THE

CEREBRAL

CORTEX

NEOCORTEX

Laminar pattern – 6 layers

10 – 20 billion neurons

95 % surface of the hemisphere

B-Slide 4

Six Layers of Cortex

LGN input

Parvo

Magno

NEOCORTEX,

types of neurons

Pyramidal neurons

Apical and basal

dendrites

Dendritic spines

Excitatory (glutamate)

Homogenous group

60 – 70 %

Non-pyramidal

neurons

Aspiny

Heterogenous group

Inhibitory (GABA)

30 – 40 %

Electroencephalography (EEG) is an

electrophysiological monitoring method to record

electrical activity of the brain. It is typically

noninvasive, with the electrodes placed along the

scalp, although invasive electrodes are sometimes

used in specific applications.

The first human EEG recording obtained by Hans

Berger in 1924

Brain Waves: State of the Brain

Normal brain function involves continuous electrical activity

Patterns of neuronal electrical activity recorded are called brain waves

Brain waves change with age, sensory stimuli, brain disease, and the chemical state of the body

An electroencephalogram (EEG) records this activity

EEGs can be used to diagnose and localize brain lesions, tumors, infarcts, infections, abscesses, and epileptic lesions, sleep disorders,

A flat EEG (no electrical activity) is clinical evidence of death

B-Slide 9

Electroencephalogram (EEG)

The EEG be recorded with Scalp electrodes through the

unopened skull or with electrodes on or in the brain.

A normal EEG

Diagrammatic

comparison of the

electrical responses

of the axon and the

dendrites of a large

cortical neuron.

2. Mechanism of EEG

Current flow to

and from active

synaptic knobs on

the dendrites

produces wave

activity, while AP

are transmitted

along the axon.

Measures brain activity

– Alpha waves = healthy resting adult

– Beta waves = concentrating adult

– Theta waves = normal children

– Delta waves = normal during sleep

Electroencephalogram (EEG)

Electroencephalogram (EEG)

Measures synaptic

potentials produced at cell

bodies and dendrites.

– Create electrical currents.

Used clinically diagnose

epilepsy and brain death.

EEG Patterns

Alpha: low-amplitude, slow, synchronous waves indicating an “idling” brain

– Recorded from parietal and occipital regions.

Person is awake, relaxed, with eyes closed.

– 10-12 cycles/sec

– 50 ~100 V.

Alpha Block: Replacement of the alpha rhythm by an asynchronous,

low-voltage beta rhythm when opening the eyes.

•Beta:high-amplitude waves seen in deep sleep and when reticular activating system is damped

–Strongest from frontal lobes near precentral gyrus.

•Produced by visual stimuli and mental activity.

•Evoked activity.

–13-25 cycles/sec.

•Theta :more irregular than alpha waves

–Emitted from temporal and occipital lobes.

•Common in newborn some sleep in adult.

•Adult indicates severe motional stress.

–5-8 cycles/sec.

•Delta: high-amplitude waves;

•Common during sleep and awake infant.

•In awake adult indicate brain damage.

–1-5 cycles/sec.

I. Electroencephalogram (EEG)1. Brain Waves

SPONTANEOUS

CORTICAL

ELECTRICAL

POTENTIALS:

THE EEG

Mechanism of EEG

Continuous graph of changing voltage fields at scalp

surface resulting from ongoing synaptic activity in

underlying cortex

Inputs from subcortical structures

– Thalamus

– Brainstem reticular formation

•EEG signals generated by cortex

•Currents in extracellular space generated by summation of EPSPs and IPSPs

Frequency range: 40 Hz to 100 Hz (Highest)

Too much: Anxiety, high arousal, stress

Too little: ADHD (Attention deficit hyperactivity

disorder), depression, learning disabilities

Optimal: Binding senses, cognition, information

processing, learning, perception, REM sleep

Increase gamma waves: Meditation

II Wakefulness and Sleep

Sleep and Dreams:

Circadian Rhythms

Circadian Rhythms (biological changes

occurring on a 24-hour cycle)

– Our energy level, mood, learning, and

alertness all vary throughout the day.

– Sections of the hypothalamus called the

suprachiasmatic nucleus (SCN) and the

pineal gland regulate these changes.

Sleep and Dreams:

Circadian Rhythms (Continued)

Disrupted circadian rhythms, through shift work, jet

lag, and sleep deprivation may cause mood

alterations, reduced concentration and motivation,

increased irritability, lapses in attention, and reduced

motor skills.

Sleep and Dreams

What happens

to humans and

other animals

while we sleep

and dream?

Sleep and EEG cont’d: Different stages of sleep and their respective brain waves:

– Stage 1: Low voltage random EEG activity (2-7 Hz)

– Stage 2: Irregular EEG pattern/negative-positive spikes (12- to 14- Hz)

– Also characterized with sleep spindle and K-complexes that could

occur every few seconds.

– Stage 3: Alternative fast activity, low/high voltage waves and high

amplitude delta waves or slow waves (2 Hz or less).

– Stage 4: Delta waves

– Stage REM (Rapid eye Movement): “episodic rapid eye movements,” low

v voltage activity.

– Stage NREM: All stage combined, but not including REM or stages that

may contain REM.

The K-complex occurs randomly in stage 2 and stage 3

– The K complex is like an awaken state of mind in that is associated with

a response to a stimulus that one would experience while awake.

Sleep Stages

Cycle through 5 sleep stages every 90 minutes

Stage 1 Sleep

– brief stage; sensation of falling

Stage 2 Sleep

– 20 minutes; spindles (bursts of brain activity)

Stage 3 Sleep

– brief; transitioning to deeper sleep

Stage 4 Sleep

– 30 min.; delta (large, slow) brain waves; deep sleep

REM Sleep

– 10 minutes; vivid dreams

Brain Waves and Sleep Stages

Sleep

– loss of

consciousness

that is:

periodic

natural

reversible

EEG Sleep Patterns

There are two major types of sleep:

– Non-rapid eye movement (NREM)

– Rapid eye movement (REM)

REM (rapid eye movement): Dreams occur.

Low-amplitude, high-frequency oscillations.

Similar to wakefulness (beta waves).

Non-Rem (resting): High-amplitude, low-frequency waves (delta waves).

Types of Sleep

One passes through four stages of NREM during

the first 30-45 minutes of sleep

REM sleep occurs after the fourth NREM stage

has been achieved

Non-REM Sleep Alpha, delta, theta activity are present in the EEG

record

– Stages 1 and 2: Alpha waves

– Stages 3 and 4: delta activity (synchronized)

Termed slow-wave sleep (SWS)

Light, even respiration

Muscle control is present (toss and turn)

Dreaming (could but not vivid, rational)

– Difficult to rouse from stage 4 SWS (resting brain?)

9.33

REM Sleep Presence of beta activity (desynchronized EEG

pattern)

Physiological arousal threshold increases

Heart-rate quickens

Breathing more irregular and rapid

Brainwave activity resembles wakefulness

Genital arousal

Pontine-Geniculate-Occipital (PGO) waves?

Loss of muscle tone (paralysis)

Vivid, emotional dreams

May be involved in memory consolidation 9.36

Pontine-geniculate-occipital (PGO) wave –

A synchronized burst of electrical activity that originates in

the pons and like a wave it activates the lateral geniculate

nucleus (first relay of visual information)

and then the occipital lobe, specifically in the visual cortex

(which receives and puts together the visual information that

comes from the lat. geniculate nucleus).

PGO waves appear seconds before and during REM sleep.

Sleep

Stage

Cycles

A typical sleep pattern alternates between REM and NREM

sleep

SWS precedes REM sleep

REM sleep lengthens over the night

Basic sleep cycle = 90 minutes

The suprachiasmatic and preoptic nuclei of the hypothalamus regulate

the sleep cycle

Neural Regulation of Arousal Electrical stimulation of the brain stem induces arousal

– Dorsal path: RF--> to medial thalamus --> cortex

– Ventral path: RF --> to lateral hypothalamus, basal ganglia, and the forebrain

Neurotransmitters involved in arousal:

– NE neurons in rat locus coeruleus (LC) show high activity during wakefulness, low activity during sleep (zero during REM sleep)

LC neurons may play a role in vigilance

– Activation of ACh neurons produces behavioral activation and cortical desynchrony

ACh agonists increase arousal, ACh antagonists decrease arousal

– 5-HT: stimulation of the raphe nuclei induces arousal whereas 5-HT antagonists reduce cortical arousal

9.39

Neural Control of SWS

The ventrolateral preoptic area (VLPA) is important

for the control of sleep

– Lesions of the preoptic area produce total insomnia,

leading to death

– Electrical stimulation of the preoptic area induces signs

of drowsiness in cats

– VLPA neurons promote sleep

Neural Control of REM Sleep

The pons is important for the control of REM sleep

– Pontine-Geniculate-Occipital (PGO) waves are the first predictor of REM sleep

– ACh neurons in the peribrachial pons modulate REM sleep

Increased ACh increases REM sleep

9.41

Sleep homeostasis: adenosine

ATP ADP AMP Adenosine

Dependent on glucose, glycogen, and O2

Brain glycogen falls with sleep deprivation

Adenosine concentration rises during wake and falls during sleep

Caffeine blocks adenosine receptors

Other somnogens: PGD2 (medial preoptic area), TNFa...

PGE2 (wakefulness)

2nd Part

Wake-promoting pathways

periaqueductal grey

(dopamine)

Wake promoting pathways

Many wake-promoting projections arise from neurons in the upper brainstem.

Cholinergic neurons (aqua) provide the major input to the thalamus, whereas

monoaminergic and (presumably) glutamatergic neurons (dark green) provide direct

innervation of the hypothalamus. basal forebrain, and cerebral cortex. The orexin

neurons in the lateral hypothalamus (blue) reinforce activity in these brainstem

arousal pathways and also directly excite the cerebral cortex and BF.

parabrachial nucleus (PB, glutamate);

PC, precoeruleus area (glutamate)

DR, dorsal raphe nucleus (serotonintuberomammillary nucleus (histamine);

vPAG, ventral periaqueductal gray (dopamine)

Sleep promoting pathways

The main sleep-promoting pathways (magenta in B) from the

ventrolateral (VLPO) and median (MnPO) preoptic nuclei inhibit

the components of the ascending arousal pathways in both the

hypothalamus and the brainstem (pathways that are inhibited are

shown as open circles and dashed lines).

Mechanisms of REM sleep

See Saper lab Nature 2006

pedunculopontine

tegmental (Ach)

Laterodorsal

tegmental nuclei (Ach)Tuberomammillary

nucleus 5-HT NE

Mechanisms of non-REM sleep

TMN=tubermammillary nucleus

waking and sleeping Shift

The ascending arousal systems are also capable of inhibiting the VLPO (C). This mutually

inhibitory relationship of the arousal- and sleep-promoting pathways produces the conditions

for a “flip-flop” switch, which can generate rapid and complete transitions between waking and

sleeping states. Abbreviations: DR, dorsal raphe nucleus (serotonin); LC, locus coeruleus

(norepinephrine); LDT, laterodorsal tegmental nucleus (acetylcholine); PB, parabrachial

nucleus (glutamate); PC, precoeruleus area (glutamate); PPT, pedunculopontine tegmental

nucleus (acetylcholine); TMN, tuberomammillary nucleus (histamine); vPAG, ventral

periaqueductal gray (dopamine)

VLPO lesions produce insomnia

Lu, et al, 2000

The flip-flop and bistability

Saper, et al, 01

What stabilizes wake and sleep?

Orexin

Hypocretin

Orexin activates arousal regions

REM-on

neurons( )

Orexin may stabilize sleep/wake behavior

Sleep and Dreams: Sleep Disorders

Two major categories:

1. Dys-somnias

(problems in amount, timing,

and quality of sleep. A dyssomnia is a disorder of getting to

sleep or staying asleep or of excessive sleepiness.)

2. Parasomnias

(abnormal disturbances during sleep including sleepwalking,

nightmares, sleep paralysis, REM sleep behavior disorder, and

sleep aggression )

Sleep and Dreams:

Three Forms of Dyssomnias

Insomnia: persistent problems in falling asleep,

staying asleep, or awakening too early

Sleep apnea: repeated interruption of breathing

during sleep

Narcolepsy: sudden and irresistible onsets of

sleep during normal waking hours

Stages of Sleep And Brain

Mechanisms

Sleep apnea is a sleep disorder characterized by the inability to breathe while sleeping for a prolonged period of time.

Consequences include sleepiness during the day, impaired attention, depression, and sometimes heart problems.

Cognitive impairment may result from loss of neurons due to insufficient oxygen levels.

Causes include, genetics, hormones, old age, and deterioration of the brain mechanisms that control breathing and obesity.

Stages of Sleep And Brain

Mechanisms Narcolepsy is a sleep disorder characterized

by frequent periods of sleepiness.

Four main symptoms include:

– Gradual or sudden attack of sleepiness.

– Occasional cataplexy - muscle weakness triggered by strong emotions.

– Sleep paralysis- inability to move while asleep or waking up.

– Hypnagogic hallucinations- dreamlike experiences the person has difficulty distinguishing from reality.

Amines (locus coeruleus, dorsal raphe,

tuber mammillary nucleus)

Acetylcholine (LDT/PPT, basal forebr.)

Orexin/Hypocretin

GABA (ventrolateral preoptic nucleus)

Wake Non-REM REM

O

O

O

O

O

Activity of state-regulatory nuclei

Sleep disorders are clinically important

15% of adults have chronic insomnia

24% of adults have chronic sleepiness

25% of motor vehicle accidents with loss of consciousness are due to falling asleep

60% of fatal truck accidents are due to sleepiness

Impaired orexin signaling and narcolepsy

Daytime sleepiness

Fragmented sleep

Cataplexy (lack of response to external stimuli and by muscular rigidity)

Sleep paralysis

Hypnagogic hallucinations

Loss of orexin neurons

HumansMice/Rats/Dogs

Lack of orexin

Loss of orexin neurons

Lack of orexin receptors

Narcolepsy

Stages of Sleep And Brain

Mechanisms

The locus coeruleus is small structure

in the pons whose axons release

norepinephrine to arouse various areas

of the cortex and increase wakefulness.

Usually dormant while asleep.

Structure Neurotransmitter(s) it

releases

Effects on Behavior

Pontomesencephalon Acetylcholine, glutamate Increases cortical arousal

Locus coeruleus Norepinephrine Increases information

storage during

wakefulness; suppresses

REM sleep

Basal forebrain

Excitatory cells Acetylcholine Excites thalamus and

cortex; increases

learning, attention;

shifts sleep from NREM

to REM

Inhibitory cells GABA Inhibits thalamus and

cortex

Hypothalamus

(posterior HT)

Histamine Increases arousal

Lateral Hypothalamus Orexin/hypocretins Maintains wakefulness

Dorsal raphe and pons Serotonin Interrupts REM sleep

Epilepsy

Epilepsy

A group of chronic CNS disorders characterized by recurrent seizures.

Seizures are sudden, transitory, and uncontrolled episodes of brain dysfunction resulting from abnormal discharge of neuronal cells with associated motor, sensory or behavioral changes.

Epilepsy

There are 2.5 million Americans with epilepsy in the US alone.

More than 40 forms of epilepsy have been identified.

Therapy is symptomatic in that the majority of drugs prevent seizures, but neither effective prophylaxis or cure is available.

Epilepsy

Causes for Acute Seizures

Trauma

Encephalitis

Drugs

Birth trauma

Withdrawal from

depressants

Tumor

High fever

Hypoglycemia

Extreme acidosis

Extreme alkalosis

Hyponatremia

Hypocalcemia

Idiopathic

I. Partial (focal) Seizures

A. Simple Partial Seizures

B. Complex Partial Seizures

II. Generalized Seizures

A. Generalized Tonic-Clonic Seizures

B. Absence Seizures

C. Tonic Seizures

D. Atonic Seizures

E. Clonic Seizures

F. Myoclonic Seizures

G. Infantile Spasms

Classification of Epileptic Seizures

I. Partial (Focal) Seizures

A. Simple Partial Seizures

B. Complex Partial Seizures.

A. Simple Partial Seizures (Jacksonian)

Involves one side of the brain at onset.

Focal w/motor, sensory or speech disturbances.

Confined to a single limb or muscle group.

No alteration of consciousness.

EEG: Excessive synchronized discharge by a small

group of neurons. Contralateral discharge.

I. Partial (Focal) Seizures

B. Complex Partial Seizures (Temporal Lobe epilepsy or Psychomotor Seizures)

Produces confusion and inappropriate or dazed behavior.

Motor activity appears as non-reflex actions. Automatisms (repetitive coordinated movements).

Wide variety of clinical manifestations.

Consciousness is impaired or lost.

EEG: Bizarre generalized EEG activity with evidence of anterior temporal lobe focal abnormalities. Bilateral.

I. Partial (focal) Seizures

II. Generalized Seizures

Generalized Tonic-Clonic Seizures

Absence Seizures

Tonic Seizures

Atonic Seizures

Clonic Seizures

Myoclonic Seizures.

Infantile Spasms

II. Generalized Seizures

In Generalized seizures, both hemispheres are widely involved from the outset.

Manifestations of the seizure are determined by the cortical site at which the seizure arises.

Present in 40% of all epileptic Syndromes.

II. Generalized Seizures

A. Generalized Tonic-Clonic Seizures Recruitment of neurons throughout the cerebrum

Major convulsions, usually with two phases:

1) Tonic phase

2) Clonic phase

Convulsions:

– motor manifestations

– may or may not be present during seizures

– excessive neuronal discharge

Convulsions appear in Simple Partial and Complex Partial Seizures if the focal neuronal discharge includes motor centers; they occur in all Generalized Tonic-Clonic Seizures regardless of the site of origin.

Atonic, Akinetic, and Absence Seizures are non-convulsive

Neuronal Correlates of Paroxysmal

Discharges

Generalized Tonic-Clonic Seizures

II. Generalized Seizures

II. Generalized Seizures

A. Generalized Tonic-Clonic Seizures

Tonic phase:

- Sustained powerful muscle contraction

(involving all body musculature) which arrests

ventilation.

EEG: Rhythmic high frequency, high voltage

discharges with cortical neurons undergoing

sustained depolarization, with protracted trains

of action potentials.

II. Generalized Seizures

A. Generalized Tonic-Clonic Seizures

Clonic phase:

- Alternating contraction and relaxation, causing a reciprocating movement which could be bilaterally symmetrical or “running” movements.

EEG: Characterized by groups of spikes on the EEG and periodic neuronal depolarizations with clusters of action potentials.

B. Absence Seizures (Petite Mal)

Brief and abrupt loss of consciousness, vacant stare.

Sometimes with no motor manifestations.

Minor muscular twitching restricted to eyelids (eyelid flutter) and face.

Typical 2.5 – 3.5 Hz spike-and-wave discharge.

Usually of short duration (5-10 sec), but may occur dozens of times a day.

No loss of postural control.

II. Generalized Seizures

Neuronal Correlates of Paroxysmal

Discharges

Generalized Absence Seizures

II. Generalized Seizures

B. Absence Seizures (con’t)

Often begin during childhood (daydreaming attitude, no participation, lack of concentration).

A low threshold Ca2+ current has been found to govern oscillatory responses in thalamic neurons (pacemaker) and it is probably involve in the generation of these types of seizures.

EEG: Bilaterally synchronous, high voltage 3-per-second spike-

and-wave discharge pattern.

Spike-wave phase:

Neurons generate short duration depolarization and a burst of action potentials, but there is no sustained depolarization or repetitive firing of action potentials.

II. Generalized Seizures

Cellular and Synaptic Mechanisms of

Epileptic Seizures

(From Brody et al., 1997)

Treatment of Seizures

Goals:

Block repetitive neuronal firing.

Block synchronization of neuronal

discharges.

Block propagation of seizure.

Minimize side effects with the simplest drug

regimen.

MONOTHERAPY IS RECOMMENDED IN MOST CASES

Treatment of Seizures

Strategies:

Modification of ion conductances.

Increase inhibitory (GABAergic) transmission.

Decrease excitatory (glutamatergic) activity.

Actions of Phenytoin on Na+

Channels

A. Resting State

B. Arrival of Action

Potential causes

depolarization and

channel opens allowing

sodium to flow in.

C. Refractory State,

Inactivation

Na+

Na+

Na+

Sustain channel in

this conformation

Ca2+ Channels

Ca 2+

B

: sites of N-linked glycosylation.

P: cAMP-dependent protein kinase

phosphorylation sites

Ion Channels

• Voltage-gated

• Multiple Ca2+ mediated

events

• Missense mutations of the

T-type Ca-channel a1H

subunit is associated with

Childhood Absence

Epilepsy in Northern

China

Drugs Used:

• Calcium Channel

Blockers

GABAergic SYNAPSE

Drugs that Act at the

GABAergic Synapse

GABA agonists

GABA antagonists

Barbiturates

Benzodiazepines

GABA uptake inhibitors

Goal : GABA Activity

GLUTAMATERGIC SYNAPSE

Excitatory Synapse.

Permeable to Na+, Ca2+ and K+.

Magnesium ions block channel in resting state.

Glycine (GLY) binding enhances the ability of GLU or NMDA to open the channel.

Agonists: NMDA, AMPA, Kianate.

Goal: GLU Activity

Mg++

Na+

AGONISTS

GLU

Ca2+

K+

GLY