Awake to Sleep2

“What does sleep have to do with it”?Update on Sleep Medicine

Jay A. Yeomans, M.D.

CMC-Internal Medicine Residency

Noon Conference

February 1, 2013

Sleep is not a passive state

we spend 1/3 of our lives sleeping

1960 the average american slept 8 & 1/2 hours/nite 2000 the average american slept 7 hours/nite

The incidence of childhood obesity and metabolic disorders has increased over the past 30 yrs - at the same time the

prevalence of chronic sleep deprivation has increased precipitously

"You'll feel better tomorrow"

American Academy of Sleep MedicineAmerican Academy of Sleep Medicine

Deja’ review sleep physiology

• The neural impact of Sleep on Memory

• The neural impact of Sleep on Emotion (MDD / PTSD)

• Chronobiology• Psychiatric Disorders

• Treatments

“Sleep, the chief nourisher of

life’s great feast”

William Shakespear (MacBeth; Act II, Scene II)

SLEEP ARCHITECTURESLEEP ARCHITECTURENREM : 1-4…orthodox, quiet, slow-wave

• Stage 1: transition phase from wakefulness & sleep EEG:EEG: activity between 3-7 Hz (Theta waves) length:length: ½ min. – 7 min. mentation: thinking no longer reality-oriented

…short dreams …hypnic myoclonia

• Stage 2: first bona fide sleep stage EEG: Sleep spindles - burst of 12-24 Hz act. (½ -2 sec) K complexes (well delineated, slow, neg. EEG deflections

followed by a ‘+’ component ) length: approx. 20 – 30 min. mentation: short, mundane fragmented thoughts

SLEEP ARCHITECTURESLEEP ARCHITECTURE

NREM

• Stage 3 & 4: deepest / SWS / high voltage Delta waves “core sleep hypothesis” – SWS serves to “repair the

effects of waking wear & tear on the cerebrum”, i.e. lower metabolic rate & brain temperature allows repair from free-radical damage

decreases with age (40 y/o ↓↓ 50% / elderly nonexistent)

SWS: ↑↑↑ GH, Prolactin, Cortisol; inhibition of TSH vagal tone increased; decrease in sympathetic NS activity, HR, BP and cerebral glucose utilization decreased

↓ Schizophrenia (Am J Psych ’08)

SLEEP ARCHITECTURESLEEP ARCHITECTUREREM

• ‘paradoxical sleep’ : ‘active’ brain /adrenaline, pulse & oxygen consumption come closest to those in wakefulness with muscle atonia

• REM: occurs approx every 90 min with each REM period progressively more dense and longer in duration (1st REM 9 min; doubles each time)

• Episodic burst of rapid eye movements• controlled by the pons (brain stem, i.e. primitive

brain) which also controls breathing & heart rate• plateaus around 20 yrs., then decreases with age

SLEEP ARCHITECTURESLEEP ARCHITECTURE

Body size is a major determinant in the total amt of sleep: opossum (18h); man (8h); elephant (3-4h)

• Smaller animals have higher metabolic rates & higher brain & body temperatures – metabolism generates free radicals. NREM repairs / mops up free radicals

PVC

LGN

PFC

The Elephant lies down during

non-REM sleep but stands

during REM sleep.


• The neural impact of Sleep on Memory

The Neural Impact of Sleep on Memory• CONTENT MEMORY (Hippocampus)

• Episodic memory (min-yrs)• explicit & declarative• Medial temporal lobes (incl hippocampus), PFC, mammillary body (Korsakoff’s, Alzheimer’s)• remembering a short story, what you had for dinner last night, what you did on your last

B’day

• Semantic memory (min-yrs)• explicit & declarative• inferolateral temporal lobes (Alzheimer’s)• Knowing who was the first president of the US, the color of a lion, how a fork differs from a

comb

• Procedural memory (min-yrs)• explicit or implicit, nondeclarative• basal ganglia, cerebellum, motor areas (Parkinson’s)• driving a car w/standard transmission (ex), learning a sequence of #s on a touch tone phone

w/out trying (im)

• Working memory (sec-min- rehearsed)• explicit & declarative• (phono) PFC, Broca’s & Wernicke’s; (spa) PFC, visual-assoc areas (nl aging, VD,

Schizophrenia)• (phonologic) keeping a phone # ‘in your head’ before dialing, (spatial) mentally following a

route or rotating an object in your mind

The Neural Impact of Sleep on Memory•

Hippocampus: Content Memory vs. Amygdala: Emotional Memory

Content Memorydual process hypothesis

Hippocampus

NREM: stage 2 Sleep spindles generated in the thalamocortical circuit

mediates sleep dependent consolidation of procedural & declarative memory

NREM: SWS important for sleep dependent memory consolidation: the consolidation of hippocampus dependent declarative memory

NREM moves newly acquired memory undisturbed from the hippocampus to the neocortex - efficiently integrated in existing

neuronal networks

REM: → pruning / consolidation (semantic)enhances procedural memory

The Neural Impact of Sleep on Memory Matthew P. Walker, PhD, University of California, Berkeley

• Roman rhetorician, Quintilian, who stated: “... it is a curious fact, of which the reason is not obvious, that the interval of a single night will greatly increase the strength of the memory...”

• 1800’s: memory associated with dreaming• 1920’s: demonstrated that sleep was associate with memory consolidation• 1950’s: discovery of REM / NREM

• ‘sleep-dependent memory processing’• memories initially formed or ‘encoded’ when the brain is engaged in an idea,

image, etc. • memory requires consolidation (stabilize memory over time - more resistant to

interference) • ability to form & retain nonemotional ‘fact based’ (‘episodic’) memory linked to

SWS • primary insomnia, >30 yrs of age associated with a decline in sleep related memory

consolidation

The Neural Impact of Sleep on Memory Matthew P. Walker, PhD, University of California, Berkeley

‘Sleep-dependent memory processing’

• Lack of sleep before a task will compromise memory formation. … need to ‘prime the brain’

• Sleep BEFORE learning is critical for initial memory formation (dry sponge to prepare for next days soaking)

• Sleep restores the next-day encoding capacity of the hippocampus

• Sleep AFTER learning is critical to consolidate new memories-supports overnight consolidation of new memory-need for adequate sleep (primarily SWS) for nonemotional

episodic declarative memory after learning

Development of Human Memory

Consolidation(hard wire)

Recall(day/wks)Encoding

(engage)

Sleep Sleep

The Neural Impact of Sleep on Memory

“Deep Sleep beats all-nighter for retaining what you learn” (USA TODAY)

• Amplification of Slow Wave Activity during sleep improves consolidation of declarative memory

increase SWS ? ...rTMS & tiagabine & gaboxadol

• “Declarative Memory Performance Is Associated w/the # of Sleep Spindles (SS) in Elderly Women”

• Hirschner, et. al., Am J Geriatr Psychiatry 20:9, Sept 2012• declarative memory performance in elderly women - high performers exhibited

greater # SS & higher Spindle density compared with low performers

decrease in SS density in Schizophrenia (Am J of Psychiatry, 2007)

Increase SS density ? ... zolpidem

“If you don’t snooze you lose”


• The neural impact of Sleep on Emotion

The Neural Impact of Sleep Loss on The Neural Impact of Sleep Loss on EmotionEmotion

Matthew P. Walker, PhDMatthew P. Walker, PhDUniversity of California, BerkeleyUniversity of California, Berkeley

• Sleep disturbance: criteria for many psychiatric disorders

• Major Depressive Disorder and Post Traumatic Sleep Disorder

• Cause / consequence or co-morbid?• Amygdala - emotional memory• What happens to the Amygdala secondary

to sleep deprivation

The Neural Impact of Sleep Loss on The Neural Impact of Sleep Loss on EmotionEmotion

Matthew P. Walker, PhDMatthew P. Walker, PhDUniversity of California, BerkeleyUniversity of California, Berkeley

• Sleep deprivation: Amygdala (L>R) hyperamplified

• The medial prefrontal cortex (mPFC) is strongly connected to the Amygdala, controlling / regulating it through inhibition

“Sleep Deprivation Impairs the Accurate Recognition of Human Emotions”

M. Walker, PhD; Sleep. Vol. 33, No. 3, 2010almost all psych & neuro mood disorders express co-occurring abnormalities in sleep - suggesting a potential interdependence

between sleep and affective brain function

used a affective face recognition tasksingle night of sleep deprivation signif disrupts the ability of the

human brain to accurately id salient emotional expressions in others particularly in the moderate intensity range of emotion

most dramatic for emotions eliciting high emotional arousal - Angry and Happy - corresponding to the greatest threat relevant and

reward relevant value, respectively

influence of sleep deprivation on emotional recognition was observed most significantly in females

findings indicate that females have a greater degree of sensitivity to the effects of sleep loss in the context of affective dysregulation

consistent with reported trends in clinical mood disorders

The Neural Impact of Sleep Loss on EmotionMatthew P. Walker, PhD

University of California, Berkeley

• Sleep deprivation obliterates positive memory• Sleep deprivation disproportionately amplifies

emotional brain reactivity • Depression / PTSD • results in amplification of emotional memory /

accentuation of negative memory • REM sleep palliative - depotentiates the

overemotional brain by consolidating emotional memory

• emotional memory memory of emotion• affective stripping as REM decreases adrenergic

tone• (prazosin: alpha-1 antagonist / AASM)

• “Sleep to forget”• sleep refreshes the emotional brain / modulates

affective memories---------------------

The Neural Impact of Sleep Loss on EmotionMatthew P. Walker, PhD

QUIET!

SLEEPING BRAIN AT WORK!

’’09 American Academy of Sleep Medicine09 American Academy of Sleep Medicine

• Chronobiology

Chronobiology• Mammalian ‘master biological clock’ (pacemaker)

located in the paired (SCN) suprachiasmatic nuclei of anterior hypothalamus

• generates circadian rhythms• External stimuli = zeitgebers – exert Circadian Rhythm

(CR) synchronizing effect • Principal entraining zeitgeber of the human endogenous

CR is the LD cycle• circadian oscillators are found in all neurons of the brain

and all cells of the body, e.g. eye, heart, liver & kidneys • misalignment / desynchronized

• Daylight Savings Time• 15% increase in MVA the next Monday

Chronobiologyr• major synchronizer or ‘Zeitgeber’ for the SCN: light • mediated through light-sensitive receptors of the retina –

distinct, non-image-forming subset of retinal ganglion cells (contain light sensitive pigment, i.e photopigment melanopsin) functions in circadian entrainment by transducing light into neural impulses that project via directly from the retina via the retinohypothalamic tract (RHT) sensitive to blue light directly to the SCN pathway

• RHT releases glutamate, inhibitory GABA - PVN (paraventricular hypothalamic nucleus

• without PVN inhibition (‘night’) - SCG (superior cervical ganglion) releases NE-promotes synthesis of the hormone melatonin (from serotonin) in the pineal gland

The Wall Street Journal: Personal JournalSeptember 26, 2012

“The Peak Time for Everything”Sue Shellenbarger

• 8AM: twitter users are in a more energetic mood shortly after waking & tend to send more cheerful tweets

• 9AM: high energy - difficult conversation best undertaken• 10AM: as body temp rises throughout the morning, cognitive skills

improve, working memory and concentration peak mid-to-late morning

• 2PM: sleepiness hits its daytime peak, esp after lunch• 4PM: eye-hand coordination rises in the afternoon - complex task

require coordination & strength best undertaken while physical strength & alertness are still high

• 5PM: muscle strength and flexibility peak late in the day thus improving performance and results from workouts or competition (lungs perform 18% better at 5PM than at midday)

• 9PM: people’s freshest, most original thinking occurs at non-peak times of the day - usually evenings

“For our body is like a clock; if one wheel be amiss, all the rest are

disordered, the whole fabric suffers; with such admirable art and harmony

is a man composed”The Anatomy of Melancholy

Robert Burton1621

Sleep & Circadian Rhythms in Affective Disorder

diurnal variation of mood and early morning awakening suggest rhythmic dysfunction

Dysregulation of circadian rhythms & sleep disturbances

core elements of affective disorders

sleep disturbances: frequent residual sxs of depression

insomnia appears before, predicts & increases risk of relapse & recurrence

misalignment of sleep & rhythms - mood fluctuation

Sleep & Circadian Rhythms in Affective Disorder

greater incidence of depressive episodes after a west flight or manic episode after flying

east

unipolar depression (seasonal affective disorder)

BAD (rapid cycling)

↓need for sleep: symptom of mania & hypomania; insomnia or hypersomnia: symptom of depression

Sleep & Circadian Rhythms in Bipolar Affective Disorder

Allison G. Harvey, PhD University of California, Berkeley

‘Sleep loss is a major symptom as well as a trigger of manic episodes & sleep deprivation is one of the most effective antidepressant

interventions’Am J Psych 165:7, July 2008: 820-829

• Sleep disturbance is among the most prominent correlates of mood episodes & inadequate recovery, yet minimally studied

• Model: recognizes a role for genetic vulnerability; suggest there is a bi-directional relationship between daytime affect regulation & nighttime sleep, e.g. escalating vicious circle of disturbance in daily affect regulation interferes w/nighttime sleep/CR

• Sleep disturbances in Bipolar I, Bipolar II & Cyclothymia

• Sleep disruption +/or circadian rhythm disturbance

• Shortcomings of the Diagnostic Criteria (subjective judgment or quantitative criteria)

Sleep & Circadian Rhythms in Bipolar Affective Disorder

Sleep Disturbance in Bipolar Disorder: Therapeutic Implications

Plante & Winkelman; Am J Psych 165:7, July 2008: 830-843Psychoeducation: identify prodromal symptoms &

lifestyle regularity (stabilize sleep-wake rhythms)

• APA Practice Guidelinesfor the Treatment of Patients with BAD:

A. Psychiatric Management• 7. Promote awareness of stressors & regular patterns of activity & sleep: …

Social rhythm disruption with disturbed sleep/wake cycles may specifically trigger manic episodes ...

• 8. Work with the patient to anticipate & address early signs of relapse: … Many patients experience changes in sleep patterns early in the development of an episode…


• Light Therapy• Wake Therapy• Dark Therapy• Melatonin

• Clinical benefits of light therapy comes from phase advancement of the Circadian Rhythm

• Unit of intensity for visible light is lux (e.g. sunlight at midday >100 K lux / ordinary room light ~180 lux)

• Wavelength (WL): visible light: 380nm (violet) to 750nm (red)• Violet / Indigo / Blue / Green …yellow-green (max. effective for

visualization) / Yellow / Orange / Red• Light Box: downward-tilted diffusion screen w/a UV filter; 10 k lux at approx.12

inches; provide broad-spectrum white illumination & filter WL lower than 450nm to min levels.

• Timing of light therapy (Horne-Ostberg Morningness-Eveningness Questionnaire)

• Dawn stimulation - naturalistic dawn (dim signal-0.001 lux (starlight) to approx. 300 lux (sunrise) during last period of pt’s sleep episode (?bedsd commercial alarm clock lamps)

Blue Light Special?

• Early studies - bright white light with mixed spectrum (7-12K lux) similar to ambient light just after dawn

• White fluorescent light (10K lux) gold standard?

• Recent studies: short wavelength blue light (~ 460nm) maximally

effective in phase shifting of circadian systems, therefore; obviating the need for high intensity,

e.g. 5 lux of LED blue light = phase shifting of 10 lux of white light

Caution: long term exposure to WL between 400-500nm can induce photochem retinal injury (blue light hazard -implicated in age related macular degeneration in high risk groups)?

Light Therapy (Rosenthal - Arch Gen Psychiatry ’84)

Disorders Responsive to light therapyCircadian Rhythm Sleep Disorders

Delayed Sleep Phase Type

Advanced Sleep Phase Type

CRSD, nonentrained

Shift Work Disorder

Jet Lag

Dementia

Mood Disorders

Non-seasonal depression (monotherapy or adjunct)

insomnia

Light Therapy

• Circadian Rhythm Sleep Disorders (CRSD) Hallmark: tenacious insomnia +/or hypersomnia relative

to the environmental clock time.

Delayed Sleep Phase (DSPT): adolescents / young adults – delayed bedtime & impaired ability to arise early or entrain to the usual daytime work schedule

Therefore; need to advance the CR: white light exposure of 2500 lux for 2 hrs in the early AM combined with light restriction after 1600 (dark goggles)

Advanced Sleep Phase (ASPT): older adults / SNF Therefore; phase delay: evening light therapy

CRSD, Non-entrained: blind population lack of CR phase sync w/the 24 hr. day thus S-W cycle

follows an approx 24.2 hr endogenous period resulting in a gradual drift over time

bright light may entrain a subpopulation

Shift Work realign the the CR with the desired work schedule /

biological clock phase reversal Jet Lag pre-flight phase advance for Eward travel and phase

delay for for W-ward travel• Dementia – due to deterioration of SCN function /

diminished exposure to zeitgebers / impaired visual receptors

• conflicting results - bright light 1900-2100 - consolidated sleep / decreased ‘Sundowning’ and nocturnal agitation in pts w/DAT

Mood DisorderSeasonal Affective Disorder (SAD)

• 1/20 adults; 10X more common in the N lat • DSM-IV-TR: Mood Disorders: Seasonal Pattern Specifier (MDD, recur; BAD

I & II, dep.)Criteria: onset & remit at characteristic times of the year (onset usually fall /

winter; remit in spring)Occur during the last 2 years / without any non-seasonal episodes … Symptoms: atypical neuroveg sxs; *hypersomnia, *hyperphagia, anergy,

weight gain, craving carbohydrateshastens and potentiates the antidep response (*positive predictor for light therapy)

benefits comes from phase advancement of the CR (Light therapy > Prozac)5000 lux/hr (10K lux for 30’ or 2500 lux for 2 h) - morning hrs - algorithm (Light therapy > Prozac)

Non-seasonal depression (monotherapy or adjunct)

Wake Therapy

slow response to most antidepressant - wake therapy most rapid response1) night of total sleep deprivation - 60% responded w/marked improvement within hours, but …2) timing sleep deprivation to 2nd half 3) shift sleep a few hours earlier - without deprivation - slower but longer laster effect4) add daily AM light therapy to antidep or lithiumEurope: newly admitted hospitalized depressed patients are given adjunctive phototherapy to speed recovery.

Wake Therapywake & light therapy reduce duration of hospitalization.

General Psych Hospital: combo of wake therapy (3 sessions/week) w/antidep resulted in d’c 3 days sooner than drug tx alone

(Benedetti, et. al. J Clin Psych: 2005; 66:1535-1540)

retrospective analysis: 3 day advantage for patients exposed to more natural light in sunny hospital rooms than those staying in dimmer rooms

(Beauchemin, et. al. J Affect Disord.1996; 40: 49-51)

Melatonin

signal of darkness

evening rise in serum melatonin level sets a thermophysiological cascade in motion (warm hand / feet, heat loss, cooling of core body temp) prepare organism for sleep

if rhythms out of sync (CRSD, depression) melatonin secreted at the wrong time and sleep disturbance is accentuated

exogenous melatonin (zeitgeber) to synchronize circadian rhythms & promote sleep onset

Melatonininitial research disappointing - depressive sxs worsen?

Carman, et. al. AmJ Psych. 1976; 133: 1181-1186

indiscriminate use / melatonin containing beverages / lack of quality control

Exogenous Melatonin: Rozerem (5-7 hrs before)

Circadin (Europe) for elderly

Tasimelteon (Vanda) completed phase 3 (CR in blind)

agomelatine (Europe) regulates sleep but has a serotonergic antagonist component

OTC

Sleep Hygiene

Sleep Hygiene

• Wake up same time every day• Relaxing bedtime routine• Get out of bed if not asleep after 15-30 min• Keep bedroom dark, cool & quiet• Eliminate naps• Avoid heavy meals / EtOH / caffeine in PM• Don’t work in bed• Etc.

Awake to Sleep2

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