is the refractory threshold
𝜏 is the refractory time constant
IPI is the interpulse interval
and A and B are unknown constants
describes the expected relationship of threshold
stimulus required to induce action potential
during the refractory period.
Having loaded the simulation, channels {m, h,
n} were changed to {Na_Leak, K_Leak,
I_Leak} measured in µA. A refractory threshold
(RT) baseline—stimulation required for action
potential—was measure, which was found to be
4 nA for a 1 ms duration. An interpulse interval
(IPI) baseline—duration between the start of the
first pulse and the beginning of the second
pulse—was then measured, and found to be
11.52 ms for two 4 nA pulses.
The baseline IPI was then divided by 30 (n = 30)
to decrease each IPI trial by 0.38 ms. Due to the
asymptote nature of the graph, the first and last 5
trials stepped in increments of 0.05 ms to better
observe end point behavior. To obtain more
accurate measurements, only the Stim1 button
was used, where IPI and applied stimulus were
varied on the second pulse generated. All pulses
were for a duration of 1 ms only. The simulation
was allowed to return to resting potential and
cleared after each trial.
Data Collection Process
Fig. 1. An example binary search algorithm of
determining successful dosage (green) compared to
ablation dosage (red) in electroporation.
Collection of RT values followed a binary
search algorithm (Fig. 1) for each independent
IPI value designated to be evaluated. Applied
stimulus was varied in integers until the
difference between integer values caused no
action potential. Between the two integer values,
applied stimulus was then incremented at the
lower value by 0.25 nA until action potential
was generated greater than or equal to ~50% of
the time. This was determined by running the
same parameters 4 to 10 times when close to
determining the corresponding RT for a given
IPI.
Once the applied stimulus was determined to
meet the above criteria, IPI, RT, the channels,
and membrane voltages, where recorded into
Microsoft Excel. This process was repeated for
each incrementally decreasing IPI.
Data Analysis Process
𝑓(𝑥) = (56834)𝑥 .
The data recorded into Excel was first plot RT
against IPI, and fit with a power trendline to best
fit (above). The Excel spreadsheet was then
imported into MATLAB R2019a, and fit using
the equation described under Initial Parameters.
Guess values for nlinfit, coefficients {A B tau}
were determined from graphical asymptotes and
the power exponent from Excel; which were
determined as {1 0 4}.
𝐴
𝜏 = −𝐼𝑃𝐼/ ln(𝐵 − )
𝑅𝑇
Once the coefficients were determined, the
values were used in the equation solved for tau.
The functions mean and std were used on the tau
array to solve for the error bounds of the
simulation data, and to see if the coefficient tau
is reasonable.
Functions corrcoef and find were used on the
trendline generated values and datapoints—for
both Excel and MATLAB trendlines—to
calculate R2.
Channel values and membrane voltages were
imported as well but only plotted to provide
visual reference for non-investigated variable.
These values plotted against IPI shows a
relationship between RT and neural membrane
factors other than the refraction time constant.
Results
The function nlinfit successfully came to a result
with the guess parameters designated under
Methods. The resulting coefficient values are as
follows:
A = -177.971
B = 3.529
𝜏 = -3.112
 Fig. 2. Graphs of the Excel power fit (left) and nlinfit using MATLAB (right). Collected data points (n = 30) are
black diamonds while the trend lines are red.
____________________________________________________________________________________

all rounded to three decimal places. The

following average value for 𝜏 was found to be
-3.092 with a standard deviation of ± 0.047.
The corresponding R2 and p values for the
trendline generated data are as follows:
Excel R2 = 0.998
MATLAB R2 = 0.999
where the non-linear fit shows overall better
confidence.
The program did determine that the coefficient
tau lies within the standard deviation of the
average tau which was calculated at all points
keeping A and B constant.

Fig. 3. Graph of measured leakages (µA) for sodium
(blue), potassium (red), and current (yellow), for the
tested IPI (ms) values.
Discussion
Data Interpretation
The plotted data in Fig. 2 accurately represents
the expected curve for refractory threshold
stimulus against interpulse interval. The
trendline generated in MATLAB visually and
numerically is a closer fit (R2 = 0.999) than the
Excel power method (R2 = 0.998). The
refraction time constant lies within the standard
deviation for all calculated tau points, aside from
the 11-12 ms region. This is likely due to the
constant values—extending beyond the baseline
values—interfering with the rate of change. Fig.
3 displays the leak experienced by the
simulation. Sodium and potassium leak are
mirrored across the current leak which is
expected. The rate of current leak slightly
changed as IPI decreased (0.001-0.0005 µA),
but is not visually significant. Considering the
accuracy of the trendline, the associated
constants, including refraction time constant, are
an accurate representation of the data and model.
Explanations and Limitations
The relationship of channel leakage (Fig. 3)
resembles that of the RT against IPI curve (Fig.
2) but more sporadic in nature. Assuming that
HH Sim is accounting for ion permeability
during action potential, as leak is proportional
the conductance, due to Ohm’s law it is expected
that leak will change as the membrane retains
greater capacitance with decreasing IPI. Larger
stimuli and shorter IPI duration can lead to
factors such as electric field consideration. It is
unknown whether HH Sim models a single
neuron, nerves, or surface (for the application of
Stokes’ theorem). The interference caused by
electromagnetic fields or extracellular potentials
will directly affect ion flow, which is shown by
Fig. 2, but not as consistent of a non-linear curve
[2].
Considering the accuracy of the fit, the
coefficients found were imported back into the
RT equation defined in Methods. Solving for the
max and indexing, further information regarding
neuron stimulation is derived. The max
extrapolated value for RT is found to be 0.0199
A, at an IPI of 3.925 ms. Due to the HH Sim
package having an upper limit of 100 nA for
stimulus, data beyond this value cannot be tested
for accuracy. However, comparing this value to
previously experimented stimulus, 0.0199 A is
0.5% differing from the theoretical 0.020 A, at
which muscle paralysis is experienced [3]. With
this context, it is expected for the neuron to stop
function properly around this value. It should be
noted that the HH Sim package does not specify
whether electrode placement is ideal, if
extracellular parameters are considered, if noise
is automatically eliminated, or if glial cells are
present and considered. These factors are
important in the context of investigating a full
biological system to obtain an accurate model
[2].
Alternative Explanations
Comparing coefficient and constant values to
previously derived values shows large numerical
differences that raises questions. For example,
the refraction time constant found to be 0.7 ms
for an exponential model [2]. The argument here
relies on the implication that methods, nerves,
and model, are the same. While the ideas are
similar and nature, being that the same
exponential model is used, there are vast
differences in parameters and biological
investigation. The methodology is not a
derivation of the refraction coefficient of a said
nerve type, rather it is a method for determining
them using an arbitrary simulation.
The HH Sim package lacks information
regarding parameters clearly outlined in other
research, a direct limitation. However, the
investigated question only asks whether it is
possible to derive a function for prediction
purposes. According to the R2 value obtained,
the fit is proper. Using the determine coefficient
values to model at extremes, as discussed in
Explanations and Limitations, neuron behavior
is a close representation to what would be
expected in vivo conditions. The hypothesis
should be taken as a ‘proof of concept’ as
opposed to accounting for all factors.
Implications
Showing that refraction time constants for
neuron models can be derived, provides hope for
implementation of new medical devices. Given
data for a specific region of the body and neural
network, it is possible to model an accurate
representation of biological limitations for cost
engineering current devices more effectively.
For developing devices, such as current research
into vagus nerve stimulation, a proper model can
be derived to increase benefits (preventing
seizures, inducing immune response, etc.) while
preventing overstimulation which can lead to
detrimental side effects (headaches, arrythmias,
etc.).
Before proceeding into using the model for
medical device parameters, the discussed
limitations should be investigated thoroughly.
Electromagnetic interference with the ion
channels is an important consideration as total
ion flow directly relates to the induced
membrane potential change. Action potential
may be generated, but as the total membrane
potential change is weaker, neurotransmitter
concentrations can be affected. This becomes
more important when working with a system
rather than individual neuron, and should be
investigated accordingly.
Concluding Statement
Nerve stimulation is an effective form of
treatment for a variety of conditions and proves
promising for current research. Optimizing these
medical devices relies on consideration for
neuron and neural network properties. It is
possible to collect data on a neural system of
interest and derive a refraction time constant in
order to engineer a medical device to fit system
parameters. Further research will be needed in
order to determine the best computer model
before implementation to uninvestigated
biological systems.
MATLAB R2019a Code:
% BME 301 Lab 1 DE Script
% jcingra2@ncsu.edu - 8/23/20
% James Ingram

% Plots the taken data points and preforms statistical analysis. Solves for
% the threshold constant as well.

clc
clear
close all

%% Init
HHData = xlsread('HHReadMATLAB.xlsx');

% Load HH Model data into specific arrays for analysis

IPI = HHData(:,1)';
RT = HHData(:,2)';
NaLeak = HHData(:,3)';
KLeak = HHData(:,4)';
ILeak = HHData(:,5)';
InitMemVolt = HHData(:,6)';
SecondMemVolt = HHData(:,7)';
PercentDiffofVolt = HHData(:,8)'*100;

trendLineEQ = @(x) 56834*x.^(-3.869); % Power trendline with a confidence of R = 0.998 from

excel
trendLineExcel = trendLineEQ(IPI);

% Refractory Threshold EQ
% RT = A/(B-e^(-IPI/tau)) where tau is the refractory time constant
% A/B are unknown constants which need to be estimated for
refractory_threshold = @(coeffs,x) coeffs(1)./(coeffs(2)-exp(-x./coeffs(3)));

% Solved EQ for tau

tau = @(refracT, InterPI, coeffs) -InterPI./(log(coeffs(2) - (coeffs(1)./refracT)));

beta0 = [1, 0, 4]; % guess values found by using desmos for 2

hours
coeffsNL = nlinfit(IPI,RT,refractory_threshold,beta0); % non-linear fit (regression)
trendLineNL = refractory_threshold(coeffsNL,IPI); % evaluation of coeffs found to plot trendline

%% Plotting
% Excel generated trendline plot
hold on
subplot(1,2,1)
plot(IPI,RT,'kd',IPI,trendLineExcel,'r')
axis([4 13 0 110])
xlabel('IPI (ms)')
ylabel('RT (nA)')
title('RT v IPI (Excel)')
legend('Data points','Excel generated trendline')
hold off

% MATLAB generated trendline plot

hold on
subplot(1,2,2)
plot(IPI,RT,'kd',IPI,trendLineNL,'r')
axis([4 13 0 110])
xlabel('IPI (ms)')
ylabel('RT (nA)')
title('RT v IPI (MATLAB)')
legend('Data points','nlinfit')
hold off

%% Tau output and stats

% refraction time constant evaluations
tauArray = tau(RT,IPI,coeffsNL);
tau_avg = mean(tauArray);
tau_std = std(tauArray);
stdArray = ones(1,30)*tau_std;
figure;
hold on
errorbar(IPI,tauArray,stdArray,'kd')
plot([IPI(1)+0.5 IPI(end)-0.5], [coeffsNL(3) coeffsNL(3)],'r','linewidth',2)
axis([5 12 -3.2 -2.9])
title('Tau values calculated at IPI')
xlabel('IPI (ms)')
ylabel('Tau')
legend('Calculated Taus','Coefficient Tau','location','best')
hold off

% calculate the associated R^2 values and p values with comparison of the
% trendline to data points (are the trendlines generated statistically
% significant and a good indicator/approximation
[R_excel, p_excel] = corrcoef(RT', trendLineExcel');
[R_nlinfit,p_nlinfit] = corrcoef(RT',trendLineNL');
[pNLr, pNLc] = find(p_nlinfit<0.05);
[pExr, pExc] = find(p_excel<0.05);
rNL = R_nlinfit(2,1);
rEx = R_excel(2,1);

% print R and p vals to command window

fprintf('Excel trendline R%c = %.3f\n',178,rEx)
fprintf('Non-Linear Fit trendline R%c = %.3f\n',178,rNL)
fprintf('\nCoeffs A = %f , B = %f , tau = %f \n',coeffsNL(1),coeffsNL(2),coeffsNL(3))
fprintf('Average tau = %f , Std of tau = %f \n',tau_avg,tau_std)

% test to see if coeff determined tau lies within the std for tau at all
% points
if tau_avg -tau_std > coeffsNL(3) > tau_avg + tau_std
 fprintf('\nTau lies within the standard deviation.\n')
else
fprintf('\nTau is outside the standard deviation.\n')
end

%% Application of Data

% Section reserved for using the found coeffs to generate expected

% stimulus values that would need to be applied for a certain IPI

newIPI = linspace(0,10,1e6);
newRT = refractory_threshold(coeffsNL,newIPI);
[limitRT,indxRT] = max(newRT);
absRP = newIPI(indxRT); % any IPI before this at a higher RT value will be in hyperpolarization
limitRT_amps = limitRT*(10^-9); % value is close to the maximum current without going into
respiratory paralysis

fprintf('\nMaximum refractory threshold as generated by the trendline %.4f A\n',limitRT_amps)

fprintf('Minimum interpulse interval as generated by the trendline %.3f ms\n',absRP)

figure;

subplot(1,2,1)
plot(IPI,NaLeak,IPI,KLeak,IPI,ILeak)
title('Leakage Measured for Ions and Current')
xlabel('IPI (ms)')
ylabel('uA')
legend('Sodium','Potassium','Current','Location','best')

subplot(1,2,2)
plot(IPI,InitMemVolt,IPI,SecondMemVolt)
title('Measured Membrane Voltage for Action Potential')
xlabel('IPI (ms)')
ylabel('Voltage (mV)')
legend('First Action Potential','Second Action Potential','location','southeast')
axis([5 12 -8 40])
References
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10.1016/j.jacc.2016.10.061.
[2] L. A. Cartee, C. van den Honert, C. C.
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measurement of membrane
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[3] “Controlling Electrical Hazards.”
https://www.osha.gov/Publications/3075
.html (accessed Aug. 28, 2020).