Chapter 2

Neurophysiology of Sleep

Thomas E. Dick and Pingfu Feng

Introduction

Consideration of the neurophysiological mechanisms of sleep and wakefulness

emerged with the ability to measure sleep via the electroencephalogram (EEG),
developed by Hans Berger in the 1920s1930s. (Interestingly, this period overlaps
Nathaniel Kleitmans work on circadian rhythm published in 1929, which has been
tied to sleep ever since.) The EEG clearly showed various patterns; the first being
what Hans Berger described were alpha waves over the occipital cortex in awake
relaxed humans with their eyes closed. In subsequent recordings, EEG synchrony
was identified during the initial stages of sleep. Desynchronized or REM sleep was
not discovered until 1953, when Aserinsky and Kleitman recorded people at night.
Thus being able to distinguish EEG in wakefulness from sleep allowed scientists to
address the neural origins of sleep.
Initial experiments began by addressing what EEG patterns were present in the
isolated the central nervous system. Two preparations, encephale isole and cerveau
isole, were created in cats. The encephale isole had the CNS transected near the
caudal medulla, and the cats were kept alive on ventilators. Following this transec-
tion the cats went through oscillating periods of EEG synchrony and desynchrony.
In contrast the cerveau isole is a transection through the midline separating the
brainstem from the hypothalamus and cortex. Following this transection, the EEG
was synchronized. One difference between the preparations was cranial sensory
input, and the chronic EEG synchrony in the absence of sensory input resulted in
deafferentation theory of sleep, sleep as a passive state resulting from the absence of

T.E. Dick, Ph.D. (*) P. Feng, M.D., Ph.D.

Division of Pulmonary, Critical Care and Sleep Medicine,
Case Western Reserve University School of Medicine,
11100 Euclid Avenue, Cleveland, OH 44106-5067, USA
e-mail: [email protected]; [email protected]

K.P. Strohl, Competencies in Sleep Medicine: An Assessment Guide, 9

DOI 10.1007/978-1-4614-9065-4_2, Springer Science+Business Media New York 2014
10 T.E. Dick and P. Feng

sensory input. However, the other difference between the two preparations was the
loss of brainstem structures. In the 1930s these were poorly defined, but since then
many nuclei that determine state have been identified. In 1943, Moruzzi and Magoun
identified the ascending reticular activating system (ARAS or RAS) and an area in
the mesencephalon, which when selectively lesioned leaving the sensory pathways
to the thalamus intact, synchronized the EEG, whereas when activated, desynchro-
nized the EEG. This finding destroyed the passive theory of sleep even though you
as an individual do your best to reduce sensory input when you go to sleep by finding
a warm comfortable place, turning off lights, and reducing noise.
The subsequent experiments combined recording activity and selective pharma-
cology with the lesioning and stimulation protocols to identify sites which are
critical to state. Multiple sites have been identified that either promote wakefulness
or promote sleep. Indeed, a current theory is that the balance between these mecha-
nisms determines your state; ideally it is toggle switch, a flip-flop mechanism.
The mutual inhibitory network between the wakefulness and sleep-promoting
mechanisms ensures stable states. We present the material in this chapter to be
consistent with both ACGME and ABIM requirements as both clearly mandate a
comprehensive knowledge of the neural mechanisms underlying state.
The chapter will not be a review of the literature (See References 13) but will
focus on findings that are fundamental to sleep practitioners knowledge and will
provide specific examples of how topics in this area could be taught and then
assessed for competency. Table 2.1 is a map of content domains showing how sub-
topics may be related to the ACGME general competencies for training in sleep
medicine. Table 2.2 lists examples of content-specific questions for generating
learning objectives and for assessing the competency regarding these objectives.
The raised questions can be the basis for instructional classes and incentives for
journal club discussions.
This chapter also provides specific examples of assessment tools. The matching
test is included to review factual knowledge of the neurophysiological basis of
sleep. As knowledge develops in this field, questions can be added or modified.
Essay questions are provided to assess an integrated understanding of an approach.
These questions can be provided in many contexts and can be adopted to provide a
direction of the discussion. The IQ cases offer examples of IQ group exercises, in
which the learning objectives are disclosed later, requiring the learners to seek and
evaluate information to achieve the learning objectives of the case. These group
discussions assist learners to share knowledge and to improve their learning tech-
niques. The IQ cases can assess where the group training is.
An illustrative PowerPoint is presented in a PDF format on the companion
website (http://competenciesinsleepmedicine.weebly.com/neurophysiology.html).
It may be reviewed by the student and the program or discussed in a group format
before or after the essay questions or IQ case
2 Neurophysiology of Sleep 11

State-specific neuronal discharge patterns

Discharge type Cell location Transmitter
Wake-on/REM-off DR, LC, PH 5HT, NE, HA
LH HCRT
REM-on LDT/PPT Ach
Wake-on/REM-on LDT/PPT Ach
BF
NREM-on POA/AH/BF GABA
State independent VTA, SN DA

Table 2.1 Cognitive Map of the Content Domains Relevant

to the Neurophysiology of Sleep and Circadian Rhythm

Knowledge Skills ACGME competency

I Epidemiology Yes Yes B, F
Demographics
Risk factors
Special populations
II Mechanisms Yes Yes A, B, E
Central nervous system
Somatic nervous system
Autonomic nervous system
III Risk factors Yes Yes A, B
Psychiatric
Genetic/gender
Developmental/aging
IV Patient assessments Yes No A, C, F
Adult
Pediatrics
Special populations
V Diagnostic measures and interpretation Yes No A, C, F
Polysomnography
History and physical examination
Patient-based testing
VI Disease management Yes Yes A, E, D, F
Decisions on therapy
Type of therapy
(continued)
12 T.E. Dick and P. Feng

(continued)
Knowledge Skills ACGME competency
VII Health and disease clinical pathways Yes Yes A, C, F
Neural disorders
Psychiatric disorders
Medical comorbidities
Code for ACGME competencies
A. Patient care D. Interpersonal skills
B. Medical knowledge E. Professionalism
C. Practice-based learning and improvement F. System-based practice

Table 2.2 Examples of Topics with Educational Objectives

Item I. Genetics
Define genetic functional systems in sleep and wakefulness GABA, orexin, and monoamines
Become familiar with the terminology of neuroscience of sleep:
1. Brain structures: suprachiasmatic nucleus (SCN), ventrolateral preoptic area (VLPO),
tuberomammillary nucleus (TMN), subparaventricular zone (SPZ), dorsomedial nucleus of
the hypothalamus (DMH), pedunculopontine tegmentum/lateral dorsal tegmentum (PPT/
LDT), retinohypothalamic tract (RHT), dorsal raph, locus coeruleus, medial pontine
reticular formation, ascending reticular activating system, lateral hypothalamus, inhibitory
area of Magoun and Rhines, peri-locus coeruleus area
2. Neurotransmitters: melatonin, orexin (hypocretin), GABA, serotonin (5HT), acetylcholine
(ACh), histamine, adenosine, catecholamines, histamine, monoamines
3. Effective drugs: modafinil, armodafinil, benzodiazepines, almorexant, Rozerem (ramelteon),
Lunesta (eszopiclone), longdaysin
List how proteins affect cortical membrane potential, hyperpolarizing versus depolarizing
Item II. Anatomy and physiology
Describe the location and role of the hypothalamus (ventrolateral preoptic (VLPO), ventrolat-
eral hypothalamus, pedunculopontine tegmentum/lateral dorsal tegmentum (PPT/LDT),
reticular activating system (RAS)
Understand the balance of excitatory and inhibitory input in controlling thalamocortical loops
Understand the difference in the neurophysiologic basis between NREM and REM sleep
Understand the control of motor activity during REM sleep
Item III. Clinical syndromes
Describe from a neural systems viewpoint
Narcolepsy
Insomnia
Restless legs syndrome
REM sleep disorders
Sleep apnea
Item IV. Diagnostic measures as a reflection of circadian and sleep neural systems
Multiple sleep latency onset
Questionnaires
Polysomnography (especially EMG)
(continued)
2 Neurophysiology of Sleep 13

(continued)

Item V. Therapeutics
Drug actions that promote wakefulness (modafinil, armodafinil)
Drug actions that promote sleepiness (benzodiazepines, nonbenzodiazepines)
Drugs actions that treat cataplexy (tricyclic antidepressant, sodium oxybate)
Item VI. Prognosis, complications, and comorbid conditions
Discuss interactions of sleep neural systems with pathophysiologic and treatments for primary
neurologic and psychiatric disorders
Understand the interaction of drug addiction and recovery and sleep neurophysiology

Matching Test

Questions

The sleep-promoting actions of this neurotransmitter are antagonized by

caffeine.
These neurons release the inhibitory neurotransmitters galanin and GABA to inhibit
the monoaminergic cell groups in the locus coeruleus, the raphe nucleus, and the
tuberomammillary nucleus.
This hypothalamic region is critical for the integrating circadian rhythms of sleep-
wakefulness, feeding, locomotion, and temperature.
G-protein-coupled receptor that binds both orexin A and orexin B and is present
mainly in GABAergic putative brainstem interneurons.
This neurotransmitter is synthesized in raphe neurons whose activity varies with
state greatest in wakefulness and least in REM sleep.
This brainstem region contains serotonergic cells that become quiescent during
REM sleep.
Its release in the cortex is high during waking and REM sleep and lowest during
deep NREM sleep.
This brainstem structure described in 1949 receives input from many sensory
modalities and sends output to the thalamus and cortex. Its activity is state depen-
dent.
Synthesized in tuberomammillary nuclei of the posterior hypothalamus, this neu-
rotransmitter is released extensively throughout the brain.
Arousing neurotransmitter; formed in the CNS by tuberomammillary neurons in the
posterior hypothalamus.
This brainstem region contains neurons that are active during, and may even initiate,
REM sleep.
Stimulation of this cranial nerve is hypnogenic.
14 T.E. Dick and P. Feng

A hormone synthesized in the paraventricular nucleus of the hypothalamus which is

released in response to stress.
Nearly 50 years before the description of REM sleep, it has been known that carba-
chol administered to this brainstem area produced a state change which we now
refer to as REM-like.
This structure is critical for integrating sleep and metabolism physiologically and
behaviorally.
A drug that enhances the action of GABA at the GABAA receptor and promotes
sleep.
Medullary area which mediates muscle atonia.
A class of neurotransmitters with an amino group connected to an aromatic ring.
Examples include histamine, catecholamines (dopamine, norepinephrine, and
epinephrine), and tryptamines (serotonin (5-HT) and melatonin).
This brainstem nucleus contains norepinephrine neurons that are active during
wakefulness.
Bilateral lesions in this pontine area result in animals acting out their dreams.
This hypothalamic structure is critical for determining circadian rhythm.
The circadian rhythm of this hormones levels is disrupted by light in the blue-light
wavelength (~440 nm).
Loss of this nucleus after bilateral destruction of the posterior hypothalamus results
in hypersomnolence.
Deficiency in this neuropeptide modulator underlies the most common form of
narcolepsy, in which the sufferer briefly loses muscle tone (cataplexy).
This hypothalamic nucleus receives a strong projection from the SCN and con-
tains subnuclei that regulate circadian rhythms of body temperature and sleep
separately.
2 Neurophysiology of Sleep 15

Answers

1. Suprachiasmatic nucleus (SCN) 20. Vagus

2. Ventrolateral preoptic area (VLPO) 21. Melatonin
3. Tuberomammillary nucleus (TMN) 22. Orexin (hypocretin)
4. Paraventricular nucleus 23. Orexin 1 receptors
5. Subparaventricular zone (SPZ) 24. Orexin 2 receptors
6. Dorsomedial nucleus of the 25. GABA
hypothalamus (DMH) 26. Glycine
7. Pedunculopontine tegmentum/lateral 27. Serotonin (5HT)
dorsal tegmentum (PPT/LDT) 28. Acetylcholine (ACh)/
8. Retinohypothalamic tract (RHT) cholinergic
9. Median preoptic nucleus 29. Histamine
10. Dorsal raph 30. Adenosine
11. Locus coeruleus 31. A1 receptors
12. Klliker-Fuse nucleus 32. A2 receptors
13. Medial pontine reticular formation 33. Caffeine
14. Ascending reticular activating system 34. Epinephrine/catecholamines
15. Pineal body 35. Histamine
16. Lateral hypothalamus 36. Monoamines
17. Inhibitory area of Magoun and Rhines 37. Catecholamines
18. Peri-locus coeruleus area 38. Excitatory amino acids
19. Pontine gray 39. Benzodiazepine
20. Vagus 40. Corticotrophin-releasing factor
16 T.E. Dick and P. Feng

Questions with Answers

The sleep-promoting actions of this neurotransmitter are antagonized by

caffeine. 30
These neurons release the inhibitory neurotransmitters galanin and GABA to inhibit
the monoaminergic cell groups in the locus coeruleus, the raphe nucleus, and the
tuberomammillary nucleus. 2
This hypothalamic region is critical for the integrating circadian rhythms of sleep-
wakefulness, feeding, locomotion, and temperature. 6
G-protein-coupled receptor that binds both orexin A and orexin B and is present
mainly in GABAergic putative brainstem interneurons. 24
This neurotransmitter is synthesized in raphe neurons whose activity varies with
state greatest in wakefulness and least in REM sleep. 27
This brainstem region contains serotonergic cells that become quiescent during
REM sleep. 10
Its release in the cortex is high during waking and REM sleep and lowest during
deep NREM sleep. 28
This brainstem structure described in 1949 receives input from many sensory
modalities and sends output to the thalamus and cortex. Its activity is state
dependent. 14
Synthesized in tuberomammillary nuclei of the posterior hypothalamus, this neu-
rotransmitter is released extensively throughout the brain. 29
Arousing neurotransmitter; formed in the CNS by tuberomammillary neurons in the
posterior hypothalamus. 35
This brainstem region contains neurons that are active during, and may even initiate,
REM sleep. 7
Stimulation of this cranial nerve is hypnogenic. 20
A hormone synthesized in the paraventricular nucleus of the hypothalamus which is
released in response to stress. 40
Nearly 50 years before the description of REM sleep, it has been known that carba-
chol administered to this brainstem area produced a state change which we now
refer to as REM-like. 13
This structure is critical for integrating sleep and metabolism physiologically and
behaviorally. 16
A drug that enhances the action of GABA at the GABAA receptor and promotes
sleep. 39
Medullary area which mediates muscle atonia. 17
A class of neurotransmitters with an amino group connected to an aromatic ring.
Examples include histamine, catecholamines (dopamine, norepinephrine, and
epinephrine), and tryptamines (serotonin (5-HT) and melatonin). 36
This brainstem nucleus contains norepinephrine neurons that are active during
wakefulness. 11
Bilateral lesions in this pontine area result in animals acting out their dreams. 18
This hypothalamic structure is critical for determining circadian rhythm. 1
2 Neurophysiology of Sleep 17

The circadian rhythm of this hormones levels is disrupted by light in the blue-light
wavelength (~440 nm). 21
Loss of this nucleus after bilateral destruction of the posterior hypothalamus results
in hypersomnolence. 3
Deficiency in this neuropeptide modulator underlies the most common form of nar-
colepsy, in which the sufferer briefly loses muscle tone (cataplexy). 22
This hypothalamic nucleus receives a strong projection from the SCN and contains
subnuclei that regulate circadian rhythms of body temperature and sleep
separately. 5
18 T.E. Dick and P. Feng

Essay Questions

Familial Advanced Sleep Phase Syndrome (FASPS)

A 22-year-old male complains of early morning (~4:00 am) wakening and difficulty
to go back to sleep. He usually gets out of bed at 5:00 am. The early wakening cannot
be explained by anxiety regarding the days commitments or by jet lag, recent travel
crossing time zones. He is energized and performs well in the morning. However,
his energy runs out much earlier than what he expected in the afternoon. He does not
watch TV or movies in the evening due to difficulty in maintaining wakefulness
after 7:30 pm. He has to go to bed at 8:30 pm. This started several years ago but over
the past 2 years has worsened. Otherwise he is generally healthy and has maintained
a good GPA at both high school and college. He knows that his father and one of his
cousins have the similar problem. His Horne-stberg score was 75. His Morningness-
Eveningness Questionnaire (MEQ) showed he is M-type.
Questions
1. What is the most likely diagnosis?
2. How may patients melatonin phase change?
3. What gene mutation may patient have?
4. What are the treatments and their long-term effectiveness/outcome?
Answers
1. Familial advanced sleep phase syndrome (FASPS): Patients with FASPS have about
a 4-h phase advance, which causes arousal in the morning and sleep onset in the
evening earlier than normal population. In general, patients arouse at 45:30 am and
fall to sleep at 7:308:30 pm. Although their biological rhythms and major sleep
timing are all advanced, they are in phase with each other much like healthy con-
trols. FASPS has familial factors. The complaints of early wakening and sleeping
and the similar symptoms of their family members are a good indication of FASPS.
2. The patients dim-light melatonin onset (DLMO) should be phase-advanced by
34 h. This phase change should be distinguished from changes due to stress,
sleep deprivation, or unconventional sleep-wake schedules.
3. The patient may have either hPER2 or CK1 gene mutation. In this scenario,
CLOCK and BMAL1 are transcriptional factors that heterodimerize and induce
the expression of Per and Cry genes by binding to their promoters at E-boxes.
CK1 isoforms bind and phosphorylate PER and CRY and subsequently cause the
degradation of Clock/Bmal1 stopping the transcription of Per and Cry. Recently,
a missense mutation at a putative phosphorylation site in hPER2, Ser-662, was
identified in patients that suffer from FASPS. This is a serine-to-glycine point
mutation in the CK1 binding domain of the hPER2 protein that resulted in hypo-
phosphorylation of PER2 in vitro. Interestingly, a mutation of CK1 was found
separately in Japanese family that suffers from FASPS as well.
4. ASPD can be treated with bright light therapy in the evenings or behaviorally
with chronotherapy. Unlike other sleep disorders, ASPD does not disrupt normal
2 Neurophysiology of Sleep 19

functioning at work during the day, and the patient does not complain of excessive
daytime sleepiness. If their ASPD is causing patients to miss evening activities,
including putting their own normal children to bed, then with this treatment they
can stay awake later than their circadian rhythm. A sufferer of ASPD will still
wake very early, and if this cycle continues, it can lead to chronic sleep depriva-
tion and other sleep disorders.

Neurophysiology of Sleep and Circadian Rhythm

A 16-year-old male finds it hard to function at school and home and in social situa-
tions because of extreme tiredness. He has trouble sleeping at night, but can fall
asleep suddenly, even in the middle of talking, eating, or other activity. When he
falls asleep suddenly, he suffers loss of muscle tone. Strong emotions can often trig-
ger these episodes, which may last seconds or minutes.
Questions
1. What is the most likely diagnosis?
2. What are the probable neurophysiologic pathways that are disrupted to cause
narcolepsy?
3. How do treatment strategies intervene in these probable pathways?
4. What neurophysiologic pathways control muscle atonia during REM sleep?
Answers
1. Narcolepsy, which is a disorder that causes periods of extreme daytime sleepi-
ness. The disorder also may cause muscle weakness.
2. Orexin-producing neurons in the lateral posterior hypothalamic nuclei (perifor-
nical area, lateral hypothalamus, and posterior hypothalamus). These orexin
neurons activate monoaminergic neurons in the hypothalamus (tuberomammil-
lary nucleus) and brainstem (raphe, locus coeruleus) that promote wakefulness.
3. Treatment strategies depend on the differential symptoms of sleepiness and cata-
plexy. Excessive daytime sleepiness (sleep attacks) is responsive to stimulant
medications that promote wakefulness. Modafinil (Provigil) has FDA approval
for the treatment of narcolepsy and may act as an agonist of the orexin receptors.
Sodium oxybate (Xyrem) is approved for use in the treatment of narcolepsy to
reduce cataplexy and excessive daytime sleepiness (EDS).
4. Muscle atonia results from two complementary mechanisms: disfacilitation,
decreased noradrenergic and serotonergic excitatory input, and inhibition, gly-
cinergic and GABAergic inputs hyperpolarizing the membrane (making the
membrane potential more negative). Both disfacilitation and inhibition are brain-
stem mechanisms that can be elicited by acetylcholine placed in the brainstem.
Disfacilitation results from the loss of noradrenaline from locus coeruleus and
serotonin from caudal raph. These neuronal transmitters decrease because
activity of the groups is state dependent and decreases in REM sleep. On the
other hand, stimulation of the inhibitory area of Magoun and Rhines in the med-
ullary reticular formation mediates inhibition in REM sleep. These pathways are
involved in the muscle atonia of REM sleep.
20 T.E. Dick and P. Feng

IQ Case

Evaluate Neurophysiology of Sleep and Diagnosis

of Insomnia for Student

Goal: Understand the tools, especially how with an available history and clinical
data one can utilize knowledge of the neurophysiology of sleep.

Case Vignette

Insomnia description: A 22-year-old girl is self-referred to the sleep clinic because

she has been unable to fall asleep every night for several years. She also cannot
maintain a good sleep during the night due to frequent wakening up. This could be
a self-wakening up or wakening up by gentle noise. She finds it very difficult to go
back to sleep again if she wakes up. She said she dreamed a lot and she can remem-
ber almost everything that happened during the night. When she goes to school in
the morning, she feels tired. She is in her last year of college and majors Biology.
She feels nervous about exams. The sleep problem would be worsened if she has an
important schedule the next day. Sometimes she feels sad and lonely and is not
interested in any classes, but that is not often and lasts very briefly. Her GPA was 3.7
in high school and is around 3.3 currently.
The predominant complaint of primary insomnia is difficulty initiating or
maintaining sleep, or nonrestorative sleep, for at least 1 month. This may cause
significant distress in the daytime or during work and impact social or occupational
functioning. The sleep disturbance may associate with daytime fatigue and be
worsened by stress overloading. Primary insomniacs do not have a history of sub-
stances usage or diagnosis of mood disorders. However, literature reports that
chronic insomnia may lead to depressive disorders.
Major symptom of insomnia is difficulty in falling asleep and maintaining sleep.
Thus, patient may have extended sleep latency, increased number of wakefulness after
sleep onset, reduced total sleep, and decreased deep sleep such as N3. If the power
spectral density of the EEG is analyzed, the delta power band may be decreased. This
could be partially reflected in the PSQI and should have all in the PSG data. Patients
diagnosed with primary insomnia should have a normal PHQ-2.
Insomnia is a highly prevalent sleep disorder, yet little is known about the role of
genetic factors in its pathophysiology. Primary insomnia may have PSG hyperarousal
and elevated hypothalamic-pituitary-adrenal (HPA) axis. Elevated brain level of CRF
or orexins may be involved. However, there is no literature regarding the measure-
ment of CSF orexin levels in primary insomniacs. Primary insomnia has to be treated
individually and can be treated with cognitive behavioral therapy such as reducing
usage of caffeine, tobacco, or alcohol near bedtime and avoiding daytime sleep.
Antidepressant trazodone has been selected as the initial treatment in a considerable
percentage of patients. Newer classes of benzodiazepine and nonbenzodiazepine are
also used substantially. Primary insomnia is treatable but may be difficult to cure.
2 Neurophysiology of Sleep 21

Evaluate Neurophysiology of Sleep and Diagnosis

of Insomnia for Facilitator

Goal: Understand the instrument available for the examination and assessment of
sleep quality and how to interpret them.
Objectives (Revealed at the End of the Session)
A. Describe the different sleep states and their neurophysiologic basis.
B. Interpret polysomnography (EEG, EOG, EMG, and cardiorespiratory) patterns.
C. Discuss the neurophysiologic basis of common sleep disorders.
D. Describe the impact of disturbed sleep on patients quality of life.
E. Propose a diagnostic plan to properly assess the neurologic function in sleep
disorders.

Case Vignette

Insomnia description: A 22-year-old girl is self-referred to the sleep clinic because

she has been unable to fall asleep every night for several years. She also cannot
maintain a good sleep during the night due to frequent wakening up. This could be
a self-wakening up or wakening up by gentle noise. She finds it very difficult to go
back to sleep again if she wakes up. She said she dreamed a lot and she can remem-
ber almost everything that happened during the night. When she goes to school in
the morning, she feels tired. She is in her last year of college and majors Biology.
She feels nervous about exams. The sleep problem would be worsened if she has an
important schedule the next day. Sometimes she feels sad and lonely and is not
interested in any classes, but that is not often and lasts very briefly. Her GPA was 3.7
in high school and is around 3.3 currently.
Probing Questions
1. What kind of sleep disorder is most probable?
2. What conditions may predispose to this disorder?
3. What complications may arise from this if left untreated?
4. How would you proceed with a diagnostic plan?
The predominant complaint of primary insomnia is difficulty initiating or
maintaining sleep, or nonrestorative sleep, for at least 1 month. This may cause
significant distress in the daytime or during work and impact social or occupational
functioning. The sleep disturbance may associate with daytime fatigue and be wors-
ened by stress overloading. Primary insomniacs do not have a history of substances
usage or diagnosis of mood disorders. However, literature reports that chronic
insomnia may lead to depressive disorders.
22 T.E. Dick and P. Feng

Probing Questions
5. What do the PSQI (Pittsburgh Sleep Quality Index) and PHQ-2 (Patient Health
Questionnaire-2) show?
6. What do the multiple sleep latency test and polysomnography show?
7. What is your diagnosis based on the PSQI and polysomnography?
8. What is the concordance between PSQI and polysomnography?
The major symptom of insomnia is difficulty in falling asleep and maintaining
sleep. Thus, the patient may have extended sleep latency, increased number of
wakefulness after sleep onset, reduced total sleep, and decreased deep sleep such as
N3. If analyzed using EEG power frequency, the delta power band may be decreased.
This could be partially reflected in the PSQI and should have all in the PSG data.
Patients diagnosed with primary insomnia should have a normal PHQ-2.
Probing Questions
9. What can you tell the patient about inheritability?
10. What is the chance of successful treatment?
11. How can you reduce the chance of other sleep and psychiatric disorders from
developing?
Insomnia is a highly prevalent sleep disorder, yet little is known about the role of
genetic factors in its pathophysiology. Primary insomnia may have PSG hyperarousal
and elevated hypothalamic-pituitary-adrenal (HPA) axis. Elevated brain level of CRF
or orexins may be involved. However, there is no literature regarding the measure-
ment of CSF orexin levels in primary insomniacs. Primary insomnia has to be treated
individually and can be treated with cognitive behavioral therapy such as reducing
usage of caffeine, tobacco, or alcohol near bedtime and avoiding daytime sleep.
Antidepressant trazodone has been selected as the initial treatment in a considerable
percentage of patients. Newer classes of benzodiazepine and nonbenzodiazepine are
also used substantially. Primary insomnia is treatable but may be difficult to cure.
Probing Questions
12. What is the long-term efficacy of treatment?
13. What other insomnia disorders can you name?

Evaluate Neurophysiology of Sleep and Diagnosis

of Insomnia: Final Handout/Objectives

Goal: Understand the instrument available for the examination and assessment of
sleep quality and how to interpret them.
2 Neurophysiology of Sleep 23

Objectives (Revealed at the End of the Session)

A. Describe the different sleep states and their neurophysiologic basis.
B. Interpret polysomnography (EEG, EOG, EMG, and cardiorespiratory) patterns.
C. Discuss the neurophysiologic basis of common sleep disorders.
D. Describe the impact of disturbed sleep on patients quality of life.
E. Propose a diagnostic plan to properly assess the neurologic function in sleep
disorders.

Evaluation of Neurophysiology of Sleep for Student

Case Vignette

A 53-year-old man is at the sleep clinic because since the age of 44 he has been
unable to fall asleep easily. When he goes to bed at night, he feels urges to move his
legs due to uncomfortable sensations coming from his legs. Stretching and even just
moving the legs brings temporary relief. However, walking for an extended period
before going to bed effectively relieved these urges in the past, but it has gotten
progressively less effective. Further, on long plane trips or long classical music
concerts, he has to get up and walk around to relieve the discomfort. In the morning,
he doesnt have these symptoms while lying in bed. He is physically fit with no
other apparent medical problems.
Restless legs syndrome (RLS) or Willis-Ekbom disease: Surprisingly up to 10 %
of the US population may have RLS, but most have a mild form of the disorder that
is relieved by physical activity and is intermittent. Nevertheless severe, sleep disrup-
tive RLS affects millions of individuals. Support groups have formed a website:
http://www.rls.org.
The patient is diagnosed with restless legs syndrome (RLS) or Willis-Ekbom
disease based on self-reported symptoms and the absence of causes due to vitamin
or iron (serum ferritin) deficiencies, vascular insufficiency, and thyroid hormone
abnormalities. No specific test exists for restless legs syndrome; rather eliminate
secondary, highly treatable causes of RLS.
More than 60 % of cases of RLS are inherited in an autosomal dominant fashion
with variable penetrance (Lavigne and Montplaisir 1994). Treatment is first to
reduce symptoms and second, if necessary, pharmacologic. Many drug treatments
have been proposed; one discussed on the restless legs website is ropinirole, a dopa-
minergic agonist. Interestingly in states that have medical marijuana laws, RLS is a
treatable illness.
24 T.E. Dick and P. Feng

Evaluation of Neurophysiology of Sleep for Facilitator

Goal: Understand the tools, especially history available to evaluate of neurophysiology

of sleep and how to interpret the data.
Objectives (Revealed at the End of the Session)
A. Describe the neurophysiologic basis of motor control during different sleep states.
B. Interpret EMG and what other measurement can be used to confirm the EMG
findings.
C. Discuss the neurophysiologic basis of NREM sleep and disorders associated
with movement during NREM sleep.
D. Discuss the neurophysiologic basis of REM sleep and disorders associated with
movement during REM sleep.

Case Vignette

A 53-year-old man is at the sleep clinic because since the age of 44 he has been
unable to fall asleep easily. When he goes to bed at night, he feels urges to move his
legs due to uncomfortable sensations coming from his legs. Stretching and even just
moving the legs brings temporary relief. However, walking for an extended period
before going to bed effectively relieved these urges in the past, but it has gotten
progressively less effective. Further, on long plane trips or long classical music
concerts, he has to get up and walk around to relieve the discomfort. In the morning,
he doesnt have these symptoms while lying in bed. He is physically fit with no
other apparent medical problems.
Probing Questions
1. What kind of sleep disorder is most probable?
2. What conditions may predispose to this disorder?
3. What complications may arise from this if left untreated?
4. How would you proceed with a diagnostic plan?
5. What would you say to the sufferer? What is the prevalence? What is the success
of treatment?
Restless legs syndrome (RLS) or Willis-Ekbom disease: Surprisingly up to 10 %
of the US population may have RLS, but most have a mild form of the disorder that
is relieved by physical activity and is intermittent. Nevertheless severe, sleep disrup-
tive RLS affects millions of individuals. Support groups have formed a website:
http://www.rls.org.
Probing Questions
6. Are there specific tests for this disorder? What will polysomnography show?
7. On what is your diagnosis based?
8. Would blood tests help?
2 Neurophysiology of Sleep 25

The patient is diagnosed with restless legs syndrome (RLS) or Willis-Ekbom

disease based on self-reported symptoms and the absence of causes due to vitamin
or iron (serum ferritin) deficiencies, vascular insufficiency, and thyroid hormone
abnormalities. No specific test exists for restless legs syndrome; rather eliminate try
to secondary, highly treatable causes of RLS.
Probing Questions
9. What can you tell the patient about inheritability?
10. What is the chance of successful treatment?
11. What other sleep disorders are associated with this disease?
More than 60 % of cases of RLS are inherited in an autosomal dominant fashion
with variable penetrance (Lavigne and Montplaisir, 1994). Treatment is first to
reduce symptoms and second, if necessary, pharmacologic. Many drug treatments
have been proposed; one discussed on the restless legs website is ropinirole a dopa-
minergic agonist.
Probing Questions
12. What is the long-term efficacy of treatment?
13. What other motor control disorders associated with sleep and its stage?

Evaluation of Neurophysiology of Sleep: Final Handout/

Objectives

Goal: Understand the tools, especially history available to evaluate of neurophysiol-

ogy of sleep and how to interpret the data.
Objectives (Revealed at the End of the Session)
A. Describe the neurophysiologic basis of motor control during different sleep states.
B. Interpret the EMG and find other signals to confirm EMG findings.
C. Discuss the neurophysiologic basis of NREM sleep and disorders associated
with movement during NREM sleep.
D. Discuss the neurophysiologic basis of REM sleep and disorders associated with
movement during REM sleep.

Selected References

1. Fuller PM, Gooley JJ, Saper CB. Neurobiology of the sleep-wake cycle: sleep architecture,
circadian regulation, and regulatory feedback. J Biol Rhythms. 2006;21:48293.
2. Saper CB, Fuller PM, Pedersen NP, et al. Sleep state switching. Neuron. 2010;68:102342.
3. Saper CB. Staying awake for dinner: hypothalamic integration of sleep, feeding, and circadian
rhythms. Prog Brain Res. 2006;153:24352.
4. Lavigne GJ, Montplaisir JY. Restless legs syndrome and sleep bruxism: prevalence and asso-
ciation among Canadians. Sleep. 1994 Dec;17(8):73943.
http://www.springer.com/978-1-4614-9064-7