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45Brain Stem Modulation of Sensation, Movement, and ConsciousnessClifford B. Saper
IN THE LAST CHAPTER WE examined the groups of interneurons
surrounding cranial nerve nuclei in the reticular formation of the
brain stem. These reticular interneurons have local projections
that mediate reflexes and simple stereotyped behaviors, such as
chewing and swallowing. In this chapter we shall explore the long
projection systems of the reticular formation: the neurons whose
axons ascend to the forebrain or descend to the spinal cord. These
neurons regulate complex functions of the central nervous system,
including the perception of pain and the control of posture and
wakefulness. Through these long projection systems the brain
stem maintains the level of activity necessary for sensory
awareness, motor responses, and arousal related to behavioral
states.
Cell Groups in the Brain Stem With Long
Projections Can Be Defined by Their
NeurotransmittersAlthough early neuroanatomists described the reticular formation
as being poorly organized, modern methods have demonstrated
that it is composed of systems of neurons with specific
neurotransmitters and connections. Such systems often extend
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beyond the borders of the nuclei defined by traditional cell and
fiber stains. To overcome this discrepancy, earlier researchers
used a combination of letters and numbers to identify clusters of
neurotransmitter-specific neurons: letters to identify the
neurotransmitter and numbers to indicate the rostrocaudal order
of the cell group. Although this nomenclature is convenient and
still widely used, it tends to
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obscure functional relationships between these cell groups and
Nissl-stained nuclei.
The Major Modulatory Systems of the
Brain
Noradrenergic Cell GroupsNoradrenergic neurons are located in two columns, one dorsal and
one ventral (Figure 45-1 ). At the level of the medulla the ventral
column contains neurons associated with the nucleus ambiguus
(A1 group); those in the dorsal column are a component of the
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nucleus of the solitary tract and the dorsal motor vagal nucleus
(A2 group). Both groups project to the hypothalamus and control
cardiovascular and endocrine functions. In the pons the ventral
column includes the A5 and A7 cell groups, located in the
ventrolateral reticular formation of the pons. These A5 and A7
groups provide mainly projections to the spinal cord that modulate
autonomic reflexes and pain sensation. The A6 cell group, the
locus ceruleus , sits dorsally and laterally in the periaqueductal and
periventricular gray matter (Figure 45-2 ). The locus ceruleus,
which maintains vigilance and responsiveness to unexpected
environmental stimuli, has extensive projections to the cerebral
cortex and cerebellum, as well as descending projections to the
brain stem and spinal cord.
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Figure 45-1 Noradrenergic and adrenergic neurons in the
medulla and pons.
A. The catecholaminergic neurons in the dorsal medulla (the
A2 noradrenergic and C2 adrenergic groups) are part of the
nucleus of the solitary tract. Those in the ventrolateral medulla
(the A1 noradrenergic and C1 adrenergic groups) are located
near the nucleus ambiguus.
B. The adrenergic projection to the spinal cord arises in the C1
neurons while the noradrenergic projection to the spinal cord
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comes from the A5 and A7 groups as well as the locus ceruleus
(LC) (A6 group) in the pons. The ascending noradrenergic input
to the hypothalamus stems from both the A1 and A2 cell
groups while adrenergic input to the hypothalamus comes from
the C1 cell group.
Figure 45-2 Noradrenergic neurons in the pons.
A. Noradrenergic neurons are spread across the pons in three
more or less distinct groups: the locus ceruleus (A6 group) in
the periaqueductal gray matter, the A7 group more
ventrolaterally, and the A5 group along the ventrolateral
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margin of the pontine tegmentum.
B. The A5 and A7 neurons mainly innervate the brain stem and
spinal cord, whereas the locus ceruleus provides a major
ascending output to the thalamus and cerebral cortex as well
as descending projections to the brain stem, cerebellum, and
spinal cord. A = amygdala; AO = anterior olfactory nucleus; BS
= brain stem; C = cingulate bundle; CC = corpus callosum; CT
= central tegmental tract; CTX = cerebral cortex; DT = dorsal
tegmental bundle; EC = external capsule; F = fornix; H =
hypothalamus; HF = hippocampal formation; LC = locus
ceruleus; OB = olfactory bulb; PT = pretectal nuclei; RF =
reticular formation; S = septum; T = tectum; Th = thalamus.
Adrenergic Cell GroupsSome neurons in the two columns of cells in the medulla identified
as catecholaminergic were later found to synthesize epinephrine.
The C1 adrenergic cell group forms a rostral extension from the A1
column in the rostral ventrolateral medulla (Figure 45-1 ). Many C1
neurons project to the spinal cord, particularly to the sympathetic
preganglionic column, where they are thought to provide tonic
excitatory input to vasomotor neurons. Other C1 neurons
terminate in the hypothalamus, where they modulate
cardiovascular and endocrine responses. The C2 adrenergic
neurons, which are a component of the nucleus of the solitary
tract, contribute to the ascending pathway to the parabrachial
nucleus (Figure 45-1 ), which is thought to transmit gastrointestinal
information. The C3 adrenergic group is located near the midline
at the rostral end of the medulla. Neurons mixed in with the C3
and C1 groups provide a major input to the locus ceruleus, but
most of the cells contributing to this pathway are not adrenergic.
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Figure 45-3 Dopaminergic neurons in the brain stem and
hypothalamus.
A. Dopaminergic neurons in the substantia nigra (A9 group)
and the adjacent retrorubral field (A8 group) and ventral
tegmental area (A10 group) provide a major ascending
pathway that terminates in the striatum, the frontotemporal
cortex, and the limbic system, including the central nucleus of
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the amygdala and the lateral septum.
B. Hypothalamic dopaminergic neurons in the A11 and A13 cell
groups, in the zona incerta, provide long descending pathways
to the autonomic areas of the lower brain stem and the spinal
cord. Neurons in the A12 and A14 groups, located along the
wall of the third ventricle, are involved with endocrine control.
Some of them release dopamine as a prolactin release
inhibiting factor in the hypophysial portal circulation.
Dopaminergic Cell GroupsThe dopaminergic cell groups in the midbrain and forebrain were
originally numbered as if they were a rostral continuation of the
noradrenergic system because identification was based on
histofluorescence, which does not distinguish dopamine from
norepinephrine very well.
The A8-A10 cell groups include the substantia nigra pars compacta
and the adjacent areas of the midbrain tegmentum (Figure 45-3 ).
They send the major ascending dopaminergic inputs to the
telencephalon, including the nigrostriatal pathway that innervates
the striatum and is thought to be involved in initiating motor
responses. Mesocortical and mesolimbic dopaminergic pathways
arising from the A10 group innervate the frontal and temporal
cortices and the limbic structures of the basal forebrain. These
pathways have been implicated in emotion, thought, and memory
storage. The A11 and A13 cell groups, in the dorsal hypothalamus,
send major descending dopaminergic pathways to the spinal cord.
These pathways are believed to regulate sympathetic
preganglionic neurons. The A12 and A14 cell groups, along the
wall of the third ventricle, are components of the
tuberoinfundibular hypothalamic neuroendocrine system.
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Dopaminergic neurons are also found in the olfactory system (A15
cells in the olfactory tubercle and A16 in the olfactory bulb) and in
the retina (A17 cells).
Figure 45-4 Serotonergic neurons along the midline of
the brain stem. Neurons in the B1-3 groups, corresponding to
the raphe magnus, raphe pallidus, and raphe obscurus nuclei in
the medulla, project to the lower brain stem and spinal cord.
Neurons in the B4-9 groups, including the raphe pontis, median
raphe, and dorsal raphe nuclei, project to the upper brain stem,
hypothalamus, thalamus, and cerebral cortex. CD = caudate
nucleus; HF = hippocampal formation; H = hypothalamus; Th
= thalamus.
Serotonergic Cell GroupsMost serotonergic neurons are located along the midline of the
brain stem in the raphe nuclei (from raphé, French for seam).
Raphe neurons in the B1-B3 cell groups along the midline of the
caudal medulla (Figure 45-4 ) send descending projections to the
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motor and autonomic systems in the spinal cord. The raphe
magnus nucleus (B4) at the level of the rostral medulla projects to
the spinal dorsal horn and is thought to modulate the perception
of pain. The serotonergic groups in the pons and midbrain (B5-B9)
include the pontine, dorsal, and median raphe nuclei and project
to virtually the whole of the forebrain. Serotonergic pathways play
important regulatory roles in hypothalamic cardiovascular and
thermoregulatory control and modulate the responsiveness of
cortical neurons.
Cholinergic Cell GroupsAcetylcholine is the transmitter used by both somatic and
autonomic motor neurons. Certain populations of cholinergic
interneurons are found in the brain stem and forebrain, and large
cholinergic neurons in the mesopontine tegmentum and basal
forebrain give rise to long ascending projections (Figure 45-5 ). The
mesopontine cholinergic neurons are divided into a ventrolateral
column (Ch6 cell group, or the pedunculopontine nucleus), close to
the lateral margin of the superior cerebellar peduncle, and a
dorsomedial column (Ch5 cell group, or the laterodorsal tegmental
nucleus), a component of the periaqueductal gray matter just
rostral to the locus ceruleus. These two cell groups send a major
descending projection to the pontine and medullary reticular
formation and provide extensive ascending cholinergic innervation
of the thalamus. These projections are thought to play an
important role in regulating wake-sleep cycles (Chapter 47 ).
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Figure 45-5 Cholinergic neurons in the upper pontine
tegmentum and basal forebrain diffusely innervate much
of the brain stem and forebrain. The basal forebrain
cholinergic groups include the medial septum (MS) (Ch1
group), nuclei of the vertical and horizontal limbs of the
diagonal band (DBv and DBh) (Ch2 and Ch3 groups), and the
nucleus basalis of Meynert (BM) (Ch4 group), which
topographically innervate the entire cerebral cortex, including
the hippocampus (Hi) and the amygdala (Am). The pontine
cholinergic neurons, in the laterodorsal (LDT) (Ch5 group), and
pedunculopontine (PPT) (Ch6 group), tegmental nuclei,
innervate the brain stem reticular formation (RF) as well as the
thalamus (Th). Ha = habenular nucleus; IPN = interpeduncular
nucleus; LH = lateral hypothalamus; MaPo = magnocellular
preoptic nucleus; OB = olfactory bulb; VTA = ventral
tegmental area.
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Figure 45-6 All of the histaminergic neurons in the brain
are located in the hypothalamus.
A. Histaminergic cells are clustered in the tuberomammillary
nucleus in the posterior lateral hypothalamus. There are two
main clusters, one located ventrolaterally along the edge of the
brain and the other dorsomedially along the edge of the
mammillary recess of the third ventricle. The photograph on
the right shows that some histaminergic cells bridge these two
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main groups.
B. The histaminergic neurons innervate the entire neuraxis,
from the cerebral cortex to the spinal cord.
Histaminergic Cell GroupsThe histaminergic neurons in the mammalian brain are located in a
major cluster in the posterior lateral hypothalamus, the
tuberomammillary nucleus , and in several minor associated
clusters (E1-E5 cell groups) (Figure 45-6 ). There are roughly as
many histaminergic neurons in the tuberomammillary nucleus as
there are noradrenergic neurons in the locus ceruleus, and their
projections are equally diverse, ranging from the spinal cord to the
entire cortical mantle. Histaminergic neurons in the
tuberomammillary nucleus may help maintain arousal in the
forebrain. Other neurons in the lateral hypothalamic area,
containing the peptide neurotransmitters orexin or melanin
concentrating hormone also have diffuse cortical, brain stem, and
spinal projections (see Figure 45-10 ) and contribute to arousal
responses.
The first cell populations in the brain stem to be defined by
neurotransmitter substance were identified by histofluorescence, a
method that visualizes nerve cells containing norepinephrine,
dopamine, and serotonin. The organization of these
monoaminergic systems was later refined by
immunocytochemistry, using antisera against specific transmitters
or the enzymes that synthesize them. Later studies showed that
some of the catecholaminergic neurons in the medulla use
epinephrine as neurotransmitter, instead of norepinephrine or
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dopamine, and that a fifth monoaminergic system of neurons in
the brain stem uses histamine. Finally, a system of cholinergic
neurons was discovered. Each of these six neuronal systems has
extensive connections in most areas of the brain and each plays a
major role in modulating sensory, motor, and arousal tone. The
major components of these systems are summarized in Box 45-1.
The largest collection of noradrenergic neurons is in the pons in
the locus ceruleus (Figures 45-1 and 45-2 ). Remarkably, although
the locus ceruleus projects to every major region of the brain and
spinal cord, in humans it
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contains only about 10,000 neurons on each side of the brain. The
locus ceruleus maintains vigilance and responsiveness to novel
stimuli. It therefore influences both arousal at the level of the
forebrain and sensory perception and motor tone in the brain stem
and spinal cord.
The largest group of dopaminergic neurons in the brain is in the
midbrain, including the substantia nigra and the adjacent ventral
tegmental area (Figure 45-3 ). These neurons provide a major
ascending input to the cerebral cortex and the basal ganglia that
is important in the initiation of behavioral responses.
Dopaminergic neurons in the hypothalamus participate in
autonomic and endocrine regulation.
Serotonergic neurons are found mainly in the raphe nuclei, located
along the midline of the brain stem from the midbrain to the
medulla (Figure 45-4 ). The rostral end of this system projects
mainly to the forebrain, where it helps regulate wake-sleep cycles,
affective behavior, food intake, thermoregulation, and sexual
behavior. In contrast, the neurons of the raphe in the lower pons
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and medulla project to the brain stem and the spinal cord, where
they participate in regulating tone in motor systems and pain
perception (see Chapter 24 ).
The largest groups of cholinergic neurons in the brain (aside from
the motor neurons) are found in the midbrain and the basal
forebrain (Figure 45-5 ). The neurons in the pedunculopontine and
laterodorsal tegmental nuclei of the midbrain provide cholinergic
innervation to the brain stem and the thalamus that is critical for
inducing a state of cortical arousal, both during wakefulness and
dreaming. The cholinergic neurons in the basal forebrain, mainly
found in humans in the nucleus basalis of Meynert, also participate
in this process. They project largely to the cerebral cortex, where
they enhance cortical responses to incoming sensory stimuli.
Histaminergic neurons are found in the tuberomammillary nucleus
in the posterior lateral hypothalamus (Figure 45-6 ). These cells
project to all major parts of the nervous system, like the locus
ceruleus. They are thought to be important in regulating the level
of behavioral arousal.
Descending Projections From the Brain
Stem to the Spinal Cord Modulate
Sensory and Motor Pathways
Pain Is Modulated by Descending
Monoaminergic ProjectionsMonoaminergic projections to the dorsal horn of the spinal cord
descend from the serotoninergic raphe magnus nucleus in the
midline of the rostral medulla and from the noradrenergic cell
groups in the pons. Activation of either of these monoaminergic
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pathways can inhibit the transmission of nociceptive information
(see Chapter 24 ).
The serotonergic neurons in the raphe magnus nucleus receive
afferents from enkephalinergic neurons in the periaqueductal gray
matter. Electrical stimulation of the periaqueductal gray matter
produces analgesia that is blocked by administering the opiate
antagonist naloxone into the raphe magnus, suggesting that the
endogenous opiates released there activate the descending
modulatory pathway.
Other, nonserotonergic neurons in the medial medullary reticular
formation adjacent to the raphe magnus have firing patterns that
are correlated with reflex responses to painful stimuli. These
neurons may also contribute to descending modulation of
nociception.
Posture, Gait, and Muscle Tone Are
Modulated by Two Reticulospinal TractsTwo long descending pathways from the reticular formation are
associated with control of posture: the medial and lateral
reticulospinal tracts. These pathways and their roles in motor
control are discussed in more detail in Chapter 41 .
The medial reticulospinal tract originates from large neurons in
the upper pontine reticular formation. It facilitates spinal motor
neurons that innervate axial muscles and extensor responses in
the legs to maintain postural support. Neurons in the mesopontine
reticular formation are also capable of producing patterned,
stereotyped movements. For example, stepping movements can be
induced by electrically stimulating the midbrain locomotor region,
an area adjacent to the cholinergic pedunculopontine nucleus with
extensive inputs from the extrapyramidal system (see Chapter 37 ).
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The lateral reticulospinal pathway arises from neurons in the
medial medullary reticular formation and inhibits the firing of
spinal and cranial motor neurons. Activity of glycinergic neurons in
this pathway causes volleys of inhibitory synaptic potentials in
motor neurons, producing a loss of motor tone, or atonia. Intense
volleys of firing of the neurons in the medial medullary reticular
formation are associated with the atonia that occurs in rapid eye
movement (REM) sleep. These volleys are thought to be under the
control of cholinergic neurons in the pedunculopontine nucleus.
Ascending Projections From the Brain
Stem Modulate Arousal and
ConsciousnessThe ascending pathways from monoaminergic cell groups in the
brain stem and hypothalamus to the cerebral
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cortex and thalamus increase wakefulness and vigilance, as well
as the responsiveness of cortical and thalamic neurons to sensory
stimuli, a state known as arousal. These pathways are joined by
ascending cholinergic inputs from the pedunculopontine and
laterodorsal tegmental nuclei and by other cell groups from the
parabrachial nucleus through the paramedian midbrain reticular
formation to form an ascending arousal system .
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Figure 45-7 Injuries to the ascending arousal system,
from the rostral pons through the thalamus and
hypothalamus (purple area), can cause loss of
consciousness.
The ascending arousal system divides into two major branches at
the junction of the midbrain and diencephalon. One branch enters
the thalamus, where it activates and modulates thalamic relay
nuclei as well as intralaminar and related nuclei with extensive
diffuse cortical projections. The other branch travels through the
lateral hypothalamic area and is joined by the ascending output
from the hypothalamic and basal forebrain cell groups, all of which
diffusely innervate the cerebral cortex. Lesions that disrupt either
of these two branches impair consciousness (Figure 45-7 ).
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Consciousness Represents the Summated
Activity of the Cerebral CortexThe nature of consciousness has been a subject of intense
philosophical concern at least since Plato's Meno. However, only
within the past 100 years has speculation on the basis of
consciousness been informed by scientific understanding of how
the brain works. Currently, there is general agreement that
consciousness is the property of being aware of oneself and one's
place in the environment. Scientifically, this is a very difficult
property to measure (see Chapter 20 ).
As a result, clinicians generally rely on a pragmatic definition
based on observation: the ability of the individual to respond
appropriately to environmental stimuli. Careful clinical
observations show that this ability to orient appropriately to
stimuli is dependent upon the summated activity of the two
cerebral hemispheres. When parts of the cerebral cortex are
damaged a patient may be unable to process certain types of
information, and thus the patient is not conscious of certain
aspects of the environment. For example, a patient with a lesion in
Wernicke's area in the dominant hemisphere may not be aware of
the semantic content of speech, and thus would use and interpret
language only for emotional gesturing. This type of “fractional”
loss of consciousness is discussed in greater detail in Chapter 19 .
According to this view of conciousness, generalized impairment of
consciousness implies diffuse dysfunction in both cerebral
hemispheres.
One problem with a definition of consciousness based on
responsiveness to stimuli emerged at the beginning of the
twentieth century, when clinicians began to report cases of
patients with injuries to the brain stem but no injuries to the
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cerebral hemispheres who were unable to respond to stimuli. Most
observers thought that the inability to respond reflected mainly
impairment of sensory and motor pathways. In the absence of an
independent measure of cortical activity, this view was difficult to
disprove.
Fortunately, in the late 1920s Hans Berger, a Swiss psychiatrist,
invented the electroencephalogram (EEG) to assess the electrical
activity of the cerebral cortex (see Box 46-1 ). During alert
wakefulness the EEG shows a pattern of low-voltage, fast (>12 Hz)
electrical activity called desynchronized. During deep sleep the
EEG is dominated by high-voltage, slow (<3 Hz) electrical activity
called synchronized (Figure 45-8 ). These patterns are discussed in
detail in Chapter 47 .
The EEG Reflects Two Modes of Firing of
Thalamic NeuronsThe EEG is important in assessing wakefulness because electrical
activity in the cerebral cortex reflects the firing patterns in the
thalamocortical system, a necessary component of maintaining a
waking state. As we shall learn in the next two chapters, electrical
activity measured from the surface of the skull reflects the
summated activity of synaptic potentials in the dendrites of
cortical neurons. The specific rhythmic pattern of the EEG
waveform thus reflects synchronized waves of
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excitatory synaptic potentials reaching the cerebral cortex from
the thalamus. The rhythmic nature of the thalamic activity is due,
in turn, to two important properties of the thalamic relay neurons.
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Figure 45-8 The electroencephalogram measures
electrical activity in the cerebral cortex.
A. Transection of the lower brain stem at the level shown in the
drawing isolates the brain from incoming sensory signals
through the spinal cord, a preparation the Belgian
neurophysiologist Frederic Bremer called the encephale isolé.
Animals with this lesion are awake, respond to trigeminal
sensory as well as visual and auditory cues, and move their
faces and eyes in a normal fashion. The electroencephalogram
(EEG) of such animals is typically low voltage and fast, a
desynchronized pattern typical of waking.
B. When a cut is made at the level indicated in the drawing,
between the superior and inferior colliculi, the cat appears to
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be sleeping, with no eye movement responses to visual stimuli.
In animals the EEG pattern is typically high voltage and slow, a
synchronized pattern consistent with sleep.
First, the thalamic relay neurons have two distinct physiological
states: a transmission mode and a burst mode (Figure 45-9 ). When
the resting membrane potential of the thalamic relay neuron is
near the firing threshold, the neuron is in transmission mode:
incoming excitatory synaptic potentials can drive the neuron to
fire in a pattern that reflects the sensory stimulus. When the
thalamic neuron is hyperpolarized by inhibitory input, it is in burst
mode.
As we shall learn in detail in Chapter 46 , the thalamic relay
neurons have a special voltage-gated calcium channel that is
inactivated when the membrane potential is near threshold. When
the relay cell is hyperpolarized incoming excitatory synaptic
potentials can trigger transient opening of the calcium channels.
These channels produce a calcium current that brings the neuron's
membrane potential above threshold for firing action potentials.
The cell now fires a burst of action potentials that produce further
calcium channel openings, until sufficient calcium has entered the
cell to trigger a calcium-activated potassium current. This
potassium current hyperpolarizes the cell, resetting it for another
cycle of burst firing.
This raises some questions. How do the thalamic relay cells
become hyperpolarized in the first place? What is the nature of the
inhibitory input? The thalamic relay neurons have a strong
reciprocal interaction with GABA-ergic inhibitory interneurons in
the reticular nucleus of the thalamus. The reticular nucleus forms
a sheet of GABA-ergic neurons that sits along the outer surface of
the thalamus. Their dendrites receive collaterals from both
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thalamocortical and corticothalamic axons that pass through it.
The reticular nucleus is topographically organized, and its neurons
project back to relay nuclei from which they receive their inputs.
When the reticular nucleus neurons fire, they hyperpolarize
thalamic relay neurons, thereby determining whether the thalamic
relay neurons will be able to reach firing threshold in response to
sensory inputs.
Both the thalamic relay nuclei and the inhibitory neurons of the
reticular nucleus enter burst mode when they are hyperpolarized.
The input from the reticular
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neurons produces inhibitory synaptic potentials in the relay
neurons that are mediated by GABA B receptors. This inhibitory
input removes inactivation of the calcium channels, and the
rebound of the membrane potential sets off a burst of action
potentials. In turn, the thalamic relay neurons provide excitatory
inputs to the reticular neurons, which trigger another burst of
firing in the reticular neurons.
The resulting rhythmic and synchronous firing of thalamic relay
neurons produces waves of excitatory postsynaptic potentials in
dendrites of cortical neurons. These waves of depolarization show
up on the EEG as rhythmic slow waves, a pattern indicating that
the thalamus is unable to relay sensory information to the cortex
(Figure 45-9 ). This synchronized pattern of EEG activity is
associated with deep sleep (Chapter 47 ) and is also seen in
pathological states in which thalamocortical transmission is
blocked, such as coma or during certain types of seizures (see
Chapter 46 ). In contrast, when the thalamus is in transmission
mode (eg, during wakefulness), the desynchronized pattern of the
EEG reflects ongoing sensory stimuli.
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During normal wakefulness the thalamus is kept in the
transmission mode by the action of cholinergic inputs from the
rostral pons and basal forebrain. The major cholinergic input to the
thalamic relay nuclei is from the pedunculopontine and
laterodorsal tegmental nuclei in the brain stem. These same
nuclei, along with cholinergic neurons in the basal forebrain,
innervate the reticular nucleus of the thalamus, reducing its
activity and thus preventing it from hyperpolarizing the thalamic
relay neurons during wakefulness.
Figure 45-9 Thalamic relay neurons have transmission
and burst modes of signaling activity.
Left. Burst mode. When thalamic neurons are hyperpolarized
by inhibitory postsynaptic potentials they respond to brief
depolarizations with a burst of action potentials ( left). Each
burst of action potentials causes a barrage of synchronized
excitatory postsynaptic potentials in the dendrites of cortical
neurons, producing an EEG slow-wave pattern known as
synchronized activity.
Right. Transmission mode. When thalamic neurons are in a
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more depolarized state, incoming excitatory potentials produce
single action potentials. In this mode the thalamic neuron
faithfully transmits sensory impulses to the cerebral cortex but
the complex patterning of thalamic firing produces nearly
constant, small-scale alterations in the dendritic potentials of
cortical neurons. The resulting EEG pattern of fast, low-voltage
waves is termed desynchronized.
Damage to Either Branch of the
Ascending Arousal System May Impair
ConsciousnessExperimental lesion studies and clinical experience indicate that
injury to either branch of the ascending arousal system—the
pathway through the thalamus or the pathway through the
hypothalamus—can impair consciousness (Figure 45-10 ).
Transection of the brain stem below the level of the rostral pons
does not affect the level of consciousness. Acute transections
rostral to the level of the inferior colliculus invariably result in
coma, a state of profound unarousability. Smaller lesions involving
just the paramedian reticular formation of the midbrain are
sufficient to produce this result, whereas large lesions of the
lateral tegmentum of the upper brain stem do not cause coma.
Lesions of the paramedian reticular formation up to the junction of
the midbrain and the diencephalon damage axons arising from all
components of the ascending arousal system and result in
impairment of consciousness.
Lesions of the posterior lateral hypothalamus interrupt the
pathway through the hypothalamus. This injury results in profound
slowing of the EEG and behavioral
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unarousability, even though the branch through the thalamus
remains intact. Conversely, injury to the thalamus or its reticular
input prevents the brain from achieving a desynchronized or
wakeful state. If the injury is sufficiently severe, the EEG rhythm
itself is lost.
Figure 45-10 The ascending arousal system consists of
the axons of cell populations in the upper brain stem,
hypothalamus, and basal forebrain. These pathways
diffusely innervate the thalamus and cerebral cortex and keep
the thalamus and cortex in a state in which they can
respectively transmit and respond appropriately to incoming
sensory information. Damage to either the main pathway in the
brain stem or its branches in the thalamus or hypothalamus
can cause loss of consciousness. RT = reticular nucleus of the
thalamus; ILT = intralaminar thalamic nuclei.
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Bilateral Forebrain Damage May Cause
Coma or Persistent Vegetative State or
Be Symptomatic of Brain DeathComa may also be caused by bilateral impairment of the cerebral
hemispheres. For example, bilateral subdural hematomas (blood
clots in the space between the dura and the arachnoid
membranes, usually as a result of head trauma) or multiple (or
very large) brain tumors or associated areas of swelling can
compress both hemispheres. More often, bilateral forebrain
impairment results from a diffuse metabolic process, such as an
imbalance of electrolytes or a lack of oxygen. If metabolic
imbalance persists, permanent diffuse cortical injury may result.
The large pyramidal neurons in the hippocampal formation and
cerebral cortex (particularly laminae III and V) are the cells most
severely damaged by inadequate oxygenation (hypoxia) or
insufficient blood flow ( ischemia). If many of these neurons are
damaged there may not be sufficient numbers of remaining normal
neurons to maintain a conscious state. After a period of 1 or 2
weeks of coma these patients enter a contentless wake-sleep cycle
called a persistent vegetative state. They appear wakeful and may
even eat food placed in the mouth, smile or cry, and fixate objects
in the environment, similar to a hydrencephalic infant. Their
actions, however, have no cognitive content and bear little
relationship to events that surround them.
The persistent vegetative state must be distinguished from brain
death, in which all brain functions cease. Brain dead patients may
have spinal level motor responses, which may include patterned
activity such as withdrawal movements or even in rare instances
sitting up or moving the arms (the Lazarus syndrome). Even so,
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there are no purposeful movements of the limbs, face, or eyes; no
brain stem reflex responses to sensory stimulation (see below);
and no respiratory movements.
An Overall ViewThe human brain stem is capable of organizing many stereotyped
behaviors ranging from eye movements, orofacial responses, and
breathing to postural control and even walking. These behaviors
are controlled by descending motor pathways from the forebrain.
At the same time, the brain stem regulates the overall level of
activity of the forebrain itself by controlling wake-sleep cycles and
modulating the passage of sensory information, especially pain, to
the cerebral cortex.
These regulatory processes are illustrated poignantly in patients
who have injury to the lower brain stem. These patients remain
awake, but the intact forebrain is unable to interact with the
external world, a condition described clinically as lockedin. This
condition is the exact opposite of patients in a persistent
vegetative state, who have extensive forebrain impairment
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as a result of hypoxia and appear to be awake but lack completely
the content of consciousness.
These unfortunate clinical examples underscore the important role
of the brain stem in modulating motor and sensory systems
through its descending pathways and regulating the wakefulness
of the forebrain through its ascending pathways.
Postscript: Examination of the Comatose
Patient
28
More than any other part of the neurological examination the
evaluation of a comatose patient must be based on an
understanding of the functional anatomy of the brain stem. Two
principles of organization are important in pinpointing the cause of
coma. First, impairment of consciousness implies dysfunction of
the ascending arousal system in the paramedian portion of the
upper pons and midbrain, its targets in the thalamus or
hypothalamus, or both cerebral hemispheres. Second, dysfunction
of cranial nerves indicates injury to the cranial nerves or their
nuclei, or the networks of local interneurons that control them.
Because the cranial nerves and nuclei are found at specific
locations, their dysfunction can indicate the level at which the
brain stem has been injured.
States of Consciousness Are Assessed
Clinically in Terms of Responsiveness to
the EnvironmentConsciousness is evaluated clinically as the ability of the patient
to respond appropriately to environmental stimuli. Loss of this
ability is generally judged as an alteration of consciousness. Two
major aspects of consciousness must be assessed. First, the level
of consciousness describes the arousability of the individual.
Patients with a mildly depressed level of consciousness are
generally classed as lethargic and can be easily aroused to full
wakefulness. Patients who cannot be fully aroused are obtunded,
and those who remain in a sleep-like state are stuporous. A patient
who cannot make a purposeful response to stimulation is
comatose.
Second, the content of consciousness may be assessed in terms of
the appropriateness of the patient's responses. We have seen in
29
Chapters 19 and 20 that accurate, purposeful behavioral response
depends on the normal function of the higher-order cognitive
processes of the forebrain. Impairment of specific cognitive
systems may leave the patient unable to appreciate or respond to
entire classes of stimuli. For example, the patient with a large
right parietal lesion and left-sided neglect is unaware of the left
side of his body or the world (Chapter 19 ). Acute multifocal or
diffuse impairment of the content of consciousness is called
encephalopathy by neurologists and acute organic brain syndrome
by psychiatrists, while chronic impairment is dementia. Delirium
occurs when a patient with diffuse cortical impairment
misinterprets sensory information, causing inappropriate
excitement or arousal.
Table 45-1 Common Causes of Metabolic Encephalopathy
Presenting as Coma
Loss of substrate of cerebral metabolism
Hypoxia
Hypoglycemia
Global ischemia
Multifocal ischemia resulting from emboli or diffuse
intravascular coagulation
Multifocal ischemia resulting from cerebral vasculitis
Derangement of normal physiology
Hyponatremia or hypernatremia
Hyperglycemia/hyperosmolar
Hypercalcemia
Hypermagnesemia
Ongoing seizures
30
Postseizure state
Postconcussive state
Hypothyroidism
Hypocortisolism
Toxins
Drugs
Hypercarbia
Liver failure
Renal failure
Sepsis
Meningitis/encephalitis
Subarachnoid blood
Loss of Consciousness May Be Either
Structural or Metabolic in OriginBecause the level of arousal of the forebrain is governed by the
ascending arousal system, impairment of consciousness reflects
either injury to this pathway or diffuse dysfunction of its targets in
the forebrain.
Both cerebral hemispheres are most commonly impaired as a
result of a metabolic or toxic insult that affects the entire brain.
The most common causes of metabolic encephalopathy are listed
in Table 45-1 . These patients are characterized by normal function
of brain stem reflex responses.
In contrast, impairment of the ascending arousal system in the
brain stem or diencephalon often results from structural injury. As
the ascending arousal system is located
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31
close to many cranial nerve nuclei, focal impairment of brain stem
reflexes is the hallmark of coma caused by structural damage.
Because the critical structures in the brain stem for supporting life
are tightly packed within a very small space, even a small
progression of an injury can be life-threatening. Hence, it is
essential for the physician to recognize focal brain stem
impairment and intervene quickly.
32
Figure 45-11 The respiratory pattern is a key indicator of
level of the brain that is not functioning properly in the
comatose patient. When there is diffuse forebrain depression
(A), as in a metabolic encephalopathy such as liver failure, the
respirations may take on a waxing-and-waning pattern, with
variable periods of apnea (no breathing), called Cheyne-Stokes
33
respiration. Injury to the midbrain (B) can cause
hyperventilation. Injury to the rostral pons may produce a
peculiar pattern of respiration known as apneusis (C), in which
the breathing halts briefly at full inspiration. When there is
injury to the lower pons or upper medulla, respirations may
become irregular and of uneven depth, known as ataxic
breathing (D). This pattern often heralds a respiratory arrest
(E).
Testing Four Functional Systems Gives
Important Clues to the Cause of
Structural ComaThe examination of the comatose patient is neither difficult nor
time-consuming. However, it does require an understanding of how
the brain stem is organized. The failure of brain function is
important, and all physicians should be able to assess patients
with coma and to start immediate lifesaving measures.
Respiratory Patterns
The first systems to be examined in a comatose patient are always
cardiovascular and respiratory. In any patient with impaired
consciousness, the first step is to make sure that there is
adequate perfusion and oxygen supply to the brain. Diffuse
forebrain impairment without brain stem injury often induces a
pattern of
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waxing-and-waning depth of respiration, with interposed apneas,
known as Cheyne-Stokes respiration (Figure 45-11 ). Injury at the
pontine level can cause apneusis (inspiratory cramps), while an
34
irregular respiratory cycle suggests involvement of the lower brain
stem. Only a bilateral lesion at the level of the ventrolateral
medulla or more caudally will cause complete apnea.
Figure 45-12 The motor response to painful stimulation
is a key indicator of the anatomical site of brain
dysfunction causing coma.
A. A patient with a diffuse metabolic encephalopathy may
respond to painful stimulation by trying to brush the examiner
away (in this case the examiner is pressing on the supraorbital
ridge, just above the eye). If one hemisphere is injured more
35
than the other, the motor response may be asymmetric. The
contralateral arm may not respond, the leg may be externally
rotated, and stimulation of the sole of the foot may cause the
big toe to flex upward (the Babinski reflex).
B. Damage to the upper midbrain may cause decorticate
posturing: the upper extremities flex, the lower extremities are
extended, and the toes extend downward.
C. Damage to the lower midbrain or upper pons causes
decerebrate posturing, in which both the upper and lower
extremities are extended. Progression from decorticate to
decerebrate posturing heralds rostro-caudal deterioration of
the brain stem, which may progress in a matter of minutes to
failure of the medulla and respiratory arrest.
Level of Arousability and Motor Responses
The patient should be able to respond to verbal instruction or local
painful stimulus (eg, rubbing the sternum, pressing on a nail bed)
with appropriate movements of all four limbs (Figure 45-12 ).
Depressed responsiveness to painful stimuli indicates the depth of
the coma. Asymmetric motor responses, eg, failure to move the
limbs on one side, are ominous, suggesting a focal injury to the
descending motor control systems. Similarly, asymmetry of the
muscle stretch reflexes (on tapping the biceps, triceps, knee or
ankle tendons) or plantar responses to noxious stimulation of the
sole of the foot indicates a focal injury to the descending motor
system.
Injury to the upper brain stem can produce posturing of the limbs,
either spontaneously or in response to pain. For example, the
patient may extend both arms and legs (decerebrate posturing), or
flex the arms and extend the legs (decorticate posturing)
36
bilaterally or unilaterally. This posturing is an ominous sign
indicating injury to the upper brain stem reticular formation and
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requires immediate intervention if the patient is to survive.
Figure 45-13 The state of the pupil represents a balance
between tone in the parasympathetic pupilloconstrictor
system (shown here) and the sympathetic pupillodilator
37
pathway (Figure 45-14 ). Pupillary constriction to light is due
to retinal ganglion cells projecting through the optic tract to
the pretectal nuclei, at the junction of the thalamus and the
midbrain. The pretectal neurons send axons through the
posterior commissure to the contralateral parasympathetic
preganglionic neurons in the Edinger-Westphal nucleus. These
cells, in turn, innervate the ciliary ganglion cells that control
the pupilloconstrictor muscle in the iris. LGN = lateral
geniculate nucleus; MLF = medial longitudinal fasciculus.
Pupillary Light Response
The pupillary light response is elicited by shining a bright light in
one eye. Retinal ganglion cell axons travel through the optic
nerve, optic chiasm, and optic tract to the pretectal area, which
then projects to the parasympathetic preganglionic neurons
associated with the oculomotor complex, in the Edinger-Westphal
nucleus and adjacent midbrain. These neurons innervate the para-
sympathetic ganglion cells in the orbit, which in turn activate the
iris constrictor muscle bilaterally, resulting in constriction of both
pupils (Figure 45-13 ).
Dilation of the pupil is provided by the sympathetic innervation of
the iris from the superior cervical ganglion (Figure 45-14 ). The
pupillary preganglionic neurons, in the upper thoracic spinal cord,
are under tonic excitatory descending control from the
hypothalamus. With diffuse forebrain impairment (eg, in metabolic
encephalopathy), the pupils are typically small in diameter but
react to light (Figure 45-15 ). Pontine injury may also produce very
small but reactive pupils because the pupillodilator pathways are
interrupted. Sedative drugs, particularly opiates, may also cause
small, reactive pupils.
38
Loss of pupillary light responses, in contrast, almost always
signifies structural injury. Damage to the dorsal midbrain involving
the pretectal area causes midposition (or slightly large) pupils that
do not react to light. Injury to the midbrain at the level of the third
nerve causes complete loss of pupillary responses (because it
generally damages the descending sympathetic pupillary dilator
system, running through the midbrain lateral to the third nerve
nuclei, as well as the pupillary constrictor system).
Unilateral pupillary dilation may result from injury to the
oculomotor nerve as it exits the brain stem (the intact sympathetic
system causes the pupil with parasympathetic loss to be large).
The most common causes of unilateral oculomotor nerve
compression in a comatose patient are either an aneurysm of the
posterior communicating artery or pressure on the oculomotor
nerve when the temporal lobe is pushed through the tentorial
opening, for example, by a tumor. Temporal or uncal herniation
(the displacement of the uncus, or medial edge of the temporal
lobe) may lead to imminent death.
Eye Movements
More than any other pathways, those concerned with eye
movements run in parallel with the ascending arousal system
through the paramedian tegmentum of the upper brain stem. In
patients with diffuse forebrain impairment the eyes often rove
aimlessly or do not move spontaneously. However, there should be
appropriate conjugate eye movement when a vestibular stimulus is
provided, by turning the head or by putting cool or warm water in
the ear canal (Figure 45-16 ). Turning the head to the right or left,
or up or down, induces eye movement in the opposite direction.
Cool water in the ear canal sets up a convection current in the
semicircular canals, resulting in conjugate deviation of
39
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the eyes toward that side; warm water has the opposite effect.
Figure 45-14 Pupillary dilation is regulated by a
descending pathway from the hypothalamus. The
pathway courses through the lateral part of the brain
stem, to the sympathetic preganglionic neurons in the
first three segments of the thoracic intermediolateral
40
cell column. These cells project to the superior cervical
ganglion from which sympathetic axons run along the carotid
artery to the orbit, where they innervate the pupillodilator
muscle in the iris.
Loss of normal reflex eye movements is evidence of brain stem
injury. A focal injury of the pons involving the abducens nerve
would cause loss only of abduction of the ipsilateral eye. A large
lesion of the lateral pontine tegmentum, damaging either the
abducens nucleus or the paramedian pontine reticular formation,
results in loss of conjugate movements of both eyes toward that
side. An injury of the medial longitudinal fasciculus, connecting
the abducens and oculomotor nuclei, would only prevent adduction
of the ipsilateral eye during contralateral gaze.
A lesion at the level of the midbrain, involving the oculomotor
nerve either within the brain stem or after it exits, causes loss of
elevation, depression, and adduction of the ipsilateral eye, as well
as loss of the pupillary light response. Nevertheless, the opposite
pupil will still constrict when a light is shined in the paralyzed eye
(the consensual pupillary light response). This response indicates
that the optic nerve is still intact, as is the dorsal midbrain and
opposite third nerve.
Emergency Care of the Comatose Patient
Can Be LifesavingAlthough the treatment of the comatose patient is beyond the
scope of this book, it is important to understand that a careful
examination of a comatose patient, based on the principles in this
chapter, is crucial to the outcome of the illness. If the examination
demonstrates a depressed level of consciousness but normal
function of the brain stem systems that run alongside the
41
ascending arousal system, then the cause of the coma is likely to
be diffuse or metabolic impairment of the cerebral hemispheres.
These patients require further evaluation with blood tests,
scanning of the brain, and often examination of the cerebrospinal
fluid during the next few
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P.907
P.908
hours to determine the cause of the coma and correct it.
42
Figure 45-15 Pupillary response can help determine the
level of the nervous system dysfunction in a comatose
patient. In patients with depressed consciousness due to
metabolic encephalopathy, drug ingestion, or diffuse pressure
on the diencephalon, the pupils are slightly smaller than
normal but respond vigorously to light (top). Pressure on the
pretectal area (eg, from a pineal tumor) prevents visual
stimulation from causing pupillary constriction, resulting in
large, unreactive pretectal pupils. Injury to the oculomotor (III)
nerve itself is usually one-sided, because of swelling in the
43
ipsilateral hemisphere causing the uncus (the medial edge of
the temporal lobe) to herniate through the tentorial opening
and crush the oculomotor nerve. A unilateral large, unreactive
pupil is an ominous sign that the brain stem is about to be
compressed from above. Damage to the midbrain tegmentum
itself causes complete loss of pupillary response to light,
although the pupils may dilate if a painful stimulus (eg,
pinching the neck) is applied, as a purely sympathetic response
(the ciliospinal response). Injury to the pons may result in
pinpoint pupils, which can be seen with a magnifying lens to
respond slightly to light. Pontine injury not only disrupts the
descending hypothalamic pupillodilator pathway but also
interrupts ascending inputs to the Edinger-Westphal nucleus
that inhibit its tone.
44
Figure 45-16 Oculomotor responses provide important
information on the level of brain dysfunction in the
45
comatose patient.
A. In patients with metabolic encephalopathy, in whom the
brain stem is intact, the eyes rotate counter to the direction of
head movement (the doll's head maneuver). Placing cold water
in the external ear canal (caloric stimulation) activates the
semicircular canals and causes the eyes to turn to the
ipsilateral side, whereas cold water in both ears causes the
eyes to look downward and warm water causes the eyes to look
upward. In a patient who is feigning unconsciousness, doll's
head eye movements are almost impossible to reproduce, and
caloric stimulation produces nystagmus.
B. Damage to the lateral pons removes the vestibular input on
one side and will block caloric responses in that ear, but the
eyes will still show doll's head responses because of input from
the other ear. More extensive injury to the pons on one side
will cause loss of movement of either eye to that side (gaze
paralysis).
C. An injury to the medial longitudinal fasciculus (MLF), which
connects the oculomotor nuclei with the pontine lateral gaze
system, results in loss of adduction of the ipsilateral eye
(internuclear ophthalmoplegia).
D. The combination of gaze paralysis in one direction and
internuclear ophthalmoplegia in the other direction indicates
an extensive paramedian pontine lesion. As a result, one eye
does not adduct and the other does not abduct or adduct,
termed by C. Miller Fisher “the one-and-a-half syndrome.”
E. A lesion involving the midbrain oculomotor nuclei allows
abduction of the eyes but not adduction or vertical eye
movement.
46
In contrast, impairment of consciousness in the presence of focal
brain system dysfunction is a medical emergency. The course of
action taken during the next few minutes can and often will save
the patient's life. Because the brain stem contains so many vital
systems packed within such a small area, pressure on the midbrain
or pons that is sufficient to cause coma can progress in a matter
of minutes to irreversible injury and respiratory arrest.
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