266 SECTION II Central & Peripheral Neurophysiology

14
Electrical Activity of the C H A P T E R
THALAMOCORTICAL PATHWAYS relay somatosensory information to the postcentral gyrus. The
ventral anterior and ventral lateral nuclei receive input from
& ASCENDING AROUSAL SYSTEM
Brain, Sleep–Wake States, THALAMIC NUCLEI
the basal ganglia and the cerebellum and project to the motor
cortex. The anterior nuclei receive input from the mammil-
lary bodies and project to the limbic cortex to influence mem-

& Circadian Rhythms
OB J E C T I VES
After studying this chapter,
you should be able to:
■■ Explain the function of the thalamocortical pathway and ascending arousal
system in the control of arousal and consciousness.
■■ Explain the interplay between brainstem neurons that contain norepinephrine,
serotonin, and acetylcholine and diencephalic histaminergic and GABAergic
neurons in mediating transitions between sleep and wakefulness.
The thalamus within the diencephalon is comprised of groups
of nuclei that participate in sensory, motor, and limbic func-
ory and emotion. Most thalamic neurons are excitatory and
release glutamate. The thalamus also contains inhibitory neu-
rons in the thalamic reticular nucleus. These neurons release
tions. The thalamus is the “gateway to the cerebral cortex”
GABA, and unlike many thalamic neurons, their axons do
because it processes virtually all information that reaches the
not project to the cortex. Rather, they are thalamic interneu-
cortex. The thalamus also receives input from the cortex.
rons and modulate the responses of other thalamic neurons to
The thalamus has two major groups of nuclei: those that
input coming from the cortex.
project diffusely to wide areas of the neocortex (midline
and intralaminar nuclei) and those that project to discrete
regions of the neocortex and limbic system (specific sensory
relay nuclei). The latter group includes the medial and lateral CORTICAL ORGANIZATION
geniculate bodies that relay auditory and visual impulses to The neocortex is arranged in six layers (Figure 14–1). Affer-
the auditory and visual cortices, respectively, and the ventral ents from the specific nuclei of the thalamus terminate pri-
posterior lateral (VPL) and ventral posteromedial nuclei that marily in layer IV; the nonspecific nuclei project to layers I–IV.

■■ Explain the physiological basis and the main clinical uses of the
electroencephalogram (EEG). Pial surface Golgi stain Nissl stain Weigert stain

■■ Describe possible causes of seizure activity and explain the differences

Molecular
I
between generalized and partial seizures. layer

■■ Identify the primary types of cortical rhythms recorded in an EEG that reflect External
different states of wakefulness and sleep. II granule

■■
cell layer
Summarize the behavioral and EEG characteristics of rapid eye movement
(REM) sleep and the four stages of non-REM sleep.
■■ Describe the pattern of normal nighttime sleep in adults and the variations in External
III pyramidal
this pattern from birth to old age.
■■
cell layer
Describe the symptoms of narcolepsy, sleep apnea, and other sleep disorders.
■■ Describe the roles of the suprachiasmatic nuclei (SCN) and melatonin in
regulation of the circadian rhythm. Internal
IV granule
cell layer

INTRODUCTION
Most of the sensory systems introduced in Chapters 8–12
relay impulses from receptors via multiunit pathways
to specific sites in the cerebral cortex. The impulses are
responsible for perception and localization of individual
sensations; however, they must be processed in the awake
brain to be perceived. There is a spectrum of behavioral states
ranging from deep sleep through alertness with focused
attention. Each distinct state is correlated with a discrete
Internal
V pyramidal
cell layer
pattern of brain electrical activity. Feedback oscillations
within the cerebral cortex and between the thalamus and
the cortex produce this activity and are determinants of
the behavioral state. Arousal can be produced by sensory
stimulation and by impulses ascending from the brainstem to VI
Multiform
layer
the thalamus and then to the cortex. Some of these activities
have rhythmic fluctuations that are approximately 24 h in
length (circadian rhythm).

White matter

FIGURE 14–1 Structure of the cerebral cortex. The cortical layers are indicated by the numbers. Golgi stain shows neuronal cell bodies
and dendrites, Nissl stain shows cell bodies, and Weigert myelin sheath stain shows myelinated nerve fibers. (Modified with permission from Ranson SW,
Clark SL: The Anatomy of the Nervous System, 10th ed. St. Louis, MO: Saunders; 1959.)

265

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 CHAPTER 14 Electrical Activity of the Brain, Sleep–Wake States, & Circadian Rhythms
B trode. If the electrode is over the primary receiving area for a
C of 5–12 ms. This is followed by a small negative wave, and then
A a larger, more prolonged positive deflection frequently occurs
D
B tion and occurs only where the pathways from a particular
Axon
FIGURE 14–2 Neocortical pyramidal cell, showing the
distribution of neurons that terminate on it. A denotes nonspecific
afferents from the brainstem and the thalamus; B denotes recurrent
collaterals of pyramidal cell axons; C denotes commissural fibers from
mirror image sites in the contralateral hemisphere; D denotes specific
afferents from thalamic sensory relay nuclei. (Based on Scheibel ME,
Scheibel AB: Structural organization of nonspecific thalamic nuclei and their
projection toward cortex. Brain Res 1967 Sep; 6(1):60–94.)
Pyramidal neurons, the most common cell type in the cortex,
have extensive vertical dendritic trees that reach toward the
cortical surface (Figure 14–2). Their cell bodies are found in
all cortical layers except layer I. The axons of pyramidal cells
have recurrent collaterals that turn back and synapse on the
superficial portions of the dendritic trees. Pyramidal neurons
are excitatory neurons that release glutamate at their termi-
nals, and they are the only projection neurons of the cortex.
The other cortical cell types are local circuit interneurons
and are classified based on their shape, pattern of projection,
and neurotransmitter. Inhibitory interneurons (basket cells and
chandelier cells) release GABA as their neurotransmitter. Bas-
ket cells have long axonal endings that surround the soma of
pyramidal neurons; they account for most inhibitory synapses
on the pyramidal soma and dendrites. Chandelier cells are a
powerful source of inhibition of pyramidal neurons because
their axonal endings terminate exclusively on the initial seg-
ment of the pyramidal cell axon. Their terminal boutons form
short vertical rows that resemble candlesticks, thus accounting
for their name. Spiny stellate cells are excitatory neurons that
release glutamate; these multipolar interneurons are located
primarily in layer IV and are a major recipient of sensory
information arising from the thalamus.
In addition to being organized into layers, the cerebral
cortex is also organized into columns. Neurons within a col-
umn have similar response properties, suggesting they com-
prise a local processing network (eg, orientation and ocular
dominance columns in the visual cortex).
Barrett_Ch14_p265-p276.indd 267
267
Evoked Cortical Potentials
The electrical events that occur in the cortex after stimulation
of a sensory receptor can be monitored with a recording elec-
particular sense, a surface-positive wave appears with a latency
with a latency of 20–80 ms. The first positive-negative wave
sequence is the primary evoked potential; the second is the
diffuse secondary response.
The primary evoked potential is highly specific in its loca-
sensory system project The positive-negative wave sequence
recorded from the surface of the cortex occurs because the
superficial cortical layers are positive relative to the initial
negativity, then negative relative to the deep hyperpolariza-
tion. The surface-positive diffuse secondary response, unlike
the primary response, is not highly localized. It appears at
the same time over most of the cortex and is due to activ-
ity in projections from the midline and intralaminar thalamic
nuclei.
ASCENDING AROUSAL SYSTEM
The ascending arousal system is a complex polysynaptic
pathway comprised of monoaminergic, cholinergic, and his-
taminergic neurons that project to the intralaminar and retic-
ular nuclei of the thalamus which, in turn, project diffusely
to wide regions of the cortex including the frontal, parietal,
temporal, and occipital cortices (Figure 14–3). Collaterals
funnel into it not only from the long ascending sensory tracts
but also from the trigeminal, auditory, visual, and olfactory
systems. The complexity of the ascending arousal system and
the degree of convergence in it abolish modality specificity,
and most neurons are activated with equal facility by different
sensory stimuli. Components of the arousal system include
norepinephrine-containing neurons in the pontine locus coe-
ruleus, serotoninergic neurons in the brainstem raphé nuclei,
cholinergic neurons in the pontine and midbrain pedunculo-
pontine and laterodorsal tegmental nuclei, and histaminergic
neurons in the hypothalamic tuberomammilary nucleus.
NEUROCHEMICAL MECHANISMS
PROMOTING SLEEP & AROUSAL
Transitions between sleep and wakefulness manifest a circa-
dian rhythm consisting of an average of 6–8 h of sleep and
16–18 h of wakefulness. Nuclei in both the brainstem and
hypothalamus are critical for the transitions between these
states of consciousness. As described above, the brainstem
ascending arousal system is comprised of several groups of
neurons that release norepinephrine, serotonin, acetylcho-
line, or histamine. The locations and wide projections of these
10/3/18 6:08 PM
268 SECTION II Central & Peripheral Neurophysiology
Frontal
cortex
Medial septal nucleus
Hypothalamus
Nucleus basalis
Temoral cortex
Reticular formation
FIGURE 14–3 Cross section through the midline of the human brain showing the ascending arousal system in the brainstem with
projections to the intralaminar nuclei of the thalamus and the output from the intralaminar nuclei to many parts of the cerebral cortex.
Activation of these areas can be shown by positive emission tomography scans when subjects shift from a relaxed awake state to an attention-
demanding task.
neuronal populations are shown in Figure 7–2. The fore-
brain is also involved in the control of the sleep–wake cycles
via hypothalamic preoptic neurons that release GABA and
tuberomamilary neurons that release histamine. Also, hypo-
thalamic neurons release orexin to play a role in switching
between sleep and wakefulness.
One theory regarding the basis for transitions from sleep
to wakefulness involves alternating reciprocal activity of differ-
ent groups of neurons in the ascending arousal system. In this
model (Figure 14–4), wakefulness and rapid eye movement
(REM) sleep are at opposite extremes. When the activity of
norepinephrine- and serotonin-containing neurons (locus coe-
ruleus and raphé nuclei) is dominant, activity in acetylcholine-
containing pontine neurons is reduced. This pattern of activity
contributes to the appearance of the awake state. The reverse
of this pattern leads to REM sleep. When there is a more even
balance between the activity of the aminergic and cholinergic
neurons, non-REM sleep occurs. The orexin released from
hypothalamic neurons may regulate the changes in activity in
these brainstem neurons. An increased release of GABA and
reduced release of histamine increase the likelihood of non-
REM sleep via deactivation of the thalamus and cortex. Wake-
fulness occurs when GABA release is reduced and histamine
release is increased.
Barrett_Ch14_p265-p276.indd 268
Thalamus
Patietal
cortex
Occipital
cortex
Brain-
stem
THE ELECTROENCEPHALOGRAM
The term electroencephalogram (EEG) refers to a recording
that represents the electrical activity of the brain. The EEG
can be recorded with scalp electrodes through the unopened
skull. The term electrocorticogram is used for the recording
obtained with electrodes on the pial surface of the cortex.
The EEG recorded from the scalp is a measure of the sum-
mation of dendritic postsynaptic potentials rather than action
potentials (Figure 14–5). The dendrites of the cortical neurons
are a forest of similarly oriented, densely packed units in the
superficial layers of the cerebral cortex (Figure 14–1). Propa-
gated potentials can be generated in dendrites. In addition,
recurrent axon collaterals end on dendrites in the superficial
layers. As excitatory and inhibitory endings on the dendrites
of each cell become active, current flows into and out of these
current sinks and sources from the rest of the dendritic pro-
cesses and the cell body. The cell body–dendrite relationship is
that of a constantly shifting dipole. Current flow in the dipole
produces wavelike potential fluctuations in a volume conduc-
tor (Figure 14–5). When the sum of the dendritic activity is
negative relative to the cell body, the neuron is depolarized
and hyperexcitable; when it is positive, the neuron is hyperpo-
larized and less excitable.
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 CHAPTER 14 Electrical Activity of the Brain, Sleep–Wake States, & Circadian Rhythms 269 270 SECTION II Central & Peripheral Neurophysiology

Brainstem nuclei that

mal seizures) are a form of nonconvulsive generalized seizures
are part of the reticular characterized by a momentary loss of consciousness. They
activating system
100 µV are associated with 3/s doublets, each consisting of a typical
Wave activity
spike-and-wave pattern of activity that lasts for about 10 s
(Figure 14–6). They are not accompanied by auras or postic-
Norepinephrine Norepinephrine tal periods. These spike and waves are likely generated by low
and and
serotonin
threshold T-type Ca2+ channels in thalamic neurons.
serotonin 1s
Tonic-clonic seizures (formerly called grand mal sei-
Dendritic tree
zure) are the most common convulsive generalized seizure. It FIGURE 14–6 Absence seizures. This is a recording of four
Acetylcholine Acetylcholine is associated with sudden onset of contraction of limb muscles cortical EEG leads from a 6-year-old boy who, during the recording,
(tonic phase) lasting about 30 s, followed by a clonic phase had one of his “blank spells” in which he was transiently unaware
with symmetric jerking of the limbs as a result of alternating of his surroundings and blinked his eyelids. Absence seizures are
associated with 3/s doublets, each consisting of a typical spike-and-
contraction and relaxation (clonic phase) lasting 1–2 min. wave pattern of activity that lasts for about 10 s. Time is indicated
Waking NREM sleep REM sleep
There is fast EEG activity during the tonic phase. Slow waves, by the horizontal calibration line. EEG, electroencephalogram.
each preceded by a spike, occur at the time of each clonic jerk; (Reproduced with permission from Waxman SG: Neuroanatomy with Clinical
200 mV
slow waves persist for a while after the attack. Correlations, 25th ed. New York, NY: McGraw-Hill; 2003.)
Axon
Activation Activation
Action potentials
The release of glutamate from astrocytes may play a role in
of the thalamus of the thalamus in the pathophysiology of epilepsy. Also, there is evidence that excitation in the epileptic brain. Clinical Box 14–1 describes
and cortex and cortex
FIGURE 14–5 Diagrammatic comparison of the electrical reorganization of astrocytes along with dendritic sprouting information on the role of genetic mutations in some forms of
responses of the axon and the dendrites of a large cortical and new synapse formation is the structural basis for recurrent epilepsy.
neuron. Current flow to and from active synaptic knobs on
Histamine Histamine the dendrites produces wave activity, while all-or-none action
potentials are transmitted along the axon. When the sum of the
dendritic activity is negative relative to the cell body, the neuron is
GABA GABA depolarized; when it is positive, the neuron is hyperpolarized. The
electroencephalogram recorded from the scalp is a measure of the CLINICAL BOX 14–1
summation of dendritic postsynaptic potentials rather than action
potentials.
Hypothalamus with Genetic Mutations & Epilepsy in origin. Mutations in voltage-gated potassium, sodium, and
circadian and Epilepsy has no geographic, racial, sex, or social bias. It can chloride channels have been linked to some forms of idiopathic
homeostatic centers
occur at any age, but is most often diagnosed in infancy, child-
TYPES OF SEIZURES hood, adolescence, and old age. It is the second most common
epilepsy. Mutated ion channels can lead to neuronal hyperex-
citability via various pathogenic mechanisms. Scientists have
FIGURE 14–4 A model of how alternating activity of Epilepsy is a condition in which there are recurring, unpro- neurologic disorder after stroke. According to the World Health
brainstem and hypothalamic neurons may influence the different recently identified the mutated gene responsible for develop-
states of consciousness. In this model, wakefulness and REM sleep voked seizures that may result from damage to the brain. The Organization, an estimated 50 million people worldwide (8.2 ment of childhood absence epilepsy (CAE); several patients
are at opposite extremes. When the activity of norepinephrine- and seizures represent abnormal, highly synchronous neuronal per 1000 individuals) experience epileptic seizures. The prev- with CAE have mutations in a subunit gene of the GABA
serotonin-containing neurons (locus coeruleus and raphe nuclei) activity. Epilepsy is a syndrome with multiple causes. In some alence in developing countries (such as Colombia, Ecuador, receptor called GABRB3. Also, SCN1A and SCN1B mutations
is dominant, there is a reduced level of activity in acetylcholine- forms, characteristic EEG patterns occur during seizures or India, Liberia, Nigeria, Panama, United Republic of Tanzania, have been identified in an inherited form of epilepsy called
containing pontine neurons leading to wakefulness. The reverse of
this pattern leads to REM sleep. A more even balance in the activity
between attacks; however, abnormalities are often difficult to and Venezuela) is more than 10 per 1000. Many affected indi- generalized epilepsy with febrile seizures. SCN1A and
of these groups of neurons is associated with non-REM (NREM) sleep. demonstrate. Seizures are divided into partial (focal) seizures viduals experience unprovoked seizures, for no apparent rea- SCN1B are sodium channel subunit genes that are widely
Increases in GABA and decreases in histamine promote non-REM and generalized seizures. son, and without any other neurologic abnormalities. These are expressed within the central nervous system. SCN1A mutations
sleep via deactivation of the thalamus and cortex. Wakefulness occurs Partial seizures originate in a small group of neurons and called idiopathic epilepsies and are assumed to be genetic are suspected in several other forms of epilepsy.
when GABA is reduced and histamine is released. (Used with permission can result from head injury, brain infection, stroke, or tumor;
from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. New York,
but often the cause is unknown. Symptoms depend on the sei-
NY: McGraw-Hill; 2008.) THERAPEUTIC HIGHLIGHTS
zure focus. They are further subdivided into simple partial
seizures (without loss of consciousness) and complex partial Only about two-thirds of those who experience seizure (decreased glutamate release), or altering ionic conduc-
seizures (with altered consciousness). An example of a simple activity respond to drug therapies. Some respond to surgi- tance. Gabapentin is a GABA analog that acts by decreas-
CLINICAL USES OF THE EEG partial seizure is localized jerking movements in one hand cal interventions (eg, those with temporal lobe seizures), ing Ca2+ entry into cells and reducing glutamate release;
The EEG can be of value in localizing neuropathological pro- progressing to clonic movements of the entire arm lasting and others respond to vagal nerve stimulation (eg, those it is used to treat generalized seizures. Topiramate blocks
cesses. When fluid collection overlies a portion of the cortex, about 60–90 s. Auras typically precede the onset of a partial with partial seizures). Prior to the 1990s, the most com- voltage-gated Na+ channels associated with glutamate
activity over this area may be damped. This fact may aid in seizure and include abnormal sensations. The time after the mon drugs used to treat seizures (anticonvulsants) receptors and potentiates the inhibitory effect of GABA; it
diagnosing and localizing conditions such as subdural hema- seizure until normal neurologic function returns is called the included phenytoin, valproate, and barbiturates. Newer is also used to treat generalized seizures. Ethosuximide
tomas. Lesions in the cerebral cortex cause local formation postictal period. drugs have become available but, as is the case with the reduces the low threshold T-type Ca2+ currents in thalamic
of transient disturbances in brain activity, marked by high- Generalized seizures are associated with widespread older drugs, they are palliative rather than curative. There neurons and is particularly effective in treatment of absence
voltage abnormal waves that can be recorded with an EEG. electrical activity and involve both hemispheres simultane- are three broad mechanisms of action of anticonvulsant seizures. Valproate and phenytoin block high-frequency
Seizure activity can occur because of increased firing of excit- ously. They are further subdivided into convulsive and non- drugs: enhancing inhibitory neurotransmission (increased firing of neurons by acting on voltage-gated Na+ channels
atory neurons (eg, release of glutamate) or decreased firing of convulsive categories depending on whether tonic or clonic GABA release), reducing excitatory neurotransmission to reduce glutamate release.
inhibitory neurons (eg, release GABA). movements occur. Absence seizures (formerly called petit

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 CHAPTER 14 Electrical Activity of the Brain, Sleep–Wake States, & Circadian Rhythms 271 272 SECTION II Central & Peripheral Neurophysiology

SLEEP–WAKE CYCLE: VARIATIONS CLINICAL BOX 14–2

Awake Sleep stage 1 2 3 4 REM

IN EEG RHYTHMS
ALPHA AND BETA RHYTHMS
In adult humans who are awake but at rest with the mind wan-
dering and the eyes closed, the most prominent component of
the EEG is a fairly regular pattern of waves at a frequency of
8–13 Hz and amplitude of 50–100 µV when recorded from
the scalp. This pattern is the alpha rhythm (Figure 14–7).
It is most marked in the parietal and occipital lobes and is
associated with decreased levels of attention. The frequency
and magnitude of the EEG rhythm can vary with age, with
the use of some drugs, and in some pathological conditions
(Clinical Box 14–2).
When attention is focused on something, the alpha
rhythm is replaced by an irregular 13–30 Hz low-voltage activ-
ity, the beta rhythm (Figure 14–7). This phenomenon is called
alpha block and can be produced by any form of sensory stim-
EOG
Variations in the Alpha Rhythm
In humans, the frequency of the dominant EEG rhythm at
EMG
rest varies with age. In infants, there is fast, beta-like activ-
ity, but the occipital rhythm is a slow 0.5–2-Hz pattern.
During childhood this latter rhythm speeds up, and the EEG
adult alpha pattern gradually appears during adolescence. 50 µV
1s
The frequency of the alpha rhythm is decreased by low
blood glucose levels, low body temperature, low levels of FIGURE 14–8 EEG and muscle activity during various stages of the sleep–wake cycle. Non-REM sleep has four stages. Stage 1 is
adrenal glucocorticoid hormones, and high arterial partial characterized by a slight slowing of the EEG. Stage 2 has high-amplitude K complexes and spindles. Stages 3 and 4 have slow, high-amplitude
pressure of CO2 (PaCO2). It is increased by the reverse con- delta waves. REM sleep is characterized by eye movements, loss of muscle tone, and a low-amplitude, high-frequency activity pattern. The higher
ditions. Forced over-breathing to lower the PaCO2 is some- voltage activity in the EOG tracings during stages 2 and 3 reflect high amplitude EEG activity in the prefrontal areas rather than eye movements.
EOG, electrooculogram registering eye movements; EMG, electromyogram registering skeletal muscle activity. (Reproduced with permission from
times used clinically to bring out latent EEG abnormalities.
Rechtschaffen A, Kales A: A Manual of Standardized Terminology, Techniques and Scoring System and Sleep Stages of Human Subjects. Los Angeles: University of California Brain
The frequency and magnitude of the alpha rhythm is also Information Service; 1968.)
decreased by metabolic and toxic encephalopathies includ-
Awake Children
ing those due to hyponatremia and vitamin B12 deficiency.
The frequency of the alpha rhythm is reduced during acute REM
anterior cingulate gyrus, but decreased activity in the prefron-

Sleep stages
ulation or mental concentration, such as solving arithmetic intoxication with alcohol, amphetamines, barbiturates, 1
phenytoin, and antipsychotics. Propofol, a hypnotic/ tal and parietal cortex. Activity in visual association areas is
problems. Another term for this phenomenon is the arousal 2
sedative drug, can induce a rhythm in the EEG that is analo- increased, but activity is decreased in the primary visual cor-
or alerting response because it is correlated with the aroused, 3
gous to the classic alpha rhythm. tex. This is consistent with increased emotion and operation of
alert state. It has also been called desynchronization because 4
a closed neural system cut off from the areas that relate brain
it represents breaking up of the obviously synchronized neu-
activity to the external world. 1 2 3 4 5 6 7
ral activity necessary to produce regular waves. However, the
rapid EEG activity seen in the alert state is also synchronized
but at a higher rate. Therefore, the term “desynchronization”
DISTRIBUTION OF SLEEP STAGES Awake Young Adults
Stage 2 of non-REM sleep is marked by the appearance of
is misleading.
sinusoidal waves called sleep spindles (7–15 Hz) and occa- REM
In a typical night of sleep, a young adult first enters non-REM
sional high voltage biphasic waves called K complexes. Muscle

SLEEP STAGES: NON-REM &
REM SLEEP
Non-REM sleep is divided into four stages (Figure 14–8).
Stage 1 non-REM sleep is the transition from wakefulness to
sleep, the EEG shows a low-voltage, mixed frequency pattern.
A theta rhythm (4–7 Hz) can be seen at this stage of sleep.
Sleep stages
1
sleep, passes through stages 1 and 2, and spends 70–100 min in
tone is reduced during this time. Stage 3 of non-REM sleep
is characterized by the appearance of a high-amplitude delta
stages 3 and 4. Sleep then lightens, and a REM period follows. 2
3
This cycle is repeated at intervals of about 90 min throughout
rhythm (0.5–4 Hz) in the EEG, reflecting a further reduction
the night (Figure 14–9). The cycles are similar, though there 4
is arousal, and a further reduction in muscle tone. Maximum
is less stage 3 and 4 sleep and more REM sleep toward morn-
slowing with large waves is seen in stage 4 of non-REM sleep. 1 2 3 4 5 6 7
ing; thus, four to six REM periods occur per night. REM sleep
Thus, the characteristic of deep sleep is a pattern of rhythmic
occupies 80% of total sleep time in premature infants and 50%
slow waves, indicative of marked synchronization of cortical
in full-term neonates. Thereafter, the proportion of REM sleep Awake Elderly
and thalamic activity; it is sometimes referred to as slow-wave
falls rapidly and plateaus at about 25% until it falls to about 20%
sleep. While the occurrence of theta and delta rhythms is nor- REM
in the elderly. Children have more total sleep time (8–10 h)
mal during sleep, their appearance during wakefulness is a

(A) Alpha rhythm (relaxed with eyes closed)
(B) Beta rhythm (alert)
Time
FIGURE 14–7 EEG records showing the alpha and beta
rhythms. When attention is focused on something, the 8–13 Hz alpha
rhythm is replaced by an irregular 13–30 Hz low-voltage activity, the
beta rhythm. This phenomenon is referred to as alpha block, arousal,
or the alerting response. (Used with permission from Widmaier EP, Raff H,
Strang KT: Vander’s Human Physiology, 11th ed. New York, NY: McGraw-Hill; 2008.)
sign of brain dysfunction.
The high-amplitude slow waves seen in the EEG during
non-REM sleep are periodically replaced by rapid, low-voltage
EEG activity in REM sleep (Figure 14–8). REM sleep gets its
name from the characteristic rapid, roving eye movements
that occur during this stage of sleep and are recorded as an
electrooculogram (EOG). Except for eye movement, there is
almost a complete loss of skeletal muscle tone in REM sleep.
The threshold for arousal from sleep by sensory stimuli is ele-
vated during this time. Another characteristic of REM sleep is
the occurrence of large phasic potentials that originate in the
cholinergic neurons in the pons and pass rapidly to the lateral
geniculate body and from there to the occipital cortex. They
are called pontogeniculo-occipital (PGO) spikes.
Positron emission tomography (PET) scans in REM sleep
show increased activity in the pontine area, amygdala, and
Sleep stages
1
compared to most adults (about 6 h).
2
Dreaming occurs in both REM and non-REM sleep stages,
3
but their characteristics differ. Dreams that occur during REM
sleep tend to be longer and more visual and emotional than 4
those that occur during non-REM sleep.
1 2 3 4 5 6 7
Hours of sleep
IMPORTANCE OF SLEEP FIGURE 14–9 Normal sleep cycles at various ages. REM sleep
is indicated by the darker colored areas. In a typical night of sleep, a
Various studies imply that sleep is needed to maintain young adult first enters non-REM sleep, passes through stages 1 and
metabolic-caloric balance, thermal equilibrium, and immune 2, and spends 70–100 min in stages 3 and 4. Sleep then lightens, and
competence. Clinical Box 14–3 describes several common a REM period follows. This cycle is repeated at intervals of about
sleep disorders. If humans are awakened every time they show 90 min throughout the night. The cycles are similar, though there is
REM sleep and then permitted to sleep without interruption, less stage 3 and 4 sleep and more REM sleep toward morning. REM
sleep occupies 50% of total sleep time in neonates; this proportion
they show a great deal more than the normal amount of REM declines rapidly and plateaus at ∼25% until it falls further in the
sleep for a few nights. Relatively prolonged REM deprivation elderly. (Reproduced with permission from Kales AM, Kales JD: Sleep disorders.
does not seem to have adverse psychological effects. N Engl J Med 1974; Feb 28; 290(9):487–499.)

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 CHAPTER 14 Electrical Activity of the Brain, Sleep–Wake States, & Circadian Rhythms
CLINICAL BOX 14–3
Sleep Disorders
Narcolepsy is a chronic neurologic disorder caused by the
brain’s inability to regulate sleep–wake cycles normally. The
affected individual experiences a sudden loss of voluntary
muscle tone (cataplexy), an eventual irresistible urge to sleep
during daytime, and possibly brief episodes of total paralysis
at the beginning or end of sleep. Narcolepsy is also charac-
terized by a sudden onset of REM sleep, unlike normal sleep
that begins with non-REM, slow-wave sleep. The prevalence
of narcolepsy ranges from 1 in 600 in Japan to 1 in 500,000 in
Israel, with 1 in 1000 Americans being affected. Narcolepsy has
a familial incidence strongly associated with a class II antigen
of the major histocompatibility complex on chromosome 6 at
the HLA-DR2 or HLA-DQW1 locus, implying a genetic suscepti-
bility to narcolepsy. The HLA complexes are interrelated genes
that regulate the immune system (see Chapter 3). Compared
to brains from healthy persons, the brains of persons with nar-
colepsy often contain fewer hypocretin (orexin)-producing
neurons in the hypothalamus. The HLA complex may increase
susceptibility to an immune attack on these neurons, leading
to their degeneration.
Obstructive sleep apnea (OSA) is the most common
cause of daytime sleepiness due to fragmented sleep at night;
it affects about 24% of middle-aged men and 9% of women in
the United States. Breathing ceases for more than 10 s during
frequent episodes of obstruction of the upper airway (espe-
cially the pharynx) due to a reduction in muscle tone. The apnea
causes brief arousals from sleep in order to reestablish upper air-
way tone. An individual with OSA typically begins to snore soon
after falling asleep. The snoring gets progressively louder until
it is interrupted by an episode of apnea, which is followed by a
loud snort and gasp as the individual tries to breathe. OSA is not
associated with a reduction in total sleep time, but individuals
with OSA experience a much greater time in stage 1 non-REM
sleep (from an average of 10% of total sleep to 30–50%) and a
marked reduction in slow-wave sleep (stages 3 and 4 non-REM
sleep). The pathophysiology of OSA includes both a reduction
in neuromuscular tone at the onset of sleep and a change in the
central respiratory drive.
Periodic limb movement disorder (PLMD) is a stereo-
typical rhythmic extension of the big toe and dorsiflexion
CIRCADIAN RHYTHMS
ROLE OF SUPRACHIASMATIC
NUCLEI
Most, if not all, living cells in plants and animals have rhyth-
mic fluctuations in their function on a circadian cycle. Nor-
mally they become entrained or synchronized to the day–night
Barrett_Ch14_p265-p276.indd 273
273
of the ankle and knee during sleep lasting for about 0.5–10 s
and recurring at intervals of 20–90 s. Movements can actually
range from shallow, continual movement of the ankle or toes,
to wild and strenuous kicking and flailing of the legs and arms.
Electromyograph (EMG) recordings show bursts of activity dur-
ing the first hours of non-REM sleep associated with brief EEG
signs of arousal. The duration of stage 1 non-REM sleep may be
increased and that of stages 3 and 4 may be decreased com-
pared to age-matched controls. PLMD is reported to occur in 5%
of individuals between the ages of 30 and 50 and increases to
44% of those over the age of 65. PLMD is similar to restless leg
syndrome or Willis–Ekbom disease in which individuals have
an irresistible urge to move their legs while at rest all day long.
Sleepwalking (somnambulism), bed-wetting (nocturnal
enuresis), and night terrors are referred to as parasomnias,
which are sleep disorders associated with arousal from non-
REM and REM sleep. Episodes of sleepwalking are more com-
mon in children than in adults and occur predominantly in
males. They may last several minutes. Somnambulists walk with
their eyes open and avoid obstacles, but when awakened they
cannot recall the episodes.
THERAPEUTIC HIGHLIGHTS
Excessive daytime sleepiness in patients with narco-
lepsy can be treated with amphetamine-like stimulants,
including modafinil, methylphenidate (Ritalin), and
methamphetamine. Gamma hydroxybutyrate (GHB)
is used to reduce the frequency of cataplexy attacks and
the incidences of daytime sleepiness. Cataplexy is often
treated with antidepressants such as imipramine and
desipramine, but these drugs are not officially approved
by the US Federal Drug Administration for such use. The
most common treatment for OSA is continuous posi-
tive airflow pressure (CPAP), a machine that increases
airway pressure to prevent airway collapse. Drugs have
generally proven to have little or no benefit in treating
OSA. Dopamine agonists, which are used to treat Par-
kinson disease, can be used to treat PLMD and restless
leg syndrome.
light cycle in the environment. If they are not entrained, they
become progressively more out of phase with the light–dark
cycle because they are longer or shorter than 24 h. In most
cases, the suprachiasmatic nuclei (SCN) play a major role
in the entrainment process (Figure 14–10). The SCN receive
information about the light–dark cycle via a special neural
pathway, the retinohypothalamic fibers. Efferent fibers from
the SCN initiate neural and humoral signals that entrain a
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274 SECTION II Central & Peripheral Neurophysiology
RHT
Light SCN PVN IML
Melatonin
Pineal SCG
FIGURE 14–10 Secretion of melatonin. The cyclic activity of the suprachiasmatic nucleus (SCN) sets up a circadian rhythm for melatonin
release. This rhythm is entrained to light/dark cycles by neurons in the retina. Light signals are relayed via the retinohypothalamic (RHT) fibers
to the SCN. GABAergic neurons in the SCN inhibit neurons in the hypothalamic paraventricular nucleus (PVN) which then reduces the activity
of sympathetic preganglionic neurons in the spinal intermediolateral nucleus (IML). These sympathetic preganglionic neurons innervate
postganglionic neurons in the superior cervical ganglion (SCG) that regulate release of melatonin from the pineal gland.
wide variety of well-known circadian rhythms including the
sleep–wake cycle and melatonin release from the richly vas-
MELATONIN & CIRCADIAN
cularized pineal gland. RHYTHMS
GABAergic neurons in the SCN inhibit neurons in the Pineal pinealocytes contain melatonin and the enzymes
hypothalamic paraventricular nucleus. From the hypothala- responsible for its synthesis from serotonin by N-acetylation
mus, descending pathways converge onto preganglionic sym- and O-methylation, and they secrete the hormone into the
pathetic neurons that innervate the superior cervical ganglion, blood and the cerebrospinal fluid (Figure 14–11). Two mela-
the site of origin of the postganglionic neurons to the pineal tonin G-protein-coupled receptors (MT1 and MT2) are found
gland. on neurons in the SCN. Activation of MT1 receptors inhibits
The SCN have two peaks of circadian activity that may adenylyl cyclase and results in sleepiness. Activation of MT2
correlate with the observation that exposure to bright light can receptors stimulates phosphoinositide hydrolysis and may
either advance, delay, or have no effect on the sleep–wake cycle function to synchronize the light–dark cycle.
depending on the time of day when it is experienced. During The diurnal change in melatonin secretion may function
the usual daytime it has no effect, just after dark it delays the as a timing signal to coordinate events with the light–dark cycle
onset of the sleep period, and just before dawn it accelerates in the environment. Melatonin synthesis and secretion are
the onset of the next sleep period. Injections of melatonin have increased during the dark period of the day and maintained at
similar effects. Clinical Box 14–4 describes circadian rhythm a low level during daylight hours (Figure 14–11). This diurnal
disorders that impact the sleep–wake state. variation in secretion is due to norepinephrine released from
CLINICAL BOX 14–4
Insomnia & Circadian Rhythm Disturbances of syndrome consistently fall asleep in early evening and awaken
the Sleep–Wake State in early morning. This is seen most often in the elderly and the
Insomnia is defined as difficulty in initiating and/or maintain- depressed.
ing sleep several times a week. Nearly 30% of the adult popula-
tion experience episodes of insomnia, and more than 50% of
those aged 65 or older have sleep problems. Individuals with
THERAPEUTIC HIGHLIGHTS
persistent episodes of insomnia are more likely to experience Light therapy is an effective treatment in individuals
accidents, a diminished work experience, and a poorer overall who experience disturbances in their circadian cycle.
quality of life. Insomnia is often comorbid with depression, and Melatonin can be used to treat jet lag and insomnia in
both disorders show abnormal regulation of corticotropin- elderly individuals. Ramelteon is a MT1 and MT2 mela-
releasing factor. tonin receptor agonist that is more effective than mela-
There are two major types of sleep disorders associated tonin in treating insomnia. Zolpidem (Ambien) is an
with disruption of the circadian rhythm. These are transient example of a sedative-hypnotic that slows brain activ-
sleep disorders (jet lag, altered sleep cycle because of shift ity to promote sleep onset. In addition to treating day-
work, and illness) and chronic sleep disorders (delayed time sleepiness in narcolepsy, modafinil has also been
or advanced sleep phase syndrome). Those with delayed
sleep phase syndrome have the inability to fall asleep in the
used successfully in the treatment of daytime sleepiness
due to shift work and to treat delayed sleep disorder
evenings and awaken in the mornings. However, they have syndrome.
a normal total sleep time. Those with advanced sleep phase
Barrett_Ch14_p265-p276.indd 274 10/3/18 6:08 PM
 CHAPTER 14 Electrical Activity of the Brain, Sleep–Wake States, & Circadian Rhythms
Serotonin
N-Acetyl-
transferase
Pineal
paren- N-Acetylserotonin
chymal
cells Hydroxyindole-
O-methyltransferase
Melatonin
Blood Melatonin
0 12 24
Time (h)
FIGURE 14–11 Diurnal rhythms of compounds involved
in melatonin synthesis in the pineal. Melatonin and the enzymes
responsible for its synthesis from serotonin are found in pineal
pinealocytes; melatonin is secreted into the bloodstream. Melatonin
synthesis and secretion are increased during the dark period (shaded
area) and maintained at a low level during the light period.
postganglionic sympathetic nerves that innervate the pineal
gland (Figure 14–10). Norepinephrine acts via β-adrenoceptors
to increase intracellular cAMP, and the cAMP in turn produces
a marked increase in N-acetyltransferase activity. This results
in increased melatonin synthesis and secretion.
CHAPTER SUMMARY
■■ The thalamus is the gateway to the cortex and includes neurons
that project diffusely to wide areas of the neocortex (midline
and intralaminar nuclei) and neurons that project to discrete
regions of the neocortex (specific sensory relay nuclei).
■■ The ascending arousal system is comprised of monoaminergic,
cholinergic, and histaminergic neurons that project to the
intralaminar and reticular nuclei of the thalamus that project
diffusely to wide regions of the cortex including the frontal,
parietal, temporal, and occipital cortices.
■■ Wakefulness and REM sleep are at opposite extremes of
consciousness. When norepinephrine- and serotonin-
containing neurons (locus coeruleus and raphé nuclei) are
most active, pontine cholinergic neurons are less active and
wakefulness ensues. The reverse of this pattern leads to REM
sleep. A more even balance of the activity in these groups of
neurons is associated with non-REM sleep. Increases in GABA
and decreases in histamine also promote non-REM sleep via
deactivation of the thalamus and cortex.
■■ The EEG reflects the electrical activity (summation of dendritic
postsynaptic potentials) of the brain and can be of value in
localizing pathologic processes and in characterizing different
types of seizures.
■■ Partial (focal) seizures originate in a small group of neurons
and are subdivided into simple (without loss of consciousness)
and complex (with altered consciousness). Generalized seizures
are associated with widespread electrical activity
Barrett_Ch14_p265-p276.indd 275
275
and are subdivided into convulsive and non-convulsive
categories depending on whether tonic or clonic movements
occur.
■■ The major rhythms in the EEG are alpha (8–13 Hz) when
awake with eyes closed, beta (13–30 Hz) when alert; theta
(4–7 Hz) and delta (0.5–4 Hz) oscillations appear during deep
sleep.
■■ Throughout non-REM sleep, there is some activity of skeletal
muscle. A theta rhythm can be seen during stage 1 of sleep.
Stage 2 is marked by the appearance of sleep spindles and
occasional K complexes. In stage 3, a delta rhythm is dominant.
Maximum slowing with large slow waves is seen in stage 4.
REM sleep is characterized by low-voltage, high-frequency
EEG activity and rapid, roving movements of the eyes.
■■ A young adult typically passes through stages 1 and 2, and
spends 70–100 min in stages 3 and 4. Sleep then lightens, and
a REM period follows. This cycle repeats at 90-min intervals
throughout the night. REM sleep occupies 50% of total sleep
time in full-term neonates; this proportion declines rapidly
and plateaus at about 25% until it falls further in old age.
■■ Narcolepsy is a sudden loss of voluntary muscle tone
(cataplexy), an irresistible urge to sleep during daytime, and a
sudden onset of REM sleep. OSA is the most common cause
of daytime sleepiness; breathing ceases for more than 10 s
during frequent episodes of obstruction of the upper airway.
Compared to normal sleep patterns, individuals spend more
time in stage 1 non-REM sleep and less time in stages 3 and 4
non-REM sleep. PLMD is a stereotypical rhythmic extension
of the big toe and dorsiflexion of the ankle and knee during
sleep lasting for about 0.5–10 s and recurring at intervals of
20–90 s.
■■ The entrainment of biologic processes to the light–dark cycle is
regulated by the SCN. The diurnal change in melatonin release
from the pineal gland may coordinate events with the light–
dark cycle.
MULTIPLE-CHOICE QUESTIONS
For all questions, select the single best answer unless otherwise
directed.
1. An MD/PhD student was comparing sleep patterns in different
age groups. What is expected to be the different about sleep as a
function of age?
A. Non-REM sleep occupies about 50% of total sleep in young
adults and falls to about 20% in the elderly.
B. Young adults experience about 4–6 episodes of REM sleep
each night, and infants experience about 5–10 episodes of
REM each night.
C. REM sleep occupies about 80% of total sleep in full-term
infants and falls to about 20% in the elderly.
D. REM sleep occupies about 80% of total sleep in premature
infants and falls until it plateaus at about 25% in adults.
E. In a typical night, a young adult spends 70–100 min in stages
3 and 4 of non-REM sleep, whereas a child spends only about
30 min in these stages of deep sleep.
2. An MD/PhD student was studying the role of thalamocortical
pathways in control of arousal. He was preparing his thesis
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276 SECTION II Central & Peripheral Neurophysiology
proposal and included the following information on the two
major types of thalamic projections to the cortex.
A. Most thalamic neurons release glutamate throughout the
cortex, but thalamic reticular neurons release GABA in the
cortex.
B. Afferents from the specific nuclei of the thalamus terminate
in cortical layer I–IV, whereas the nonspecific afferents
terminate primarily on spiny stellate cells of layer IV.
C. Afferents from the specific nuclei of the thalamus terminate
primarily on pyramidal neurons in layer IV, whereas the
nonspecific afferents terminate primarily on inhibitory basket
calls of layer IV.
D. Thalamic projections to wide regions of the neocortex
originate from the midline and intralaminar nuclei; thalamic
projections to discrete regions of the neocortex originate in
specific sensory relay nuclei.
3. In a healthy, alert adult sitting with their eyes closed, the
dominant EEG rhythm observed with electrodes over the
occipital lobes is
A. delta (0.5–4 Hz).
B. theta (4–7 Hz).
C. alpha (8–13 Hz).
D. beta (18–30 Hz).
E. fast, irregular low-voltage activity.
4. A 35-year-old man spent the evening in a sleep clinic to
determine if he had obstructive sleep apnea. The tests showed
that non-REM sleep accounted for over 30% of his total sleep
time. Which of the following pattern of changes in central
neurotransmitters or neuromodulators are associated with the
transition from non-REM to wakefulness?
A. Decrease in norepinephrine, increase in serotonin, increase in
acetylcholine, decrease in histamine, and decrease in GABA.
B. Decrease in norepinephrine, increase in serotonin, increase in
acetylcholine, decrease in histamine, and increase in GABA.
C. Decrease in norepinephrine, decrease in serotonin, increase
in acetylcholine, increase in histamine, and increase in
GABA.
D. Increase in norepinephrine, increase in serotonin, decrease in
acetylcholine, increase in histamine, and decrease in GABA.
E. Increase in norepinephrine, decrease in serotonin, decrease in
acetylcholine, increase in histamine, and decrease in GABA.
5. A healthy medical student participated in a research project on
the effect of sleep deprivation on their EEG. During the baseline
testing phase, no abnormalities were found. The following
behavioral and EEG characteristics were likely recorded during
stage 2 of non-REM sleep.
A. Skeletal muscle movements were observed and the EEG
showed a mixture of sleep spindles and theta waves.
B. Skeletal muscle tone was reduced and sleep spindles and K
complexes appeared in the EEG.
Barrett_Ch14_p265-p276.indd 276
C. Skeletal muscle movements were detected and the dominant
rhythm in the EEG was delta waves.
D. There was a complete absence of eye movements and the
dominant rhythm in the EEG was theta waves.
E. There was an absence of skeletal muscle and eye movements
and the EEG was desynchronized.
6. For the past several months, a 67-year-old woman experienced
difficulty initiating and/or maintaining sleep several times a
week. A friend suggested that she take melatonin to regulate her
sleep–wake cycle. Endogenous melatonin secretion would be
increased by
A. reducing the synthesis of serotonin.
B. inhibition of the paraventricular nucleus.
C. stimulation of the superior cervical ganglion.
D. stimulation of the optic nerve.
E. by blockade of hydroxyindole-O-methyltransferase.
7. Childhood absence epilepsy was diagnosed in a 10-year-old boy.
His EEG showed a bilateral synchronous, symmetric 3-Hz spike-
and-wave discharge. Absence seizures are a form of
A. nonconvulsive generalized seizures accompanied by
momentary loss of consciousness.
B. complex partial seizures accompanied by momentary loss of
consciousness.
C. nonconvulsive generalized seizures without a loss of
consciousness.
D. simple partial seizures without a loss of consciousness.
E. convulsive generalized seizures accompanied by momentary
loss of consciousness.
8. A child diagnosed with absence epilepsy began treatment with
ethosuximide. What is the mechanism of action by which
ethosuximide is an effective antiseizure drug?
A. It is a GABA analog that decreases Ca2+ entry into cells.
B. It blocks voltage-gated Na+ channels associated with
glutamate receptors.
C. It potentiates GABA transmission.
D. It is a dopamine receptor agonist.
E. It inhibits T-type Ca2+ channels.
9. A 57-year-old professor at a medical school experienced
numerous episodes of a sudden loss of muscle tone and an
irresistible urge to sleep in the middle of the afternoon. The
diagnosis was narcolepsy, which
A. is characterized by a sudden onset of non-REM sleep.
B. has a familial incidence associated with a class II antigen of
the major histocompatibility complex.
C. may be due to the presence of an excessive number of orexin-
producing neurons in the hypothalamus.
D. is often effectively treated with dopamine receptor agonists.
E. is the most common cause of daytime sleepiness.
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