CHAPTER 60

States of Brain Activity—Sleep, Brain

UNIT XI
Waves, Epilepsy, Psychoses, and Dementia
All of us are aware of the many different states of brain in young adults. When a person is extremely sleepy, each
activity, including sleep, wakefulness, extreme excite- bout of REM sleep is short and may even be absent. As
ment, and even different levels of mood such as exhila- the person becomes more rested through the night, the
ration, depression, and fear. All these states result from durations of the REM bouts increase.
different activating or inhibiting forces generated usually REM sleep has several important characteristics:
within the brain. In Chapter 59, we began a partial discus- 1. It is an active form of sleep usually associated with
sion of this subject when we described different systems dreaming and active bodily muscle movements.
that are capable of activating large portions of the brain. 2. The person is even more difficult to arouse by sen-
In this chapter, we present brief surveys of specific states sory stimuli than during deep slow-­wave sleep, and
of brain activity, beginning with sleep. yet people usually awaken spontaneously in the
morning during an episode of REM sleep.
3. Muscle tone throughout the body is exceedingly
SLEEP
depressed, indicating strong inhibition of the spinal
Sleep is defined as unconsciousness from which a per- muscle control areas.
son can be aroused by sensory or other stimuli. It is to 4. Heart rate and respiratory rate usually become ir-
be distinguished from coma, which is unconsciousness regular, which is characteristic of the dream state.
from which a person cannot be aroused. There are mul- 5. Despite the extreme inhibition of the peripheral
tiple stages of sleep, from very light sleep to very deep muscles, irregular muscle movements do occur in
sleep. Sleep researchers also divide sleep into two entirely addition to the rapid movements of the eyes.
different types of sleep that have different qualities, as 6. The brain is highly active in REM sleep, and overall
described in the following section. brain metabolism may be increased as much as 20%.
An electroencephalogram (EEG) shows a pattern
TWO TYPES OF SLEEP—SLOW-­WAVE of brain waves similar to those that occur during
SLEEP AND RAPID EYE MOVEMENT SLEEP wakefulness. This type of sleep is also called para-
Each night, a person goes through stages of two major doxical sleep because it is a paradox that a person
types of sleep that alternate with each other (Figure 60-­1). can still be asleep, despite the presence of marked
These types are called (1) rapid eye movement sleep (REM activity in the brain.
sleep), in which the eyes undergo rapid movements even In summary, REM sleep is a type of sleep in which
though the person is still asleep, and (2) slow-­wave sleep the brain is quite active. However, the person is not fully
or non-­REM (NREM) sleep, in which the brain waves are aware of the surroundings and therefore is truly asleep.
strong and of low frequency, as we discuss later. Slow-­Wave Sleep
REM sleep occurs in episodes that occupy about 25%
of the sleep time in young adults; each episode normally We can understand the characteristics of deep slow-­wave
recurs about every 90 minutes. This type of sleep is not sleep by remembering the last time we were kept awake for
so restful, and it is often associated with vivid dreaming. more than 24 hours and the deep sleep that occurred dur-
Most sleep during each night is of the slow-­wave (NREM) ing the first hour after going to sleep. This sleep is exceed-
variety, which is the deep, restful sleep that the person ingly restful and is associated with decreases in peripheral
experiences during the first hour of sleep after having vascular tone and many other vegetative functions of the
been awake for many hours. body. For example, 10% to 30% decreases occur in blood
pressure, respiratory rate, and basal metabolic rate.
REM (Paradoxical, Desynchronized) Sleep Although slow-­wave sleep is frequently called “dream-
In a normal night of sleep, bouts of REM sleep lasting 5 less sleep,” dreams and sometimes even nightmares do
to 30 minutes usually appear on average every 90 minutes occur during slow-­wave sleep. The difference between

753
UNIT XI The Nervous System: C. Motor and Integrative Neurophysiology

Alert wakefulness (beta waves)

Awake

Quiet wakefulness (alpha waves)

REM REM REM REM REM
REM
REM sleep (beta waves)

Stage 1
Stage 1 sleep (low voltage and spindles)

Stage 2
50 µV
Stages 2 and 3 sleep (theta waves)
Stage 3

Stage 4
Stage 4 slow-wave sleep (delta waves)

1 sec
1 2 3 4 5 6 7 8
Time (hours)
Figure 60-­1. Progressive change in the characteristics of the brain waves during alert wakefulness, rapid eye movement (REM) sleep, and stages
one through four of sleep.

the dreams that occur in slow-­wave sleep and those that the midline. Nerve fibers from these nuclei spread
occur in REM sleep is that those of REM sleep are associ- locally in the brain stem reticular formation and
ated with more bodily muscle activity. Also, the dreams also upward into the thalamus, hypothalamus, most
of slow-­wave sleep are usually not remembered because areas of the limbic system, and even the neocortex
consolidation of the dreams in memory does not occur. of the cerebrum. In addition, fibers extend down-
ward into the spinal cord, terminating in the poste-
BASIC THEORIES OF SLEEP rior horns, where they can inhibit incoming sensory
signals, including pain, as discussed in Chapter 49.
Sleep Is Caused by an Active Inhibitory Process.
Many nerve endings of fibers from these raphe neu-
An earlier theory of sleep was that the excitatory ar-
rons secrete serotonin. When a drug that blocks the
eas of the upper brain stem, the reticular activating
formation of serotonin is administered to an animal,
system, simply became fatigued during the waking day
the animal often cannot sleep for the next several
and became inactive as a result. An important experi-
days. Therefore, it has been assumed that serotonin
ment changed this thinking to the current view that
is a transmitter substance associated with the pro-
sleep is caused by an active inhibitory process, because
duction of sleep.
it was discovered that transecting the brain stem at the
2. Stimulation of some areas in the nucleus of the trac-
level of the midpons creates a brain cortex that never
tus solitarius can also cause sleep. This nucleus is
goes to sleep. In other words, a center located below
the termination in the medulla and pons for visceral
the midpontile level of the brain stem appears to be
sensory signals entering by way of the vagus and
required to cause sleep by inhibiting other parts of the
glossopharyngeal nerves.
brain.
3. Sleep can be promoted by stimulation of several re-
Neuronal Centers, Neurohumoral gions in the diencephalon, including (1) the rostral
Substances, and Mechanisms That Can part of the hypothalamus, mainly in the suprachi-
Cause Sleep—Possible Role for Serotonin asmal area, and (2) an occasional area in the diffuse
nuclei of the thalamus.
Stimulation of several specific areas of the brain can pro-
duce sleep with characteristics near those of natural sleep. Lesions in Sleep-­
Promoting Centers Can Cause In-
Some of these areas are the following: tense Wakefulness. Discrete lesions in the raphe nuclei
1. The raphe nuclei in the lower half of the pons and lead to a high state of wakefulness. This phenomenon is
in the medulla is the most conspicuous stimulation also true of bilateral lesions in the medial rostral suprachi-
area for causing almost natural sleep. These nuclei asmal area in the anterior hypothalamus. In both cases,
comprise a thin sheet of special neurons located in the excitatory reticular nuclei of the mesencephalon and

754
 Chapter 60 States of Brain Activity—Sleep, Brain Waves, Epilepsy, Psychoses, and Dementia

upper pons seem to become released from inhibition, Therefore, once wakefulness begins, it has a natural ten-
thus causing intense wakefulness. Indeed, sometimes le- dency to sustain itself because of all this positive feedback
sions of the anterior hypothalamus can cause such intense activity.
wakefulness that the animal actually dies of exhaustion. Then, after the brain remains activated for many hours,
even the neurons in the activating system presumably
Other Possible Transmitter Substances Related to

UNIT XI
become fatigued. Consequently, the positive feedback
Sleep. Experiments have shown that the cerebrospinal
cycle between the mesencephalic reticular nuclei and
fluid and the blood or urine of animals that have been kept
the cerebral cortex fades and the sleep-­promoting effects
awake for several days contain a substance or substances
of the sleep centers take over, leading to rapid transition
that will cause sleep when injected into the brain ven-
from wakefulness back to sleep.
tricular system of another animal. One likely substance
This overall theory could explain the rapid transitions
has been identified as muramyl peptide, a low-­molecular-­
from sleep to wakefulness and from wakefulness to sleep.
weight substance that accumulates in the cerebrospinal
It could also explain arousal—that is, the insomnia that
fluid and urine in animals kept awake for several days.
occurs when a person’s mind becomes preoccupied with a
When only micrograms of this sleep-­ producing sub-
thought—and the wakefulness that is produced by bodily
stance are injected into the third ventricle, almost natural
physical activity.
sleep occurs within a few minutes, and the animal may
stay asleep for several hours. Role of Orexin Neurons in Arousal and Wakefulness.
Another substance that has similar effects in causing Orexin (also called hypocretin) is produced by neurons in
sleep is delta sleep–inducing peptide, a nonapeptide found the hypothalamus that provide excitatory input to many
in the cerebrospinal fluid after electrical stimulation of the other areas of the brain where there are orexin receptors.
thalamus to induce sleep. Several other potential sleep Orexin neurons are most active during waking and almost
factors, mostly peptides, have been isolated from the stop firing during slow wave and REM sleep. Loss of orexin
cerebrospinal fluid or neuronal tissues of the brain stem of signaling as a result of defective orexin receptors or de-
animals kept awake for days. It is possible that prolonged struction of orexin-­producing neurons causes narcolepsy,
wakefulness causes progressive accumulation of a sleep a sleep disorder characterized by overwhelming daytime
factor or factors in the brain stem or cerebrospinal fluid drowsiness and sudden attacks of sleep that can occur,
that lead(s) to sleep. even when a person is talking or working. Patients with
narcolepsy may also experience a sudden loss of muscle
Possible Cause of REM Sleep. It is not understood why tone (cataplexy) that can be partial or even severe enough
slow-­wave sleep is broken periodically by REM sleep. to cause paralysis during the attack. These observations
However, drugs that mimic the action of acetylcholine point to an important role for orexin neurons in maintain-
increase the occurrence of REM sleep. Therefore, it has ing wakefulness, but their contribution to the normal daily
been postulated that the large acetylcholine-­ secreting cycle between sleep and wakefulness is unclear.
neurons in the upper brain stem reticular formation
might, through their extensive efferent fibers, activate SLEEP HAS IMPORTANT PHYSIOLOGICAL
many portions of the brain. This mechanism theoretically FUNCTIONS
could cause the increased activity that occurs in certain There is little doubt that sleep has important functions. It
brain regions in REM sleep, even though the signals are exists in all mammals, and after total deprivation there is
not channeled appropriately in the brain to cause normal usually a period of “catch-­up” or “rebound” sleep; after selec-
conscious awareness that is characteristic of wakefulness. tive deprivation of REM or slow-­wave sleep, there is also
a selective rebound of these specific stages of sleep. Even
Cycle Between Sleep and Wakefulness mild sleep restriction over a few days may degrade cogni-
The preceding discussions have merely identified neuro- tive and physical performance, overall productivity, and the
nal areas, transmitters, and mechanisms that are related health of a person. The essential role of sleep in homeostasis
to sleep; they have not explained the cyclical, reciprocal is perhaps most vividly demonstrated by the fact that rats
operation of the sleep-­wakefulness cycle. There is as yet deprived of sleep for 2 to 3 weeks may actually die. Despite
no definitive explanation. Therefore, we might suggest the obvious importance of sleep, our understanding of why
the following possible mechanism for causing the sleep-­ sleep is an essential part of life is still limited.
wakefulness cycle. Sleep causes two major types of physiological effects:
When the sleep centers are not activated, the mesen- first, effects on the nervous system, and second, effects on
cephalic and upper pontile reticular activating nuclei are other functional systems of the body. Mammals, and even
released from inhibition, which allows the reticular acti- invertebrate animals, sleep more in the setting of infec-
vating nuclei to become spontaneously active. This spon- tious as well as non-­infectious illnesses. Sickness-­induced
taneous activity in turn excites both the cerebral cortex sleep has been suggested to be a beneficial response that
and the peripheral nervous system, both of which send diverts the organism’s energy resources from neural and
numerous positive feedback signals back to the same motor demands to fighting off infectious or injurious
reticular activating nuclei to activate them still further. insults.
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UNIT XI The Nervous System: C. Motor and Integrative Neurophysiology

Lack of sleep certainly affects the functions of the Alpha

central nervous system. Prolonged wakefulness is often
associated with progressive malfunction of the thought
processes and sometimes even causes abnormal behav- Beta
ioral activities. We are all familiar with the increased
sluggishness of thought that occurs toward the end of a
prolonged wakeful period, but in addition, a person can
Theta
become irritable or even psychotic after forced wake-
fulness. Therefore, we can assume that sleep in multiple
ways restores both normal levels of brain activity and nor-
mal “balance” among the different functions of the central 50 µV
Delta
nervous system.
Sleep has been postulated to serve many functions, 1 sec
including the following: (1) neural maturation; (2) facilita- Figure 60-­2. Different types of brain waves in the normal electro-
tion of learning or memory; (3) targeted erasure of syn- encephalogram.
apses to “forget” unimportant information that might
clutter the synaptic network; (4) cognition; (5) clearance Eyes open Eyes closed
of metabolic waste products generated by neural activ-
ity in the awake brain; and (6) conservation of metabolic
energy. There is some evidence for each of these func- Figure 60-­3. Replacement of the alpha rhythm by an asynchronous,
tions, but evidence supporting each of these ideas has low-­voltage beta rhythm when the eyes are open.
been challenged. We might postulate that the principal
value of sleep is to restore natural balances among the neu- Their voltage is usually about 50 microvolts. During deep
ronal centers, which is necessary for overall health. The sleep, the alpha waves disappear.
specific physiological functions of sleep, however, remain When the awake person’s attention is directed to some
a mystery and are the subject of much research. specific type of mental activity, the alpha waves are replaced
by asynchronous, higher frequency but lower voltage beta
waves. Figure 60-­3 shows the effect on the alpha waves of
Brain Waves
simply opening the eyes in bright light and then closing the
Electrical recordings from the surface of the brain or even eyes. Note that the visual sensations cause immediate ces-
from the outer surface of the head demonstrate that there is sation of the alpha waves and that these waves are replaced
continuous electrical activity in the brain. Both the intensity by low-­voltage, asynchronous beta waves.
and the patterns of this electrical activity are determined by Beta waves occur at frequencies greater than 14 cycles/
the level of excitation of different parts of the brain resulting sec and as high as 80 cycles/sec. They are recorded mainly
from sleep, wakefulness, or brain disorders such as epilepsy from the parietal and frontal regions during specific activa-
or even psychoses. The undulations in the recorded electrical tion of these parts of the brain.
potentials, shown in Figure 60-­2, are called brain waves, and Theta waves have frequencies between four and 7 cy-
the entire record is called an electroencephalogram (EEG). cles/sec. They occur normally in the parietal and temporal
The intensities of brain waves recorded from the sur- regions in children, but they also occur during emotional
face of the scalp range from 0 to 200 microvolts, and their stress in some adults, particularly during disappointment
frequencies range from once every few seconds to 50 or and frustration. Theta waves also occur in many brain dis-
more per second. The character of the waves is dependent orders, often in degenerative brain states.
on the degree of activity in respective parts of the cerebral Delta waves include all the waves of the EEG with fre-
cortex, and the waves change markedly between the states quencies less than 3.5 cycles/sec, and they often have volt-
of wakefulness and sleep and coma. ages two to four times greater than most other types of brain
Much of the time, the brain waves are irregular and waves. They occur in very deep sleep, in infancy, and in per-
no specific pattern can be discerned in the EEG. At other sons with serious organic brain disease. They also occur in
times, distinct patterns do appear, some of which are char- the cortex of animals that have had subcortical transections
acteristic of specific abnormalities of the brain such as epi- in which the cerebral cortex is separated from the thalamus.
lepsy, which is discussed later. Therefore, delta waves can occur strictly in the cortex inde-
In healthy people, most waves in the EEG can be classi- pendent of activities in lower regions of the brain.
fied as alpha, beta, theta, and delta waves, which are shown
in Figure 60-­2. Origin of Brain Waves
Alpha waves are rhythmical waves that occur at fre- The discharge of a single neuron or single nerve fiber in
quencies between 8 and 13 cycles/sec and are found in the the brain can never be recorded from the surface of the
EEGs of almost all healthy adults when they are awake and head. Instead, many thousands or even millions of neurons
in a quiet, resting state of cerebration. These waves occur or fibers must fire synchronously for the potentials from the
most intensely in the occipital region but can also be re- individual neurons or fibers to summate enough to be re-
corded from the parietal and frontal regions of the scalp. corded through the skull. Thus, the intensity of the brain

756
 Chapter 60 States of Brain Activity—Sleep, Brain Waves, Epilepsy, Psychoses, and Dementia

Surgical Sleep Psychomotor Relaxation Attention Tonic-clonic

anesthesia Deteriorated epileptics Fast component
of absence seizure
Confusion

UNIT XI
1 second
Figure 60-­4. Effect of varying degrees of cerebral activity on the basic rhythm of the electroencephalogram.

waves from the scalp is determined mainly by the numbers despite markedly increased cortical activity, as shown in
of neurons and fibers that fire in synchrony with one an- Figure 60-­3.
other, not by the total level of electrical activity in the brain.
In fact, strong nonsynchronous nerve signals often nullify Changes in the EEG at Different Stages of Wakeful-
ness and Sleep
one another in the recorded brain waves because of oppos-
ing polarities. This phenomenon is demonstrated in Figure Figure 60-­1 shows typical EEG patterns in different stages
60-­3, which shows, when the eyes were closed, synchro- of wakefulness and sleep. Alert wakefulness is character-
nous discharge of many neurons in the cerebral cortex at a ized by high-­frequency beta waves, whereas quiet wakeful-
frequency of about 12/sec, thus causing alpha waves. Then, ness is usually associated with alpha waves, as demonstrat-
when the eyes were opened, the activity of the brain in- ed by the first two EEGs of the figure.
creased greatly, but synchronization of the signals became Slow-­wave sleep is divided into four stages. In the first
so little that the brain waves mainly nullified one another. stage, a stage of light sleep, the voltage of the EEG waves
The resultant effect was low voltage waves of generally high becomes low. This stage is broken by “sleep spindles” (i.e.,
but irregular frequency, the beta waves. short spindle-­shaped bursts of alpha waves that occur pe-
Origin of Alpha Waves. Alpha waves will not occur in riodically). In stages 2, 3, and 4 of slow-­wave sleep, the fre-
the cerebral cortex without cortical connections with the quency of the EEG becomes progressively slower until it
thalamus. Conversely, stimulation in the nonspecific layer reaches a frequency of only one to three waves per second
of reticular nuclei that surround the thalamus or in “dif- in stage 4; these waves are delta waves.
fuse” nuclei deep inside the thalamus often sets up elec- Figure 60-­1 also shows the EEG during REM sleep. It is
trical waves in the thalamocortical system at a frequency often difficult to tell the difference between this brain wave
between 8 and 13/sec, which is the natural frequency of pattern and that of an awake, active person. The waves are
the alpha waves. Therefore, alpha waves are thought to re- irregular and of high frequency, which are normally sug-
sult from spontaneous feedback oscillation in this diffuse gestive of desynchronized nervous activity as found in the
thalamocortical system, possibly including the reticular ac- awake state. Therefore, REM sleep is frequently called de-
tivating system in the brain stem as well. This oscillation synchronized sleep because there is lack of synchrony in the
presumably causes the periodicity of the alpha waves and firing of the neurons despite significant brain activity.
the synchronous activation of literally millions of cortical
neurons during each wave. Seizures and Epilepsy
Origin of Delta Waves. Transection of the fiber tracts Seizures are temporary disruptions of brain function
from the thalamus to the cerebral cortex, which blocks tha- caused by uncontrolled excessive neuronal activity. De-
lamic activation of the cortex and thereby eliminates the pending on the distribution of neuronal discharges, seizure
alpha waves, nevertheless does not block delta waves in the manifestations can range from experiential phenomena
cortex. This indicates that some synchronizing mechanism that are barely noticeable to dramatic convulsions. These
can occur in the cortical neuronal system by itself—mainly temporary symptomatic seizures usually do not persist if
independent of lower structures in the brain—to cause the the underlying disorder is corrected. They can be caused by
delta waves. multiple neurological or medical conditions, such as acute
Delta waves also occur during deep slow-­wave sleep, electrolyte disorders, hypoglycemia, drugs (e.g., cocaine),
which suggests that the cortex then is mainly released from eclampsia, kidney failure, hypertensive encephalopathy,
the activating influences of the thalamus and other lower meningitis, and so forth. Approximately 5% to 10% of the
centers. population will have at least one seizure in their lifetime.
In contrast to symptomatic seizures, epilepsy is a chronic
Effect of Varying Levels of Cerebral Activity on the condition of recurrent seizures that can also vary from brief
Frequency of the EEG and nearly undetectable symptoms to periods of vigorous
There is a general correlation between level of cerebral ac- shaking and convulsions. Epilepsy is not a single disease.
tivity and average frequency of the EEG rhythm, with the Its clinical symptoms are heterogeneous and reflect multi-
average frequency increasing progressively with higher ple underlying pathophysiological mechanisms that cause
degrees of activity. This is demonstrated in Figure 60-­4, cerebral dysfunction and injury, such as trauma, stroke,
which shows the existence of delta waves in surgical anes- tumors, infection, or degenerative changes. Hereditary fac-
thesia and deep sleep, theta waves in psychomotor states, tors appear to be important, although a specific cause can-
alpha waves during relaxed states, and beta waves during not be identified in many patients and several factors may
periods of intense mental activity or fright. During periods coexist, reflecting an acquired brain pathology and genetic
of mental activity, the waves usually become asynchronous predisposition. Epilepsy is estimated to affect approximate-
rather than synchronous, so the voltage falls considerably ly 1% of the population, or 65 million people worldwide.
757
UNIT XI The Nervous System: C. Motor and Integrative Neurophysiology

At a basic level an epileptic seizure is caused by a disrup- Seizure focal region

tion of the normal balance between inhibitory and excita-
tory currents or transmission in one or more regions of the Propagation to Propagation to
brain. Drugs or pathological factors that increase neuronal contralateral ipsilateral
excitation or impair inhibition tend to be epileptogenic (i.e., cortex cortex
predisposing a person to epilepsy), whereas effective antie-
pileptic drugs attenuate excitation and facilitate inhibition.
In cases in which a person has brain injury due to trauma,
stroke, or infection, there may be a delay of several months
or years after the injury before the seizures begin.
Epileptic seizures can be classified into two major types:
(1) focal seizures (also called partial seizures) that are lim-
ited to a focal area of one cerebral hemisphere, and (2) gen-
A
eralized seizures that diffusely involve both hemispheres of
the cerebral cortex. However, partial seizures may some- Seizure focal region Activation of both
times evolve into generalized seizures. hemispheres via
projections to
Focal (Partial) Epileptic Seizures thalamus
Focal epileptic seizures begin in a small localized region
of the cerebral cortex or deeper structures of the cer-
ebrum and brain stem and have clinical manifestations
that reflect the function of the affected brain area. Most
often, focal epilepsy results from some localized organic
lesion or functional abnormality, such as (1) scar tissue Thalamus
in the brain that pulls on the adjacent neuronal tissue, (2)
a tumor that compresses an area of the brain, (3) a de-
stroyed area of brain tissue, or (4) congenitally deranged
local circuitry.
B
These lesions 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 presum-
ably result from localized reverberating circuits that may Primary
gradually recruit adjacent areas of the cortex into the epi- generalized
leptic discharge zone. The process spreads to adjacent areas seizure
at a rate as slow as a few millimeters per minute to as fast as
several centimeters per second.
Focal seizures can spread locally from a focus or more re- Thalamus
motely to the contralateral cortex and subcortical areas of the
brain through projections to the thalamus, which has wide-
spread connections to both hemispheres (Figure 60-­5). When
such a wave of excitation spreads over the motor cortex, it C
causes a progressive “march” of muscle contractions through- Figure 60-­5. A, Propagation of seizures from focal regions of the
out the opposite side of the body, beginning most characteris- cortex can occur through fibers in the same cerebral hemisphere or
tically in the mouth region and marching progressively down- fibers that connect to the contralateral cortex. B, Secondary generali-
ward to the legs but at other times marching in the opposite zation of a focal seizure can sometimes occur by spread to subcortical
areas through projections to the thalamus, resulting in activation of
direction. This phenomenon is called Jacksonian march.
both hemispheres. C, Primary generalized seizure spreads rapidly and
Focal seizures are often classified as simple partial sei- simultaneously to both cerebral hemispheres through interconnec-
zures when there is no major change in consciousness or as tions between the thalamus and cortex.
complex partial seizures when consciousness is impaired.
Simple partial seizures may be preceded by an aura, with The time after the seizure, prior to the return of normal neu-
sensations such as fear, followed by motor signs, such as rological function, is called the postictal period.
rhythmic jerking or tonic stiffening movements of a body Psychomotor, temporal lobe, and limbic seizures are
part. A focal epileptic attack may remain confined to a single terms that have been used in the past to describe many
area of the brain, often the temporal lobe, but in some cases of the behaviors that are now classified as complex partial
strong signals spread from the focal region, and the person seizures. However, these terms are not synonymous. Com-
may lose consciousness. Complex partial seizures may also plex partial seizures can arise from regions other than the
begin with an aura followed by impaired consciousness and temporal lobe and do not always involve the limbic system.
strange repetitive movements (automatisms), such as chew- Also, automatisms (the “psychomotor” element) are not
ing or lip smacking. After recovery from the seizure the per- always present in complex partial seizures. Attacks of this
son may have no memory of the attack, except for the aura. type frequently involve part of the limbic portion of the

758
 Chapter 60 States of Brain Activity—Sleep, Brain Waves, Epilepsy, Psychoses, and Dementia

that the abnormal neuronal circuitry responsible for the at-

100 µV tack strongly involves the basal regions of the brain that
drive the two halves of the cerebrum simultaneously.
Electrical recordings from the thalamus, as well as from
Generalized tonic-clonic seizure the reticular formation of the brain stem during the gen-
eralized tonic-­clonic seizure, show typical high-­voltage ac-

UNIT XI
50 µV
tivity in both of these areas similar to that recorded from
the cerebral cortex. Therefore, a generalized tonic-­clonic
seizure presumably involves not only abnormal activation
Absence seizure of the thalamus and cerebral cortex but also abnormal acti-
vation in the subthalamic brain stem portions of the brain-­
50 µV activating system.
What Initiates a Generalized Tonic-­
Clonic Seizure?
Psychomotor The majority of generalized seizures are idiopathic,
Figure 60-­6. Electroencephalograms in different types of epilepsy. which means that the cause is unknown. Many people
who have generalized tonic-­clonic attacks have a heredi-
brain, such as the hippocampus, the amygdala, the septum, tary predisposition to epilepsy, a predisposition that oc-
and/or portions of the temporal cortex. curs in about 1 of every 100 persons. In these people,
The lowest tracing of Figure 60-­6 demonstrates a typi- factors that can increase the excitability of the abnormal
cal EEG during a psychomotor seizure, showing a low-­ “epileptogenic” circuitry enough to precipitate attacks
frequency rectangular wave with a frequency between 2 include (1) strong emotional stimuli, (2) alkalosis caused
and 4/sec and with occasional superimposed 14/sec waves. by overbreathing, (3) drugs, (4) fever, and (5) loud noises
or flashing lights.
Generalized Seizures Even in people who are not genetically predisposed,
Generalized epileptic seizures are characterized by diffuse, certain types of traumatic lesions in almost any part of the
excessive, and uncontrolled neuronal discharges that at the brain can cause excess excitability of local brain areas, as
outset spread rapidly and simultaneously to both cerebral we discuss shortly. These local brain areas also sometimes
hemispheres through interconnections between the thala- transmit signals into the activating systems of the brain to
mus and cortex (Figure 60-­5). However, it is sometimes elicit tonic-­clonic seizures.
difficult clinically to distinguish between a primary general- What Stops the Generalized Tonic-­Clonic Attack? The
ized seizure and a focal seizure that spreads rapidly. Gener- extreme neuronal overactivity during a tonic-­clonic attack
alized seizures are subdivided primarily on the basis of the is presumed to be caused by massive simultaneous activa-
ictal motor manifestations which, in turn, depend on the tion of many reverberating neuronal pathways throughout
extent to which subcortical and brain stem regions partici- the brain. Although the factors that terminate the attack
pate in the seizure. are not well understood, it is likely that active inhibition oc-
curs by inhibitory neurons that have been activated by the
Generalized Tonic-­Clonic (Grand Mal) Seizures) attack.
Generalized tonic-­clonic seizures, previously called grand
Absence Seizures (Petit Mal Seizures)
mal seizures, are characterized by an abrupt loss of con-
sciousness and extreme neuronal discharges in all areas of Absence seizures, formerly called petit mal seizures, usu-
the brain—the cerebral cortex, the deeper parts of the cer- ally begin in childhood or early adolescence and account
ebrum, and even the brain stem. Also, discharges transmit- for 15% to 20% of epilepsy cases in children. Absence sei-
ted all the way into the spinal cord sometimes cause gen- zures almost certainly involve the thalamocortical brain
eralized tonic seizures of the entire body, followed toward activating system. They are usually characterized by 3 to 30
the end of the attack by alternating tonic and spasmodic seconds of unconsciousness or diminished consciousness,
muscle contractions called tonic-­clonic seizures. Often the during which time the person often stares and has twitch-
person bites or “swallows” his or her tongue and may have like contractions of muscles, usually in the head region,
difficulty breathing, sometimes to the extent that cyanosis especially blinking of the eyes; this phase is followed by a
occurs. Also, signals transmitted from the brain to the vis- rapid return of consciousness and resumption of previous
cera frequently cause urination and defecation. activities. The total sequence is called the absence syndrome
The usual generalized tonic-­clonic seizure lasts from a or absence epilepsy.
few seconds to 3 to 4 minutes. It is also characterized by The patient may have one such attack in many months
postseizure depression of the entire nervous system; the or, in rare cases, may have a rapid series of attacks, one after
person remains in stupor for 1 minute to many minutes the other. The usual course is for the absence seizures to
after the seizure attack is over and then often remains se- appear first during childhood or adolescence and then to
verely fatigued and asleep for hours thereafter. disappear by the age of 30 years. On occasion, an absence
The top recording of Figure 60-­6 shows a typical EEG seizure will initiate a generalized tonic-­clonic (grand mal)
from almost any region of the cortex during the tonic phase attack.
of generalized tonic-­clonic seizure. This demonstrates that The brain wave pattern in a person with absence seizure
high-­voltage, high-­frequency discharges occur over the en- epilepsy is demonstrated by the middle recording of Figure
tire cortex. Furthermore, the same type of discharge occurs 60-­6, which is typified by a spike and dome pattern. The
on both sides of the brain at the same time, demonstrating spike and dome can be recorded over most or all of the

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UNIT XI The Nervous System: C. Motor and Integrative Neurophysiology

cerebral cortex, showing that the seizure involves much or lose their appetite and sex drive and have severe insomnia.
most of the thalamocortical activating system of the brain. Often associated with these symptoms is a state of psycho-
In fact, animal studies suggest that it results from oscilla- motor agitation despite the depression.
tion of (1) inhibitory thalamic reticular neurons (which are Moderate numbers of norepinephrine-­secreting neurons
inhibitory gamma-­aminobutyric acid [GABA]-­producing are located in the brain stem, especially in the locus ceruleus.
neurons) and (2) excitatory thalamocortical and cortico- These neurons send fibers upward to most parts of the brain
thalamic neurons. limbic system, thalamus, and cerebral cortex. Also, many
serotonin-­producing neurons located in the midline raphe
Treatment of Epilepsy nuclei of the lower pons and medulla send fibers to many ar-
Most of the currently available drugs used to treat epi- eas of the limbic system and to some other areas of the brain.
lepsy appear to block the initiation or spread of seizures, A principal reason for believing that depression might
although the precise mode of action for some drugs is un- be caused by diminished activity of norepinephrine-­and
known or may involve multiple actions. Some of the major serotonin-­secreting neurons is that drugs that block se-
effects of various antiepileptic drugs include the following: cretion of norepinephrine and serotonin, such as reser-
(1) blockade of voltage-­dependent sodium channels (e.g., pine, frequently cause depression. Conversely, about 70%
carbamazepine and phenytoin); (2) altered calcium cur- of depressive patients can be treated effectively with drugs
rents (e.g., ethosuximide); (3) an increase in GABA activity that increase the excitatory effects of norepinephrine and
(e.g., phenobarbital and benzodiazepines); (4) inhibition of serotonin at the nerve endings, for example, as follows: (1)
receptors for glutamate, the most prevalent excitatory neu- monoamine oxidase inhibitors, which block destruction of
rotransmitter (e.g., perampanel); and (5) multiple mecha- norepinephrine and serotonin once they are formed, and
nisms of action (e.g., valproate and topiramate, which block (2) tricyclic antidepressants, such as imipramine and ami-
voltage-­dependent sodium channels and increase GABA triptyline, which block reuptake of norepinephrine and ser-
levels in the brain). The choice of antiepileptic drug rec- otonin by nerve endings so that these transmitters remain
ommended by current guidelines depends on the type of active for longer periods after secretion.
seizure, the age of the patient, and other factors, but cor- Some patients with mental depression alternate be-
rection of the underlying cause of the seizures is the best tween depression and mania, which is called either bipolar
option when possible. disorder or manic-­depressive psychosis, and fewer patients
Epilepsy can usually be controlled with appropriate exhibit only mania without the depressive episodes. Drugs
medications. However, when the epilepsy is medically in- that diminish the formation or action of norepinephrine
tractable and does not respond to treatments, the EEG can and serotonin, such as lithium compounds, can be effective
sometimes be used to localize abnormal spiking waves origi- in treating the manic phase of the condition.
nating in areas of organic brain disease that predispose to It is presumed that the norepinephrine and serotonin
focal epileptic attacks. Once such a focal point is found, sur- systems normally provide drive to the limbic areas of the
gical excision of the focus frequently prevents future attacks. brain to increase a person’s sense of well-­being and to cre-
ate happiness, contentment, good appetite, appropriate sex
Roles of Specific Neurotransmitter Systems in drive, and psychomotor balance—although too much of a
Brain Disorders good thing can cause mania. In support of this concept is
Clinical studies of patients with different psychoses or dif- the fact that pleasure and reward centers of the hypothala-
ferent types of dementia have suggested that many of these mus and surrounding areas receive large numbers of nerve
conditions result from diminished function of neurons endings from the norepinephrine and serotonin systems.
that secrete a specific neurotransmitter. Use of appropriate
drugs to counteract loss of the respective neurotransmitter Schizophrenia—Possible Exaggerated Function of Part
of the Dopamine System
has been successful in treating some patients.
In Chapter 57, we discussed the cause of Parkinson's Schizophrenia comes in many varieties. One of the most
disease, which results from loss of neurons in the substan- common types is seen in the person who hears voices and
tia nigra, whose nerve endings secrete dopamine in the cau- has delusions, intense fear, or other types of feelings that
date nucleus and putamen. Also in Chapter 57, we pointed are unreal. Many schizophrenics are highly paranoid, with
out that in Huntington's disease, loss of GABA-­secreting a sense of persecution from outside sources. They may de-
neurons and acetylcholine-­secreting neurons is associated velop incoherent speech, dissociation of ideas, and abnor-
with specific abnormal motor patterns plus dementia oc- mal sequences of thought, and they are often withdrawn,
curring in the same patient. sometimes with abnormal posture and even rigidity.
There are reasons to believe that schizophrenia results
Depression and Manic-­Depressive Psychoses— from one or more of three possibilities: (1) multiple areas in
Decreased Activity of the Norepinephrine and the cerebral cortex prefrontal lobes in which neural signals
Serotonin Neurotransmitter Systems
have become blocked or where processing of the signals be-
Evidence has accumulated suggesting that mental depres- comes dysfunctional because many synapses normally excit-
sion psychosis, which occurs in more than 8 million people ed by the neurotransmitter glutamate lose their responsive-
in the United States, might be caused by diminished for- ness to this transmitter; (2) excessive excitement of a group
mation in the brain of norepinephrine or serotonin, or both. of neurons that secrete dopamine in the behavioral centers of
(New evidence has implicated still other neurotransmit- the brain, including in the frontal lobes; and/or (3) abnormal
ters.) Depressed patients experience symptoms of grief, function of a crucial part of the brain’s limbic behavioral con-
unhappiness, despair, and misery. In addition, they often trol system centered around the hippocampus.

760
 Chapter 60 States of Brain Activity—Sleep, Brain Waves, Epilepsy, Psychoses, and Dementia

The reason for believing that the prefrontal lobes are in- disease approximately doubles with every 5 years beyond
volved in schizophrenia is that a schizophrenic-­like pattern age 65, with about 30% of 85-­year-­olds having the disease.
of mental activity can be induced in monkeys by making Alzheimer's Disease Is Associated With Accumulation
multiple minute lesions in widespread areas of the prefron- of Brain Beta-­Amyloid Peptide. Pathologically, one finds
tal lobes. increased amounts of beta-­amyloid peptide in the brains of
Dopamine has been implicated in schizophrenia be- patients with Alzheimer's disease. The peptide accumulates

UNIT XI
cause schizophrenic-­like symptoms develop in many pa- in amyloid plaques, which range in diameter from 10 mi-
tients with Parkinson's disease when they are treated with crometers to several hundred micrometers and are found
the drug called l-­dopa. This drug releases dopamine in the in widespread areas of the brain, including in the cerebral
brain, which is advantageous for treating Parkinson's dis- cortex, hippocampus, basal ganglia, thalamus, and even
ease, but at the same time it depresses various portions of the cerebellum. Thus, Alzheimer's disease appears to be a
the prefrontal lobes and other related areas. metabolic degenerative disease.
It has been suggested that in persons with schizophre- A key role for excess accumulation of beta-­amyloid pep-
nia, excess dopamine is secreted by a group of dopamine-­ tide in the pathogenesis of Alzheimer's disease is suggested by
secreting neurons whose cell bodies lie in the ventral teg- the following observations: (1) all currently known mutations
mentum of the mesencephalon, medial and superior to the associated with Alzheimer's disease increase the production
substantia nigra. These neurons give rise to the so-­called of beta-­amyloid peptide; (2) patients with trisomy 21 (Down
mesolimbic dopaminergic system that projects nerve fibers syndrome) have three copies of the gene for amyloid precur-
and dopamine secretion into the medial and anterior por- sor protein and develop neurological characteristics of Alz-
tions of the limbic system, especially into the hippocam- heimer's disease by midlife; (3) patients who have abnormality
pus, amygdala, anterior caudate nucleus, and portions of of a gene that controls apolipoprotein E, a blood protein that
the prefrontal lobes. All these areas are powerful behavioral transports cholesterol to the tissues, have accelerated deposi-
control centers. tion of amyloid and greatly increased risk for Alzheimer's dis-
An even more compelling reason for believing that ease; (4) transgenic mice that overproduce the human amyloid
schizophrenia might be caused by excess production of precursor protein have learning and memory deficits in as-
dopamine is that many drugs that are effective in treating sociation with the accumulation of amyloid plaques; and (5)
schizophrenia, such as chlorpromazine, haloperidol, and generation of anti-­amyloid antibodies in humans with Alzhei-
thiothixene, all either decrease secretion of dopamine at mer's disease appears to attenuate the disease process.
dopaminergic nerve endings or decrease the effect of do- Vascular Disorders May Contribute to Progression of
pamine on neurons. Alzheimer's Disease. There is also accumulating evidence
Finally, possible involvement of the hippocampus in that cerebrovascular disease caused by hypertension and
schizophrenia was discovered when it was learned that in atherosclerosis may play a key role in dementia associated
persons with schizophrenia, the hippocampus is often re- with Alzheimer's disease. Cerebrovascular disease is the
duced in size, especially in the dominant hemisphere. second most common cause of acquired cognitive impair-
ment and dementia and likely contributes to cognitive de-
Alzheimer's Disease—Amyloid Plaques and
cline in persons with Alzheimer's disease. In fact, many of
Depressed Memory
the common risk factors for cerebrovascular disease, such
Alzheimer's disease is defined as premature aging of the as hypertension, diabetes, and hyperlipidemia, are also rec-
brain, usually beginning in mid adult life and progressing ognized to greatly increase the risk for developing dementia
rapidly to extreme loss of mental powers—similar to that and progression of Alzheimer's disease. About 10% to 20%
seen in very old age. The clinical features of Alzheimer's of brains from individuals with dementia show evidence of
disease include (1) an amnesic type of memory impair- vascular dementia alone. In older individuals with Alzhei-
ment, (2) deterioration of language, and (3) visuospatial mer’s disease, vascular disease is common with about 50% of
deficits. Motor and sensory abnormalities, gait distur- patients having pathologic evidence of “silent strokes”—small
bances, and seizures are uncommon until the late phases of brain infarcts that cause no readily apparent symptoms but
the disease. One consistent finding in Alzheimer's disease could contribute to cognitive impairment.
is loss of neurons in the part of the limbic pathway that
drives the memory process. Loss of this memory function
is devastating. Bibliography
Alzheimer's disease is a progressive and fatal neuro-
degenerative disorder that results in impairment of the Anafi RC, Kayser MS, Raizen DM: Exploring phylogeny to find the
function of sleep. Nat Rev Neurosci 20:109, 2019.
person’s ability to perform activities of daily living, as well
Arrigoni E, Chee MJS, Fuller PM: To eat or to sleep: That is a lateral
as a variety of neuropsychiatric symptoms and behavioral
hypothalamic question. Neuropharmacology 154:34, 2019.
disturbances in the later stages of the disease. Patients with Besedovsky L, Lange T, Haack M: The sleep-­ immune crosstalk in
Alzheimer's disease usually require continuous care within health and disease. Physiol Rev 99:1325, 2019.
a few years after the disease begins. Butterfield DA, Halliwell B: Oxidative stress, dysfunctional glucose me-
Alzheimer's disease is a common form of dementia tabolism and Alzheimer disease. Nat Rev Neurosci 20:148, 2019.
in elderly persons; more than 5.5 million people in the Buysse DJ: Insomnia. JAMA 309:706, 2013.
United States are estimated to be afflicted by this disorder. Geis C, Planagumà J, Carreño M, et al: Autoimmune seizures and
About two-­thirds of Americans with Alzheimer’s disease epilepsy. J Clin Invest 129:926, 2019.
are women. The percentage of persons with Alzheimer's Henstridge CM, Hyman BT, Spires-­ Jones TL: Beyond the neuron-­
cellular interactions early in Alzheimer disease pathogenesis. Nat
Rev Neurosci 20:94, 2019.

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