[karen d davis] new techniques for examining the (bookfi)

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.

New Techniques for Examining the Brain

Copyright © 2007 by Infobase Publishing

All rights reserved. No part of this book may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, or by any information storage or retrieval systems, without permission in writing from the publisher. For information contact:

Chelsea House An imprint of Infobase Publishing 132 West 31st Street New York NY 10001 Library of Congress Cataloging-in-Publication Data Davis, Karen D. New techniques for examining the brain / Karen D. Davis. p. cm. — (Gray matter) 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 literature. I. Title. II. Series.

RC386.6.D52D38 2007 616.8’04754—dc22 2007001837 Chelsea House books are available at special discounts when purchased in bulk quantities for businesses, associations, institutions, or sales promotions. Please call our Special Sales Department in New York at (212) 967-8800 or (800) 322-8755.

You can find Chelsea House on the World Wide Web at http://www.chelseahouse.com Text and cover design by Terry Mallon

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All links and Web addresses were checked and verified to be correct at the time of publication. Because of the dynamic nature of the Web, some addresses and links may have changed since publication and may no longer be valid.

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

1

Introduction to New Brain 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 functions 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

New Techniques for Examining the Brain

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 technologies, 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 functions 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 function 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 happening inside our brains when we are thinking, feeling, and doing activities.

New Techniques for Examining the Brain

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 damaged during the accident. Pictured above is Gage’s death mask and skull.

Introduction to New Brain Exploration Technologies

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 removing 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 studied 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 temporal 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 procedures 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.

New Techniques for Examining the Brain

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 activity, 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 provides a link between the function of molecules and cells, behavior, and consciousness.

Checking Textbook Facts Modern brain imaging not only allows us to make new discoveries 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 representation 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 damage to important regions during surgical procedures (such as removing a tumor).

Introduction to New Brain Exploration Technologies

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 neurosurgeon Wilder Penfield used a technique called macrostimulation 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

New Techniques for Examining the Brain

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 macroelectrode 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

Introduction to New Brain Exploration Technologies

and motor somatotopic maps. So, what could be wrong with these maps? Remember that they were created by macrostimulation that delivers an electrical current that can spread to a fairly large area of the brain. Also, they were created by observations 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 magnetic 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 sophisticated 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.

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A Primer on Brain 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 functions, 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 midbrain, 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 cerebellum 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

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Figure 2.1  The top diagram is a side view of the outside of the brain, and the bottom diagram is a side view taken from the middle of the brain.

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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), hippocampus (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.

A Primer on Brain Structure and Function

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 functional 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 vessels. 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 neuron, 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 neuron (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

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New Techniques for Examining the Brain

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.

A Primer on Brain Structure and Function

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Figure 2.3  The basic structure of a neuron includes dendrites (to receive information), a cell body, and an axon to conduct action potentials. Information is conveyed to the next neuron via release of neurotransmitter from the axon terminal into the synaptic cleft to bind to its receptor on the next (postsynaptic) neuron.

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potentials move along the axon one after another organized in a regular flow at a certain frequency, or bunched together several 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 transmit 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 potentials throughout the entire time that the skin is indented. The greater the indentation, the more action potentials are generated. 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 information 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 neurotransmitter. 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.

A Primer on Brain Structure and Function

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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 receptors (Meisner’s and Pacinian corpuscles) generate action potentials at the beginning 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 information using specialized chemical messengers called neurotransmitters. There are more than 40 different neurotransmitters. Some examples of neurotransmitters are dopamine, norepinephrine, serotonin, and acetylcholine. As noted above, when action

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potentials arrive at the end of the neuron’s axon, they trigger 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 postsynaptic neuron from generating action potentials. ■Learn more about the contents of this chapter Search the Internet for Brodmann areas, neurotransmitter, and touch receptors.

3

Classic Methods to Study Brain 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 information 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 without the use of any fancy equipment.

Early brain atlases were constructed from brains that had been preserved with a chemical fixative (for example, formalin) 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 pictures 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.

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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 hamburger bun; these slices show the brain viewed from the top or bottom.

Classic Methods to Study Brain Anatomy and Function

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

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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 possible 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 tracers 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 transport 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

Classic Methods to Study Brain Anatomy and Function

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

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directions. It is also important to consider all possible ways that a neuron may have been labeled—either intentionally or unintentionally. 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 hybridization can be used to visualize neurons that contain a specific neurotransmitter or protein.

A special technique, called the 2-deoxyglucose (2DG) method, 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.

Classic Methods to Study Brain Anatomy and Function

Single Unit Electrophysiology Single unit (also known as single cell) electrophysiology is a powerful 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 somatosensory 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

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tip of the microelectrode (a technique called microstimulation) to excite (depolarize) the neurons close to its tip. The experimenter 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 sensations 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

Classic Methods to Study Brain Anatomy and Function

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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 sensations—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 conduction (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 experimental setup requires three electrodes. First, a microelectrode is

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placed into brain area A to determine the properties of the neurons 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 recording 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 projecting 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 microphoresis, an electrical current is used to inject a tiny amount of a

Classic Methods to Study Brain Anatomy and Function

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 activity 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 frontal lobe and brought about by anxiety or opening the eyes.

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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 timelocked 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 provide 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. â– Learn more about the contents of this chapter Search the Internet for neuronal tracers, antidromic activation, and phantom sensations.

4

Modern Techniques to 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 animals 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.

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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 person 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 environments 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 structural 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 manual approach or an automated approach from high-resolution,

Modern Techniques to Observe Human Brain Anatomy

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

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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 analysis 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

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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 dysplasia. 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 neuroticism), 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

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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 visualization 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 magnetic 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 thalamus 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, anatomical 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. â– Learn more about the contents of this chapter Search the Internet for voxel-based morphometry and diffusion tensor imaging.

5

Linking Behavior to 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 magnetic 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 stimulation 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

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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 signals (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 magnetic resonance imaging (fMRI). We now know that active neurons 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

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 several times). During each run, the brain is scanned many times and each brain image is divided into slices that contain threedimensional 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 equipment, 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

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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 common 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 manipulation 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

Linking Behavior to Brain Function in Humans

because the brain signal changes that occur due to an experimental manipulation are small and sometimes overshadowed by nonbiological “noise” induced by the scanner, subject movement, and other factors. Repetition of the manipulation is usually 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 manipulation is performed. This provides important data about how the brain is working during the manipulation. But these functional

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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 preprocessed (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 highresolution 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 coordinate 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) dimension, 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 highresolution 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.

Linking Behavior to Brain Function in Humans

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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 experimental 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 covers a space of about 240 mm by 240 mm, and imaging software can assess the MRI signal intensity within each square millimeter. 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 voxels 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

Linking Behavior to Brain Function in Humans

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 experiment 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 mechanisms 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 statistical 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).

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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 population based on studying a small group of subjects.

Linking Behavior to Brain Function in Humans

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 statistical significance or probability) produced by the experimental manipulation. Typically, “hot” colors like red, orange, and yellow 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 language 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 information can be described with five types of descriptors using anatomy and/or function: 1. Cortical lobe: This is the most general type of anatomical descriptor. The name of the lobe (frontal, parietal,

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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 anatomical 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

Linking Behavior to Brain Function in Humans

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 commissure 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 complex. 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 contamination 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

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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 subject’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 contaminating 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 attention 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 receiving information, assessing the information, and making judgments 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 performed 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. â– Learn more about the contents of this chapter Search the Internet for functional brain imaging and Talairach atlas.

6

Modern Techniques to 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 magnetoencephalography (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

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B

C

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

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Figure 6.2  The brain activations detected with fMRI are due to a blood oxygenation 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 (deoxyhemoglobin, but not oxyhemoglobin, is ferromagnetic).

5. There is an increase in the fMRI signal due to the blood oxygenation 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

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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 mathematical 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 experimental 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.”

Modern Techniques to Observe Human Brain Function

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 interference. 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

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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 ferromagnetic 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 orthopedic 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 metabolism. 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 scanning 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 electromagnetic 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

Modern Techniques to Observe Human Brain Function

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 (millimeters) 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

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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 create a clear picture of the location of the PET data.

What Does PET Measure?

There are several aspects of brain function that can be measured 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 radioactive water (H215O) is injected intravenously into the subject.

The water distributes itself throughout the brain via the cerebral 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 measures 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 manufactured! 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 somewhat variable and so scientists like to repeat their experiments

Modern Techniques to Observe Human Brain Function

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 second 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 mechanism, the general ideas involve glucose transport and metabolism 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 neurotransmitters at their specific receptor binding sites. Receptor

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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 intermediate 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-ferromagnetic devices.

When you watch a PET scanner at work, you might wonder 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 environment. 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.

Modern Techniques to Observe Human Brain Function

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 radiochemical 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 measures. Rather, MEG uses the direct link between an electrical current and a magnetic field.

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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 direction 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 activity. 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

Modern Techniques to Observe Human Brain Function

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 superconducting 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 location 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 timing of brain responses with millisecond accuracy, and when it is combined with MRI it can provide good localization. One limitation of MEG is that it only provides a point source of activity rather than an area of brain activity. Also, MEG is not as sensitive 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

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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 electrophysiological data with MRI to aid in localization. There are now mathematical models (similar to those that aid in localizing MEG dipoles) that help localize the source of the EEG/ ERP signals in the brain. The merged technique is known as neuroelectric source imaging. â– Learn more about the contents of this chapter Search the Internet for BOLD fMRI, positron emission tomography, and magnetoencephalography.

7

Modern Techniques to Observe Brain Chemicals at Work

It is now possible to use brain imaging to study chemical

effects on the brain. Brain imaging can be used to measure 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 spectroscopy, 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

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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 subject (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 nonpharmacological 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

kinetics of the drug (as with the direct effects) and other nonpharmacological effects. But, there is another experimental 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 measure 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 radiation 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.

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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 palpation 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 measurement to detect abnormalities that occur throughout widespread regions of the brain. For example, several types

Modern Techniques to Observe Brain Chemicals at Work

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 obtaining 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 possibilities in both neurology and psychiatry, but the data acquisition 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 neurotransmitters 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 neurotransmitters 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 important aspect of receptor-binding PET is to manufacture a positron-emitting radiopharmaceutical tracer that is chemically 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

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Table 7.1 Metabolites Identified with Proton Magnetic Resonance Spectroscopy (MRS) Metabolites

Location on Spectrum

Physiologic Significance

N-acetyl aspartate (NAA)

2.02 parts per million (ppm)

Seen only in neural tissue.

Marker of neuronal integrity.

Reduces with most types of insults to the brain. Increases in Canavan’s disease.

Choline and other choline-containing compounds (Cho)

3.2 ppm

Linked to cell membrane turnover, as in rapid cell division or breakdown. Tumors or demyelination can increase levels.

Creatine and phosphocreatine (Cr)

3.03 and 3.94 ppm

Represents compounds related 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 breakdown products. Increase has been noted in necrotic tumors and acute inflammation.

Lactate (Lac)

1.32 ppm– doublet

Not detected in normal brain.

Presence indicates anaerobic metabolism or failure of oxidative phosphorylation as in mitochondrial 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 glutamine (Gln)

2.1 and 2.4 ppm

Increases in hepatic encephalopathy/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.

Modern Techniques to Observe Brain Chemicals at Work

neurotransmitter’s receptor so that it can stick to the receptor. The amount and location of receptor binding can then be measured with the PET scanner.

Receptor-binding PET studies can locate normal or abnormal 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 endogenous 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 previously known to be involved in pain perception and pain modulation.

Receptor-binding studies with PET are very useful to determine whether there is a deficit in a particular type of neurotransmitter-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 contributions to the method of nuclear magnetic resonance (NMR).

In 2002, Kurt WĂźthrich 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.

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patients with Parkinson’s disease are known to have a reduced amount of dopamine, and PET scanning has shown the location of this deficit to be in the basal ganglia. ■Learn more about the contents of this chapter Search the Internet for phMRI, MR spectroscopy, and PET receptors.

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Modern Techniques 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 provides 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-stimulation 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 depression 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.

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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 magnetic 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 neurons. 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 necessitated 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 stimulation (rTMS).

Modern Techniques to Stimulate the Human Brain

Figure 8.1  A TMS coil is placed on the scalp to deliver magnetic stimulation through the skull and into the brain. The magnetic stimulation 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 abnormalities. 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

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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 example, 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 movement, 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 dramatically 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,

Modern Techniques to Stimulate the Human Brain

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 surgical 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 electrophysiological 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

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A

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.

Modern Techniques to Stimulate the Human Brain

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 inhibitory 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 factor 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 performing 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).

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A

B

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 mentallychallenging task. (B) The microelectrode recordings obtained during a neurosurgical procedure show how individual neurons in the cingulate cortex respond during a mentally-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 functional 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 disease, chronic pain, and depression.

■ Learn more about the contents of this chapter Search the Internet for electroconvulsive therapy, transcranial magnetic stimulation, and deep brain stimulation.

9

The Future of 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 fundamental 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 undertaking any study, it is best to identify the key questions. Are you interested in anatomy, neurochemistry, or function? Do 81

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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 neuroradiology, neurology, neurosurgery, and psychiatry. The contribution 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 overactive 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.

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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 people 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 motorized 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

The Future of Brain Exploration

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 trials 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 example, 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 stimulation before surgery can provide valuable information to neurosurgeons and possibly reduce or avoid functional deficits.

This application of neuroimaging for presurgical mapping is common in large academic surgical centers. Presurgical mapping 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.

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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 neuroimaging 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 specific brain area.

Image-guided Neurosurgery Global positioning systems (GPS) have revolutionized the way geographic locations can be found and tracked. A similar concept 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 threedimensional 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

The Future of Brain Exploration

combined image of instrument and anatomy can then be displayed to the surgeon on a computer screen. Image-guided surgery 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 mechanisms that underlie normal brain function and behavior. For example, neuroimaging has identified differences in brain function 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 abnormal 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 clinically 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 disease, 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 cortex in patients with Alzheimer’s disease. A recent study brought

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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 developing 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 associated 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

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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 sensitivity. 1 = thalamus; 2 = nucleus accumbens; 3 = ventral pallidum.

experience pain. They found that the metabolism of catecholamines 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 associated 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 sensitivity and the amount of opioids released and bound to certain

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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 useful in medicine. Metabolic imaging with PET is being developed to assist with the diagnosis of many diseases. The most developed 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.

■ Learn more about the contents of this chapter Search the Internet for brain machine interface, image guided neurosurgery, and brain imaging genetics.

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The Impact of Brain-exploration 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 understand what they are doing and why their work is important.

There is now widespread media coverage of scientific discoveries 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 information 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, neuromarketing, and neuroeconomics.

Neuroethics Neuroethics is a relatively new field focused on bioethical issues as they pertain to the recent explosion of new 91

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brain-exploration technologies. Bioethics has been an active area of study for quite some time. The development of cloning technology 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 public 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 material 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 agencies 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

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 genetics 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 introduction 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.

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medicine, but there is always the possibility for misuse of technology. Therefore, it is prudent to have open, informed, and balanced discussions about neuroethics.

Neuromarketing For decades, companies have relied on behavioral and psychological studies to guide marketing campaigns. Now, the development 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 buying 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 neurological 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

Perhaps you have heard of the Pepsi® Challenge. This was a much-publicized test set up at county fairs and malls throughout 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 challenge, there has been much said about the validity of the blinding 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 imaging 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 subjects 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 enhancement of the brain response to drinking Coca-Cola® when subjects 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.

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This book provides a brief look at the technology and procedures that allow us to “see� inside the human brain. These techniques 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. ■Learn more about the contents of this chapter Search the 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.

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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).

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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.

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Further Reading Haines, D.E. Neuroanatomy: An Atlas of Structures, Sections, and Systems.

Philadelphia: Lippincott Williams & Wilkins, 2003.

Kandel, E.R., J.H. Schwartz, and T.M. Jessell. Principles of Neural Science. New York: McGraw Hill, 2000.

Sapru, H.N. and A. Siegel. Essential Neuroscience. Philadelphia: Lippincott Williams & Wilkins, 2005.

Scott, S.H. “Neuroscience: Converting Thoughts into Action.” Nature 442 (2006): 141–142.

Web Sites Alcohol and the Adolescent Brain http://www.duke.edu/~amwhite/Adolescence The Brain from Top to Bottom http://www.thebrain.mcgill.ca/flash/index_i.html Brains Rule http://www.brainsrule.com/index.htm Dana Foundation. DANA BrainWeb & Brain Information http://www.dana.org/brainweb/ fMRI for Newbies http://www.ssc.uwo.ca/psychology/culhamlab/Jody_web/ fmri4newbies.htm How Stuff Works http://health.howstuffworks.com International Brain Research Organization: Educational Resources http://www.ibro.info/Pub_IBROEDU_Resources_Listing.asp Library of Congress. Webcasts on Neuroethics http://www.loc.gov/today/cyberlc/feature_wdesc.php?rec=3716 http://www.loc.gov/today/cyberlc/feature_wdesc.php?rec=3715 National Institutes of Health http://www.nih.gov/health/chip/od/radiation/ National Library of Medicine. EEG. Medline Plus http://www.nlm.nih.gov/medlineplus/ency/article/003931.htm 104

Neuroscience for Kids http://faculty.washington.edu/chudler/neurok.html The Secret Life of the Brain: Scanning the Brain http://www.pbs.org/wnet/brain/scanning/index.html TMS at BioMag http://www.biomag.hus.fi/tms/index.html What Is Image-Guided Surgery? http://www.stealthstation.com/patient/faq.jsp Wired to Win http://www.wiredtowinthemovie.com/theBrain.html

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Picture Credits 2: © The Granger Collection, New York 4: © The Granger Collection, New York 7: © Infobase Publishing 8: © Infobase Publishing 11: © Infobase Publishing 14: © Infobase Publishing 15: © Infobase Publishing 17: © Infobase Publishing 20: © Infobase Publishing 23: © Infobase Publishing 27: © Infobase Publishing 34: B. Draganski, C. Gaser, G. Kempermann, H.G. Kuhn, J. Winkler, C. Buchel, and A. May, “Temporal and Spatial Dynamics of Brain Structure Changes During Extensive Learning.” Journal of Neuroscience 26 (2006): 6314– 6317. © 2006 by the Society for Neuroscience 35: Reprinted from Neuroimage, vol.

22, S.K. Lee, D.I. Kim, S. Mori, J. Kim, H.D. Kim, K. Heo, and B.I. Lee, “Diffusion Tensor MRI Visualizes Decreased Subcortical Fiber Connectivity in Focal Cortical Dysplasia, pp. 1826–1829, © 2004 with permission from Elsevier 43: Reprinted with permission: M. Brett, I.S. Johnsrude, and A.M. Owen, “The Problem of Functional Localization in the Human Brain.” Nature Review Neuroscience 3 (2002): 243–249.

46: © Infobase Publishing 48: © Infobase Publishing 52: (a) © Mark Harmel/Photo Researchers, Inc.; (b) © Phanie/Photo Researchers, Inc.; (c) © Hank Morgan/Photo Researchers, Inc. 53: © Infobase Publishing

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57: © Infobase Publishing 62: © Infobase Publishing 68: Reprinted with permission: M. Baliki, J. Katz, D.R. Chialvo, and A.V. Apkarian, “Single Subject Pharmacological-MRI (phMRI) Study: Modulation of Brain Activity of Psoriatic Arthritis Pain by Cyclooxygenase-2 Inhibitor.” Molecular Pain 1 (2005): 32.

75: © Infobase Publishing 78: (a) © Infobase Publishing; (b) Courtesy of Dr. J. Dostrovsky; (c) Courtesy of Dr. J. Dostrovsky 80: Karen D. Davis 83: (top box and bottom box) Reprinted from Neuron, vol no. 3, H.S. Mayberg, A.M. Lozano, V. Voon, H.E. McNeely, D. Seminowicz, C. Hamani, J.M. Schwalb, and S.H. Kennedy. “Deep Brain Stimulation for Treatment-resistant Depression,” pp 651-660, copyright 2005 with permission from Elsevier 88: E.M. Reiman, K. Chen, G.E. Alexander, R.J. Caselli, D. Bandy, D. Osborne, A.M. Saunders, and J. Hardy.

“Correlations Between Gene Dose and Brain-imaging Measurements of Regional Hypometabolism.” Proceedings of the National Academy of Science USA 102 (2005): 8299.

Copyright 2005 National Academy of Sciences, U.S.A. 89: Reprinted with permission from J.K. Zubieta, M.M. Heitzeg, Y.R. Smith, J.A. Bueller, K. Xu, Y. Xu, R.A. Koeppe, C.S. Stohler, and D. Goldman. “COMT val158met Genotype Affects Mu-opioid Neurotransmitter Responses to a Pain Stressor.” Science 299 (2003): 1240-3. Copyright © 2003 AAAS.

Index Acetylcholine, 17 Action potential and neurons, 13, 16–18, 26, 28, 38, 63, 73 Adenosine triphosphate (ATP) energy source, 38–39 Aging effects on brain, 6, 35, 81 Alzheimer’s disease, 60 research, 87 risk for, 87–88, 90 Amygdala functions, 12 Anterograde transport, 22–24 ATP. See Adenosine triphosphate Attention control of, 35 study of, 30 Auditory information control of, 12 improvements, 84 stimuli, 40 Axons damaged, 21–22, 24, 36 functions, 13, 16, 18, 27–28, 63, 79 myelin of, 21–22, 31, 36, 76 splitting, 28 terminus, 21–23, 26–28, 95 Basal ganglia deficits or damage in, 72, 76 functions, 12 BDNF. See Brain-derived neurotrophic factor Behavior, 2, 6 and brain function, 37–50 control of, 12 and genetics, 87 modification, 93 stimulation, 77 tasks, 40, 94

Benzodiazepine receptors, 60 Biocytin, 22 Bioethics, 92 Blindness, 36 Blood oxygenation level-dependent (BOLD) effect and fMRI, 53–54 BOLD effect. See Blood oxygenation level-dependent (BOLD) effect Brain basic anatomy, 19–21 damage and disability, 3, 6, 9, 19, 26, 29–30, 36–37, 45, 68, 81, 85 drug effects on, 40, 65–72, 84 functional systems, 10–18, 37–64 modern techniques, 1, 3, 31–39, 51–64, 79–82, 84 planes, 19–21 protection, 32 structures, 1, 10–18, 21–24, 31–36 study of functions and structure, 1, 3, 6, 19–30, 38, 66, 73–75, 79, 81–82, 85, 87, 89–90, 93, 95–96 Brain-derived neurotrophic factor (BDNF), 90 Brain imaging and axon pathways, 22 basic steps to, 39–42, 44–45, 47–49 direct measures of, 38 functional, 13 future of, 81–90 importance, 3 indirect vascular-based measures of, 38–39 interpretation of, 49–50 modern techniques, 1, 3, 6, 31–32, 37–39, 51–64, 81–90 uses, 6–9, 40, 91–96 Brain-machine interface uses, 84–85

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Brain stem functions, 10 structures, 10, 36 Brain stimulation, 55 effects of, 37–38, 82 and epilepsy, 5 importance, 9, 93 modern techniques, 1, 73–80, 85 and recording, 3 Brodmann, Korbinian areas of brain functioning, 13, 44, 49 research, 82 Canavan’s disease, 70 Cell body, 31 changes in, 21–23 functions, 26–28 structures, 13, 75 Cerebellum functions, 10 structures, 10 Cerebral blood flow measurement, 58–59 Cerebral cortex, 31 corpus callosum, 12 functions, 12–13 gyri, 12, 19, 44, 48–49 lobes, 12, 19, 47–48 macrostimulation of, 7–9 research, 13, 36 sulci, 12, 19, 44, 48–49 and TMS, 74, 76 Cerebral glucose metabolism measurement, 58–59 Cerebrospinal fluid (CSF), 33 function, 32 Cerebrum. See Cerebral cortex Chudler, Eric, 92 Cochlear implants, 84 Cognitive functions, 10 control, 12 studies, 30, 50

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Computed tomography (CT), 56, 61 structures seen with, 31–32 Conscious thoughts, 6 control of, 10, 12 Cortical thickness analysis (CTA) uses, 35–36 Corticospinal tract neurons, 75–76 CSF. See Cerebrospinal fluid CT. See Computed tomography CTA. See Cortical thickness analysis Dana Foundation, 91 Data analyzing, 44–45 gathering, 41–42 preprocessing, 42, 44 DBS. See Deep brain stimulation Deep brain stimulation (DBS), 37 how it works, 76–77, 79–80 as treatment, 73, 76–77, 80, 82, 84, 86, 93 Degeneration, 21–22 Dendrites, 22, 31 functions, 13 Depression, 60 risk for, 87 treatment of, 73, 76–77, 80, 8 2, 84 Dextrans, 22 Diffusion tensor imaging (DTI) uses, 36 Dopamine, 17–18, 89 levels in Parkinson’s disease, 72 receptors, 60 DTI. See Diffusion tensor imaging Dystonia, 76 ECT. See Electroconvulsive therapy EEG. See Electroencephalography Electroconvulsive therapy (ECT), 73

Electroencephalography (EEG) improvements, 64 with MRI, 38, 64 uses, 29–30, 85 waves, 29–30 Electromagnetic radiation, 67 Electron microscopy, 21 Electrophysiological techniques, 64, 84 and neuronal studies, 24, 26–28 single unit, 25–26 tract tracing, 26–28, 95 Emotions control of, 12 study of, 30 Epilepsy and seizures, 60 diagnosis, 29 research and treatment, 5, 7–9, 86 Ernst, Richard, 71 ERPs. See Event-related potentials Event-related potentials (ERPs) improvements, 64 uses, 30 Experimental manipulation types of, 40–42, 44–45, 47–49 FDG, 59 Ferromagnetic items, 53, 55–56, 60 Florescent dyes, 22 fMRI. See Functional magnetic resonance imaging Forebrain, 10 structures, 12 Frontal lobe EEG waves, 29 functions, 12, 47 Functional brain imaging, 13 Functional magnetic resonance imaging (fMRI), 38–39 bold signal, 53–54 data analysis, 44 with DBS, 79–80

early, 49–50 goals of, 54 how it works, 53–54 improvements, 87 pharmacological, 65–67 procedure, 51 pros and cons of, 55, 60–61 safety issues, 55–56 temporal resolution of, 50 uses, 39, 85–86, 92–94 GABA. See Gamma aminobutyric acid Gage, Phineas, 3 Gamma aminobutyric acid (GABA), 18 Genetics and behavior, 87 modification, 93 risks, 87–90 testing, 87–90, 93 Glial cells functions, 13 Glycine, 18 Gray matter, 19 components of, 31–36, 95 density, 33–34 differences, 35 and sMRI, 32–36 Hemodynamic response function (HRF), 54 Hepatic encephalopathy, 70 Hindbrain, 12 structures of, 10 Hippocampus disorders of, 5 functions, 3, 12, 34–35, 90 removal, 5 H.M. case, 3, 5 Homeostasis, 10 Homunculus, 6 Horseradish peroxidase (HRP), 22

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HRF. See Hemodynamic response function HRP. See Horseradish peroxidase Human Brain Mapping, 81 Huntington’s disease, 36 treatment, 76 Hybridization (in situ), 24 Hyperammonemias, 70 Hypothalamus functions, 12 Immunocytochemistry, 24 Informed consent, 39–40 Injuries, brain effects of, 3, 19, 36, 81 prevention, 6 recovery, 6, 36, 84 research, 19, 26 Intelligence, 1 acquisition, 35 International Brain Research Organization, 92 Language control, 12 deficits, 86 tests, 85–86 Lauterbur, Paul C., 71 Learning control of, 90 Lobotomy, prefontal, 93

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Macrostimulation of the cerebral cortex, 7–9 Magnetic resonance imaging (MRI), 69 with DBS, 77 with EEG, 38, 64 fundamental concept of, 32 medical application of, 71 with MEG, 63 with PET scans, 58 safety measures, 40, 55–56

statistical analysis of, 42, 44–45, 47, 50 structures seen with, 31–32 types of, 32–36, 51–67, 79–80, 85–87, 92–94 Magnetic resonance spectroscopy (MRS) and brain chemicals, 65, 67–69 dynamic, 69 how it works, 67 metabolites, 69–70 multivoxel, 69 proton, 67 single-voxel, 68–69 Magnetic source imaging (MSI), 63 Magnetoencephalography (MEG), 38, 61, 92 how it works, 61–63 with MRI, 63 procedure, 51, 85–86 pros and cons of, 63–64 Mansfield, Peter, 71 Medicine impacts on, 1, 6, 9, 71, 82, 91 misuses, 93–94 new treatments, 55, 59, 82, 84, 96 Medulla oblongata, 10 MEG. See Magnetoencephalography Memory control of, 3, 5, 12, 35, 90 problems with, 5 research, 5 studies of, 30, 50 Mental illnesses treatment, 73–74, 76 MEP. See Motor-evoked potential Microphoresis, 28–29 Microstimulation and neuronal activity, 26–29 recording, 26, 28 Midbrain, 10 functions, 12

Migraine treatment, 76 Milner, Brenda, 5 Morse code, 16 Motor cortex, 6 control, 7–8, 12, 25 injury, 36, 75–76 stimulation, 77 studies of, 84–85 Motor-evoked potential (MEP), 76 Motor neurons output, 10 synapses, 75 Movement and reflexes brain maps of, 40–41 control of, 6, 10, 12, 25 disorders, 73, 75–77, 80, 84–85 MRI. See Magnetic resonance imaging MRS. See Magnetic resonance spectroscopy MSI. See Magnetic source imaging Multiple sclerosis, 76 Myelination, 13 around axons, 21–22, 31, 36, 76 damage to, 76 Neocortex, 12 Nervous system functions of, 17, 38 Neuroeconomics, 91 Neuroelectric source imaging, 38, 64 Neuroethics, 91, 94 history of, 92–93 Neuroimage, 81 Neurological disorders treatment of, 74, 76 Neuromarketing, 91, 94–95 Neurons and action potential, 13, 16–18, 26, 28, 38, 63, 73 chemical effects on, 28–29 degeneration, 21–22

functions and activity of, 1, 24–28, 37–39, 53, 57–59, 63, 75–76, 79 injury, 35 metabolic needs of, 57 stimulation, 73–76, 79, 82 structures of, 13, 16–18, 21–24, 26–28, 31, 53–54, 75, 79, 95 studies, 21–24, 26–28 types of, 10, 16, 18, 27, 37–38, 54, 75 Neuroprosthetics, 84–85 Neuroscience advances in, 3, 92 early, 21 Neurosurgery image-guided, 86–87 Neurotransmitters functions of, 56, 69 metabolism, 88 receptors, 69, 71 release, 13, 16–18, 24, 28–29 types, 17–18, 59–60, 72, 79, 89 NMR. See Nuclear magnetic resonance Nobel Prize, 71 Norepinephrine, 17, 89 Nuclear magnetic resonance (NMR), 67 spectroscopy, 71 Nuremberg war crimes trial, 93 Obsessive-compulsive disorder, 76 Occipital lobe functions, 12, 25, 48 Olfactory system stimuli, 40 Opiates, 71 Organization for Human Brain Mapping, 81 Pain chronic, 60, 73, 76–77, 80, 87 genetic risk for, 87, 89–90

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modulation, 71 perception, 71 studies, 50 Paralysis and BMI, 84–85 Parietal lobe cortex, 84 functions, 12, 25, 47 Parkinson’s disease, 9, 60, 72 diagnosis, 90 treatment, 76–77, 80 Penfield, Wilder research of, 5, 7–9 Pepsi® Challenge, 95 Personality, 1 injury effects on, 3, 35 PET. See Positron emission tomography PHA-L. See Phaseolus vulgaris leucoagglutinin “Phantom” sensations, 26 Pharmacological MRI (phMRI) direct effects, 66 how it works, 65–67 modulation effects, 66–67 Phaseolus vulgaris leucoagglutinin (PHA-L), 22 phMRI. See Pharmacological MRI Phrenology maps, 1–3, 6–7 unscientific nature of, 2 Pons, 10 Positron emission tomography (PET), 38–39 and brain chemicals, 65 with DBS, 80 early, 50 how it works, 56–58, 72 improvements in, 56, 87 measurements, 58–60 with MRI, 58 procedure, 51

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pros and cons of, 60–61 radioactive injections, 56, 58–61 receptor binding with, 69, 71–72 safety issues, 39, 61 uses, 39, 82, 84–85, 88–90, 92 Postsynaptic cell receptors, 17–18 Presurgical mapping, 85–86 Radionuclide, 56 Receptor binding measurement, 58–60 Reporting experimental findings Brodmann area, 49 cortical lobe, 47–48 functional designation, 49 stereotactic coordinate, 48–49 sulcus or gyrus, 48 Research on cerebral cortex, 13, 36 and disease and injuries, 5, 7–9, 19, 26 on genetic applications, 87–90 on learning and memories, 5 in neuroscience, 3, 21 on new treatments, 82, 84, 91–96 Results visualizing, 47 Retrograde transport, 22–24 Robotics, 93 Roy, Charles S., 38 Schizophrenia, 36 treatment, 84 Sensory cortex, 6 control of, 7–8, 12 stimulation, 77 Sensory neurons input, 10 receptors, 16 Serotonin, 17 Sherrington, Charles S., 38 Sleep disorders, 29

sMRI. See Structural MRI Society for Neuroscience, 92 Somatosensory cortex, 25 primary, 49 Somatotopic maps history of, 6–9 Spinal cord injuries, 76 protection, 32 stimulation, 55 structures, 10, 75–76 Stroke, 36 diagnosis, 69 treatment, 76, 84 Structural MRI (sMRI) and cortical gray matter, 32–36 CTA, 35–36 uses, 32 VBM, 33–35 Superconducting quantum interference device (SQUID) magnetometers, 63 Synapse and motor neurons, 75 and neurotransmitters, 16

Touch circuits, 69 Transcranial magnetic stimulation (TMS), 37 how it works, 73–74 repetitive pulse, 74, 76 single or paired pulse, 74–75 as treatment, 73–74, 76 Tumors, 36 biopsies, 86 deficits after removal, 45, 85 diagnosis, 69, 90 necrotic, 70 presurgical mapping, 85–86 Tuskegee syphilis experiment, 93

Talairach and Tournoux system atlases, 42, 44, 49–49 Taste stimuli, 40 Temporal lobe functions, 12, 48 resection, 5 stimulation, 5 Thalamus, 12, 36 damage in, 76–77 functions, 26 Touch control of, 6, 12, 25 stimuli, 40

Wada test, 85 Wallerian degeneration, 22 White matter, 19, 33 components of, 31–32, 36, 95 connections, 36 Wilson’s disease diagnosis, 90 World War II, 93 Wüthrich, Kurt, 71

Unconscious state, 29 VBM. See Voxel-based morphometry (VBM) Visual cortex, 25 Visual information control of, 12, 25 stimuli, 40 Voxel-based morphometry (VBM) uses, 33–34, 39, 42, 54

Xenon inhalation method, 51

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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 BehaviourSystems 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 scientific journals and books. The main focus of Dr. Davis’s work is in the area of pain, plasticity, and cognition, and she has developed 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 changes 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 educational materials to help students learn about the brain.

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