the neurobiology of sleep and sleep disorders

The Neurobiology of Sleep and Sleep Disorders

Tamara Blutstein, Ph.D.Department of Neuroscience

Tufts University School of MedicineMay 1, 2013

What is Sleep?

“a natural periodic state of rest for the mind and body, in which the eyes usually close and

consciousness is completely or partially lost so that there is a decrease in bodily movement and

responsiveness to external stimuli”

The Function of Sleep

• Important to overall health and well being– Severe cognitive and physical consequences of sleep deprivation – Strong rebound of sleep following sleep loss – Evolutionarily conserved

• There are a number of sleep disorders– Insomnia, sleep apnea, restless leg syndrome, narcolepsy

• Sleep disruptions are associated with a number of neurological disorders– Parkinson’s disease, Alzheimer’s disease, depression

Two Process Model of Sleep• Balance between sleep and wake determined by 2 factors

– Circadian • 24hr cyclic rhythm generated by the SCN that entrains the sleep-wake cycle to the daily

light-dark cycle– Homeostatic

• Determined by sleep need• Homeostatic drive to sleep increases with time awake and peaks just before the beginning

of the sleep period

Lu and Zee 2010

Sleep Stages

Wake- desynchronized EEG and high EMG activity

NREM sleep- high amplitude, slow-wave EEG (delta frequency 0.5-4Hz) and low EMG activity relative to wakefulness

REM sleep- regular theta activity (4-8Hz) on EEG, coupled with low EMG activity relative to that of NREM sleep

WAKE

NREM

REM

EEG

EEG

EEG

EMG

EMG

EMG

Human SleepWAKE

NREM SleepDivided into 4 stages

Stage 12-5% of TST

Transition from wake to sleepStage 2

45-55% of TSTIncreased slow waves, presence of sleep

spindles and K complexesStage 3 and 4 10-20% of TST

Slow-wave sleep (SWS), greatest early in sleep period

REM Sleep20-25% TST

Episodes longer as sleep progresses

Stiller and Postolache 2005

Neurobiology of Sleep:Wake-Promoting Systems

Espana and Scammell 2011

Neurobiology of Sleep:NREM

Espana and Scammell 2011

Regulation fo Wake and Sleep:Flip-Flop Switch

Lu and Zee 2010

Neurobiology of Sleep:REM

Espana and Scammell 2011

Neurotransmitters Involved in Sleep/Wake

Espana and Scammell 2011

International Classification of Sleep Disorders

• Insomnias• Sleep-related breathing disorders• Hypersomnias of central origin• Circadian rhythm sleep disorders• Parasomnias• Sleep-related movement disorders • Isolated symptoms (apparently normal variants

and unresolved issues)• Other sleep disorders

Insomnias

• Most common• Difficulty initiating and maintaining sleep,

early morning awakening, non-restorative sleep

• Occurs 3-4 times per week and persisting for more than a month

• Sleep difficulty occurs despite adequate opportunity and circumstances for sleep and associated with daytime dysfunction

Primary Insomnias

• Adjustment insomnia• Psychophysiological insomnia• Paradoxical insomnia• Idiopathic insomnia• Inadequate sleep hygiene• Behavioral insomnia of childhood

Secondary Insomnias

• Insomnia due to a drug or substance• Insomnia due to a medical condition• Insomnia not due to a substance or known

physiological condition• Physiologic Insomnia, unspecified

Causes of Insomnia

• Hyperactivity of HPA axis• Imbalance of flip-flop switch regulating

transition from sleep to wake

Treatment for Insomnias:Cognitive-Behavioral

Buysse 2013

Treatment for Insomnias:Pharmacology

Buysse 2013

Treatment for Insomnias:Pharmacology

Buysse 2013

Sleep-Related Breathing Disorders

• Characteristic feature: disordered ventilation during sleep

• Primary central sleep apnea• Primary sleep apnea of infancy• Sleep-related hypoventilation/hypoxemic

syndromes• Obstructive sleep apnea

Obstructive Sleep Apnea

CPAP

Ioachimescu and Collop 2012

Hypersomnia of Central Origin

• Primary complaint is daytime sleepiness and the cause is not disturbed nocturnal sleep or misaligned circadian rhythms

• Daytime sleepiness: inability to stay alert and awake during the major waking episodes of the day, resulting in unintended lapses into sleep

• Recurrent hypersomnia• Idiopathic hypersomina with or without

long sleep time• Hypersomnia due to a medical condition• Narcolepsy-cataplexy syndrome

Hypersomnia of Central Origin

Narcolepsy-Cataplexy Syndrome

• Onset in adolescents and young adults • Narcolepsy with cataplexy, without, and

secondary narcolepsy • Irresistible desire to fall asleep in

inappropriate circumstances• Triggered by emotional factors such as

laughter, rage or anger

• Video

Narcolepsy-Cataplexy Syndrome

Narcolepsy-Cataplexy Syndrome

Burgess and Scammell 2012

Circadian Rhythm Sleep Disorders

• Delayed sleep phase• Advanced Sleep

Phase• Jet lag• Shift work

Drake 2010

Circadian Rhythm Sleep Disorders

• Changes in the period length of the circadian clock

• Impaired response to light• Altered function of clock genes or products• Behavior therapy, Light therapy and

Chronotherapy

Parasomnias

Tinuper et al 2012

• NREM parasomnias, impaired arousal mechanisms and the persistence of sleep drive result in a failure of the brain to fully transition into wake

• REM parasomnias-failure of mechanisms that induce muscle atonia

• Most treatments are similar to those used for insomnia

• Safety measures

Parasomnias

Sleep-Related Movement Disorders

• Characterized by relatively simple, stereotyped movements that disturb sleep

• Bruxism • Rhythmic movement disorder• Nocturnal leg cramps• Restless leg syndrome

Isolated Symptoms, Apparently Normal Variants and Unresolved Issues

• Long sleepers• Short sleepers• Snoring• Sleep talkers• Sleep related sexual disorders

Espana and Scammell 2011

Drug Effects on Sleep

Consequences of Sleep Loss

Wulff et al 2010

Consequences of Sleep Loss

Wulff et al 2010

Consequences of Sleep Loss

Wulff et al 2010

Neurological Disorders and Sleep

Wulff et al 2010

Sleep in Psychiatric Disease

Wulff et al 2010

Sleep in Psychiatric Disease

Wulff et al 2010

Sleep in Psychiatric Disease

Wulff et al 2010

Sleep in Neurodegenerative Disease

Wulff et al 2010

• Therapeutic target• Mechanistic overlap• Identification of risk

factors and vulnerability

Neurological Disorders and Sleep

Questions?

Contact infoEmail: Tamara.Blutstein@tufts.edu