New Methods in Brain Imaging

New Techniques for
Examining the Brain

Biofeedback
Brain Development
Brain Disorders
Brain Facts
Cells of the Nervous System
Emotion and Stress
The Forebrain
The Hindbrain
Learning and Memory
Meditation and Hypnosis
The Midbrain
The Neurobiology of Addiction
New Techniques for Examining the Brain
Pain
Sensation and Perception
Sleep and Dreaming
Speech and Language
The Spinal Cord
The Teen Brain
New Techniques for
Examining the Brain
Karen D. Davis, Ph.D.
Series Editor
Eric H. Chudler, Ph.D.

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Davis, Karen D.
New techniques for examining the brain / Karen D. Davis.
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Includes bibliographical references and index.
ISBN-13: 978-0-7910-8959-0 (hardcover)
ISBN-10: 0-7910-8959-2 (hardcover)
1. Brain—Imaging—Juvenile literature. 2. Imaging systems in medicine—Juvenile
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Contents
1. Introduction to New Brain Exploration Technologies . . . . . . . . 1
2. A Primer on Brain Structure and Function. . . . . . . . . . . . . . . 10
3. Classic Methods to Study Brain Anatomy and Function. . . . . 19
4. Modern Techniques to Observe Human Brain Anatomy. . . . . 31
5. Linking Behavior to Brain Function in Humans . . . . . . . . . . . 37
6. Modern Techniques to Observe Human Brain Function. . . . . 51
7. Modern Techniques to Observe Brain Chemicals at Work . . . 65
8. Modern Techniques to Stimulate the Human Brain . . . . . . . . 73
9. The Future of Brain Exploration. . . . . . . . . . . . . . . . . . . . . . . 81
10. The Impact of Brain-exploration Techniques on Society. . . . . 91
Glossary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
Bibliography. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Further Reading. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
Introduction to New Brain
1 Exploration Technologies
You have probably seen colorful pictures showing the

“brain at work” in newspaper articles, on television, or even
in movies. But, how are they formed and what do they really
mean? Several modern brain imaging techniques can now
be used to “see” what is going on in your brain. There are
also other types of modern technologies that can be used to
examine the electrical properties and function of individual
nerve cells and the overall structure of the brain. This book
explores the fundamental organization of the brain, how it
has been studied in the past, and modern methods of human
brain imaging and brain stimulation. It will also look at some
of the exciting things that can be learned about the brain
using new technologies, and the impact of such information
on science, medicine, and society.
Moving Beyond Phrenology

The idea that different parts of the brain have different func-
tions has been around for a long time. Back in the early part
of the 1800s, phrenologists thought that the bumps on a
person’s skull related to specific traits such as personality
or intelligence (Figure 1.1). Over time, phrenology “maps”
became quite complex and the general public tried to use

Figure 1.1 This phrenological chart was created in France during the nineteenth
century. Phrenologists related the bumps on the head to different brain functions.
A modern version of the concept of functional representation in the brain can be
studied with brain imaging technologies.
the maps to explain all sorts of human behaviors. Eventually,

the unscientific nature of phrenology was recognized and the
idea fell out of favor, although phrenology-type cartoons now
occasionally appear in popular culture. Even though the idea
Introduction to New Brain Exploration Technologies
of phrenology now seems absurd, it did open discussion about

brain function and localization.
Before the invention of modern brain-exploration tech-
nologies, much of our knowledge about the human brain came
from observing the effects of injuries or disease. For example,
certain areas of the brain were implicated in personality func-
tions following the well-known case of Phineas Gage, a railway
construction worker who suffered a dramatic injury to his brain
(Figure 1.2). Likewise, the case of patient H.M. (see sidebar on
page 5) demonstrated the critical role of the hippocampus in
the formation of new memories. However, there are now much
more controlled ways to find out about how the brain works.
There are two basic ways to gain information about the
human brain: stimulation and recording. One approach is to
observe what happens to a person when the brain is stimulated
electrically or magnetically. For example, if stimulation of a
particular area of the brain produces a muscle twitch, then that
brain area likely plays a role in movement. The other approach
is to record the workings of the brain when a person performs
a task. For example, brain areas involved in movement can be
found by recording the activity of the brain when a person is
moving a part of his or her body. This book will explore some of
the ways that the brain can be stimulated and some of the ways
to record the activity of the brain.
Why Is Brain Imaging Important?

Neuroscientists have been exploring the structure and func-
tion of the brain for centuries, but modern brain imaging
offers exciting new opportunities to learn about the brain.
For the first time, it is possible to peer into the human brain
and watch how it functions in a variety of situations without
opening the skull! Brain imaging allows a view of what is hap-
pening inside our brains when we are thinking, feeling, and
doing activities.
Figure 1.2 Phineas Gage was a construction foreman known to be a reliable and
capable man. In 1848, Gage was working on a railway site in Vermont when an
explosion caused a metal rod to be driven through his head, his eye, and the left
frontal lobe of his brain. Gage was treated and recovered from the accident without
any change in his speech, memory, or intelligence. But soon afterward he showed
a dramatic change in personality, becoming impatient, hot-tempered, and violent.
After Gage died, his brain was examined to determine the area that had been dam-
aged during the accident. Pictured above is Gage’s death mask and skull.
The Case of H.M.

A neurosurgeon and a psychologist working at McGill University
in Montreal made key discoveries about the mechanisms of
memory through careful observations in surgical patients. First,
in the 1940s and 1950s, the renowned neurosurgeon Wilder
Penfield applied electrical stimuli to the brain during surgical
procedures for epilepsy to map critical functions before remov-
ing the brain tissue presumed to be producing the seizures. Dr.
Penfield observed that stimulation of the temporal lobe during
surgery (the patients are awake during the surgery, which is
performed under local anesthesia) could cause the patients to
experience vivid memories.
After Penfield’s discoveries, psychologist Brenda Milner stud-
ied the case of a 29-year-old epilepsy patient, known as H.M. His
seizures did not respond to anticonvulsant medication and were
so severe and frequent that he could not work. To control the
seizures, H.M. had a surgical procedure called bilateral medial
temporal lobe resection to remove large portions of his tempo-
ral lobes, including the hippocampus. The surgery reduced the
severity of his seizures but it soon became apparent that he had
severe memory problems. Dr. Milner was brought into the case
to carefully perform a psychological exam. Dr. Milner did not
find any personality or intelligence impairment in H.M. but did
observe striking deficits in his ability to retain new information.
Dr. Milner continued to test H.M. for decades. Her data on H.M.
and other patients who had undergone similar surgical proce-
dures with a common region of damage to the hippocampus
showed persistent memory deficits. This data provided critical
evidence for the role of the hippocampus in the formation of
new memories.
A Link Between Molecules, Cells, Behavior,

and Consciousness
Brain imaging can be used to monitor changes in brain activity
while it is working. This information can be used to determine
how the brain functions during training or practice of an activ-
ity, during recovery from an injury, after a medical treatment,
or as a result of aging. Brain imaging can also be used to study
the similarities and differences between people, perhaps related
to their genetics or abilities. In other words, brain imaging pro-
vides a link between the function of molecules and cells, behav-
ior, and consciousness.
Checking Textbook Facts

Modern brain imaging not only allows us to make new discov-
eries about brain function, but also to reassess the “facts” that
appear in textbooks to see if they are accurate. One “textbook
fact” that has been reexamined is the sensory and motor rep-
resentation of the body, known as the homunculus (Figures
1.3 and 1.4). It has been known for decades that many areas
of the brain contain an orderly representation of the body. For
example, there is a “somatotopic map” in the somatosensory
cortex (the area of the brain devoted to body sensations) and in
the motor cortex (the area of the brain devoted to movement).
Some body regions, such as the hands and the face, have a
very large representation in these maps. In the somatosensory
cortex, the size of the representation is related to the ability
to sense touch. In the motor cortex, a large representation is
related to fine motor skills in these body regions. The precise
organization of these maps is important because it helps us
understand how we feel and move. Neurosurgeons are also
interested in these maps so that they can try to prevent dam-
age to important regions during surgical procedures (such as
removing a tumor).
Figure 1.3 This diagram is an approximation of the somatosensory cortex in the

post-central gyrus that contains an orderly map of the body (somatotopy) to signal
touch sensation.
The history of these maps begins in the 1940s, when neuro-

surgeon Wilder Penfield used a technique called macrostimula-
tion to find out how the body was represented in the sensory
and motor cortex in patients who were having brain surgery for
epilepsy. During the surgery, he delivered an electrical current
to different areas of the cerebral cortex using a large electrode
called a macroelectrode. Each time he stimulated the brain, he
Figure 1.4 This diagram is an approximation of the motor cortex in the pre-central
gyrus that controls movement of different parts of the body.
asked the patients (who were awake during the procedure) to

describe what they felt and where they felt it. When the mac-
roelectrode stimulated the sensory cortex, the patients felt a
tingling sensation and when it stimulated the motor cortex, one
of the patients’ muscles would twitch. Dr. Penfield (and other
neurosurgeons) performed this mapping procedure on many
patients and used the results to create the well-known sensory
and motor somatotopic maps. So, what could be wrong with

these maps? Remember that they were created by macrostimu-
lation that delivers an electrical current that can spread to a
fairly large area of the brain. Also, they were created by observa-
tions in patients with epilepsy, and these patients’ brains may
be different from those of healthy people. But now, modern
brain imaging can be used to map the healthy brain carefully
and to check whether our “textbook truths” about these motor
and touch maps are accurate. Neuroimaging can also be used
to make somatotopic maps that represent the other sensations,
like pain.
Why Is Brain Stimulation Important?

The idea that we can stimulate the brain with electrical or mag-
netic devices sounds both strange and exciting, and also maybe
a bit scary. Yet brain stimulation plays a crucial role in medical
science. Modern methods of brain stimulation provide sophis-
ticated and controlled ways to study brain function. These
techniques can also be used to alter abnormal brain activity
that produces debilitating symptoms in patients with a variety
of serious medical conditions, such as the severe tremor suffered
by people with Parkinson’s disease.
■ Learn more about the contents of this chapter Search the
Internet for somatotopy, phrenology, and cerebral cortex.
A Primer on Brain
2 Structure and Function
The brain is organized into anatomical (the structures) and

physiological (the functions) systems that interact with each
other to do three basic jobs:
1. Receive information from the outside world—this is the
sensory input.
2. Generate a response—this is the motor output.
3. Assess and integrate information, maintain body func-
tions, perceive, think, feel, and make decisions—this is
the essence of consciousness, cognition, and homeostasis.
Basic Organization and Structure of the

Human Brain
The brain has three major parts: the forebrain, the mid-
brain, and the hindbrain (Figure 2.1). The hindbrain is the
lower part of the brain and contains the medulla oblongata,
which emerges from the spinal cord. Moving upward, the
medulla joins into an area called the pons. The cerebel-
lum sits on top of the pons and plays a role in movement
and balance. The cerebellum is known as the little brain
(Latin) because it has its own cortex and inner nuclei. The
brain stem is the region between the upper midbrain and
the spinal cord. The brain stem contains areas that control
functions that are critical for maintaining life (heart rate,
10
A Primer on Brain Structure and Function 11
Figure 2.1 The top diagram is a side view of the outside of the brain, and the bot-
tom diagram is a side view taken from the middle of the brain.
12 New Techniques for Examining the Brain
breathing, and blood pressure). The midbrain plays a role in

movements, vision, and hearing and connects the hindbrain to
the forebrain. Finally, the top part of the brain is the forebrain.
This division contains many structures, such as the thalamus
(a relay of sensory information to the cortex), hypothalamus
(controls body temperature), basal ganglia (motor areas), hip-
pocampus (involved with memory), amygdala (involved in
emotion), and neocortex.
The Cerebral Cortex

The cerebral cortex, also known as the cerebrum, is the outer
part of the brain. The term cortex derives from the Latin term
for tree bark. The human cerebral cortex is distinguished from
other areas of the brain because of its characteristic grooves
(called sulci, singular is sulcus) and bulges or ridges (called gyri,
singular is gyrus). The cerebral cortex is about 2 to 5 mm (.08
to .20 inches) in thickness and is divided into two hemispheres
(left, right), each of which has four lobes. The two hemispheres
communicate with each other through a connecting bundle of
nerve fibers known as the corpus callosum.
The Four Lobes

The human cerebral cortex is a complex part of the brain that
is involved in all the complexities of human consciousness,
behavior, emotion, and thoughts. The frontal lobe sits at the
front of the brain and is involved with generating movements,
problem solving, and other higher intellectual functions. The
parietal lobe is located in the middle and side of the brain and
is involved with sensory functions such as touch, language, and
attention. The temporal lobe is at the side and bottom of the
brain and is involved with hearing, speech, and complex visual
perceptions. The occipital lobe is located at the back of the brain
and its main role concerns vision.
Functional Areas of the Cerebral Cortex

Korbinian Brodmann was a German physician and scientist
who studied the mammalian cerebral cortex in the early 1900s.
Brodmann subdivided the brain into 47 areas based on regions
with similar cellular structure (Figure 2.2). This system is still in
use today. Although the different areas were based on anatomy,
more recent data show a relationship between the “Brodmann
areas” and particular brain functions. This universal naming
system has tremendous utility because all scientists can use this
system to communicate their ideas and findings in a way that
everyone can understand. The use of Brodmann areas in func-
tional neuroimaging is especially important, as will be further
described in Chapter 5.
Neurons, Action Potentials, and Neurotransmitter Release

The human brain weighs about 3 pounds (1.4 kg) and contains
neurons (nerve cells), glial cells (support cells), and blood ves-
sels. The main processing and communication of information
in the brain is done by the neurons—and there are about 100
billion of them in the human brain. Each neuron has fingerlike
projections (processes) called dendrites to receive information
from other neurons, a cell body that contains the machinery
(such as mitochondria) that keeps the cell’s engine running,
and an axon to take the information message to another neu-
ron, muscle, or gland (Figure 2.3). The system of information
transmission in a neuron is an electrical signal called an action
potential, or nerve impulse. Action potentials move along the
axon at different speeds depending on the structure of the neu-
ron (e.g., diameter, presence of myelin insulation). For example,
the action potential conduction speed is extremely fast along
large motor axons; up to 100 meters per second—that is more
than 220 miles per hour! Rarely does a message consist of a
single action potential moving along the axon. Usually, action
Figure 2.2 Korbinian Brodmann created a system of naming different areas of the
cortex based on cell structure. The original map (not shown) was drawn to depict
different cell types. The map above is a transformation of this map to highlight the
functions assigned to each area.
Figure 2.3 The basic structure of a neuron includes dendrites (to receive infor-
mation), a cell body, and an axon to conduct action potentials. Information is
conveyed to the next neuron via release of neurotransmitter from the axon ter-
minal into the synaptic cleft to bind to its receptor on the next (postsynaptic)
neuron.
potentials move along the axon one after another organized in

a regular flow at a certain frequency, or bunched together sev-
eral at a time in a bursting fashion. This creates a neural code
that has meaning, like the dots and dashes of the Morse code
that communicates words. Some sensory neurons can “code”
certain features of a stimulus. For example, there are several
types of sensory receptors (connected to neurons) in the skin
to encode information about the strength of the stimulus and
the speed of the stimulus (Figure 2.4). Let’s say that somebody
quickly pokes your hand with the end of a pencil. This will
activate rapidly adapting neurons that produce a rapid stream
of action potentials that mirror the rate of skin indentation.
In general, rapidly adapting neurons will generate and trans-
mit action potentials at the same frequency as the stimulus.
But, if the pencil is gently pushed and held against your hand,
slowly adapting neurons take over the encoding job because
these neurons will generate a steady stream of action poten-
tials throughout the entire time that the skin is indented. The
greater the indentation, the more action potentials are gener-
ated. This is quite a simple example of stimulus feature coding.
A more elaborate coding system occurs in the brain so that we
can have elaborate sensory experiences.
Action potentials carry information along an individual
axon. However, a different process is used to transfer informa-
tion from one neuron to the next: a chemical synapse. When an
action potential reaches the end of an axon, a series of events is
triggered, including release of a chemical called a neurotrans-
mitter. This chemical diffuses across the synapse and binds
with a receptor site on the next neuron to trigger a response.
This response increases or decreases the likelihood that an
action potential will be generated in this next neuron. In this
way, information can be maintained or modified as it is moved
around the brain.
Figure 2.4 This illustration shows the four main types of touch receptors in the
skin and how they respond to a stimulus that indents the skin. Two of these recep-
tors (Meisner’s and Pacinian corpuscles) generate action potentials at the begin-
ning and end of the touch and so they are called rapidly-adapting receptors. Merkel
cells and Ruffini endings (stretch receptors) generate action potentials throughout
a maintained touch stimulus and so are called slowly adapting receptors. Each tick
in the spike train represents one action potential.
The nervous system has an interesting way to move informa-

tion using specialized chemical messengers called neurotransmit-
ters. There are more than 40 different neurotransmitters. Some
examples of neurotransmitters are dopamine, norepinephrine,
serotonin, and acetylcholine. As noted above, when action
potentials arrive at the end of the neuron’s axon, they trig-

ger the release of a neurotransmitter chemical messenger that
flows across the space (called a synapse) to the next neuron, the
postsynaptic neuron. The neurotransmitter will then bind to
specialized parts of the postsynaptic neuronal membrane called
receptors (Figure 2.3). The structure of each receptor is highly
specialized so that it attracts only a certain neurotransmitter;
therefore many receptors are named for the neurotransmitter
that binds to it. For example, the neurotransmitter dopamine
will bind to one of a variety of dopamine receptors. This type
of interaction between a specific neurotransmitter and its
receptor can be thought of as a key fitting into and opening up
a lock. There are two types of neurotransmitter effects. Some
neurotransmitters, such as acetylcholine and glutamate, will
stimulate the postsynaptic neuron to start generating its own
action potentials, but other neurotransmitters, such as glycine
and GABA (gamma aminobutyric acid), inhibit the postsynap-
tic neuron from generating action potentials.
Internet for Brodmann areas, neurotransmitter, and touch
receptors.
Classic Methods to Study Brain
3 Anatomy and Function
Classically, the study of the brain has used methods to look

at anatomy, function, and changes that result from disease
or injury. Most of these methods are used in experimental
animal studies, but some can also be used in humans. These
methods have undergone technological improvements and
continue to be used today to discover fundamental informa-
tion about brain anatomy and function.
Basic Anatomy
The basic anatomy and structure of the brain—its lobes, gyri
and sulci, and areas of gray and white matter—can be clearly
seen without a microscope, by just looking at the brain with-
out the use of any fancy equipment.
Early brain atlases were constructed from brains that had
been preserved with a chemical fixative (for example, forma-
lin) and then carefully cut into slices so that the anatomy and
morphology (form and structure of cells) could be observed.
Some structures of the brain are easier to understand from
different angles, and so brain atlases typically provide pic-
tures of the brain sliced in three ways (Figure 3.1):
1. The sagittal plane divides the brain into left and right
sides; these slices show the brain as viewed from the side.
19
Figure 3.1 Schematic diagrams illustrating anatomical directions and

planes.
2. The horizontal (also known as axial) plane divides the

brain from top to bottom, similar to slicing open a ham-
burger bun; these slices show the brain viewed from the
top or bottom.
Classic Methods to Study Brain Anatomy and Function 21
3. The coronal (also known as frontal) plane divides the brain

from front to back, similar to slices of bread; these slices
show the brain as viewed from the front or back.
Four other anatomical terms are used to describe brain
locations:
1. The superior (or dorsal) aspect of the brain is toward the
top.
2. The inferior (or ventral) aspect of the brain is toward the
bottom.
3. The anterior (or rostral) aspect of the brain is toward the
front.
4. The posterior (or caudal) aspect of the brain is toward
the back.
Classic Anatomical Methods to See

Brain Structure
The fine details about the structure of neurons can be seen with
various staining techniques and microscopes, especially the
electron microscope (EM). But microscopic pictures alone are
not sufficient to trace the pathways of neurons, from where they
start to where they go. To do this, neuroscientists have used two
approaches in experimental animal models: degeneration and
axonal transport. There are many types of stains that can be
used to highlight specific structures. For example, stains such
as cresyl violet specifically color neuronal cell bodies, whereas
myelin stains specifically color axons that have a myelin (a fatty
insulating substance) coating.
Tracing Nerve Pathways Using Degeneration

When a neuron is cut, it undergoes degeneration and eventually
dies. Changes in the cell body are not always easily seen,
but changes to the myelin along the axon are more readily
visualized. The process, known as Wallerian degeneration,

refers to the degeneration of the axon far away (the distal axon)
from the cell body to where it is injured. Thus, a neural pathway
in experimental animals can be traced by cutting the pathway
and visualizing Wallerian degeneration. This technique does
not let you see the exact location of the axon terminals and
so it is not widely used today. But, new advances in brain
imaging methods are beginning to take advantage of Wallerian
degeneration to visualize axon pathways.
Tract Tracing Using Retrograde and Anterograde Transport

Following where a neuron goes or where it came from is pos-
sible because of a phenomenon called axonal transport (Figure
3.2). Many chemical tracers and dyes can be injected into a
nerve to follow the path of the nerve. Some popular trac-
ers include horseradish peroxidase (HRP), phaseolus vulgaris
leucoagglutinin (PHA-L), dextrans, biocytin, and florescent
dyes. These tracers produce colorful pictures of the structures
they label. Tract tracing studies are done by injecting the tracer
directly into the brain area of interest in an anesthetized animal
(usually a mouse or rat). Time must be given to allow the trans-
port of the tracer in the neuron (typically several millimeters
per day). After the right amount of time has passed, the animal
is anesthetized again, and a fixation liquid is injected to preserve
the brain. The brain is then removed and cut into sections to
look for the tracer. Each tracer has different characteristics that
can be used to microscopically visualize where the tracer was
injected and where it went. Florescent dyes can be used to trace
multiple neuronal paths at the same time because each dye has
a different color.
Anterograde tracers get taken up by the neuron’s dendrites
and cell body and travel along its axon to the terminal at a
known transport rate. Most anterograde tracers cannot leak
out of the nerve terminal and so these anterograde tracers are
Figure 3.2 The top row shows an anterograde tracer that flows from
the cell body to the axon terminal and a retrograde tracer that can
travel in the reverse direction from an axon terminal back to the cell
body. The bottom row shows the orthodromic (normal) direction of
action potential propagation and the antidromic direction of action
potential conduction.
used to find the target site of where neurons are traveling. Other
anterograde tracers (such as the rabies virus) can flow across a
synapse from one neuron to another. With careful planning and
consideration of transport times and distances between brain
areas, these special transynaptic tracers can be used to visualize
multisynaptic pathways.
Retrograde tracers get taken up by the axon terminals and
then travel “backward” to the neuron’s cell body. So, if you inject
a retrograde tracer into one area of the brain, you can then find
out the origin of the neurons that connect to that area.
The choice of tracer is important because some tracers only
flow retrogradely, some only anterogradely, and others go in both
directions. It is also important to consider all possible ways that

a neuron may have been labeled—either intentionally or unin-
tentionally. For example, damaged axons can also take up some
tracers and so just placing a needle into the brain to inject the
tracer can label some axons damaged by the needle that are just
“passing through” the injection site and not actually ending there.
Other Localization Techniques

There are a variety of other tracing techniques that are based
on the location of certain chemicals present within neurons.
Methods such as immunocytochemistry and in situ hybridiza-
tion can be used to visualize neurons that contain a specific
neurotransmitter or protein.
A special technique, called the 2-deoxyglucose (2DG) meth-
od, is used in experimental animals to locate active areas of
the brain. This method is based on the use of glucose by active
neurons. When a molecule similar to glucose (2-deoxyglucose)
is injected into an experimental animal, it is taken up by active
neurons and stays within the cell because it is not degraded by
enzymes. To determine which area of the brain is active during
a certain behavior or event, a radioactively labeled form of 2DG
is injected, and then the brain is removed and examined for the
location of the radioactive label.
Classic Electrophysiological Techniques to

Study Brain Function
The brain is essentially a complex information center that
receives, integrates, and transmits information within neurons
and from one neuron to another. This communication is mostly
done through electrical signals known as action potentials.
Electrophysiological techniques provide the most direct way to
study these signals. Electrophysiology can be used to study single
neurons or large groups of neurons in animals and humans.
Single Unit Electrophysiology

Single unit (also known as single cell) electrophysiology is a pow-
erful technique that provides information about the functional
properties of individual neurons. Typically, a microelectrode (a
very small insulated metal probe) is inserted into the brain area
of interest in an anesthetized animal, or into an isolated “slice”
preparation (a section of the brain that has been removed from
an experimental animal to allow for better access and control
of the chemical environment), or in some special cases into
the human brain. Microelectrodes, depending on their size and
properties, can pick up activity from one single neuron (from
either outside or inside the cell), or from several neurons close
to its tip. A special type of electrode can be used to study the
current flowing across a tiny part of the neuron cell membrane
(an ion channel) with a technique called patch clamp.
A microelectrode can be used to detect and measure the
electrical activity of a single neuron (such as voltage changes),
usually in response to a stimulus that the experimenter controls.
For example, to study how neurons in the visual system code
a specific type of visual information, say a colored pattern or
picture, a microelectrode is placed into the visual cortex of the
occipital lobe to measure the cell activity in response to visual
images. On the other hand, to study how the brain controls
movements, a microelectrode can be inserted into the motor
cortex to measure neuronal responses to a moving part of the
body. To study how the brain integrates sensory information
from the skin, a microelectrode can be placed into the somato-
sensory cortex of the parietal lobe to record activity evoked by
touching a part of the body. In all these examples, the activity of
a neuron can be defined by how it responds to a stimulus.
Microelectrodes can also be used to determine the outcome
of neuronal activity—its “output properties.” To do this, a small
amount of electrical current is injected into the brain from the
tip of the microelectrode (a technique called microstimulation)

to excite (depolarize) the neurons close to its tip. The experi-
menter can then observe the behavioral result of activating
these neurons. For example, if the microelectrode is placed in
the motor cortex, microstimulation would cause a small muscle
twitch in one muscle.
Microelectrode recording and microstimulation have revealed
some very interesting aspects of brain function in patients with
disease or injuries. One example comes from a study of patients
with an amputated limb who experience “phantom” sensations,
unpleasant sensations that feel like they are coming from the
missing limb (Figure 3.3). Microelectrode mapping in these
patients found that, despite their losing a limb, stimulation in
a part of the brain called the thalamus could produce a strong
phantom sensation, even though the neurons in that part of
the brain had become rewired to respond to other parts of the
body. So, it seemed that the patients’ brains had only partially
rewired. The inputs to those neurons were different than before
the amputation but the output of those neurons retained their
original assignment to produce limb sensations. This type of
study demonstrates that patients experiencing phantom sen-
sations do so because part of their brain that represented the
amputated limb continues to be active.
Tract Tracing with Electrophysiology

It is possible to track the course of a single neuron (from its cell
body to where its axons terminate) using electrophysiological
methods. These methods are based on an interesting property
of action potential conduction: They can actually travel along
an axon in either direction! Normally, action potentials travel
from the neuronal cell body along its axon to its terminals. This
is called orthodromic conduction. But, if for some reason an
action potential is initiated somewhere along the axon (either
artificially in an experiment or sometimes in real life like when
Figure 3.3 Mapping the brains of patients who had amputations found that
some neurons become rewired and gain new inputs from intact parts of body
near the site of amputation. However, these patients experience phantom sensa-
tions—abnormal feelings that appear to come from their missing limb. A possible
explanation for these sensations is that some neurons in the thalamus retain their
original wiring to the area of the cortex that represents the missing limb and may
be spontaneously activated.
you hit your “funny bone”), or even at the terminal, it can travel
backward toward the cell body. This is called antidromic con-
duction (Figure 3.2). Scientists use this electrical property of
neurons to figure out brain circuitry.
Let’s say that you want to know whether brain area A contains
neurons that send their axons to communicate with brain area
B. Maybe you also wish to test whether brain area A contains two
types of neurons: one type that projects to area B and another
type that projects to area C. To test this possibility, the experi-
mental setup requires three electrodes. First, a microelectrode is
placed into brain area A to determine the properties of the neu-

rons there. Microelectrode recordings often preferentially pick
up activity from cell bodies rather than the much smaller axons.
This selectivity and also the characteristic type of action potential
shape picked up from a cell body (it is more prolonged than from
an axon) can help determine whether the microelectrode is re-
cording from a cell body or an axon. Next, brain area B and brain
area C are electrically stimulated with electrodes (which can be
a microelectrode or a larger macroelectrode). Current delivered
through these stimulating electrodes generates action potentials
at axon terminals near the electrode tip that propagate to their
cell body. Now, the crucial step is to assess what is going on with
the activity being recorded by the microelectrode recordings in
area A. Antidromically conducting action potentials have several
characteristic features (not discussed here) that distinguish them
from action potentials caused by some other type of connection
via a synaptic communication that introduces a synaptic delay
due to neurotransmitter release. Therefore, an antidromic action
potential recorded from stimulating area B indicates that the
neuron projects from A to B. An antidromic potential recorded
due to stimulation of area C indicates that the neuron projects
from A to C. If, however, the neuron is antidromically activated
from both B and C, then the neuron in brain area A must be pro-
jecting to both area B and C—that is, its axon splits (bifurcates)
to project to and communicate with both areas.
Chemical Effects on Neurons

Electrophysiological techniques can also be used to study how a
drug or neurotransmitter directly affects the activity of neurons.
There are several ways to deliver a chemical to a specific area of
the brain. The chemical can simply be injected into or near the
neuron. Another technique called microphoresis can be used to
examine the effect of small amounts of a chemical. With micro-
phoresis, an electrical current is used to inject a tiny amount of a
chemical (such as a neurotransmitter) right onto the neuron that

is being monitored with a microelectrode.
Electroencephalography and
Event-related Potentials
Electroencephalography (EEG) is one of the oldest and most
established methods to record electrical activity of the human
brain. The activity is recorded by numerous electrodes placed
on the skull, usually held in place with a flexible cap. EEG can be
used to evaluate the normal, fundamental response of the brain
to various types of conditions and stimuli. EEG is also a standard
clinical tool that provides information about abnormal function.
For example, the type and location of abnormal electrical activ-
ity can be used to diagnose epilepsy. EEG is also a valuable tool
to diagnose sleep disorders, evaluate states of unconsciousness,
and to confirm brain death in comatose patients.
EEG measures the voltage output of the averaged activity
of a large number of neurons in different parts of the brain.
It is a “fast” technique that shows exactly when the activity is
occurring with millisecond precision. An EEG trace consists
of “waves” of electrical activity that can be assessed in terms of
the frequency of the waves (the number of waves per second,
or Hertz [Hz]) and the amplitude and shape of the waves. The
various wave shapes suggest the neuronal sources. For example,
a short, sharp spike is likely due to a large number of neurons
firing synchronously. Different wave shapes can also indicate
abnormalities, including epilepsy and brain damage. There are
four basic categories of EEG waves:
1. Alpha: Waves that occur during a relaxed state and with the
eyes closed, derived mostly from the posterior part of the
brain and occurring at 8 to 13 Hz.
2. Beta: Fast waves (13–30 Hz) normally derived from the fron-
tal lobe and brought about by anxiety or opening the eyes.
3. Theta: Slow waves (4–7 Hz) normally present in children

under 13 years old during sleep but absent in normal, awake
adults. Theta waves in awake adults are suggestive of several
brain disorders.
4. Delta: Slowest waves (0.5–4Hz) also having the greatest
amplitudes. Delta waves are present normally during stage
3 and stage 4 sleep, but can be disturbed in several brain
disorders.
An electroencephalogram is a continuous record over time
of electrical activity in the brain. However, a variation of EEG
can also be used to record the electrical responses that are time-
locked to a specific stimulus or external event. These responses
are called event-related potentials (ERPs). The electrical signal
produced by a single event is very small and so ERPs are derived
from averaging numerous presentations of the stimulus or
event. The averaging process is used because it reduces the effect
of noise and amplifies consistent (time-locked) brain signals.
The electrical signals for an ERP study are recorded by a large
number of electrodes that are attached to the scalp via a cap
that looks like a hairnet. The advantage of ERPs is that they pro-
vide information about both where and when there is a brain
response to a stimulus. The timing information from ERPs can
be displayed as waves of voltage changes and the location of the
activity can be displayed as color maps. ERPs are commonly
used to study cognitive processes such as memory, attention,
and emotion.
Internet for neuronal tracers, antidromic activation, and phan-
tom sensations.
Modern Techniques to
4 Observe Human Brain Anatomy
The techniques that have been used in the past to see brain
anatomy are described in Chapter 3. Many of these classic
techniques are restricted for use in either experimental ani-
mals or in postmortem human brain tissue. This chapter will
describe some of the newer approaches that can be used to
see and measure anatomical structures in the intact, living
human brain.
What Type of Structures Can Be Seen?

Imaging techniques such as computed tomography (CT,
three-dimensional images created from a series of X-rays)
and magnetic resonance imaging (MRI) can be used to see
different structures of the brain. The human brain can be
divided into three basic compartments:
1. Gray matter: This compartment contains neuronal cell
bodies, some dendrites, and supporting tissues. For
example, the cerebral cortex and deep nuclei within the
brain are part of the gray matter.
2. White matter: This compartment contains neuronal axons.
Myelin, the insulating material that surrounds many
axons, has a white appearance—hence the term “white
matter.” Large bundles of projection fibers can be seen as
prominent areas of white matter in the brain.
31
3. Cerebrospinal fluid (CSF): The compartment contains the

clear, colorless fluid that helps move harmful chemicals
and waste products into the blood for excretion, and also
helps distribute hormones throughout the brain. CSF can
be found in the brain cavities (called ventricles) and also
surrounds the brain and spinal cord to act as a cushion to
protect these tissues from damage and pressure.
Structural MRI: What Can Brain Anatomy

Tell Us?
Brain anatomy can provide clues about how the brain functions
normally and can also reveal abnormalities due to disease or
injury. The fundamental concept of MRI involves an extremely
strong cylindrical magnet and radio frequency waves. The per-
son being scanned lies on his or her back and is placed inside
the large magnet. The strong magnetic field and radio frequency
waves will cause the hydrogen atoms in the brain to align with
this field, precess (a wobbly spinning motion like a toy top), and
emit a signal that can be detected by the scanner. The hydrogen
in the water molecules in different types of tissue in the body
(muscle, fat, CSF, gray matter, etc.) experience different envi-
ronments and so emit different signals as the atoms return to
their original positions. These different signals are used to create
the anatomical image.
Several types of MRI scans have been developed to see struc-
tural details of the brain. Structural MRI (sMRI) can measure
brain characteristics such as the shape, volume, and thickness
of cortical gray matter and show white matter connections in
fine detail.
Cortical Gray Matter Morphology

Cortical structure (morphology) can be studied using a man-
ual approach or an automated approach from high-resolution,
Modern Techniques to Observe Human Brain Anatomy 33
three-dimensional sMRI images. In the manual approach, the

borders of the brain area of interest are drawn by simply looking
at MRI images and marking the borders of the structure using
a computer drawing tool. Software is then used to calculate the
total volume and thickness of the region of interest. This is fairly
straightforward for brain structures that have clear borders with
white matter, ventricles, or neighboring areas that look more or
less dense (due to different neuronal packing). However, this
method can be time-consuming and tedious because border
marking needs to be done at each and every brain slice that
includes the brain area of interest.
More recently, automated software has been developed to
study gray matter morphology without the need for manual
border marking. This type of automated approach involves
a three-step computer algorithm. First, the MRI images that
contain brain tissue are identified. This step is important to
exclude the bone and nonbrain tissues from outside the skull
(because an MRI image will also include the eyes, head muscles,
etc.) from the analysis. Second, the algorithm transforms the
remaining brain information into a standard reference space
like the Talairach and Tournoux system (described in more
detail in the next chapter). The third step of the algorithm is
called “segmentation.” Segmentation is important to identify
and separate each part in the MRI images as belonging to one of
three brain compartments—gray matter, white matter, or CSF.
The final result of this three-step algorithm is a brain stripped
of white matter, CSF, and bone, and thus consisting strictly of
gray matter. Statistical analysis is then used to measure the gray
matter and compare the findings between different groups of
subjects or within the same subject at different points in time
(for example, before and following a medical treatment).
A widely used automated software is called voxel-based
morphometry (VBM). VBM can find differences in regional gray
Figure 4.1 MRI and voxel-based morphometry (VBM) were used to measure gray
matter changes associated with learning in medical students. The students had
MRI scans 3 months before their medical exams (scan 1), during their exams (scan
2), and then 3 months after their exams (scan 3). The analysis showed an increase
in gray matter in the posterior parietal cortex (A) and the hippocampus (B) during
the learning period.
matter density between two groups of subjects. A VBM analy-

sis can also include additional factors to assess the effect of
specific individual attributes such as age, gender, and disease
severity. VBM can also be used to track changes within the
same subject over time. For example, one study has shown that
extensive learning can increase the gray matter density within
the hippocampus (an area of the brain involved in knowledge
Modern Techniques to Observe Human Brain Anatomy 35
Figure 4.2 The utility of diffusion tensor imaging (DTI) is apparent in this example
of a 9-year-old girl with epilepsy. This girl was diagnosed with focal cortical dyspla-
sia. This is a small area of cortex that developed abnormally. This abnormality is
difficult to see on a standard MRI (T2WI), but a PET scan showed abnormally low
metabolism in the occipital lobe. The DTI scan was used to show decreased white
matter connections (tractography map) and branching in this area of the occipital
cortex. The map labeled “ROI Location” was used to create the tractography map.
“ROI” stands for “region of interest,” while “pcr” is the posterior part corona
radiata and “scr” is the superior part corona radiata.
acquisition and memory) and the posterior parietal cortex (an

area involved in attention and memory) (Figure 4.1).
Although VBM is a relatively new technique, it has already
been used in hundreds of studies that have identified gray
matter differences attributed to psychiatric and neurological
conditions, nerve injury, personality factors (such as neuroti-
cism), gender, aging, handedness, and even training. Another
sMRI technique is called cortical thickness analysis (CTA). CTA
is used to directly quantify cortical morphology, providing a
measure of cortical thickness (in millimeters) at every point in

every cortical region. CTA has been used to interrogate cortical
thickness in healthy subjects as well as those with diseases such
as schizophrenia and Huntington’s disease.
White Matter Connections

A new, exciting MRI-based technique called diffusion tensor
imaging (DTI) is now being used to visualize specific connections
between brain regions. The basic concept of DTI relies on visu-
alization of the diffusion of water molecules in the brain. The
dominant direction of water diffusion in the brain tends to be
along the long axis of axons in white matter. When diffusion is
restricted to a certain direction (such as within white matter) it
is referred to as anisotropic diffusion. In the presence of a mag-
netic field, DTI can visualize white matter tracts. Fiber tracking
with DTI can be used to identify the connections of a particular
area of interest and also the size and degree of myelination of a
white matter tract. DTI has been used to delineate anatomical
connections between cortical areas, and also between the cortex
and subcortical regions (including the brain stem and thala-
mus in healthy subjects). DTI has many scientific and clinical
applications (Figure 4.2). For example, DTI has been used to
examine the condition of tracts potentially damaged by stroke,
brain injury, tumors, and blindness. DTI has also been used to
assess cortical motor recovery following brain injury, anatomi-
cal changes associated with cognitive decline, and recovery from
a minimally conscious state. DTI holds great promise as both a
research and clinical tool because the technique is noninvasive
and relatively straightforward to carry out.
Internet for voxel-based morphometry and diffusion tensor
imaging.
Linking Behavior to
5 Brain Function in Humans
New emerging technologies to study the human brain pro-

vide a link between brain function and brain anatomy and
behavior in health and disease. These methods can be used
to study the mechanisms of movement, the senses, thoughts,
and memory. The modern methods to study brain function
do so either by directly or indirectly measuring the electrical
activity of the brain or by observing the effects of stimulating
the brain.
Inferring Brain Function from the Effects

of Brain Stimulation
Neurons in the brain can be stimulated directly with an
electrical pulse (voltage, current) or indirectly from a mag-
netic field. (Drugs, of course, will also stimulate or suppress
neurons but are not the topic of this book.) Modern brain
stimulation methods include deep brain stimulation (DBS)
and transcranial magnetic stimulation (TMS). Subjects are
awake during both DBS and TMS and so the effect of stimu-
lation can be assessed by observing the subjects’ behavior
or simply asking them to describe what they feel during the
stimulation. DBS and TMS effects are complex and can be
due to exciting neurons, suppressing neurons, or a mix of
both, depending on the stimulation parameters and the types
37
of neurons stimulated. Therefore, the term “stimulation” can

be somewhat misleading because, in some cases, the final effect
is inhibitory, sometimes even producing a temporary lesion.
These technologies are discussed in detail in Chapter 8.
Direct Measures of Imaging Brain Function

Fundamentally, neurons work by generating electrical sig-
nals (action potentials). Therefore, the nervous system can be
viewed as an enormously complex world of voltage changes and
current flowing from one place to another. One way to study
how the brain works is to use machines that can directly and
quickly detect where and how much electrical activity occurs
inside the brain. For example, as mentioned above, EEG is an
established method to study the electrical activity of the brain,
but it provides only an approximate position of the origin of
this activity. However, EEG can now be combined with MRI
to show the location of the electrical activity more precisely.
This approach, known as neuroelectric source imaging, is an
example of the direct modern imaging techniques that are based
on measuring electrical or magnetic signals. Another technique
in this category is magnetoencephalography (MEG). Chapter 6
describes these techniques in more detail.
Indirect Vascular-based Measures of

Brain Function
More than 100 years ago, British scientists Charles S. Roy and
Charles S. Sherrington made the important discovery that
linked blood flow in the brain to neuronal activity. This key
observation set the stage for modern neuroimaging techniques
such as positron emission tomography (PET) and functional mag-
netic resonance imaging (fMRI). We now know that active neu-
rons need an energy source. The source of energy can be ATP
(adenosine triphosphate) generated by glycolysis. The blood
Linking Behavior to Brain Function in Humans 39
vessels of the brain can deliver this energy source to where it is

needed via oxygenated blood. Modern vascular-based imaging
detects neuronal activity indirectly by measuring an aspect of
hemodynamics such as blood flow, oxygenation, or metabolism.
The most popular vascular-based imaging methods now being
used to study brain function are fMRI and PET.
Functional Brain Imaging in a Nutshell

A typical functional brain-mapping experiment using fMRI
or PET is straightforward. Typically, a study involves imaging
many subjects. Each of these subjects is imaged in one session,
or in some cases subjects may be imaged on several occasions
to follow an effect over time. During each imaging session, data
are collected during one or more runs. The amount of data that
can be collected at one time is limited by computer and other
technical capacities and so data are collected in chunks of time
called “runs”; a run being an amount of time of imaging during
which the experimental manipulation is presented (usually sev-
eral times). During each run, the brain is scanned many times
and each brain image is divided into slices that contain three-
dimensional rectangular boxes (the third dimension comes
from the thickness of the slice) called voxels. Statistics are used
to analyze how the manipulation has changed each voxel.
The seven basic steps to an imaging study are:
Step 1 — Obtaining Informed Consent

Before a study can begin, the person (the subject) who will be
scanned must be given information about the scanning equip-
ment, the experiment, and any possible risks of the procedures.
Most types of imaging are safe, although PET scanning requires
the injection of a small amount of radioactive chemical that
decays quickly (see Chapter 6). Based on all this information,
the subject must decide whether to participate. This is called
informed consent. Part of an informed consent ensures that

the subject knows that they are free to end the study at any
time. If the experiment is being done in an MRI scanner, the
subject is informed that they must remove all metal parts that
they are wearing such as belts, jewelry, watches, and some eye
glasses, and also that they must empty their pockets of all coins
and credit cards with magnetic strips (otherwise the cards are
demagnetized!).
Step 2 — The Experimental Manipulation

The actual experiment may not be very complicated. The
purpose of most imaging studies is to find out how the brain
responds to some sort of manipulation. There are three basic
types of experimental manipulations:
1. Do something to the subject. This usually means that some
sort of stimulus is presented or applied to the subject. For
example, if you want to study the senses, the stimuli would
be visual (a flashing light), auditory (a sound), olfactory (an
odor), gustatory (a taste), or tactile (touching the skin).
2. Have the subject perform a motor or behavioral task. A com-
mon motor task is to ask the subject to sequentially touch
his or her thumb to each finger on that hand. A behavior
task can involve making a judgment or decision or recalling
past events.
3. Treat the subject with a drug. There are many ways to find
out how a drug affects the brain. The study can look at the
response of the brain to the drug alone, or it can also look
at how the drug changes to brain response to a stimulus
or task.
A typical brain-imaging experiment will repeat the manipu-
lation many times. This is done to check whether the effect
is consistent and repeatable and not due to a chance event.
Repeated measures also help increase the “signal-to-noise” ratio
because the brain signal changes that occur due to an experi-

mental manipulation are small and sometimes overshadowed
by nonbiological “noise” induced by the scanner, subject move-
ment, and other factors. Repetition of the manipulation is usu-
ally done in a block or single-trial design. In a block design, an
approximately 15-to-30 second block of task (or stimulus) is
followed by an approximately 15-to-30 second block of rest or a
control task, followed by another task block, and so on for many
repetitions. Within each block, the task (or stimulus) is repeated
several times or maintained. In the single-trial (also known as
event-related design) design, each single task (or stimulus) is
separated in time from the next repetition by 10 to 30 seconds.
For example, to create a brain map of motor activity related to
hand movement, a block design could have the subject make a
fist over and over again for 30 seconds, then do nothing for 30
seconds, and then make a fist repeatedly again for another 30
seconds, and so on. This same experiment could be done with
an event-related design—the subject would make a fist once,
then rest before making a fist again, and so on. Why are there
two types of designs? The block design is quite popular because
it produces a stronger signal than the event-related design.
However, scientists prefer the event-related design when they
want to examine the effect of a short, specific task or stimulus
in isolation or when it is important to test a variety of tasks in a
random order, which would be too time-consuming to do with
a block design.
Step 3 — Gathering the Data

The gathering of data is called data acquisition. The exact
way this is done depends on the type of imaging method. All
experiments use a functional type of scan to acquire many
pictures of brain function while the experimental manipula-
tion is performed. This provides important data about how the
brain is working during the manipulation. But these functional
images are fuzzy to look at and so it is hard to see the brain

anatomy clearly. Consequently, another type of brain scan is
often acquired with the MRI to show fine anatomical detail of
the brain. Then, during data preprocessing (see next step), the
functional pictures can be superimposed onto the anatomical
pictures so that the location of the brain responses can be seen.
Step 4 — Preprocessing the Data

Before the data can be statistically analyzed, they must be pre-
processed (Figure 5.1). First, all the images have to be realigned
because the subject may have moved during the scanning. This
is like neatly stacking a deck of cards so that all the edges of
each card are lined up. This is an important step because, later,
the statistical analysis needs to examine the MRI signal at each
specific part of the brain (voxel) throughout the course of the
experiment. Next, the fuzzy-looking functional images need
to be aligned and coregistered (superimposed) with the high-
resolution anatomical images. Finally, the images need to be
normalized into a standard brain space system, such as the
Talairach and Tournoux system. This atlas was published in
1988 and soon became the standard coordinate system used to
describe the locations of structures in the brain. The atlas was
based on the brain of a 60-year-old French woman. The coor-
dinate system uses three dimensions to describe any location in
the brain in millimeters: X defines the left-right (lateral-medial)
dimension, Y defines the front-back (anterior-posterior) dimen-
sion, and Z defines the up-down (dorsal-ventral) dimension.
Figure 5.1 (right) The basic preprocessing steps in an imaging experiment include
aligning all the functional images and coregistering their positions to a high-
resolution structural image, morphing the images to fit a standard stereotactic
space (e.g., the Talairach and Tournoux atlas), performing a statistical analysis on
each voxel in the brain, and finally displaying the results in color-coded maps.
The atlas also includes labels for the names of the gyri, sulci, and
Brodmann areas.
Step 5 — Analyzing the Data

Data analysis is the critical step to determine the effect of the
experimental manipulation on the brain. An incredible amount
of data is acquired during a brain-imaging experiment and so
it is not possible to simply look at the data and figure out what
happened during the experiment. Not convinced? Consider a
typical fMRI experiment in which an image of the entire brain
is acquired every 2 seconds for 10 minutes during the experi-
mental manipulation (which is repeated several times to ensure
that the effect is reproducible)—that is a total of 300 pictures
of the brain. Now consider that each brain image can consist
of 28 two-dimensional horizontal slices, from the top of the
head down through the brain. Each of these brain slices cov-
ers a space of about 240 mm by 240 mm, and imaging software
can assess the MRI signal intensity within each square milli-
meter. Now, let’s do the math: 240 mm x 240 mm x 28 slices =
1,612,800 mm2 . So, the effect of the experimental manipulation
must now be checked at each of the more than 1.6 million vox-
els in the brain. Remember that there were 300 pictures taken
over the 10-minute experiment and so the data analysis requires
an assessment of each of the 1.6128 million voxels across the
300 time points—an enormous amount of data to look at!
And this is just in one subject. Consider that a typical imaging
experiment involves 10 to 30 subjects and that all this data must
be combined somehow. Fortunately, there are several free and
commercially available software programs that can handle this
staggering amount of data and perform statistical analyses to
reveal the effect of the experimental manipulation.
Statistical analyses can be complex, but the basic idea is to
see whether the MRI signal within specific areas of the brain
increases or decreases by a significant and consistent amount

during the experimental manipulation. It is also possible to
use statistics to determine whether other aspects of the experi-
ment or subjects themselves correlate with a change in brain
activity. For example, brain activity could vary with individual
subject characteristics (gender, age, personality, health, etc.),
how they perceive or perform the experimental task, or some
other effect of the experimental manipulation (such as drug
effect). Statistical analyses can be used to examine the effect of
an experimental manipulation (a treatment, training over time,
etc.) in individual people or in a group of people. The so-called
group analysis is a powerful way to study basic brain mecha-
nisms in healthy people and also to study brain abnormalities
in patients suffering from a specific disease. In a group study,
an inference is made about the entire population based on an
analysis of an experimental group of subjects (typically from 10
to 30 people) (Figure 5.2).
Statistics are used to determine whether a hypothesis is
supported by the experimental findings based on a specific
criterion, such as a certain level of statistical probability. The
neuroimaging field has some very general guidelines about sta-
tistical criteria, but there are no exact statistical thresholds that
are accepted by everyone in the field. Therefore, scientists must
decide for themselves what criteria they feel are valid for the
type of experiment being assessed. Remember, neuroimaging
cannot say with 100% certainty whether a specific area of the
brain is activated by a task. In some cases, it makes more sense
to err on the conservative side and in other types of studies it is
wiser to be more liberal with decision-making. This is a difficult
decision to make, especially if the results will guide a clinical
decision such as how much brain tissue can be safely removed
without causing permanent deficits during an operation for a
tumor (see Chapter 9).
Figure 5.2 Functional brain imaging can evaluate the effect of a

manipulation in an individual after a treatment or due to some sort of
training (such as playing a musical instrument). Brain imaging studies
can be done on groups of subjects so that the results can be compared
between groups (for example, between healthy people and patients).
Statistical methods can be used to infer an effect in the real popula-
tion based on studying a small group of subjects.
Step 6 — Visualizing the Results

Most statistical analysis imaging software programs will display
the results of the statistical analysis in colorful images. This can
often be the most dramatic and efficient way to communicate
the results of an imaging study. So, what’s with all those colored
blobs? The visual display of brain-imaging data is typically a
statistical map. The statistical analysis that was done in Step 5 is
simply converted into a color-coded map to show the location
and amount of difference in response during an experimental
task versus a control task within a group (or between groups).
Colors are used to indicate the amount of change (such as statis-
tical significance or probability) produced by the experimental
manipulation. Typically, “hot” colors like red, orange, and yel-
low are used to show increased brain activity and “cold” colors
like blue and green are used to show decreased brain activity.
Step 7 — Reporting the Experimental Findings

Now that all the analysis is done and the colorful pictures are
displayed, it is important to describe which parts of the brain
were “activated” in the experiment in a way that everybody can
understand. Imagine the chaos if all your friends spoke their
own personal language! How could you communicate your
ideas to each other? It is the same with brain-imaging ideas.
A standard system is needed so that everybody speaks the lan-
guage to describe or name brain areas (Figure 5.3). This “brain
language” should provide information about the exact brain
location and possible function of that location. Brain infor-
mation can be described with five types of descriptors using
anatomy and/or function:
1. Cortical lobe: This is the most general type of anatomi-
cal descriptor. The name of the lobe (frontal, parietal,
Figure 5.3 The five types of descriptors used to describe a location

within the brain.
temporal, or occipital) describes a general location and

implies a function.
2. Sulcus or gyrus: The name of the sulcus or gyrus is a more
specific anatomical descriptor than the general lobe name.
Gyri and sulci are also associated with functions. For
example, the postcentral gyrus is the first gyrus immediately
posterior to (behind) the central sulcus and is known to be
involved in body sensations.
3. Stereotactic coordinate: This is the most precise anatomi-
cal descriptor. A three-dimensional coordinate system has
been created to describe any location in the brain with an
X, Y, Z coordinate—the X is the left-right descriptor, the Y
is the front-back (anterior-posterior) descriptor, and the Z
is the up-down (dorsal-ventral) descriptor. A widely used
system is based on a standard brain atlas called the Talairach
and Tournoux atlas. In this system, the x-coordinate is the

distance (in millimeters) to the right (positive numbers)
or left (negative numbers) of the center of the brain. The
y-coordinate is the distance anterior (in front of, positive
numbers) or posterior (toward the back, negative numbers)
of the anterior commissure, which is one of the fiber paths
connecting the left and right hemispheres. The z-coordinate
is the distance above (positive numbers) or below (negative
numbers) the horizontal line connecting the anterior com-
missure to the posterior commissure.
4. Functional designation: This descriptor provides the general
function associated with a particular brain area. Functional
areas consist of either single gyri/sulci or larger regions.
For example, the postcentral gyrus is known as the primary
somatosensory cortex.
5. Brodmann area: This descriptor provides a fairly precise
location. Each Brodmann area is also associated with one or
more functions (see Chapter 2 for more information about
Brodmann areas).
Interpretation of Brain-imaging Findings

There has been an explosion of brain-imaging studies over
the past decade and so it is now time to think about what all
these data mean. Interpretation of neuroimaging data is com-
plex. Ultimately, data interpretation should provide interesting
insight into the mystery of brain function. However, before this
can happen, scientists must rule out sources of data contami-
nation due to technical complications, statistical uncertainties
(discussed above), and other nonspecific effects.
One technical question that must be asked is whether the
imaging machine is sensitive enough to detect the kind of brain
activity that is being studied. For example, in the early days of
fMRI, scanners had very low field strength and thus could not
generate a signal large enough to be distinguished above the

background noise of the system. Also, the spatial resolution
of low-field MRI machines and some older-generation PET
machines was not adequate to separate brain signals from small,
neighboring brain regions. The temporal resolution of fMRI
and PET is also limiting because these methods rely on slow
vascular responses.
Nonspecific physiological effects, such as changes in the sub-
ject’s attention and level of arousal (measured in heart rate and
blood pressure), can also contribute to the brain activations.
Therefore, the best way to avoid these effects from contaminat-
ing the results is to control for them in the experimental design.
For example, a study of brain mechanisms of pain can include
control scans that include nonpainful tasks that demand atten-
tion or increase heart rate.
The next question to consider in data interpretation is the
cause of the brain response. Sometimes the answer is obvious.
For example, if the task is to open and close your fist, then it
is likely that the brain response has something to do with the
control of movement. However, brain responses in studies of
cognition, memory, and pain are not that straightforward. In
these types of studies, the brain is doing many things. It is receiv-
ing information, assessing the information, and making judg-
ments about what to do with the information. Sometimes, clever
experimental designs and analyses can be used to separate the
brain activity related to the task (task-related activity) being per-
formed or the stimulus (stimulus-related activity) being applied
from the perception (percept-related activity) experienced by
the subject. Considering the timing of the different effects in the
data analysis can help separate these different effects.
Internet for functional brain imaging and Talairach atlas.
Modern Techniques to
6 Observe Human Brain Function
The most popular modern methods to image the human

brain are positron emission tomography (PET), functional
magnetic resonance imaging (fMRI), and magnetoencepha-
lography (MEG) (Figure 6.1). Older generation imaging
techniques (such as the xenon inhalation method) produced
only very low-resolution pictures of human brain function.
PET was the first modern higher resolution technique for
brain imaging, and was introduced in the 1970s. In the early
1990s, fMRI and MEG were developed.
Subjects are scanned in a supine position (lying on the
back, face up) for PET and fMRI, but some MEG machines
allow for subjects to sit upright. Scanning in both PET and
MEG machines is very quiet and not too claustrophobic so
subjects need to be engaged in a task to make sure they are
alert. MRI machines, on the other hand, make very loud
banging noises and so alertness is not a problem. Earplugs are
sometimes worn in the MRI machine to make the experience
more comfortable.
Functional Magnetic Resonance Imaging

Over the last decade, fMRI has become the most popular
method to study brain function in humans because it is
noninvasive and produces high-resolution pictures of the
51
A B
Figure 6.1 Three types of machines used to study brain function. (A) Functional
magnetic resonance imaging. (B) Magnetoencephalography. (C) Positron emission
tomography.
Modern Techniques to Observe Human Brain Function 53
Figure 6.2 The brain activations detected with fMRI are due to a blood oxygen-
ation level-dependent (BOLD) signal produced in response to neuronal activity.
working brain that can be used to localize brain function with

good accuracy (within millimeters).
How Does fMRI Work?

Functional MRI is an indirect measure of brain function
because it is based on the response of the vascular system in the
brain during neuronal activity. The fMRI signal occurs because
of a series of events, set in motion by the needs of active neurons
for oxygenated blood (Figure 6.2). The following summarizes
these events:
1. Neuronal and synaptic activity creates a local metabolic
demand.
2. The metabolic demand increases local blood flow beyond
what is usually needed.
3. The oversupply of oxygenated blood decreases the ratio of
deoxyhemoglobin to oxyhemoglobin.
4. The local magnetic field is altered because it is sensitive to
the local concentration of deoxyhemoglobin (deoxyhemo-
globin, but not oxyhemoglobin, is ferromagnetic).
5. There is an increase in the fMRI signal due to the blood oxy-
genation level-dependent (BOLD) effect.
6. A statistical comparison of the BOLD fMRI signal within a
voxel of the brain between the time of the task and a control
period will determine whether there was increased brain
activity in that voxel during the task (see Chapter 5 for

details).
The fMRI BOLD Signal

The response of the vascular system during neuronal activity is
the key aspect of fMRI. The BOLD effect is modeled by a math-
ematical function called a hemodynamic response function
(HRF) that describes when it occurs and its magnitude. The
typical HRF for an fMRI experiment starts at the beginning of
the task (or stimulus), gradually increases in strength over about
4 to 6 seconds and then slowly decreases in strength for another
6 to 8 seconds. This means that for a very brief burst of neuronal
activity, for example in visual cortex neurons responding to a
flash of light, the HRF lasts about 10 to 14 seconds. For a longer
or repeated task or stimulus (block design), the HRF also takes
several seconds to reach its peak amplitude, but stays at a high
level throughout the block and then returns to a baseline level
several seconds after the block is terminated.
The goal of fMRI is to locate specific brain functions.
Because fMRI does not measure the electrical activity of the
neurons directly, the HRF is very important because it is the
indirect representation of the neuronal response to the experi-
mental manipulation being studied. But how is the HRF used
in a typical fMRI study? Most fMRI analysis software creates a
predictor function that represents all the HRFs that occur in
the experiment. So, if there are 20 repetitions of the task, then
20 HRFs are strung together according to the timing of the
experiment to produce the overall predictor function. Then,
the software searches the entire brain to find the voxels that
have an MRI signal that is similar to the predictor function. A
statistical threshold is set to decide how close the voxel’s signal
must match the predictor function in order to be deemed an
“activated voxel.”
Pros and Cons of fMRI

The key advantages of fMRI compared to all other imaging
technologies is that it is relatively safe, noninvasive, widely
available (most hospitals and research centers now have an
MRI machine), and scans can be obtained in the same person
over and over again. These attributes of fMRI make it an ideal
method to study changes in a person during learning, training,
or due to a medical treatment. However, no method is without
its disadvantages. First, lying within the long bore of the magnet
is claustrophobic for some people and can cause serious anxiety.
Before placing people in the MRI, it is important to ask them
if they are prone to claustrophobia. Second, the strong magnet
needed for fMRI imposes restrictions on the type of equipment
used in the MRI room that could cause ferromagnetic inter-
ference. There are also serious safety regulations that must be
met to prevent injury to the subject being scanned (see below).
Another limitation of fMRI is that it does not actually provide
a numerical measure of ongoing brain activity (unlike PET, see
below), but rather identifies differences in brain signals between
states like a task and control.
Safety Issues
MRI is generally considered to be a safe, noninvasive technology.
However, there are several critically important safety measures
that must be adhered to for safe imaging because the strength
of the magnetic field in an MRI scanner is enormous and will
move any ferromagnetic item, no matter how light or heavy.
This is a serious issue. For example, even small movements of
the metal particles in some eye makeup can cause serious eye
damage. MRI in a person with an implanted pacemaker device
or aneurysm clip can be fatal. Therefore, careful screening for
metals or implants such as spinal or brain stimulators is needed
because some of these materials are ferromagnetic. The United
States Food and Drug Administration provides guidelines for

safe MRI imaging and worldwide each hospital and academic
center follows strict safety rules. These safety measures protect
the person being scanned but also ensure that the MRI machine
is not damaged. Before imaging, all subjects go through a
screening process to ensure that they do not have any ferromag-
netic metal items on their clothing, on their body, or inside their
body. Some safeguards include emptying pockets of coins and
credit cards and removing belts, shoes, and eye makeup (some
cosmetics have tiny metal particles) and any other items that
are ferromagnetic. Note that some metals are not ferromagnetic
such as those used in most dental braces and implanted ortho-
pedic screws. Additional screening that is done before an MRI
includes excluding subjects that are claustrophobic and women
that are or may be pregnant.
Positron Emission Tomography

The PET method was introduced in the 1970s but since then
the technology has been refined due to improvements in the
detection of positrons. PET is an imaging technique that can
detect biological parameters such as blood flow and metabo-
lism. These measurements provide information about neuronal
activity. PET can also be used to detect molecular events (for
example, neurotransmitters) at work.
How Does PET Work?

A PET scanner looks a bit like other types of brain scan-
ning machines (such as MRI or CT), but the way it works is
quite different (Figure 6.3). There are many detectors within
the scanner that are sensitive to photons (packets of electro-
magnetic energy). To create a PET image, the subject being
scanned is given an intravenous injection of a tracer substance
(a radionuclide) that has been made to be radioactive. The
Figure 6.3 The basis of PET imaging is the emission of a positron

(from a decaying radioactive tracer) that will release two photons
(gamma rays) when it collides with an electron. The location of
the radioactive tracer can be determined by the detection of the
gamma rays.
tracer distributes itself throughout the brain according to the

metabolic need of neurons, which is an indirect reflection of
neuronal activity. As the radioactivity in the tracer decays, it
emits a positron. This positron travels a small distance (mil-
limeters) and then collides with an electron. This causes the
release of two photons (also called gamma rays), that travel
out in opposite directions. The sensors in the PET scanner that
surround the head detect these gamma rays, and these signals
are used to determine the location of the positron emissions.
The images generated by a PET scanner are a bit fuzzy and so
sometimes a high-resolution MRI image of the subject’s brain
is also obtained and superimposed onto the PET image to cre-
ate a clear picture of the location of the PET data.
What Does PET Measure?

There are several aspects of brain function that can be meas-
ured with PET, depending on the type of radiochemical tracer
injected and its radioactive (half-life) properties. Some of the
commonly used positron emitters are 15O, 11C, 13N, and 18F. A
particle accelerator called a cyclotron makes these compounds.
The main types of PET brain function measurements are
cerebral blood flow, cerebral glucose metabolism, and receptor
binding.
Cerebral blood flow

To measure cerebral blood flow, a small amount of radioac-
tive water (H215O) is injected intravenously into the subject.
The water distributes itself throughout the brain via the cere-
bral blood flow according to the demands of active neurons.
Therefore neuronal activity is indirectly assessed based on the
amount of radioactivity detected. This type of PET scan mea-
sures the amount of radioactivity within the brain in about
60 seconds. The most important aspect of the H215O tracer is
its very short half-life (two minutes). This means that half of
its radioactivity is gone two minutes after the tracer is manu-
factured! Such a short half-life creates a tricky situation: The
special machine (the cyclotron) used to create the radioactive
compound must be very close to the PET machine so that the
tracer can be made, immediately injected into the subject, and
a scan obtained. Remember that brain responses can be some-
what variable and so scientists like to repeat their experiments
several times to get a reliable measure of brain function. Now

consider that a tracer with such a short half-life has mostly been
eliminated in about 10 minutes. After about 10 minutes, a sec-
ond injection of H215O can be made to acquire a second PET
scan, and after another 10 minutes a third injection can be made
for a third PET scan, and so on. This short half-life tracer is very
useful to collect multiple PET measurements without having to
keep the subject in the scanner for long periods of time.
Cerebral glucose metabolism

A tracer called FDG (18fluorodeoxyglucose) is commonly used
in medicine because it can detect cancerous tumors throughout
the body. The radioactive component of this tracer is 18F, which
has a half-life of 110 minutes. When the tracer is injected, it will
accumulate in tissues and cells throughout the body. The tracer
can indicate the amount of cell metabolism, and because it
accumulates faster in cancerous tumors cells than normal cells,
it has become a valuable tool to detect and monitor cancerous
tumor activity and evaluate the stage of cancer.
FDG is also used as a tracer to measure glucose metabolism
in the brain. What does this have to do with brain activity? It is
well known that most of the brain’s energy source comes from
glucose (ATP is derived from glucose) and so you can locate
where neurons are active by monitoring how much and where
glucose is metabolized. Scientists are still trying to determine
the exact way that FDG works to show neuronal activity in the
brain. Although there are many theories regarding this mecha-
nism, the general ideas involve glucose transport and metabo-
lism in both neurons and supporting cells in the brain.
Receptor binding
An exciting application of PET is for molecular imaging. PET
tracers can be made to compete with different types of neuro-
transmitters at their specific receptor binding sites. Receptor
binding studies are very useful to understand normal receptor

function and neurological and psychiatric disorders such as
epilepsy, Parkinson’s disease, Alzheimer’s disease, depression,
and chronic pain. Many tracers use 11C, which has an inter-
mediate half-life of about 20 minutes. For example, dopamine
receptor binding can be detected with [11C]-Raclopride, opiate
receptors with [11C]-Carfentanil, and benzodiazepine receptors
with [11C]-Flunitrazepam.
The Pros and Cons of PET

The most unique and powerful feature of PET is its ability to
detect the receptor binding of neurotransmitters and drugs.
Another great feature of PET scanning is that you are able to
observe how the brain is working at rest, without imposing a
task. This type of application is not possible with fMRI because
it is based on detecting changes between two states within a
scan. From a technical design and logistics view, the advantage
of PET scanning over MRI is that you do not need to worry
about magnetic fields. This means that anyone can have a PET
scan and you do not need to buy or design special non-ferro-
magnetic devices.
When you watch a PET scanner at work, you might won-
der if the machine is working because it does not make any
noise, unlike the extremely loud banging sounds made by
an MRI scanner. This quiet environment is actually one of
the advantages of PET scanning. But, if you do not want to
image a “sleeping brain,” you need to engage your subjects in
some task or else they may fall asleep in the calm environ-
ment. Another advantage of PET is that, unlike the long tube
of most MRI scanners, most PET scanners surround only
the head. This is less frightening and claustrophobic for the
subject. This open design also makes it easy to deliver stimuli
to the limbs.
Over the last 25 years, PET imaging has been restricted

because of the low availability of PET scanning centers with
cyclotrons. In recent years, there has been a significant increase
in the number of PET scanners, particularly in the United
States, but few of these scanning centers have a cyclotron and
so only clinical or experimental studies with very long half-life
tracers can be obtained.
The biggest disadvantage of PET imaging is that it requires
an intravenous injection of a radioactive compound. Every
country has strict controls over the use of radioactivity and
the amount that can be safely injected into an individual each
year. This limit dictates how many scans can be obtained in
each person. Finally, the spatial and temporal resolutions of
PET are not as refined as those of other imaging methods.
PET images typically cannot resolve spatial features less than
about 5 millimeters or temporal activity faster than a minute.
Safety Issues
PET imaging relies on positron emissions from an injection
of a small amount of a short-lived radioactive isotope tracer.
Academic and clinical institutions and federal agencies set strict
safety regulations that must be adhered to for the safe use of
radioactivity. These regulations cover both the type of radio-
chemical used and the amount that can be injected into an
individual in a given period of time. In general, the amount of
radioactivity that a subject is exposed to for a typical water scan is
similar to the exposure of a transatlantic air flight or a CT scan.
Magnetoencephalography
The MEG technique is a more direct measure of brain activity
than fMRI or PET because it does not rely on blood flow mea-
sures. Rather, MEG uses the direct link between an electrical
current and a magnetic field.
Figure 6.4 MEG and the right-hand rule. (A) The right-hand rule
describes the direction of the magnetic field that is generated by an
electrical current. With your right hand, point your thumb up and curl
your fingers. In this position, when your thumb points in the direc-
tion of the current, your curled fingers then show the direction of the
induced magnetic field. In the diagram, the rod represents the axon of
a neuron. (B) A MEG device has over 120 detectors that can record
the tiny magnetic fields that are produced by neuronal electrical activ-
ity. A mathematical model is used to compute the estimated source of
the original neuronal signal in the brain.
How Does MEG Work?

To understand how MEG works, you need to remember a basic
rule in physics that your science teacher may have taught you:
the right-hand rule (Figure 6.4). The right-hand rule shows the
direction of a magnetic field (your right-hand fingers curled

up) induced by an electrical current (the direction of your right
thumb sticking up).
Now think about what happens when a neuron is active. The
action potentials that move along the axon are voltage changes
that create electrical currents. These neuronally-generated
electrical currents will induce a perpendicularly oriented
magnetic field based on the right-hand rule. These magnetic
fields are very small, but when many neurons are active at the
same time, the summated signal can be detected just outside
the brain by special MEG detectors called as superconduct-
ing quantum interference device (SQUID) magnetometers.
In order to locate the source of the magnetic field precisely,
a MEG machine has many detectors placed around the head
in a device that looks like an old-fashioned hair dryer. Special
mathematical formulas are then used to locate the source of
the detected dipoles. The point source of the dipole relates
to the center of the greatest synchronous activity. Recently,
software has been developed to superimpose MEG data onto
high-resolution MRI anatomical scans to pinpoint the loca-
tion of the brain activity. This combined technique is known
as magnetic source imaging (MSI).
Pros and Cons of MEG

The most appealing aspect of MEG is that it is a noninvasive
technique that can provide precise information about the tim-
ing of brain responses with millisecond accuracy, and when it is
combined with MRI it can provide good localization. One limi-
tation of MEG is that it only provides a point source of activity
rather than an area of brain activity. Also, MEG is not as sensi-
tive to brain activity deep within the brain, and it cannot detect
radial (perpendicular) activity.
The use of MEG is restricted to a few centers in the world
because it is an extremely expensive machine and requires a
special shielded room to house the machine and protect it from
outside electromagnetic interference. Also, there are few highly

specialized scientists trained to operate the machine and analyze
the data with complicated computational modeling.
Neuroelectric Source Imaging

The EEG technique is one of the oldest methods to record
brain activity (see Chapter 3). As discussed in Chapter 3, ERPs
are a special type of EEG recording that show time-locked
responses to repeated stimuli. In recent years, the localization
of brain activity using EEG and ERP has been improved by
increasing the number of electrodes and merging the electro-
physiological data with MRI to aid in localization. There are
now mathematical models (similar to those that aid in local-
izing MEG dipoles) that help localize the source of the EEG/
ERP signals in the brain. The merged technique is known as
neuroelectric source imaging.
Internet for BOLD fMRI, positron emission tomography, and
magnetoencephalography.
Modern Techniques
to Observe Brain
7 Chemicals at Work
It is now possible to use brain imaging to study chemical

effects on the brain. Brain imaging can be used to mea-
sure the effects of chemicals such as over-the-counter and
prescription medications, chemicals naturally released
within the brain, and even illicit drugs. There are three
types of imaging technology used to investigate brain
chemicals at work: pharmacological MRI, MRI spectros-
copy, and PET.
Pharmacological MRI
Pharmacological MRI (phMRI) is a specific application of
fMRI designed to reveal the function of a drug. The basics of
experimental design of fMRI are described in Chapters 4 and
6. Remember that in a typical fMRI study, the task of interest
is done repeatedly, interwoven with some sort of control task,
and the action of the brain is determined by comparing the
brain activity between the two tasks. This design needs to be
modified to study the effect of a drug because different drugs
have different pharmacodynamics (their properties and times
of action).
In order to examine how a drug affects the brain with
phMRI, it is very important to have a basic understanding
65
of the properties of the drug. For example, it is crucial to know

how fast the drug can reach the brain, how fast it is expected
to have an effect, and how long the effect is expected to last.
This information will guide the timing of how the experiment
is run and also how the data will be analyzed.
Two aspects of brain function can be assessed with phMRI:
1. Direct effects: PhMRI can be used to study how a drug
directly changes brain activity. In this type of study, the brain
is monitored for a period of time to obtain resting, baseline
levels of activity. The drug is then administered to the sub-
ject (who stays in the MRI machine), usually by intravenous
injection, and the brain is monitored for changes in activity.
In this type of study, MRI data are continuously acquired
throughout the preinjection, injection, and postinjection
times. There are several limitations to this type of study.
First, only drugs with a rapid action can be studied because
subjects cannot lie in an MRI scanner for very long periods
of time. Thus, a drug that acts within seconds or minutes is
ideal. Second, it is difficult to control for nonpharmacologi-
cal effects (such as stress and anticipation), because the drug
is given only once.
2. Modulation effects: PhMRI can be used to study how a
drug modulates the brain’s activity during a task. This
type of phMRI combines the type of experimental design
of a typical fMRI study and the design of the direct effects
phMRI. Just as in the direct effects design, MRI data are
collected before, during, and after injection of a drug. In
addition, throughout the entire experiment, the subject
repeatedly performs a task of interest and a control task.
Now, the effect of the drug on the brain response to the
task can be examined. This design is also limited by the
Modern Techniques to Observe Brain Chemicals at Work 67
kinetics of the drug (as with the direct effects) and other
nonpharmacological effects. But, there is another experi-
mental design that can be used to study modulation effects
of drugs that last for a longer period of time (Figure 7.1).
This design requires three sessions, each of which consists
of the subject performing the tasks. There is one control
session (without the drug), one drug session (done after
the drug is given), and one placebo control session (done
after a placebo drug is given). In this clever design, the
subject does not know which drug is the real drug being
studied and which is the placebo drug.
Magnetic Resonance Spectroscopy (MRS)

Nuclear magnetic resonance (NMR) has been used for more
than 50 years in chemistry to determine chemical structures.
More recently, a modern technique called magnetic resonance
spectroscopy (MRS) was developed from the same principle
as NMR. MRS is a noninvasive method that is used to mea-
sure the concentration of more than 20 specific biochemical
compounds in the brain. The physical properties of nuclei
within these compounds determine whether they can be
observed with MRS. A phenomenon known as the chemical
shift occurs due to the difference in electromagnetic radia-
tion frequencies of NRM active nuclei, such as protons (1H)
or phosphorus (31P) in different chemical environments,
when placed in an external magnetic field. The chemical
shift is measured in parts per million (ppm). For example,
proton MRS (the most widely used type of MRS) generates
a frequency spectrum that includes several metabolites that
naturally occur in the brain (Table 7.1). This information can
provide clues about neurological abnormalities, psychiatric
abnormalities, or developmental abnormalities in children.
Figure 7.1 Pharmacological MRI (phMRI) was used to study the modulation
of pain due to an analgesic medication in a patient with painful arthritis. The
pain was made worse each time the subject’s joints were palpated (gray bars
in A). The brain images in part B show fMRI activations due to the joint palpa-
tion before treatment and a dramatic reduction in this activation after being
treated with a pain medication called COX-2i. The effect of a placebo control is
not shown.
There are three types of MRS methods:

1. Single-voxel MRS (“metabolic biopsy”) is a type of MRS
that measures spectra within one voxel in the brain to
produce a metabolic biopsy. This can be a sufficient mea-
surement to detect abnormalities that occur throughout
widespread regions of the brain. For example, several types
of metabolic or toxic disorders can be detected throughout

the brain. Single-voxel MRS can be used to study discrete
lesions, tumors, or strokes that involve areas of the brain
easily seen on an MRI. A single-voxel MRS is fast and has
high sensitivity and high resolution.
2. Multivoxel MRS (“metabolic brain map”) involves obtain-
ing spectra from several voxels at the same time. This can
be very useful to compare information between different
regions of the brain. For example, a “metabolic map” can
be derived with a multivoxel MRS. This type of study is an
exciting application of MRS with many clinical possibili-
ties in both neurology and psychiatry, but the data acquisi-
tion is quite time consuming.
3. Dynamic MRS is a variation of single or multivoxel MRS
that is used to study the effect of a drug or treatment over
time. With dynamic MRS, several measurements are made
before, during, and after a treatment. For example, the
effect of a drug on specific metabolites and neurotransmit-
ters can be followed over time with dynamic MRS.
Receptor Binding with PET

Receptor-binding studies with PET are used to examine the
action of neurotransmitters in the brain (see Chapter 6 for
an overview of PET and Chapter 2 for an overview of neu-
rotransmitters and receptors). In this type of study, different
experimental designs are used to measure the amount and
location of a specific type of receptor binding. The impor-
tant aspect of receptor-binding PET is to manufacture a
positron-emitting radiopharmaceutical tracer that is chemi-
cally similar to the neurotransmitter system that is being
studied. This tracer must be able to get into the brain after
being injected and must also have a strong affinity for the
Table 7.1 Metabolites Identified with Proton Magnetic Resonance

Spectroscopy (MRS)
Metabolites Location on Physiologic Significance

Spectrum
N-acetyl aspartate 2.02 parts per Seen only in neural tissue.
(NAA) million (ppm) Marker of neuronal integrity.
Reduces with most types of
insults to the brain. Increases
in Canavan’s disease.
Choline and other 3.2 ppm Linked to cell membrane turn-
choline-containing over, as in rapid cell division or
compounds (Cho) breakdown. Tumors or demy-
elination can increase levels.
Creatine and 3.03 and 3.94 Represents compounds related
phosphocreatine (Cr) ppm to energy storage. Often used as
an internal reference because it
is relatively stable in metabolic
disease.
Lipids 0.9–1.5 ppm Not seen in normal brain.
Represents membrane break-
down products. Increase has
been noted in necrotic tumors
and acute inflammation.
Lactate (Lac) 1.32 ppm– Not detected in normal brain.
doublet Presence indicates anaerobic
metabolism or failure of oxida-
tive phosphorylation as in mito-
chondrial diseases, ischemia,
inflammation, and tumors.
Myo-inositol 3.56 ppm Glial marker. Increased in some
forms of dementia and HIV
encephalopathy. High in infant
brain.
Glutamate (Glu) and 2.1 and 2.4 ppm Increases in hepatic encepha-
glutamine (Gln) lopathy/hyperammonemias.
Source: S.K. Gujar, S. Maheshwari, I. Bjorkman-Burtscher, and P.C. Sundgren, “Magnetic Resonance
Spectroscopy,” Journal of Neuro-Ophthalmology 25 (2005): 217–226.
neurotransmitter’s receptor so that it can stick to the recep-

tor. The amount and location of receptor binding can then
be measured with the PET scanner.
Receptor-binding PET studies can locate normal or abnor-
mal neurotransmitter binding during a behavioral task, as a
result of a stimulus, or due to drug treatment. For example,
PET scans using a tracer that binds to opiate receptors have
discovered that the brain normally releases its own endog-
enous opiates during pain. The more pain we have, the greater
amount of opiates is released to try to combat the pain. The
study also found that the opiate binding was at the sites pre-
viously known to be involved in pain perception and pain
modulation.
Receptor-binding studies with PET are very useful to deter-
mine whether there is a deficit in a particular type of neu-
rotransmitter-receptor system due to a disease. For example,
Nobel Prizes Related to MRI

Several Nobel Prizes have been awarded to scientists working
in the field of magnetic resonance. In 1991, Richard Ernst
was awarded the Nobel Prize in Chemistry for his contribu-
tions to the method of nuclear magnetic resonance (NMR).
In 2002, Kurt Wüthrich was also awarded a Nobel Prize in
Chemistry. His work applied NMR spectroscopy to determine
the three-dimensional structure of biological macromolecules
in solution. Then, in 2003, the Nobel Prize in Physiology
or Medicine was awarded to Paul C. Lauterbur and Peter
Mansfield, who both made key technological developments
that led to the use of magnetic resonance imaging in humans
for medical applications.
patients with Parkinson’s disease are known to have a reduced

amount of dopamine, and PET scanning has shown the loca-
tion of this deficit to be in the basal ganglia.
Internet for phMRI, MR spectroscopy, and PET receptors.
Modern Techniques
8 to Stimulate the Human Brain
Neurons in the human brain can be stimulated by deliv-

ering current directly to the brain tissue or by indirectly
inducing a current in the brain via a magnetic field placed
outside the brain. Two modern approaches are deep brain
stimulation (DBS) and transcranial magnetic stimulation
(TMS). With both techniques, the stimulation is localized
to a specific area of the brain and acts to trigger neuronal
action potentials or conversely may block conduction of
action potentials. Brain stimulation via TMS or DBS pro-
vides information about brain function and is used to treat
a variety of illnesses, including movement disorders, chronic
pain, and mental illnesses.
Electroconvulsive therapy (ECT) is an older brain-stimula-
tion method that was developed in the 1930s as a treatment
for depression. The early use of ECT on awake patients was
controversial, partly because of its side effects. However, the
modern use of ECT of the brain is administered under a
short-acting general anesthetic (with a muscle relaxant) and
is considered an effective and safe treatment for severe depres-
sion not managed with conventional therapies. The modern
methods of DBS and TMS differ from ECT in that they can
be used safely without general anesthesia and produce their
effect from focal stimulation of a limited area of the brain.
73
Transcranial Magnetic Stimulation

Transcranial magnetic stimulation (TMS) is a noninvasive method
that can be used to stimulate neurons in the brain of awake,
conscious humans. TMS can also be used to briefly disrupt
brain activity. The TMS technique was developed in the 1980s
and 1990s and is now a popular method that is used to explore
human brain function and to treat a variety of neurological and
psychiatric disorders.
How Does TMS Work?

TMS uses an insulated coil of wire that is held over the subject’s
head (Figure 8.1). A strong magnetic field is induced by sending
a brief electric current through the coil. This produces a mag-
netic field perpendicular to the coil (based on Faraday’s law) that
can penetrate into the brain. Once in the brain, the magnetic
field induces an electrical current at right angles to the magnetic
field, and the induced electric current can then stimulate neu-
rons. This may seem like a complicated way to excite neurons.
However, attempts to directly stimulate the brain with electrical
current (transcranial electrical stimulation) failed because the
high resistance of the skull and scalp to electrical current neces-
sitated very large voltages which spread to scalp tissues and were
painful. However, TMS avoids these problems because the skull
has a low impedance to the magnetic field. The volume of brain
tissue that is affected by TMS depends on the shape and size of
the coil. TMS can be directed to a specific area of the cerebral
cortex. There are several ways to determine where to place the
coil, including observing muscle twitches, using scalp landmarks,
and coregistrating the head and MRI-derived anatomy.
Single Pulse and Repetitive TMS

There are two ways to deliver TMS: brief, single, or paired
pulses of stimulation; and repetitive, high-frequency stimula-
tion (rTMS).
Modern Techniques to Stimulate the Human Brain 75
Figure 8.1 A TMS coil is placed on the scalp to deliver magnetic

stimulation through the skull and into the brain. The magnetic stimu-
lation induces an electrical current that excites neurons.
Stimulation pulses that are delivered in the single or paired

pulse method are spaced apart by at least one second. This
type of TMS is used to study brain neurophysiology in healthy
people and can also help evaluate motor function abnormali-
ties. For example, TMS at different locations of the motor cortex
can produce twitches of specific muscles and so can be used to
map the representation of muscles of the body. The speed of
brain neural conduction and the excitability of neurons, or how
easily neurons can be excited or fatigued, can also be studied
using TMS. For example, low-intensity TMS over the motor
cortex excites corticospinal tract neurons. These neurons are
the cells with cell bodies in the motor cortex that synapse onto
motor neurons in the spinal cord, which in turn cause muscle
contraction. A precise measure of the speed of conduction from
the motor cortex to the muscle can be made by using TMS and
monitoring the motor-evoked potential (MEP) in the muscle.
This is an important clinical measure because abnormal MEPs
suggest pathology in the corticospinal tract, such as in a stroke
or disease that affects the myelin sheath of neurons (for exam-
ple, multiple sclerosis).
TMS not only excites neurons but also can disrupt neural
function and provide information about the function of certain
brain areas. For example, high-intensity TMS over the motor
cortex can delay a subject’s ability to make a voluntary move-
ment, TMS over the occipital cortex can interfere with vision,
and TMS at other areas of the cortex can briefly interfere with
behavior or perception.
The rTMS technique uses pulses delivered at high frequency
of 1 to 100 pulses per second (Hz). These rapid pulses will
add up to produce a more powerful and prolonged effect than
single-pulse TMS. Like the single-pulse TMS technique, rTMS
can also be used to examine fundamental aspects of cortical
function. In addition, TMS is being developed for treatment
of neurological disorders such as stroke, migraine, and chronic
pain and for psychiatric illnesses including depression.
Deep Brain Stimulation

Deep brain stimulation (DBS) is a form of macrostimulation
delivered to the brain. DBS was developed to treat movement
disorders such as Parkinson’s disease, dystonia, and Huntington’s
disease. The brain target for movement disorders is in the basal
ganglia or thalamus. The success of DBS to reduce Parkinsonian
tremor is remarkable. In most patients, their tremor is dramati-
cally reduced or completely stopped as soon as the DBS device
is turned on. DBS has also been used to treat chronic pain and
obsessive-compulsive disorder, although it is not as effective for
these disorders as it is for Parkinson’s disease. Recently, however,
there has been a successful trial of DBS (within the cingulate

cortex) for depression (see Chapter 9).
How Are the Electrodes Implanted in the Brain?

DBS surgery is a multistage process that involves two surgi-
cal procedures. Because everyone’s brain is slightly different
in size, an MRI is obtained before the first surgery to identify
the location of the target brain area. To alleviate symptoms of
Parkinson’s disease and other movement disorders, the target
is either the motor thalamus or basal ganglia. For chronic pain
control, the target is the sensory thalamus and for depression the
target is in the cingulate cortex. The surgical procedure to insert
the DBS electrode is usually done under only local anesthesia
of the scalp so the patient can remain alert to provide feedback
to the surgeon during a mapping procedure and insertion of
the electrode. The mapping procedure involves determining the
behavioral, sensory, and motor effects of brief electrical stimuli
delivered through the electrode to several locations in the brain.
The aim of this mapping is to find the optimal location that
produces reduction of the patient’s symptom (for example,
stopping the tremor of Parkinson’s disease) without adverse
effects. In some academic centers, a detailed electrophysiologi-
cal functional mapping procedure is also performed with a fine
microelectrode to record the activity of individual neurons.
Different areas of the brain contain different types of neurons
with electrophysiological “signatures” and so microelectrode
mapping can provide important information that helps refine
the proposed target site.
After the DBS electrode has been inserted and implanted
at the target brain site, the electrode leads are connected to
a device called a pulse generator that controls the frequency
and intensity of the stimulation pulses. In a second surgical
procedure while the patient is under general anesthesia, the
B C
Figure 8.2 Deep brain stimulation involves insertion of an electrode

deep into the brain to deliver electrical current. (A) The electrode
is connected via a lead and extension (buried under the skin) to a
pulse generator that controls the amount and frequency of the current
pulses. (B) The MRI image shows a sagittal view of the location in the
thalamus of an implanted DBS electrode. (C) The X-ray image shows
two DBS electrodes and their leads.
pulse generator is implanted under the skin in the chest and

the wire leads from the electrode to the pulse generator buried
under the skin (Figure 8.2), similar to how a heart pacemaker
controller is placed in the chest wall.
How Does DBS Work?

The mechanisms underlying the effects of DBS are a topic of
intense research. One possibility is that DBS effects are due to
excitation of neurons near the electrode tip. However, it is also
possible that DBS actually blocks neuronal or synaptic activity.
The type of neurons near the electrode is an important factor
that determines the final impact of DBS. Some neurons release
excitatory neurotransmitters and other neurons release inhibi-
tory neurotransmitters. Furthermore, some neurons have long
axons that carry their effects to other areas of the brain. Other
neurons act locally. The stimulation frequency is another fac-
tor that may determine whether DBS acts to excite or block
neuronal activity.
Combining Techniques
Electrophysiological stimulation and neuroimaging techniques
can sometimes be used together to provide complementary
data. For example, fMRI can provide a broad view of how the
brain functions during a task. Figure 8.3 shows the location of
responses in the cingulate cortex when a subject was perform-
ing a mentally challenging task. The microelectrode recording
shown in the figure shows the response of single neurons in the
cingulate cortex during another difficult mental task. In this
case, the information from the fMRI tells you the approximate
location of the brain function, and the electrophysiological
experiments provide data about how the actual cells behave.
Combining different techniques is now popular for presurgical
planning (see Chapter 9).
Figure 8.3 Functional

MRI can provide a
visual image of the
location of the brain’s
response during a
task. (A) The image
shows responses in
the cingulate cortex
during a mentally-
challenging task. (B)
The microelectrode
recordings obtained
during a neurosurgical
procedure show how
B individual neurons in
the cingulate cortex
respond during a men-
tally-challenging task
(indicated by
the bars).
Some scientists use brain imaging to determine the effects

of DBS. Although there are safety concerns for doing MRI in
a patient with DBS electrodes, this method can be used under
carefully monitored and controlled conditions. However, it is
technically difficult to obtain clear fMRI pictures in a patient
who has implanted electrodes and wires. Therefore, most func-
tional brain imaging studies of DBS effects have used PET.
This approach has been used to examine DBS in patients being
treated for many types of disorders, including Parkinson’s dis-
ease, chronic pain, and depression.
Internet for electroconvulsive therapy, transcranial magnetic
stimulation, and deep brain stimulation.
The Future of
9 Brain Exploration
The new brain-exploration techniques reviewed in this

book have led to great discoveries about brain function and
structure over the last decade—discoveries about funda-
mental mechanisms of how we move, experience the world,
think, age, deteriorate following injury or with disease,
and respond to therapies. This information creates a better
understanding of the human brain, from birth until death,
how we change over time or adapt to our environment, and
how modern medical treatments work. Over the past decade,
new scientific societies (such as the Organization for Human
Brain Mapping) and research journals (such as Neuroimage
and Human Brain Mapping) have been established to help
disseminate and discuss all this new information. As will be
discussed in Chapter 10, this information comes with great
responsibility about how it is used.
Which Technique Is Best?

The classic and modern brain-exploration techniques all have
their own advantages and limitations. The choice of which
technique to use for a particular study is partly dependent
on practical, technical, and budgetary issues. Before under-
taking any study, it is best to identify the key questions. Are
you interested in anatomy, neurochemistry, or function? Do
81
you need to know something about the exact timing of brain

responses? Do you want to know something about how a single
neuron, a group of neurons, or an entire brain area responds
to a stimulus? Do you want to know how neurons talk to each
other? Each technique can tell you something interesting about
molecules or cells or brain networks.
How Do New Brain-exploration Techniques

Help Medicine?
Modern brain exploration techniques have the potential for
great impact on many branches of medicine, including neurora-
diology, neurology, neurosurgery, and psychiatry. The contribu-
tion of these exciting technical developments is already evident
in the areas described below.
New Treatments
The fundamental information about brain function discovered
with brain imaging and stimulation techniques can be used
to develop new ideas for medical treatment. A successful new
treatment for depression illustrates how neuroimaging can
guide and validate new treatment strategies. A series of PET
studies in patients with clinical depression showed that an area
in the cingulate cortex known as Brodmann area 25 was overac-
tive in treatment-resistant depression. This raised the question
of whether DBS could be used to modulate area 25. The first
trial of DBS in area 25 was carried out in six patients. The trial
Figure 9.1 (right) Combining MRI, PET, and DBS to treat depression. Patients
with severe depression have been treated with DBS within area 25 of the cingulate
cortex. (top box) The target area was first localized using MRI and then confirmed
with microelectrode mapping in the operating room. MRI scans after surgery
showed that the DBS electrode was correctly placed in the target area. (bottom
box) PET studies in these patients before and after DBS found that the abnormal
cingulate cortex blood flow was reversed by the DBS in the patients that improved
with treatment.
The Future of Brain Exploration 83
led to a remission of severe depression in four of these patients

and PET scanning in these patients showed a reduction of blood
flow in area 25 (Figure 9.1).
In the future, brain imaging may also guide planning for
treatment and rehabilitation strategies in patients with stroke,
nerve damage, and other injuries. This type of personalized
therapy will be possible if brain imaging can detect early
markers of therapeutic benefit. For example, how a person’s
brain is wired or how it changes early after an injury could be
predictive of potential improvement with one type of therapy
compared to another. It may also be possible to measure the
effect of a particular medication in the brain so that the dose
can be adjusted according to the individual’s response. In fact,
assessing an individual’s receptors for specific drug therapy
(for example, drugs used to treat symptoms of schizophrenia
or depression) could help predict which type of drug will be
the most effective treatment.
The Brain-machine Interface and Neuroprosthetics

The first neuroprosthetic devices were developed to allow peo-
ple who are deaf to hear. Cochlear implants convert different
frequencies of external sounds into stimuli that activate neural
cells (hair cells) within the ear, and these hair cells activate the
auditory cortex so that a person can perceive sounds.
A brain-machine interface (BMI) is a device that is controlled
by brain activity. Imagine if paralyzed patients could control the
movement of a computer cursor, a prosthetic arm, or a motor-
ized wheelchair just by thinking! This type of futuristic device
is becoming a reality. The construction and implementation
of these devices requires the collaboration of basic scientists,
physicians, engineers, and computer software specialists. The
vast knowledge gained from electrophysiological studies of the
motor cortex and parietal cortex is now being used to generate
models of how we move. Basically, a BMI translates the activity

of a large number of neurons recorded from a multi-electrode
device implanted in the cortex (or via EEG) while the patient
is thinking about moving, into the action of a device. Early tri-
als of this concept in a small number of patients have shown
that BMI can work. In one trial, electrodes were implanted
into the motor cortex of a patient paralyzed following a spinal
cord injury. Through a BMI, the patient was able to control the
movement of a computer cursor. This enabled the patient to
read his e-mail, watch different TV stations and even control a
robotic device to handle objects.
Presurgical Mapping
Some neurosurgical procedures destroy brain tissue, for exam-
ple, to remove tumors or treat epilepsy. Surgeons must decide
how much tissue can be removed without causing devastating
side effects such as paralysis or loss of speech. Identification of
brain function with imaging (PET, fMRI, MEG) and stimula-
tion before surgery can provide valuable information to neu-
rosurgeons and possibly reduce or avoid functional deficits.
This application of neuroimaging for presurgical mapping is
common in large academic surgical centers. Presurgical map-
ping is required because the precise location and size of an
essential brain area for a particular function can vary from
person to person. One example of presurgical mapping is to
localize language function. The standard test for localizing
language used to be the Wada test. In this test, sodium amytal
is injected into the left or right internal carotid artery so that
either the left or right brain is temporarily put into a sleep
mode. The patient is then shown pictures and asked to name
them to test language and memory. Although the Wada test
is usually done without complications, it is invasive and tells
only if language is located primarily in the left or right brain.
The fMRI-based test for language is safer and also provides

more precise information about language localization. This
information can be considered before epilepsy surgery to
minimize severe language deficits.
The concept of statistical analysis of functional neuroimag-
ing data introduced in Chapter 5 becomes extremely important
for presurgical mapping studies. Remember that the pictures
of brain function that are created from neuroimaging data
are simply a representation of brain activity that increases (or
decreases) during a task based on statistical decisions as to what
constitutes a significant enough change in activity. Scientists
must decide whether to err on the conservative side or the liberal
side. These decisions can be crucial if the result is being used for
surgical decisions. Because there is no way of being absolutely
sure about a result, neurosurgeons use additional information
from other sources (such as macrostimulation) to guide final
surgical decision. Presurgical mapping with fMRI and/or MEG
can also supplement electrophysiological data obtained during
surgery to help guide placement of DBS electrodes into a spe-
cific brain area.
Image-guided Neurosurgery
Global positioning systems (GPS) have revolutionized the way
geographic locations can be found and tracked. A similar con-
cept is being developed for neurosurgery. In the future, many
types of neurosurgical procedures (including tumor removal
and biopsies) will use image-guided systems to help locate and
treat a specific part of the brain or spinal cord. Advances in MRI
technology combined with localization software and robotics
are now being introduced into neurosurgical operating rooms.
Before surgery, a patient will undergo MRI to create a three-
dimensional model of his or her brain anatomy (and in some
cases also functional information). This information can be
registered to the location of the surgeon’s instruments, and the
combined image of instrument and anatomy can then be dis-

played to the surgeon on a computer screen. Image-guided sur-
gery enables surgeons to be more precise in making their initial
incision and in reaching the area to be operated on regardless
of visual obstacles.
Individual Variability, Diagnostics, and Genetic Testing

There is tremendous variation in human behavior. Neuroimaging
is now being used to study individual differences in brain mech-
anisms that underlie normal brain function and behavior. For
example, neuroimaging has identified differences in brain func-
tion and structure associated with traits such as handedness,
age, gender, and sexual orientation in healthy individuals. A
tremendous research effort is also under way to examine abnor-
mal variations in brain function and structure in patients with
neurological and psychiatric disorders. Finally, there is ongoing
research into the “criminal mind.” For example, structural and
functional imaging has shown abnormalities in the brains of
psychopaths and pedophiles. These studies raise ethical, legal,
and societal questions discussed in Chapter 10.
Neuroimaging can also be used to study the link between
brain function and genetics. The goal of these types of clini-
cally related studies is to establish indicators of susceptibility
for certain diseases. Recent advances in both fMRI and PET may
provide new tests to assess the genetic risk for Alzheimer’s dis-
ease, depression, chronic pain, and other conditions for which a
genetic factor is identified.
A large research effort has focused on finding genetic
variables associated with Alzheimer’s disease. Neuroimaging
studies have also identified abnormal brain metabolism and
task-related brain activity in patients with Alzheimer’s disease
and other milder forms of cognitive impairment. PET studies
showed abnormally low metabolism in certain areas of the cor-
tex in patients with Alzheimer’s disease. A recent study brought
Figure 9.2 This PET study discovered reduced cerebral metabolism in several
brain areas in healthy people who have a high APOE4 gene dose (i.e., the number
of alleles). Low metabolism in these brain areas was previously found in patients
with Alzheimer’s disease. This suggests that these people may be at risk for devel-
oping Alzheimer’s disease. PT=parietotemporal, F= left frontal, PCu=precuneus,
PC=posterior cingulate cortex.
together the fields of genetics and imaging. This study (Figure

9.2) found that people with more alleles (alternate forms of
a gene) of the apolipoprotein E type 4 (APOE4) gene have
reduced blood flow in certain areas of the brain that are associ-
ated with an increased risk of developing Alzheimer’s disease.
Another example of using PET to study genetic variability
comes from a recent study of pain sensitivity. The scientists were
interested in exploring a link between a genetic variability in the
metabolism (breakdown) of neurotransmitters and how people
Figure 9.3 Catechol-O-methyltransferase (COMT) is an enzyme that metabolizes

catecholamines such as noradrenaline and dopamine. This PET receptor binding
study demonstrated a COMT val158met polymorphism (genetic variation) is linked
to the response of the endogenous opiate system in several brain regions during
pain. These and other data (not shown) linked the presence of particular forms of
the COMT gene with diminished release of brain opiates and greater pain sensitiv-
ity. 1 = thalamus; 2 = nucleus accumbens; 3 = ventral pallidum.
experience pain. They found that the metabolism of catechol-

amines by the enzyme catechol-O-methyltransferase (COMT)
can vary in different people because of a genetic variation of
COMT. Catecholamines are a group of neurotransmitters that
include norepinephrine (noradrenaline) and dopamine. The
noradrenergic and dopaminergic systems have been associ-
ated with opiate function in the brain. A PET study of brain
responses to painful stimuli in people with these different forms
of COMT found a link between the polymorphism, pain sensi-
tivity and the amount of opioids released and bound to certain
pain and analgesic areas in their brain (Figure 9.3). This showed
how genetic variability contributes to individual differences in
our ability to feel and combat pain.
In another example, voxel-based morphometry was used to
show that a genetic variation (polymorphism) of the gene for
a protein called brain-derived neurotrophic factor (BDNF) is
associated with decreased gray matter in key areas of the brain
(the hippocampus) involved in learning and memory.
More direct applications of neuroimaging have become use-
ful in medicine. Metabolic imaging with PET is being developed
to assist with the diagnosis of many diseases. The most devel-
oped application uses 18F-FDG to detect tumors. PET can also
be used as one of the technologies used to test for Parkinson’s
disease, Wilson’s disease, and dementias such as Alzheimer’s
disease. In the future, further developments of PET tracers may
provide diagnostic testing for other neurological conditions.
Internet for brain machine interface, image guided neurosur-
gery, and brain imaging genetics.
The Impact of
Brain-exploration
10 Techniques on Society
Neuroscientists and cognitive psychologists previously

studied biological and psychological problems quite isolated
from the public eye. Perhaps this is why the scientific world
may have appeared to be very mysterious to those outside of
research and medicine. However, more and more, scientists
are “going public” with their work so that society can under-
stand what they are doing and why their work is important.
There is now widespread media coverage of scientific discov-
eries and ventures that help the public understand some of
the fascinating work being done to solve the great mysteries
of the brain. To further raise awareness and funding for brain
research, the United States Congress declared the 1990s as the
Decade of the Brain. In 1999, the United States Postal Service
issued a stamp to commemorate the advances in medical
imaging. The explosion of the Internet now means that infor-
mation about neuroscience and technology is available at the
click of a mouse. The amazing new technologies discussed in
this book and public awareness of these technologies has led
to the development of new fields such as neuroethics, neuro-
marketing, and neuroeconomics.
Neuroethics
Neuroethics is a relatively new field focused on bioethi-
cal issues as they pertain to the recent explosion of new
91
brain-exploration technologies. Bioethics has been an active area

of study for quite some time. The development of cloning tech-
nology re-ignited discussion of bioethics, including the concept
of eugenics.
The Dana Foundation and scientific organizations such as
the Society For Neuroscience (SfN) and International Brain
Research Organization (IBRO) are raising scientific and pub-
lic awareness of neuroethics through dialogue, seminars, and
publications that address the history of neuroscience ethics.
Furthermore, many universities and research institutes provide
their students and established scientists with educational mate-
rial about historical ethical violations concerning human and
animal experimentation. There are strict ethics guidelines that
must be adhered to for approval of any study involving human
and animal subjects. Most recently, many public funding agen-
cies and academic centers have made it mandatory for their
researchers to complete an ethics course that includes historical
material about abuses of human experimentation.
The new brain-exploration techniques discussed in this book
raise some key ethical questions such as the following, as noted
at neuroscientist Dr. Eric Chudler’s Web site “Neuroscience
for Kids.”
What if machines could read your mind?
What if machines could predict a future neurological or
mental disease?
What if drugs, machines or genetic engineering could
increase your memory and intelligence?
What if memories could be erased?
What if the brain could be controlled from a distance?
Not that long ago, these questions would have seemed to
be in the realm of science fiction. But now, the questions
are not that farfetched and need to be considered given the
development of technologies such as fMRI, PET, MEG, and
The Impact of Brain-exploration Techniques on Society 93
DBS, and in combination with other technologies such as

robotics and genetic analysis. Brain recording and stimulation
techniques for military, private, and public applications have
legal, social, and privacy implications. Currently, the accuracy
of most imaging and stimulation methods is not quite good
enough to be used for such things as mind reading, although
there has been some discussion in the justice system about the
use of fMRI as a lie detector. Drugs currently on the market
(such as Ritalin) can and have been used to modify behavior
and so issues about the mind and behavioral modification
have long been considered. Similarly, the advances in genet-
ics have opened serious discussion about the ethical issues
of genetic modification. Is there any reason to worry about
these new technologies? Most scientists agree that these new
technologies offer promising new ways to improve health and
Key Moments in the History of Neuroethics

In the late nineteenth and early twentieth centuries, the intro-
duction of prefrontal lobotomies generated much public outcry.
The Nuremberg war crimes trial in 1945–1946 focused on the
gruesome human experiments carried out by the Nazis during
World War II. Early in the 1970s, the public became aware of
the Tuskegee syphilis experiment (1932–1972) that withheld
treatment in 399 black men who were in the late stages of
syphilis. This led to the formation of special committees within
scientific organizations to discuss social issues. In addition, the
National Institutes of Health Belmont report set out guidelines
for the ethical treatment of human subjects. Further advances
in the protection of human subjects, public awareness, and
scientific discussion of ethics continue today.
Source: J. Illes and S.J. Bird, “Neuroethics: A Modern Context for Ethics in
Neuroscience,” Trends in Neuroscience 29 (2006): 511–517.
medicine, but there is always the possibility for misuse of tech-

nology. Therefore, it is prudent to have open, informed, and
balanced discussions about neuroethics.
Neuromarketing
For decades, companies have relied on behavioral and psycho-
logical studies to guide marketing campaigns. Now, the devel-
opment of brain imaging techniques has ignited the fields of
neuromarketing and neuroeconomics. These fields are looking
at brain responses to different foods, tastes, and smells, and
the impact of advertising and other cultural influences on the
choices we make—the neurological basis of choice. A few groups
are using brain imaging to try to determine how to predict buy-
ing habits. Why would companies use such sophisticated and
expensive brain-imaging techniques to study brand preferences
and tastes when all they have to do is hold focus groups and
simply ask people what they like? Well, some neuroimaging data
suggest that sometimes people are not aware that they have a
strong preference for one brand over another. Perhaps buying
decisions are due to activity in the brain’s reward or pleasure
areas in response to one item compared to another item. Indeed,
using fMRI to study reward systems and decision-making is an
active research area.
There is solid science behind this new field of the neuro-
logical basis of choice. For many years it has been known that
there is cross-talk between the sensory systems. Our overall
perception depends on an integrated response to what we see,
feel, taste, smell, and hear. Behavioral choices such as the kind
of food or drink we prefer can be influenced by all the senses
and also by expectation, and by cultural and social factors.
Brain imaging provides a readout of the integration of all
these factors.
The Impact of Brain-exploration Techniques on Society 95
Perhaps you have heard of the Pepsi® Challenge. This was a

much-publicized test set up at county fairs and malls through-
out North America in the 1970s in which people were asked to
select which of two unmarked colas (Coca-Cola® or Pepsi®)
tasted better. Slightly more people chose Pepsi® even though
Coca-Cola® had been outselling Pepsi®. Since the original chal-
lenge, there has been much said about the validity of the blind-
ing of the two drinks. Regardless, the challenge raised the issue
that people develop brand loyalty for a variety of reasons, and
not solely because of a taste distinction. Recently, a brain imag-
ing by Read Montague at Baylor College of Medicine looked
more closely at brain responses in the Pepsi® challenge. In this
study, when the drinks were unmarked, about half of the sub-
jects that said they preferred Pepsi® actually chose Coca-Cola®
and vice versa. However, when the subjects knew which drink
was Coca-Cola®, more said that it tasted better. The imaging
results showed greater activity in an area of the prefrontal cortex
in subjects that chose Coca-Cola® and there was an enhance-
ment of the brain response to drinking Coca-Cola® when sub-
jects were told to expect that they were being given Coca-Cola®.
This study illustrates that marketing and preconceptions can
alter preferences and brain responses.
SUMMARY
The brain is extraordinarily complex but can be thought of
as a map of small roads and highways that connect one place
to another. In the brain, white matter tracks (axons) are the
roads and highways that connect and provide communication
between relay and integration stations, which contain neurons
(the gray matter). Many types of methods using anatomical
tracers, electrophysiology, or imaging can be used to see where
the roads go and what the stations look like.
This book provides a brief look at the technology and proce-

dures that allow us to “see” inside the human brain. These tech-
niques will no doubt unravel some of the fascinating secrets of
the brain and improve medical practice, but will also introduce
important ethical and societal issues.
Internet for neuroethics and neuromarketing.
Glossary
Action potential An electrical current that propagates along a
neuron’s axon.
Blood oxygenation level-dependent (BOLD) Functional magnetic
resonance imaging (fMRI) depends upon the BOLD effect, so the
brain response in fMRI is known as the BOLD response (or
BOLD signal).
Cerebrospinal fluid (CSF) This compartment contains clear, colorless
fluid that helps move harmful chemicals and waste products into the
blood for excretion and also helps distribute hormones throughout
the brain.
Cognition Mental functions related to thoughts or perceptions.
Deep brain stimulation (DBS) Electrical stimulation of the brain
delivered by an electrode implanted into a cortical or subcortical
region of the brain.
Diffusion tensor imaging (DTI) An MRI-based technique to visualize
white matter connections.
Electroencephalography (EEG) A technique that uses skull surface
electrodes to record the electrical activity of the brain.
Event-related potential (ERP) A variant of EEG that shows electrical
activity of the brain that is time-locked to an event or stimulus.
Ferromagnetic Highly magnetic; a substance that is attracted by
a magnet.
Functional magnetic resonance imaging (fMRI) An imaging technique
that indirectly locates and measures brain function based on changes
in brain blood flow and oxygenation.
Gray matter One of the compartments of the nervous system, which
contains neuronal cell bodies, dendrites, and supporting tissues.
Gyrus A ridge (top part) of the surface of the cerebral cortex.
Hertz A unit of frequency in cycles per second, abbreviated as Hz.
Magnetic resonance imaging (MRI) A technique that produces
images of brain structure.
Magnetoencephalography (MEG) An imaging technique that locates
the source of electrical activity in the brain.
97
Motor cortex An area of the brain that controls movement.
Myelin A fatty substance that surrounds and insulates some
nerve fibers.
Neuron A nerve cell.
Neurotransmitter A chemical that acts as a messenger from one
neuron to the next. It is released at the end of a nerve terminal
into a synapse to influence the activity of the next neuron.
Positron A particle that is positively charged and has the mass of
an electron.
Positron emission tomography (PET) An imaging technique that
indirectly measures brain function (based on blood flow) and brain
chemical action (based on neuroreceptor binding).
Radionuclide An unstable form (isotope) of an element that
is radioactive.
Repetitive transcranial magnetic stimulation (rTMS) A variant of
the TMS technique that uses magnetic fields to induce electrical
stimulation of specific regions of the brain.
Structural magnetic resonance imaging (sMRI) A variation of MRI
used to produce detailed images of gray matter or white matter.
Somatosensory cortex An area of the brain involved in sensations
such as touch and pain.
Statistical parametric mapping (SPM) Software that is used to analyze
brain-imaging data and produce functional brain maps.
Sulcus A groove in the depths of the cerebral cortex.
Synapse The gap between two nerve cells where communication takes
place.
Transcranial magnetic stimulation (TMS) A technique that uses
magnetic fields to induce electrical stimulation of specific regions
of the brain.
Voxel-based morphometry (VBM) Software that assesses gray
matter density. A voxel is a three-dimensional unit of structure
(as opposed to a pixel, which is a two-dimensional unit).
98
White matter A compartment of the nervous system that
contains axons. White matter is so named because of its light
appearance due to the fatty insulating substance called myelin that
surrounds axons.
99
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105
Picture Credits
2: © The Granger Collection, 57: © Infobase Publishing
New York 62: © Infobase Publishing
4: © The Granger Collection, 68: Reprinted with permission: M.
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20: © Infobase Publishing 75: © Infobase Publishing
23: © Infobase Publishing 78: (a) © Infobase Publishing;
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34: B. Draganski, C. Gaser, (c) Courtesy of Dr. J. Dostrovsky
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106
Index
Acetylcholine, 17 Benzodiazepine
Action potential receptors, 60
and neurons, 13, 16–18, 26, 28, 38, Biocytin, 22
63, 73 Bioethics, 92
Adenosine triphosphate (ATP) Blindness, 36
energy source, 38–39 Blood oxygenation level-dependent
Aging (BOLD) effect
effects on brain, 6, 35, 81 and fMRI, 53–54
Alzheimer’s disease, 60 BOLD effect. See Blood oxygenation
research, 87 level-dependent (BOLD) effect
risk for, 87–88, 90 Brain
Amygdala basic anatomy, 19–21
functions, 12 damage and disability, 3, 6, 9, 19,
Anterograde transport, 22–24 26, 29–30, 36–37, 45, 68, 81, 85
ATP. See Adenosine triphosphate drug effects on, 40, 65–72, 84
Attention functional systems, 10–18, 37–64
control of, 35 modern techniques, 1, 3, 31–39,
study of, 30 51–64, 79–82, 84
Auditory information planes, 19–21
control of, 12 protection, 32
improvements, 84 structures, 1, 10–18, 21–24, 31–36
stimuli, 40 study of functions and structure,
Axons 1, 3, 6, 19–30, 38, 66, 73–75, 79,
damaged, 21–22, 24, 36 81–82, 85, 87, 89–90, 93, 95–96
functions, 13, 16, 18, 27–28, Brain-derived neurotrophic factor
63, 79 (BDNF), 90
myelin of, 21–22, 31, 36, 76 Brain imaging
splitting, 28 and axon pathways, 22
terminus, 21–23, 26–28, 95 basic steps to, 39–42, 44–45,
47–49
Basal ganglia direct measures of, 38
deficits or damage in, 72, 76 functional, 13
functions, 12 future of, 81–90
BDNF. See Brain-derived importance, 3
neurotrophic factor indirect vascular-based measures
Behavior, 2, 6 of, 38–39
and brain function, 37–50 interpretation of, 49–50
control of, 12 modern techniques, 1, 3, 6, 31–32,
and genetics, 87 37–39, 51–64, 81–90
modification, 93 uses, 6–9, 40, 91–96
stimulation, 77 Brain-machine interface
tasks, 40, 94 uses, 84–85
107
Brain stem Computed tomography (CT), 56, 61
functions, 10 structures seen with, 31–32
structures, 10, 36 Conscious thoughts, 6
Brain stimulation, 55 control of, 10, 12
effects of, 37–38, 82 Cortical thickness analysis (CTA)
and epilepsy, 5 uses, 35–36
importance, 9, 93 Corticospinal tract
modern techniques, 1, 73–80, 85 neurons, 75–76
and recording, 3 CSF. See Cerebrospinal fluid
Brodmann, Korbinian CT. See Computed tomography
areas of brain functioning, 13, CTA. See Cortical thickness
44, 49 analysis
research, 82
Dana Foundation, 91
Canavan’s disease, 70 Data
Cell body, 31 analyzing, 44–45
changes in, 21–23 gathering, 41–42
functions, 26–28 preprocessing, 42, 44
structures, 13, 75 DBS. See Deep brain stimulation
Cerebellum Deep brain stimulation (DBS), 37
functions, 10 how it works, 76–77, 79–80
structures, 10 as treatment, 73, 76–77, 80, 82,
Cerebral blood flow 84, 86, 93
measurement, 58–59 Degeneration, 21–22
Cerebral cortex, 31 Dendrites, 22, 31
corpus callosum, 12 functions, 13
functions, 12–13 Depression, 60
gyri, 12, 19, 44, 48–49 risk for, 87
lobes, 12, 19, 47–48 treatment of, 73, 76–77, 80, 8
macrostimulation of, 7–9 2, 84
research, 13, 36 Dextrans, 22
sulci, 12, 19, 44, 48–49 Diffusion tensor imaging (DTI)
and TMS, 74, 76 uses, 36
Cerebral glucose metabolism Dopamine, 17–18, 89
measurement, 58–59 levels in Parkinson’s disease, 72
Cerebrospinal fluid (CSF), 33 receptors, 60
function, 32 DTI. See Diffusion tensor imaging
Cerebrum. See Cerebral cortex Dystonia, 76
Chudler, Eric, 92
Cochlear implants, 84 ECT. See Electroconvulsive therapy
Cognitive functions, 10 EEG. See Electroencephalography
control, 12 Electroconvulsive therapy
studies, 30, 50 (ECT), 73
108
Electroencephalography (EEG) early, 49–50
improvements, 64 goals of, 54
with MRI, 38, 64 how it works, 53–54
uses, 29–30, 85 improvements, 87
waves, 29–30 pharmacological, 65–67
Electromagnetic radiation, 67 procedure, 51
Electron microscopy, 21 pros and cons of, 55, 60–61
Electrophysiological techniques, 64, safety issues, 55–56
84 temporal resolution of, 50
and neuronal studies, 24, 26–28 uses, 39, 85–86, 92–94
single unit, 25–26
tract tracing, 26–28, 95 GABA. See Gamma aminobutyric
Emotions acid
control of, 12 Gage, Phineas, 3
study of, 30 Gamma aminobutyric acid (GABA),
Epilepsy and seizures, 60 18
diagnosis, 29 Genetics
research and treatment, 5, 7–9, 86 and behavior, 87
Ernst, Richard, 71 modification, 93
ERPs. See Event-related potentials risks, 87–90
Event-related potentials (ERPs) testing, 87–90, 93
improvements, 64 Glial cells
uses, 30 functions, 13
Experimental manipulation Glycine, 18
types of, 40–42, 44–45, 47–49 Gray matter, 19
components of, 31–36, 95
FDG, 59 density, 33–34
Ferromagnetic differences, 35
items, 53, 55–56, 60 and sMRI, 32–36
Florescent dyes, 22
fMRI. See Functional magnetic Hemodynamic response function
resonance imaging (HRF), 54
Forebrain, 10 Hepatic encephalopathy, 70
structures, 12 Hindbrain, 12
Frontal lobe structures of, 10
EEG waves, 29 Hippocampus
functions, 12, 47 disorders of, 5
Functional brain imaging, 13 functions, 3, 12, 34–35, 90
Functional magnetic resonance removal, 5
imaging (fMRI), 38–39 H.M. case, 3, 5
bold signal, 53–54 Homeostasis, 10
data analysis, 44 Homunculus, 6
with DBS, 79–80 Horseradish peroxidase (HRP), 22
109
HRF. See Hemodynamic response statistical analysis of, 42, 44–45,
function 47, 50
HRP. See Horseradish peroxidase structures seen with, 31–32
Human Brain Mapping, 81 types of, 32–36, 51–67, 79–80,
Huntington’s disease, 36 85–87, 92–94
treatment, 76 Magnetic resonance spectroscopy
Hybridization (in situ), 24 (MRS)
Hyperammonemias, 70 and brain chemicals, 65, 67–69
Hypothalamus dynamic, 69
functions, 12 how it works, 67
metabolites, 69–70
Immunocytochemistry, 24 multivoxel, 69
Informed consent, 39–40 proton, 67
Injuries, brain single-voxel, 68–69
effects of, 3, 19, 36, 81 Magnetic source imaging (MSI),
prevention, 6 63
recovery, 6, 36, 84 Magnetoencephalography (MEG), 38,
research, 19, 26 61, 92
Intelligence, 1 how it works, 61–63
acquisition, 35 with MRI, 63
International Brain Research procedure, 51, 85–86
Organization, 92 pros and cons of, 63–64
Mansfield, Peter, 71
Language Medicine
control, 12 impacts on, 1, 6, 9, 71, 82, 91
deficits, 86 misuses, 93–94
tests, 85–86 new treatments, 55, 59, 82, 84, 96
Lauterbur, Paul C., 71 Medulla oblongata, 10
Learning MEG. See Magnetoencephalography
control of, 90 Memory
Lobotomy, prefontal, 93 control of, 3, 5, 12, 35, 90
problems with, 5
Macrostimulation research, 5
of the cerebral cortex, 7–9 studies of, 30, 50
Magnetic resonance imaging Mental illnesses
(MRI), 69 treatment, 73–74, 76
with DBS, 77 MEP. See Motor-evoked potential
with EEG, 38, 64 Microphoresis, 28–29
fundamental concept of, 32 Microstimulation
medical application of, 71 and neuronal activity, 26–29
with MEG, 63 recording, 26, 28
with PET scans, 58 Midbrain, 10
safety measures, 40, 55–56 functions, 12
110
Migraine functions and activity of, 1, 24–28,
treatment, 76 37–39, 53, 57–59, 63, 75–76, 79
Milner, Brenda, 5 injury, 35
Morse code, 16 metabolic needs of, 57
Motor cortex, 6 stimulation, 73–76, 79, 82
control, 7–8, 12, 25 structures of, 13, 16–18, 21–24,
injury, 36, 75–76 26–28, 31, 53–54, 75, 79, 95
stimulation, 77 studies, 21–24, 26–28
studies of, 84–85 types of, 10, 16, 18, 27, 37–38,
Motor-evoked potential (MEP), 76 54, 75
Motor neurons Neuroprosthetics, 84–85
output, 10 Neuroscience
synapses, 75 advances in, 3, 92
Movement and reflexes early, 21
brain maps of, 40–41 Neurosurgery
control of, 6, 10, 12, 25 image-guided, 86–87
disorders, 73, 75–77, 80, 84–85 Neurotransmitters
MRI. See Magnetic resonance imaging functions of, 56, 69
MRS. See Magnetic resonance metabolism, 88
spectroscopy receptors, 69, 71
MSI. See Magnetic source imaging release, 13, 16–18, 24, 28–29
Multiple sclerosis, 76 types, 17–18, 59–60, 72, 79, 89
Myelination, 13 NMR. See Nuclear magnetic
around axons, 21–22, 31, 36, 76 resonance
damage to, 76 Nobel Prize, 71
Norepinephrine, 17, 89
Neocortex, 12 Nuclear magnetic resonance
Nervous system (NMR), 67
functions of, 17, 38 spectroscopy, 71
Neuroeconomics, 91 Nuremberg war crimes trial, 93
Neuroelectric source imaging,
38, 64 Obsessive-compulsive disorder, 76
Neuroethics, 91, 94 Occipital lobe
history of, 92–93 functions, 12, 25, 48
Neuroimage, 81 Olfactory system
Neurological disorders stimuli, 40
treatment of, 74, 76 Opiates, 71
Neuromarketing, 91, 94–95 Organization for Human Brain
Neurons Mapping, 81
and action potential, 13, 16–18, 26,
28, 38, 63, 73 Pain
chemical effects on, 28–29 chronic, 60, 73, 76–77, 80, 87
degeneration, 21–22 genetic risk for, 87, 89–90
111
modulation, 71 pros and cons of, 60–61
perception, 71 radioactive injections, 56, 58–61
studies, 50 receptor binding with, 69, 71–72
Paralysis safety issues, 39, 61
and BMI, 84–85 uses, 39, 82, 84–85, 88–90, 92
Parietal lobe Postsynaptic cell
cortex, 84 receptors, 17–18
functions, 12, 25, 47 Presurgical mapping, 85–86
Parkinson’s disease, 9, 60, 72
diagnosis, 90 Radionuclide, 56
treatment, 76–77, 80 Receptor binding
Penfield, Wilder measurement, 58–60
research of, 5, 7–9 Reporting experimental findings
Pepsi® Challenge, 95 Brodmann area, 49
Personality, 1 cortical lobe, 47–48
injury effects on, 3, 35 functional designation, 49
PET. See Positron emission stereotactic coordinate, 48–49
tomography sulcus or gyrus, 48
PHA-L. See Phaseolus vulgaris Research
leucoagglutinin on cerebral cortex, 13, 36
“Phantom” sensations, 26 and disease and injuries, 5, 7–9,
Pharmacological MRI (phMRI) 19, 26
direct effects, 66 on genetic applications, 87–90
how it works, 65–67 on learning and memories, 5
modulation effects, 66–67 in neuroscience, 3, 21
Phaseolus vulgaris leucoagglutinin on new treatments, 82, 84, 91–96
(PHA-L), 22 Results visualizing, 47
phMRI. See Pharmacological MRI Retrograde transport, 22–24
Phrenology Robotics, 93
maps, 1–3, 6–7 Roy, Charles S., 38
unscientific nature of, 2
Pons, 10 Schizophrenia, 36
Positron emission tomography treatment, 84
(PET), 38–39 Sensory cortex, 6
and brain chemicals, 65 control of, 7–8, 12
with DBS, 80 stimulation, 77
early, 50 Sensory neurons
how it works, 56–58, 72 input, 10
improvements in, 56, 87 receptors, 16
measurements, 58–60 Serotonin, 17
with MRI, 58 Sherrington, Charles S., 38
procedure, 51 Sleep disorders, 29
112
sMRI. See Structural MRI Touch circuits, 69
Society for Neuroscience, 92 Transcranial magnetic stimulation
Somatosensory cortex, 25 (TMS), 37
primary, 49 how it works, 73–74
Somatotopic maps repetitive pulse, 74, 76
history of, 6–9 single or paired pulse, 74–75
Spinal cord as treatment, 73–74, 76
injuries, 76 Tumors, 36
protection, 32 biopsies, 86
stimulation, 55 deficits after removal, 45, 85
structures, 10, 75–76 diagnosis, 69, 90
Stroke, 36 necrotic, 70
diagnosis, 69 presurgical mapping, 85–86
treatment, 76, 84 Tuskegee syphilis experiment, 93
Structural MRI (sMRI)
and cortical gray matter, 32–36 Unconscious state, 29
CTA, 35–36
uses, 32 VBM. See Voxel-based morphometry
VBM, 33–35 (VBM)
Superconducting quantum Visual cortex, 25
interference device (SQUID) Visual information
magnetometers, 63 control of, 12, 25
Synapse stimuli, 40
and motor neurons, 75 Voxel-based morphometry (VBM)
and neurotransmitters, 16 uses, 33–34, 39, 42, 54
Talairach and Tournoux system Wada test, 85

atlases, 42, 44, 49–49 Wallerian degeneration, 22
Taste White matter, 19, 33
stimuli, 40 components of, 31–32, 36, 95
Temporal lobe connections, 36
functions, 12, 48 Wilson’s disease
resection, 5 diagnosis, 90
stimulation, 5 World War II, 93
Thalamus, 12, 36 Wüthrich, Kurt, 71
damage in, 76–77
functions, 26 Xenon inhalation method, 51
Touch
control of, 6, 12, 25
stimuli, 40
113
About the Author
Karen D. Davis, Ph.D., is a full professor in the Department of
Surgery at the University of Toronto. She is a senior scientist
and head of the Division of Brain, Imaging and Behaviour-
Systems Neuroscience at the Toronto Western Research Institute,
University Health Network. She also holds a Canada Research
Chair in Brain and Behavior and is the ‘pain measurement and
imaging’ section editor for the premier international journal
Pain. Dr. Davis is the author of more than 100 articles in scien-
tific journals and books. The main focus of Dr. Davis’s work is
in the area of pain, plasticity, and cognition, and she has devel-
oped cutting-edge functional magnetic resonance imaging to
study the underlying brain mechanisms. An exciting approach
in her lab is the integration of information derived from brain
imaging, electrophysiological and behavioral studies to explore
fundamental aspects of pain and cognition, as well as the chang-
es that occur in disease.
About the Editor

Eric H. Chudler, Ph.D., is a research neuroscientist who has
investigated the brain mechanisms of pain and nociception
since 1978. He is currently a research associate professor in the
University of Washington Department of Bioengineering and
director of education and outreach at University of Washington
Engineered Biomaterials. Dr. Chudler’s research interests focus
on how areas of the central nervous system (cerebral cortex and
basal ganglia) process information related to pain. He has also
worked with other neuroscientists and teachers to develop edu-
cational materials to help students learn about the brain.
114

New Methods in Brain Imaging

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New Methods in Brain Imaging

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New Techniques for

Examining the Brain

Library of Congress Cataloging-in-Publication Data

Text and cover design by Terry Mallon

This book is printed on acid-free paper.

2. A Primer on Brain Structure and Function. . . . . . . . . . . . . . . 10

3. Classic Methods to Study Brain Anatomy and Function. . . . . 19

4. Modern Techniques to Observe Human Brain Anatomy. . . . . 31

5. Linking Behavior to Brain Function in Humans . . . . . . . . . . . 37

6. Modern Techniques to Observe Human Brain Function. . . . . 51

7. Modern Techniques to Observe Brain Chemicals at Work . . . 65

8. Modern Techniques to Stimulate the Human Brain . . . . . . . . 73

9. The Future of Brain Exploration. . . . . . . . . . . . . . . . . . . . . . . 81

10. The Impact of Brain-exploration Techniques on Society. . . . . 91

Further Reading. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

You have probably seen colorful pictures showing the

Moving Beyond Phrenology

the maps to explain all sorts of human behaviors. Eventually,

of phrenology now seems absurd, it did open discussion about

Why Is Brain Imaging Important?

The Case of H.M.

A Link Between Molecules, Cells, Behavior,

Checking Textbook Facts

Figure 1.3 This diagram is an approximation of the somatosensory cortex in the

The history of these maps begins in the 1940s, when neuro-

asked the patients (who were awake during the procedure) to

and motor somatotopic maps. So, what could be wrong with

Why Is Brain Stimulation Important?

The brain is organized into anatomical (the structures) and

Basic Organization and Structure of the

breathing, and blood pressure). The midbrain plays a role in

The Cerebral Cortex

The Four Lobes

Functional Areas of the Cerebral Cortex

Neurons, Action Potentials, and Neurotransmitter Release

potentials move along the axon one after another organized in

The nervous system has an interesting way to move informa-

potentials arrive at the end of the neuron’s axon, they trig-

Classically, the study of the brain has used methods to look

Figure 3.1 Schematic diagrams illustrating anatomical directions and

2. The horizontal (also known as axial) plane divides the

3. The coronal (also known as frontal) plane divides the brain

Classic Anatomical Methods to See

Tracing Nerve Pathways Using Degeneration

visualized. The process, known as Wallerian degeneration,

Tract Tracing Using Retrograde and Anterograde Transport

directions. It is also important to consider all possible ways that

Other Localization Techniques

Classic Electrophysiological Techniques to

Single Unit Electrophysiology

tip of the microelectrode (a technique called microstimulation)

Tract Tracing with Electrophysiology

placed into brain area A to determine the properties of the neu-

Chemical Effects on Neurons

chemical (such as a neurotransmitter) right onto the neuron that

3. Theta: Slow waves (4–7 Hz) normally present in children

What Type of Structures Can Be Seen?

3. Cerebrospinal fluid (CSF): The compartment contains the

Structural MRI: What Can Brain Anatomy

Cortical Gray Matter Morphology

three-dimensional sMRI images. In the manual approach, the

matter density between two groups of subjects. A VBM analy-

acquisition and memory) and the posterior parietal cortex (an