Passive versus Active Theories of Sleep

The discovery on which the neurobiology of control of the arousal state is built
belonged to Frederic Bremer (1892-1982). In 1935, Bremer demonstrated that
transection of the caudal medulla, although producing paralysis requiring
mechanical ventilation, also produced an animal that remained alert, with normal
sleep-wake cycles. Conversely, transection through the mesencephalon,
immediately caudal to the nucleus of the third cranial nerve, yielded an animal that
breathed spontaneously but was unresponsive and displayed a continuous sleep
pattern in its electroencephalogram (EEG) ( Fig. 11-1 ). Bremer's discovery formed
the foundation for the passive theory of sleep. However, passive notions of sleep
predate Bremer. The roots for this idea exist in the surviving sixth century bc
writings of the Greek philosopher Alcemaeon and were known to Aristotle, who
expounded on them in his treatise De Somno et Vigilia (On Sleep and Waking).
Bremer's experimental evidence lent credence to the ancient Greek idea that sleep
is caused by isolation of the brain from the rest of the body. Bremer hypothesized
that sleep results anytime that the brain is deprived of its tonic sensory input. Under
this passive view, sleep was nothing more than a default state produced by
cessation of the active statewaking. A student of Bremer's, Giuseppe Moruzzi
(1910-1986), fortified his mentor's hypothesis in collaboration with the physiologist
Horace Magoun (1907-1991). Using electrical stimulation of the brainstem reticular
formation (which falls in between Bremer's mesencephalic and caudal medullary
lesion sites), Moruzzi and Magoun stimulated wakefulness while suppressing sleep
and in so doing made the first description of the ascending reticular activating
system.[6] Together, they also narrowed the window for inducing a persistent state
of sleep by demonstrating that lesions through the midpontine pretrigeminal area of
the cat did not affect the cyclic nature of control of the arousal state but confirmed
that a lesion only a few millimeters more cephalad through the rostral pons at the
level of the inferior colliculus produced the identical comatose syndrome as
Bremer's ( Fig. 11-2 ).

Figure 11-1 Brainstem transections may radically alter the state of arousal. A,
Bremer's cerveau isole cat in which transection at the collicular level prevents
brainstem and hypothalamic arousal-promoting signals from reaching the forebrain,

thereby producing a state of deep coma. B, This contrasts with the enephale isole
cat, in which transection through the caudal medulla disrupts spontaneous
ventilation but leaves control of the arousal state intact. (Modified from Steriade M,
Constantinescu E, Apostol V: Correlations between alterations of the cortical
transaminase activity and EEG patterns of sleep and wakefulness induced by brainstem transections. Brain Res 13:177-180, 1969.)

Figure 11-2 Schematic horizontal sections through the cat's brainstem depicting the
production of a comatose state resembling continuous sleep in the cat that is
immensely similar, if not identical to, the results of barbiturate-induced hypnosis. A,
Midpontine pretrigeminal lesions that ablate the laterodorsal tegmental (LDT) and
pedunculopontine tegmental (PPT) cholinergic neuronal projections to the thalamus
and basal forebrain and produce continuous slow-frequency, large-amplitude
patterns characteristic of sleep on the electroencephalogram (EEG) in both the right
(F.d.) and left (F.s.) frontal EEG leads. B, Transections several millimeters more
caudad through the rostral pons spare brainstem cholinergic neurons and their
projections and lead to preservation of arousal as typified by the fast-frequency lowamplitude patterns on the EEG that characterize normal wakefulness. (Modified
from Batini C, Moruzzi G, Palestini M, et al: Persistent patterns of wakefulness in the
pretrigeminal midpontine preparation. Science 128:30-32, 1958.)

Nathaniel Kleitman (1895-1999) was another early proponent of the passive theory
of sleep genesis. Among his important discoveries was recognition of the
paradoxical stage of sleep, termed rapid eye movement (REM) sleep. This state
differed dramatically from slow-wave or non-REM (NREM) sleep, as discussed later.
For all his careful observations of sleep stages, however, Kleitman pointed out that
it was the genesis of wakefulness that required explanation. Before leaving Bremer
and the concept of passive sleep, we should return to his studies of the cerveau
isole cat, in which a mesencephalic lesion deprives the forebrain of all sensory input
(save olfactory and visual stimuli, which are carried by cranial nerves I and II).
Bremer's insights have direct relevance for anesthetic action. In fact, Bremer's
original description of the cerveau isole cat likened the resulting state as being
immensely similar, if not identical to barbiturate anesthesia, as well as to natural
sleep,[7] a concept to which we shall return in this chapter.

An alternative theory accounting for sleep requires its active genesis. According to
the active sleep hypothesis, sleep is generated when specific neuronal systems
increase their firing rates and thus inhibit the output of other neuronal structures
required for wakefulness. Evidence for an active genesis of sleep has accumulated.
During World War I, an outbreak of viral encephalitis reached pandemic proportions.
Although many survivors experienced symptoms of profound and prolonged
sleepiness (hypersomnolence), a smaller subset of survivors exhibited profound and
prolonged insomnia. Based on postmortem neuropathologic observations and
correlations with the premortem clinical condition, Baron Constantine von Economo
(1876-1931) astutely noticed that the insomniacs had sustained damage within the
anterior hypothalamus around the preoptic area, as well as damage to the basal
forebrain. Those exhibiting hypersomnolence had sustained posterior hypothalamic
damage. von Economo correctly predicted the existence of a sleep-promoting region
of brain within the anterior hypothalamus near the optic chiasm, in addition to a
wake-promoting region in the posterior hypothalamus.[8] His predictions made
more than three quarters of a century ago have withstood the scrutiny of time.
Experimental evidence for a hypnogenic center in the preoptic area of the
hypothalamus was confirmed in rats and cats inasmuch as insomnia also resulted
after lesions to the preoptic area, [9] [10] as well as after bilateral microinjection of
muscimol, a -aminobutyric acid (GABA) agonist, into the preoptic area.[11] Finally,
the discovery of a population of inhibitory GABAergic neurons whose activity
displays state-dependent firing patterns,[12] with the highest discharge rates
occurring during sleep[13] and whose efferent projections inhibit wake-promoting

centers (reviewed by Saper and colleagues[14]), fulfills all the criteria for the active
generation of sleep.

Although controversy between active and passive mechanisms of the genesis of

sleep still remains, these modes need not be mutually exclusive. As we discuss
later, the hypnogenic neural substrates that promote sleep antagonize the wakepromoting regions in brain. In the absence of neuropathology, synchronized
communication between these sleep- and wake-active neural populations ensures
smooth and appropriately timed transitions between arousal states.[15]

Physiologic Patterns of Wakefulness and Sleep

The states of sleep and wakefulness may be characterized physiologically by

recording the EEG and electromyogram (EMG). Wakefulness is identified by a fastfrequency, low-amplitude rhythm on the EEG that is desynchronized, together
with the presence of maximal motor activity on the EMG ( Fig. 11-3 ). Broadly
speaking, sleep may be subdivided into two distinct patterns, REM sleep and NREM
sleep, which is also known as slow-wave sleep. During NREM sleep, the EEG displays
large-amplitude, slow frequencies in the range of 0.5 to 4 Hz that dominate the
power spectrum. Motor tone is lower during NREM sleep than during wakefulness
( Fig. 11-3 ). NREM sleep patterns contrast dramatically with wakefulness, in which
the EEG is desynchronized and exhibits low-amplitude, fast frequencies. During REM
sleep, the EEG is also desynchronized and is virtually indistinguishable from
wakefulness. However, as opposed to wakefulness, EMG activity during REM sleep is
minimal to absent. The presence of activity (4 to 8 Hz) is also an abundant feature
of REM sleep, as is eye movement, which may be recorded with an electrooculogram (EOG) (for review see Harris[16]).

Figure 11-3 Cortical manifestation of wakefulness, rapid eye movement (REM)

sleep, and non-REM (NREM) sleep with corresponding muscle tone. Wakefulness is
defined by a desynchronized, low-amplitude, fast-frequency electroencephalogram
(EEG) with prominent muscle activity. REM sleep shows similar signs of cortical

activation with a desynchronized, low-amplitude, fast-frequency EEG in which

rhythms of 4 to 8 Hz dominate the power spectrum. However, unlike wakefulness,
motor activity is minimal in this state. NREM sleep has an EEG appearance that is
markedly different from the other two states. During NREM sleep, the EEG displays
slow-frequency, large-amplitude oscillations. Motor tone during NREM is
dramatically reduced. (Courtesy of Yihan Chen, University of Pennsylvania,
unpublished