68 IEEE TRANSACTIONS ON BlO-MEDICAL ELECTRONICS April

Electronic Simulation of Daily Rhythm

in Nocturnal Animals*
A. P. SAGEt, MEMBER, IEEE AND J. L. MELSAt

Summary-The term biological clock is used to designate the technology or aided in the solution of similar electronic
phenomenon, displayed by organisms, of pacing activity in a problems. It is reasonable to assume that the same may
cyclic manner related to environment. Many nocturnal animals, be true of this study. The relation of the biological clock
for example, are capable of entraining the onset of their activity
with the light-to-dark transition in a periodic light-dark regime to many problems in electronic systems engineering should
in which the period or ratio of light to darkness varies widely. be noted. Adaptation, the ability of self-adjustment or self-
This paper presents the development of an electronic model for modification in accordance with changing conditions, is a
simulation of the adaptation of the endogenous circadian rhythm fundamental attribute of the biological clock as well as liv-
of nocturnal animals due to light stimuli. ing organisms in general. Adaptation is certainly a desir-
able attribute for an electronic system. The growing in-
terest in the design of adaptive electronic systems is evi-
denced by the number of papers on the subject which
INTRODUCTION have appeared in recent years. A possible use of the
LECTRONIC simulation of the biological clock in- "biological clock" to entrain the movement of a digital
volves reproducing certain biological characteris- computer memory drum with computer clock pulses has
tics of the "clock" by use of electronic circuitry. been investigated [1].
This will necessitate simplifying assumptions or general- There are two forms which simulation models may take.
izations to reduce the amount of circuitry to a practical The first is the exact or "one-to-one" model in which each
amount, since the true biological model contains large element of the item to be simulated is matched by an ele-
amounts of feedback and redundancy. The electronic ment in the model. The second type of model attempts only
model will run on a much reduced time scale as compared to reproduce certain external characteristics. In general,
to the true biological model. the model presented here is of the latter type, although
There are three basic reasons for electronic simulation some attempt at "one-to-one" simulation is made. For
of the biological clock. First, the mathematical formula- simplicity, this paper will discuss only the adaptation of
tion of the features of the "clock" which is necessary for the onset of activity and will not consider the variations of
the development of a model may indicate inadequacies in length of activity.
the biological data. Many of these "gaps in information"
would not become evident except under the concise or- BIOLOGICAL DATA
ganization needed for "model making." To determine the biological effects which describe the
Second, the model will make possible the acquisition of action of the "clock" phenomenon, an extensive survey
greater knowledge of the "clock" phenomenon. By using a of the available literature [2]-[9] was made. Emphasis
reduced time scale, the electronic model will develop data was placed on the general trend and qualitative nature
for several years of biological experiments within a few of the results rather than specific or quantitative factors.
hours. Thus, unusual and original experiments may assist The response due to light stimuli is shown for continuous
the biologist in recognizing new features of the clock to light or dark signals, periodic light-dark regimes and non-
be investigated. In this manner, the model may improve periodic and random light shocks.
or extend the basic theories of the "clock" action. Since
man has been shown to display at least a "pseudo-clock," Continuous Light or Darkness
greater knowledge of the phenomenon may prove valuable To study the results of continuous light or darkness,
to future space travelers. animals were kept in constant darkness for a control pe-
Third, previous electronic simulation of features of the riod, then subjected to constant light and finally returned
"life" sciences has led to advances in the state of electronic to constant darkness. The persistence of some biological
rhythm such as activity or metabolic rate under constant
* Received December 11, 1962; revised manuscript received conditions is, of course, prerequisite in these studies. Per-
March 13, 1963. This research was supported in part by the Bionics sistence is, in fact, the primary evidence of the existence
and Computer Branch, Electronic Technology Laboratory, Aero- of an internal pacemaker.
nautical Systems Division, U.S. Air Force Systems Command, No.
AF 33(616)-7677. In constant darkness, most nocturnal animals display a
t Department of Electrical Engineering, University of Arizona, period less than twenty-four hours. The period in con-
Tucsotn, Ariz.

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1963
stant darkness has been shown by DeCoursey [2] to be
the endogenous or free-running period for a nocturnal
animal. In constant light, most nocturnal animals display
a basic period greater than twenty-four hours, which is
accomplished by delaying the onset of activity each day.
Typical results are shown in Fig. 1 which is obtained from
a continuous strip recording of activity by cutting it into
twenty-four-hour pieces and placing them consecutively
down the page.
Periodic Light-Dark Regimes
To study the entrainment process in nocturnal animals,
animals were maintained for several days in constant dark-
ness and then exposed to an artificial day of ten hours
of light and fourteen hours of darkness [3]. The animals
were returned to constant darkness following the experi-
ment.
Fig. 2, also obtained from continuous strip recording,
presents the results of this experiment for animals with
TIME OF ACTIVITY-ONSET (hours)
0 4
Sage and Melsa: Simulation of Rhythm in Nocturnal Animals 69
an endogenous period less than twenty-four hours. The
leading edge of the activity cycle was entrained with the
dusk (light to dark) transition.
Light Shocks
Animals were subjected to light shocks of varying in-
tensity and duration in order to determine the transient
effects of light upon the basic clock mechanism. An exact
measure of the effects of a light shock on the "clock" can
be made by determining the difference between the ex-
pected and actual time of onset of activity on the night
after the shock. Typical results from an experiment of this
type are shown in Fig. 3.
By the use of many such experiments, it is possible to
develop a plot of the shift of the following day's onset
of activity by a light shock vs the time at which the shock
was applied relative to the onset of activity. This plot is
commonly called a sensitivity curve; a typical sensitivity
curve is shown in Fig. 4.
When a delay shock and advancing shock are given in
the same activity period, the response is equal to a delay
8 12 16 20 24
shock alone, indicating that a delaying signal overrides the
advancing signal.

I--
z
TIME OF ACTIVITY-ONSET (hours)
w
2
0 4 8 12 16 20 24
0 I i i
o:
w
a.
x
w 4.
IL
0 1 8 .
z LIGHT SHOCK
APPLIED
0 Ft 12 , EARLY IN ,f
ACTIVITY /
aQ-
16 I. CYCLE'

o 20
Fig. 1-Onset of activity for nocturnal animals in constant light -o- LIGHT
or constant darkness. <24 SHOCK
APPLIED
28 LATE IN
ACTIVITY
TIME OF ACTIVITY-ONSET (hours) CYCLE
.n tl

Fig. 3-Effect of ten-minute light shocks on the onset of activity.

z
uLi ta + 40-.
0
*

ai. S
x
F +20
.4
0 -J
U
Uf)
U.
4
0 o 0-
z
0
4 -204 III
-' u *4 +8 +12 416
Fig. 2-Entrainment of activity onset for nocturnal animals to TIME OF LIGHT SHOCK AFTER ACTIVITY-ONSET (hours)
twenty-four-hour periodic light-dark cycles. Fig. 4-Sensitivity curve.

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70 IEEE TRANSACTIONS ON BIO-MEDICAL ELECTRONICS Apr-il
THE MATHEMATICAL MODEL From the available data [2], it appears that the amount
The next step in the development of the simulation of phase shift should be proportional to the effective in-
model is the formulation of a mathematical model for tensity of light to some power "K" if all other variables
the adaptation of the onset of activity. As can be noted are held constant. The effective light intensity may be
from the sensitivity curve in Fig. 4, the onset of activity will different from the actual intensity due to saturation ef-
follow the beginning of the sensitivity curve by some fects. Then
amount of time which is fixed for a given animal. There- phase shift a jeK
fore, this paper will determine the time for the beginning where
of the sensitivity curve. The onset of activity may then be effective light intensity.
detemined by a simple fixed delay. This should be con-
i, = (2)
trasted with the obviously more difficult method of de- The sensitivity curve describes the relation between the
termining the time for onset of activity and advancing it amount of phase shift and the time at which the shock is
to find the beginning of the sensitivity curve. applied. Then for a very short shock (i.e., short enough
The time between successive initiations of the sensitivity that the duration is unimportant), phase shift is given by
curve will be equal to the free-running period plus the
amount of phase shift accumulated on previous days. For phase shift = IK(t) c(t) (3)
the majority of animals studied, transients induced by where
light shocks are essentially one day in duration. Thus, the fe = normalized effective light intensity.
ultimate phase shift is reached on the day after the stimu- The relation of shock duration to the amount of phase
lus was applied. Since the free-running period is assumed shift was not easily established. The data [2] indicate that
to be an innate and constant characteristic of each animal, the amount of phase shift is practically independent of
the determination of the time for the beginning of the shock duration. This information does not tell which value
sensitivity curve is basically one of deternining the phase of phase shift, given by the above equation, to use if a
shift caused by external stimuli. The problem may then be light shock extends over a large portion of the sensitivity
stated: Should a phase shift be made? If so, should it be an curve. The most logical solution was that the animal would
advance or delay and how much? use the maximum amount of phase shift available. Thus
The first two parts of the problem can be answered in a the peak-holding theory was formed. As noted previously
digital manner-that is, by a simple yes or no answer- there appears to be some maximum amount of phase shift
while the third question needs an analog answer-that is, that an animal can receive on any given day. Thus, the
one in which a solution must be generated continuously. amount of phase shift for any given day from a single
A thorough investigation of the biological data indi- light shock is given by
cated that previous theories did not provide a complete
solution and, therefore, the development of a new model phase shift - IeKC(t) max (4)
was undertaken. with the constraint that phase shift < maximum phase
In general, it is easier to characterize a time-varying shift for a single light shock.
system by its impulse response than by its steady-state For multiple light shocks, the amount of phase shift is
response. For this reason, light shock data will initially be the summation of the phase shift received from each shock,
used in the development of the model rather than en- again subject to some constraint on the maximum amount
trainment (steady-state) information. of phase shift for any given day.

Digital Model
The Peak-Holding Theory
The following logical statements have been developed
A peak-holding theory for determination of the amount from the biological data to decide when the beginning of
of phase shift is presented here. To date, the authors have the sensitivity curve should be advanced or delayed:
found no mention of any similar theory and, therefore, 1) The animal should receive a delaying phase shift
some background for this decision needs to be presented. if the light is on and the time is during the positive part
Basically, the amount of phase shift depends on three of the sensitivity curve.
factors: 1) intensity of light, 2) time at which the light 2) The animal should receive an advancing phase
shock is applied and 3) duration of the light shock. Sym- shift if the light is on and the time is during the nega-
bolically, tive portion of the sensitivity curve and there has been
no delaying signal on this day.
phase shift f(i, t, d) The above statements are simply a logical form of pre-
where vious statements for the biological data and describe a
i = intensity of light problem in sequential logic for which standard techniques
(1) [ 10] may be used to solve. Table I gives a list of the symbols
t time at which the shock is applied
usedl and a definition of their logical "1" state. (Note that
=

d = duration of the shock.

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1963 Sage and Melsa: Simulation of Rhythm in Nocturnal Animals 71

TABLE I
LOGIC SYMBOLS AND DEFINITIONS
Symbol Represents Definition of Logical "1" State
S Animal State Animal is Awake
L Light Light is On
C Sensitivity Function c(t) is Positive
D Delay DelayingPhaseShiftShould Be Made
Ao Advance Onset AdvancingPhaseShift Should Be Made
F Secondary State -

Fig. 5-Block diagram of proposed model.

the negative portion of the sensitivity curve is symbolized
by the condition C O0 and S = 1.)
The output and excitation functions may then be
written
D = lc (5)
Ao slc'f'
= (6)
F sf + Ic + cf. (7)
By use of the above logic equations and the peak-hold-
ing theory, the phase shift to be received from any light
stimuli can be determined.
l SENSITIVITY SENSIT ~~~~MASTER
CLOCK
THE ELECTRONIC MODEL CURVE AND
SIMULATOR TRIGGER
The third step in forming the simulation model is the
development of electronic circuits which operate in the - - -
ENDOGENOUS CLOCK UNIT
manner described by the mathematical model. Fig. 6-General block diagram of proposed electronic model.
General Philosophy of Proposed Model
The general philosophy of the proposed model is shown Fig. 6 shows a general block diagram of the electronic
in pictorial form in Fig. 5. Basically, the model consists model for the biological clock. The advancing or delaying
of three functional units: 1) endogenous clock unit, 2) signal from the conditional response controller is sent to
conditional response unit and 3) decision unit. the master clock and trigger which is pacing the model's
The endogenous clock unit is used to pace the model's internal rhythm. This phase-shifting signal causes the on-
internal rhythm and to supply information concerning the set of the sensitivity curve to be advanced or retarded.
present state of the "clock" to the conditional response and When the correct time is reached, the circuit triggers and
decision units. sends a signal to the sensitivity curve simulator and the
The conditional response unit comprises the analog por- conditional response controller indicating that the time has
tion of the model and is used to determine the amount of been reached for the beginning of the sensitivity curve.
phase shift that should be applied to the beginning of the This trigger signal causes the sensitivity curve simula-
sensitivity curve. The decision or logic unit makes all of tor to start the generation of the sensitivity curve. The
the required decisions for the model in terms of past and data concerning the sensitivity curve are sent to the con-
present information concerning the endogenous clock unit ditional response controller in analog form and to the de-
and external stimuli. cision circuits in digital form. At some fixed time after the
beginning of the sensitivity curve, the sensitivity curve
General Block Diagram of Electronic Model simulator indicates that the correct time for the onset of
The model as presented here runs at approximately 0.1 activity has been reached. The model then changes to the
cps, corresponding to twenty-four hours of actual time. active state, remaining in this state until the end of the
This speed appears best when recording equipment, circuit sensitivity curve. The length of the sensitivity curve is de-
complexity and ease of entering external stimuli are taken termined by a signal from the conditional response con-
into account. troller.

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 6
I
72 IEEE TRANSACTIONS ON BIO-MEDICAL ELECTRONICS April
The decision circuits determine whether the onset of the +40
sensitivity curve should be advanced or delayed. After the >. +30
decision circuits determine that a phase shifting signal a,, +20
should be computed, the conditional response controller 0U. +10
will determine the amount of delay or advance to be sent z, 0
to the master clock and trigger. 0
-Ia D

More detailed block diagrams and actual circuits may be 2 -20

found elsewhere [11]-[13]. -30
MODEL TIME (SECONDS)
EXPERIMENTAL DATA I-- --
I
1
0 4 8 12 16 20 24
The last step in any simulation process is a verification EQUIVALENT ANIMAL TIME (HOURS)
of the model's validity. A lack of specific biological data Fig. 7-Sensitivity curve generated by simulation model.
for a given species of animal has made it impossible to
simulate actual data for specific animals. However, by use
of reasonable parameters for the model, it has been pos-
sible to perform a large number of experiments. These CONSTANT
DARKNESS
initial simulation experiments have shown a high degree of
correlation with typical biological data.
Fig. 7 shows a typical sensitivity curve developed by the
model. The similarity of this curve to Fig. 4 should be CONSTANT
noted. The fact that nine seconds of model time is equiv-
zS
LIGHT

alent to twenty-four hours of animal time enables the

model to simulate a year of biological experiments in ap- 0

proximately one hour.

The results of a continuous light and continuous dark-
ness simulation experiment are presented in Fig. 8. As
CONSTANT
noted previously, the period in constant darkness is less 10 DARKNESS

than twenty-four hours, while the period in constant light

is greater than twenty-four hours. 12-
As a final example of simulation results, Fig. 9 shows TIME OF DAY (HOURS)
the entrainment of the model to a periodic light-dark
regime. As pointed out in the section on biological data, Fig. 8-Simulation of the biological clock in constant conditions.
the amount of phase shift during the approach to entrain-
ment is relatively constant. When the model is returned
to constant darkness, it shows an endogenous period less
than twenty-four hours.

CONCLUSION
- i7
This paper has presented the development of an elec-
tronic simulation model for the biological clock phenome- _ E . ._*.ii
non. While there is no reason to believe that this is the
REGIME

only possible model, there is good functional correspond-

ence between the biological data and the model.
The electronic model is composed of a sequential logic
unit, a conditional response unit and an endogenous clock 0 9

unit. The sequential logic unit makes all decisions for the i 10

model in terms of external stimuli and the present and

past state of the "clock." The conditional response unit,
which is essentially analog in nature, determines the
amount of control to be exerted on the endogenous clock
CONSTANT
unit. The endogenous clock unit maintains the present DARKNESS
state of the model and applies all control signals for
state changes.
Thus, it appears that the model represents a rather com- TIME OF DAY (hOurs) .1,
plex hybrid (digital-analog) adaptive control system, a
Fig. 9-Simulation of the biological clock for twenty-four-hour
type of system which hopefully may lead to improvements entrainment.

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1963 Pressman and Newgard: External Measurement of Blood Pressure 73

in the performance of many existing control and com- Squirrel," Ph.D. dissertation, University of Wisconsin, Madi-
munications systems. son; 1959.
[3] S. K. Roberts, "Circadian Activity Rhythms in Cockroaches,"
The model was designed to match the actual biological Ph.D. dissertation, Princeton University, Princeton, N.J.;
1959.
data at certain known "points." It is hoped that the model [4] C. S. Pittendrigh, "Circadian rhythms and the circadian
will be capable of interpolating or extrapolating the data organization of timing systems," Symp. on Quantitative Biol-
ogy, Long Island Biological Assoc., Long Island, N.Y., vol. 25,
betweern these points. The model can, however, relate the pp. 159-184; 1960.
behavior of the "clock" to various stimuli more accurately [5] and V. C. Bruce, "An oscillator model for biological
than an intuitive idea of the "clock's" functioning could. clocks," in "Rhythmic and Synthetic Processes in Growth,"
Princeton University Press, Princeton, N.J., pp. 75-109; 1957.
The electronic model of the biological clock is also [6] K. Klotter, "Theoretical analysis of some biological models,"
valuable because of its role as an organizer. The model Symp. on Quantitative Biology, Long Island Biological Assoc.,
Long Island, N.Y., vol. 25, pp. 189-196; 1960.
collects together a large variety of facts into a compact [7] K. E. Justice, "Nocturnalism in Three Species of Desert
diagram and interrelates them, one to another. The model Rodents," Ph.D. dissertation, University of Arizona, Tucson;
1960.
serves to consolidate the experience obtained thus far [8] V. C. Bruce, "Environmental entrainment of circadian
with the biological prototype and simplifies the task of rhythms," Symp. on Quantitative Biology, Long Island Bio-
logical Assoc., Long Island, N.Y., vol. 25, pp. 2948; 1960.
formulating new biological experiments. [9] R. Wever, "Possibilities of phase control, demonstrated by
As the model is evolved through successive prototypes, an electronic model," Symp. on Quantitative Biology, Long
Island Biological Assoc., Long Island, N.Y., vol. 25, pp. 197-
the functional correspondence will become better. It is ex- 206; 1960.
pected that the acquisition of new biological information [10] S. H. Caldwell, "Switching Circuits and Logical Design,"
John Wiley and Sons, Inc., New York, N.Y.; 1958.
will lead to even greater refinements in the model. [11] J. L. Melsa, "Electronic Simulation of the Biological Clock,"
M.A. thesis, University of Arizona, Tucson; 1962.
[12] A. P. Sage, et al., "Study and Research on Electronic Simu-
lation of the Biological Clock," Wright Patterson Air Force
BIBLIOGRAPHY Base, Ohio, No. ASD-TDR-62-191; 1962.
[13] A. P. Sage, et al., "Study and Research on Electronic Simu-
[1] G. E. Warner, "Electronic Methods for Recording a Clock lation of the Biological Clock, II," Wriglht Patterson Air Force
Timing Signal on a Magnetic Drum," M.A. thesis, University Base, Ohio, No. ASD-TDR-63-136; 1963.
of Arizona, Tucson; 1962. [14] G. A. Korn and T. Korn, "Electronic Analog Computers,"
[2] P. J. DeCoursey, "Daily Activity Rhythms in the Flying McGraw-Hill Book Co., Inc., New York, N.Y.; 1957.

A Transducer for the Continuous External

Measurement of Arterial Blood Pressure*
G. L. PRESSMANt, MEMBER, IEEE AND P. M. NEWGARDt

Summary-The objective of the research was to develop a mental transducers gave results consistent with the predictions
transducer to measure arterial blood pressure. It was required of the model. These transducers have been used to measure
that the transducer provide a continuous measure of blood pres- blood pressure at large superficial arteries, with results com-
sure, that it not encumber the subject and that it not require parable to sphygmomanometer determinations.
cannulation. Two basic techniques were investigated both ana-
lytically and experimentally. T WO TECHNIQUES are commonly employed to
First, an indirect measurement of blood pressure based on
arterial deflection was attempted. Difficulties of calibration; and obtain arterial blood pressure. The sphygmoma-
sensitivity to physiological changes of skin and tissue around nometer provides only intermittent measurements
the artery led to the decision to attempt a more direct measure- of the systolic and diastolic levels. Intra-arterial catheter-
ment of arterial blood pressure. In this second approach, arterial ization requires surgical procedures that limit its applica-
deflection is restrained by the transducer and the resultant tion to clinical environments. Attempts have been made to
restraining force is measured.
A mathematical model of the transducer artery system was measure blood pressure by other methods, including the
developed and was used as a guide for the design of the experi- measurement of arterial distention,' of pulse wave velocity,2
mental prototype transducers. Tests performed on these experi-

* Received February 12, 1962; revised manuscript received

1R. W. Correll, "Theoretical Analysis and Preliminary Devel-
opment of an Indirect Blood Pressure Recording System," M.S.
March 4, 1963. This work was supported by the National Aeronau- thesis, Massachusetts Inst. of Tech., Cambridge, Mass.; June, 1959.
tics and Space Administration under Contract No. NAS-2-515. 2G. Weltman, "The Continuous Measurement of Pulse Wave
t Stanford Research Institute, Menlo Park, Calif. Velocity," M.S. thesis, University of California, Los Angeles; 1959.

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