Sleep Physiology-basic mechanisms of sleep & arousal

1. Sleep Physiology-basic mechanisms of sleep & arousal • In 1940’s Moruzzi & Magoun found that electrically + certain areas in the brain and brainstem produced cortical activation • arousal states appear to be determined by an interaction among the brainstem, hypothalamus, thalamus & basal forebrain • Dampening of arousal systems with concomitant active inhibition by thalamo-cortical systems produces sleep

2. Basic mechanisms of sleep (cont) • Areas maintaining wakefulness include • oral pontine reticular formation • midbrain central tegmentum • posterior hypothalamus • Sleep promoting areas are located: • midline brainstem • dorsolateral medullary reticular formation • anterior hypothalamic preoptic region

3. Interaction between sleep & wakefulness areas • Magnocellular nucleus basalis of Meynert located in the forebrain • intermingling of both sleep & arousal systems • sleep modulating center • both sleep and waking active sites • projections to neocortex and midbrain reticular formation • acetylcholine projections

4. Sleep • Sleep is a behavioral state that differs from wakefulness by a readily reversible loss of reactivity to event’s in one’s environment. • Sleep is divided into stages based on: • electroencephalography (EEG) • electro-occulogram (EOG) • electromyogram (EMG)

5. Sleep Stages • Non Rem (NREM) or slow wave sleep • I (light) theta, delta (low amplitude) horizontal eye • II (light) theta, delta, sleep spindles, K complexes • III (deep) high amplitude delta (20-50%) • IV (deep) high amplitude delta (>50%) • Rapid eye movement (REM) • EEG resembles awake state or NREM stage I • dramatic decrease in EMG activity

6. Jet Lag

7. Sleep • Electrical stimulation of nucleus tractus solitarius (NTS) produces slow wave sleep • Lesions in NTS produces cortical desynchronization (waking pattern of EEG) • NTS appears to inhibit more rostrally situated neurons in the ascending reticular activating system • Direct connections between NTS & major areas of the limbic system exist (ant. thalamus, hypothalamus, amygdala)

8. Effect of pentobarbital on sleep

9. Sleep (cont.) • Lesions in serotonin rich raphe nucleus produces insomnia • Parachlorophenylalanine (PCPA) a trytophan hydroxylase inhibitor also produces insomnia by blocking production of serotonin • SWS can be restored in PCPA induced insomnia by administration of 5 Hydroxytrytophan (5HTP)

10. Sleep (cont) • Serotonin appears to modulate sleep through its effect on other hyponogenic factors in the anterior hypothalamus and suprachiasmatic nucleus • Serotonin is a melatonin precursor • Melatonin is synthesized and released by the pineal gland through sympathetic activation from the retino-hypothalamic tract

11. Sleep (cont.) • Melatonin enhances sleep • prolonged bright light stimulation suppresses melatonin and sleep while subsequent melatonin injections can restore normal sleep patterns • Preoptic nucleus of ant. Hypothalamus appears to inhibit waking areas in the rostral midbrain and mesopontine reticular core

12. Sleep (cont) • Prostaglandin D2 which is highly concentrated in the preoptic nucleus and induces both SWS and REM sleep • Prostaglandin inhibition by indomethacin can decrease diurnal sleep • The anterior hypothalamus may also promote sleep by inhibiting the waking area in the posterior hypothalamus • Factors such as triazolam, 5HTP, muramyl peptides, PGD2 have hypnogenic effects by acting on the anterior hypothalamus

13. Slow wave sleep (SWS) • Sleep spindles and delta waves are physiologic events involving GABAergic neurons via inhibition promote brain deafferentation • Sedatives (barbituates) and hypnotics (benzodiazepines) stimulate GABA receptors and facilitate sleep • Sleep spindles are rhythmic cortical waveforms generated by oscillatory activity in nucleus reticularis of the thalamus

14. Slow wave sleep (SWS) • Slow waves (delta) are generated in neocortical circuits arising in all cortical layers • An increase in GABAergic anterior hypothalamic preoptic and basal forebrain neurons is associated with SWS • Afferent input to anterior hypothalamus, serotonin, muramyl peptides, interleukins, PG’s that produce temp increase resulting in heat loss may induce SWS

15. REM sleep • Cortical EEG is highly desynchronized (similar to waking) • Associated with pontine geniculate occipital spikes (PGO) • PGO spikes are associated with many phasic events such as rapid eye movements, changes in respiration, heart rate, muscle twitches, and dreaming

16. REM sleep (cont.) • PGO spikes originate from REM-ON cells in medial pontine reticular formation & adjacent reticular tegmental nucleus • In animals REM sleep has been eliminated by placing lesions ventral to locus ceruleus • REM sleep can be induced by cholinergic stimulation of the pons • REM-OFF cells are represented by noradrenergic cells of locus ceruleus which become silent during REM

17. REM sleep (cont.) • Many antidepressants are REM suppressors; which increase activity of norepinephrine and/or serotonin • Progressive decrease in muscle tone associated with hyperpolarization of motor neurons • Rheobase 30% greater in REM sleep

18. REM behavior disorder • Normally REM sleep is associated with a progressive decrease in muscle tone associated with hyperpolarization of motor neurons • In this disorder there is persistant muscular tone during REM • Characterized by bursts of excessive limb & body movements • Cause in humans unknown • In cats lesions of the pons that destroy area just ventral to the locus ceruleus

19. Other changes in sleep • Reduction in body and brain temperature at onset of sleep associated with vasodilation • general decrease in metabolism • reduced thermosensitivity of hypothalamic preoptic nucleus • Suprachiasmatic nucleus serves as an endogenous clock influencing both sleep and body temperature in a closely coupled fashion.

20. Other changes in sleep (cont) • Brain metabolism decreases 20-35% in SWS • Cerebral blood flow decreases during SWS • Adenosine appears to be a somnogenic neurotransmitter (caffeine blocks hypothalamic adenosine receptors) • Sleep onset is associated with inhibition of TSH, cortisol, & stimulation of GH & Prolactin

21. Potential Sleep Promoting Factors • Many also have immune functions • Muramyl peptides • Lipopolysaccharides • Prostaglandin D2 • Interleukin I • Interferon alpha2 • Tumor necrosis factor • Delta sleep-inducing peptide • Vasoactive intestinal peptide • Serotonin/melatonin • Prolactin

22. Function of Sleep • Restores normal levels of brain activity and normal balance among different parts of CNS (restore natural balance) • Physiologic effects on the rest of the body • decreased SNS, increased Para effects in slow wave sleep • enhanced immune function • common factors

23. Link between sleep & weight loss • Sleep deprivation • can raise cortisol • Cortisol  insulin which promotes fat storage • Can contribute to insulin resistance • Linked to obesity, CV disease, type II diabetes • High fat, high sugar diet can lead to insulin resistance •  slow wave sleep (stage III and IV non REM) • Linked with  levels of growth hormone • Has an important role in fat loss and muscle growth • Individuals who sleep longer (>9 hr) less likely to be obese than individuals who sleep shorter (<6 hr) (I.J.Obesity&Metabolic Disorders 24; 1683, 2000.)

24. Epilepsy (seizures) • Uncontrolled excessive activity of either part or all of the CNS “electrical storm” • Predisposition greater than incidence • Disrupts normal brain function • Epileptogenic circuitry • lowered threshold and/or facilitation

25. Epilepsy • Causes • Trauma • Oxygen Deprivation • Tumors • Infections • Toxic States • (In1/2 of all cases the cause is unknown). • Incidence • .5-1% of population (2nd most common neurological disease)

26. Epilepsy • Precipitating causes of a seizure • strong emotional stimuli • alkalosis (hyperventilation) • drugs • fever • loud noises or flashing lights • Termination of a seizure • neuronal fatigue • active inhibition (inhibitory NT)?

27. Types of Seizures • Grand Mal (Tonic-Clonic) • Petite Mal (Absence) • Psychomotor (Focal) • Jacksonian • Myoclonic • Atonic • Status Epilepticus

28. Grand Mal • Aura • altered sensation prior to seizure, e.g. tingling • Tonic phase • rigid stiffening of body, loss of consciousness • Tonic-clonic phase • strong muscle contractions & convulsions, over within minutes • Post-ictal phase • return to consciousness; may be associated with confusion, stupor, slurred speech, weakness

29. Epilepsy • Treatment • Drugs • phenobarbital • dilantin • tegratol • depekene (Valproic Acid) • Surgery • excision of epileptic foci • Vagal stimulator • Chiropractic adjustments

30. Evoked Potentials (EP) • Sensory EP is a change in EEG resulting from stimulation of a sensory pathway • Sensory EP is extracted from EEG using computer averaging techniques • EEG is recorded during repetitive natural stimulation (eg. tap on skin or flash of light) • Computers samples the EEG before & after stimulation & sample data are averaged.

31. Evoked Potentials (cont) • Sensory EP consist of multiple components related to various aspects of subcortical & cortical processing (scalp electrodes) • Clinically useful for assessing the function of sensory systems or evaluating demyelinating diseases (eg. M.S.) • Destruction of myelin causes conduction velocity to decrease which increase latencies

32. Mental Illness • Affect core elements that define humanity • personality, goal directed behavior, language, creativity, abstract thinking, emotion, mood, social organization • Neural disruptions are probably complex, multiple, not readily observable • occur at biochemical or molecular level • range from mild to severe

33. Mental Illness • Mild • obsessive-compulsive personality • antisocial personality • Severe • dementias • schizophrenia • bipolar disorder • major depression • anxiety disorders (e.g. panic attacks)

34. Schizophrenia (shattered mind) • Characterized by a mixture of S/S of which no single one is necessarily present • significant deterioration in functioning • relatively chronic course • very incapacitating (60% morbidity) • onset early in life (late teens-early twenties) • Is a disease of neural connectivity caused by multiple factors that affect brain development • Multiple hits • Some combination of genetic and non genetic factors

35. Schizophrenia - symptoms • Positive symptoms • distortions or exaggerations of normal cognitive or emotional functions • delusions • hallucinations • disorganized speech • bizarre behavior • mesolimbic • ventral tegmental area to many areas of limbic system

36. Schizophrenia-symptoms • Negative symptoms • loss or decrease of normal functions • alogoria -poverty of speech or empty content • flat affect-decrease in ability to express emotion • anhedonia-inability to experience pleasure • avolition -inability to initiate or persist in goal directed behavior • attentional impairment • tend to impair the persons ability to function in daily life more so than positive symptoms • mesocortical • ventral tegmental area to neocortex

37. Schizophrenia • Various symptoms suggest possible involvement of a variety of cortical and subcortical areas • Anatomical abnormalities include enlargement of ventricles and prominent sulci due to abnormal brain development • Mixture of genes and environment as causative factors

38. Schizophrenia-causes • Genetics • Concordance in monozygotic twins- 40% • Concordance in dizygotic twins- 10% • Non genetic factors • poor nutrition • infections during pregnancy or childhood • toxins-damage neurons or affect NT systems • radiation-mutations

39. Schizophrenia-Dopamine • Exaggerated Dopamine activity (working hypothesis but is oversimplified) • at key sites-limbic areas, language areas • dopamine receptor blockers (type 2) • increased dopamine receptors • L-dopa causing schizophrenic symptoms • increased levels of dopamine metabolites

40. Disorders of Mood • Depression • Mania • Anxiety Disorders

41. Terms • Mood • sustained emotional state • Affect is a sign- what can be observed • Normal affective responses • Euphoria, elation, pleasure, surprise, anger, anxiety, disappointment, sadness, grief, despair, depression

42. Unipolar Depresssion • First described in Hippocratic writings in 5th century B.C. • Moods were thought to depend upon the balance of the four humors • blood, phlegm, yellow bile, black bile • An excess of black bile was thought to cause depression • melancholia means black bile

43. Unipolar Depression • Most likely several disorders • Untreated, typically lasts 4-12 months • Characterized by pervasive unpleasant mood that is present most of the day • inability to experience pleasure (anhedonia) • generalized loss of interest

44. Unipolar Depression • Additional symptoms (3 to make Dx) • disturbed sleep • diminished appetite (sometimes overeating) • loss of E • decreased sex drive • restlessness • retardation of thoughts/actions • difficultly in concentrating • indecisiveness • low self esteem • guilt/pessimistic thoughts • thoughts about dying & suicide

45. Unipolar depression • Additionally symptoms may show a diurnal variation usually worse in mornings • schizophrenia & other neurological diseases need to be excluded • Incidence-5% of population (U.S.= 8 mil) • Average age 30 • Subtypes • (endogenous) melacholic • reactive

46. Bipolar (Manic-Depressive) • Gives rise to Euphoria (Manic phase) • Similar to unipolar depression with mania • Mania • elevated expansive or irritable mood which lasts at least a week • overactivity (including speech) • social intrusiveness • increased energy & libido • decreased need for sleep • reckless involvements

47. Depression (in general) • Strong genetic predisposition • concordance in monozygotic twins =50% (even when reared apart) • Incidence of suicide in biologic relatives of depressed adoptees 6-10 X higher than biologic relatives of normal adoptees • stress can play a role • average age of onset has declined over last 60 years

48. Triad Brain Shrinkage Depression Chronic low Back pain

49. Treatment of Depression • Electroconvulsive therapy (ECT)- 90% • Drugs-70% • MAO inhibitors • Tricyclic • Specific Serotonin uptake blockers • Lithium Salts • Alternatives-?% • St. John’s Wort • Chiropractic • Omega 3 Fatty Acids

50. ECT • In use for over 50 years • full remission or marked improvement in about 90% of patients with well defined major depression • 6-8 trts at 2 day intervals over 2-4 wks. • Anesthesia with complete muscle relaxation • therapeutic change in aminergic receptor sensitivity