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.