L72. Physiology - Sleep Medicine

Thalamocortical Model and Brain Changes

• The thalamocortical model sets the context for understanding brain changes across sleep and waking
• Psychological aspects of brain function are based on thalamocortical (TC) loops
• Perception, thinking, memory, and executive functions are outputs of different TC loops
• TC loops give content to consciousness

Specific Relay Pathways of TC Loops

• Loops involving the lateral geniculate nucleus (LGN) give rise to visual experience
• Loops involving the medial geniculate nucleus (MGN) give rise to hearing
• Loops involving the ventral posterolateral (VPL) and ventral posteromedial (VPM) nuclei give rise to somatosensation, pain, and temperature perception
• Loops with the prefrontal cortex give executive functions
• Loops with motor cortices give rise to motor output commands

Brain Consciousness and TC Loops

• TC loops involving nonspecific pathways impact the level of brain consciousness
• The brain can range from fully awake to tired to unconscious to a coma
• Consciousness level is independent of the contents of consciousness

Cerebral Cortex and Memory Systems

• Specific TC loops form a feedforward pathway in the cerebral cortex
• Sensory areas project to executive control areas, which in turn project to motor output areas
• There are memory systems for each major functional division
• Sensory memory is declarative, formed by the hippocampus and surrounding temporal lobe
• Executive function memory is generated in the prefrontal cortex and is called working memory
• Motor/procedural memories are learned complex patterns of muscle movement stored across the motor system

Reticular Activating System (RAS)

• The RAS causes the feedforward pathway to alternate between waking, NREM sleep, and REM sleep
• This system functions independently of peripheral sensory and motor systems
• The thalamocortical loop machine operates independent of sensory input or skeletal muscle movement
• Brain function is a closed, self-contained "virtual reality" generating system
• Sensory input and motor output occur only during the waking state

The Sleep Cycle

• The sleep cycle, discovered by Aserinsky and Kleitman in 1952, is the alternation between NREM and REM sleep
• A complete sleep cycle occurs approximately every 90 minutes, about 5 times during an 8-hour sleep period
• NREM dominates early sleep; REM dominates late sleep

NREM Sleep Stages

• NREM sleep, also called synchronized or slow-wave sleep, is divided into 4 stages
• Stage 1 is marked by alpha waves on EEG, decreased awareness of sensory stimuli, and is marked by relatively easy arousal
• Stage 2 is marked by sleep spindles and K complexes on EEG, a drop in body temperature, and further dissociation from sensory stimuli
• Stage 3 exhibits delta waves and spindles on EEG, a fall in blood pressure, slowed breathing, and a further drop in body temperature
• Stage 4 shows the greatest amount of delta waves without spindles on EEG, a high arousal threshold, and a release of growth hormone early in the night
• Delta sleep of NREM is caused by the thalamocortical BURST MODE and causes massive synchronization of cortical neurons

REM Sleep Characteristics

• REM sleep, also called paradoxical or desynchronized sleep, shows beta, alpha, and theta frequencies on EEG, similar to waking or NREM stage 1
• Peripheral atonia, or lack of muscle tone, is present, except for oculomotor, middle ear, and respiratory muscles
• Motor cortices are highly active during REM, despite peripheral atonia
• Highly erratic autonomic behavior occurs, including loss of thermoregulation, increased blood pressure, and increased respiration frequency and irregularity
• Penile erection also occurs
• REM sleep, like waking, is associated with thalamocortical TONIC MODE

RAS Pathways and Neurotransmitters

• Specific pathways in the CNS carry sensory, motor, memory, and executive control information
• Nonspecific pathways project diffusely to specific pathways and modulate them
• The reticular activating system (RAS) pathways originate in the brainstem, diencephalon, and cerebrum
• RAS pathways are defined by the neuromodulators they release
• The RAS has many functions, including generating the sleep-wake cycle
• Norepinephrine's location is the locus coeruleus; it controls phasic and tonic excitability of the cortex and maintains the waking state
• Dopamine's locations are the nigrostriatal, mesocortical, and tuberohypophysial areas
• Dopamine functions to regulate cognition, assist in motor output, and provide phasic waking and motivational effects
• Histamine is located in the tuberomamillary nucleus of the hypothalamus, and it maintains the tonic waking state
• Serotonin is located in the raphe nuclei, and its function is waking
• Acetylcholine locations are the basal forebrain, pontine lateral dorsal tegmentum (LDT), and pedunculopontine tegmental (PPT) nucleus (parabrachial)
• Acetylcholine controls excitability during both waking (basal forebrain) and sleeping (LDT-PPT), with LDT-PPT mediating REM sleep

Brain Control of Sleep

• People believed a chemical built up in the bloodstream that led to sleep
• The chemical that was thought to have induced sleep was called a somnogen, but experiments did not support this view
• Brain lesion studies in the brainstem were found to alter sleeping in animals, leading to the idea that sleep was neurally controlled
• Hobson and McCarley identified the neuromodulators and brainstem regions whose activity strongly correlated with waking, REM, and NREM
• The brainstem regions are the locus coeruleus (LC), dorsal raphe (DR), & the pedunculopontine tegmental (PPT) and pontine lateral dorsal tegmentum (LDT) regions (PPT-LDT) that release acetylcholine (Ach)
• The reciprocal innervation model is the first theory of how the brain causes itself to fall asleep
• During waking, aminergic brainstem nuclei (LC and DR) are active and inhibit brainstem cholinergic activity in the PPT-LDT
• During sleep, the cholinergic PPT-LDT inhibits the LC and DR.
• PPT-LDT action is gradual so that aminergic and cholinergic activity is about equal in NREM
• During REM, PPT-LDT cholinergic activity is maximum, and LC and DR aminergic activity is minimum

Modifications to the Reciprocal Innervation Model

• More brain regions have been identified to participate in control of the sleep-wake cycle
• The PPT-LDT activates the LC and DR during sleep
• Researchers discovered the vital role hypothalamic nuclei and the basal forebrain play during sleep

Brain Regions Controlling the Sleep-Wake Cycle

• Regions with a pro-waking effect have a "+"
• Regions with a pro-sleep effect have a "-"
• Brainstem nuclei related to sleep include the locus coeruleus (LC), dorsal raphe (DR) and PPT-LDT
• Hypothalamic nuclei related to sleep include the ventrolateral preoptic nucleus (VLPO), tuberomamillary nucleus (TMN) and lateral hypothalamic nucleus (LH)
• The basal forebrain (BF) releases Ach during waking and inhibits the VLPO, promoting a waking state
• Adenosine, a somnogen, builds up over the day in the CSF, inhibiting the BF

Sequence of Events in Sleep and NREM/REM Alternations

• The reciprocal innervation model is the core of this sequence
• PPT-LDT activates the LC and DR
• Hypothalamus and basal forebrain play a role
• Sleep is controlled by neural circuits and adenosine
• Waking: LC, DR, TMN and LH are active; VLPO is inactive and inhibited by the basal forebrain
• Orexin release stabilizes the LC, DR, and TMN, while the LC and DR inhibit the PPT and LDT
• Accumulation of adenosine in the basal forebrain shifts the balance between pro-sleep and pro-waking nuclei
• Adenosine inhibits the basal forebrain, lifting inhibition of the VLPO
• VLPO inhibits all the wake-promoting nuclei (DR, LC, LH, TMN), leading to NREM sleep
• As NREM progresses through stages 1-4, DR, LC, LH, and TMN are increasingly inhibited
• Once a point of inhibition is reached, their inhibition on the LDT and PPT is lifted, with the LDT and PPT becoming active
• During REM, DR, LC, LH and TMN are maximally inhibited, though the LDT and PPT activate the LC and DR
• The brain cycles back and forth between NREM and REM, about 5-6 times a night
• During the night, adenosine gets depleted, the inhibition on the basal forebrain is lifted, leading again to inhibition of the VLPO and activation of all the pro-wake regions (LH, TMN, LC, DR)
• Circadian rhythms help keep the pro-wake nuclei active

REM Atonia, Paradoxical EEG, and Mental States

• Activation of PPT-LDT during REM explains REM atonia and the paradoxical EEG
• REM leads to activation of PPT-LDT
• PPT-LDT activates perilocus coeruleus via Ach
• Perilocus coeruleus activates medullary nucleus with glutamate
• The medullary nucleus projects to the ventral horn and releases glycine (inhibitory), inhibiting motor neurons
• Motor commands via the corticospinal pathway are shut off in the spinal cord, disengaging skeletal muscles
• Ach from PPT inhibits the thalamic reticular nucleus, disinhibiting thalamic relay neurons and making them more depolarized
• Ach from PPT activates thalamic relay neurons and cortical neurons, even without sensory input
• Thalamocortical loops become active during REM sleep without sensory input
• EEG resembles waking EEG with a lot of alpha and some beta
• Tonic mode during REM and burst mode during NREM explain the mental states that occur during sleep

NREM Mental States

• Hypnagogia is associated with Stage 2 NREM and involves vivid perceptions (visual, auditory, or tactile) that do not occur in a unified sensorium
• Sleep terrors occur during NREM with little apparent content to consciousness and are characterized by nonspecific feelings of terror without associated perceptions
• NREM mentation lacks a rich sensorium, involves repetitive, banal, or nonsensical thoughts when awakened, and occurs when the thalamus is in BURST MODE, preventing communication with the senses but not preventing cognitive activity
• Sleepwalking cannot occur during REM because of paralysis and thus is an NREM phenomenon
• Sleepwalkers show no perceptual, emotional, or cognitive content, are unaware of external stimuli, and their faces are expressionless
• Sleepwalking can also be an expression of complex motor activities in the absence of any mental activity resembles automatisms of epilepsy
• Sleepwalking affects 1-5% of adult males and has a higher incidence in children
• Sleepwalking is associated with delta EEG that precedes movement

REM Mental States

• Nonlucid dreams include a lack of awareness of dreaming, submersion in a sensorium with sensory modalities and no access to voluntary recall
• Nonlucid dreams occur in 80% of REM awakenings and 25% of NREM awakenings and contain formal bizarreness and high incidence of anxiety-provoking content
• Lucid dreams include a person being aware that they are dreaming, implying access to voluntary recall
• Lucid dreams are common with narcoleptics because they can transition directly from waking to REM sleep
• Sleep paralysis occurs at REM to waking transition, when the mind wakes before the body, and the person is aware of REM atonia
• Sleep paralysis can occur in a dream immediately preceding awakening

REM and TONIC MODE

• The function served by the brain going into TONIC MODE during sleep is not actually known, but evolutionary advantages for rehearsing dangerous situations is a candidate
• Neurotransmitter balances prevent sensory input and motor output from passing through the thalamus, but higher-order associative cortices are highly active during REM
• Electrical stimulation of the temporal lobe induces "waking dreams," as discovered by Wilder Penfield
• If wanting to see the Penfield surgery patient video, there is a "Click Here" button in the original document (not something I can act upon)

Summary of Mental Function

• During waking cognitive functions work together in a coordinated way, making it difficult to identify discreet functions
• Thalamocortical loops are dominated by tonic mode and reticular formation neurotransmission
• Binding of all psychological functions are done by gamma waves
• During NREM, forms of NREM mentation represent highly discreet aspects of psychological function
• Binding is absent and sensory input is absent/hallucinations
• During REM, binding increases, tonic mode dominates, and psychological functions are coordinated
• There is no sensory input or motor output, hallucination
• The difference between dreams and waking is not defective executive function, but promiscuous access to long-term declarative memories in nonlucid dreaming

Sleep Disorders

• Sleep Apnea involves frequent periodic cessation of breathing during sleep, with obstruction of the airway through collapse of the throat through lost muscle tone, or by inhibition of respiratory centers in the medulla.
• Sleep Apnea is most common in overweight males who snore
• Nocturnal Enuresis includes bed wetting, affects 3-6% of the population including children and young adults and is associated with stage 4 NREM
• Sensations associated with wet clothes may appear in subsequent REM period with Nocturnal Enuresis
• REM sleep behavior disorder (RBD) is characterized by the intermittent loss of REM sleep atonia and by the appearance of elaborate motor activity associated with dream mentation
• Findings in some patients suggest that diffuse lesions of the hemispheres, bilateral thalamic abnormalities, or primary brain-stem lesions may result in RBD
• RBD has been often documented to precede or to co-occur with neurodegenerative disorders, such as dementia, Parkinson's disease and multiple system atrophy
• Insomnia is the inability to fall asleep and is readily diagnosable and treatable with Clonazepam
• Chronic insomnia afflicts approximately 5-10% of the adult population in Western industrialized countries
• Insomnia presents as trouble falling asleep (long-sleep latency), trouble staying asleep with excessive or prolonged awakenings, or feeling nonrestored from sleep
• Insomnia can be secondary or primary
• Persistent untreated insomnia becomes a strong risk factor for major depression
• Narcolepsy includes is a spontaneous onset of sleep (sleep attacks) and is perhaps the canonical sleep disorder
• Sleep attacks in Narcolepsy can last 5-30 min and can occur anytime without warning in activities such as driving
• Cataplexy (loss of muscle tone) occurs with Narcolepsy
• Someone with Narcolepsy may experience hypnagogia, or pass continuously from waking to dreaming
• Consciousness involves direct passage from waking to REM and experience lucid dreaming
• Narcolepsy has both genetic and nongenetic factors and appears to be autoimmune etiology
• Neurotransmission as key to narcolepsy pathophysiology includes abnormalities in hypothalamic orexin (hypocretin)
• Most patients with narcolepsy-cataplexy are orexin deficient mutations or polymorphisms in orexin related genes are extremely rare