Term
Give an example of a biological function that follows each of the following rythms:
1) Circadian
2) Ultradian
3) Infradian |
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Definition
1) 24h (melatonin and cortisol)
2) <24h (Cardiac, respiratory rhythms)
3) >24h (menstrual cycle) |
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Term
How can sleep-wake and temperature/melatonin rhythms become "desynchronized"?
What is this called? |
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Definition
Internal De-synchrony
-Humans can only be entrained to days of 23-26 hours.
- If organism is forced into day length that is 30 hours, for example, sleep-wake cycle will accommodate, but other biological rhythms will not (Internal de-synchrony) |
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Term
| What does it mean for a rhythm to be "free running"? |
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Definition
| When humans are studied in environment with no time cues, observed rhythms are said to be "free running" at endogenous period length (24h 6 minutes for humans) |
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Term
| What does it mean for some endogenous rhythms to be "masked"? |
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Definition
When patients are forced to stay awake, body temperature will have a lower trough of body temperature then if they sleep (e.g. it is "masked" by the lack of sleep).
Sleep cannot mask melatonin rhythms! |
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Term
| What does it mean for circadian rhythms to be entrained by "Zeitgebers"? |
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Definition
Zeitgebers such as light, are "time givers."
- In animals that live in dark 24 hours a day, sleep-wae cycle can be entrained by timing of a light pulse (gradual change)
- Think about "jet lag." Light slowly "phase-shifts" the sleep-wake cycle (depends upon intensity and duration of light). |
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Term
| What is the neuroanatomy of the circadian system? |
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Definition
Master clock is Suprachiasmatic nuclei (SCN) of hypothalamus, located above optic chiasm at base of 3rd ventricle.
1) Afferent
- melanopsin-containing retinal ganglion cells (transmit in absence of visual perception) project through retino-hypothalamic tract to SCN
2) Efferent (4 paths)
- Subparaventricular nucleus of hypothalamus (regulate sleep-wake states)
- Medial pre-optic area (circadian temperature)
- Anterior and lateral hypothalamus
- Lateral genicular nuclei of thalamus |
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Term
| Which efferent circadian tract influences temperature regulation? |
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Definition
| SCN to medial pre-optic area |
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Term
| What evidence suggests that the SCN is the pacemaker for circadian rhythms? |
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Definition
1) Bilateral lesions abolish circadian rhythms in free-running animals
2) Transplant of SCN tissue restores rhythmicity
3) SCN tissue cultured ex vivo shows robust 24h rhythms of glucose metabolism and action potentials |
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Term
| Explain the molecular biological basis for circadian rhythm generation. |
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Definition
Evolutionarily conserved group of 9 genes
1) Clock genes transcribe mRNA during daylight
2) RNA is translated in cytoplasm
3) Proteins form complexes that translocate back to nucleus generating positive and negative feedback on their transcription
4) Protein products are "read" by cytoplasmic mechanisms of SNCN cells, leading to changes in membrane potential, which alters effector signaling. |
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Term
| How does light regulate timing of the molecular clock within the SCN? |
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Definition
1) Pineal gland produces melatonin, which binds to receptors in SCN (light-sensitive)
2) Second messenger cascade leads to phosphorylation of CREB and transcription of clock genes in SCN cells.
**Pathways are differentially sensitive to various circadian phases, forming basis for phase-response curves** |
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Term
| What are the 3 major characteristic features of sleep? |
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Definition
1) Periodicity
2) Reduced interaction with environment (not absent)
3) Rapid reversibility (vs. coma) |
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Term
| What methods are available for assessing sleep-wake status? |
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Definition
1) Self report/Sleep-awake diaries
2) Actigraphy (body movement measurment)
- Useful long-term
3) Polysomnography (PSG)
- Modified EEG for EEG, eye movements and surface EMG (submentalis muscle)
- Distinguishes between wakefulness, NREM and REM sleep. |
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Term
| Describe the characteristics of Wakefulness, NREM (N1-N3) and REM sleep states on PSG. |
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Definition
1) Wakefulness
- fast frequency, mixed/low amplitude EEG (regular alpha, 8-12 Hz) when eyes closed.
- EMG high and variable
- EOG shows frequent saccadic and volitional eye movement in all directions
- Full O2, Co2 response
2) NREM (N1)
- EEG are slower, higher amplitude
- EMG is reduced
- EOG shows slow rolling
- Lowest level of arousal
3) NREM (N2)
- EEG shows sleep spindles (12-16hz bursts) and K complexes (single large amplitude, slow waves)
- EOG has little movement
- EMG is low
4) NREM (N3)
- Large amplitude, slow frequency delta waves (0.5-4hz)
- EOG shows no eye movements
- EMG is low, but not absent
5) REM
- EEG is low amplitude, high (mixed) frequency
- EMG is atonic, except for brief twitches
- EOG has rapid eye movements in dreams |
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Term
| How can you tell between NREM stages 1-3? |
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Definition
1) N1
- EEG are slower, higher amplitude
- EMG is reduced
- EOG shows slow rolling
2) N2
- EEG shows sleep spindles (12-16hz bursts) and K complexes (single large amplitude, slow waves)
- EOG has little movement
- EMG is low
3) N3
- Large amplitude, slow frequency delta waves (0.5-4hz)
- EOG shows no eye movements
- EMG is low, but not absent |
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Term
| Explain the basic structure of the sleep histogram. |
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Definition
1) Wakefulness transitions to NREM sleep, progressing from light to deeper sleep stages
2) After 60-100 minutes, sleep "lightens" and REM begins
3) REM, NREM cycles every 90-100 minutes (REM bouts get longer as night progresses) |
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Term
| Distinguish between "Hemeostatic" and "Circadian" Regulation of Sleep-Wake states. |
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Definition
1) Homeostatic (drives initiation of sleep)
- increasing sleep tendency with increasing hours of wakefulness
- With increasing duration of wakefulness, EEG theta activity (4-8 hz) increases (as do slow eye movements)
- Delta EEG activity increases during subsequent sleep as saturating logarithmic function of prior wake duration (can reach ceiling)
2) Circadian (keeps us asleep during second half of night)
- 24 variation in sleep propensity (highest between 5-9 am!)
- Integrates with homeostatic to govern sleep timing and duration |
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Term
| What is the neuroanatomical basis of "wakefulness"? |
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Definition
1) Ascending RAS sends ascending projections to dorsal diencephalic path (thalamic nuclei...cortex) and ventral path (basal forebrain cholinergic nuclei...cortex)
- Dorsal path links to EEG pattern of wakefulness
- Ventral path linked to behavioral aspects of arousal
2) Tuberomamillary nuclei of post. hypothalamus projects to cortex (receives direct input from SCN to integrate circadian information)
3) Hypocretin (orexin) system in perifornical area of lateral hypothalamus (project to brain stem arousal systems like locus coeruleus)
4) Cholinergic nuclei of basal forebrain
5) Cerebral cortex and limbic system (voluntary behavior and emotional tone) |
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Term
| What sub-components are found in the Ascending RAS that promote wakefulness? |
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Definition
Pontine nuclei
1) NA locus coeruleus
2) 5-HT raphe nuclei
3) Cholinergic pedunculopontine tegmentum and laterodorsal tegmentum |
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Term
| What is the neuroanatomical basis of "NREM Sleep"? |
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Definition
Brainstem and Diencephalon (also neocortex and limbic)
1) Brainstem solitary tract neurons (follow dorsal/ventral paths of "wakefulness" structures)
- important for "normal" NREM sleep
2) "Sleep Switch" Ventrolateral and median preoptic areas (VLPO and MnPO) of hypothalamus
- VLPO has GABAergic and galaninergic neurons that are selectively more active during NREM sleep than wakefulness
- VLPO has reciprocal innervation to tuberomamillary nucleus of posterior hypothalamus and provides inhibitory innervation to ARAS and hypocretin-containing cells of lateral hypothalamus
-MnPO gets input from SCN
3) Thalamocortical circuits generate NREM EEG sleep rhythms (thalamic hyperpolarization produces sleep spindles in N2 and delta waves in N3)
4) "Sleep homeostat" in basal forebrain that produces extracellular adenosine (buildup during wakefulness and decrease during NREM sleep) |
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Term
| What are the "sleep switch" and "sleep homeostat" of NREM sleep? |
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Definition
1) "Sleep Switch" Ventrolateral and median preoptic areas (VLPO and MnPO) of hypothalamus
- VLPO has GABAergic and galaninergic neurons that are selectively more active during NREM sleep than wakefulness
- VLPO "turns off" wakefulness centers (has reciprocal innervation to tuberomamillary nucleus of posterior hypothalamus and provides inhibitory innervation to ARAS and hypocretin-containing cells of lateral hypothalamus"
2) "Sleep homeostat" in basal forebrain that produces extracellular adenosine (buildup during wakefulness and decrease during NREM sleep) |
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Term
| How does caffeine inhibit sleep? |
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Definition
| Blocks adenosine receptors in basal forebrain, thereby decreasing NREM sleep via "sleep hemeostat" |
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Term
| What is the neuroanatomical basis of "REM Sleep"? |
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Definition
In Rostral Pons
1) Cholinergic and Cholinoreceptive neurons PPT and LDT nuclei promote own activity via positive feedback loops and stimulate "REM off" neurons in locus coeruleus and raphe nuclei
2) As neurons in LC and RN become more active, they inhibit cholinergic nuclei and "shut off" REM sleep. |
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Term
1) Where does muscle atonia during REM sleep arise from?
2) What about rapid eye movements? |
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Definition
1) Bulbospinal inhibitory RF and SC
2) Medial pontine RF through stimulation of nuclei of CN II, IV and VI. |
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Term
| Explain the basic idea behind the integration of "wakefulness," "NREM" and "REM" sleep signals. |
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Definition
1) Wakefulness arises from tonic activation of brainstem and hypothalamic centers (adenosine builds up in basal forebrain)
2) As adenosine builds up, "sleep switch" of VLPO is tripped, and inhibition of hypothalamic and brain stem wake-promoting systems occurs.
3) As NREM progresses, 5-HT and NA nuclei gradually decline and REM sleep sets in, builds up and is then suppressed by LC/RN (via stimulation by PPT and LDT in pons, which first initiated REM with ACh release) |
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Term
What is the role of each of the following neurotransmitters in Sleep-Wake states?
1) NA/5-HT
2) ACh
3) Histamine
4) DA
5) GABA
6) Adenosine
7) NO |
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Definition
*all modified by NO
Wakefulness
- High spontaneous NA, 5-HT
- Adenosine builds up (Basal forebrain) and DA modifies expression of wakefulness
- Histaminergic nuclei
- ACh (pontine tegmentum) if "quiet wakefulness"
NREM
- GABA (VLPO of hypothalamus- sleep switch)
- Decreased NA and 5-HT
REM
- ACh in pontine tegmentum (PPT and LDT)
- No 5-HT/NA
1) NA and 5-HT
- Highest spontaneous firing during "wakefulness"
- Decreased in NREM
- Silent in REM
2) ACh (pontine tegmentum)
- Active during REM
- Inhibited during active "wakefulness," but activate during "quiet wakefulness".
3) Histaminergic nuclei only active during "wakefulness"
4) DA "modifies wakefulness
5) GABA is onset and promotion of NREM (VLPO)
6) Adenosine (basal forebrain) regulates sleep homeostasis (builds up during wakefulness)
7) Nitrous Oxide modifies NT action in both sleep and circadian function |
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Term
| Other then neurotransmitters, what other compounds regulate sleep-wake states? |
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Definition
1) Hypocretin and Neuropeptide Y (Peptides)
2) Fatty acid oleoamide
3) Interleukins and IFNs
4) GH, melatonin and cortisol (Hormones) |
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Term
| What is the relevance of the "local sleep" view for clinical disorders or sleep? |
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Definition
Sleep is, at least in part, an emergent phenomena deriving from the coupling of individual neurons and neuronal assemblies switching from higher to lower rates of firing
- Provides basis for observation of "sleep" and "wake" activity simultaneously. |
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Term
| How are Circadian Rhythms integrated with Sleep-Wake states? |
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Definition
- SNC efferents to subparaventricular nucleus and medial pre-optic area of anterior hypothalamus provide link between circadian clock and sleep-wake regulators.
- SCN directly projects to posterior hypothalamic "wake promoting" centers (tuberomamillary nuclei) and indirectly to the locus coerulius (NA)
- presence of sleep and wake states feedback to SCN system (inhibit light input during sleep) |
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Term
| What are "sleep spindles" and "K complexes" and what are they associated with? |
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Definition
| EEG shows sleep spindles (12-16hz bursts) and K complexes (single large amplitude, slow waves) during N2 NREM sleep. |
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Term
| How is REM and NREM sleep cyclically generated/suppressed? |
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Definition
Waves of NA/5-HT (NREM) and ACh (REM)
1) As NREM progresses, cholinergic activity from PPT and LDT of pons promote REM sleep and gradually decrease NA/5-HT
2) During REM, PPT and LDT also activate "REM off" neurons in RN (5-HT) and LC (NA), which inhibit PPT and LDT and switch back towards NREM. |
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Term
| What are the major types of Sleep disorders according to the ICSD-2? |
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Definition
1) Insomnia
2) Sleep-related Breathing Disorders (obstructive sleep apnea, central sleep apnea and sleep-related hypoventilation)
3) Hypersomnias of Central Origin (Narcolepsy and idiopathic hypersomnia)
4) Circadian Rhythms Disorders (Delayed and Advanced sleep phase syndromes)
5) Parasomnias (NREM-sleep walking/terror. REM- nightmare disorder)
- some are not associated with particular cycle (head-exploding syndrome)
6) Sleep-related movement disorders (restless leg syndrome) |
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Term
| What are the major components of an accurate sleep history? |
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Definition
1) Twenty-four hour history (start with bedtime usually)
2) Bed partner
3) Sleep-wake diary |
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Term
| What diagnoses indicate confirmation with PSG? |
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Definition
1) Obstructive Sleep Apnea
2) Narcolepsy
3) Parasomnia
4) Movement disorders |
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Term
| What is Multiple Sleep Latency Testing (MSLT)? |
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Definition
Standardized test to evaluate degree of daytime sleepiness.
- 4-5 brief PSG studies during course of a day (each terminated after 20 minutes if subject cannot sleep)
- average latency in normal population is 10-13 minutes |
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Term
A patient presents with excessive daytime sleepiness, Cataplexy, Hypnogogic hallucinations at sleep-wake transitions and Sleep paralysis.
What objective findings would confirm your diagnoses? |
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Definition
These are the 4 classic symptoms of Narcolepsy
1) Very short latencies on nocturnal PSG and MSLT
2) Rapid entry in REM sleep
3) Mean MSLT value < 8 minutes
4) CSF hypocretin lowering is 100% specific/50 % sensitive for narcolepsy with cataplexy (less so for other forms)
5) HLA DQB1*0602 is very sensitive/30 % specific for narcolepsy. |
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Term
A patient who has been falling asleep during the day submits to an MSLT study.
You discover 3 naps with REM sleep and the patient is cataplexic during sleep.
What other objective findings would you expect to see in this patient? |
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Definition
>2 naps with REM confirms narcolepsy
1) CSF hypocretin decrease is 100% specific for cataplexic narcolepsy
2) DQB1*0602 is very sensitive for all types of narcolepsy |
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Term
| What is the pathophysiology/treatment of the sleep disorder characterized by Excessive daytime sleepiness, cataplexy, hypnogogic/pompic hallucinations and Sleep paralysis? |
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Definition
This is Narcolepsy (0.05% of population, appears in end decade of life)
1) Autoimmune destruction of hypocretin-containing neurons in lateral hypothalamus in genetically-predisposed individuals
These neurons are found in the perifornical area of lateral hypothalamus, projecting to brainstem arousal centers such as LC and RN (NA and 5-HT)
2) NO CURE
- Dextroamphetamine, methylpheidate and modafinil control sleepiness, but do not return MSLT values to normal range
- Cataplexy (Gamma-hyroxybutyrate), hallucinations and paralysis can be treated with 5-HT and NA antidepressants |
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Term
A patient comes in to your office complaining of poor concentration, depression and morning headaches.
Their partner reports very odd, loud snoring.
What is the pathophysiology/treatment for this sleep disorder? |
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Definition
Obstructive Sleep Apnea Syndrome (OSAS)
1)
- Occlusion of upper airway (at level of velopharynx or hypopharynx) caused by obesity, neurological, or respiratory control deficits
- mental slowing comes from repeated sleep interruptions and intermittent hypoxia (altered chemoresponsivity to hypoxic stress)
2) Treatment
- Assisted non-invasive ventilation (continuous positive airway pressure (CPAP) or bi-level positive airway pressure (COMPLIANCE IS ISSUE)
- Surgical for nasal or palatal obstructions, or maxillo-mandibular advancement (or gastric bi-pass) |
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Term
| What objective findings would you look for to diagnose OSAS? |
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Definition
4-10% of adult males ad 2-5% adult females (increasing with age and BMI), typically arising during middle age and progressing thereafter
.1) PSG is diagnostic for apnea
- Breathing pauses >10s
- in obstructive case, there are evident "efforts" of breathing (not in neurologic case)
2) Common features
- Obesity
- retrognathia, tonsillar hypertrophy or macroglossia
- HT, CVD and impaired glucose tolerance |
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Term
| What risks are associated with OSAS? |
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Definition
1) HTN
2) CHD
3) Stroke
4) Accidents |
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Term
A patient arrives in your office complaining of difficulty falling asleep and both frequent and prolonged awakenings during sleep.
They complain that they are feeling irritable and forgetful, and that they can't concentrate.
What is the pathophysiology/treatment of this condition? |
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Definition
Insomnia
1) Pathophysiology ("local sleep" issue)
- 24 hyper-arousal disorder linked to increased EEG beta activity, perhaps related to HPA axis activity.
- Conscious perception curing EEG-defined sleep period
- Enhanced cortical/limbic activity and decreased "switching off" of thalamic and diencephalic structures during sleep
2) Treat (Behavioral best documented)
- Regularize sleep-wake schedule
- Reduce time in bed to induce homeostatic regulation
- Benzo receptor agonists (BzRA), melatonic receptor agonists, low-dose sedating anti-depressents (evidence lacking) |
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Term
| What epidemiological features define Insomnia? |
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Definition
1) PSG normal in 10-15%
2) Begins early in adulthood with 5-10% adults reporting persistent symptoms (30-40% intermittently) with daytime impairment/distress
3) > with age and women>men |
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Term
A patient comes into your office complaining of episodes of both insomnia and excessive sleepiness at different times during the day.
What is the pathophysiology/treatment of this disorder? |
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Definition
Circadian Rhythm Sleep DIsorders (CRSD) (can be Delayed or Advanced)
1) Pathophysiology
- mismatch between endogenous pacemaker and desired sleep-wake hours
- SNPs in circadian rhythm genes have been discovered
- DPSD common in adolescents and young adults.
Treatment
1) Timed application of zeitgebers (bright light) to re-entrain circadian system
- give light in early morning for DSPD or early evening for ASPD)
- give melatonin in early morning for ASPD and early evening for DSPD (12 hours out of phase with light)
2) Behavioral chronotherapy for DSPD (go to be LATER each night until good schedule arrived upon |
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Term
| Why do some people who have worked night shifts for many years still not adjust? |
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Definition
| People with circadian rhythm disorders who have worked night shift for years cannot adjust because bright light exposure resets the circadian clock when returning from work (i.e. zeitgeber exposure re-starts problem) |
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Term
| What objective findings indicate CRSD? |
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Definition
DSPD is 7% in adolescents but 0.7% in adults
1) PSG will show prolonged latency (DSPD) or early awakening (ASPD) if patient is forced into "normal" schedule
2) Actigraphy and sleep-wake diaries document abnormal schedule
3) Temperature/Melatonin show abnormal phase position |
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Term
A patient comes into your office complaining of an urge to move their legs and toes, accompanied by dysthesia.
They say that it comes on strongest at night and prevents them from falling asleep
Their partner reports observing dorsiflexion of foot and flexion at hip and knee of patient during their sleep.
What is the pathophysiology/treatment of this condition? |
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Definition
Restless Legs Syndrome/Periodic Limb MOvement Disorder (RLS/PLMD)
1) Pathophysiology (lack of iron for DA sythesis)
- Reduction of DA in basal ganglia
- Abnormalities in iron metabolism, which is necessary cofactor for TH enzyme in DA synthesis (low serum and CSF ferritin with reduced iron in Substantia nigra)
2) Treat
- DA agonists (pramipexole or pergolide)
- L-dopa (frequent rebound during daytime)
- Benzos/opiates |
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Term
A patients PSG findings include considerable movements in legs while lying quietly before sleep. These movements continue into NREM sleep, with twitches every 20-90 seconds that are associated with EEG arousals
What is going on?
What is the epidemiology of this condition? |
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Definition
1) Since it continues into NREM sleep, this is Periodic Limb Movement Disorder (PLMD). Otherwise, could be RLS
2) population prevalence of 5-10%, mostly occurring during second decade of life with familial predisposition. |
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Term
A patient's partner calls you because the patient has been walking in their sleep and suffering from sleep terrors, but denies both.
What is the pathophysioogy/treatment of this condition? |
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Definition
Sleep Walking and Sleep Terrors (deep NREM sleep early in night)
1) Pathophysiology
- incomplete phase transitions from deep NREM
- precipitated by psychosocial stress, sleep deprivation, alcohol and meds.
2) Treat
- BzRA hypnotics
- Prevent by avoiding sleep deprivation, alcohol and caffein (also can try "pre-emptive awakening") |
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Term
A patient's PSG shows higher than normal N3 sleep, with "awake episodes" during synchronous delta EEG activity. No ictal activity is seen on EEG>
What is the epidemiology of this condition? |
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Definition
This is sleep walking/sleep terrors associated with deep NREM sleep (ictal activity would be seizures)
1) Common in middle childhood (25%)
2) 1% in adults (less common with increased age) |
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Term
A patient's partner calls you because the patient has been having violent outbreaks while sleeping, usually in the early morning hours.
The patient can recall the dreams from beginning to end.
What is the pathophysiology/treatment of this condition? |
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Definition
REM sleep behavior disorder (RBD)
1) Pathophysliogy
- Associated with brainstem lesions, which release voluntary muscles from atonia in REM sleep.
- Associated with Lewy Body disease (alpha synnclein)
2) Treatment
- Benzodiazepine to suppress motor activity
- Gabapentin and DA receptor agonists
- Imagery rehearsal and retraining
- Anti-depressents may exacerbate RBD! |
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Term
A patient's PSG shows increased muscle activity during REM sleep , with twitches and bursts of motor activity.
What is the epidemiology of this condition? |
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Definition
REM Sleep Behavioral Disorder (RBD)
- Arises in middle-aged patients and men > women (instead of child onset for sleep walking/ night terrors in NREM 3 sleep)
- Stable or mildly progressive (contrast with sleep walking/night terrors, which usually get better with age) |
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