NEOCORTEX. Laminar pattern 6 layers billion neurons 95 % surface of the hemisphere

Transcription

1 THE CEREBRAL CORTEX

2 NEOCORTEX Laminar pattern 6 layers billion neurons 95 % surface of the hemisphere

3

4 Six Layers of Cortex LGN input Parvo Magno B-Slide 4

5 NEOCORTEX, types of neurons Pyramidal neurons Apical and basal dendrites Dendritic spines Excitatory (glutamate) Homogenous group % Non-pyramidal neurons Aspiny Heterogenous group Inhibitory (GABA) %

6

7 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

8 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

9 Electroencephalogram (EEG) B-Slide 9

10

11 The EEG be recorded with Scalp electrodes through the unopened skull or with electrodes on or in the brain. A normal EEG

12 2. Mechanism of EEG Diagrammatic comparison of the electrical responses of the axon and the dendrites of a large cortical neuron. Current flow to and from active synaptic knobs on the dendrites produces wave activity, while AP are transmitted along the axon.

13 Electroencephalogram (EEG) Measures brain activity Alpha waves = healthy resting adult Beta waves = concentrating adult Theta waves = normal children Delta waves = normal during sleep

14 Electroencephalogram (EEG) Measures synaptic potentials produced at cell bodies and dendrites. Create electrical currents. Used clinically diagnose epilepsy and brain death.

15 Alpha: low-amplitude, slow, synchronous waves indicating an idling brain Recorded from parietal and occipital regions. Person is awake, relaxed, with eyes closed cycles/sec 50 ~100 V. EEG Patterns

16 Alpha Block: Replacement of the alpha rhythm by an asynchronous, low-voltage beta rhythm when opening the eyes.

17 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 cycles/sec.

18 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.

19 Delta: highamplitude waves; Common during sleep and awake infant. In awake adult indicate brain damage. 1-5 cycles/sec.

20 I. Electroencephalogram (EEG) 1. Brain Waves

21 SPONTANEOUS CORTICAL ELECTRICAL POTENTIALS: THE EEG

22 Mechanism of EEG EEG signals generated by cortex Currents in extracellular space generated by summation of EPSPs and IPSPs 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

23 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

24 II Wakefulness and Sleep

25 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.

26 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.

27 Sleep and Dreams What happens to humans and other animals while we sleep and dream?

28 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.

29 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

30 Brain Waves and Sleep Stages Sleep loss of consciousness that is: periodic natural reversible

31 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).

32 Types of Sleep One passes through four stages of NREM during the first minutes of sleep REM sleep occurs after the fourth NREM stage has been achieved

33 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

34

35

36 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

37 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.

38 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

39 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 9.39 whereas 5-HT antagonists reduce cortical arousal

40 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

41 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

42 Sleep homeostasis: adenosine ATP ADP AMP Adenosine Dependent on glucose, glycogen, and O 2 Brain glycogen falls with sleep deprivation Adenosine concentration rises during wake and falls during sleep Caffeine blocks adenosine receptors Other somnogens: PGD 2 (medial preoptic area), TNFa... PGE2 (wakefulness)

43 2 nd Part

44 Wake-promoting pathways periaqueductal grey (dopamine)

45 Wake promoting pathways parabrachial nucleus (PB, glutamate); PC, precoeruleus area (glutamate) DR, dorsal raphe nucleus (serotonin tuberomammillary nucleus (histamine); vpag, ventral periaqueductal gray (dopamine) 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.

46 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).

47 Mechanisms of REM sleep pedunculopontine tegmental (Ach) Tuberomammillary nucleus 5-HT NE Laterodorsal tegmental nuclei (Ach) See Saper lab Nature 2006

48 Mechanisms of non-rem sleep TMN=tubermammillary nucleus

49 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)

50 VLPO lesions produce insomnia Lu, et al, 2000

51 The flip-flop and bistability Saper, et al, 01

52 What stabilizes wake and sleep?

53 Orexin Hypocretin

54 Orexin activates arousal regions ( REM-on) neurons

55 Orexin may stabilize sleep/wake behavior

56 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 )

57 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

58 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.

59 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.

60 Activity of state-regulatory nuclei Wake Non-REM REM Amines (locus coeruleus, dorsal raphe, tuber mammillary nucleus) O Acetylcholine (LDT/PPT, basal forebr.) O Orexin/Hypocretin O O GABA (ventrolateral preoptic nucleus) O

61 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

62 Impaired orexin signaling and narcolepsy Mice/Rats/Dogs Lack of orexin Loss of orexin neurons Lack of orexin receptors Humans Loss of orexin neurons Narcolepsy Daytime sleepiness Fragmented sleep Cataplexy (lack of response to external stimuli and by muscular rigidity) Sleep paralysis Hypnagogic hallucinations

63 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.

64 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

65 Epilepsy

66 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.

67 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.

68 Epilepsy

69 Causes for Acute Seizures Trauma Encephalitis Drugs Birth trauma Withdrawal from depressants Tumor High fever Hypoglycemia Extreme acidosis Extreme alkalosis Hyponatremia Hypocalcemia Idiopathic

70 Classification of Epileptic Seizures 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

71 I. Partial (Focal) Seizures A. Simple Partial Seizures B. Complex Partial Seizures.

72 I. Partial (Focal) 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.

73 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.

74 II. Generalized Seizures Generalized Tonic-Clonic Seizures Absence Seizures Tonic Seizures Atonic Seizures Clonic Seizures Myoclonic Seizures. Infantile Spasms

75 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.

76 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

77 II. Generalized Seizures Neuronal Correlates of Paroxysmal Discharges Generalized Tonic-Clonic Seizures

78 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.

79 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.

80 II. Generalized Seizures 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 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.

81 II. Generalized Seizures Neuronal Correlates of Paroxysmal Discharges Generalized Absence Seizures

82 II. Generalized Seizures B. Absence Seizures (con t) Often begin during childhood (daydreaming attitude, no participation, lack of concentration). A low threshold Ca 2+ 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 spikeand-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.

83 Cellular and Synaptic Mechanisms of Epileptic Seizures (From Brody et al., 1997)

84 Goals: Treatment of Seizures 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

85 Treatment of Seizures Strategies: Modification of ion conductances. Increase inhibitory (GABAergic) transmission. Decrease excitatory (glutamatergic) activity.

86 Actions of Phenytoin on Na + Channels A. Resting State Na + B. Arrival of Action Potential causes depolarization and channel opens allowing sodium to flow in. Na + C. Refractory State, Inactivation Sustain channel in this conformation Na +

87 Ca 2+ Channels Ca 2+ B : sites of N-linked glycosylation. P: camp-dependent protein kinase phosphorylation sites Ion Channels Voltage-gated Multiple Ca 2+ mediated events Missense mutations of the T-type Ca-channel a 1H subunit is associated with Childhood Absence Epilepsy in Northern China Drugs Used: Calcium Channel Blockers

88 GABAergic SYNAPSE Drugs that Act at the GABAergic Synapse GABA agonists GABA antagonists Barbiturates Benzodiazepines GABA uptake inhibitors Goal : GABA Activity

89 GLUTAMATERGIC SYNAPSE Na + Ca 2+ GLY K + Mg ++ AGONISTS GLU Excitatory Synapse. Permeable to Na +, Ca 2+ 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