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• Biological rhythm:

Circadian rhythm

Menstrual rhythm

Time stimulus like dark/light ,temperature are zeitgeber.

They organize circadian rhythm.

There are two sleep drives, one homeostatic and the other circadian.

The homeostatic drive increases with the duration of wakefulness, whereas the circadian signals are controlled by the suprachiasmatic nucleus of the hypothalamus.

Recent evidence has shown that neurons of the ventrolateral preoptic nucleus of the hypothalamus are sleep active and sleep promoting, confirming old observations that lesions in this area induce insomnia.

These neurons express the inhibitory transmitters, galanin and GABA, and innervate wake-promoting areas ,including:

The hypocretin (also known as orexin) containing neurons of the posterolateral hypothalamus,

histaminergic neurons of the tuberomammillary nucleus, the serotonergic dorsal raphe, norepinephrine containing neurons of the locus ceruleus, and the cholinergic neurons of the dorsal midbrain and pons.

In turn, monoaminergic wake-promoting areas inhibit the ventrolateral preoptic nucleus, thereby resulting in reciprocal inhibition that self-reinforces

Orexin

Orexin is subject both to circadian and homeostatic regulation as the ablation of the suprachiasmatic nucleus abolishes its production, while its levels are enhanced by sleep deprivation .

Therefore, orexin seems to be an essential component of the mechanisms maintaining prolonged wakefulness and opposing to homeostatic sleep propensity.

As for REM sleep it has been found that the

Tuberomammilary nucleus, Locus ceruleus andRaphe nuclei contain Orexin receptors exerting

an Inhibitory effect on REM sleep

Therefore the absence of excitatory orexin input would augment the strength of REM mechanisms, thus facilitating more frequent transitions to REM sleep.

Circadian rhythms generated by the central pace-maker in the suprachiasmatic nucleus (SCN) control the timing of wake and REM sleep , perhaps in part via projections to orexin neurons that then relay this information to sleep-regulatory and wake-regulatory regions .

It has been hypothesized that daytime sleepiness and fragmented sleep of human narcolepsy could be caused by impaired circadian control since circadian signals help time and consolidate sleep-wake behavior .

Oscillatory EEG patterns arise because of pacemaker cells, in which membrane voltage fluctuates spontaneously, or because of the reciprocal interaction of excitatory and inhibitory neurons in circuit loops.

The human EEG shows activity over the range of 1 to 30 Hz, with amplitudes in the range of 20 to 300 µV.

thalamocortical connections are critical in the synchronization of electrical activity, such as sleep spindles.

It has been estimated that each EEG electrode “sees” the summed activity of roughly 6 cm2 of underlying cortex.

These pathological waves of cortical excitation and subsequent inhibition affecting broad regions of excessively synchronized cortex are thought to underlie the spikes, sharp waves, and sharp and slow wave complexes we recognize as pathological correlates in routine EEG interpretation.

Alpha rhythm As with all repeating rhythms, it is most important to note the

frequency and the location of the activity, its amplitude, and its reactivity. The alpha rhythm oscillation is between 8 and 12 Hz and is most prominent over the more posterior aspects of the head. Its amplitude or voltage in a bipolar (P4–O2) derivation is any-where from 15 to 65 µV. This is reactive or responsive to mental activity and to eye opening or closure. The rhythm is partially or completely blocked by mental activity or by eye opening . Likewise, it is enhanced by relaxation and by eye closure (Fig. 1). In a few healthy subjects (<2%), no apparent alpha rhythm can be seen. in some subjects (<7%), a very low-voltage alpha rhythm is observed. Because recordings are bipolar, one can improve on alpha detections by increasing the inter-electrode distances.

There may be a side-to-side amplitude asymmetry, noted in approximately 60% of people, in which the right side tends to be of slightly higher amplitude.

The left side may be more predominant in left handed individuals.

The difference in amplitude between the two hemispheres is not more than 50%.

Beta activity (>12 Hz) is defined by three relatively distinct frequency bands: 18 to 25 Hz activity, which is the most frequently encountered; 14 to 17 Hz activity, which is less common; and the still rarer, greater than 25 Hz activity. The first two frequencies are seen commonly over the frontal regions and become more prominent as the subject gets drowsy. These two beta rhythms are usually of low voltage (<25 µV). It can be markedly increased by the use of some drugs, most notably the benzodiazepines and barbiturates. However, in those

Mu Rhythm

The mu rhythm is a centrally located rhythm with a frequency of 8 to 10 Hz. It is thought to be the resting rhythm of the pre- and post-Rolandic cortex.

Theta

• Theta activity is defined as activity between 4 and 7 Hz. Although theta activity is often a sign of disease or of sleep onset, it may also be seen as part of a normal awake EEG. Although some intermittent low-voltage theta activity is seen over the frontal–central regions in healthy people while resting and awake, this is usually not a well-developed nor regular rhythm. Under a circumstance in which the subject is performing some moderately difficult mental task, such as spelling or mathematics, one can occasionally see a well-developed theta rhythm in the frontal midline region . A small amount of left temporal theta activity during wakefulness is also expected as a normal factor in aging, starting around the age of 50 yr .

Lambda wave

• These waves may be quite asymmetric,They will then have the patient close their eyes, whichwill block the normal lambda wave but usually not have an effect on the abnormal activity.They will then have them open their eyes and look at a plain piece of paper, which also blocksthe normal lambda wave but will not effect the epileptiform discharges, which are most oftenmistaken for a lambda wave (3).

lamda

Stage I

The first suggestion that a patient is going to sleep is that there is a sudden drop in the voltage of their background alpha rhythm, followed by intermittent theta activity noted over the more posterior head regions (Fig. 4). This presleep or twilight state is usually followed by early Stage II.

STAGE II This stage’s onset is identified by the appearance of

spindles. They are frontal–centrally predominant waves that occur as a cluster lasting for one to several seconds in duration. The spindle frequency is between 11 and 15 Hz and, in healthy adults, they are bilateral and synchronous in their appearance, with an amplitude up to 30 µV. Spindles may appear by themselves or following a vertex wave. In that latter situation, the wave is called a “K complex”.

During the progression into deeper aspects of Stage II, the background rhythm continues to slow into the slower theta ranges, and high voltage generalized and frontally predominant delta slow waves are noted (<4 Hz).

STAGE III

Occasionally a patient may go on to Stage III sleep. In this phase, there are still vertex waves, spindles, and K-complexes, but they occur less frequently and seem to be over-whelmed by the more prominent delta wave activity (<4 Hz). This slow wave activity is widespread but has a frontal and central predominance. It should be the most frequently noted rhythm and should be present for 20 to 50% of the record .

Stage III and the later Stage IV of sleep are most often associated with increases in the interictal discharges of temporal lobe epilepsy.

Stage III

STAGE IV

Stage IV also has rudimentary vertex waves, spindles, and K-complexes, but shows further slowing and a more persistent delta-frequency background. In this stage, most (>50%) of the time of the recording is associated with continuously appearing delta activity .

This stage is only rarely achieved in the routine EEG recording.

REM

In sleep laboratories, the REM stage is divided into tonic and phasic components based on the simultaneous recording of other physiological parameters not routinely monitored during EEG acquisitions .

The other recordings include respiration effort and pulse oximetry, and chin and leg EMG activity.

From a strictly EEG perspective, the background rhythm returns to what seems to be a drowsy or wakeful state, with low-voltage theta and alpha frequency activity, and with large, slow lateral eye movements .

This stage of sleep is also rarely encountered in routine EEG.

• REM and NREM sleep differ physiologically. • REM sleep is characterized by both phasic and tonic

changes in physiology. The drop in baseline EMG correlates with a tonic change.

• Tonic physiological changes also include impaired thermo regulation, reduction in ventilatory chemosensitivity, hypotension, bradycardia, increased cerebral blood flow, and intracranial pressure, increased respiratory rate, and penile erection.

• Phasic changes include vasoconstriction, increased blood pressure, tachycardia, and further increases in cerebral blood flow and respiratory rate.

• During NREM sleep, the physiological state is more stable, with an overall reduction in blood pressure, heart rate, cardiac output, and respiratory rate. One characteristic feature of NREM, slow-wave sleep is the secretion of growth hormone.

narcolepsy

leptin

Reduced circulating leptin levels may be involved in the pathogenesis of obesity in narcoleptic patients.

The fact that narcoleptic patients are obese in the face of hypophagia suggests that they spend less energy, which is supported by early observations.

Leptin is critically involved in the control of energy expenditure and hypoleptinemia is associated with a lower metabolic rate in obese animal models.

Alternatively ,hypocretin deficiency may reduce basal metabolism directly via its inhibitory impact on the sympathetic nervous system.

adenosine It has been described that approximately 30% of Hcrt cells express A1

adenosine receptor. Adenosine is hypnogenic molecule that inhibits wakefulness promoting neurons via a postsynaptic action mediated through A1 adenosine receptor.

Caffeine is a xanthine derivative. The mechanism of action of caffeine on wakefulness involves nonspecific adenosine receptor antagonism. Adenosine is an endogenous sleep-promoting substance with neuronal inhibitory effects.

In animals, sleep can be induced after administration of metabolically stable adenosine analogues with adenosine A1 receptors (A1R) or A2A receptors (A2AR) agonistic properties.

Adenosine content is increased in the basal forebrain after sleep deprivation.

Adenosine has thus been proposed to be a sleep-inducing substance accumulating in the brain during prolonged wakefulness .

• During slow wave sleep, activity of hcrt neurons diminishes and results in disinhibition of GABAergic neurons in the ventrolateral preoptic area. During REM sleep, hcrt neurons are silent and disinhibit REM-on neurons in the brainstem (16). In narcolepsy, the absence of hypocretin neurons results in lack of integration and coordination of excitatory signals that modulate wakefulness (17).

Sleep disorders

• Pseudoinsomnia

• Idiopathic insomnia

• Delayed sleep phase insomnia

• Drug insomnia

• Secondary insomnia

• Narcolepsia

• somnambolism

• Hypocretin neurons are activated by CRF in response to stimuli that cause stress and this activation may be responsible for the extended arousal.

• stress is known to promote relapse of drug seeking (21). Using an animal paradigm of cocaine self-administration, we have shown that a single injection of hypocretin can reinstate cocaine seeking behavior in extinguished animals (22).

• Among the regions innervated by the hypocretin neurons are the ventral tegmental area(VTA), the locus ceorulus (LC), the prefrontal cortex, the hippocampus, the nucleus accumbens, the amygdala, the ventral pallidum and the TMN (14, 19, 20). Defined as the mesocorticolimbic dopamine system, these neurons are related to brain mechanisms of reward, reinforcement, and emotional arousal. In accordance to this, we have inves-tigated whether the hypocretinergic system has a role in the hyperaroused state that is associated with stress and drug addiction. We hypothesized that corticotrophin-releasing factor, a hormone that initiates the stress response and activates the hypothalamo-pituitary-adrenal axis, exerted an effect on hypocretin neurons. Indeed,CRF-containing synaptic terminals contact hypocretin neurons and hypocretin neurons express CRF receptors.