PHYSIOLOGY AND
PATHOPHYSIOLOGY OF
CONSCIOUSNESS AND COMA
The Ascending Arousal System
In the late 19th century, the great British neu-
rologist John Hughlings-Jackson
17
proposed that
consciousness was the sum total of the activity
in human cerebral hemispheres. A corollary was
that consciousness could only be eliminated by
lesions that simultaneously damaged both cere-
bral hemispheres. However, several clinical ob-
servations challenged this view. As early as 1890,
Mauthner
18
reported that stupor in patients
with Wernicke’s encephalopathy was associated
with lesions involving the gray matter surround-
ing the cerebral aqueduct and the caudal part of
posterior hypothalamic lesions, as they were beginning to recover. These indi-
viduals would develop episodes of sleep attacks during which they had an over-
whelming need to sleep. He noted that they also had attacks of cataplexy in which
they lost all muscle tone, often when excited emotionally. Von Economo noted
accurately that these symptoms were similar to the rare condition previously
identified by Gelinaux as narcolepsy. S.A. Kinnier Wilson described a cohort of
similar patients in London in 1928.
24
He also noted that they had developed
symptoms of narcolepsy after recovering from encephalitis lethargica with pos-
terior hypothalamic lesions. Wilson even described examining a patient in his
office, with the young house officer McDonald Critchley, and that the patient
indeed had atonic paralysis, with loss of tendon reflexes and an extensor plantar
response during the attack.
Von Economo’s theory was highly influential during this period, and a great
deal of what was subsequently learned about the organization of brain systems
controlling sleep and wakefulness owes its origins to his careful clinicopath-
ologic observations and his imaginative and far-reaching vision about brain
organization.
Figure B1–1B. Von Economo’s original drawing of the localization of the lesions in the brain that
caused excessive sleepiness and insomnia. (Modified from von Economo,
19
with permission.)
Pathophysiology of Signs and Symptoms of Coma
11
the third ventricle. The nascent field of neuro-
surgery also began to contribute cases in which
loss of consciousness was associated with lesions
confined to the upper brainstem or caudal di-
encephalon. However, the most convincing
body of evidence was assembled by Baron Con-
stantin von Economo,
19
a Viennese neurologist
who recorded his observations during an epide-
mic of a unique disorder, encephalitis lethargica,
that occurred in the years surrounding World
War I. Most victims of encephalitis lethargica
were very sleepy, spending 20 or more hours
per day asleep, and awakening only briefly to
eat. When awakened, they could interact in a
relatively unimpaired fashion with the examiner,
but soon fell asleep if not continuously stimu-
lated. Many of these patients suffered from
oculomotor abnormalities, and when they died,
they were found to have lesions involving the
paramedian reticular formation of the midbrain
at the junction with the diencephalon. Other
patients during the same epidemic developed
prolonged wakefulness, sleeping at most a few
hours per day. Movement disorders were also
common. Von Economo identified the causa-
tive lesion in the gray matter surrounding the
anterior part of the third ventricle in the hypo-
thalamus and extending laterally into the basal
ganglia at that level.
Von Economo suggested that there was spe-
cific brainstem circuitry that causes arousal or
wakefulness of the forebrain, and that the hy-
pothalamus contains circuitry for inhibiting this
system to induce sleep. However, it was difficult
to test these deductions because naturally oc-
curring lesions in patients, or experimental
lesions in animals that damaged the brainstem,
almost invariably destroyed important sensory
and motor pathways that complicated the inter-
pretation of the results. As long as the only tool
for assessing activity of the cerebral hemispheres
remained the clinical examination, this problem
could not be resolved.
In 1929, Hans Berger, a Swiss psychiatrist,
reported a technologic innovation, the electro-
encephalogram (EEG), which he developed to
assess the cortical function of his psychiatric
patients with various types of functional impair-
ment of responsiveness.
25
He noted that the
waveform pattern that he recorded from the
scalps of his patients was generally sinusoidal,
and that the amplitude and frequency of the
waves in the EEG correlated closely with the
level of consciousness of the patient.
Shortly afterward, in 1935, the Belgian neu-
rophysiologist Frederic Bremer
28
(see also
29
) ex-
amined the EEG waveforms in cats into which
he had placed lesions of the brainstem. He
found that after a transection between the me-
dulla and the spinal cord, a preparation that he
called the encephale isole, or isolated brain, ani-
mals showed a desynchronized (low voltage, fast,
i.e., waking) EEG pattern and appeared to be
fully awake. However, when he transected the
neuraxis at the level between the superior and
inferior colliculus, a preparation he called the
cerveau isole, or isolated cerebrum, the EEG
showed a synchronized, or high-voltage, slow-
wave pattern indicative of deep sleep and the
animals were behaviorally unresponsive. Bremer
concluded that the forebrain fell asleep due to
the lack of somatosensory and auditory sen-
sory inputs. He did not address why the ani-
mals failed to respond to visual inputs either
with EEG desynchronization or by making ver-
tical eye movements (as do patients who are
locked in).
This issue was addressed after World War II
by Moruzzi and Magoun,
30
who placed more
selective lesions in the lateral part of the mid-
brain tegmentum in cats, interrupting the as-
cending somatosensory and auditory lemniscal
pathways, but leaving the paramedian reticular
core of the midbrain intact. Such animals were
deaf and did not appear to appreciate somato-
sensory stimuli, but were fully awake, as indi-
cated both by EEG desynchronization and mo-
tor responses to visual stimuli. Conversely, when
they placed lesions in the paramedian reticu-
lar formation of the midbrain, the animals still
showed cortical-evoked responses to somato-
sensory or auditory stimuli, but the background
EEG was synchronized and the animals were
behaviorally unresponsive. Later studies showed
that electrical stimulation of the midbrain re-
ticular core could excite forebrain desynchro-
nization.
31
These observations emphasized the
midbrain reticular core as relaying important
arousing influences to the cerebral cortex, and
this pathway was labeled the ascending reticular
activating system. The origin of the pathway was
not established in this early work.
Subsequent studies, in which transecting
lesions were placed sequentially at different
levels of the brainstem in cats, demonstrated
that transections at the midpontine level or
caudally down to the lower medulla resulted in
animals that acutely spent most of their time in
12
Plum and Posner’s Diagnosis of Stupor and Coma