Notes on slide 1 page 45

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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

P.904

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

P.906

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.

Selected ReadingsBasbaum AI, Fields HL. 1984. Endogenous pain control systems:

brain stem spinal pathways and endorphin circuitry. Annu Rev

Neurosci 7:309–338.

Black PM. 1978. Brain death. N Engl J Med 299:338-344, 393–401.

Celesia GG, Breuer AC, Goldblatt D, Rottenberg DA, Saper CB,

Scneck SA, Schutta H, Trauner DA, Whitehouse PJ. 1993. Persistent

vegetative state: report of the American Neurological Association

committee on ethical affairs. Ann Neurol 33:386–390.

Fisch BJ. 1991. Spehlmann's EEG Primer , 2nd ed. Amsterdam:

Elsevier.

Hökfelt T, Johansson O, Goldstein M. 1984. Chemical anatomy of

the brain. Science 225:1326–1334.

Jennett B, Plum F. 1972. Persistent vegetative state after brain

damage. Lancet 1:734–737.

Levy DE, Caronna JJ, Singer BH, Lapinski RH, Frydman H, Plum F.

1985. Predicting outcome from hypoxic-ischemic coma. JAMA

253:1420–1426.

Max MB, Lynch SA, Muir J, Shoaf SE, Smoller B, Dubner R. 1992.

Effects of desipramine, amitriptyline, and fluoxetine on pain in

diabetic neuropathy. N Engl J Med 326:1250–1256.

Plum F, Posner JB. 1980. The Diagnosis of Stupor and Coma , 3rd

ed., Philadelphia: Davis.

47

Saper CB. 1987. Diffuse cortical projection systems: Anatomical

organization and role in cortical function. In: F Plum (ed).

Handbook of Physiology. V, The Nervous System , pp. 169-210.

Bethesda, MD: American Physiological Society.

Steriade M, Llinás RR. 1988. The functional states of the thalamus

and the associated neuronal interplay. Physiol Rev 68:649–742.

Steriade M, McCormick DA, Sejnowski TJ. 1993. Thalamocortical

oscillations in the sleeping and aroused brain. Science 262:679–

685.

ReferencesAston-Jones G, Ennis M, Shipley MT, Williams JT, Pieribone V. 1990.

Restricted afferent control of locus coeruleus neurones revealed

by anatomical, physiological and pharmacological studies. In: CA

Marsden, DJ Heal (eds). The Pharmacology of Noradrenaline in the

Central Nervous System , pp. 187-247. Oxford: Oxford Univ. Press.

Bittencourt JC, Presse F, Arias C, Peto C, Vaughan J, Nahon JL, Vale

W, Sawchenko PE. 1992. The melanin-concentrating hormone

system of the rat brain: an immunohistochemical and hybridization

histochemical characterization. J Comp Neurol 319:218–245.

Bremer F. 1935. Cerveau isolé et physiologie du sommeil. C R Soc

Biol (Paris) 118:1235–1242.

Cechetto DF, Saper CB. 1988. Neurochemical organization of the

hypothalamic projection to the spinal cord in the rat. J Comp

Neurol 272:579–604.

Dahlström A, Fuxe K. 1964. Evidence for the existence of

monoamine-containing neurons in the central nervous system. I.

Demonstration of monoamines in the cell bodies of brain stem

neurons. Acta Physiol Scand 232:1-55 (Suppl. 62).

Fisher CM. 1967. Some neuro-ophthalmological observations. J

Neurol Neurosurg Psychiatry 30:383–392.

48

Garcia-Rill E, Skinner RD. 1987. The mesencephalic locomotor

region. II. Projections to reticulospinal neurons. Brain Res 411:13–

20.

Grant SJ, Aston-Jones G, Redmond DE Jr. 1988. Responses of

primate locus ceruleus neurons to simple and complex sensory

stimuli. Brain Res Bull 21:401–410.

Hallanger AE, Levey AI, Lee HJ, Rye DB, Wainer BH. 1987. The

origins of cholinergic and other subcortical afferents to the

thalamus in the rat. J Comp Neurol 262:105–124.

Hodge CJ Jr., Apkarian AV, Stevens RT. 1986. Inhibition of

dorsalhorn cell responses by stimulation of the Kolliker-Fuse

nucleus. J Neurosurg 65:825–833.

Hökfelt T, Fuxe K, Goldstein M, Johansson O. 1974.

Immunohistochemical evidence for the existence of adrenaline

neurons in the rat brain. Brain Res 66:235–251.

Kwiat GC, Basbaum AI. 1992. The origin of brainstem nor-

adrenergic and serotonergic projections to the spinal cord dorsal

horn in the rat. Somatosens Mot Res 9:157–173.

Lai YY, Siegel JM. 1990. Cardiovascular and muscle tone changes

produced by microinjection of cholinergic and glutamatergic

agonists in dorsolateral pons and medial medulla. Brain Res

514:27–36.

Lin JS, Sakai K, Jouvet M. 1988. Evidence for histaminergic arousal

mechanisms in the hypothalamus of cat. Neuro-pharmacology

27:111–122.

Lindvall O, Bjorklund A. 1974. The organization of the ascending

catecholamine neuron systems in the rat brain as revealed by the

glyoxylic acid fluorescence method. Acta Physiol Scand Suppl

412:1–48.

49

Loewy AD, McKellar S, Saper CB. 1979. Direct projections from the

A5 catecholamine cell group to the intermediolateral cell column.

Brain Res 174:309–314.

P.909

Magoun HW, Rhines R. 1946. An inhibitory mechanism in the

bulbar reticular formation. J Neurophysiol 9:165–171.

Mason P, Back SA, Fields HL. 1992. A confocal laser microscopic

study of enkephalin-immunoreactive appositions onto

physiologically identified neurons in the rostral ventromedial

medulla. J Neurosci 12:4023–4036.

McCarley RW, Nelson JP, Hobson JA. 1978. Ponto-geniculo-occipital

(PGO) burst neurons: correlative evidence for neuronal generators

of PGO waves. Science 201:269–272.

Mesulam MM, Mufson EJ, Levey AI, Wainer BH. 1983. Cholinergic

innervation of cortex by the basal forebrain: cytochemistry and

cortical connections of the septal area, diagonal band nuclei,

nucleus basalis (substantia innominata) and hypothalamus in the

rhesus monkey. J Comp Neurol 214:170–197.

Moruzzi G, Magoun HW. 1949. Brain stem reticular formation and

activation of the EEG. Electroencephalogr Clin Neurophysiol 1:455–

473.

Panula P, Airaksinen MS, Pirvola U, Kotilainen E. 1990. A

histamine-containing neuronal system in human brain.

Neuroscience 34:127–132.

Rye DB, Saper CB, Lee HJ, Wainer BH. 1987. Pedunculopontine

tegmental nucleus of the rat: cytoarchitecture, cytochemistry, and

some extrapyramidal connections of the mesopontine tegmentum.

J Comp Neurol 259:483–528.

50

Saper CB. 1984. Organization of cerebral cortical afferent systems

in the rat. II. Magnocellular basal nucleus. J Comp Neurol 222:313–

342.

Saper CB. 1985. Organization of cerebral cortical afferent systems

in the rat. II. Hypothalamocortical projections. J Comp Neurol

237:21–46.

Saper CB, Plum F. 1985. Disorders of consciousness. In: JAM

Frederiks (ed). Handbook of Clinical Neurology. Vol 45, Clinical

Neuropsychology, pp. 107-128. Amsterdam: Elsevier.

Skagerberg G, Lindvall O. 1985. Organization of diencephalic

dopamine neurons projecting to the spinal cord in the rat. Brain

Res 342:340–351.

Stevens RT, Hodge CJ Jr., Apkarian AV. 1982. Kolliker-Fuse nucleus:

the principal source of pontine catecholaminergic cells projecting

to the lumbar spinal cord of cat. Brain Res 239:589–594.

Wilson MA, Molliver ME. 1991. The organization of serotonergic

projections to cerebral cortex in primates: retrograde transport

studies. Neuroscience 44:555–570.

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