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1 second from the activating influences of the thalamus and other lower centers.

Effect of Varying Levels of Cerebral Activity on the Frequency of the EEG

There is a general correlation between level of cerebral activity and average frequency of the EEG rhythm, the average frequency increasing progressively with higher degrees of activity. This is demonstrated in Figure 59-3, which shows the existence of delta waves in stupor, surgical anesthesia, and deep sleep; theta waves in psychomotor states and in infants; alpha waves during relaxed states; and beta waves during periods of intense mental activity. During periods of mental activity, the waves usually become asynchronous rather than synchronous, so that the voltage falls considerably, despite markedly increased cortical activity, as shown in Figure 59-2.

Changes in the EEG at Different Stages of Wakefulness and Sleep

Figure 59-4 shows EEG patterns from a typical person in different stages of wakefulness and sleep. Alert wakefulness is characterized by high-frequency beta waves, whereas quiet wakefulness is usually associated with alpha waves, as demonstrated by the first two EEGs of the figure.

Slow-wave sleep is divided into four stages. In the first stage, a stage of very light sleep, the voltage of the EEG waves becomes very low; this is broken by "sleep spindles," that is, short spindle-shaped bursts of alpha waves that occur periodically. In stages 2, 3, and 4 of slow-wave sleep, the frequency of the EEG becomes progressively slower until it reaches a frequency of only 1 to 3 waves per second in stage 4; these are delta waves.

Finally, the bottom record in Figure 59-4 shows the EEG during REM sleep. It is often difficult to tell the difference between this brain wave pattern and that of an awake, active person. The waves are irregular and high-frequency, which are normally suggestive of desyn-chronized nervous activity as found in the awake state. Therefore, REM sleep is frequently called desynchro-nized sleep because there is lack of synchrony in the firing of the neurons, despite significant brain activity.

Epilepsy

Epilepsy (also called "seizures") is characterized by uncontrolled excessive activity of either part or all of the

Alert wakefulness (beta waves)

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Quiet wakefulness (alpha waves)

Stage 1 sleep (low voltage and spindles)

Stages 2 and 3 sleep (theta waves)

Stage 4 slow wave sleep (delta waves)

REM sleep (beta waves) 1 sec

Figure 59-4

Progressive change in the characteristics of the brain waves during different stages of wakefulness and sleep.

central nervous system. A person who is predisposed to epilepsy has attacks when the basal level of excitability of the nervous system (or of the part that is susceptible to the epileptic state) rises above a certain critical threshold. As long as the degree of excitability is held below this threshold, no attack occurs.

Epilepsy can be classified into three major types: grand mal epilepsy, petit mal epilepsy, and focal epilepsy.

Grand Mal Epilepsy

Grand mal epilepsy is characterized by extreme neuronal discharges in all areas of the brain—in the cerebral cortex, in the deeper parts of the cerebrum, and even in the brain stem. Also, discharges transmitted all the way into the spinal cord sometimes cause generalized tonic seizures of the entire body, followed toward the end of the attack by alternating tonic and spasmodic muscle contractions called tonic-clonic seizures. Often the person bites or "swallows" his or her tongue and may have difficulty breathing, sometimes to the extent that cyanosis occurs. Also, signals transmitted from the

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Grand mal

Grand mal

Petit mal

Petit mal

Psychomotor

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Figure 59-5

Electroencephalograms In different types of epilepsy.

brain to the viscera frequently cause urination and defecation.

The usual grand mal seizure lasts from a few seconds to 3 to 4 minutes. It is also characterized by postseizure depression of the entire nervous system; the person remains in stupor for 1 to many minutes after the seizure attack is over, and then often remains severely fatigued and asleep for hours thereafter.

The top recording of Figure 59-5 shows a typical EEG from almost any region of the cortex during the tonic phase of a grand mal attack. This demonstrates that high-voltage, high-frequency discharges occur over the entire cortex. Furthermore, the same type of discharge occurs on both sides of the brain at the same time, demonstrating that the abnormal neuronal circuitry responsible for the attack strongly involves the basal regions of the brain that drive the two halves of the cerebrum simultaneously.

In laboratory animals and even in human beings, grand mal attacks can be initiated by administering a neuronal stimulant such as the drug pentylenetetrazol, or they can be caused by insulin hypoglycemia, or by passage of alternating electrical current directly through the brain. Electrical recordings from the thalamus as well as from the reticular formation of the brain stem during the grand mal attack show typical high-voltage activity in both of these areas similar to that recorded from the cerebral cortex. Presumably, therefore, a grand mal attack involves not only abnormal activation of the thalamus and cerebral cortex but also abnormal activation in the subthalamic brain stem portions of the brain activating system itself.

What Initiates a Grand Mal Attack? Most people who have grand mal attacks have hereditary predisposition to epilepsy, a predisposition that occurs in about 1 of every 50 to 100 persons. In such people, factors that can increase the excitability of the abnormal "epileptogenic" circuitry enough to precipitate attacks include (1) strong emotional stimuli, (2) alkalosis caused by overbreathing, (3) drugs, (4) fever, and (5) loud noises or flashing lights.

Even in people who are not genetically predisposed, certain types of traumatic lesions in almost any part of the brain can cause excess excitability of local brain areas, as we discuss shortly; these, too, sometimes transmit signals into the activating systems of the brain to elicit grand mal seizures.

What Stops the Grand Mal Attack? The cause of the extreme neuronal overactivity during a grand mal attack is presumed to be massive simultaneous activation of many reverberating neuronal pathways throughout the brain. Presumably, the major factor that stops the attack after a few minutes is neuronal fatigue. A second factor is probably active inhibition by inhibitory neurons that have been activated by the attack.

Petit Mal Epilepsy

Petit mal epilepsy almost certainly involves the thala-mocortical brain activating system. It is usually characterized by 3 to 30 seconds of unconsciousness (or diminished consciousness) during which time the person has twitch-like contractions of muscles usually in the head region, especially blinking of the eyes; this is followed by return of consciousness and resumption of previous activities. This total sequence is called the absence syndrome or absence epilepsy. The patient may have one such attack in many months or, in rare instances, may have a rapid series of attacks, one after the other. The usual course is for the petit mal attacks to appear first during late childhood and then to disappear by the age of 30. On occasion, a petit mal epileptic attack will initiate a grand mal attack.

The brain wave pattern in petit mal epilepsy is demonstrated by the middle recording of Figure 59-5, which is typified by a spike and dome pattern. The spike and dome can be recorded over most or all of the cerebral cortex, showing that the seizure involves much or most of the thalamocortical activating system of the brain. In fact, animal studies suggest that it results from oscillation of (1) inhibitory thalamic reticular neurons (which are inhibitory gamma-aminobutyric acid [GABA]-producing neurons) and (2) excitatory thalamocortical and corticothalamic neurons.

Focal Epilepsy

Focal epilepsy can involve almost any local part of the brain, either localized regions of the cerebral cortex or deeper structures of both the cerebrum and brain stem. Most often, focal epilepsy results from some localized organic lesion or functional abnormality, such as (1) scar tissue in the brain that pulls on the adjacent neuronal tissue, (2) a tumor that compresses an area of the brain, (3) a destroyed area of brain tissue, or (4) congenitally deranged local circuitry.

Lesions such as these can promote extremely rapid discharges in the local neurons; when the discharge rate rises above several hundred per second, synchronous waves begin to spread over adjacent cortical regions. These waves presumably result from localized reverberating circuits that gradually recruit adjacent areas of the cortex into the epileptic discharge zone. The process spreads to adjacent areas at a rate as slow as a few millimeters a minute to as fast as several centimeters per second.When such a wave of excitation spreads over the motor cortex, it causes progressive "march" of muscle contractions throughout the opposite side of the body, beginning most characteristically in the mouth region and marching progressively downward to the legs but at other times marching in the opposite direction. This is called jacksonian epilepsy.

A focal epileptic attack may remain confined to a single area of the brain, but in many instances, the strong signals from the convulsing cortex excite the mesencephalic portion of the brain activating system so greatly that a grand mal epileptic attack ensues as well.

Another type of focal epilepsy is the so-called psychomotor seizure, which may cause (1) a short period of amnesia; (2) an attack of abnormal rage; (3) sudden anxiety, discomfort, or fear; and/or (4) a moment of incoherent speech or mumbling of some trite phrase. Sometimes the person cannot remember his or her activities during the attack, but at other times, he or she is conscious of everything that he or she is doing but unable to control it. Attacks of this type frequently involve part of the limbic portion of the brain, such as the hippocampus, the amygdala, the septum, and/or portions of the temporal cortex.

The lowest tracing of Figure 59-5 demonstrates a typical EEG during a psychomotor seizure, showing a low-frequency rectangular wave with a frequency between 2 and 4 per second and with occasional superimposed 14-per-second waves.

Surgical Excision of Epileptic Foci Can Often Prevent Seizures.

The EEG can be used to localize abnormal spiking waves originating in areas of organic brain disease that predispose to focal epileptic attacks. Once such a focal point is found, surgical excision of the focus frequently prevents future attacks.

Psychotic Behavior and Dementia—Roles of Specific Neurotransmitter Systems

Clinical studies of patients with different psychoses or different types of dementia have suggested that many of these conditions result from diminished function of neurons that secrete a specific neurotransmitter. Use of appropriate drugs to counteract loss of the respective neurotransmitter has been successful in treating some patients.

In Chapter 56, we discussed the cause of Parkinson's disease. This disease results from loss of neurons in the substantia nigra whose nerve endings secrete dopamine in the caudate nucleus and putamen. Also in Chapter 56, we pointed out that in Huntington's disease, loss of GABA-secreting neurons and acetylcholine-secreting neurons is associated with specific abnormal motor patterns plus dementia occurring in the same patient.

Depression and Manic-Depressive Psychoses—Decreased Activity of the Norepinephrine and Serotonin Neurotransmitter Systems

Much evidence has accumulated suggesting that mental depression psychosis, which occurs in about 8 million people in the United States, might be caused by diminished formation in the brain of norepinephrine or serotonin, or both. (New evidence has implicated still other neurotransmitters.) Depressed patients experience symptoms of grief, unhappiness, despair, and misery. In addition, they often lose their appetite and sex drive and have severe insomnia. Often associated with these is a state of psychomotor agitation despite the depression.

Moderate numbers of norepinephrine-secreting neurons are located in the brain stem, especially in the locus ceruleus. These neurons send fibers upward to most parts of the brain limbic system, thalamus, and cerebral cortex. Also, many serotonin-producing neurons located in the midline raphe nuclei of the lower pons and medulla send fibers to many areas of the limbic system and to some other areas of the brain.

A principal reason for believing that depression might be caused by diminished activity of norepinephrine- and serotonin-secreting neurons is that drugs that block secretion of norepinephrine and serotonin, such as reserpine, frequently cause depression. Conversely, about 70 per cent of depressive patients can be treated effectively with drugs that increase the excitatory effects of norepinephrine and serotonin at the nerve endings—for instance, (1) monoamine oxidase inhibitors, which block destruction of norepinephrine and serotonin once they are formed; and (2) tricyclic antidepressants, such as imipramine and amitriptyline, which block reuptake of norepinephrine and serotonin by nerve endings so that these transmitters remain active for longer periods after secretion.

Mental depression can be treated by electroconvul-sive therapy—commonly called "shock therapy." In this therapy, electrical current is passed through the brain to cause a generalized seizure similar to that of an epileptic attack. This has been shown to enhance norepine-phrine activity.

Some patients with mental depression alternate between depression and mania, which is called either bipolar disorder or manic-depressive psychosis, and a few people exhibit only mania without the depressive episodes. Drugs that diminish the formation or action of norepinephrine and serotonin, such as lithium compounds, can be effective in treating the manic phase of the condition.

It is presumed that the norepinephrine and serotonin systems normally provide drive to the limbic areas of the brain to increase a person's sense of well-being, to create happiness, contentment, good appetite, appropriate sex drive, and psychomotor balance—although too much of a good thing can cause mania. In support of this concept is the fact that pleasure and reward centers of the hypothalamus and surrounding areas receive large numbers of nerve endings from the norepinephrine and serotonin systems.

Schizophrenia—Possible Exaggerated Function of Part of the Dopamine System

Schizophrenia comes in many varieties. One of the most common types is seen in the person who hears voices and has delusions of grandeur, intense fear, or other types of feelings that are unreal. Many schizophrenics (1) are highly paranoid, with a sense of persecution from outside sources; (2) may develop incoherent speech, dissociation of ideas, and abnormal sequences of thought; and (3) are often withdrawn, sometimes with abnormal posture and even rigidity.

There are reasons to believe that schizophrenia results from one or more of three possibilities: (1) multiple areas in the cerebral cortex prefrontal lobes in which neural signals have become blocked or where processing of the signals becomes dysfunctional because many synapses normally excited by the neurotransmit-ter glutamate lose their responsiveness to this transmitter; (2) excessive excitement of a group of neurons that secrete dopamine in the behavioral centers of the brain, including in the frontal lobes; and/or (3) abnormal function of a crucial part of the brain's limbic behavioral control system centered around the hippocampus.

The reason for believing that the prefrontal lobes are involved in schizophrenia is that a schizophrenic-like pattern of mental activity can be induced in monkeys by making multiple minute lesions in widespread areas of the prefrontal lobes.

Dopamine has been implicated as a possible cause of schizophrenia because many patients with Parkinson's disease develop schizophrenic-like symptoms when they are treated with the drug called l-dopa. This drug releases dopamine in the brain, which is advantageous for treating Parkinson's disease, but at the same time it depresses various portions of the prefrontal lobes and other related areas.

It has been suggested that in schizophrenia excess dopamine is secreted by a group of dopamine-secreting neurons whose cell bodies lie in the ventral tegmentum of the mesencephalon, medial and superior to the sub-stantia nigra. These neurons give rise to the so-called mesolimbic dopaminergic system that projects nerve fibers and dopamine secretion into the medial and anterior portions of the limbic system, especially into the hippocampus, amygdala, anterior caudate nucleus, and portions of the prefrontal lobes. All of these are powerful behavioral control centers.

An even more compelling reason for believing that schizophrenia might be caused by excess production of dopamine is that many drugs that are effective in treating schizophrenia—such as chlorpromazine, haloperi-dol, and thiothixene—all either decrease secretion of dopamine at dopaminergic nerve endings or decrease the effect of dopamine on subsequent neurons.

Finally, possible involvement of the hippocampus in schizophrenia was discovered recently when it was learned that in schizophrenia, the hippocampus is often reduced in size, especially in the dominant hemisphere.

Alzheimer's Disease—Amyloid Plaques and Depressed Memory

Alzheimer's disease is defined as premature aging of the brain, usually beginning in mid-adult life and progressing rapidly to extreme loss of mental powers—similar to that seen in very, very old age. The clinical features of Alzheimer's disease include (1) an amnesic type of memory impairment, (2) deterioration of language, and (3) visuospatial deficits. Motor and sensory abnormalities, gait disturbances, and seizures are uncommon until the late phases of the disease. One consistent finding in Alzheimer's disease is loss of neurons in that part of the limbic pathway that drives the memory process. Loss of this memory function is devastating.

Alzheimer's disease is a progressive and fatal neu-rodegenerative disorder that results in impairment of the person's ability to perform activities of daily living as well as a variety of neuropsychiatric symptoms and behavioral disturbances in the later stages of the disease. Patients with Alzheimer's disease usually require continuous care within a few years after the disease begins.

Alzheimer's disease is the most common form of dementia in the elderly and about 5 million people in the United States are estimated to be afflicted by this disorder. The percentage of persons with Alzheimer's disease approximately doubles with every five years of age, with about 1 percent of 60-year-olds and about 30 percent of 85-year-olds having the disease.

Alzheimer's Disease Is Associated with Accumulation of Brain

Beta-Amyloid Peptide. Pathologically, one finds increased amounts of beta-amyloid peptide in the brains of patients with Alzheimer's disease. The peptide accumulates in amyloid plaques, which range in diameter from 10 micrometers to several hundred micrometers and are found in widespread areas of the brain, including in the cerebral cortex, hippocampus, basal ganglia, thalamus, and even the cerebellum. Thus, Alzheimer's disease appears to be a metabolic degenerative disease.

A key role for excess accumulation of beta-amyloid peptide in the pathogenesis of Alzheimer's disease is suggested by the following observations: (1) all currently known mutations associated with Alzheimer's disease increase the production of beta-amyloid peptide; (2) patients with trisomy 21 (Down syndrome) have three copies of the gene for amyloid precursor protein and develop neurological characteristics of Alzheimer's disease by midlife; (3) patients who have abnormality of a gene that controls apolipoprotein E, a blood protein that transports cholesterol to the tissues, have accelerated deposition of amyloid and greatly increased risk for Alzheimer's disease; (4) transgenic mice that overproduce the human amyloid precursor protein have learning and memory deficits in association with the accumulation of amyloid plaques; and (5) generation of anti-amyloid antibodies in humans with Alzheimer's disease appears to attenuate the disease process.

Vascular Disorders May Contribute to Progression of Alzheimer's

Disease. There is also accumulating evidence that cerebrovascular disease caused by hypertension and atherosclerosis may play a role in Alzheimer's disease. Cerebrovascular disease is the second most common cause of acquired cognitive impairment and dementia and likely contributes to cognitive decline in Alzheimer's disease. In fact, many of the common risk factors for cerebrovascular disease, such as hypertension, diabetes, and hyperlipidemia, are also recognized to greatly increase the risk for developing Alzheimer's disease.

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