Basic Science of Representative Normal Human EEG Potentials Seyed M Mirsattari, MD, PhD, FRCPC Departments of Clinical Neurological Sciences, Medical Biophysics, Diagnostic Imaging, Psychology University of Western Ontario London, Ontario EEG Course, CNSF, Vancouver, BC Thursday June 16, 2011
Objectives To 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, awake
Alpha rhythm posterior dominant rhythm bilateral lies in the posterior head regions frequency= 8-13 Hz attenuated with eye opening
Alpha rhythm more 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 rhythms 4-7 Hz frequencies of varying amplitude and morphologies about 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 regions In the teenage years and up to the early 20s, central σ may occupy 10-20% of the recording enhanced by HV, drowsiness and sleep intermittent 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 rhythms Frequency: <4 Hz can occupy <10% of the normal awake EEG by age 10 yrs can be a normal finding in wakefulness in the very young and in the elderly with 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 years at the onset of drowsiness in response to HV slow wave sleep
Intermittent L mid-t θ during transition to drowsiness in a normal 84 YO
NREM sleep Low neuronal activity Metabolic rate and brain temp. are at their lowest. Sympathetic outflow decreases and HR and BP drop Parasympathetic activity increases and then dominates Constricted pupils Intact muscle tone and reflexes Four characteristic stages
Stage 1 sleep: NREM 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 sleep Transition from wakefulness to the onset of sleep Lasts several minutes. Low-voltage EEG activity 10-30 uv 16-25 Hz Then, sinusoidal alpha
Normal sleep Vertex 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
K-complex Normal sleep 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 sleep Slow 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 sleep
REM sleep Rapid 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 head regions induced by rapid eye movements
Sleep architecture and neurophysiological characteristics 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 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 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 Ca 2+ spikes Ca 2+ enters through voltage sensitive channels open when the cell is relatively hyperpolarized After the Ca 2+ 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 Ca 2+ potential (LTCP) in the TC neurons. Depolarization of TC neurons produces action potentials and cortical EPSPs and IPSPs EEG records sleep spindles
Thalamo-cortico cortico-thalamicthalamic loop Cerebral Cortex Pyramidal cell Thalamoreticular Neuron (TC) Low threshold Ca 2+ potential (LTCP) in TC neurons Thalamocortical relay neuron Thalamus Inhibitory interneuron Nucleus Reticularis Thalami (NRT) 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 Ca v 1.1 Ca v 1.2 Ca v 1.3 Ca v 1.4 CACNA1S CACNA1C CACNA1D CACNA1F Neurons, Skeletal Muscle, ventricular myocytes, bone Cav1.1: Malignant hyperthermia, hypokalemic periodic paralysis. Cav1.2: congenital stationary night blindness Cav1.3: upregulated in aging brain P/Q-type High voltage Ca v 2.1 CACNA1A Neurons Famlial Hemiplegic Migraine, Episodic Ataxia associated with primary generalized epilepsy. N-type High voltage Ca v 2.2 CACNA1B Neurons unknown R-Type Intermediate voltage Ca v 2.3 CACNA1E Neurons unknown T-type Low-voltage Ca v 3.1 Ca v 3.2 Ca v 3.3 CACNA1G CACNA1H CACNA1I 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 Ca 2+ 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 I Twindow 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, serotonergic neurons of the raphe nuclei, and hypocretincontaining 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 gray LDT = lateral-dorsal tegmental nucleus LC = locus ceruleus PPN = pedunculopontine nucleus PT = pyramidal tract 6 = nucleus of the CN 6 7G = genu of the CN VII 5ME = 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. 4 th 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-on cells REM sleep 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 sleep REM-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;
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.
Conclusions Sleep follows a circadian rhythm Not uniform NREM and REM stages NREM sleep has 4 stages REM sleep = an active form of sleep Different neural systems promote arousal and sleep NREM sleep is regulated by interacting sleep- inducing and arousal mechanisms REM sleep is regulated primarily by nuclei located at the junction of the midbrain and Pons T-type Ca 2+ channels play a critical role in NREM sleep, alpha and theta waves.