Basic Science of

Representative Normal

Human EEG PotentialsSeyed M Mirsattari, MD, PhD, FRCPCDepartments of Clinical Neurological

Sciences, Medical Biophysics, Diagnostic Imaging, Psychology

University of Western OntarioLondon, Ontario

EEG Course, CNSF, Vancouver, BCThursday June 16, 2011

ObjectivesTo understand the basic science of common human

EEG potentials

Representative normal EEG waveforms in wakefulness

and sleep

Wakefulness (alpha, theta)

NREM sleep (sleep spindles, K complex, theta,

delta)

REM sleep

Disclosure statement

Dr. Mirsattari has nothing to disclose

EEG scalp recording: normal, awakeEEG scalp recording: normal, awake

Alpha rhythm

posterior dominant rhythm

bilateral

lies in the posterior head regions

frequency= 8 - 13 Hz

attenuated with eye opening

Alpha rhythmmore than one site generates it within both cortical and subcortical regions

Electrode locations

Perez-Borja C et al., Electroencephal Clin Neurophysiol 1962;14:171-182

Theta rhythms4-7 Hz frequencies of varying amplitude and morphologiesabout 35% of normal young adults show intermittent 6-7 Hz σ of <15 µV during relaxed wakefulness that is maximal in the frontal or F-C regionsIn the teenage years and up to the early 20s, central σ may occupy 10-20% of the recordingenhanced by HV, drowsiness and sleepintermittent 4-5 Hz σ in the bi-T regions (even with a lateralized predominance, usually L > R) may occur in the elderly population

Incidence= ~ 35%not an abnormal finding

Normal F-C theta in an awake 18 YO

Delta rhythmsFrequency: <4 Hzcan occupy <10% of the normal awake EEG by age 10 yrscan be a normal finding in wakefulness in the very young and in the elderlywith advancing age, the normal elderly population may demonstrate rare irregular θ slowing in the T regions

similar to T σ in the distribution (i.e. L>R)<1% of the recording

may be seen normally:in individuals > 60 yearsat the onset of drowsinessin response to HVslow wave sleep

Intermittent L mid-T θ during transition to drowsiness in a normal 84 YO

NREM sleepLow neuronal activityMetabolic rate and brain temp. are at their lowest.Sympathetic outflow decreases and HR and BP dropParasympathetic activity increases and then dominates

Constricted pupilsIntact muscle tone and reflexesFour characteristic stages

NREM sleepStage 1 sleep:

defined by the presence of vertex waves

Stage 2 sleep:

defined by the presence of sleep spindles

and K complexes

has the same features as stage 1 with

progressive slowing of background

frequencies

Stage 1 NREM sleepTransition from wakefulness to the onset of

sleep

Lasts several minutes.

Low-voltage EEG activity

10 - 30 uV

16 - 25 Hz

Then, sinusoidal alpha

Normal sleepVertex waves (V waves)

typically 200 msec

diphasic sharp transients (maximal negativity

at Cz)

bilateral, synchronous, symmetric

may be induced by auditory stimuli

can be apiculate (esp. in children)

never consistently lateralizes

may be seen in stage 1 to 3 sleep

Normal sleep

Sleep spindles

transient, sinusoidal 12-14 Hz

waxing and waning in amplitude

seen in the central regions

slower frequencies (10-12 Hz) in the F regions

Normal sleepK-complex

a high-amplitude diphasic wave with an

initial sharp transient followed by a high

amplitude slow wave

often associated with a sleep spindle in

the F-C regions

may be evoked by a sudden auditory

stimulus

persistent asymmetry of >50% is abnormal

on the side of reduction

Stage 2 sleep with prominent POSTs, F-C sleep spindles and a T4 small sharp spike

Normal sleepSlow wave sleep:

non-REM deep sleep

1-2 Hz θ waves occupying variable amounts of the background

Stage 3:θ occupying 20-50% of the recording with voltages of >75 µV

stage 4:θ occupying >50% of the recording

Slow wave sleep, intermittent POSTs and sleep spindles

EEG waves of NREM sleepEEG waves of NREM sleep

REM sleepRapid eye movements

Loss of muscle tone

Sawtooth waves in the EEG

Alternates with non-REM deep sleep in cycles

4-6X during a normal night's sleep

non-REM sleep predominates the first part

of the night

REM sleep occurs in the last third of the

night

REM sleep with lateral rectus potentials in the anterior-lateral headregions induced by rapid eye movements

Sleep architecture and neurophysiologicalcharacteristics of sleep stages

Diekelmann S, BornNature J. Neuroscience Review. 2010;11:114-126.

NREM sleep• Generated by neurons in the preoptic

region of the hypothalamus and adjacent

basal forebrain

• Lesions in these regions cause

insomnia

• Stimulation of these regions rapidly

produces sleep onset

NREM sleep• Hypothalamus role in NREM sleep

• modulates thalamic and cortical activity

• controls brainstem arousal systems

• Encephalitis lethargica (von-Economo C. J Nerv

Ment Dis 1930;71: 249-59)

• Damage to the posterior hypothalamus results in

excessive sleepiness

• Damage to the anterior hypothalamus results in

insomnia.

NREM sleep•Two populations of GABAergic neurons:

• the ventrolateral preoptic region

active during spontaneous sleep

• the median preoptic region

• active during spontaneous sleep

• active during waking in sleep-deprived

states, suggesting that this cell population

mediates sleep debt.

•Median preoptic sleep active neurons • control the transitions from wake to NREM

sleep• mediate sleepiness

• active in waking in the sleep-deprived animal and increase activity prior to sleep onset

•Cells in the ventrolateral preoptic neurons are important in maintaining sleep continuity and in the homeostatic control of REM sleep.

• They are inactive during waking• They maintain elevated levels of activity

throughout NREM sleep

NREM sleep

Gvilia I et al. J Neurosci 2006;26:9426-33; Szymusiak R et al. Ann N Y Acad Sci 2008;1129:275-86

NREM sleep• One subgroup of median and ventrolateral

preoptic neurons maintains their NREM sleep

activity in REM sleep

• The remaining sleep active neurons are maximally

active in NREM and have greatly reduced activity in

REM sleep.

Gvilia I et al. J Neurosci 2006;26:9426-33; Szymusiak R et al. Ann N Y Acad Sci 2008;1129:275-86

Physiology of sleep spindles• generated from the activity of rhythmically firing neurons.

• nucleus reticularis thalami (NRT) & thalamocortical neurons (TC)

• nucleus reticularis:• GABAergic neurons• Firing rate = 7-14 Hz• low threshold Ca2+ spikes• Ca2+ enters through voltage sensitive channels

• open when the cell is relatively hyperpolarized•After the Ca2+ spikes, membrane currents return the cell to the hyperpolarized state, restarting the process.Steriade M. Sleep, epilepsy and thalamic reticular inhibitory neurons.Trends Neurosci 2005;28:317-24.

Physiology of sleep spindles•Thalamocortical neuron (TC)

• RTN - induced IPSPs

• Rebound depolarization

• Hyperpolarization activates low threshold

Ca2+ potential (LTCP) in the TC neurons.

• Depolarization of TC neurons produces

action potentials and cortical EPSPs and

IPSPs

• EEG records sleep spindles

ThalamoThalamo--corticocortico--thalamicthalamic looploop

Pyramidal cell

Inhibitory interneuron

Thalamocortical relay neuron

Cerebral Cortex

Nucleus ReticularisThalami (NRT)

ThalamoreticularNeuron (TC) Thalamus

Low threshold Ca2+ potential (LTCP) in TC neurons

Crunelli V, et al. Cell Calcium 2006;40(2):175-190.

Calcium Channels• Display Selective permeability to calcium (voltage-gated)

Type Gated by Protein Gene Location Function

L-type High voltage Cav1.1Cav1.2Cav1.3Cav1.4

CACNA1SCACNA1CCACNA1DCACNA1F

Neurons, Skeletal Muscle, ventricular

myocytes, bone

Cav1.1: Malignant hyperthermia, hypokalemic periodic paralysis. Cav1.2: congenital stationary night blindnessCav1.3: upregulated in aging brain

P/Q-type High voltage Cav2.1 CACNA1A Neurons Famlial Hemiplegic Migraine, Episodic Ataxia associated with primary

generalized epilepsy.

N-type High voltage Cav2.2 CACNA1B Neurons unknown

R-Type Intermediate voltage

Cav2.3 CACNA1E Neurons unknown

T-type Low-voltage Cav3.1Cav3.2Cav3.3

CACNA1GCACNA1HCACNA1I

Neurons, Cardiac Myocytes

Are enhanced in several animal models of epilepsy,

no monogenetic defects reported yet in humans.

T-type calcium Channels

Talavera K, Nilius B. Cell Calcium 2006;40:97-114.

Current view of T-type Ca2+

channel neurophysiology

Crunelli V, et al. Cell Calcium 2006;40(2):175-190.

Sleep theta waves and HTBs

Thalamocortical relay neuron

Crunelli V, et al. Cell Calcium 2006;40(2):175-190.

Sleep K-complex and the role of ITwindow in slow (< 1Hz) oscillation

Crunelli V, et al. Cell Calcium 2006;40(2):175-190.

Physiology of sleep spindles

Thalamocortical relay neuron

Crunelli V, et al. Cell Calcium 2006;40(2):175-190.

Physiology of delta waves and the slow (<1 Hz) sleep oscillations

Thalamocortical relay neuron

Crunelli V, et al. Cell Calcium 2006;40(2):175-190.

Physiology of delta waves

• Similar to sleep spindles

• Higher levels of membrane hyperpolarization

• Slower membrane oscillations

NREM sleep•The histamine-containing neurons of the posterior hypothalamus are important in maintaining the waking state.

•They are tonically active in waking, greatly reduce discharge in NREM sleep and become nearly silent in REM sleep.

•This discharge profile is shared by noradrenergic neurons of the locus coeruleus, serotonergicneurons of the raphe nuclei, and hypocretin-containing neurons of the hypothalamus, all of which have been shown to increase waking when activated.

Nuclei in the pontine region critical for REM

Nucleus pontis oralis/caudalis (RPO/RPC) CG = central grayLDT = lateral-dorsal tegmental nucleus LC = locus ceruleusPPN = pedunculopontine nucleus PT = pyramidal tract6 = nucleus of the CN 6 7G = genu of the CN VII5ME = mesencephalic nucleus of the CN V

Circuitry involved in the control of REM sleep

Activation of the GABA-ergic neurons in the pons causes inhibition of noradrenergic and serotonergic neurons and the activation (or disinhibition) of cholinergic neurons in the pons.Kandel ER, Schwartz JH, Jessell TM. Principles of Neural Science. 4th Ed. 2000. Ch 47

Mechanism of altered muscle tone in REM sleep

•The cholinergic neurons of the pons excite glutamatergic neurons in the pons.•The glutamatergic neurons project to the medulla, where they terminate on interneurons that release glycine onto motor neurons. •Glycine hyperpolarizes the motor neurons, producing the motor paralysis of REM sleep. •Reduced release of serotonin and norepinephrine may also contribute to muscle tone reduction by disfacilitating motor neurons.

Mechanism of EEG changes in REM sleep

•A pontine system with ascending connections causes the reduction in EEG voltage during REM sleep. •Some cholinergic cells and adjacent noncholinergic cells activated during REM sleep project to GABAergic cells in the thalamus. The release of acetylcholine by these cells blocks the burst firing mode of thgese neurons. It is the burst firing mode that produces high voltage waves in the EEG.

REM sleep•REM-on cells

• maximally active in REM sleep• involved in various aspects of this state.

•REM-off cells• minimally active in REM sleep• include noradrenergic, adrenergic and

serotonergic cells in the brainstem and histaminergic cells in the forebrain.

• Most skeletal motor neurons have a similar pattern.

Neurotransmitter of REM-on cells:• GABA, Ach, glutamate, glycine

Neurotransmitter of REM-off cells:• norepinephrine, epinephrine, serotonin,

histamine, GABA

REM sleep•Non-REM-on cells: located in the anterior hypothalamus and basal forebrain

involved in the generation of NREM sleepREM-waking-on cells: predominate in the brainstem reticular formation

active in both waking and REM sleep. Many excite motor neurons; others affect EEG

PGO-on pontine cells: fire in high-frequency bursts before PGO waves in LGN.•Damage to the pons and/or caudal midbrain can cause abnormalities in REM sleep.•The persistent sleepiness of narcolepsy is a result of a loss of hypocretin function.

Patterns of activity of key cell groups during waking, NREM and REM sleep in a cat.

•Increased firing rate of cortical and thalamic cells during NREM and REM sleep. Their bursts are synchronized with sleep spindles and slow waves•Non-REM-on cells: located in the anterior hypothalamus and basal forebrain. They are involved in the generation of NREM sleep•REM-waking-on cells: predominate in the brainstem reticular formation. They are active in both waking and REM sleep. Many excite motor neurons; others affect EEG.

Top: intact cat. Bottom: forebrain 4 d after transection at the pontomedullary junction.

Siegel JM. Seminars in Neurology 2009;29:277-296

Tonic features of REM sleep• Reduced amplitude of cortical EEG waveforms

• Theta rhythm in the hippocampus (cats)

• Suppressed muscle tone

• Erections in males

• Reduced thermoregulation

• body Temp. drift toward environmental temp.

• Constricted pupils

• parasympathetic dominance in the control of the iris

Phasic features of REM sleep• Changes that occur episodically in REM

sleep

• Eye movements are correlated with

contractions of the middle ear muscles

• protective response to loud noise

• Other muscles may also contract

• brie breaks in muscle atonia

• Periods of marked irregularity in

respiration and HR

Ponto – geniculo - occipital (PGO)

spikes in REM sleep

• large amplitude, isolated potentials ≥ 30 s

before REM onset

• During REM, bursts of 3 - 10 waves

• correlate with rapid eye movements

• PGO linked potentials in the motor nuclei

of the extraocular muscles

• rapid eye movements

• present in other thalamic and cortical

neurons

Decerebrate rigidity

• Removal of the forebrain with a

transection through the neuraxis in the

coronal plane at the rostral border of the

superior colliculus

• Tonic excitation of the “antigravity

muscles” or extensors

• Show periodic limb relaxation

• periodic muscle atonia of REM sleep

Transection Studies

• Separating the forebrain from the

brainstem at the midbrain level

• No clear evidence of REM sleep

• The isolated forebrain had slow wave

sleep states and possibly waking, but no

clear evidence of REM sleep.

The memory function of REM sleep• REM sleep:

• de-synchronization of neuronal networks

• disengagement of memory systems

• Act to stabilize the transformed memories by

enabling undisturbed synaptic consolidation

• A key complementary role to SWS in memory

consolidation

• synaptic consolidation

The memory function of sleep• During SWS, active system consolidation involves the repeated re-activation of the memories newly encoded in the temporary store, which drives concurrent re-activation of respective representations in the long-term store together with similar associated representations.

• Promotes reorganization and integration of the new memories in the network of pre-existing long-term memories.

• Consolidation during SWS acts on the background of a global synaptic downscaling process that prevents saturation of synapses during reactivation.

ConclusionsSleep follows a circadian rhythmNot uniform

NREM and REM stagesNREM sleep has 4 stages REM sleep = an active form of sleepDifferent neural systems promote arousal and sleepNREM sleep is regulated by interacting sleep- inducing and arousal mechanismsREM sleep is regulated primarily by nuclei located at the junction of the midbrain and PonsT-type Ca2+ channels play a critical role in NREM sleep, alpha and theta waves.