Ns 2006 Sleep Sens Disorders

EEG, SLEEP and Coma physiology, neuroanatomy, pharmacology Neuroscience, 2008 Dr. C. Chan June 24 (Tu)

Ultradian rhythm during wakefulness and sleep

Discreet stages within each sleep cycle

90 min

90 min

Duration and architecture of sleep cycles change with age

REM time/sleep time: infants: 50% age 2: 30-35% adults: 25% (~1.5 h)

Stage 4: Exponential decline Age 60: near 0%

Young adults: stage 2:

50%

stage 3+4: 15% stage REM:20-25%

Physiologic characteristics of slow-wave sleep • Muscle relaxed, with some tone remaining • Parasympathetic neural activities dominate thus, HR=

; G.I. motility=

; etc.

• Threshold of awakening increases from stage 1 to 4 • Associated disorders: – Somnambulism – Nocturnal enuresis

Physiologic characteristics of REM sleep • Profound loss of skeletal muscle tone – Due to strong descending inhibition of spinal motoneurons – but: middle-ear, extraocular muscles maintain tone • Sympathetic neural activites dominant – Very high metabolic rate, HR etc. – Exception: penile erection, clitoral engorgement • High threshold of awakening • Eye movements: rapid eye movements + slower eye rolling • Desynchronized EEG pattern: Low-voltage, hi-freq • Ponto-geniculo-occipital EEG spikes assoc. /w R.E.M. • Story-rich dreams, more intense in later sleep cycles

EEG characteristics of the 5 sleep stages First, A primer on EEG…

EEG Basics

Typical EEG (not PSG) and electrode placement

Electroencephalogram is a summed voltage recording of slower electrical activities (typically postsynaptic potentials; very rarely action potentials) of many cells Exceptions:____________

Which waveforms summate more effectively? Random?

Action potentials?

or

or

Synchronized?

Synaptic potentials?

Beta activity > 13 Hz Alpha activity 8 Hz-13 Hz

Theta activity 4 Hz-7 Hz

Delta activity < 4 Hz

Spike and wave activity

Typical EEG waveforms

EEG and the underlying neuronal activities (In this case a seizure is in progress)

EEG waveforms can suggest sources of active synaptic input if afferent pathways have been independently mapped out.

Characteristic EEG Patterns during Wakefulness and the 5 Sleep Stages

Summary of stage-specific EEG waves • Awake: beta (8-30cps), alpha (8-12cps) waves • Both low voltage, high frequency, desynchronized • Stage 1: • alpha; occasionally:4-6cps waves • Stage 2: • alpha • sleep spindles (13-15cps, clusters of relatively high voltage) • K-complexes • Stage 3: • Some delta (1-4 cps, high voltage, synchronized) waves • Stage 4: • more delta; some theta (4-7cps) • Stage REM: • desynchronised; resemble awake (above), but EMG differ • ponto-geniculo-0ccipital waves (PGO waves) concurrent with rapid eye movements

What are groups of neurons actually doing during these sleep stages?

Activity patterns of specific neuronal groups Do not memorize details; but note stage-associated activity patterns

Major brain areas that control sleep onset

Anterior hypoth

Lateral hypoth

Medul. raphe

• What causes sleep on-set?

– Activation of medullary raphe neurons • Inhibits arousal centers in pons (REM-waking-on cells) • Also inhibits arousal centers in midbrain reticular formation – Activation of anterior hypothalamic GABAergic neurons • Inhibits histamine-releasing arousal neurons in posterior hypothalamus • Also inhibits orexin (hypocretin)-releasing neurons in lateral hypothalamus – [Both histamine- and orexin- releasing nurons activate basal forebain areas to maintain wakefulness]

Neuronal circuits that control sleep stages Nuc. Reticularis neuron with low-threshold Ca2+ channels

Thalamocortical neurons

RPO

• What causes EEG synchronization (spindles, delta waves) in slow-wave sleep? ---a summary of the last slide – Function of synchronized slow waves: occlude thalamocortical action potential traffic, thus blinding out the cortex – GABAergic neurons in nucl. Reticularis has a novel lowthreshold Ca2+ channel, which opens when hyperpolarized, causing Ca2+ influx – But Ca2+ influx depolarizes these same neurons causing a burst of action potentials. – Action Potentials’ after-potential (& Ca-activated K channels---gKCa ) hyperpolarize neuron, starting a new cycle. – These cycles cause bursts of GABA release (caused by Action potential bursts). – These Nuc. reticularis neurons synapse on thalamocorical relay neurons – The end result: bursts of (sunchronized) EPSP in cortical neurons

Neuronal circuits that control sleep stages Nuc. Reticularis neuron with low-threshold Ca2+ channels

Thalamocortical neurons

REM-waking-on neurons in RPO

What

turns these cortical bursts on or off?

–Cholinergic “REM-waking-on neurons” in Nuc.

Reticularis pontis oralis are active in waking or REM stages. They depolarize the above-mentioned GABA ergic neurons in nuc. reticularis, thus closing the low threshold Ca2+ channels. This desynchronizes cortical EPSPs (thus low-voltage and high-frequency) –Conversely, inhibition of these pontine neurons

turns on slow waves

So, summarizing: During onset of slow wave sleep, 1) pontine GABAergic neurons are inhibited (reason unknown), 2) which disinhibits 5-HT and NE-ergic neurons… 3) …allowing the latter neurons to inhibit cholinergic REMwake 0n neurons in reticuloponto-oralis/caudalis nucleus, 4)… leading to hyperpolarization of thalamic GABAergic neurons (in nucleus reticularis). 5) This opens low-threshold Ca channels on these GABAergic neurons, leading to oscillation of membrane potential and bursting discharge of action potentials, 6) which leads to bursts of GABA release onto thalamocortical neurons, causing them to oscillate in synchrony 7) The oscillatory discharge send synchronized EPSP to cortical pyramidal cells, recordable as EEG slow waves 7a) The oscillation blanks out meaningful sensory data.

Neuronal circuits that control REM sleep

REM-off

REM-on:

REM-waking on Too strong:

cataplexy, sleep apnea Too weak:

REM-sl. behav. disorder

The nucleus reticularis pontis oralis is also important in turning on REM sleep – For unclear reasons, the same pontine GABAergic “REM-on cells” will be turned on after a long period of slow-wave sleep, The opposite to the above slides happens: These activated cells inhibit locus coeruleus NE and mid-brain raphe serotonergic cells to disinhibit (activate) “REM-waking-on cells” in pons (RPO/C). As you have just learned, these latter cells fire to inhibit the slow waves, causing desynchronization. – Cholinergic “PGO-on cells” fires bursts to initiate PGO waves (which are relevant to rapid eye movement but irrelevant to REM stage on-set) – Other “REM-on cells” (ACH, Glu) are disinhibited by these GABA cells. They stimulate medullary Glycinergic cells, which inhibit spinal motoneurons: Thus no muscle tone.

What have been speculated about the functions of sleep? • Sleep keeps vulnerable humans away from nocturnal danger • Neurochemical repair – Believed to occur in deep synchronized sleep • Dreams: may be for consolidation of memory traces • Dreams: may be for erasure of wrong associations • Dreams: Freud… – allow the mind to discharge upsetting concerns of the previous day – allow the mind to work out unsatisfied repressed impulses

Endogenous sleep-promoting substances

• Candidates with some potency: – – – – – – –

A muramyl peptide Interleukin-1 Adenosine Delta-sleep-inducing peptide (in serum) Prostaglandin D2 A fatty acid primary amide melatonin

Dreaming… 1.

During stage REM, correlates with rapid eye movement? 2. Intensity of imagery and emotion increases in later cycles of sleep. 3. Accurate sense of time in dreams 4. Physiologic correlates:  incl. Strong inhibiton of spinal motoneurons  Penile erection etc.

 During slow-wave sleep, dreams are less frequent.  Dreams in slow-wave sleep: low story/imagery content, but situational. = nightmares; night terror (in children).

Long-term alteration of consciousness • Confusion – Clouding of consciousness, slow thinking, inattentive, poor speech.

• Stupor – Awakened only by strong stimuli; then minimally conscious

• Coma – Cannot be aroused

• Cerebral death (brain death) – Irreversible coma

Coma • • • •

Uncounsciousness is complete Depressed metabolism (unlike in sleep) Complete amnesia upon awakening Causes: 1. Metabolic Coma is caused by: – Impaired neurotransmission incuduced by • Hypoxia, hypoglycemia, pH or electrolyte imbalance or toxin induced • 2. lesion of thalamus or reticular formation.

• 3. disruption of ascending pathways from brainstem to thalamus – Supratentorial lesions: causes incremental damage due to intracranial pressure and reduced blood flow • Uncal herniation (through tentoral notch). Pressure on medulla can cause Cheyne-Stokes respiration and even cessation of breathing • Often the 3rd cranial nerve is compressed unilaterally: 3rd nerve palsy and loss of light reflex. • Pressure on cerebral peduncle leads to upper motor neuron signs in extremity – Infratentorial lesions: • Sudden on-set • Cranial nerve symptoms (lesion-location dependent): vertego, nausea, deafness, facial paralysis • EEG shows slow-wave sleep pattern because cerebral cortex is not directly affected.

Uncal herniation