1 and 2

Images.com/Corbis

Learning Objectives

After completing this chapter, you should be able to:

• Describe the five stages of brain development. • Explain how chemical and physical insults, disease, malnutrition, and genetic variations can interfere with

brain development and cause permanent brain damage. • List the causes of prenatal, perinatal, and postnatal brain damage. • Define the three types of head trauma: concussion, contusion, and laceration. • Compare the brain damage caused by infectious and noninfectious diseases. • Describe the effects of alcoholism on the brain. • Give examples of structural versus functional recovery from brain damage. • Contrast medical and surgical treatments for brain damage. • Explain the difference between normal aging of the brain and the effects of senile dementia. • Describe how brain damage is assessed.

13

Developmental Disorders and Brain Damage

Marka/SuperStock

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CHAPTER 13Section 13.1 Brain Development

In the last semester of her senior year of college, Krista was having fun. She had planned her last semester so that her course load was light and easy so she had plenty of time to party. Krista figured that it was her last semester with her friends before they went off into the “real world,” and she wanted to enjoy every last moment with them. Every night she went out with friends to bars on the “strip.” There she would dance the night away, drinking six or more beers a night, go home at closing, and sleep until her first class at 12:30 p.m. She was proud of the way she had planned the semester and was pleased that it was going so well.

Many mornings Krista woke up feeling nauseous. Sometimes she even vomited because she felt so ill. But she chalked it up to a good hangover, sipped on a cola, and felt better after a while. Because her menstrual cycles were irregular, Krista never worried when her periods were late. In fact, that semester Krista didn’t have one period all semester, but that didn’t worry her a bit. Often, when she ran track, she didn’t have a period throughout the track season. However, she wasn’t running track that year. It was her last semester of her senior year, and she didn’t want to be bothered with track.

About a week before graduation, while she was studying for finals, Krista felt a distinct thrust in her abdomen, as if her intestines had just moved violently. Then there was another. Then it stopped. When the bumping in her abdomen started up a few days later, she went to the college infirmary to find out what was wrong. The physician very quickly reached a diagnosis: Krista was pregnant.

At the time she was nearly 5 months pregnant, although it didn’t show. Krista thought she’d gotten a bit of a beer belly. After talking with her parents and her boyfriend, she decided to keep the baby. She had a full-term pregnancy, but her new son was unusually small at birth. He also had abnormal facial features, including abnormally small eyes, a cleft palate, and a broad, flat nose. As her son grew older, he was hyperactive and behaved impulsively, showing little self-control. Neuropsycho- logical testing confirmed that he had fetal alcohol syndrome.

Krista drank heavily during the first 5 months of her pregnancy, causing irreparable harm to the developing brain of her son. To understand how this would happen, you need to learn about brain development. In this chapter we will examine how the brain develops. We will also examine how physical and chemical insults to the developing brain affect brain development and subsequent behavior. In addition, we will look at the effects of brain damage that are incurred during child- hood or adulthood. Let’s begin with a discussion of the stages of brain development.

13.1 Brain Development

The embryo begins as a single fertilized egg that rapidly divides and redivides until a ball of cells, called a blastocyst, is formed. This ball of cells grows and folds in on itself, forming a groove called the neural tube (Figure 13.1). Neurons develop along the borders of this neural tube, and they migrate to their final position in the nervous system with the help of glial cells that direct the movement of the neurons to their final destination. Each neuron has a final destination, and the glial cells help move it to that destination.

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CHAPTER 13Section 13.1 Brain Development

Figure 13.1: Stages of embryonic development

Can you explain brain development at each stage?

Placenta

Placenta

Embryo Forebrain

Midbrain

Hindbrain

Fetus (all organ systems have formed)

Cerebrum

Brainstem

E.

D.

A. Fertilized egg

B. Blastula (ball of cells)

C. Blastula folds in on itself, producing neural tube

Neural tube

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CHAPTER 13Section 13.1 Brain Development

Thus, the first two stages of brain development are cell proliferation and cell migration (Figure 13.2). Cell proliferation is the first stage and begins 4 weeks after fertilization of the egg by sperm. During this stage, neurons are formed at a rate of about 250,000 cells per minute. You can imagine that anything that disrupts this stage can lead to disastrous effects on brain development.

Cell migration, the second stage of brain development, begins about 6 weeks after fertilization. This is an important stage, during which neurons move from the boundary of the neural tube to their final position in the nervous system. Each neuron is born with a given address, and it migrates to that address under the direction of glial cells and protein signals that act as signposts for the migrating neuron (Curran & D’Arcangelo, 1998). Neurons that are born first migrate to positions close to the neural tube. Later-developing neurons migrate past the earlier-born cells to reach their final destinations (Anderson, Eisenstat, Shi, & Rubenstein, 1997). Thus, the brain develops from the inner layers out, with the cerebral cortex developing last. It is extremely important that each neuron reaches its final destination because a neuron can function only if it is where it should be. Any insult that interferes with migration of neurons during this critical period will disrupt brain function after birth.

At 8 weeks after conception, all of the organs of the embryo have formed, including the brain. At this point, the embryo becomes a fetus. Most gross developmental abnormalities occur during the embryonic stage, and the chances of miscarriage are higher during the embryonic stage. The main task of the fetus is to grow. Bones grow, and organs do, too. Growth of the brain during the fetal stage is due to the growth of dendrites and axons. Although some neurons develop long after birth, neuron proliferation takes place almost exclusively in the embryonic stage.

The third stage of brain development is cell differentiation. During this stage, which begins 7 to 8 weeks following fertilization, immature neurons begin to change shape to attain their final mature form. That is, during this stage, pyramidal cells begin to look like pyramids, stellate cells begin to look like stars, and so forth.

The fourth stage, the stage of axonal and dendritic growth, is a continuation of the third stage of brain development. During this fourth stage, neurons begin to sprout processes that become dendrites and axons. This stage begins about 8 to 10 weeks after conception and continues long after birth. With the help of glial cells and special signaling proteins called neurotrophins, axons and dendrites grow in length and form synaptic connections with other neuronal processes. Rita Levi-Montalcini (1965, 1966) first identified nerve growth factor (NGF), a protein that promotes the survival of specific neurons in the peripheral and central nervous system during development and maturation. She received a Nobel Prize in 1986 for that discovery.

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CHAPTER 13Section 13.1 Brain Development

Figure 13.2: Effects of damage to the developing brain

What are the differences between the different effects of damage on the brain?

Exposed to insult during cell proliferation stage

A. Hypoplasia

Exposed to insult during cell migration stage

B. Ectopsia

Exposed to insult during cell differentiation stage

C. Dysplasia

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CHAPTER 13Section 13.1 Brain Development

Throughout life, synaptic connections continue to be made in the human brain. As axons mature, they grow in diameter and become myelinated. At birth, most sensory axons are myelinated. Motor pathways, particularly the corticospinal tract (part of the pyramidal system, which coor- dinates fine motor control), and axons in the frontal and temporal lobes are not completely myelinated until late childhood or adolescence (Paus et al., 1999). This means that some motor and language functions are not fully mature until the teenage years.

Cell death occurs during the fifth and last stage of brain development. This programmed cell death of unwanted neurons is referred to as apoptosis, and it appears to be regulated by gluta- mate (Ikonomidou et al., 1999). Some authors estimate that nearly 50% of neurons present at birth die within the next 12 years (Raff et al., 1993). In addition, about 50% of the synapses pres- ent in the brain at age 2 disappear by the time the individual is 16 years old. In order for a neuron to survive, it must make appropriate presynaptic and postsynaptic connections. During the first 12 to 13 years of life, we lose the neurons that we do not use through programmed cell death.

Damage to the Developing Brain

Damage to the developing brain can be caused by chemical or physical insults, disease, malnu- trition, or genetic errors. Insults at particular developmental stages (proliferation, migration, differentiation) will result in different types of abnormalities (Berger-Sweeney & Hohmann, 1997). For example, insults occurring during the cell proliferation stage will produce hypoplasia, in which fewer cells are found in a given region of the brain (hypo- means “less than normal” in Greek) (Figure 13.2). In contrast, an insult that interferes with cell migration may produce ectopsia, in which neurons do not migrate to their normal positions in the brain (ecto- means “outside” in Greek). When an ectopsia is present, one or more areas of the brain will contain disorganized clusters of different types of neurons. Insults that occur during the cell differentia- tion stage will produce dysplasia, in which neurons retain immature shapes or grow abnormal dendrites and axons (dys- means “bad” in Greek) (Figure 13.2).

Chemical Insults Chemical insults can be produced by chemical agents such as poisons or toxins to which the mother is exposed. For example, chronic ingestion of alcohol, cocaine, or benzodiazepines dur- ing the pregnancy causes permanent damage to the central nervous system of the developing embryo. Babies born to mothers who regularly consumed benzodiazepines (such as Valium) dur- ing the pregnancy have abnormalities of the central and peripheral nervous systems, with exten- sive damage to the cranial nerves (Laegreid, Olegard, Walstrom, & Conradi, 1989). As a result of the cranial nerve damage, these babies have sullen, expressionless faces. The brains of these babies are smaller than normal, and autopsy of one brain revealed disturbed migration of neurons throughout the brain.

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CHAPTER 13Section 13.1 Brain Development

Cocaine use by the mother can impair the development of her embryo’s brain, but the damage is subtle. Children who were exposed to cocaine during fetal development have trouble concentrat- ing for long periods of time and blocking out distracting stimuli (Carmody, Bennett, & Lewis, 2011; Fisher et al., 2011; Kosofsky, 1998; Lester, LaGasse, & Seifer, 1998).

Fetal alcohol syndrome occurs in embryos whose mothers drink excessively during their preg- nancy. The damage to the developing brain produced by alcohol causes long-term behavioral and cognitive problems in the offspring. Although alcohol interferes with all stages of brain develop- ment, the stage of cell migration appears to be most affected by alcohol consumption by the mother (Clarren, Alvord, Sumi, Streissguth, & Smith, 1978; Guerri, 1998; Lewis, 1985; Miller, 1993). Recall that, during the stage of migration, neurons move from their birthplace along the walls of the neural tube to their final destination in the nervous system. Alcohol causes the glial cells to lose control of the migration process. Neurons migrate in a haphazard fashion, often never reaching their correct address.

This is best seen in the cerebral cortex of children with fetal alcohol syndrome. Whereas the cortex of a healthy child has distinct layers of neurons, the cerebral cortex of a child with fetal alcohol syndrome has neurons from many different cell lines (for example, pyramidal, stellate, granular cells) mixed together. (That is, ectopsia is observed.) Abnormal development of the cerebral cor- tex, the hippocampus, and the cerebellum is believed to produce the many behavioral and cogni- tive deficits, including mental retardation, attention and memory deficits, and hyperactivity, seen in children with this disorder (Guerri, 1998; Olson, Feldman, Streissguth, Sampson, & Bookstein, 1998; Sood et al., 2001).

Physical Insults Physical damage to the developing brain will also alter its structure and function. Trauma, such as an automobile accident, that the mother experiences can damage the embryo’s brain. The extent of the damage depends on the circumstances of the accident and the stage of brain development at the time of the accident. For example, a motor disorder known as cerebral palsy results from any number of causes, including premature rupture of the fetal sac that holds the baby (Ernest, 1998). Blood coagulation problems that cause blood clots to form in the blood vessels of the pla- centa and the brain of the fetus are also associated with the development of cerebral palsy (Kraus & Acheen, 1999). Any infection or inflammation in the uterus can predispose the fetus to cerebral palsy, as can interruption of the oxygen supply to the brain (Nelson & Grether, 1999).

Exposure to radiation will damage the developing brain, producing mental retardation and other behavioral abnormalities. Fetuses are exposed to radiation when their mothers receive radiation for treatment of cancer or during nuclear accidents such as radiation leaks from nuclear power plants. Embryos exposed to radiation during the explosion of atomic bombs over Nagasaki and Hiroshima in Japan during World War II showed variable amounts of brain damage as a result. The embryos most affected by the radiation were the ones whose brains were in the cell migra- tion stage of brain development. Radiation halted the migration of neurons in the brains of these embryos, producing profound mental retardation.

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CHAPTER 13Section 13.1 Brain Development

Disease and Malnutrition The health of a pregnant woman undeniably affects the development of her fetus’s nervous sys- tem. A woman who is diabetic or has a thyroid condition must carefully monitor her hormone levels because hyperglycemia or abnormal thyroid hormone levels can affect the growth of the fetus. Infectious diseases caused by bacteria and viruses can also damage brain development. A baby born to a pregnant woman who is infected with syphilis can be born with a number of nervous system disorders, such as deafness and absence of the vestibular system (Brun, 1972; Wendel, 1988). Viral infections, like rubella (also known as German measles) and chicken pox, which the pregnant woman transmits to her unborn fetus, result in blindness, deafness, neuro- muscular disorders, and autism in the offspring (Chess, 1977; Chess & Fernandez, 1980; Depino, 2013). MRI studies of individuals who were exposed to rubella before birth indicate that these individuals have smaller brains, with significantly reduced gray matter in the cerebral cortex and enlarged lateral ventricles (Lim et al., 1995).

Maternal malnutrition can harm brain growth and development and produce long-term intel- lectual deficits in children (Santos de Souza, Fernandes, & Das Gracas Taveres do Carmo, 2011). Depending on when the malnutrition occurs, its effect on brain development is variable. Mal- nutrition that occurs early in embryonic life, during the stage of cell proliferation, will produce abnormalities in the shape and form of the brain. Later in brain development, malnutrition can interfere with cell migration, differentiation of neurons, myelination of axons, and the develop- ment of synapses (Morgane et al., 1993). For many pregnant women in developing countries, malnutrition continues throughout the pregnancy and into the infant’s early years, producing permanent deficits that affect cognitive and intellectual function (Brown & Pollitt, 1996).

Genetic Abnormalities Over three dozen genetic abnormalities can interfere with brain development, leading to impair- ment of the cerebrum (Cooper et al., 1996). In Chapter 2 you learned about fragile X syndrome and Down syndrome, which both produce mental retardation. Fragile X syndrome is produced by a genetic variation on the X chromosome, which causes the chromosome to have long, fragile arms. Down syndrome is produced by the presence of three chromosomes, instead of paired chromosomes, for chromosome 21. In both disorders the chromosomal abnormality contributes to faulty development of the brain, particularly the cerebrum, which contributes to impairment of cognition.

For most other forms of developmental abnormalities affecting the brain, the specific genetic variant that produced the abnormality is unknown. For example, researchers are searching for the gene responsible for holoprosencephaly, a developmental brain disorder that affects 1 in every 10,000 children and is believed to cause thousands of miscarriages each year (Muenke & Cohen, 2000). Individuals with holoprosencephaly have only one cerebral hemisphere, due to a genetic variation that stopped their brains from dividing into left and right hemispheres early in brain development (Barkovich, Simon, Clegg, Kinsman, & Hahn, 2002). This disorder causes a variety of disabilities, including motor problems, seizures, inability to speak or eat solid foods, and facial defects such as a misshapen head, eyes pushed together, or a single eye centered in the face.

Chromosomes can also have subtle effects on the brain that cannot be detected under a micro- scope. That is, some developmental disorders caused by genetic variants produce behavioral problems that have not been associated with specific brain damage. For example, males are more

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CHAPTER 13Section 13.1 Brain Development

susceptible to developmental disorders that affect language and social functions, such as autism, learning disabilities, and hyperactivity. Recall that women normally have two X chromosomes, one inherited from each parent, whereas men have one X and one Y chromosome (the X chromo- some being inherited from the mother and the Y from the father). Recent research with girls with Turner’s syndrome, who have one X chromosome only (see Chapter 10), revealed that girls who inherited the X chromosome from their fathers have better social skills than girls who inherited their mother’s X chromosome (McGuffin & Scourfield, 1997). In fact, girls who inherited their mother’s X chromosome have severe behavioral difficulties, such as offensive or disruptive behav- ior (Figure 13.3). Skuse and his colleagues (1997) concluded that a gene associated with social functioning is switched off on the mother’s X chromosome. That is, the gene is active only if it is inherited from the father. Because all males receive their X chromosomes from their mothers, they are more likely to have deficient social skills and are more susceptible to developmental dis- orders that affect social functioning.

Figure 13.3: Genetics of Turner’s syndrome

Individuals with Turner’s syndrome have only one sex chromosome (X), which can come from the mother (A) or the father (C). Individuals with Turner’s who inherit the X chromosome from their fathers have much better social skills than those individuals with Turner’s who inherit the X chromo- some from their mothers.

When considering the effects of genetics on brain development, we must not forget that the environment plays an important role in behavioral development. Nurturing, environmental stimu- lation, and other external experiences can interact with existing neural processes to improve or worsen the behavioral disturbance that is associated with a specific genetic variant.

Mother Father

X X X Y

A. Turner’s syndrome (45, XO)

C. Turner’s syndrome (45, XO)

B. Normal (46, XX)

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CHAPTER 13Section 13.2 Brain Damage

Hydrocephalus

Some types of brain damage are associated with more than one of the factors that we have already discussed, such as genetics, disease, and trauma or physical insults. For example, hydrocephalus is a disorder that has many causes (Stone et al., 2013). Infants with hydrocephalus have enlarged heads due to blockage of the ventricles of the brain. Recall from Chapter 4 that the ventricles pro- vide for circulation of cerebrospinal fluid from the lateral ventricles in the cerebrum through the third ventricles to the aqueduct of Sylvius in the midbrain and the fourth ventricle in the hindbrain and on down the central canal of the spinal cord. If this canal system becomes blocked for any reason, cerebrospinal fluid cannot flow down this pathway and builds up in the brain. In the infant the sutures between the bones of the skull have not hardened, which means that pressure inside the brain can force the bones of the skull to separate, permitting the head to swell. This is exactly what happens in hydrocephalus. The ventricles become blocked, and fluid pressure within the ventricles causes the head to swell.

Many cases of hydrocephalus are associated with an X-linked recessive gene. This gene causes blockage of the narrowest part of the ventricular system, the aqueduct of Sylvius. However, an aberrant autosomal chromosome can also produce blockage of the aqueduct of Sylvius in rare cases (Hamada et al., 1999). Some infectious diseases such as tuberculosis can also cause hydro- cephalus (Ozates et al., 2000). In addition, brain tumors and other forms of cancer such as leuke- mia are associated with blockage of cerebrospinal fluid (Fisher & Chiello, 2000). Brain injury due to trauma can also result in hydrocephalus (Guyot & Michael, 2000). Injured brain tissue swells, which compresses the ventricles, preventing the flow of cerebrospinal fluid.

Although the infant’s brain swells in response to a blockage in one of the ventricles, pressure does build up inside the infant’s brain, producing brain damage. Over time a child with hydrocephalus will often suffer a decline in intellectual, sensory, and motor functioning. For many individuals, hydrocephalus is treated with a shunt, or tube, that allows blocked cerebrospinal fluid to flow from the blockage in the brain directly into a vein. The shunt prevents the build-up of pressure within the brain and allows the brain to function normally.

13.2 Brain Damage

Brain damage can occur during the prenatal stage, the perinatal stage, or the postnatal stage. The prenatal stage is the period before birth (pre- means “before” and -natal means “birth” in Latin). We discussed the various causes of prenatal brain damage in the previous section. In general, prenatal brain damage interferes with brain development, altering cell proliferation, migration, or maturation, which affects brain function later in life. Perinatal refers to the period surrounding the time of birth (peri- means “around” in Latin), and postnatal refers to the period after birth (post- means “after” in Latin).

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CHAPTER 13Section 13.2 Brain Damage

Perinatal brain damage is most often caused by anoxia, or lack of oxygen (a- means “without” and -oxia refers to “oxygen” in Greek), that the infant experiences due to a difficult birth or the umbilical cord being wrapped around its neck. Perinatal asphyxia results in a cessation of cerebral function due to lack of oxygen. If the infant is deprived of oxygen for more than a few seconds, neurons die, resulting in permanent brain damage. About 25% of all cases of cerebral palsy are associated with interruption of the supply of oxygen to the fetus’s brain at birth (Nelson & Grether, 1999; Suvanand, Kapoor, Reddaiah, Singh, & Sundaram, 1997). Trauma at birth can also cause brain damage. For example, neonates can suffer a fractured skull during the delivery process when the mother’s vagina is misshapen or inadequate to allow passage of the infant. A baby born with a fractured skull may appear lifeless, unresponsive to stimuli, and lack normal reflexes such as the sucking reflex.

Brain Damage Produced by Trauma

Postnatal brain damage can be caused by trauma or disease. Head trauma can be classified into three categories, in order of increasing severity: (1) concussions, (2) contusions, and (3) lacera- tions. A concussion is caused by a blow to the head that bruises the brain (Figure 13.4). The bruis- ing causes tiny blood vessels, or capillaries, in the brain to rupture, which compromises blood supply to the neurons supported by those capillaries. As you learned in Chapter 8 when we dis- cussed comas, if the head slams against a solid object, bruising can take place at two points in the brain: at the point of impact (called the coup) where the head hits the object and on the opposite side of the head (the contrecoup) due to recoil of the brain from the first impact.

Three grades of concussion have been distinguished (Kelly & Rosenberg, 1997). A Grade 1 concus- sion is characterized by confusion that lasts for less than 15 minutes, with no loss of conscious- ness. A Grade 2 concussion is characterized by confusion that lasts for more than 15 minutes, with no loss of consciousness. A Grade 3 concussion is characterized by any loss of consciousness that lasts for a few seconds to several minutes. Upon regaining consciousness, the individual will be confused and will often not recall the circumstances of the trauma.

American football players sustain an elevated number of concussions, especially professional players (Pellman, Lovell, Viano, & Casson, 2000; Pellman, Lovell, Viano, Casson, & Tucker, 2004). Research indicates that there are 0.41 concussions per National Football League (NFL) game, with the quarterbacks and wide receivers being most likely to sustain a concussion (Pellman et al., 2004). Although most NFL players show no impairments in neuropsychological functioning within days of the injury, those who receive multiple minor traumatic brain injuries over time show impairments in memory and information processing (Amen et al., 2011a, 2011b).

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CHAPTER 13Section 13.2 Brain Damage

Figure 13.4: Concussion, contusion, and laceration

Figure A illustrates head trauma following an impact injury. Figure B is an image of a cerebral contusion. Figure C is a laceration.

3. Impact twists the brain

4. The brain swells

Brain stem 2. Brain strikes inside of

skull (“contrecoup”)

1. Initial impact (“coup”)

Skull fragments

Bullet

Laceration

Gunshot entry

A.

B. C.

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CHAPTER 13Section 13.2 Brain Damage

A contusion refers to head trauma in which the head is jarred with such force that the brain becomes shifted in the skull and is badly bruised (Figure 13.4). Unconsciousness following a con- tusion may last for minutes or months. Brain contusions may be complicated by bleeding and by increased pressure within the brain due to bleeding, which kills neurons and produces lasting behavioral or cognitive dysfunction.

Cerebral laceration is caused by tearing of the brain, particularly the outer surface of the brain (Figure 13.4). Objects such as bullets that penetrate the skull will enter the brain and rip through brain tissue, unraveling neural connections and causing massive bleeding, or hemorrhage. If the skull is fractured, pieces of the skull may be depressed into the brain and produce laceration of brain tissue. In addition to hemorrhage, which deprives neurons of oxygen and needed nutrients, the blood that leaks into the brain tissue can form blood clots, or hematomas. These hematomas can be deadly because they increase pressure within the brain, which disrupts neuronal function. Individuals who suffer head trauma that results in cerebral laceration will typically be unconscious for hours or months following the injury. Survival and functional outcome depend on the location and extent of the damage.

Boxers who sustain repeated blows to the head can suffer multiple concussions and contusions. Numerous sites of pinpoint bleeding can be identified in the brains of some boxers. This pin- point bleeding, called petechial hemorrhage, is found throughout the brain and is associated with abnormal cognitive and motor function, including memory loss, reduced reaction time to stimuli, and tremor. For some boxers, the brain damage sustained is so severe that they develop a debilitating disorder called dementia pugilistica (Erlanger, Kutner, Barth, & Barnes, 1999), which is characterized by loss of orientation for time and place, delusions, abnormal affect, and cognitive disturbance, as you learned in Chapter 12. Muhammad Ali, a world champion boxer in the 1960s and 1970s, shows many of the effects of repeated head trauma that he sustained during his boxing career, including motor dysfunctions, memory loss, and abnormal affect.

Any abrupt head movement that causes the brain to slam against the skull can produce a trau- matic injury to the brain. The meninges provide a protective cushion around the brain, but a rapid change in acceleration can override this protective mechanism and cause brain damage. A recent case report (Kettaneh, Biousse, & Bousser, 2000) describes brain damage in several young adults who rode the same roller-coaster rides repeatedly. Certain roller-coaster rides produce sudden flexion and extension of the head and neck, which can result in brain hemorrhage due to torn arteries, hematomas, or leakage of cerebrospinal fluid into the brain.

Brain Damage Caused by Disease

A number of infectious and noninfectious diseases can cause brain damage. Infectious diseases are those that are caused by microorganisms such as bacteria or viruses. Noninfectious diseases such as cancer or heart disease are those that are not caused by infectious microorganisms. We will examine both classes of brain damage in this section.

Meningitis In general, bacteria cannot cross the blood-brain barrier and thus cannot directly produce brain damage. Meningitis, an infection of the meninges that is produced by bacteria, produces swelling and inflammation of the meninges. As the meninges swell, they put pressure on the brain and spi- nal cord, killing neurons, as you learned in Chapter 2. Sometimes meningitis will result in temporary

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CHAPTER 13Section 13.2 Brain Damage

disorientation for time and place, impaired memory and confusion, and hallucinations. In addition, some individuals have residual motor and cognitive difficulties following a bout of meningitis, and some die as a result of the damage to the central nervous system caused by the illness.

Syphilis The sexually transmitted disease called syphilis is an infection produced by a spirochete bacte- rium. In the tertiary or final stage of syphilis, the infection gets into the brain, particularly in the frontal lobes, causing extensive cognitive and emotional dysfunction. A psychotic disorder known as general paresis can be the end result of syphilis. General paresis is a degenerative condition produced by the bacterial spirochete that causes syphilis. It is practically nonexistent in Western society today, although cases abound in less developed parts of the world where medical care is not readily available. As syphilis progresses, the rapidly multiplying spirochetes destroy brain tis- sue. Damage to the frontal lobes is evident as the syphilitic patient exhibits rude or socially unac- ceptable behavior, becomes inattentive and careless about his or her personal appearance, and eventually develops symptoms of dementia and psychosis, including thought disorder, confusion, delusions, hallucinations, and inappropriate affect (Ballas, Kohler, & Pickholtz, 2000; Fujimoto et al., 2001; Kodama et al., 2000).

Encephalitis Some viruses, due to their minute size, can pass through the blood-brain barrier to infect the brain (Chapter 2). Viral encephalitis is caused by a virus that is transmitted by mosquitoes. As the virus invades the neurons, swelling of the brain ensues, killing neurons and disrupting brain function, particularly cerebral function. Nearly 50% of all people infected by this virus will die, and most others will show residual behavioral or cognitive deficits if they recover.

AIDS-Related Dementia A direct infection of the brain by the human immuno- deficiency virus (HIV) results in AIDS-related demen- tia. AIDS-related dementia is frequently observed in individuals who have been infected with the human immunodeficiency virus and who have symptoms of full-blown acquired immune deficiency syndrome, or AIDS. The human immunodeficiency virus produces both atrophy of the cerebral cortex and lesions in white matter underlying the cortex (Adams & Fer- raro, 1997). Approximately 35% of all AIDS patients will ultimately undergo personality changes and show signs of dementia. Aberrant social behavior (including carelessness in personal habits), apathy, confusion, emotional blunting, and cognitive difficulty are com- mon symptoms in patients with end-stage AIDS. These symptoms are likely the result of brain damage caused by HIV or opportunistic infections by bacteria, fungi, protozoa, or other viruses, which invade the brains of individuals with compromised immune systems.

SPL/Science Source

Photo 13.1 This image is of brain dam- age in an AIDS patient. This patient might experience apathy and emotional blunting because of this damage.

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CHAPTER 13Section 13.2 Brain Damage

Creutzfeldt-Jakob Dementia A progressive but fortunately very rare dementia, Creutzfeldt-Jakob dementia, is associated with an infectious process. This disorder produces a rapid decline in motor and mental functioning over a period of months. Intellectual deterioration advances quickly, producing dementia, and the patient usually dies within 1 or 2 years (Buchwald & Vorstrup, 1996). The cause of Creutzfeldt- Jakob dementia is believed to be a prion, which is a simple protein that causes a form of brain dam- age known as spongiosis, in which the brain loses its normal appearance and looks like a sponge, with tiny empty spaces called vacuoles (Prusiner & DeArmond, 1994). Prions are normally found throughout the body, particularly in the brain, although no one knows what they do. And prions come in two forms, depending on how the protein is folded. If folded one way, prions are benign; if folded the other way, prions cause brain deterioration (Figure 13.5) (DebBurman, Raymond, Caughey, & Lindquist, 1997). Recently an upsurge in Creutzfeldt-Jakob cases has been associated with “mad cow disease,” which is caused by eating the meat of cows infected with the “bad” form of the prion (Glatzel & Aguzzi, 2001; Prusiner & DeArmond, 1994; Roberts & James, 1997).

Figure 13.5: Two forms of prions

Prions are harmless when found in their normal form (top). In the infectious form of the prion (bottom), the backbone of the protein is stretched out and forms pleated sheets.

Normal Prion

Infectious Prion

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CHAPTER 13Section 13.2 Brain Damage

Cardiovascular Disease The two leading causes of death in adults in the United States today are cardiovascular disease and cancer, and both can produce brain damage. Cardiovascular disease refers to disorders of the heart and blood vessels. For example, a typical American diet results in fatty deposits accumulat- ing along the inner walls of major blood vessels, producing atherosclerosis. These deposits narrow the internal diameter of the blood vessels, which can increase blood pressure. As the diameters of arteries are reduced, blood flow to the brain is reduced, and neurons receive less oxygen and nutrients than normal, impairing cognitive function (Loeb & Meyer, 1996). Over time, the fatty deposits become mineralized and harden, which reduces the elasticity of the walls of arteries and other blood vessels. Elasticity of blood vessel walls is necessary in order that the blood vessels expand or shrink in diameter to compensate for changes in blood pressure. With increased blood pressure, the hardened arteries cannot expand and are apt to burst. This is exactly what happens when a person has a stroke: An artery in the brain bursts due to increased blood pressure, and blood rushes out of the artery and into the extracellular spaces in the brain (Morris, 1996).

Strokes produce brain damage in several ways. Ischemic strokes result from clogged arteries in the brain, which decrease blood flow. When blood flow to neurons is disrupted, neurons are deprived of oxygen and nutrients, and they die. Hemorrhagic strokes occur when blood vessels rupture, permitting blood to pool in extracellular spaces in the brain. The hemorrhage produced by the stroke can increase the intracranial pressure, or the pressure within the skull. This, too, will kill neurons. The blood that escapes from the burst artery can produce a hematoma, or blood clot, which can also increase intracranial pressure to fatal levels. The neurons that die as a result of the stroke release glutamate into the extracellular space, which overstimulates and kills nearby neu- rons (Choi, 1992). These dead neurons, in turn, release excess glutamate, killing their neighbors. Thus, a vicious cycle begins that results in the death of many neurons. The resultant brain damage can produce symptoms of dementia, including confusion, delusions, and cognitive dysfunction, especially when the stroke occurs in the frontal or temporal lobe.

Cancer Cancer is a disorder that is characterized by the uncontrolled growth of abnormal tissue called tumors. As you learned in Chapter 12, tumors can occur in the brain. These tumors usually consist of abnormal glial cells that are rapidly multiplying, or they are metastatic in nature, which means that they are derived from cancer cells elsewhere in the body (Figure 13.6). As tumors grow in the brain, they put pressure on nearby neurons, interfering with their function and eventually killing them. The result of this damage depends on the location and size of the tumor. For example, a tumor in the motor cortex will interfere with motor function, and one in Broca’s area will interfere with the patient’s speech. The “Case Study” describes the case of a very gentle man who devel- oped a tumor in his temporal lobe.

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CHAPTER 13Section 13.2 Brain Damage

Case Study: A Tumor in the Limbic System

Conrad was a kind, gentle, 54-year-old man, beloved by members of his family and the congregation of his church, where he was a deacon. A farmer his whole life, Conrad worked from dawn to dusk every day of the year. Only when his sons grew old enough to run the farm did he take a much-needed vacation with his wife, Betty, to visit distant family members in another part of the country. He returned from the vacation rested and eager to return to work.

Shortly after he returned to work, Conrad’s behavior began to change. Betty noticed that he cursed under his breath a lot. This was unusual behavior for her husband, ordinarily a calm, respectful man who never swore or used bad language. Conrad began to have angry outbursts that resembled temper tantrums when he was frustrated or some- thing went wrong. One day a grandchild left the door to the chicken house open, and dozens of hens flew into a nearby field. Conrad’s reaction was quite uncharacteristic. He picked up a small tree branch and swatted the child across the legs and back, yelling and swearing angrily. When reproached by his son and daughter-in-law for hitting his grandchild, Conrad turned his anger and aggression on them. (continued)

Living Art Enterprises, LLC/Science Source

Photo 13.2 Can you see where the tumor is in this MRI scan?

Figure 13.6: Glioma and metastatic brain tumor

Figure A shows glioma, and Figure B shows metastasis of brain cancer (bright red density in central part of image).

Scott Camazine/Science Source Living Art Enterprises, LLC/Science Source

A. B.

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CHAPTER 13Section 13.2 Brain Damage

Case Study: A Tumor in the Limbic System (continued)

Betty and her children became increasingly disturbed by Conrad’s behavior. One morning Betty acci- dentally dropped a frying pan on the floor of the kitchen. Conrad responded by pitching his empty juice glass at the back of her head. The glass bounced off Betty’s head and broke on the floor at her feet. Tears welled up in Betty’s eyes, and she began to weep. Conrad remained seated at the table, filled with remorse.

Betty told him quietly that she was going to leave him if he didn’t go for help. She told him that he was not acting like himself and that he needed help. Being an old farmer, Conrad resisted the idea of seeing a psychologist and made an appointment with his longtime doctor instead. Betty went with her husband to see the doctor and described for him Conrad’s abnormally angry and aggressive behaviors.

Because Conrad did not have a history of domestic violence or any other type of violent behavior, the doctor ordered a brain scan (an MRI) to see if something was wrong inside his head. Ordinarily, a person does not develop impulsive violent behavior overnight, and the doctor was worried by Con- rad’s symptoms. As the doctor suspected, the MRI scan revealed a rather large tumor located deep in Conrad’s temporal lobe.

Conrad and Betty then met with a neurosurgeon to plan for the removal of the tumor. The surgery was performed shortly after that, and a tumor that stretched from Conrad’s medial temporal lobe to his third ventricle was removed. Conrad required skilled nursing care for nearly 2 months following his neurosurgery, but he eventually was able to return home and help his sons out with the work on the farm. His angry, violent behavior disappeared with the removal of his brain tumor.

Alcoholism Alcoholism can produce brain damage via several routes. Alcohol is a toxin that can directly kill neurons by interfering with protein synthesis (Tewari & Noble, 1971). In addition, malnutrition produced by the alcoholism can result in brain damage (Charness, 1993). People who drink heav- ily also suffer from liver disease. As liver function becomes progressively more compromised due to alcoholism, ammonia builds up in the blood, producing a condition known as ammonemia (ammon- mean “ammonia” and -emia means “in the blood” in Greek). Ammonemia is associated with brain damage, too, because the high levels of ammonia in the blood kill neurons. High levels of ammonia are associated with lesions in the cerebrum that produce symptoms of dementia (Banciu et al., 1982). Alcohol can also produce high blood pressure, contractile spasms of cerebral blood vessels, and strokes in heavy drinkers (Altura, Altura, & Gebrewold, 1983). Brain damage associated with alcoholism includes gross shrinkage of the cerebellum and cerebral cortex, espe- cially the frontal lobes, which results in cognitive dysfunction, including memory loss for recent events and confusion (Smith, 1997; Zahr, Kaufman, & Harper, 2011).

Although alcohol-induced dementia may be a reversible condition that is caused by short-term alcohol overintoxication, most forms of alcohol-induced dementia are not treatable because of extensive brain damage. The term hepatic encephalopathy refers to a brain disorder associated with liver function or, more correctly in the case of alcoholics, liver dysfunction. Because more than 95% of alcohol consumed is metabolized by the liver, this organ suffers the brunt of long-term

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CHAPTER 13Section 13.3 Recovery from Brain Damage

alcohol abuse, and all alcoholics eventually develop liver damage, especially cirrhosis of the liver, which interferes with liver function.

Korsakoff’s syndrome is a cogni- tive disorder observed in long-term alcoholics, characterized by mem- ory and cognitive disturbance, confusion, and loss of orientation for time and place. Poor nutrition, especially a deficiency of thiamine (vitamin B

1 ), has been implicated as

the cause of Korsakoff’s syndrome (Leong, Oliva, & Butterworth, 1996). Many chronic alcoholics do not eat well but, instead, consume a good deal of their calories as alco- hol. Alcohol also interferes with the

absorption of B vitamins. A deficiency of thiamine interferes with the brain’s ability to break down glucose and can cause brain damage, which produces the symptoms of Korsakoff’s (Photo 13.3).

13.3 Recovery from Brain Damage

Neurons that are destroyed by damage to the brain typically are not replaced by other neurons (Lowenstein & Parent, 1999). In the peripheral nervous system, neurons can (and do) regen- erate. Thus, injury to the peripheral nervous system produces temporary dysfunction, whereas injury to the brain can be long lasting and devastating. However, people with brain damage often regain some function. In this section we will examine the processes that promote recovery from brain damage.

Age and Recovery from Brain Damage

The age at which brain damage occurs can directly influence recovery from brain damage. At the beginning of this chapter, you learned that brain development takes place in stages and that disruption of any of these stages could permanently affect brain development and function. How- ever, there is a good deal of evidence that recovery from brain damage is optimal if the damage occurs before the maturation of the nervous system (Armand & Kably, 1993).

Some of the earliest experiments on the effects of infant brain damage were conducted by Mary Kennard, who studied recovery of motor function following brain damage in infant monkeys (Kennard, 1939). Kennard’s observation that behavioral function develops normally when brain damage occurs in infancy is known as the Kennard effect (Finger & Wolf, 1988). Since Ken- nard’s early studies, investigators have discovered that recovery or sparing of behavioral func- tion appears to be associated with a critical period in brain development. For example, Bryan Kolb and Robbin Gibb (1991) performed bilateral frontal lobe lesions on newborn rats, rats that

Pascal Goetgheluck/Science Source

Photo 13.3 A brain scan showing an alcoholic’s brain at three intervals: 10 days after detoxification, 21 days after detoxifica- tion, and 30 days after detoxification.

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CHAPTER 13Section 13.3 Recovery from Brain Damage

were 10 days old, and adult rats. Compared to newborn and adult lesioned rats, rats that were lesioned at 10 days of age showed the most recovery from brain damage. Thus, the neurons in the frontal lobes of 10-day-old rats were at their optimal stage of development (the stage of dendritic and axonal growth) for recovery from brain damage.

Structural Versus Functional Recovery

My dog, Brutus, loved to chase cars. One day, a driver didn’t see the furry little demon lunging for his front tire, and he accidentally ran over Brutus’s left hind leg. The leg was badly fractured and didn’t heal well, which necessitated its amputation. At first Brutus had a difficult time walking about on three legs. But within a few weeks, he was running as fast as he was before the amputa- tion and chasing cars once again.

Brutus lost a leg, but he recovered function. He was able to walk and run almost as well after the loss of the leg as before. His recovery was not due to recovered structure, because he didn’t grow a new leg. His recovery was due to the fact that he learned to compensate for the missing leg.

Recovering from brain damage is very much like learning to walk on three legs after the fourth has been amputated. For most individuals, the structures lost by brain damage are not replaced, and the structures that remain must compensate for the missing structures. That is, a great deal of recovery from brain damage is due to functional recovery and not structural recovery. However, this does not mean that structural recovery does not take place. Let’s look at the various forms of structural changes that take place following brain damage.

Structural Recovery

In Chapter 7 we discussed examples of plasticity in the brain, particularly in the cerebral cortex. For example, you learned that compared to nonmusicians, highly trained musicians devote large areas of their cerebral cortex to processing music. PET studies of individuals with brain damage indicate that their brains are capable of changing, too. People who sustain damage to the left cerebral hemisphere, for example, tend to use the right hemisphere to process language more than healthy controls do. This is especially true for individuals who suffered left hemispheric injury before the age of 5 years: These individuals use the right hemisphere almost exclusively to process language (Muller et al., 1999).

Studies of individuals between the ages of 2 months and 20 years who have undergone surgical removal of a cerebral hemisphere, called a hemispherectomy, also reveal the amazing plasticity of the brain (Vining et al., 1997). For more than 30 years, neurosurgeons have performed hemispher- ectomies to treat people with progressively severe seizures who do not respond to medication. The entire cortex on one side of the brain is removed, along with underlying white matter. Fol- lowing the surgery, patients can usually walk and run, and some have gone on to run marathons. Younger children show the least impairment following surgery because their brains can more eas- ily compensate for the missing hemisphere. Removal of the left hemisphere does not interfere with the development of speech and language in children younger than 4 years of age.

How do these structural changes take place? Six mechanisms of structural recovery from brain damage have been identified: (1) regrowth of neurons, (2) waste product removal, (3) regrowth

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CHAPTER 13Section 13.3 Recovery from Brain Damage

of axons, (4) collateral sprouting of axons, (5) dendritic branching, and (6) denervation hypersen- sitivity. These mechanisms cannot account for all the recovery that is observed following injury to the brain, and other mechanisms will undoubtedly be discovered in the near future. Let’s examine these six mechanisms.

Regrowth of Neurons Although brain damage cannot be reversed, the brain has the potential to produce new neurons and repair damaged areas (Kempermann & Gage, 1999; Lowenstein & Parent, 1999). Progenitor cells, or stem cells, that are capable of producing new neurons are found in the human brain. The newly formed neurons migrate to the injured area, differentiate, and are incorporated into the nervous tissue (Figure 13.7). These stem cells can differentiate into various types of glial cells, as well as neurons, depending on the growth factors present (Palmer, Takahashi, & Gage, 1997). The “For Further Thought” box describes the treatment of brain damage in rats with neural stem cells.

Figure 13.7: Repair of the brain

After injury to a site in the brain, precursor stem cells may migrate to the site, and inactive (dormant) progenitor cells at the site may differentiate into neurons and glia.

From “Brain, Heal Thyself” by Daniel H. Lowenstein, Jack M. Parent. In Science 19 February 1999: Vol. 283 no. 5405 pp. 1126–1127. Reprinted with permission from AAAS.

Precursor cell

“Dormant” progenitor cell

Differentiating neurons migrating toward injury

Oligodendrocyte

Astrocytes

“Normal” granule cell

Injured area

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CHAPTER 13Section 13.3 Recovery from Brain Damage

For Further Thought: Repair of Brain Damage with Neural Stem Cells

Research with rats and mice has led to major break- throughs in our ability to stimulate repair following dam- age to the central nervous system. Stem cells derived from the hippocampus of mice have been implanted into the brains of rats, producing significant improvements in function following brain damage. For example, Helen Hodges and her colleagues at the Institute of Psychiatry at Kings College London reduced blood flow in the brains of rats by blocking four arteries, which damaged the hip- pocampus and impaired cognitive function in rats, inter- fering with their ability to learn new information (Hodges et al., 2000). Implantation of mouse stem cells into the forebrains of these rats produced an increase in the number of neurons in the hippocampus and improve- ments in the rats’ cognitive function.

When neurons that release acetylcholine were destroyed in the hippocampus, memory deficits were observed in rats learning spatial information. These memory deficits were reversed after mouse hip- pocampal stem cells were implanted into the rats’ forebrain (Sinden et al., 2000). Stem cell implants also reversed cognitive impairments caused by normal aging processes in rats (Hodges et al., 2000). Old rats showed improved ability to remember the location of an underwater platform in a water maze test after receiving a hippocampal stem cell transplant, compared to age-matched rats that did not receive a transplant. In addition, when the middle cerebral artery (a common site for strokes in people) of a rat is blocked, specific sensory and motor deficits are produced, depending on the hemi- sphere affected. Implantation of hippocampal stem cells into the forebrain leads to an improvement in motor and sensory function in rats (Sinden et al., 2000).

Thus, hippocampal stem cell implants appear to be able to repair many different types of brain inju- ries, producing improvements in cognitive, sensory, and motor function. However, these stem cells cannot reverse damage in all areas of the brain. For example, hippocampal stem cells do not reverse lesions to the nigrostratal dopamine pathway, which produce symptoms of Parkinson’s disease in rats. Another line of mouse stem cells (not hippocampal stem cells) has been shown to repair spinal cord injuries in rats. These stem cells differentiate into neurons, oligodendrocytes, and astroglial cells in the area of the spinal cord lesion, producing improvements in gait and reflexes (McDonald et al., 1999; Bozkurt et al., 2010).

These lines of research suggest the possibility that damage to the brain and spinal cord in humans may be reversed by stem cell implants. A number of stem cell lines will need to be developed from different brain areas in order to treat the many disorders arising from brain damage. In time stem cells may be used to treat cognitive problems associated with stroke, normal aging, and Alzheimer’s disease; degenerative disorders like Parkinson’s and amyotrophic lateral sclerosis; and spinal cord and traumatic brain injuries.

Waste Product Removal Damage to the brain results in dead neurons, an excess of extracellular glutamate, white blood cells, and other toxins in the area of damage. It takes glial cells days or weeks to clear all this debris away from the site. As the debris is removed, intact neurons in the area regain their function.

Hemera/Thinkstock

Photo 13.4 These tests in which mouse stem cells were placed in the forebrains of rats helped explain how brain damage could be healed.

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CHAPTER 13Section 13.3 Recovery from Brain Damage

Thus, the removal of waste products from the damaged site will enhance brain function. This phenomenon is seen in many individuals recovering from a stroke, for example. At first, the stroke victim may be unable to speak, and movement on one side of the body (contralateral to the site of brain damage) may be absent. However, within a few weeks, speech will slowly return, as will motor function to the impaired side. This improvement in function is not due to the regrowth of neurons; rather, it is due to the removal of substances that were interfering with neuronal function.

Regrowth of Axons There is evidence that some axons can and do regrow after damage to that axon. A damaged axon releases nerve growth factor, which stimulates the regrowth of the axon and promotes sprouting of nearby axons and dendrites. However, although an axon may regrow and reach its target, last- ing sensory or motor deficits may be evident (Freed, de Medinaceli, & Wyatt, 1985).

Collateral Sprouting of Axons Sometimes, following brain damage, other neurons come to assume the work of the dead neu- rons. For example, following removal of a tumor from the motor cortex, the affected individual will show impaired motor function. Over time, that individual might show improved motor func- tion in the affected area. This improvement is due to changes in neurons near the damaged site in the brain. The intact neurons near the site of damage produce sprouts on their axons that grow, forming synapses with neurons that formerly received input from the dead neurons. Reor- ganization of the somatosensory cortex following amputation or damage to a limb, which you learned about in Chapter 7, is most likely due to the sprouting of neuronal processes in the cortex (Florence et al., 1998).

Dendritic Branching Dendrites also respond to brain damage with increased branching. Rats that received frontal lobe lesions when they were 10 days old were observed to recover almost completely from the severe behavioral deficits produced by this brain damage (Kolb & Gibb, 1991). Examination of brain tis- sues of these recovered animals revealed a striking increase in dendritic branching compared to control rats that received no lesions. An increase in dendritic branching does occur in adults, too, but is most dramatic in young animals. Kolb and Gibb (1991) have suggested that age-related differences in dendritic branching may explain the Kennard effect, the observation that young animals recover from brain damage more completely than adults.

Denervation Hypersensitivity When neurons die, they can no longer send messages to their postsynaptic neurons. That is, the postsynaptic cells become denervated due to the death of their presynaptic neurons. This loss of innervation means that the postsynaptic neurons fire less than before. However, over a period of a few weeks, denervation hypersensitivity develops in the postsynaptic neurons, which causes the denervated neuron to become supersensitive to excitatory messages from the remaining pre- synaptic neurons and to fire vigorously to input that previously was below threshold. Thus, just a little bit of stimulation makes these postsynaptic neurons excited and produces action potentials in them.

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CHAPTER 13Section 13.4 Aging of the Brain

Surgical and Medical Treatment of Brain Damage

Throughout this book we have examined treatments for various brain disorders. Most treatments attempt to compensate for neurotransmitter or hormonal dysfunctions that produce neurological or behavioral problems. For example, in Chapter 12 we considered pharmacological treatments for schizophrenia, and in Chapter 3 we considered various treatments for depression. Surgical interventions for brain disease or brain damage take one of two forms: removing damaged tissue or transplanting healthy tissue. In Chapter 11 you learned about the surgical removal or lesioning of brain tissue in individuals with damage to the temporal lobe that impaired amygdaloid function.

Transplantation of brain tissue is not generally feasible because neurons do not spontaneously make connections with newly transplanted neurons. Thus, a surgeon cannot take an amygdala from one person and implant it into the brain of another, as is done with kidney transplants. The transplanted amygdala would not function and would ultimately be rejected and destroyed by glial cells. However, transplants consisting of donor cells from the substantia nigra of fetuses have been

used successfully to treat symp- toms of Parkinson’s disease, as you learned in Chapter 5. Fetal brain tissue is not rejected by the host brain, and it readily adapts to the demands of its new environment.

More recently, exciting research with embryonic stem cells suggests that brain transplants may become a common surgical intervention for brain damage in the future. Embry- onic stem cells have the capacity to transform into any type of human tissue, as you learned earlier in this chapter. Under the right conditions, these stem cells have transformed themselves into glial cells that form myelin in myelin-deficient rats (Schiff, Rosenbluth, Dou, Liang, & Moon, 2002). Research with

human neural stem cells has demonstrated that these cells, when injected into the brains of baby mice, differentiated into the cell type of the surrounding neurons and became functional. When injected into mice with a defective gene that prevents granule cells from developing in the cer- ebellum, these human stem cells migrated to the appropriate layer of the cerebellum and dif- ferentiated into normal mouse granule cells (Sikorski & Peters, 1998). This research opens the possibility that, in the near future, functional grafts of embryonic stem cells in the central nervous system may be used to repair damaged tissue and correct defects.

13.4 Aging of the Brain

A recent study of centenarians (that is, people who are 100 years of age or older) revealed some very depressing information about the minds of the very elderly: All of them showed signs of cognitive decline, including memory deficits (Blansjaar, Thomassen, & Van Schaick, 2000).

Glasshouse Images/SuperStock

Photo 13.5 Embryonic stem cell research suggests that brain transplants may become a common surgical intervention for brain damage in the future.

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CHAPTER 13Section 13.4 Aging of the Brain

This decline is related to the signs of aging that have been observed in the human brain. Let’s examine the changes that take place in the brain as we age.

Changes in the Normal Aging Brain

The most obvious change in the aging brain is the reduction in intracellular and extracellular fluid (Metcalfe, 1998; Chang, Ernst, Poland, & Jenden, 1996). This loss of fluid is associated with an increase in the concentration of protein in the aging brain. In addition, there is a loss of myelin with aging (La Rue, 1992). This loss of myelin leads to a decrease in the volume of white matter in the brain. As a result of atrophy of white matter, the sulci (the grooves or fissures between the gyri on the surface of the cerebrum, which you learned about in Chapter 4) get wider, and the ventricles get larger with increasing age. These changes are greater in men than in women, and men’s brains show greater shrinkage with age than women’s (Metcalfe, 1998).

In addition to the loss of myelin, neurons themselves die at a rate of approximately 100,000 per day. This normal loss of neurons does not appear to affect function until very late in life. Although cell loss occurs in all parts of the brain, neuronal death associated with aging is concentrated in the cerebellum and the substantia nigra. By the ninth decade of life, nearly 40% of the neurons of the locus coeruleus have died, which means less norepinephrine is available for cognitive tasks requiring vigilance and arousal (Wilson et al., 2013).

In the cerebral cortex, dendrites shrink to little stubs in some neurons, inactivating the neurons. Up to 20% of the neurons in the frontal lobe are lost by age 70, with the greatest loss occurring in the dorsolateral prefrontal cortex (Woodruff-Pak, 1999). PET imaging studies reveal reduced activity in the prefrontal cortex in the elderly during facial recognition and word retrieval tasks (Parkin & Walter, 1992). Changes in the hippocampus appear to affect NMDA receptors, which are important in the formation of new long-term memories (McEwen, 1999; Haettig et al., 2011). Atrophy of this region of the hip- pocampus is greater in elderly men than in elderly women (de Leon et al., 1995).

When neurons die, their axons degenerate, triggering the release of nerve growth factor. Nerve growth factor stimulates surviv- ing neurons to sprout branches to compensate for the death of nearby neurons. Dendritic trees in the brains of 70-year-olds are significantly more exten- sive than those in the brains of 50-year-olds. However, dendritic trees stop growing after the age of 70, which means the aging brain loses its ability to com- pensate for the loss of neurons (Metcalfe, 1998).

age fotostock/SuperStock

Photo 13.6 The changes in the brain that accompany normal aging are responsible for the many behavioral changes observed in the elderly, including disturbed sleep, increased anxiety, decreased motor activity, and declining mental function.

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CHAPTER 13Section 13.4 Aging of the Brain

The changes in the brain that accompany normal aging are responsible for the many behavioral changes observed in the elderly, including disturbed sleep, increased anxiety, decreased motor activity, and declining mental function. Declines in serotonin function affect sleep, appetite, mood, aggression, and control of impulses (Meltzer et al., 1998; Woodruff-Pak, 1999). Decreases in dopamine impair motor function, and decreases in norepinephrine impair mental function. In addition, degeneration of neurons that produce acetylcholine is associated with learning and memory deficits (Muir, 1997; Jawhar, Trawicka, Jenneckens, Bayer, & Wirths, 2012).

Brain Disorders Associated with Aging

Senile dementia is a progressive cognitive disorder that occurs in patients older than 65 years of age. It is characterized by memory dysfunction, disorientation for time and place, and other cognitive deficits. These cognitive disturbances are associated with significantly reduced levels of acetylcholine in the cerebral cortex and hippocampus, which are due to the massive loss of neurons in the nucleus basalis (or basal nucleus), a forebrain structure that supplies acetyl- choline to the cerebrum and hippocampus (Figure 13.8) (Coyle, Price, & DeLong, 1983; White- house et al., 1982). Cardiovascular disease related to hardening of the arteries or stroke can produce a form of senile dementia called vascular dementia. Senile dementia also occurs in elderly individuals who suffer from any of a number of degenerative brain disorders, including Alzheimer’s disease, Pick’s disease, and Parkinson’s disease. Let’s compare the brain anomalies associated with each of these disorders.

Figure 13.8: Acetylcholine pathways from the nucleus basalis (basal nucleus)

Some types of dementia, such as dementia associated with Alzheimer’s disease, directly affect the ace- tylcholine pathways.

Hippocampus

Parietal cortex

Frontal cortex

Basal nucleus

Occipital cortex

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CHAPTER 13Section 13.4 Aging of the Brain

Alzheimer’s Disease The most common senile dementia is Alzheimer’s disease, which accounts for over half of all dementia cases (Jellinger, 1996). Today, approximately 5 million people in the United States are afflicted with Alzheimer’s disease (Alzheimer’s Association, 2013). People with Alzheimer’s dis- ease show many of the symptoms of psychosis, particularly as the disease progresses. Prevalent symptoms include memory and related cognitive deficits, disorientation for time and place, inap- propriate emotional responses, agitation, hallucinations, and sometimes hostility and paranoia, with a progressive decline in all intellectual and physical functions that leads to death. Although the senile form of Alzheimer’s disease is more common, Alzheimer’s can occur in middle age. In fact, Dr. Alois Alzheimer, the physician-scientist for whom the disease is named, first described these symptoms in a 51-year-old woman (Alzheimer, 1907).

The exact cause of Alzheimer’s disease is still being debated. Numerous abnormalities have been noted in the brains of those afflicted with this devastating condition. Acetylcholine and gluta- mate levels in the brains of Alzheimer’s patients are significantly lower than normal, which could account for their memory and motor deficits. Structural abnormalities include (1) symmetrical atrophy of the brain and enlarged lateral ventricles due to the loss of neurons in the frontal and

temporal lobes, (2) extensive structural damage in the hippocampus, (3) microscopic neurofibrillary tangles, and (4) amyloid plaques (de Leon et al., 1995).

MRI, PET, and CT imaging techniques have demon- strated bilateral atrophy of the hippocampus and enlarged ventricles in the brains of Alzheimer’s patients (Photo 13.7). First described by Dr. Alzheimer nearly 100 years ago, neurofibrillary tangles are twisted masses of protein located in the cytoplasm of neurons. These tangles are especially prevalent in the hippocampus and surrounding temporal lobe regions. Interestingly, neurofibrillary tangles are also found in the brains of boxers with dementia pugilistica (Stern, 1991). Amyloid plaques are enormous (larger than the largest neurons) masses of extracellular beta-amyloid protein and swollen neuronal processes usually found in the hippocampus and frontal cortex (Photo 13.7).

Head injury in youth is associated with the develop- ment of Alzheimer’s disease in later years (Amen et al., 2011a; Roses & Saunders, 1997; Schmidt, Zhuka- reva, Newell, Lee, & Trojanowski, 2001). It may be that

head injury promotes the formation of neurofibrillary tangles that ultimately destroy the host neuron. Recall that neurofibrillary tangles are also found in the neurons of boxers with dementia pugilistica (Schmidt et al., 2001).

Dr. W. Crum, Dementia Research Group, Tim Beddow/ Science Source

Photo 13.7 This MRI scan shows enlarged ventricles in an Alzheimer’s patient.

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CHAPTER 13Section 13.5 Assessing Brain Damage

Parkinson’s Disease Dementia is also common in persons with Parkinson’s disease. In the later stages of Parkinson’s, more than 65% will show signs of dementia (Geldmacher & Whitehouse, 1996; Morris, 1996). Bradyphrenia, or a slowing of thinking, is a common complaint in Parkinson’s and is one of the earliest signs of dementia. Parkinson’s dementia is progressively debilitating, ultimately leaving the victim unable to understand or store new information, follow directions, or change behavior to meet the demands of the situation.

Most people who develop Parkinson’s dementia have abnormal structures, called Lewy’s bod- ies, located in the cytoplasm of their neurons. Lewy’s bodies have filaments that radiate from a central core, producing a fuzzy contour when observed under the microscope (Forno, Eng, & Selkoe, 1989). The role that Lewy’s bodies play in the development of Parkinson’s dementia is unknown. They may be a by-product, rather than a cause, of the neural degeneration associated with Parkinson’s disease.

13.5 Assessing Brain Damage

The best time to assess brain damage is during an autopsy, when the brain is examined for gross abnormalities and then sectioned into slices for microscopic examination. Only then can a diagnostician be really certain of the cause and extent of the brain damage. However, an autopsy is not useful or convenient for a person who wants to know about the source of his or her disability while still alive. For a living patient, two types of tests allow a clinician to diagnose the cause of a behavioral or cognitive impairment: brain-imaging and recording techniques and neuropsychological testing.

Neuropsychological Testing

Brain-imaging techniques can give the clinician important information about the presence or absence of brain damage and brain disease. These techniques were discussed in Chapter 1. Neuropsychological testing is a key tool used by clinical neuropsychologists to assess the impact of brain damage or brain disease. Brain-injured patients are routinely referred to clinical neuro- psychologists for assessment of function. Clinical neuropsychologists are trained to evaluate the skills and abilities of a patient and to relate these to brain function. When assessing a patient, a clinical neuropsychologist has a number of tests available for evaluating different types of abili- ties. Although it would be convenient and easy if one test could be used to evaluate brain dam- age, no such test exists to date. Instead, a clinical neuropsychologist will use a group of different tests to test for brain damage.

A typical neuropsychological evaluation may take 2 to 3 hours, although patients with cognitive deficits may require over 6 hours to complete a test battery. A basic test battery will test a wide variety of functions, including attention, visual perception, visual reasoning, memory and learn- ing, verbal functions, academic skills, concept formation, self-regulation, motor ability, and emo- tional status. However, there are special test protocols for particular disabilities. For example, patients with seizures will also be evaluated with 24-hour EEG monitoring, in addition to the basic test battery. A test for patients with multiple sclerosis is usually limited in duration (less than 2 hours) because these patients fatigue quickly.

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CHAPTER 13Section 13.5 Assessing Brain Damage

A number of ready-made, commercially available neuropsychological test batteries are available, including the Halstead-Reitan and the Luria-Nebraska test batteries. These batteries test for a wide variety of functions and indicate the strengths, as well as the weaknesses, of the patient. Of the test batteries that are available, the Halstead-Reitan has received the most study and is the most thoroughly validated (Jarvis & Barth, 1997). Originally, in 1947 Halstead put together a battery of 27 tests of cerebral function, and he eventually reduced this battery to 10 mea- sures, which he called the Halstead Impairment Index. Reitan further modified Halstead’s battery by eliminating some measures. The end result is the Halstead-Reitan Neuropsychological Test Battery, which today consists of eight tests that measure problem solving, judgment, memory, abstract reasoning, concept formation, mental efficiency, verbal and nonverbal auditory discrimi- nation, attention, and motor coordination. A special test to screen for aphasia is added, as is a measure of sensory perception, in which tactile, auditory, and visual modalities are tested.

Most neuropsychologists supplement commercial neuropsychological test batteries with addi- tional tests, depending on the patient’s needs. An intelligence test may be given, as well as a personality inventory, such as the Minnesota Multiphasic Personality Inventory (MMPI). Other memory tests or measures of language ability may be used to get a fuller picture of the patient’s impairment. After scoring the tests, the clinical neuropsychologist will look at the pattern of scores to assess the patient’s strengths and weaknesses. This information is used to determine the prog- nosis for the brain-injured individual, as well as to plan his or her treatment and rehabilitation.

In Conclusion

Thus, we conclude our discussion of the biological foundations of behavior. By now, I hope you have gained an appreciation of all the research that has been conducted on the brain and behav- ior. In this chapter we looked at how research has enabled us to identify, treat, and prevent brain damage. We reviewed the stages of brain development and various disorders associated with damage to the developing brain. We also examined the behavioral dysfunctions that result from infectious and noninfectious disease. Finally, we considered the aging brain and changes associ- ated with normal aging and those associated with senile dementias.

Throughout this book, I have related known brain functions to pathological states. We started out by looking at the structure and function of neurons. Then we considered the function of brain structures and groups of neurons. In every instance, I introduced disorders related to dysfunction of the nervous system. Dysfunctions provide us with a lot of insight into normal brain functioning. We learn quite a lot about the workings of the brain, based on the behavioral dysfunctions that are evident following damage to particular neurons in the central nervous system.

In this book we have considered the wide range of human behaviors and experience. We exam- ined the role of the nervous system in movement, sensation, and perception. Next we reviewed research concerning learning and consciousness. Behaviors associated with motivational states, such as sleep, temperature regulation, eating, drinking, and sex, were discussed. We concluded our study of the brain and behavior with a focus on emotion, stress, and psychopathology. In every chapter we moved from a discussion of the normal to a discussion of the abnormal. Although the last chapter focused almost entirely on brain damage and dysfunction, every chapter in this text- book presented behavioral disorders associated with known neurochemical or brain pathology.

Dealing with brain damage is one of the most daunting challenges that science has yet to meet. Maybe some of you will join us in this endeavor. We still have a long way to go before we thor- oughly understand the workings of the brain and how it initiates, organizes, and controls behavior.

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CHAPTER 13Section 13.6 Chapter Summary

13.6 Chapter Summary Brain Development

• Neurons develop along the borders of the neural tube in an embryo, and they migrate to their final position in the nervous system with the help of radioglial cells.

• Brain development occurs in five stages: cell proliferation, cell migration, cell differentiation, axonal and dendritic growth, and programmed cell death.

• During the first stage of brain development, called cell proliferation, neurons are formed at a rate of 250,000 per minute.

• During the second stage, called cell migration, neurons move from the border of the neural tube to their final position.

• Immature neurons begin to transform and achieve their final form during the third stage of brain development, called cell differentiation.

• During the fourth stage of brain development, the stage of axonal and dendritic growth, neurons begin to sprout processes that become dendrites and axons.

• The fifth and final stage of brain development is characterized by programmed cell death. • Chemical and physical insults, disease, malnutrition, and genetic variations can interfere

with brain development and cause permanent brain damage. Fetal alcohol syndrome results in embryos whose mothers drink excessively during their pregnancies.

• Physical insults to the developing brain may produce a motor disorder known as cerebral palsy.

• A number of genetic variations can interfere with brain development and produce a num- ber of disorders, including holoprosencephaly, a disorder in which affected individuals develop only one cerebral hemisphere.

• Blockage of the ventricles during brain development can result in hydrocephalus.

Brain Damage • Brain damage can occur during the prenatal stage (before birth), perinatal stage (at birth),

or postnatal stage (after birth). • Perinatal damage occurs as a result of anoxia and trauma, whereas postnatal damage can

be caused by trauma or disease. • Head trauma can be classified into three categories: concussion (least severe), contusion,

and laceration (most severe). Boxers who sustain repeated blows to the head can develop pinpoint bleeding in the brain (called petechial hemorrhage) or, in more severe cases, dementia pugilistica, characterized by cognitive and emotional disturbances.

• Infectious diseases caused by bacteria or viruses can produce a number of disorders that cause brain damage, including meningitis (bacterial infection of the protective covering on the brain), general paresis (associated with syphilis), encephalitis (viral infection of the brain), AIDS-related dementia (caused by the human immunodeficiency virus, or HIV), and Creutzfeldt-Jakob dementia (associated with a simple protein called a prion, which is neither a bacterium nor a virus).

• Two noninfectious diseases, cardiovascular disease (disorders of the heart and blood vessels) and cancer (characterized by uncontrolled growth of tumors), can produce brain damage.

• When fatty deposits bind to the inside of blood vessels, producing atherosclerosis, blood flow to the brain is disrupted. Two types of stroke can produce brain damage, ischemic strokes (caused by clogged blood vessels, reducing blood flow) and hemorrhagic strokes (when blood vessels in the brain rupture). Neurons that die as a result of a stroke release glutamate, which kills nearby neurons.

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CHAPTER 13Section 13.6 Chapter Summary

• Alcoholism can produce brain damage in several ways: through malnutrition (which pro- duces Korsakoff’s syndrome and pellagra), through liver disease (which causes ammonia to build up in the blood, resulting in ammonemia), and through its effect on the cardiovas- cular system (including high blood pressure or stroke).

Recovery from Brain Damage • Recovery from brain damage can be structural or functional in nature, with best recovery

associated with damage that occurs early in life. The observation that behavioral function recovers and develops normally when brain damage occurs in infancy is known as the Kennard effect.

• Most recovery from brain damage is due to functional recovery, rather than structural recovery.

• Structural recovery can occur by means of six mechanisms: (1) regrowth of neurons (neu- rogenesis in the hippocampus, for example), (2) waste product removal (clearing away debris and toxins from damage site), (3) regrowth of axons (stimulated by nerve growth factor), (4) collateral sprouting of axons (formation of synapses with neurons that for- merly received input from dead neurons), (5) dendritic branching, and (6) denervation hypersensitivity (increased response to remaining presynaptic neurons).

• Medical treatments for brain damage attempt to correct hormonal or neurotransmitter dysfunctions. Surgical interventions for brain damage include removal of damaged tissue and transplantation of healthy tissue. Although mature brain tissue cannot be successfully transplanted, research has revealed that transplants consisting of donor cells from human fetuses or embryonic stem cells can be used to repair brain damage.

Aging of the Brain • Normal aging of the brain is accompanied by a reduction in intracellular and extracel-

lular fluid in the brain, a loss of myelin, atrophy of white matter, shrinkage of dendrites, the accumulation of insoluble pigments, and neuronal death, which all contribute to the sleep, mood, and cognitive disturbances observed in the elderly.

• Cell death associated with normal aging is concentrated in the cerebellum and substantia nigra.

• Dendritic branching increases to compensate for the death of nearby neurons in older adults, although this branching fails to occur after the age of 70.

• Senile dementia is a progressive cognitive disorder that occurs in people over 65 years of age.

• The most common form of senile dementia is Alzheimer’s disease, which is characterized by numerous abnormalities in the brain, including loss of neurons in the frontal and tem- poral lobes and extensive damage to the hippocampus, due to neurofibrillary tangles and amyloid plaques.

• Parkinson’s disease can also produce senile dementia, which is associated with abnormal structures called Lewy’s bodies in the cytoplasm of neurons.

Assessing Brain Damage • The best way to assess brain damage is at postmortem autopsy. For a living patient, the

extent and prognosis for recovery from brain damage can be assessed using brain imag- ing, EEG recording, and neuropsychological testing.

• A neuropsychologist uses a group of different tests to assess brain damage. The best known neuropsychological test batteries are the Halstead-Reitan and the Luria-Nebraska test batteries, which test problem-solving judgment, memory, abstract reasoning, concept formation, perceptual discrimination, attention, and motor coordination.

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CHAPTER 13Key Terms

AIDS-related dementia A cognitive disorder produced by direct infection of the brain by the human immunodeficiency virus.

Alzheimer’s disease The most common form of senile dementia, whose symptoms include memory and related cognitive deficits, with a progressive decline in all intellectual and physical functions that leads to death; associ- ated with neurofibrillary tangles and amyloid plaques.

amyloid plaques A sign of neuronal degenera- tion, consisting of amyloid protein, glial cells, white blood cells, and degenerating axons and dendrites.

anoxia A lack of oxygen.

apoptosis The programmed death of unwanted neurons.

atherosclerosis A disorder in which the inner walls of major blood vessels become coated with fatty deposits that harden at a later date.

cancer A disease characterized by the uncon- trolled growth of abnormal tissue called tumors.

cardiovascular disease Disorders of the heart and blood vessels.

cell differentiation The third stage of brain development, beginning 7 to 8 weeks fol- lowing fertilization, during which immature neurons begin to change shape to attain their final mature form.

Questions for Thought

1. What would be the effect of a chemical insult that interfered with cell proliferation? What would be the effect of the same insult that interfered with cell migration? What about its effect on cell differentiation?

2. Identify the prenatal and postnatal effects of alcoholism. 3. What sort of abilities do neuropsychological test batteries assess? How are these abili-

ties related to specific brain structures? 4. What are the five stages of brain development? 5. Describe the effects of prenatal exposure to radiation, rubella, malnutrition, and trauma

on the developing brain. 6. What is the difference between a concussion, a contusion, and a cerebral laceration? 7. Identify the six mechanisms of structural recovery from brain damage. 8. Contrast the changes in the normal aging brain with those in the brain of a person with

dementia.

Web Links

The Alzheimer’s Association’s website provides an interactive tutorial of the three major parts of the brain. The slides offer a basic overview of what each part does, how the parts interact, and the changes that occur with Alzheimer’s disease. http://www.alz.org/braintour/3_main_parts.asp

The Brain Injury Institute’s website is an excellent resource for learning about the symptoms, types, causes and treatments of brain damage caused by trauma. http://www.braininjuryinstitute.org/

Key Terms

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CHAPTER 13Key Terms

cell migration The second stage of brain development, beginning about 6 weeks after fertilization, during which neurons move from the boundary of the neural tube to their final position in the nervous system.

cell proliferation The first stage of brain devel- opment, beginning 4 weeks after fertilization of the egg by sperm, during which neurons are formed at a rate of about 250,000 cells per minute.

cerebral laceration Head trauma caused by tearing of the outer surface of the brain.

concussion Head trauma that is caused by a blow to the head that bruises the brain.

contusion Head trauma in which the head is jarred with such force that the brain becomes shifted in the skull and is badly bruised.

Creutzfeldt-Jakob dementia A rare, progres- sive dementia associated with an infection by a prion.

denervation hypersensitivity An increase in sensitivity in postsynaptic neurons following damage to their presynaptic neurons, which causes the denervated neuron to become supersensitive to excitatory messages from the remaining presynaptic neurons and to fire vigorously to input that previously was below threshold.

Down syndrome A disorder, characterized by mental retardation, that is associated with the presence of three chromosomes for chromo- some 21.

embryo A single fertilized egg that rapidly divides and redivides until a ball of cells, called a blastocyst, is formed.

embryonic stem cells Stem cells from an embryo, which have the capacity to transform into any type of human tissue.

fetal alcohol syndrome A disorder, character- ized by behavioral and cognitive deficits, that results from exposure of an embryo to alcohol during the early stages of brain development.

fetus A stage of development in which all of the organs have developed and are present in the body.

fragile X syndrome A disorder, characterized by mental retardation, that is associated with a genetic variation on the X chromosome.

general paresis A psychotic disorder caused by an untreated syphilis infection.

hemispherectomy The surgical removal of a cerebral hemisphere.

hepatic encephalopathy A brain disorder associated with liver dysfunction.

holoprosencephaly A developmental disor- der in which only one cerebral hemisphere develops.

hydrocephalus A disorder, caused by any number of insults to the brain, in which the flow of cerebrospinal fluid becomes blocked, and fluid pressure within the ventricles increases.

Kennard effect The observation that behav- ioral function recovers and develops normally when brain damage occurs in infancy.

Korsakoff’s syndrome A cognitive disorder observed in long-term alcoholics that is char- acterized by memory and cognitive distur- bance, confusion, and loss of orientation for time and place.

nerve growth factor (NGF) A protein that pro- motes the survival of specific neurons in the peripheral and central nervous systems during development and maturation, stimulating the regrowth of axons and sprouting of nearby axons and dendrites.

neurofibrillary tangles Twisted masses of pro- tein located in the cytoplasm of neurons seen in brains of persons with Alzheimer’s disease but not in normal brains.

perinatal Refers to the period surrounding the time of birth.

petechial hemorrhage Pinpoint bleeding asso- ciated with cerebral laceration.

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CHAPTER 13Key Terms

postnatal Refers to the period after the time of birth.

prenatal Refers to the period before birth.

senile dementia A progressive cognitive disor- der that occurs in patients over 65 years of age.

stage of axonal and dendritic growth The fourth stage of brain development, in which neurons begin to sprout processes that become dendrites and axons.

syphilis A sexually transmitted bacterial infec- tion that can interfere with brain development in the fetus.

vascular dementia A form of senile dementia related to cardiovascular disease, particularly hardening of the arteries or stroke.

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