The course () aims to introduce system theory and engineering relevant analytical

tools with applications from bioengineering and physiology. The analytical tools will include differential
equations, linear and nonlinear systems, feedback and stability, the complementary nature of time and frequency
domain methods, etc.
To encourage students exploring the potential of the analytical techniques introduced in this course, the lecturer
will offer some physiology relevant applications, including musculoskeleton properties and
dynamics, vestibular system, pupil control system and cardiovascular regulation. In addition to
homework set, along the course some designed numerical laboratory works based on Matlab and
Opensim have to be completed, aiming to cultivate the hand-on experience of the students. The
laboratory works include neural models, feedback control systems, properties of muscle, and
cardiovascular function.

Harvard University
Division of Engineering and Applied Sciences
ES 145 - Physiological Systems Analysis
Fall 2009
Introduction to Physiological Systems

Course Overview
This course is the merger, or perhaps the intersection, of two well defined fields: systems
analysis and physiology. A system is anything around which we can draw a dotted line and
define inputs to and outputs from. You may have been exposed to a variety of systems
in previous courses: electrical, chemical, thermodynamic, mechanical, physiological, etc.
We can extend this to economic and/or social issues as well. The techniques that we will
develop in this course can be used to analyze the behavior of any arbitrary system whose
behavior can be described mathematically.
Systems analysis is traditionally a course that is first taught to engineering students at the
undergraduate level, and focuses on well characterized physical systems and ways of describing the dynamics of these systems. The typical systems that are studied include mechanical
systems such as spring-mass-damper systems or fluid systems, and electrical circuits. In
this course, we will introduce those concepts as well, but with the real motivation being
to characterize and understand the dynamics of physiological systems. Many physiological systems are physical systems that pump fluids, transmit electrical currents, generate
forces, etc., and can often be described quite well with analogous engineering systems. Well
cover basic biophysical models of the neuron, muscle physiology, the vestibular system, and
the cardiovascular system, all under the framework of a systems analysis course. So we
will find ourselves bouncing back and forth between engineering perspectives and the basic
physiology, each reinforcing our knowledge of the other.
Mathematical models of certain systems can be created from the basic laws of physics. We
will see several examples in this course where we understand the elements of the system
so well, that we can analytically describe the behavior using first principles. On the other
hand, many systems are often sufficiently complex such that a certain amount of empirical
evidence must first be gathered before mathematical descriptions can be inferred. This is
not to paint the modeling process as taking one of these two pathways. On the contrary,
modeling the dynamics of systems typically involves the iterative process of experimental
observation and the inference of the underlying mechanisms through first principles.
Why is it important to describe a system mathematically? There are a variety of reasons
you might think of, but they all boil down to two things: prediction and control. Often
we can observe the behavior of a system in a particular situation, but we might want to
predict the behavior in a different situation. This can obviously increase our understanding
of the system, but the prediction can also be useful in itself. For example, if I could make
a model from past information on the stock market, I might understand something about

ES145 - Introduction

the relationship between society and the economy, but perhaps more importantly to some
would be the ability to predict future stock prices.
In some cases, if we understand the system well enough, we develop a model of the underlying mechanisms so that we may control the systems behavior. For example, if we could
completely understand how a drug is processed by the body, we could develop a methodology for precisely controlling the resulting effect of the drug. Our understanding of complex
biological systems is still somewhat limited, and so much of scientific research is focused
on the development of models for basic understanding of physiological principles, but the
ultimate goal of understanding the underlying physiology is for control.

Systems
Our loose definition of a system is one in which any number of inputs come in, and any
number of outputs leave, and the system represents the mapping from the input space to
the output space. The picture that we have in mind in any of these cases is illustrated in
Figure 1.
Figure 1: The systems perspective

Inputs

Outputs
System

Note that weve drawn this as if there are always clearly defined inputs and outputs. We
will see examples from engineering that have a clearly defined output, but no such input.
In biological systems, it is often very difficult to define just what we mean by inputs and
outputs. So try to keep an open mind when we are discussing systems, and do not just
restrict yourself to systems that have clearly defined inputs and outputs.
Here are some examples of systems that we frequently encounter:
The relationship between the amount of fuel you supply to the engine while pressing
down the accelerator in your car and the resulting speed.
The resulting vibrations of a bridge when excited by wind disturbances.
The relationship between the voltage you apply across a resistor, and the resulting
current that passes through it.
The effect of your spending habits on the gross national product.
The relationship between the amount of rainfall and the resulting pollen count in the
air.

ES145 - Introduction

The list goes on and on. It becomes fairly difficult to think of examples that are not systems,
if posed in the right manner.
Here are some examples of biological systems:
The relationship between light entering your eye, and the electrical activity in the
brain tissue.
The maintenance of blood flow to the brain in the presence of incredible perturbations
in metabolic demand from the body.
The relationship between the muscle movements you make in your vocal system, and
the resultant sounds that come from your mouth.
The relationship between the food that you intake, and the resulting metabolic energy
that is derived from it by your digestive tract.
The relationship between the amount of a drug that enters the body, and the resultant
effect that the drug has on the body.
The maintenance of a relatively constant body weight, in the presence of large fluctuations in food intake and exercise.
We will develop methodologies in this course that can be used to describe both biological
and non-biological systems, all within the same general framework.
For the moment, let us consider an arbitrary system that has a single input and a single
output. Let us denote the input as u and the output as y. For the purpose of this course,
well typically be interested in systems in which the output of the system varies as a function
of the input of the system over time:
y(t) = f (u(t))
where the function f () can be any function mapping the input to the output. This map
can have a number of properties, a few of which are outlined below.

Static vs. Dynamic

Suppose that we have a see-saw, where the position of one end of the board is u and the
position of the other end of the board is y, as shown in Figure 2. By controlling u, we
are generating changes in y. However, the current position of the far end of the see-saw
depends only on the current position of the end that were controlling. This is a called a
static system. The value of y at time t only depends on the value of u at time t, and nothing
else.
On the other hand, consider a tank that were pouring water into, as shown in Figure 3.
The tank is empty at time t = 0. Let u(t) be the rate of flow that were using to fill the tank
(in volume/time), and let y(t) be the volume of water in the tank. Obviously y depends on
u, but in a more complicated way as compared to our see-saw example. Now, y at time t

ES145 - Introduction

Figure 2: A static system

depends not only on u at time t, but also on all past values of Ru. Specifically it depends on
the integrated value of u from 0 to t, or mathematically y(t) = 0t u( )d . This is a dynamic
system.
Figure 3: A dynamic system
u(t) = flow rate

y(t) = volume

Linearity
Consider the static system y = f (u), where y(t) depends only on u(t). The map from u
to y is, in general, nonlinear. To help us define what is meant by nonlinear, we first define
precisely what we mean by linear. Let y1 = f (u1 ) and y2 = f (u2 ). The function f is a
linear function if and only if:
f (a u1 + b u2 ) = a y1 + b y2
for all constants, a and b. If b = 0 and a = 2, this is simply asking the question Does
doubling the input result in a doubling of the output? So obviously if you were to do an
experiment with this kind of system, all of the data points would lie on a straight line. A
nonlinear system is any system that does not pass this test, and is therefore not linear. It
is clear then, that y = m u is linear, but what about y = m u + b, a straight line with a
non-zero intercept?
Figure 4: A static linear system
y
y2

y1
u1

u2

The same argument applies to dynamic systems as well. Suppose we go back to our water

ES145 - Introduction

tank filling example. Let y(t) = f (u(t)) = 0t u( )d . Is this linear? We can apply the test
in exactly the same manner as above. Let y1 (t) = f (u1 (t)) and y2 (t) = f (u2 (t)). We then
have:
f (a u1 (t) + b u2 (t)) =

Z t
0

= a

[a u1 ( ) + b u2 ( )]d
Z t
0

u1 ( )dt + b

Z t
0

u2 ( )d

= a y1 (t) + b y2 (t)
So this system is linear in its relationship between the input flow and the tank volume. It
turns out that most systems are at least slightly nonlinear in their behavior, but can often
be described quite well with a linear approximation.

Time-invariant vs. time-varying

Consider a static system, y(t) = a u(t), where the a is a constant. If at time t1 , the input
u(t1 ) = u
, then the output will be y(t1 ) = a u
. Suppose that at time t2 that the input
is again u(t2 ) = u
, we again have y(t2 ) = a u
. So it really doesnt matter what time we
apply the input u
, we still get the same output. The system is called time-invariant. If,
instead, a is no longer a constant, but is a time varying quantity a = a(t). We then have
y(t1 ) = a(t1 ) u
and y(t2 ) = a(t2 ) u
. These two are not equivalent. This system is called
time-varying.
Similar arguments hold for dynamic systems. Consider a dynamic system, y(t) = a(t)
0 u( )d , where a(t) is a time-varying quantity. Suppose that at time T , we reset y to 0
and repeat the exact same input pattern we used from 0 to T over the interval from T to
2T . If a were a constant, then the volume would follow precisely the same path. However,
since a(t) is a function of time, the volume can follow a totally different path. This dynamic
system is considered time-varying.
Rt

Stability
A major issue in a lot of systems has to do with the stability of the input/output behavior.
If I apply a finite input to the system, does the output of the system remain finite? A
heuristic example has to do with a PA system, as shown in Figure 5. The input to the
microphone, is your voice, which for most people can be considered finite. The microphone
transduces the pressure waves of your voice to a small voltage signal, which is then amplified
and sent to loudspeakers. Suppose that the output is the intensity of sound generated by the
loudspeakers. A situation that often arises is when the microphone receives the loudspeaker
output as an input, along with your voice. This input is then amplified and sent to the
loudspeaker, and the process continues. This is known as a positive feedback loop, and is
in fact unstable.
All of these properties of systems will be covered in the course in more detail, but its helpful
to think about these issues every time we encounter a new system.

ES145 - Introduction

Figure 5: An unstable system

sound
intensity

voice
Mic.

Amp.

Spk.

An Example from Physiology

An interesting example from physiology is temperature regulation in the human body.
Were all familiar with temperature regulation in our houses. A thermostat measures the
current temperature, compares with a desired temperature, and when the house is too cold,
the heating system is turned on. Alternatively, when the temperature gets too high, the
heating system is turned off. But how is temperature regulated in the body? Warm-blooded
animals, such as humans, strive to maintain a relatively constant internal temperature
in the face of large changes in heat generated internally, as well as wild swings in the
external conditions. There are a number of mechanisms that exist for helping us achieve
this goal. Blood flow is constantly being diverted and rerouted through the body depending
on temperature conditions. Dilation of blood vessels near the surface of the skin causes the
blood to flow into the extremities, allowing the transfer of heat from the blood to the
outside world when the internal temperature is too high. Constriction of blood vessels near
the surface of the skin prevent blood from flowing to the extremities, avoiding heat loss to
the outside world when the internal temperature starts to drop. Similarly, sweating is a
mechanism that helps us reduce our internal temperature through the evaporation of sweat
into the environment. Shivering, on the other hand, is a mechanism that helps us increase
internal temperature. The increase in the metabolic rate in the muscles generate heat within
the muscles. Cold-blooded animals, such as most reptiles, dont have these mechanisms and
therefore take on the temperature of their environment. One effect of the increased muscle
activity is that there is increased blood flow to the muscles, which counters some of the
effects of shivering [1].
Take as an example, the act of shivering. Shivering is a means for increased heat production
by skeletal muscle, which is highly aerobic and can generate quite a bit of heat. Prior to
the onset of shivering, vasoconstriction has reached its maximum, diverting flow away from
the periphery. What mechanisms generate the physical act of shivering? The following are
some key elements:
In the region of the brain associated with hunger and thirst, called the hypothalamus,
neural nuclei have been identified that are key elements in temperature regulation.
Pathways for shivering mechanisms lie within cerebellum and spinal cord.
Prior to shivering, there is an increase in muscle tone which generates initial thermogenesis.
Thermal receptors are located in the surface of the skin, and in the hypothalamus
itself.

ES145 - Introduction

The basic elements involved in the shivering reflex are shown in Figure 6.
Figure 6: Control of Shivering
Hypo

Cerebellum

Spinal
Cord

Body
Tissue

Muscles

skin
temperature

Cool
Receptor

Control of shivering mechanisms in the body. Cool receptors at the surface of the skin, and within
the hypothalamus, signal the hypothalamus, which activates the muscles through the cerebellum
and spinal cord. The internal heat generated by the muscle activity increases the temperature of
the body tissue, achieving the desired objective. Adapted from Schwan [1].

In the figure, note that receptors in the skin detect less than desirable cool temperatures,
triggering activity in the hypothalamus. Through the cerebellum and the spinal cord, the
hypothalamus activates muscle groups and generates the shivering behavior. As a result
of the increased metabolism of the now-activated muscle groups, the body temperature is
raised, turning off the reflex. Further increase in the cold stress produces a general increase
in the metabolic rate throughout the whole body [1].
Just from this simple diagram, we can begin to ask questions from our previous discussion.
What aspects of the system are static, versus dynamic? Which elements are linear? How
might we describe any non-linearities we see? How are the signals generated in the cerebellum in order to produce the oscillatory behavior we see in the spinal cord and skeletal
muscle during shivering? This simple example gives a taste of things to come, as we will be
analyzing physiological systems from this perspective throughout the course.

Reading
Required reading: Chapter 1 from Ogata [2]

References
[1] H. Schwan. Biological Engineering. McGraw Hill, New York, 1969.
[2] K. Ogata. System Dynamics. Prentice-Hall, New Jersey, fourth edition, 2004.