Sleep Study PDF

Sleep Oleg Osadchii 1 Sleep is a normal physiological process present in all species of animals. 2 Sleep is a reversible state of reduced responsiveness to the environment. An adult typically spends about 8 hours a day sleeping, meaning that sleep con...

Sleep Oleg Osadchii 1 Sleep is a normal physiological process present in all species of animals. 2 Sleep is a reversible state of reduced responsiveness to the environment. An adult typically spends about 8 hours a day sleeping, meaning that sleep consumes one-third of our lives.  The value of sleep (i) The brain is resting and restoring its cognitive abilities. (ii) Consolidation of memories. (iii) Enhancement of immune system. (iv) Maturation of the brain. Sleep deprivation impairs attention, memory, performance and immunity. 4 Attachment of electrodes to the scalp during electroencephalography. 5 Electroencephalography is a recording of the brain waves. 6  Electroencephalogram  The brain neurons generate multiple postsynaptic potentials (EPSPs and IPSPs). Taken together, they are called brain waves.  The brain waves generated by the neurons of the cerebral cortex can be detected by placing electrodes on the forehead and scalp.  The process of recording the brain waves is called electroencephalography. 7 The two main electrical parameters of the brain wave are its amplitude and frequency. Examples of the EEG waves that differ in amplitude and frequency.  Parameters of the brain waves  The brain wave frequency and amplitude vary with the degree of neural activity in the cerebral cortex.  In general, the more alert a person is, the higher the frequency of the brain wave. For example, the wave frequency is low during sleep, but high when a person is awake. 10  Parameters of the brain waves  The more synchronized is the activity of cortical neurons, the larger the amplitude of the brain waves. For example, during sleep, when cortical neurons generate electrical activity in a synchronous pattern, the brain waves have a large amplitude. In the awake state, because the sensory inputs selectively activate different parts of the brain cortex, the electrical activity of cortical neurons is desynchronized. As a result, the amplitude of the brain waves is low. 11  Types of the brain waves  Four types of the brain waves can be recorded on EEG – alpha, beta, theta, and delta waves. 12  Types of the brain waves (i) Alpha waves occur at a frequency of 8-13 Hz and have a small amplitude. They are present on EEG when a person is awake and quiet (resting with the eyes closed). Alpha waves disappear during sleep. (ii) Beta waves occur at a frequency of 14-30 Hz and have the smallest amplitude compared to other waves. They appear when the nervous system is active, i.e. during periods of sensory input and mental activity. (iii) Theta waves occur at a frequency of 4-7 Hz and have an amplitude that is larger than alpha or beta waves. These waves normally occur during sleep. 13  Types of the brain waves (iv) Delta waves occur at a frequency of 1-5 Hz and have the largest amplitude compared to other types of the brain waves. The delta-waves occur during deep sleep in adults, but they are normal in awake infants. The presence of delta waves on EEG in awake adult suggests the brain damage. 14  Types of the brain waves  In general, when the brain is involved in processing information (during active state), the neurons fire rapidly, but not synchronously with their neighbors. Hence the EEG rhythm has a high frequency, but low amplitude (i.e., the beta-rhythm).  In contrast, during sleep, the activation of cortical neurons is slow, but synchronized (large amount of neurons are phasically excited by a common, slow, rhythmic input). This translates to an EEG wave of low frequency, but high amplitude (e.g. theta- or delta-rhythms). 15 Alpha-waves are recorded on EEG when the eyes are closed and the mind is relaxed. They are transformed to beta-waves upon opening the eyes. Polysomnography is used to study sleep in humans.  Phases of sleep (i) Non-REM sleep (ii) REM-sleep (the eyes move rapidly back and forth under closed eyelids.  When we fall asleep, we enter first the non-REM sleep, and then may progress to the REM sleep.  Multiple, but short-lasting episodes of the REM sleep occur throughout the night sleep. The rest of the time is spend in the non-REM sleep. 19  Distinction 1: Non-REM Comparison of EEG during REM sleep vs. NREM sleep REM and the awake state. Distinction 2. 21  Non-REM vs. REM sleep (i) Non-REM sleep - heart rate, respiratory rate, blood pressure, and skeletal muscle tone are decreased. (ii) REM-sleep - heart rate, respiratory rate and blood pressure are increased. Muscle tone is significantly decreased (the muscles are actually paralyzed). 22 Distinction 3. REM sleep is associated with dreams. The dreams are rare during non-REM sleep (if they occur, they are less vivid, less emotional, and more logical). Changes in activity of the brain cortex when we fall asleep 24  EEG dynamics when we fall asleep (i) During awake state, the electrical activity of the brain cortex is fast and desynchronized. This translates to recording beta-rhythm on EEG (high-frequency and low-amplitude activity). (ii) When the subject becomes drowsy and relaxed, the cortical activity becomes slower and more synchronized, translating to alpha-rhythm on EEG. (iii) Stage 1, non-REM sleep - along with alpha-waves, single theta-waves (slow, but high-amplitude waves) are recorded on EEG. 26  EEG dynamics when we fall asleep (iv) Stage 2, non-REM sleep - sleep spindles (the burst of high-frequency activity) and K-complexes (sharp bidirectional waves) are recorded on EEG. This is a stage of the light sleep, in which the person is easy to awake. (v) Stage 3/4, non-REM sleep - slow-frequency but large-amplitude delta-waves are recorded on EEG. It is a period of deep sleep. (vi) During REM sleep, the EEG activity resembles that of waking (a mixture of beta-waves and alpha-waves). 27  EEG dynamics when we fall asleep  Overall, as the person becomes drowsy and then enters progressively deeper stages of the non-REM sleep, EEG becomes progressively higher in amplitude and slower in frequency.  In contrast, during REM sleep, the EEG shows low-amplitude but high-frequency waves, resembling those when the person is awake and alert. 28 Cycles during the night sleep 29 Sleep hypnogram (structure of the night sleep). Note that duration of the REM sleep progressively increases from one cycle to another (horizontal red line). Non-REM stage 3 sleep has the opposite tendency. Few episodes of brief awakenings may occur during the night sleep.  Structure of the night sleep  Intervals of NREM and REM sleep alternate throughout the night.  Initially, a person falls asleep by sequentially going through the stages 1 to 4 of the NREM sleep in about 45 min.  Then the person goes through these stages in the reverse order (from stage 4 to stage 1) in the next 45 min, before entering a period of REM sleep.  Afterwards, the person again ascends and descends through the stages of NREM sleep to enter another period of REM sleep. 32  Structure of the night sleep  During a typical 8 hour sleep period, there are 4-5 these NREM-to-REM cycles.  The first episode of REM sleep lasts 10-20 min.  REM periods occur approximately every 90 min, and gradually lengthen, with the final one lasting about 50 min.  In adults, REM sleep takes 90-120 min during 8 hour night sleep. 33 Changes on EEG during transition through different stages of sleep. Factors that control sleep (i) Homeostatic (ii) Allostatic (iii) Circadian 35  Homeostatic factors  The duration of daily sleep is a homeostatic variable, which is maintained constant.  For example, if we go without sleep for a long time, we will eventually become sleepy, and once we sleep, we will be sleeping longer than usual to compensate for the sleep debt.  The primary homeostatic factor that controls sleep is adenosine, which accumulates in the brain during wakefulness and is destroyed during sleep. 36  Adenosine and sleep  The duration of slow-wave sleep in a given person is determined by genetic factors, including the activity of a gene that encodes an enzyme adenosine deaminase, which is involved in the breakdown of adenosine.  During slow-wave sleep, neurons in the brain rest, and astrocytes renew their stock of glycogen. This reduces the extracellular concentration of adenosine.  Caffeine blocks adenosine receptors, and hence prevents the sleep-promoting effect of adenosine. 37  Allostatic factors  Under some conditions, it is important for us to stay awake – for example, when we are threatened by a dangerous situation, or when we are dehydrated and are looking for some water to drink.  This allostatic control refers to the reactions to stressful events in the environment, and serves to override homeostatic control.  Allostatic control is mediated by noradrenaline released during stress, and neuropeptides (e.g. orexin) involved in hunger and thirst. 38  Circadian sleep-wake cycle  Humans sleep and awaken in a circadian rhythm (24 hour cycle).  The transition between wakefulness and sleep is regulated by a mechanism that involves the SCN of hypothalamus and pineal gland that produces hormone melatonin. 39 Structures involved in regulation of the circadian sleep-wakefulness cycle.  Pineal gland  Pineal gland is a pea-sized gland located behind the thalamus. It is considered part of the endocrine system because it secretes the hormone melatonin.  Melatonin helps regulate circadian rhythm established by the suprachiasmatic nucleus of hypothalamus.  In response to visual input from the retina, SCN causes the pineal gland to secrete melatonin in a rhythmic pattern, with low levels secreted during the day, and high levels secreted at night (called the darkness hormone). 41 Pineal gland is a secretory circum- ventricular organ devoid of the blood- brain barrier. This allows to secrete melatonin directly into the blood.  Melatonin  Melatonin is mostly secreted by the pineal gland during the night time.  Melatonin acts as a chemical messenger considered to be intermidiary between the SCN and the brain centers that control body functions. To these centers, melatonin sends info about the dark-light cycle.  The changing levels of melatonin promote rhythmic changes in sleep, wakefulness, hormone secretion, and body temperature. 43  Two-process model of sleep regulation. The need for the sleep and its timing (onset and termination) are determined by the balance between the homeostatic drive for sleep and the circadian drive for wake.  Two-process model of sleep regulation  Homeostatic drive promotes sleep. It builds up during wakefulness throughout the day, and dissipates during sleep at night. Homeostatic drive is related to adenosine accumulation in the brain during wakefulness.  Circadian drive promotes wakefulness during day-time. This drive is established by the SCN and melatonin from the pineal gland.  When sleep pressure is high (peak of the homeostatic drive) and wake pressure is low (through of the circadian drive), sleep is initiated.  Dissipation of the homeostatic drive along with an increase in the wake drive during the night result in waking up. 45  Brain structures involved into the waking and sleeping mechanisms 46  Brain structures that regulate the waking and sleeping  There is no single sleep center or waking center in the brain.  There is a variety of structures that integrate the timing of the SCN with homeostatic information about physical conditions, e.g. fatigue, time awake, etc. 47  Waking  Waking is the state when we are conscious, aware, and responsive to external stimuli.  The waking state is maintained through activation of the cortical areas, due to the signals send from the thalamus (more specifically, the intralaminar nucleus which is a central region of the thalamus). 48 Stimulation of the thalamus can produce cortical arousal and wakefulness in individuals who have been minimally conscious for years. 49  Waking centers in the brain. Indirect pathway (blue) and direct pathway (green) for cortical stimulation are shown. 50  Waking centers in the brain  In addition to the thalamus, there are several clusters of neurons in the brainstem and hypothalamus that contribute to maintaining the waking state. Brainstem – (i) Pedunculopontine and laterodorsal tegmental nuclei (PPT/LDT) send axons to the intralaminar nucleus of the thalamus, in order to activate it. These axons release acetylcholine as a neurotransmitter. (ii) Raphe nucleus sends axons directly to the cerebral cortex, which activate it by releasing serotonin. (iii) Locus coeruleus sends axons directly to the cerebral cortex, which activate it by releasing noradrenaline. 51  Waking centers in the brain Hypothalamus – Posterior hypothalamic nuclei send axons directly to the cerebral cortex, in order to activate it by releasing histamine and orexin as neurotransmitters. The neurons at these locations within the brainstem and the hypothalamus are called “waking-on” neurons because they are continuously active (and releasing their neurotransmitters) during waking. Activity of these neurons is associated with desynchronized EEG (low-amplitude, high-frequency beta-waves). 52 The reticular activating system. 53  Reticular activating system  The nuclei of the pons (including the raphe nuclei, locus coeruleus, LDT nuclei, PPT nuclei) are part of the reticular formation of the brainstem.  During wakefulness, the reticular formation receives sensory inputs from somatic receptors of the skin, joints and muscles, as well as receptors of the eyes, ears, and nose.  Once the RAS is activated, it sends the signals to the cerebral cortex through the ascending activating pathways. 54  Histamine and sleep  In the brain, histamine is produced by neurons in the tuberomammillary nucleus of the hypothalamus.  The activity of these neurons is high during waking, but low during sleep.  The axons of these neurons project to the cerebral cortex, thalamus, and forebrain, and produce activation and arousal.  Antihistamine agents which are prescribed to treat allergies can produce drowsiness as a side effect, due to blocking cortical activation caused by histamine. 55  Waking centers in the brain  Many stimulant drugs enhance the action of neurotransmitters released by the waking-on neurons.  The best known stimulants are cocaine and the amphetamines, which produce arousal effects primarily by increasing the levels of noradrenaline at the synaptic sites within the brain cortex.  Nicotine produces its psychostimulant effects through nicotinic cholinergic receptors in the cortical neurons. 56 Summary of the waking mechanisms. 57  Brain sleeping centers: Different structures regulate the REM- and non-REM sleep. 58  Non-REM sleep: Two initiating mechanisms. 59 Mechanism 1. Activation of the preoptic area of hypothalamus. 60  Mechanism 1 for Non-REM sleep  Onset of the non-REM sleep is related to activation of neurons in the preoptic area in the anterior hypothalamus.  These sleep-on neurons send axons to the waking centers in the brainstem and hypothalamus, and inhibit them by releasing GABA as a neurotransmitter.  Damage of these neurons results in lost ability to sleep. 61 Mechanism 2. Disconnection of thalamus and cortex. 62  Mechanism 2 for non-REM sleep  During the waking state, the cortical arousal is maintained by sending the signals from the thalamic relay neurons (which relay to cortex info received from special senses, i.e. visual, auditory, tactile).  During non-REM sleep, the reticular neurons of the thalamus inhibit activity of the relay neurons. This prevents the relay neurons from sending sensory info to the cortex, which suppresses cortical arousal, and induces non-REM sleep. 63 + Summary of the non-REM sleep mechanisms. 64 REM sleep 65 The experiments on cat have demonstrated that a forebrain cannot enter the REM sleep when it is disconnected from pons. 66  REM sleep  The REM sleep is initiated by neurons in the pons.  In experiments on cats, when the brain cut is made to leave the cortex and thalamus on one side, and the brainstem (pons and medulla) on the other, the animals, after recovery from surgery, may get into the slow-wave sleep, but have no the REM sleep.  The REM sleep, however, was inducible when a cut was made below the pons, so its connection with a forebrain was preserved. 67 REM sleep center. 68  REM sleep  The most important REM sleep center in the pons is the sublaterodorsal nucleus, which governs switching in and out of REM sleep.  This nucleus sends a signal to the PPT/LDT nuclei, which generate the ponto-geniculate-occipital waves (PGO waves).  These waves travel from the pons through the lateral geniculate nucleus of the thalamus to the occipital cortex. 69  REM sleep  The PGO waves induce EEG desynchrony during transition from the non-REM to the REM sleep.  Activation of the occipital cortex by these waves may account for the visual imagery of dreaming during the REM sleep.  The subthalamodorsal nucleus also sends axons to the magnocellular nucleus in the medulla, which inhibits spinal motor neurons that maintain the muscle tone. This accounts for atonia typically seen during the REM sleep. 70 Summary of the REM sleep mechanisms. 71 The flip-flop model of regulation of the wake-sleep cycle. vlPOA is the ventrolateral preoptic area of the hypothalamus.  Flip-flop model of the wake/sleep cycle  In the brain, the sleep centers (such as preoptic area of the hypothalamus) and the waking centers (such as tuberomammillary nucleus of the hypothalamus and the raphe nucleus and the locus coeruleus in the brainstem) are in reciprocal relationships.  This means the activation of the sleep centers is associated with inhibition of the wake centers, and the other way around.  The flip-flop assumes one of two states, i.e. “on” or “off”. 73