BIOPSYCHOLOGY, 6/e

© 2006
John P.J. Pinel

ISBN: 0-205-42651-4

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 chapter

Brain Damage and

Neuroplasticity
10
Can the Brain Recover from Damage?

10.1 Causes of Brain Damage

10.2 Neuropsychological
Diseases
10.3 Animal Models
of Human
Neuropsychological
Diseases
10.4 Neuroplastic Responses
to Nervous System
Damage: Degeneration,
Regeneration,
Reorganization, and
Recovery
10.5 Neuroplasticity and the
Treatment of Nervous
System Damage
232 Chapter 10 ~ Brain Damage and Neuroplasticity www.ablongman.com/pinel6e

T he study of human brain damage serves two pur-

poses: It increases our understanding of the healthy
brain, and it serves as a basis for the development
of new treatments. The first three sections of this chap-
ter focus on brain damage itself. The last two sections
It was about a year later that Professor P. sat star-
ing at the illustration of the cranial nerves. By then he
had begun to experience numbness on the right side
of his mouth; he was having minor problems swallow-
ing; and his right tear ducts were not releasing enough
continue the neuroplasticity theme that was introduced tears. There he sat staring at the point where the au-
in Chapter 9: The fourth focuses on the recovery and ditory and vestibular nerves come together to form
reorganization of the brain after damage, and the fifth cranial nerve VIII (the auditory-vestibular nerve).
discusses exciting new neuroplasticity-promoting treat- He knew it was there, and he knew that it was large
ments. But first, the continuation of the ironic case of enough to be affecting cranial nerves V through X as
Professor P., whom you first met in Chapter 5, relates the well, but he didn’t know what it was: a tumor, a stroke,
personal tragedy of brain damage. an angioma, an infection? Was he going to die? Was
his death going to be terrible and lingering as his brain
and intellect gradually deteriorated?
He didn’t make an appointment with his doctor
The Ironic Case of Professor P. right away. A friend of his was conducting a brain MRI
study, and Professor P. volunteered to be a control sub-
One night Professor P. sat at his desk staring at a ject, knowing that his problem would show up on the
drawing of the cranial nerves, much like the one in Ap- scan. It did: a large tumor sitting, as predicted, on the
pendix III of this book. As he mulled over the location right cranial nerve VIII.
and function of each cranial nerve (see Appendix IV), Then, MRI in hand, Professor P. went back to his
the painful truth became impos- doctor, who referred him to a neurologist, who in turn
Clinical
Implications sible for him to deny. The irony of referred him to a neurosurgeon. Several stressful weeks
the situation was that Professor P. later, Professor P. found himself on life support in the
was a neuroscientist, all too familiar with what he was intensive care unit of his local hospital, hands tied to
experiencing. the bed and tubes emanating seemingly from every
His symptoms started subtly, with slight deficits part of his body. You see, the tumor was so convolut-
in balance. He probably wouldn’t have even noticed ed that it took 6 hours to remove; and during the 6
them except that his experience as a mountaineer had hours that Professor P.’s brain was exposed, air entered
taught him to pay attention to such things. Professor P. his circulatory system, and he developed pneumonia.
chalked these occasional lurches up to aging—after Near death and hallucinating from the morphine,
all, he thought to himself, he was past his prime, and Professor P. thought he heard his wife, Maggie, call-
things like this happen. Similarly, his doctor didn’t ing for help and tried to go to her assistance: That is
seem to think that it was a problem worth looking why he was tied down. One gentle morphine-steeped
into, but Professor P. monitored his symptoms care- professor was no match for five burly nurses intent on
fully nevertheless. Three years later, his balance prob- saving his life.
lems still unabated, Professor P. really started to worry. Professor P.’s auditory-vestibular nerve was tran-
He was trying to talk with a colleague on the phone sected during his surgery, which has left him perma-
but was not having much success because of what he nently deaf and without vestibular function on the
thought was a bad connection. Then, he changed the right side. He was also left with partial hemifacial pa-
phone to his other ear, and all of a sudden, the faint ralysis, including serious blinking and tearing prob-
voice on the other end became louder. He tried this lems, but these facial symptoms have largely cleared
switch several times over the ensuing days, and the up.
conclusion became inescapable: Professor P. was go- Professor P. has now returned ON THE CD
ing deaf in his right ear. to his students, his research, and Visit the
Professor P. immediately made an appointment his writing, hoping that the tu- module My
with his doctor, who referred him to a specialist. After mor was completely removed and Tumor and
a cursory and poorly controlled hearing test, the spe- that he will not have to endure an- Welcome To It.
Pinel, relaxing in
cialist gave him good news. “You’re fine, Professor P.; other surgery. Indeed, at the very his own garden,
lots of people experience hearing loss when they reach moment that I am writing these describes his
middle age, and your problems are not serious enough words, Professor P. is working on struggle with a
to worry about.” To this day, Professor P. regrets that he the forthcoming edition of his text- brain tumor.
did not insist on a second opinion; his problem would book. . . . If it has not yet occurred
have been so much easier to deal with at that stage. to you, I am Professor P.
 10.1 ~ Causes of Brain Damage 233

10.1 Causes of Brain Damage

This section provides an introduction to six causes of About 10% of brain tumors do not originate in the
brain damage: brain tumors, cerebrovascular disorders, brain. They grow from infiltrating tumor fragments
closed-head injuries, infections of carried to the brain by the bloodstream from some
Clinical the brain, neurotoxins, and genetic other part of the body. (The brain is a particularly fer-
Implications
factors. It concludes with a discus- tile ground for tumor growth.) These tumors are called
sion of programmed cell death, which mediates many metastatic tumors; metastasis refers to the transmission
forms of brain damage. of disease from one organ to another. Most metastatic
brain tumors originate as cancers of the lungs. Obvi-
ously, the chance of recovering from a cancer that has
Brain Tumors
already attacked two or more separate sites is slim at
A tumor, or neoplasm (literally, “new growth”), is a best. Figure 10.2 on page 234 illustrates the ravages of
mass of cells that grows independently of the rest of the metastasis.
body (see Wechsler-Reya & Scott, 2001). In other words, Fortunately, my tumor was encapsulated. Encapsu-
it is a cancer. lated tumors that grow on cranial nerve VIII are referred
About 20% of tumors found in the human brain to as acoustic neuromas (neuromas are tumors that grow
are meningiomas (see Figure 10.1)—tumors that grow on nerves or tracts). Figure 10.3 on page 234 is an MRI
between the meninges, the three membranes that cover scan of my acoustic neuroma, the very same scan that I
the central nervous system. All meningiomas are en- took to my doctor.
capsulated tumors—tumors that grow within their
own membrane. As a result, they are particularly easy to
Cerebrovascular Disorders
identify on a CT scan, they can influence the function of
the brain only by the pressure they exert on surrounding Strokes are sudden-onset cerebrovascular disorders
tissue, and they are almost always benign tumors—tu- that cause brain damage. There are two major types of
mors that are surgically removable with little risk of fur- strokes: those resulting from cerebral hemorrhage and
ther growth in the body (see Grimson et al., 1999). those resulting from cerebral ischemia (pronounced “iss-
Unfortunately, encapsulation is the exception rather KEEM-ee-a”). In the United States, stroke is the third
than the rule when it comes to brain tumors. Aside from leading cause of death and the most common cause of
meningiomas, most brain tumors are infiltrating. Infil- adult disability (Janardhan & Qureshi, 2004). Common
trating tumors are those that grow diffusely through consequences of stroke are amnesia, aphasia (language
surrounding tissue. As a result, they are usually malig- difficulties), paralysis, and coma. The area of dead or dy-
nant tumors; it is difficult to remove or destroy them ing tissue produced by a stroke is called an infarct.
completely, and any cancerous tissue that remains after
surgery continues to grow. Cerebral Hemorrhage Cerebral hemorrhage (bleed-
ing in the brain) occurs when a cerebral blood vessel rup-
tures and blood seeps into the surrounding neural tissue
and damages it. Bursting aneurysms are a common cause
of intracerebral hemorrhage. An aneurysm is a patholog-
ical balloonlike dilation that forms in the wall of a blood
vessel at a point where the elasticity of the vessel wall is
defective. Aneurysms can be congenital (present at birth)
or can result from exposure to vascular poisons or infec-
tion (see Kalaria, 2001). Individuals who have aneurysms
should make every effort to avoid high blood pressure.

Cerebral Ischemia Cerebral ischemia is a disrup-

tion of the blood supply to an area of the brain. The
three main causes of cerebral ischemia are thrombosis,
embolism, and arteriosclerosis. In thrombosis, a plug
called a thrombus is formed and blocks blood flow at the
FIGURE 10.1 A meningioma. (Courtesy of Kenneth site of its formation. A thrombus may be composed of
Berry, Head of Neuropathology, Vancouver General Hospital.) a blood clot, fat, oil, an air bubble, tumor cells, or any
234 Chapter 10 ~ Brain Damage and Neuroplasticity www.ablongman.com/pinel6e

FIGURE 10.2 Multiple metastatic brain tumors. The arrows indicate some of the more
advanced areas of metastatic tumor development.

combination thereof. Embolism is similar except that embolus is just a thrombus that has taken a trip. In ar-
the plug, called an embolus in this case, is carried by teriosclerosis, the walls of blood vessels thicken and the
the blood from a larger vessel, where it was formed, to channels narrow, usually as the result of fat deposits; this
a smaller one, where it becomes lodged; in essence, an narrowing can eventually lead to complete blockage of
the blood vessels (Libby, 2002). The angiogram in Figure
10.4 illustrates partial blockage of one carotid artery.
Much of the damage produced by cerebral ischemia
takes a day or two to develop fully, and, paradoxically,

FIGURE 10.4 An angiogram that illustrates narrowing

of the carotid artery (see arrow), the main pathway of blood
FIGURE 10.3 An MRI of Professor P.’s acoustic to the brain. Compare this angiogram with the normal
neuroma. The arrow indicates the tumor. angiogram in Figure 5.1.
 10.1 ~ Causes of Brain Damage 235

some of the brain’s own neurotransmitters play a key role receptors. As a result, large numbers of Na+ and Ca2+
in its development (Wahlgren & Ahmed, 2004). Much ions enter the postsynaptic neurons.
of the brain damage associated with stroke is a conse- The excessive internal concentrations of Na+ and
quence of excessive release of excitatory amino acid neu- 2+
Ca ions affect the postsynaptic neurons in two ways:
rotransmitters, in particular glutamate, the brain’s most They trigger the release of excessive amounts of gluta-
prevalent excitatory neurotransmitter. mate from them, thus spreading the toxic cascade to yet
Here is how this mechanism is thought to work (see other neurons; and they trigger a sequence of internal
Dirgnagl, Iadecola, & Moskowitz, 1999). After a blood reactions that ultimately kill the postsynaptic neurons.
vessel becomes blocked, many of the blood-deprived (See Figure 10.5.)
neurons become overactive and release excessive quan- Ischemia-induced brain damage has three impor-
tities of glutamate. The glutamate in turn overactivates tant properties (Krieglstein, 1997). First, it takes a while
glutamate receptors in the membranes of postsynaptic to develop. Soon after a temporary cerebral ischemic
neurons; the glutamate receptors that are most involved episode, say, one 10 minutes in duration, there usu-
in this reaction are the NMDA (N-methyl-D-aspartate) ally is little or no evidence of brain damage; however,

Blood vessel
1 becomes
blocked.

2 Neurons that are

affected by the
ischemia release
Blockage excessive glutamate.

Glutamate

3 Excessive
glutamate
binds to NMDA
receptors, thus
Na+ triggering an
Ca2+ excessive influx of
Na+ and Ca2+ ions
into postsynaptic
neurons.

NMDA
receptor

Degeneration

4 The excessive influx

of Na+ and Ca2+ ions
eventually kills postsynaptic
neurons, but first it triggers
the excessive release of
glutamate from them, thus
spreading the toxic
cascade.
FIGURE 10.5 The cascade
of events by which the stroke-
induced release of glutamate kills
neurons.
236 Chapter 10 ~ Brain Damage and Neuroplasticity www.ablongman.com/pinel6e

substantial neuron loss can often be detected a day or

two later. Second, ischemia-induced brain damage does
not occur equally in all parts of the brain; particularly
susceptible are neurons in certain areas of the hippo-
campus (Ohtaki et al., 2003). Third, the mechanisms of
ischemia-induced damage vary somewhat from struc-
ture to structure within the brain.
An exciting implication of the discovery that exces-
sive glutamate release causes much of the brain damage
associated with stroke is the possibility of preventing
stroke-related brain damage by blocking the glutaminer-
gic cascade. The search is on for a glutamate antagonist
that is effective and safe for use in human stroke victims
(Leker & Shohami, 2002; Lo, Dalkara, & Moskowitz,
2003). Several have proved to be effective in laboratory
animals, but so far none has been shown to limit brain
damage from strokes in humans. Wahlgren and Ahmed
(2004) have argued that if such treatments are to be ef-
fective, they need to be initiated in the ambulance, not
hours later in the hospital.

Closed-Head Injuries
It is not necessary for the skull to be penetrated for the FIGURE 10.6 A CT scan of a subdural hematoma.
brain to be seriously damaged. In fact, any blow to the Notice that the subdural hematoma has displaced the left
lateral ventricle.
head should be treated with extreme caution, particu-
larly when confusion, sensorimotor disturbances, or
loss of consciousness ensues. Brain injuries produced by drunk syndrome is the dementia (general intellectual
blows that do not penetrate the skull are called closed- deterioration) and cerebral scarring that is observed in
head injuries. boxers and other individuals who experience repeated
Contusions are closed-head injuries that involve concussions. If there were no damage associated with a
damage to the cerebral circulatory system. Such damage single concussion, the effects of many concussions could
produces internal hemorrhaging, which results in a he- not summate to produce severe damage (McCrory &
matoma. A hematoma is a localized collection of clotted Berkovic, 1998).
blood in an organ or tissue—in other words, a bruise. One of the most dangerous aspects of concussion
It is paradoxical that the very hardness of the skull, is the complacency with which it is regarded. Flippant
which protects the brain from penetrating injuries, is the references to it, such as “having one’s bell rung,” do little
major factor in the development of contusions. Contu- to communicate its hazards.
sions from closed-head injuries occur when the brain
slams against the inside of the skull. As Figure 10.6 il-
lustrates, blood from such injuries can accumulate in The Case of Jerry
the subdural space—the space between the dura mater
and arachnoid membrane—and severely distort the sur- Quarry, Ex-Boxer
rounding neural tissue.
It may surprise you to learn that contusions fre- Jerry Quarry thumps his hard belly
Clinical
quently occur on the side of the brain opposite the side with both fists. Smiles at the sound. Implications
struck by a blow. The reason for such so-called contre- Like a stone against a tree.
coup injuries is that the blow causes the brain to strike “Feel it,” he says proudly, punching himself again
the inside of the skull on the other side of the head. and again.
When there is a disturbance of consciousness fol- He pounds big, gnarled fists into meaty palms.
Cocks his head. Stares. Vacant blue eyes. Punch-drunk
lowing a blow to the head and there is no evidence of
at 50. Medical name: Dementia pugilistic [punch-drunk
a contusion or other structural dam- syndrome]. Cause: Thousands of punches to the head.
Thinking
Critically age, the diagnosis is concussion. It A top heavyweight contender in the 1960s and ’70s,
is commonly assumed that concus- Quarry now needs help shaving, showering, putting
sions entail a temporary disruption of normal cere- on shoes and socks. Soon, probably, diapers. His older
bral function with no long-term damage. However, the brother, James, cuts meat into little pieces so he won’t
punch-drunk syndrome suggests otherwise. The punch- choke. Jerry smiles like a kid. Shuffles like an old man.
 10.1 ~ Causes of Brain Damage 237

Slow, slurred speech. Random thoughts snagged on Viruses may play a far greater role in neuropsy-
branches in a dying brain. Memories twisted. Voices no chological disorders than is currently thought. Their
one else hears. (Steve Wiltstein, Associated Press, 1995) involvement in the etiology (cause) of disorders is often
difficult to recognize because they may lie dormant for
many years before producing symptoms.
Infections of the Brain
An invasion of the brain by microorganisms is a brain Neurotoxins
infection, and the resulting inflammation is encepha- The nervous system can be damaged by exposure to any
litis. There are two common types of brain infections: one of a variety of toxic chemicals, which can enter gen-
bacterial infections and viral infections. eral circulation from the gastrointestinal tract, from the
lungs, or through the skin. For example, heavy metals
Bacterial Infections When bacteria infect the brain, such as mercury and lead can accumulate in the brain
they often lead to the formation of cerebral abscesses— and permanently damage it, producing a toxic psychosis
pockets of pus in the brain. They also often attack (chronic insanity produced by a neurotoxin). Have you
and inflame the meninges, creating a disorder known ever wondered why Alice in Wonderland’s Mad Hatter was
as meningitis, which is fatal in 25% of adults (Nau & a mad hatter and not a mad something else? In 18th- and
Brück, 2002). Penicillin and other antibiotics sometimes 19th-century England, hatmakers were commonly driven
eliminate the infection, but they cannot reverse brain mad by the mercury employed in the preparation of the
damage that has already been produced. felt used to make hats. In a similar vein, the word crackpot
Syphilis is one bacterial brain infection you have originally referred to the toxic psychosis observed in some
likely heard about. Syphilis bacteria are passed from in- people in England—primarily the poor—who steeped
fected to noninfected individuals through contact with their tea in cracked ceramic pots with lead cores.
genital sores. The infecting bacteria then go into a dor- Sometimes, the very drugs used to treat neurologi-
mant stage for several years before they become virulent cal disorders prove to have toxic effects. For example,
and attack many parts of the body, including the brain. some of the antipsychotic drugs introduced in the early
The syndrome of insanity and dementia that results 1950s produced effects of distressing scope. By the late
from a syphilitic infection is called general paresis. 1950s, millions of psychotic patients were being main-
Syphilis has a particularly interesting history (see tained on these new drugs. However, after several years
Klawans, 1990). The first Europeans to visit America of treatment, many of the patients developed a motor
stripped the natives of their gold and left smallpox in disorder termed tardive dyskinesia (TD). Its primary
return. But the deal was not totally one-sided; the booty symptoms are involuntary smacking and sucking move-
carried back to Europe by Columbus’s sailors and the ments of the lips, thrusting and rolling of the tongue,
adventurers that followed included a cargo of syphilis lateral jaw movements, and puffing of the cheeks. Safer
bacteria. Until then, syphilis had been restricted to the antipsychotic drugs have since been developed.
Americas, but it quickly spread to the rest of the world. Brain damage from the effects of recreational drugs
is also a serious problem. You learned in Chapter 1 that
Viral Infections There are two types of viral infections alcohol produces brain damage through a combination
of the nervous system: those that have a particular affinity of its direct neurotoxic effects and its effects on thiamine
for neural tissue and those that attack neural tissue but metabolism. Do you remember the case of Jimmie G.?
have no greater affinity for it than for other tissues. Some neurotoxins are endogenous (produced by the
Rabies, which is usually transmitted through the bite patient’s own body). For example, the body can produce
of a rabid animal, is a well-known example of a viral infec- antibodies that attack particular components of the ner-
tion that has a particular affinity for the nervous system. vous system (see Newsom-Davis & Vincent, 1991).
The fits of rage caused by the virus’s effects on the brain
increase the probability that rabid animals that normally
attack by biting (e.g., dogs, cats, raccoons, bats, and mice)
Genetic Factors
will spread the disorder. Although the effects of the ra- Normal human cells have 23 pairs of chromosomes;
bies virus on the brain are ultimately lethal, the virus does however, sometimes accidents of cell division occur, and
have one redeeming feature: It does not usually attack the the fertilized egg ends up with an abnormal chromo-
brain for at least a month after it has been contracted, thus some or with an abnormal number of normal chromo-
allowing time for a preventive vaccination. somes. Then, as the fertilized egg divides and redivides,
The mumps and herpes viruses are common exam- these chromosomal anomalies are duplicated in every
ples of viruses that can attack the nervous system but cell of the body.
have no special affinity for it. Although these viruses Most neuropsychological diseases of genetic origin
sometimes spread into the brain, they typically attack are caused by abnormal recessive genes that are passed
other tissues of the body. from parent to offspring. (In Chapter 2, you learned about
238 Chapter 10 ~ Brain Damage and Neuroplasticity www.ablongman.com/pinel6e

one such disorder, phenylketonuria.) Inherited neuropsy- Programmed Cell Death

chological disorders are rarely associated with dominant
genes because dominant genes that disturb neuropsy- You learned in Chapter 9 that neurons and other cells
chological function tend to be eliminated from the gene have genetic programs for suicide, that the process by
pool—every individual who carries one is at a major which cells destroy themselves is called apoptosis (pro-
survival and reproductive disadvantage. In contrast, indi- nounced “A-poe-toe-sis”), and that apoptosis plays a
viduals who inherit one abnormal recessive gene do not critical role in early development by eliminating some
develop the disorder, and the gene is passed on to future of the excessive neurons that are initially created. Apop-
generations. tosis also plays a role in brain damage. Indeed, each of
There are, however, two possible situations in which the six causes of brain damage that have already been
neurological disorders can be associated with dominant discussed in this chapter (tumors, cerebrovascular disor-
genes. One is the case in which an abnormal dominant ders, closed-head injuries, infections, toxins, and genetic
gene manifests itself only in rare environmental cir- factors) appears to produce its effect, in part, by activat-
cumstances. The other is the case in which an abnormal ing apoptotic programs of self-destruction (Allsop &
dominant gene is not expressed until the individual is Fazakerley, 2000; Dirnagl, Simon, & Hallenbeck, 2003;
well past puberty. Nijhawan, Honarpour, & Wang, 2000).
Down syndrome is a genetic disorder that is caused It was once assumed that the death of neurons fol-
not by a faulty gene, but by a genetic accident, which lowing brain damage was totally necrotic—necrosis is
occurs in 0.15% of births. The usual cause is an accident passive cell death resulting from injury. It now seems
that happens during ovulation. During ovulation an ex- that if cells are not damaged too severely, they will at-
tra chromosome 21 is created in the egg; thus, when the tempt to marshal enough resources to commit suicide.
egg is fertilized, there are three rather than two in the zy- However, cell death is not an either-or situation: Some
gote. The consequences of the superfluous chromosome damaged and dying cells display signs of both necrosis
21 are unfortunate. In addition to characteristic disfig- and apoptosis (see Elibol et al., 2001).
urement—flattened skull and nose, folds of skin over the It is easy to understand why apoptotic mechanisms
inner corners of the eyes, and short fingers (see Figure have evolved: Apoptosis is clearly more adaptive than ne-
10.7)—intellectual development is retarded, and there crosis. In necrosis, the damaged neuron swells and breaks
are often serious medical complications. The probability apart, beginning in the axons and dendrites and ending in
of giving birth to a child with Down syndrome increases the cell body. This fragmentation leads to inflammation,
with advancing maternal age (Carothers et al., 2001). which can damage other cells in the vicinity. Necrotic cell
Rapid progress is being made in locating and charac- death is quick, it is typically complete in a few hours. In
terizing the faulty genes that are associated with some neu- contrast, apoptotic cell death is slow, typically requiring
ropsychological disorders. Once this goal is achieved, it will a day or two. Apoptosis of a neuron proceeds gradually,
open up a variety of new treatment and prevention strate- starting with shrinkage of the cell body. Then, as parts of
gies, such as splicing in healthy genes to replace faulty ones the neuron die, the resulting debris is packaged in vesicles.
and developing specific DNA-binding proteins that can As a result, there is no inflammation, and damage to near-
enter neurons and block the expression of faulty genes. by cells is kept to a minimum.

FIGURE 10.7 A child with Down

syndrome before and after plastic surgery.
The purpose of these photographs is not to
promote cosmetic surgery but to challenge
our culture’s reaction to patients with Down
syndrome. The little girl on the left and the
little girl on the right are the same girl; they
deserve the same respect and consideration.
(Courtesy of Kenneth E. Salyer, Director,
International Craniofacial Institute.)
 10.2 ~ Neuropsychological Diseases 239

10.2 Neuropsychological Diseases

The preceding section focused on the causes of human

brain damage. This section considers five diseases that
are associated with brain damage:
Clinical epilepsy, Parkinson’s disease, Hun-
Implications
tington’s disease, multiple sclerosis,
and Alzheimer’s disease.

Epilepsy
The primary symptom of epilepsy is the epileptic sei-
zure, but not all persons who suffer seizures are consid-
ered to have epilepsy. It is not uncommon for an other-
wise healthy person to have a seizure during temporary
illness or following exposure to a convulsive agent. The
label epilepsy is applied to only those patients whose sei- FIGURE 10.8 Cortical electroencephalogram
zures appear to be generated by their own chronic brain (EEG) record from various locations on the scalp during
dysfunction. About 1% of the population are diagnosed the beginning of a complex partial seizure. The letters and
numbers to the left of each trace indicate the conventional
as epileptic at some point in their lives.
locations of the electrodes over the frontal (F), temporal (T),
In view of the fact that epilepsy is characterized by parietal (P), and occipital (O) lobes.
epileptic seizures—or, more accurately, by spontaneous-
ly recurring epileptic seizures—you might think that the
task of diagnosing this disorder would be an easy one.
But you would be wrong. The task is made difficult by that epileptic discharges did occur during the test but
the diversity and complexity of epileptic seizures. You were not recorded through the scalp electrodes.
are probably familiar with seizures that take the form of Some epileptics experience peculiar psychological
convulsions (motor seizures); these often involve trem- changes just before a convulsion. These changes, called
ors (clonus), rigidity (tonus), and loss of both balance epileptic auras, may take many different forms—for ex-
and consciousness. But many seizures do not take this ample, a bad smell, a specific thought, a vague feeling of
form; instead, they involve subtle changes of thought, familiarity, a hallucination, or a tightness of the chest.
mood, or behavior that are not easily distinguishable Epileptic auras are important for two reasons. First, the
from normal ongoing activity. nature of the auras provides clues concerning the loca-
There are many causes of epilepsy. Indeed, all of the tion of the epileptic focus. Second, because the epilep-
causes of brain damage that have been described in this tic auras experienced by a particular patient are often
chapter—including viruses, neurotoxins, tumors, and similar from attack to attack, they warn the patient of an
blows to the head—can cause epilepsy, and over 70 dif- impending convulsion.
ferent faulty genes have been linked to it (Noebels, 2003). Once an individual has been diagnosed as epileptic,
Many cases of epilepsy appear to be associated with faults it is usual to assign the epilepsy to one of two general
at inhibitory synapses that cause large numbers of neu- categories—partial epilepsy or generalized epilepsy—and
rons to fire in synchronous bursts (Köhling, 2002). then to one of their respective subcategories. The vari-
The diagnosis of epilepsy rests heavily on evidence ous seizure types are so different from one another that
from electroencephalography (EEG). The value of scalp epilepsy is best viewed not as a single disease but as a
electroencephalography in confirming suspected cases number of different, but related, diseases. Supporting
of epilepsy stems from the fact that epileptic seizures are this view is the fact that epilepsy has no single cause; al-
associated with bursts of high-amplitude EEG spikes, most any kind of brain disturbance can cause seizures.
which are often apparent in the scalp EEG during an at-
tack (see Figure 10.8), and from the fact that individual Partial Seizures A partial seizure is a seizure that
spikes often punctuate the scalp EEGs of epileptics be- does not involve the entire brain. The epileptic neurons
tween attacks. (Cohen et al., 2002). Although the obser- at a focus begin to discharge together in bursts, and it is
vation of spontaneous epileptic discharges is incontro- this synchronous bursting of neurons (see Figure 10.9
vertible evidence of epilepsy, the failure to observe them on page 240) that produces epileptic spiking in the EEG.
does not always mean that the patient is not epileptic. It The synchronous activity may stay restricted to the focus
could mean that the patient is epileptic but did not hap- until the seizure is over, or it may spread to other areas
pen to experience epileptic discharges during the test or of the brain—but, in the case of partial seizures, not to
240 Chapter 10 ~ Brain Damage and Neuroplasticity www.ablongman.com/pinel6e

FIGURE 10.9 The bursting

of an epileptic neuron, recorded by
extracellular unit recording.

the entire brain. The specific behavioral symptoms of a prise, he found that his salary had been raised. (Len-
partial epileptic seizure depend on where the disruptive nox, 1960, pp. 237–238.)
discharges begin and into what structures they spread.
Because partial seizures do not involve the entire brain,
they are not usually accompanied by a total loss of con- Although patients appear to be conscious through-
sciousness or equilibrium. out their complex partial seizures, they usually have little
There are two major categories of partial seizures: or no subsequent recollection of them. About half of all
simple and complex. Simple partial seizures are partial cases of epilepsy are of the complex partial variety—the
seizures whose symptoms are primarily sensory or mo- temporal lobes are particularly susceptible to epileptic
tor or both; they are sometimes called Jacksonian sei- discharges.
zures after the famous 19th-century neurologist Hugh-
lings Jackson. As the epileptic discharges spread through Generalized Seizures Generalized seizures involve
the sensory or motor areas of the brain, the symptoms the entire brain. Some begin as focal discharges that
spread systematically through the body. gradually spread through the entire brain. In other cas-
In contrast, complex partial seizures are often re- es, the discharges seem to begin almost simultaneously
stricted to the temporal lobes, and those who experi- in all parts of the brain. Such sudden-onset generalized
ence them are often said to have temporal lobe epilepsy. seizures may result from diffuse pathology or may begin
During a complex partial seizure, the patient engages focally in a structure, such as the thalamus, that projects
in compulsive, repetitive, simple behaviors commonly to many parts of the brain.
referred to as automatisms (e.g., doing and undoing a Like partial seizures, generalized seizures occur in
button) and in more complex behaviors that appear al- many forms. One is the grand mal (literally, “big trouble”)
most normal. The diversity of complex partial seizures is seizure. The primary symptoms of a grand mal seizure
illustrated by the following four cases. are loss of consciousness, loss of equilibrium, and a vio-
lent tonic-clonic convulsion—a convulsion involving both
tonus and clonus. Tongue biting, urinary incontinence,
The Subtlety of Complex and cyanosis (turning blue from excessive extraction of
Partial Seizures: Four Cases oxygen from the blood during the convulsion) are com-
mon manifestations of grand mal convulsions. The hy-
poxia (shortage of oxygen supply to tissue, for example,
A war veteran subject to many autom- to the brain) that accompanies a grand mal seizure can
Clinical
Implications atisms read in the newspaper about a itself cause brain damage, some of which develops slowly
man who had embraced a woman in after the attack and is mediated by the excessive release of
a park, followed her into a women’s toilet, and then
excitatory amino acid neurotransmitters.
boarded a bus. From the description given, he realized
he was the man. A second major category of generalized seizure is the
petit mal (literally, “small trouble”) seizure (see Crunelli
One morning a doctor left home to answer an emer- & Leresche, 2002). Petit mal seizures are not associated
gency call from the hospital and returned several hours with convulsions; their primary behavioral symptom
later, a trifle confused, feeling as though he had experi- is the petit mal absence—a disruption of consciousness
enced a bad dream. At the hospital he had performed a that is associated with a cessation of ongoing behavior, a
difficult . . . [operation] with his usual competence, but
vacant look, and sometimes fluttering eyelids. The EEG
later had done and said things deemed inappropriate.
of a petit mal seizure is different from that of other sei-
A young man, a music teacher, when listening to a con- zures; it is a bilaterally symmetrical 3-per-second spike-
cert, walked down the aisle and onto the platform, cir- and-wave discharge (see Figure 10.10). Petit mal seizures
cled the piano, jumped to the floor, did a hop, skip, and are most common in children, and they frequently cease
jump up the aisle, and regained his senses when part at puberty. They often go undiagnosed; thus, children
way home. He often found himself on a trolley [bus] with petit mal epilepsy are sometimes considered to be
far from his destination.
“daydreamers” by their parents and teachers.
A man in an attack went to his employer and said, “I Although there is no cure for epilepsy, the frequency
have to have more money or [I] quit.” Later, to his sur- and severity of seizures can often be reduced by anti-
 10.2 ~ Neuropsychological Diseases 241

major neurotransmitter released by most neurons of the

substantia nigra, there is little dopamine in the substantia
Left nigra and striatum of long-term Parkinson’s patients.
frontal
As you saw in the case of d’Orta, the symptoms of
Parkinson’s disease can be alleviated by injections of L-
Right
frontal dopa—the chemical from which dopamine is synthe-
sized. However, L-dopa is rarely a permanent solution; it
Left typically becomes less and less effective with continued
temporal use, until its side effects (e.g., involuntary movements;
see Bezard, Brotchie, & Gross, 2001) outweigh its ben-
Right efits. This is exactly what happened to d’Orta. L-Dopa
temporal
therapy gave him a 3-year respite from his disease, but
ultimately it became totally ineffective. His prescription
1 second
was then changed to another dopamine agonist, and
again his condition improved—but again the improve-
FIGURE 10.10 The bilaterally symmetrical, 3-per- ment was only temporary. We will return to d’Orta’s
second spike-and-wave EEG discharge that is associated with roller-coaster case later in this chapter.
petit mal epileptic seizures.
About 10 different gene mutations have been linked
to Parkinson’s disease (see Dawson & Dawson, 2003;
Le & Appel, 2004). This has led many people to believe
convulsant medication. Brain surgery is sometimes pre- that a cure is just around the corner. However, it is im-
scribed in life-threatening situations. portant to realize that each of these
Thinking
gene mutations has been discovered Critically
in a different family, each of which
Parkinson’s Disease
had members suffering from a rare form of early-on-
Parkinson’s disease is a movement disorder of middle set Parkinson’s disease that runs in families. Thus, these
and old age that affects about 0.5% of the population mutations are unlikely to be factors in typical forms of
(see Strickland & Bertoni, 2004). It is about 2.5 times the disease. Still, the study of the effects of these gene
more prevalent in males than in females (see Sawada & mutations may eventually lead to a better understanding
Shimohama, 2000; Wooten et al., 2004). of the physiological changes that underlie the symptoms
The initial symptoms of Parkinson’s disease are of the disorder (see Vila, Wu, & Przedborski, 2001).
mild—perhaps no more than a slight stiffness or tremor of
the fingers—but they inevitably increase in severity with
advancing years. The most common symptoms of the full-
Huntington’s Disease
blown disorder are a tremor that is pronounced during Like Parkinson’s disease, Huntington’s disease is a pro-
inactivity but not during voluntary movement or sleep, gressive motor disorder of middle and old age; but, un-
muscular rigidity, difficulty initiating movement, slowness like Parkinson’s disease, it is rare, it has a strong genetic
of movement, and a masklike face. Pain and depression of- basis, and it is associated with severe dementia.
ten develop before the motor symptoms become severe. The first motor signs of Huntington’s disease are of-
Although Parkinson’s patients often display some ten increased fidgetiness; as the disorder develops, rapid,
cognitive deficits, dementia is not typically associated complex, jerky movements of entire limbs (rather than
with the disorder. In essence, Parkinson’s disease victims individual muscles) begin to predominate. Eventually
are thinking people trapped inside bodies they cannot the motor and intellectual deterioration become so se-
control. Do you remember from Chapter 4 the case of vere that sufferers are incapable of feeding themselves,
“The Lizard”—Roberto Garcia d’Orta? controlling their bowels, or recognizing their own chil-
Like epilepsy, Parkinson’s disease seems to have no dren. There is no cure; death typically occurs about 15
single cause; faulty genes, brain infections, strokes, tu- years after the appearance of the first symptoms.
mors, traumatic brain injury, and neurotoxins have all Huntington’s disease is passed from generation to
been implicated in specific cases (see Greenamyre & generation by a single dominant gene; thus, all of the
Hastings, 2004). However, in the majority of cases, no individuals carrying the gene develop the disorder, as
cause is obvious, and there is no family history of the do about half their offspring. The Huntington’s gene
disorder (see Calne et al., 1987). is readily passed from parent to child because the first
Parkinson’s disease is associated with degeneration of symptoms of the disease do not appear until the parent is
the substantia nigra—the midbrain nucleus whose neu- well past the peak reproductive years (at about age 40).
rons project via the nigrostriatal pathway to the striatum The abnormal dominant gene that causes Hunting-
of the basal ganglia. Although dopamine is normally the ton’s disease was identified and characterized in 1993.
242 Chapter 10 ~ Brain Damage and Neuroplasticity www.ablongman.com/pinel6e

The abnormal protein produced by the Huntington’s

gene has also been isolated and characterized. However,
the precise effect of this protein, which has been named
huntingtin, has not yet been determined (see McMurray,
2001). Curiously, huntingtin is produced in all parts of
the brains of Huntington’s sufferers, yet brain damage is
largely restricted to the striatum and cerebral cortex (see
DiFiglia et al., 1997; Jakel & Maragos, 2000).
If one of your parents were to develop Huntington’s
disease, the chance would be 50/50 that you too would
develop it. If you were in such a situation, would you
want to know whether or not you would suffer the same
fate? Medical geneticists have developed a test that can
tell relatives of Huntington’s patients whether they are
carrying the gene (Gilliam, Gusella, & Lehrach, 1987; FIGURE 10.11 Areas of sclerosis (see arrows) in the
Martin, 1987). Some choose to take the test, and some white matter of a patient with MS.
do not. One advantage of the test is that it permits the
relatives of Huntington’s patients who have not inher-
ited the gene to have children without the fear of passing people who spent their childhood in a cool climate, even if
on the disorder. they subsequently moved to a warm climate. In contrast,
Shortly after the first edition of evidence of genetic involvement comes from the finding
Clinical this textbook appeared in print, I re- that multiple sclerosis is rare among certain groups, such
Implications
ceived the letter reproduced on the as Africans and Asians, even when they live in environ-
next page. I have altered it slightly to protect the identity ments in which the incidence of the disease is high in
of its author and his family. It speaks for itself. other groups. The disorder occurs in 0.15% of Caucasians
and is about twice as common in females (Steinman et
al., 2002). Research indicates that there is a strong genetic
Multiple Sclerosis predisposition to multiple sclerosis, with involvement of
Multiple sclerosis (MS), is a progressive disease that at- a large number of different genes, each making a small
tacks the myelin of axons in the CNS. It is particularly contribution (Hemmer, Archelos, & Hartung, 2002).
disturbing because it typically attacks young people just Multiple sclerosis is an autoimmune disorder—a dis-
as they are beginning their adult life. First, there are mi- order in which the body’s immune system attacks part
croscopic areas of degeneration on myelin sheaths; but of the body, as if it were a foreign substance. In mul-
eventually there is a breakdown of both the myelin and tiple sclerosis, myelin is the focus of the faulty immune
the associated axons, along with the development of reaction. Indeed, an animal model of multiple sclerosis,
many areas of hard scar tissue (sclerosis means “harden- termed experimental autoimmune encephalomyelitis,
ing”). Figure 10.11 illustrates degeneration in the white can be induced by injecting laboratory animals with
matter of a patient with multiple sclerosis. myelin and a preparation that stimulates the immune
Diagnosing multiple sclerosis is difficult because system. One of the puzzles of multiple sclerosis is that
the nature and severity of the disorder depend on the the healing response of remyelination, which occurs in
number, size, and position of the sclerotic lesions. Fur- animal models and in the early stages of most human
thermore, in some cases, there are lengthy periods of re- cases, eventually fails (Franklin, 2002).
mission (up to 2 years), during which the patient seems There are a number of drugs that retard the progres-
almost normal; however, these are usually just oases in sion of multiple sclerosis or block some of its symptoms.
the progression of the disorder. Common symptoms However, there is no cure.
of advanced multiple sclerosis are visual disturbances,
muscular weakness, numbness, tremor, and ataxia (loss
Alzheimer’s Disease
of motor coordination).
Epidemiological studies of multiple sclerosis have Alzheimer’s disease is the most common cause of de-
provided evidence of the environmental and genetic fac- mentia. It sometimes appears in individuals as young
tors that influence its development. Epidemiology is the as 40, but the likelihood of its development becomes
study of the various factors, such as diet, geographic lo- greater with advancing years. About 10% of the general
cation, age, sex, and race, that influence the distribution population over the age of 65 suffer from the disease,
of a disease in the general population. and the proportion is about 35% in those over 85 (St.
Evidence that environmental factors influence the George-Hyslop, 2000).
development of multiple sclerosis comes from the find- Alzheimer’s disease is progressive. Its early stages are
ing that the incidence of multiple sclerosis is far greater in often characterized by a selective decline in memory; its
 10.2 ~ Neuropsychological Diseases 243

S. Miller
Mr. Walter rn-Langdon Rd.
Se ve
1500 N. cut 22022
, Connecti
Manchester
Z9/900–854 91
19
August 5,

J. Pinel
Dr. John P. of Psychology
Depa rt me nt Columbia
of British Y7.
University B. C. Canada V6T.,1
Vancouver,
, I am
Dear Dr. Pi
nel: re. In fact
dr en an d their futu you are my friend
chil that
d about my book I feel
I am worrie After reading your
d si ck . tu rn .
worrie nowhere el
se to s ago, and
and I have ase 7 year g
th Hu nt in gton’s dise f. I have three youn
me down wi of hersel herited my
My wife ca t walk or take care see if they have in h adds to
can’ to , whic
today she I take them ently incarcerated uld take
Where can es on, and co answers.
children. cted cells? I am pr be re le as ed so
d ge t
in fe to lp an
wife’s . I look find he
gical pain y wheres to
my psycholo kids just about an ea tly
my wife an
d would be gr
at yo u co uld give us ank you for any
advice th th
I wish to
Any kind of me and my family.
d by
appreciate that you can give. I
assistance and peace!
s His love
d gi ve yo u and your
you an rds.
God bless rmest personal rega
wa
remain with
yours, THE UN
Very truly IVERSIT
Y OF BR
ITISH C
OLUMBI
A
Department of
Psychology
Miller 2136 West Ma
Walter S. Vancouver, B.
ll
C. Canada V6
Tel: (604) 822– T 1Z4
WSM: 2755
November 25 Fax: (604) 822–
6923
, 1991
Mr. Walter S.
Miller
1500 N. Severn
-Langdon Road
Manchester, Co
nnecticut 2202
U.S.A. 2

Dear Mr. Mill

er:
I was sadden
ed to learn of
that you unde your unhapp
rstand that I am y state of affair
sessment. a scientist, no s. In requestin
t a physician. g my advice,
In any case, th I hope
e following is
If your wife do my as-
es in fact have
der, each of yo Huntington’s
ur children ha disease and no
I am sure that s a 50/50 chan t some other ne
you are aware ce of developin urological diso
that there is cu g Huntington r-
rre ntly no cure. ’s disease in ad
I advise you to ulthood.
seek the advice
and provide yo of a local neur
u with the advi ologist, who ca
not to subject ce and suppor n explain your
your children t that you sore options to you
carrying the H to the tests th ly need. You m
untington’s ge at are require ust decide whe
ne . One option w d to de ter m ine whether or ther or
and then allow ould be to wait
them to make for your child not they are
Huntington’s the decision fo ren
disease decid r themselves. to reach legal
important for e to take the tes Some people age
them not to ris t; others decid whose parent
k passing on th e not to. In eit s develop
e Huntington her case, it is
I am sorry that ’s gene to futu extremely
I cannot prov re generations
situation is to ide you with a .
o serious for more optimist
as soon as poss me to be less ic assessment,
ible. than totally fra but your child
nk. Again, plea ren’s
se consult a ne
Do not lose ho urologist
pe. There is a
ton’s gene. I w chance (1/8) th
ish you, your at none of your
wife, and your children is carry
children good ing the Huntin
fortune. g-
Cordially,

John P. J. Pine
l
Professor
244 Chapter 10 ~ Brain Damage and Neuroplasticity www.ablongman.com/pinel6e

intermediate stages are marked by confusion, irritability, Although neurofibrillary tangles, amyloid plaques,
anxiety, and deterioration of speech; and in its advanced and neuron loss tend to occur throughout the brains of
stages, the patient deteriorates to the point that even Alzheimer’s patients, they are more prevalent in some
simple responses such as swallowing and controlling the areas than in others. For example, they are particularly
bladder are difficult. Alzheimer’s disease is terminal. prevalent in medial temporal lobe structures such as
Because Alzheimer’s disease is not the only cause of the entorhinal cortex, amygdala, and hippocampus—all
dementia, it cannot be diagnosed with certainty on the structures that are involved in various aspects of mem-
basis of its behavioral symptoms—definitive diagnosis of ory (see Collie & Maruff, 2000; Selkoe, 2002). They are
Alzheimer’s disease must await autopsy. The two defining also prevalent in the inferior temporal cortex, posterior
characteristics of the disease are neurofibrillary tangles parietal cortex, and prefrontal cortex—all areas that me-
and amyloid plaques. Neurofibrillary tangles are threadlike diate complex cognitive functions. (See Figure 10.13.)
tangles of protein in the neural cytoplasm, and amyloid There is a difficulty in studying the genetics of Al-
plaques are clumps of scar tissue composed of degenerat- zheimer’s disease: Its carriers often die of natural causes
ing neurons and a protein called amyloid, which is present before their Alzheimer’s symptoms can be manifested.
in normal brains in only very small amounts. In addition, Nevertheless, it is clear that Alzheimer’s disease has a
there is substantial neuron loss. The presence of amyloid major genetic component. People with an Alzheimer’s
plaques in the brain of a patient who died of Alzheimer’s victim in their immediate family have a 50% chance of
disease is illustrated in Figure 10.12. being stricken by the disease if they survive into their 80s
(Breitner, 1990).
Much of the research on the genetics of Alzheimer’s
disease has focused on rare early-onset familial forms of
the disease. Several gene mutations have been found to
be associated with early-onset Alzheimer’s disease, and
all of them have been implicated in the synthesis of am-
yloid or tau, a protein found in neurofibrillary tangles
(see St. George-Hyslop, 2000).
The massive research effort currently aimed at devel-
oping a cure for Alzheimer’s disease is fueled by a combi-
nation of two factors. One is the severity of the problem.
The other is that a major advance seems feasible—
because Alzheimer’s is a disease of old age, the number
of cases could be halved by a treatment that would slow
its development by even 5 years.

Posterior
parietal
cortex
Prefrontal
cortex

Amygdala

Entorhinal
cortex Inferior
temporal
Hippocampus cortex

FIGURE 10.13 The typical distribution of neurofibrillary

tangles and amyloid plaques in the brains of patients with
FIGURE 10.12 Amyloid plaques (see arrows) in the advanced Alzheimer’s disease. (Based on Goedert, 1993, and
brain of a patient with Alzheimer’s disease. Selkoe, 1991.)
 10.3 ~ Animal Models of Human Neuropsychological Diseases 245

SCAN YO U R B R AI N
This is a good place for you to pause to scan your brain. Are learned about? Fill in the following blanks. The correct answers
you ready to progress to the following section, which discuss- are provided at the bottom of this page. Before proceeding,
es animal models of some of the disorders that you have just review material related to your errors and omissions.

1. The two major categories of epileptic seizures 6. Genetic studies of Parkinson’s disease and
are _______________________ and Alzheimer’s disease have focused on early-onset
_______________________. _______________________ forms of the disorder.
2. _______________________ are simple repetitive re- 7. Experimental autoimmune encephalomyelitis is
sponses that occur during complex partial seizures. an animal model _______________________ of
3. The disorder characterized by tremor at rest is _______________________.
_______________________ disease. 8. The most common cause of dementia is
4. Parkinson’s disease is associated with degeneration in _______________________ disease.
the _______________________ dopamine pathway. 9. Two major neuropathological symptoms of Alzheimer’s
5. _______________________ disease is passed from gen- disease are _______________________ tangles and
eration to generation by a single dominant gene. _______________________ plaques.

One factor complicating the search for a treatment tylcholine levels were among the earliest neurochemical
or cure for Alzheimer’s disease is that it is still not clear changes appearing in patients. Cholinergic agonists are
which symptom is primary (see Lee, still sometimes prescribed, but, except for a few minor
Thinking
Critically 2001; Mudher & Lovestone, 2002). benefits early in the disorder, they have proven ineffective.
This is a key issue because an effective Several other treatment approaches are currently under
treatment is most likely to be developed only by research development (see Hardy & Selkoe, 2002). Arguably, the
focusing on the primary symptom. The most popular most promising of these is the immunotherapeutic ap-
candidate is the amyloid plaques; the amyloid hypothesis proach (see Ingram, 2001; Schenk, 2002). This approach
holds that the development of these plaques is the pri- has used an amyloid vaccine to reduce plaque deposits
mary symptom of the disorder, which causes all other and improve performance on memory tasks in a trans-
symptoms (see Hardy & Selkoe, 2002). However, others genic mouse model of Alzheimer’s disease (which we’ll
believe that the development of tau and neurofibrillary discuss further in the next section). Human trials have
tangles is the primary symptom, and still others support been mixed: Therapeutic effects have been observed, but
other contenders—for example, a disruption of calcium dangerous inflammation occurred in the CNSs of 5% of
regulation—for this role (see LaFerla, 2002). the patients (see Monsonego & Weiner, 2003).
The first efforts to develop treatments for Alzhei-
mer’s disease focused on the fact that declines in ace-

10.3 Animal Models of Human Neuropsychological Diseases

The first two sections of this chapter focused on neuro- It is important to appreciate that even the best ani-
psychological diseases and their causes, but they also pro- mal models of neuropsychological diseases display only
vided some glimpses into the ways in some of the features of the diseases they are modeling (see
Evolutionary
Perspective which researchers have attempted to Maries et al., 2003). Consequently, an-
solve the many puzzles of neurological imal models must be employed with Thinking
Critically
dysfunction. This section focuses on one of these ways: the caution. Studying an animal model is
experimental investigation of animal models. Because the
experimentation necessary to identify the neuropatholog- (8) Alzheimer’s, (9) neurofibrillary and amyloid.
ical basis of human neuropsychological diseases is seldom (5) Huntington’s, (6) familial, (7) multiple sclerosis,
possible on the patients themselves, animal models of the order, (2) Automatisms, (3) Parkinson’s, (4) nigrostriatal,
diseases play an important role in such investigation (see Scan Your Brain answers: (1) partial and generalized in either
Cenci, Whishaw, & Schallert, 2002).
246 Chapter 10 ~ Brain Damage and Neuroplasticity www.ablongman.com/pinel6e

like exploring a section of an unknown maze. One enters Much of the interest in kindling stems from the fact
an unfamiliar section with little more than a hope that that it models epilepsy in two ways. First, the convulsions
its exploration will prove fruitful, and it is only after each elicited in kindled animals are similar in many respects
of its arms has been carefully explored that it is possible to those observed in some types of human epilepsy. Sec-
to know whether the decision to enter the section was ond, the kindling phenomenon itself is comparable to
wise. In the same way, it is not possible to evaluate animal the epileptogenesis (the development, or genesis, of epi-
models of neuropsychological dysfunction that are cur- lepsy) that can follow a head injury: Some individuals
rently under investigation until each has been thoroughly who at first appear to have escaped serious injury after a
explored. Surely, only a few animal models will lead to- blow to the head begin to experience convulsions a few
ward the goals of understanding and prevention, but only weeks later, and these convulsions sometimes begin to
time and effort can tell which ones these are. recur more and more frequently and with greater and
This section of the chapter discusses three animal greater intensity.
models that are currently the focus of intensive inves- It must be stressed that the kindling model as it is
tigation: the kindling model of epilepsy, the transgenic applied in most laboratories is different from epilepsy in
mouse model of Alzheimer’s disease, and the MPTP one important respect. You will recall from earlier in this
model of Parkinson’s disease. chapter that epilepsy is a disease in which epileptic attacks
recur spontaneously; in contrast, kindled convulsions are
elicited. However, a model that overcomes this shortcom-
Kindling Model of Epilepsy
ing has been developed in several species. If subjects are
In 1969, Goddard, McIntyre, and Leech delivered one kindled for a very long time—about 300 stimulations in
mild electrical stimulation per day to rats through im- rats—a syndrome can be induced that is truly epileptic, in
planted amygdalar electrodes. There was no behavioral the sense that the subjects begin to display spontaneous
response to the first few stimulations, but soon each seizures and continue to display them even after the regi-
stimulation began to elicit a convulsive response. The men of stimulation is curtailed (e.g., Pinel, 1981; Shouse
first convulsions were mild, involving only a slight trem- et al., 1990; Wada, Sato, & Corcoran, 1974).
or of the face. However, with each subsequent stimula- One interesting and potentially important develop-
tion, the elicited convulsions became more generalized, ment in the study of kindling is that some researchers
until each convulsion involved the entire body. The pro- have started to focus on interictal behavior (behavior that
gressive development and intensification of convulsions occurs in epileptics between their seizures). For some hu-
elicited by a series of periodic brain stimulations became man epileptics, particularly those who suffer from com-
known as the kindling phenomenon. plex partial seizures, pathological changes in interictal
Although kindling is most frequently studied in rats behavior are more distressing and more difficult to treat
subjected to repeated amygdalar stimulation, it is a re- than the seizures themselves (Leung, Ma, & McLachlan,
markably general phenomenon. For example, kindling 2000). Several studies of kindling have shown that kindled
has been reported in mice (Leech & McIntyre, 1976), rab- subjects display a variety of changes in interictal emotion-
bits (Tanaka, 1972), cats (Adamec, 1990), dogs (Wauqui- al behavior that are similar to those observed in human
er, Ashton, & Melis, 1979), and various primates (Wada, epileptics (Kalynchuk, 2000; Wintink et al., 2003).
1990a). Moreover, kindling can be produced by the re-
peated stimulation of many brain sites other than the Transgenic Mouse Model
amygdala, and it can be produced by the repeated applica-
of Alzheimer’s Disease
tion of initially subconvulsive doses of convulsive chemi-
cals (Cain, 1986; Mori & Wada, 1990; Post et al., 1990). Perhaps the most exciting development in the study of
There are many interesting features of kindling (see Alzheimer’s disease has been the transgenic model of
Racine & Burnham, 1984; Wada, 1990b), but two war- the disorder. Transgenic refers to animals into which
rant emphasis. The first is that the neural changes un- the genes of another species have been introduced (see
derlying kindling are permanent. A subject that has been Carter et al., 1999).
kindled and then left unstimulated for several months One difficulty in studying Alzheimer’s disease is
still responds to each low-intensity stimulation with a that only humans and a few related primates develop
generalized convulsion (Goddard, McIntyre, & Leech, amyloid plaques, considered by many to be the primary
1969; Wada & Sato, 1974). The second is that kindling is symptom of the disorder. As a result, experimental stud-
produced by distributed, as opposed to massed, stimu- ies of Alzheimer’s disease have been difficult to conduct,
lations. If the intervals between successive stimulations and fundamental questions of causation have been dif-
are shorter than an hour or two, it usually requires many ficult to address. For example, the causal role of amyloid
more stimulations to kindle a subject; and under normal plaques in Alzheimer’s disease has not yet been sorted
circumstances, no kindling at all occurs at intervals of out: Some investigators believe that amyloid deposi-
less than about 20 minutes (Racine et al., 1973). tion triggers neuron degeneration, thereby causing the
 10.3 ~ Animal Models of Human Neuropsychological Diseases 247

behavioral symptoms; others believe that the amyloid or MPTP. . . . There has been no sign of remission, and
plaques are the result, not the cause, of the neural de- most are becoming increasingly severe management
generation (Neve & Robakis, 1998). This lack of prog- problems. (Langston, 1985, p. 79)
ress in answering fundamental causal questions about
Alzheimer’s disease is why the development of the trans- Researchers immediately turned the misfortune of
genic mouse model of the disorder is such an important these few to the advantage of many by developing a much-
contribution. needed animal model of Parkinson’s disease (Langston,
There are several forms of the transgenic mouse 1986). It was quickly established that nonhuman primates
model. In one (Hsiao et al., 1996), genes that acceler- respond like humans to MPTP. The brains of primates ex-
ate the synthesis of human amyloid are injected into posed to MPTP have cell loss in the substantia nigra simi-
newly fertilized mouse eggs, which are then injected into lar to that observed in the brains of Parkinson’s patients.
a foster mother to develop. When the transgenic mice Considering that the substantia nigra is the major source
mature, their brains contain many amyloid plaques like of the brain’s dopamine, it is not surprising that the level
those of human Alzheimer’s patients. Moreover, the dis- of dopamine is greatly reduced in both the MPTP model
tribution of the amyloid plaques is comparable to that and in the naturally occurring disorder. However, it is
observed in human Alzheimer’s patients, with the high- curious that in a few monkeys MPTP produces a major
est concentrations occurring in structures of the medial depletion of dopamine without producing any gross mo-
temporal lobes (e.g., hippocampus, amygdala, and ento- tor symptoms (Taylor et al., 1990).
rhinal cortex). The MPTP animal model has already benefitted pa-
Although the transgenic mice of Hsiao and her col- tients with Parkinson’s disease. For example, it was dis-
leagues arguably provide the best animal model of Al- covered that deprenyl, a monoamine agonist, blocks the
zheimer’s disease, the model is not without its problems. effects of MPTP in an animal model, and it was subse-
For example, the mice show no neurofibrillary tangles, quently shown that deprenyl administered to early Par-
and the degree of memory impairment changes little as kinson’s patients retards the progression of the disease
the mice mature and develop more plaques. However, (Tetrud & Langston, 1989)—see Figure 10.14
an animal model does not have to mimic the human Several transgenic mouse models of Parkinson’s dis-
disorder in every respect to be useful: As you learned ease have been developed. However, the MPTP model is
in the preceding section, the trangenic mouse model of still regarded as the best (Beal, 2001).
Alzheimer’s disease has been used to develop an amyloid
vaccine that is being tested on human patients.

MPTP Model of Parkinson’s Disease

The preeminent animal model of Parkinson’s disease 14
of Parkinson’s Motor Symptoms
Average Rate of Development

grew out of an unfortunate accident, which resulted in

12
the following anomalous cases of Parkinson’s disease.
10

The Case of the Frozen Addicts 8

6
Clinical Parkinson’s disease . . . rarely occurs
Implications before the age of 50. It was somewhat 4
of a surprise then to see a group of
young drug addicts at our hospital in 1982 who had 2
developed symptoms of severe and what proved to be
irreversible parkinsonism. The only link between these
patients was the recent use of a new “synthetic heroin.” Placebo Deprenyl-
They exhibited virtually all of the typical motor fea- Control Treated
tures of Parkinson’s disease, including the classic triad Patients Patients
of bradykinesia (slowness of movement), tremor and
rigidity of their muscles. Even the subtle features, such
as seborrhea (oiliness of the skin) and micrographia FIGURE 10.14 Average rate of motor symptom
(small handwriting), that are typical of Parkinson’s dis- development in early Parkinson’s patients treated with
ease were present. After tracking down samples of this deprenyl (a monoamine oxidase inhibitor) or with a placebo.
substance, the offending agent was tentatively identi- Deprenyl slowed the progression of the disease by 50%.
fied as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (Based on Tetrud and Langston, 1989.)
248 Chapter 10 ~ Brain Damage and Neuroplasticity www.ablongman.com/pinel6e

Neuroplastic Responses to Nervous System Damage:

10.4 Degeneration, Regeneration, Reorganization, and Recovery
Damage to the nervous system may trigger four neuro- Neural Regeneration
plastic responses: degeneration, regeneration, reorga-
Neural regeneration—the regrowth of damaged neu-
nization, and recovery of function. Each of these four
rons—does not proceed as successfully in mammals and
responses is discussed in this section.
other higher vertebrates as it does in most invertebrates
and lower vertebrates. The capacity for accurate axonal
growth, which is possessed by higher vertebrates during
Neural Degeneration
their original development, is lost once they reach ma-
A widely used method for the controlled study of the turity. Regeneration is virtually nonexistent in the CNS
responses of neurons to damage is to cut their axons. of adult mammals, and is at best a hit-or-miss affair in
Two kinds of neural degeneration (deterioration) ensue: the PNS.
anterograde degeneration and retrograde degeneration In the mammalian PNS, regrowth from the proxi-
(see Coleman & Perry, 2002; Raff, Whitmore, & Finn, mal stump of a damaged nerve usually begins 2 or 3 days
2002). Anterograde degeneration is the degeneration after axonal damage. What happens next depends on the
of the distal segment—the segment of a cut axon be- nature of the injury (see Tonge & Golding, 1993); there
tween the cut and the synaptic terminals. Retrograde are three possibilities. First, if the original Schwann cell
degeneration is the degeneration of the proximal seg- myelin sheaths remain intact, the regenerating periph-
ment—the segment of a cut axon between the cut and eral axons grow through them to their original targets
the cell body. at a rate of a few millimeters per day. Second, if the pe-
Anterograde degeneration occurs quickly following ripheral nerve is severed and the cut ends become sepa-
axotomy, because the cut separates the distal segment rated by a few millimeters, regenerating axon tips often
of the axon from the cell body, which is the metabolic grow into incorrect sheaths and are guided by them to
center of the neuron. The entire distal segment becomes incorrect destinations; that is why it is often difficult to
badly swollen within a few hours, and it breaks into frag- regain the coordinated use of a limb affected by nerve
ments within a few days. damage even if there has been substantial regeneration.
The course of retrograde degeneration is different; it And third, if the cut ends of a severed mammalian pe-
progresses gradually back from the cut to the cell body. In ripheral nerve become widely separated or if a lengthy
about 2 or 3 days, major changes become apparent in the section of the nerve is damaged, there may be no mean-
cell bodies of most axotomized neurons. These early cell ingful regeneration at all; regenerating axon tips grow
body changes are either degenerative or regenerative in in a tangled mass around the proximal stump, and the
nature. Early degenerative changes to the cell body (e.g., neurons ultimately die. These three patterns of mam-
a decrease in size) suggest that the neuron will ultimately malian peripheral nerve regeneration are illustrated in
die—usually by apoptosis but sometimes by necrosis or a Figure 10.16 on page 250.
combination of both (Syntichaki & Tavernararkis, 2003). Why do mammalian PNS neurons regenerate, and
Early regenerative changes (e.g., an increase in size) indi- mammalian CNS neurons do not? The obvious answer
cate that the cell body is involved in a massive synthesis is that PNS neurons are inherently capable of regenera-
of the proteins that will be used to replace the degener- tion while CNS neurons are not, but this answer has
ated axon. But early regenerative changes in the cell body proved to be incorrect. CNS neurons are capable of re-
do not guarantee the long-term survival of the neuron; if generation if they are transplanted to the PNS, whereas
the regenerating axon does not manage to make synaptic PNS neurons are not capable of regeneration if they are
contact with an appropriate target, the neuron eventu- transplanted to the CNS. Clearly, there is something
ally dies. about the environment of the PNS that promotes re-
Sometimes, degeneration spreads from damaged generation and something about the environment of the
neurons to neurons that are linked to them by synaps- CNS that does not (Goldberg & Barres, 2000). Schwann
es; this is called transneuronal degeneration. In some cells are the key.
cases, transneuronal degeneration spreads from dam- Schwann cells, which myelinate PNS axons, pro-
aged neurons to the neurons on which they synapse; this mote regeneration in the mammalian PNS by producing
is called anterograde transneuronal degeneration. And both neurotrophic factors and cell-adhesion molecules
in some cases, it spreads from damaged neurons to the (CAMs). The neurotrophic factors released by Schwann
neurons that synapse on them; this is called retrograde cells stimulate the growth of new axons, and the cell-
transneuronal degeneration. Neural and transneuronal adhesion molecules on the cell membranes of Schwann
degeneration are illustrated in Figure 10.15. cells provide the paths along which regenerating PNS
 10.4 ~ Neuroplastic Responses to Nervous System Damage: Degeneration, Regeneration, Reorganization, and Recovery 249

Axotomy: Anterograde Retrograde Transneuronal

The axon of a Degeneration: Degeneration: Degeneration:
neuron is cut. Then, the distal portion Then, the proximal portion Then, neurons that
of the damaged neuron of the damaged neuron synapsed on the
degenerates. may degenerate. damaged neuron
may degenerate (i.e.,
retrograde transneuronal
degeneration) and so too
may neurons on which the
damaged neuron synapsed
(i.e., anterograde trans-
neuronal degeneration).

FIGURE 10.15 Neuronal and transneuronal degeneration following axotomy.

axons grow. In contrast, oligodendroglia, which myelin- in both the CNS and the PNS, and it Evolutionary
ate CNS axons, do not stimulate or guide regeneration; is accurate even when the regenerat- Perspective
indeed, they release factors that actively block regenera- ing axons do not grow into remnant
tion (Filbin, 2003; Fournier & Strittmatter, 2001). Schwann cell myelin sheaths. The accuracy of regenera-
In contrast to neural regeneration in mammals, that tion in lower vertebrates offers hope of a medical break-
in lower vertebrates is extremely accurate. It is accurate through: If the factors that promote accurate regeneration
250 Chapter 10 ~ Brain Damage and Neuroplasticity www.ablongman.com/pinel6e

FIGURE 10.16 Three

patterns of axonal regeneration in
mammalian peripheral nerves. When a nerve is
damaged without
severing the Schwann
cell sheaths (e.g., by
crushing), individual
axons regenerate to
their correct targets.

When a nerve is
damaged and
the severed ends of the
Schwann cell sheaths
are slightly separated,
individual axons often
regenerate up incorrect
sheaths and reach
incorrect targets.

When a nerve is
damaged and the
severed ends of the
Schwann cell sheaths
are widely separated,
there is typically no
functional regeneration.

in lower vertebrates can be identified and applied to the thought to be limited to the subtle functional changes that
human brain, it might be possible to cure currently un- mediate learning and memory. However, as you learned
treatable brain injuries. in Chapter 9, it was recently discovered that adult mam-
When an axon degenerates, axon branches grow malian brains retain the ability to reorganize themselves
out from adjacent healthy axons and synapse at the sites in response to experience. They also retain the ability to
vacated by the degenerating axon; this is called collat- reorganize themselves in response to damage.
eral sprouting. Collateral sprouts may grow out from
the axon terminal branches or the nodes of Ranvier on Examples of Cortical Reorganization Following
adjacent neurons. Collateral sprouting is illustrated in Nervous System Damage Most studies of neural
Figure 10.17. reorganization following damage have focused on adult
sensory and motor systems (see Donoghue, 1995; Wall,
Xu, & Wang, 2002). Sensory and motor systems are ide-
Neural Reorganization
ally suited to the study of neural reorganization because
It has long been assumed that major changes in mamma- of their topographic layout. The damage-induced reor-
lian nervous systems were limited to the period of early ganization of the primary sensory and motor systems
development: Adult mammalian nervous systems were has been studied in two fundamentally different condi-
 10.4 ~ Neuroplastic Responses to Nervous System Damage: Degeneration, Regeneration, Reorganization, and Recovery 251

Working with rats, Sanes, Suner, and Donoghue

A B A B (1990) transected the motor neurons that controlled the
muscles of the rats’ vibrissae (whiskers). A few weeks later,
stimulation of the area of motor cortex that had previous-
ly elicited vibrissae movement now activated other mus-
cles of the face. This result is illustrated in Figure 10.18.

Mechanisms of Neural Reorganization Two kinds

of mechanisms have been proposed to account for the re-
organization of neural circuits: a strengthening of existing
connections, possibly through release from inhibition, and
the establishment of new connections by collateral sprout-
ing (see O’Leary, Ruff, & Dyck, 1994). Support for the first
mechanism comes from two observations: Reorganiza-
tion often occurs too quickly to be explained by neural
growth, and rapid reorganization never involves changes
of more than 2 millimeters of cortical surface. Support for

Motor cortex–normal layout

Eye and Trunk Hindlimb
Axotomy of neuron A Degeneration of neuron A
eyelid
and collateral sprouting of
neuron B.
Vibrissae

FIGURE 10.17 Collateral sprouting after neural

degeneration.

tions: following damage to peripheral nerves and follow-

ing damage to the primary cortical areas (Buonomano &
Merzenich, 1998). Let’s consider some studies that illus-
trate these two approaches.
Kaas and colleagues (1990) assessed the effect of Mouth
and neck Forelimb
making a small lesion in one retina and removing the
other. Several months after the retinal lesions were made,
primary visual cortex neurons that originally had recep-
Motor cortex–after transection
tive fields in the lesioned area of the retina were found to
have receptive fields in the area of the retina next to the Eye and Trunk Hindlimb
lesion; remarkably, this change began within minutes of eyelid
the lesion (Gilbert & Wiesel, 1992).
Pons and colleagues (1991) mapped the primary
somatosensory cortex of monkeys whose contralateral
arm sensory neurons had been cut 10 years before. They
found that the cortical face representation had system-
atically expanded into the original arm area. This study
created a stir because the scale of the reorganization was
far greater than had been assumed to be possible: The
primary somatosensory cortex face area had expanded
its border by well over a centimeter, likely as a conse- Mouth
quence of the particularly long (10-year) interval be- and neck Forelimb
tween surgery and testing.
Jenkins and Merzenich (1987) removed the area of FIGURE 10.18 Reorganization of the rat motor cortex
monkey somatosensory cortex that responded to touch- following transection of the motor neurons that control
es of the palm of the contralateral hand. Several weeks movements of the vibrissae. The motor cortex was mapped
later, they found that neurons adjacent to the lesion now by brain stimulation before transection and then again a few
responded to touches of the palm. weeks after. (Adapted from Sanes, Suner, & Donoghue, 1990.)
252 Chapter 10 ~ Brain Damage and Neuroplasticity www.ablongman.com/pinel6e

the second mechanism comes from the observation that Little is known about recovery of function after ner-
the magnitude of long-term reorganization can be too vous system damage for two reasons. The first is that it
great to be explained by changes in existing connections. is difficult to conduct controlled experiments on popu-
Figure 10.19 illustrates how these two mechanisms might lations of brain-damaged patients. The second is that
account for the reorganization that occurs after damage to nervous system damage may result
Thinking
a peripheral somatosensory nerve. in a variety of compensatory changes Critically
that can easily be confused with true
recovery of function. For example, any improvement
Recovery of Function
in the week or two after damage could reflect a decline
after Brain Damage in cerebral edema (brain swelling) rather than a recov-
Understanding the mechanisms that underlie the recov- ery from the neural damage itself, and any gradual im-
ery of function after nervous system damage is a high provement in the months after damage could reflect the
priority for neuroscientists. If these mechanisms were learning of new cognitive and behavioral strategies (i.e.,
understood, steps could be taken to promote recovery. substitution of functions) rather than the return of lost
However, recovery of function after nervous system functions (see Wilson, 1998). Consequently, true recov-
damage is a poorly understood phenomenon. ery of function is less common than most believe (see

Intact somatosensory
system

Original cortical area

responding to touches
at B

Original cortical area

Skin Skin responding to touches
area B area A at A

Two days after damage

to nerve B

Area released from

inhibition responds to
touches at A

Original area responding

to touches at A

Six months after damage Area into which sprouting

to nerve B has occurred responds to
touches at A
Area released from
inhibition responds to
touches at A
FIGURE 10.19 The two-stage
model of neural reorganization: Original area responding
(1) strengthening of existing to touches at A
connections through release from
inhibition and (2) establishment
of new connections by collateral
sprouting.
 10.4 ~ Neuroplastic Responses to Nervous System Damage: Degeneration, Regeneration, Reorganization, and Recovery 253

100
FIGURE 10.20 Percentage
Percentage of Brain-Damaged
Motor Somatosensory Visual
Defects Defects Defects of patients showing improvement
Patients Who Improved 80 following brain injury. Teuber (1975)
assessed the deficits of brain-
damaged soldiers within a week of
60
their injury and again 20 years later.

40

20

17–20 21–25 26+ 17–21 22–25 26+ 17–19 20–25 26+

Age of Patients

Figure 10.20). However, substantial recovery of function for this hypothesis has been indirect (see Hallett, 2001).
is most likely when lesions are small and the patient is The strongest evidence comes from a study in which the
young (see Payne & Lomber, 2001). degree of motor recovery in stroke patients was found to
Cognitive reserve (roughly equivalent to education be correlated with the degree of motor cortex reorgani-
and intelligence) is thought to play an important role in zation (Lipert et al., 2000).
the apparent recovery of cognitive function after brain For years, neural reorganization seemed to be the
damage. Kapur (1997) conducted a biographical study only explanation for recovery from CNS damage. How-
of doctors and neuroscientists with brain damage, and ever, the discovery of adult neurogenesis raised another
he observed a great deal of cognitive recovery. He con- possibility: Perhaps the growth of new neurons plays a
cluded that the observed improvement did not occur role in such recovery, particularly when the damage af-
because these patients had actually recovered lost cogni- fects the hippocampus. It has recently been shown (see
tive function but because their cognitive reserve allowed Kokaia & Lindvall, 2003) that cerebral ischemia, which
them to accomplish cognitive tasks in alternative ways. preferentially damages the hippocampus, increases adult
The mechanisms of recovery of function remain neurogenesis; that many of the new cells become part of
unknown. It seems likely that neural reorganization the hippocampus; and that these new cells establish syn-
contributes to recovery, but so far most of the evidence apses and develop into mature neurons—see Figure 10.21.

FIGURE 10.21 Increased neurogenesis in the dentate gyrus following damage. The left panel
shows (1) ion electrolytic lesion in the dentate gyrus (damaged neurons are stained turquoise) and (2)
the resulting increase in the formation of new cells (stained red), many of which develop into mature
neurons (stained dark blue). The right panel displays the comparable control area in the unlesioned
hemisphere, showing the normal number of new cells (stained red). (These beautiful images are courtesy
of my good friends Carl Ernst and Brian Christie, Department of Psychology, University of British Columbia.)
254 Chapter 10 ~ Brain Damage and Neuroplasticity www.ablongman.com/pinel6e

It is thus possible that an increase in adult neurogenesis shown to increase adult neurogenesis (Holmes et al., 2004;
contributes to recovery from stroke, but there is currently Van Praag et al., 2002)—could prove to be therapeutic for
no direct evidence for this attractive hypothesis. Howev- patients with hippocampal damage.
er, if this hypothesis is proven, exercise—which has been

10.5 Neuroplasticity and the Treatment of Nervous System Damage

The study of neuroplasticity is currently one of the most explain why several brain disorders (e.g., Parkinson’s
active and exciting areas of research in neuroscience. This disease) are more prevalent in males than in females.
section reveals the major reason for all the excitement: In general, molecules that limit neural degeneration
The dream that recent discoveries about neuroplastic- also promote regeneration. This point leads us to the
ity—with which you are now familiar—can be applied next subsection.
to the treatment of brain damage in human patients.
The following four subsections de-
Evolutionary Promoting Recovery from CNS
Perspective scribe research on some major new
treatment approaches. Most of this Damage by Promoting Regeneration
research has focused on animal models, but some of it Although regeneration does not normally occur in the
has progressed to clinical trials with human patients. mammalian CNS, several studies have shown that it can
be induced. The following three studies are particularly
Reducing Brain Damage by promising because they have shown that such regenera-
tion can be associated with functional recovery.
Blocking Neurodegeneration
Eitan and colleagues (1994) transected the left optic
Several studies have shown that it may be possible to re- nerves of rats. In the control rats, the retinal ganglion
duce brain damage by blocking neural degeneration in cells, which compose the left optic nerve, permanently
human patients. For example, in one study, Xu and col- degenerated. The experimental rats received injections
leagues (1999) induced cerebral ischemia in rats by lim- of an agent that is toxic to oligodendrocytes, thus elimi-
iting blood flow to the brain. This had two major effects nating these cells’ ability to block regeneration. In these
in the control group of rats: It produced damage in the experimental subjects, the optic nerves regenerated, and
hippocampus, a structure that is particularly susceptible 6 weeks after the injury, evoked potentials could be re-
to ischemic damage, and it produced deficits in the rats’ corded from the optic nerve in response to light flashes
performance in the Morris water maze (see Chapter 5). presented to the left eye.
The hippocampuses of rats in the experimental group Cheng, Cao, and Olson (1996) transected the spinal
were treated with viruses genetically engineered to re- cords of rats, thus rendering them paraplegic (paralyzed
lease apoptosis inhibitor protein. Amazingly, the apopto- in the posterior portion of their bodies). The research-
sis inhibitor protein prevented both the loss of hippo- ers then transplanted sections of myelinated peripheral
campal neurons and the deficits in Morris water maze nerve across the transection. As a result, spinal cord neu-
performance. rons regenerated through the implanted Schwann cell
In addition to apoptosis inhibitor protein, several myelin sheaths, and the regeneration allowed the rats to
other neurochemicals have been shown to block the de- regain use of their hindquarters.
generation of damaged neurons. The most widely stud- A similar study involved transplanting olfactory en-
ied of these is nerve growth factor (see Sofroniew, Howe, sheathing cells rather than Schwann cells. Olfactory en-
& Mobley, 2001). You may be surprised to learn that es- sheathing cells, which are similar to Schwann cells, were
trogens have a similar effect (see Behl, 2002; Sawada & selected because the olfactory system is unique in its abil-
Shimohama, 2000; Stein, 2001; Wise et al., 2001). Estro- ity to support continual growth of axons from new PNS
gens are a class of steroid hormones that are released in neurons into the CNS (i.e., into the olfactory bulbs). Li,
large amounts by the ovaries (the female gonads). These Field, and Raisman (1998) made lesions in the corticospi-
hormones have several important effects on the matu- nal tract of rats and then implanted bridges of olfactory
ration of the female body, which you will learn about ensheathing cells across the lesion. Axons grew through
in Chapter 13, but they also have a variety of influences the lesion, and the motor function of the affected paw was
on the brain. Estrogens have been shown to limit or de- partially restored. Although it is not yet clear how this re-
lay neuron death in animal models and in cell cultures, covery occurs, these findings have generated considerable
and there are also some supportive findings from human optimism (see Barnett & Chang, 2004; Edgerton & Roy,
patients. These neuroprotective effects of estrogens may 2002; Keyvan-Fouladi, Li, & Raisman, 2002).
 10.5 ~ Neuroplasticity and the Treatment of Nervous System Damage 255

Promoting Recovery from CNS large-scale clinical trial was premature. Researchers do
Damage by Neurotransplantation not yet know how to maximize the survival and growth of
neurotransplants and how to minimize their side effects.
A few years ago, the idea of brain transplantation was It is important to achieve a balance between the pressure
little more than science fiction. Today, the treatment of to develop new treatments quickly and the need to base
brain damage by transplanting neural tissue is approach- treatments on a carefully constructed foundation of sci-
ing reality. Efforts to treat CNS damage by neurotrans- entific understanding (see Döbrössy & Dunnett, 2001).
plantation have taken two different approaches (see In Chapter 4, you were introduced to Roberto Garcia
Björklund & Lindvall, 2000). The first is to transplant d’Orta—the Lizard. D’Orta, who suffered from Parkin-
fetal tissue; the second is to transplant stem cells. son’s disease, initially responded to L-dopa therapy; but,
after 3 years of therapy, his condition worsened. Then he
Transplanting Fetal Tissue The first approach to responded to treatment with a dopamine agonist, but
neurotransplantation was to replace a damaged struc- again the improvement was only temporary. D’Orta, was
ture with fetal tissue that would develop into the same in a desperate state when he heard about adrenal medulla
structure. Could the donor tissue develop and become autotransplantation (transplanting a patient’s own adre-
integrated into the host brain, and in so doing alleviate nal medulla cells into her or his striatum, usually for the
the symptoms? This approach focused on Parkinson’s treatment of Parkinson’s disease). Adrenal medulla cells
disease. Parkinson’s patients lack the dopamine-releasing release small amounts of dopamine, and there were some
cells of the nigrostriatal pathway: Could they be cured by early indications that adrenal medulla autotransplanta-
transplanting the appropriate fetal tissue into the site? tion might alleviate the symptoms of Parkinson’s disease.
Early signs were positive. Bilateral transplantation of D’Orta demanded adrenal medulla autotransplan-
fetal substantia nigra cells was successful in treating the tation from his doctor. When his doctor refused, on the
MPTP monkey model of Parkinson’s disease (Bankie- grounds that the effectiveness of the treatment was still
wicz et al., 1990; Sladek et al., 1987). Fetal substantia in doubt, d’Orta found himself another doctor—a neu-
nigra transplants survived in the MPTP-treated mon- rosurgeon who was not nearly so cautious.
keys; they innervated adjacent striatal tissue, released
dopamine, and, most importantly, alleviated the severe
poverty of movement, tremor, and rigidity produced by The Case of Roberto Garcia
the MPTP.
Soon after the favorable effects of neurotransplants
d’Orta: The Lizard Gets
in the MPTP monkey model were reported, neurotrans- an Autotransplant
plantation was offered as a treatment for Parkinson’s dis-
ease at major research hospitals. The results of the first Roberto flew to Juarez. The neurosurgeon there greeted
case studies were promising. The fetal substantia nigra him with open arms. As long as Roberto could afford
implants survived, and they released dopamine into the the cost, he’d be happy to do an adrenal implant on
host striatum (see Sawle & Myers, 1993). More impor- him. . . .
tantly, some of the patients improved. Were there any dangers?
The results of these case studies triggered a large- The neurosurgeon seemed insulted by the ques-
scale double-blind evaluation study of patients suffering tion. If Señor d’Orta didn’t trust him, he could go else-
from advanced Parkinson’s disease. The study was ex- where. . . .
tremely thorough; it even included placebo controls— Roberto underwent the procedure.
He flew back home two weeks later. He was no bet-
patients who received surgery but no implants. The ini-
ter. He was told that it took time for the cells to grow
tial results were encouraging: Although control patients and make the needed chemicals. . . .
showed no improvement, the implants survived in the Then I received an unexpected call from Roberto’s
experimental patients, and some displayed a modest im- wife. Roberto was dead. . . .
provement. Unfortunately, however, about 15% of these He’d died of a stroke. . . . Had the stroke been a
patients started to display a variety of uncontrollable complication of his surgery? It was more than a mere
writhing and chewing movements about a year after the possibility. (Klawans, 1990, pp. 63–64)
surgery (Greene et al., 1999).
The results of this first double-blind placebo-con-
trolled clinical trial of the effectiveness of fetal tissue
transplants created widespread debate (see Dunnett, Transplanting Stem Cells In Chapter 9, you learned
Björklund, & Lindvall, 2001).The incidence of adverse about embryonic neural stem cells, which are multipo-
motor side effects is likely to stifle future attempts to tent (having the capacity to develop into many types
develop neurotransplantation as a treatment for Parkin- of mature neurons). Investigators are trying to develop
son’s disease. However, many still believe that this is an procedures for repairing brain damage by injecting em-
extremely promising therapeutic approach, but that the bryonic neural stem cells into the damaged site. Once
256 Chapter 10 ~ Brain Damage and Neuroplasticity www.ablongman.com/pinel6e

injected, the stem cells could develop and replace the Strokes Small strokes produce a core of brain dam-
damaged cells, under guidance from surrounding tis- age, which is often followed by a gradually expanding
sue. This line of research received a major boost from loss of neural function around this core. Nudo and col-
the development of renewable cultures of stem cells (see leagues (1996) produced small ischemic lesions (lesions
Wakayama et al., 2001), which can serve as a source for produced by an interruption of blood supply) in the
transplantation and research (Gage, 2000). The study by hand area of the motor cortex of monkeys. Then, 5 days
McDonald and colleagues (1999) illustrates the poten- later, a program of hand training and practice was ini-
tial of this method. tiated. During the ensuing 3 or 4 weeks, the monkeys
McDonald and colleagues injected embryonic neu- plucked hundreds of tiny food pellets from food wells of
ral stem cells into an area of spinal damage. Their sub- different sizes. This practice substantially reduced the ex-
jects were rats that had been rendered paraplegic by a pansion of cortical damage. The monkeys that received
blow. The stem cells migrated to different areas around the rehabilitative training also showed greater recovery
the damaged area, where they developed into mature in the use of their affected hand.
neurons. Remarkably, the rats receiving the implants One of the principles that has emerged from the
became capable of supporting their weight with their study of neurodevelopment is that neurons seem to be
hindlimbs and walking, albeit awkwardly. in a competitive situation: They compete with other
The study by McDonald and colleagues and several neurons for synaptic sites and neurotrophins, and the
similar ones triggered widespread media attention and a losers die. Weiller and Rijntjes (1999) designed a reha-
frenzy of research activity. Effective treatment for severe bilitative program based on this principle, tested it on
CNS damage appeared to be within reach. However, it monkeys, and then tested it on unilateral stroke patients
quickly became apparent that much research still needs who had difficulty using one arm. Their procedure,
to be done (see Rossi & Cattaneo, 2002; Wexler & Palmer, called constraint-induced therapy (Taub, Uswatte, & El-
2002). First, effective methods of propagating popula- bert, 2002), was to tie down the functioning arm for 2
tions of neural stem cells must be developed (see Gott- weeks while the affected arm received intensive training.
lieb, 2002). Because sources of embryonic stem cells have Performance with the affected arm improved markedly
been limited by law in some parts of the world, efforts over the 2 weeks, and there was an increase in the area of
have focused on harvesting neural stem cells from adult motor cortex controlling that arm.
brains or on trying to cause other types of adult stem
cells (e.g., blood stem cells) to develop into neural stem
Spinal Injury In one approach to treating patients
cells. Neither approach has as yet achieved unqualified
with spinal injuries (see Rossignol, 2000; Wolpaw & Ten-
success (see Temple, 2001; Wagers et al., 2002). Second,
nissen, 2001), patients incapable of walking were sup-
techniques for promoting the survival and appropriate
ported by a harness over a moving treadmill. With most
maturation of the neural stem cells once they have been
of their weight supported and the treadmill providing
implanted need to be developed. Third, the factors that
appropriate feedback, the patients gradually learned to
promote the establishment of correct connections with
make walking movements. Then, as they improved, the
surviving cells need to be identified. And fourth, meth-
amount of support was gradually reduced. In one study
ods for encouraging functional recovery have to be de-
using this technique, over 90% of the trained patients
veloped. For example, little attention has been paid to
eventually became independent walkers, compared with
the behavioral treatment of patients with neural stem
only 50% of those receiving conventional physiotherapy.
cell implants, which is likely to be an important factor in
their recovery. In short, although therapeutic neural stem
cell transplantation is one of the most exciting subjects Phantom Limbs Most amputees continue to experi-
of investigation in all of neuroscience, the ultimate goal ence limbs that have been amputated—a condition re-
is an ambitious one whose achievement will take longer ferred to as phantom limb. The most striking feature of
than once thought (see Zoghbi, Gage, & Choi, 2000). phantom limbs is their reality. Their existence is so com-
pelling that a patient may try to jump out of bed onto a
Promoting Recovery from CNS nonexistent leg or to lift a cup with a nonexistent hand.
In most cases, the amputated limb behaves like a normal
Damage by Rehabilitative Training
limb; for example, as an amputee walks, a phantom arm
Several demonstrations of the important role of expe- seems to swing back and forth in perfect coordination
rience in the organization of the developing and adult with the intact arm. However, sometimes an amputee
brain kindled a renewed interest in the use of rehabili- feels that the amputated limb is stuck in a peculiar posi-
tative training to promote recovery from CNS damage. tion. For example, one amputee felt that his phantom arm
The following innovative rehabilita- extended straight out from the shoulder, and as a result,
Clinical tive training programs were derived he turned sideways whenever he passed through door-
Implications from such findings. ways (Melzack, 1992).
 10.5 ~ Neuroplasticity and the Treatment of Nervous System Damage 257

About 50% of amputees experience chronic severe

pain in their phantom limbs. A typical complaint is that
an amputated hand is clenched so tightly that the finger-
nails are digging into the palm of the hand. Occasionally,
phantom limb pain can be treated by having the ampu-
tee concentrate on opening the amputated hand. How-
ever, when this does not work, the pain can become so
intense that desperate measures are attempted. 2 3 5
Based on the premise that phantom limb pain re-
1
sults from irritation at the stump, many efforts to con-
trol it involved cutting off the stump or surgical destruc-
tion of various parts of the neural pathway between
the stump and the cortex. Unfortunately, none of these
surgical interventions provided patients with relief from
the pain or eliminated the phantom limb (see Melzack,
1992). Still, the idea that phantom limbs and phantom
limb pain result from irritation of nerves in the stump
5
persisted. There seemed to be no other possibility. 3
This chapter ends with the stories of two patients 1 2

suffering from phantom limb pain and their exceptional

doctor. The patients were Tom and Philip, and their phy-
sician was the neuropsychologist V. S. Ramachandran. In
the process of treating Tom and Philip, Dr. Ramachan-
dran solved a long-standing neuropsychological puzzle
and developed a new treatment to boot.
FIGURE 10.22 The places on Tom’s body where
touches elicited sensations in his phantom hand.
(Adapted from Ramachandran & Blakeslee, 1998.)
The Cases of Tom and
Philip: Phantom Limbs
and Ramachandran some warm water was dropped on his face, he felt it
running down his phantom hand. A second map of his
Dr. Ramachandran read an article about a study hand was found on his shoulder (see Figure 10.22).
you have already encountered in this chapter, the study Philip, another patient of Dr. Ramachandran, suf-
by Pons and colleagues (1991). In this study, severing fered from severe chronic pain in his phantom arm.
the sensory neurons in the arms of For a decade, Philip had been unable to move the
Clinical monkeys led to a reorganization of joints of the phantom arm: It was frozen in an awk-
Implications
somatosensory cortex: The area of ward position (Ramachandran & Rogers-Ramachan-
the somatosensory cortex that originally received in- dran, 2000), and Philip suffered great pain in all of its
put from the damaged arm now received input from joints, particularly the elbow.
areas of the body normally mapped onto adjacent Dr. Ramachandran applied a bit of biopsycholog-
areas of somatosensory cortex. Ramachandran was ical ingenuity to the problem. Could he relieve Phil-
struck by a sudden insight: Perhaps phantom limbs ip’s pain by teaching him to move his phantom arm?
were not in the stump at all, but in the brain; perhaps Knowing how important feedback is in movement (see
the perception of a phantom arm Chapter 8), Dr. Ramachandran constructed a special
Thinking
Critically originated from parts of the body feedback apparatus for Philip. This was a box divided
that now innervated the original in two by a vertical mirror. Philip was instructed to
arm area of the somatosensory cortex (see Ramachan- put his good right hand into the box
Thinking
dran & Blakeslee, 1998). through a hole in the front and view Critically
Excited by his hypothesis, Dr. Ramachandran it through a hole in the top. When he
asked one of his patients, Tom, if he would participate looked at his hand, he could see it and its mirror im-
in a simple test. He touched various parts of Tom’s age. He was instructed to put his phantom limb in the
body and asked Tom what he felt. Remarkably, when he box and try to position it, as best he could, so that it
touched the side of Tom’s face on the same side as his corresponded to the mirror image of his good hand.
amputated arm, Tom felt sensations from various parts Then, he was instructed to make synchronous, bilater-
of his phantom hand as well as his face. Indeed, when ally symmetrical movements of his arms—his actual
258 Chapter 10 ~ Brain Damage and Neuroplasticity www.ablongman.com/pinel6e

right arm and his phantom left arm—while viewing “What are you talking about?”
his good arm and its mirror image. “You know, my phantom arm, which I had for 10
years. It doesn’t exist anymore. All I have is my phan-
“Oh my God! Oh my God, doctor! This is unbelievable. tom fingers and palm dangling from my shoulder.”
It’s mind-boggling.” He was jumping up and down like . . . “Philip—does this bother you?”
a kid. “My left arm is plugged in again. It’s as if I’m in “No, no, no. . . . On the contrary. You know the ex-
the past. . . . I can move my arm again. I can feel my cruciating pain that I always had in my elbow? . . . Well,
elbow moving, my wrist moving. It’s all moving again. now I don’t have an elbow and I don’t have that pain
(Ramachandran & Blakeslee, 1998, pp. 47–48) anymore.” (Ramachandran & Blakeslee, 1998, p. 49)
But when Philip shut his eyes or removed his arms
from the apparatus, his phantom limb was frozen once
again . . . and the pain was as bad as ever. So, Ramach- I hope that I have managed to communicate to you
andran sent Philip home with the box and instruc- some of the excitement that is being generated by the dis-
tions to use it. Three weeks later, Philip phoned. covery that the adult human brain is plastic. The possi-
“Doctor,” he exclaimed, “it’s gone!” bilities of applying neuroplastic processes to repair brain
“What’s gone?” (I thought maybe he had lost the damage are truly exciting. I am optimistic that there will
mirror box.) soon be a breakthrough because, as you have just learned,
“My phantom is gone.” progress is being made on so many different fronts.

Themes Revisited
Because this entire chapter dealt with clinical issues, the primary symptom of Alzheimer’s ON THE CD
the clinical implications tab made numerous appear- disease, and about recovery of func- See Hard
ances. In particular, it drew attention tion. Particularly interesting were the Copy for ad-
Clinical
Implications to the many cases that appeared in insightful approaches that Dr. Ramach- ditional readings
the chapter: the ironic case of Pro- andran took in treating Tom and Philip, for Chapter 10.
fessor P.; Jerry Quarry, the punch-drunk ex-boxer; the who suffered from phantom limb pain.
cases of complex partial epilepsy; Walter S. Miller, the The evolutionary perspective was
Evolutionary
man whose wife had Huntington’s disease; the cases of also highlighted at several points. You Perspective
MPTP poisoning; and Tom and Philip, the amputees were introduced to the concept of ani-
with phantom limbs. mal models, which is based on the comparative approach,
The chapter stressed clear thinking about biopsy- and you learned that most of the research on neural re-
chology in several places. Attention was drawn to think- generation and reorganization following brain damage
ing about the cumulative effects of concussions, about has been done with animal models. Finally, you learned
the relation between genes and Par- that research into the mechanisms of neural regeneration
Thinking
Critically kinson’s disease, about animal mod- has been stimulated by the fact that this process occurs
els of disease, about the identity of accurately in some species.

Think about It
1. An epileptic is brought to trial for assault. The lawyer 4. Total dementia often creates less suf- ON THE CD
argues that her client is not a criminal and that the fering than partial dementia. Discuss. Studying for
assaults in question were psychomotor attacks. She 5. In order to be useful, animal models an exam? Try the
points out that her client takes her medication faith- do not have to have all of the features Practice Tests for
fully, but that it does not help. The prosecution lawyer Chapter 10.
of the disorder they are modeling.
argues that the defendant has a long history of violent Discuss.
assault and must be locked up. What do you think the
6. Major breakthroughs in the treatment of CNS dam-
judge should do?
age are on the horizon. Discuss.
2. Describe a bizarre incident you have observed that
7. The first evaluation of the effectiveness of neurotrans-
you think in retrospect might have been a complex
plantation in the treatment of Parkinson’s disease
partial or petit mal seizure.
suggested that the treatment, as administered, was
3. The more that is known about a disease, the easier not effective. What do you think should be the next
it is to diagnose; and the more accurately it can be step?
diagnosed, the easier it is to find things out about it.
Explain and discuss.
 Key Terms 259

Key Terms
Alzheimer’s disease (p. 242) Down syndrome (p. 238) Malignant tumors (p. 233) Strokes (p. 233)
Amyloid (p. 244) Embolism (p. 234) Meningiomas (p. 233) Substantia nigra (p. 241)
Aneurysm (p. 233) Encapsulated tumors (p. 233) Meningitis (p. 237) Tardive dyskinesia (TD)
Anterograde degeneration Encephalitis (p. 237) Metastatic tumors (p. 233) (p. 237)
(p. 248) Epidemiology (p. 242) Multiple sclerosis (MS) (p. 242) 3-per-second spike-and-wave
Apoptosis (p. 238) Epilepsy (p. 239) NMDA (N-methyl-D-aspartate) discharge (p. 240)
Arteriosclerosis (p. 234) Epileptic auras (p. 239) receptors (p. 235) Thrombosis (p. 233)
Ataxia (p. 242) Epileptogenesis (p. 246) Neural regeneration (p. 248) Toxic psychosis (p. 237)
Benign tumors (p. 233) Estrogens (p. 254) Nigrostriatal pathway (p. 241) Transgenic (p. 246)
Cerebral hemorrhage (p. 233) Experimental autoimmune Oligodendroglia (p. 249) Transneuronal degeneration
Cerebral ischemia (p. 233) encephalomyelitis (p. 242) Parkinson’s disease (p. 241) (p. 248)
Collateral sprouting (p. 250) General paresis (p. 237) Partial seizures (p. 239) Tumor (neoplasm) (p. 233)
Complex partial seizures Generalized seizures (p. 240) Petit mal seizure (p. 240)
(p. 240) Glutamate (p. 235) Phantom limb (p. 256) ON THE CD
Concussion (p. 236) Grand mal seizure (p. 240) Proximal segment (p. 248)
Need some
Congenital (p. 233) Hematoma (p. 236) Punch-drunk syndrome
help studying
Contrecoup injuries (p. 236) Huntington’s disease (p. 241) (p. 236)
the key terms
Contusions (p. 236) Hypoxia (p. 240) Retrograde degeneration for this chapter?
Convulsions (p. 239) Infiltrating tumors (p. 233) (p. 248) Check out the
Dementia (p. 236) Kindling phenomenon (p. 246) Schwann cells (p. 248) electronic flash
Deprenyl (p. 242) L-Dopa (p. 241) Simple partial seizures (p. 240) cards for Chap-
Distal segment (p. 248) MPTP (p. 242) Striatum (p. 241) ter 10.