Alert Behavior, Sleep, & the Electrical Activity of the Brain At least in mammals, there is a spectrum of behavioral states

s ranging from deep sleep through light sleep, REM sleep, and the two wake states: 1. Relaxed awareness and 2. Awareness with concentrated attention. There are patterns of brain electrical activity that correlate with each of these states, including electroencephalographic (EEG) (A system for recording the electric potentials of the brain derived from electrodes attached to the scalp) patterns. Arousal and the wake patterns of the EEG and thalamic discharges can be produced by sensory stimulation and by impulses ascending in the reticular core of the midbrain. Sleep and sleep patterns can be produced by stimulating the basal forebrain and other "sleep zones." THE THALAMUS & THE CEREBRAL CORTEX Thalamic Nuclei On developmental and topographic grounds, the thalamus can be divided into three parts: the epithalamus, the dorsal thalamus, and the ventral thalamus. The epithalamus has connections to the olfactory system The dorsal thalamus can be divided into nuclei that project diffusely to the whole neocortex and nuclei that project to specific discrete portions of the neocortex and limbic system. The nuclei that project to all parts of the neocortex are the midline and intralaminar nuclei. The nuclei of the dorsal thalamus that project to specific areas include the specific sensory relay nuclei and the nuclei concerned with efferent control mechanisms. The specific sensory relay nuclei include the medial and lateral geniculate bodies, which relay auditory and visual impulses to the auditory and visual cortices; and the ventrobasal group of nuclei, which relay somatesthetic (the conscious awareness of the body) information to the postcentral gyrus. The nuclei concerned with efferent control mechanisms include several nuclei that are concerned with motor function. They receive input from the basal ganglia and the cerebellum and project to the motor cortex. Also included in this group are the anterior nuclei, which receive afferents from the mamillary bodies and project to the limbic cortex. Cortical Organization The neurons are mostly pyramidal cells with extensive vertical dendritic trees that may reach to the cortical surface. The axons of these cells usually give off recurrent collaterals that turn back and synapse on the superficial portions of the dendritic trees. Afferents from the specific nuclei of the thalamus terminate primarily in cortical layer 4, whereas the nonspecific afferents are distributed to layers 1-4. THE RETICULAR FORMATION & THE RETICULAR ACTIVATING SYSTEM The reticular formation, the phylogenetically old reticular core of the brain, occupies the midventral portion of the medulla and midbrain. It is primarily an anatomic area made up of various neural clusters and fibers with discrete functions. For example, it contains the cell bodies and fibers of many of the serotonergic, noradrenergic, and adrenergic systems It also contains many of the areas concerned with regulation of heart rate, blood pressure, and respiration. Some of the descending fibers in it inhibit transmission in sensory pathways in the spinal cord. Various reticular areas and the pathways from them are concerned with spasticity and adjustment of stretch reflexes. The reticular activating system (RAS) is a complex polysynaptic pathway.

Collaterals funnel into it not only from the long ascending sensory tracts but also from the trigeminal, auditory, and visual systems and the olfactory system. The complexity of the neuron net and the degree of convergence in it abolish modality specificity, and most reticular neurons are activated with equal facility by different sensory stimuli. The system is therefore nonspecific, whereas the classic sensory pathways are specific in that the fibers in them are activated by only one type of sensory stimulation. Part of the RAS bypasses the thalamus to project diffusely to the cortex. Another part ends in the intralaminar and related thalamic nuclei and, from them, is projected diffusely and nonspecifically to the whole neocortex

EVOKED CORTICAL POTENTIALS If the exploring electrode is over the primary receiving area for the particular sense, a surface-positive wave appears with a latency of 5-12 ms. This is followed by a small negative wave, and then there is frequently a larger, more prolonged positive deflection with latency of 20-80 ms. The first positive-negative wave sequence is the primary evoked potential; the second is the diffuse secondary response. The primary evoked potential is highly specific in its location and can be observed only where the pathways from a particular sense organ end. The surface-positive diffuse secondary response, unlike the primary, is not highly localized. It appears at the same time over most of the cortex and is due to activity in projections from the midline and related thalamic nuclei. THE ELECTROENCEPHALOGRAM Introduction It denotes the record of the variations in brain potential. The term electrocorticogram (ECoG) is sometimes used for the record obtained with electrodes on the pial surface of the cortex. EEG records may be bipolar or unipolar. Bipolar records show fluctuations in potential between two cortical electrodes; unipolar records show potential differences between a cortical electrode and a theoretically indifferent electrode on some part of the body distant from the cortex. Alpha Rhythm In adult humans who are awake but at rest with the mind wandering and the eyes closed, the most prominent component of the EEG is fairly regular pattern of waves at a frequency of 8-12 Hz and amplitude of 50-100 uV when recorded from the scalp. This pattern is the alpha rhythm. It is most marked in the parieto-occipital area, though it is sometimes observed in other locations. Other Rhythms In addition to the dominant rhythm, 18-30 Hz patterns of lower amplitude are sometimes seen over the frontal regions. This beta rhythm may be a harmonic of the alpha. Gamma oscillations at 30-80 Hz are often seen when an individual is aroused and focuses attention on something. This is often replaced by irregular fast activity as the individual initiates motor activity in response to the stimulus. A pattern of large-amplitude, a regular 4-7 Hz wave called the theta rhythm occurs in children and is generated in the hippocampus in experimental animals Large, slow waves with a frequency of less than 4 Hz are sometimes called delta waves. Variations in the EEG In humans, the frequency of the dominant EEG rhythm at rest varies with age. In infants, there is fast, beta-like activity, but the occipital rhythm is a slow 0.5-2 Hz pattern.

During childhood this latter rhythm speeds up, and the adult alpha pattern gradually appears during adolescence. The frequency of the alpha rhythm is decreased by a low blood glucose level, a low body temperature, a low level of adrenal glucocorticoid hormones, and a high arterial partial pressure of CO2 (PaCO2). It is increased by the reverse conditions. Forced overbreathing to lower the PaCO2 is sometimes used clinically to bring out latent EEG abnormalities.

Alpha Block When attention is focused on something, the alpha rhythm is replaced by fast, somewhat irregular low-voltage activity. This phenomenon is called alpha block. A breakup of the alpha pattern is also produced by any form of sensory stimulation or mental concentration such as solving arithmetic problems. A common term for this replacement of the regular alpha rhythm with irregular low-voltage activity is the arousal or alerting response, because it is correlated with the aroused, alert state. It has also been called desynchronization, because it represents breaking up of the obviously synchronized neural activity necessary to produce regular waves. Sleep Patterns There are two different kinds of sleep: rapid eye movement (REM) sleep and non-REM (NREM), or slow-wave sleep. NREM sleep is divided into four stages. 1. A person falling asleep first enters stage 1, which is characterized by low-amplitude, highfrequency EEG activity. 2. Stage 2 is marked by the appearance of sleep spindles. These are bursts of alpha-like, 10-14 Hz, 50 uV waves. 3. In stage 3, the pattern is one of lower frequency and increased amplitude of the EEG waves. 4. Maximum slowing with large waves is seen in stage 4. Thus, the characteristic of deep sleep is a pattern of rhythmic slow waves, indicating marked synchronization. In stages 2-4, the electroencephalogram becomes more synchronized (lower frequency, higher amplitude) and the subject becomes more difficult to arouse. REM Sleep The high-amplitude slow waves seen in the EEG during sleep are sometimes replaced by rapid, low-voltage EEG activity, which in primates, including humans, resembles that seen in stage 1 sleep. However, sleep is not interrupted; indeed, the threshold for arousal by sensory stimuli and by stimulation of the reticular formation is sometimes elevated. This condition is sometimes called paradoxical sleep, since the EEG activity is rapid. There are rapid, roving movements of the eyes during paradoxical sleep, and it is for this reason that it is also called REM sleep. There are no such movements in slow-wave sleep, which consequently is often called NREM sleep. Another characteristic of REM sleep is the occurrence of large phasic potentials, in groups of three to five, which originate in the pons and pass rapidly to the lateral geniculate body and from there to the occipital cortex. For this reason, they are called ponto-geniculo-occipital (PGO) spikes. There is a marked reduction in the tone of the skeletal muscles in the neck during REM sleep. Other muscles keep their tone, but there is a relative paralysis of voluntary activity that is dependent on the locus ceruleus. In cats with locus ceruleus lesions, REM sleep is associated with thrashing about, as if they were acting out their dreams.

 (REM) sleep (also known as active sleep or dreaming sleep). Studies indicate that dreaming occurs mainly during REM sleep Non-REM (NREM) sleeps (also known as quiet sleep or slow-wave sleep). If REM sleep is selectively blocked by wakening the subject at the beginning of REM sleep, a specific "REM debt" builds up, and the subject does not feel adequately rested. After the initial slow-wave sleep stages, the electroencephalographic pattern usually shifts abruptly to the desynchronized (higher frequency, lower amplitude) pattern seen in stage 1 sleep. Despite some similarity with the "waking" electroencephalographic pattern, it is difficult to waken subjects in this stage of sleep. This is sometimes referred to as "paradoxic sleep." Because one of the most striking features of this stage is intermittent rapid eye movements, this stage is termed REM sleep. PHYSIOLOGIC BASIS OF THE EEG, CONSCIOUSNESS, & SLEEP Introduction The EEG is the record of electrical activity of cortical neural units in a volume conductor. It is usually recorded through the skull and scalp and is therefore of much lower voltage than it would be if recorded directly from the cortex. Recording from the cortical surface or scalp registers a positive wave when net current flow is toward the electrode and a negative wave when net current flow is away from the surface. Cortical Dipoles The presence of waves in almost all situations in the EEG indicates that activity is waxing and waning in the cerebral cortical area sampled by the EEG. If activity were random, discharges would cancel out and no waves would be produced. There is solid evidence that the waves are due to oscillating activity within the cortex and to oscillation in feedback circuits between the thalamus and the cortex. The dendrites of the cortical cells are a forest of similarly oriented, densely packed units in the superficial layers of the cerebral cortex Current flow in this dipole produces wave-like potential fluctuations in a volume conductor When the sum of the dendritic activity is negative relative to the cell, the cell is hypopolarized and hyperexcitable; when it is positive, the cell is hyperpolarized and less excitable. Thalamocortical Oscillations The other source of the EEG waves is the reciprocal oscillating activity between the midline thalamic nuclei and the cerebral cortex The thalamic neurons are hyperpolarized and discharge only in sleep spindle-like phasic bursts during slow wave sleep. During the aware state, they are partially depolarized and fire tonically at rapid rates. This is associated with a more rapid firing rate of cortical neurons The state of the thalamic neurons can be shifted from hyperpolarized phasic firing to depolarized tonic firing by sensory stimulation that produces arousal. Conversely, the neurons can be shifted from depolarized to hyperpolarized by stimulation of sleep zones. There is reason to believe that when the neurons are hyperpolarized and firing only on phasic bursts, activity in the thalamocortical oscillations prevents cortical neurons from receiving or processing specific inputs. Mechanisms Producing EEG Arousal Replacement of a rhythmic EEG pattern with low-voltage, rapid activity is produced by stimulation of the specific sensory systems up to the level of the midbrain, but stimulation of these systems above the midbrain, stimulation of the specific sensory relay nuclei of the thalamus, or stimulation of the cortical receiving areas themselves does not produce the alerting response.

On the other hand, high-frequency stimulation of the midbrain reticular formation produces the EEG alerting response and arouses a sleeping animal. Large bilateral lesions of the lateral and superior portions of the midbrain that interrupt the medial lemnisci and other ascending specific sensory systems fail to prevent EEG alerting produced by sensory stimulation, but lesions in the midbrain tegmentum that disrupt the RAS without damaging the specific systems are associated with a slow-wave synchronized pattern that is unaffected by sensory stimulation. Animals with the former type of lesion are awake; those with the latter type are comatose for long periods. Patients with lesions that interrupt the RAS are also somnolent or comatose. Thus, the ascending activity responsible for the EEG alerting response following sensory stimulation passes up the specific sensory systems to the midbrain, enters the RAS via collaterals, and continues through the interlaminar nuclei of thalamus and the nonspecific thalamic projection system to the cortex.

Genesis of Slow-Wave Sleep Slow waves in the EEG and their behavioral correlate, slow-wave sleep, can be produced by stimulation of at least three subcortical regions. I. The diencephalic sleep zone is in the posterior hypothalamus and the nearby intralaminar and anterior thalamic nuclei. The stimulus frequency must be about 8 Hz; faster stimuli produce arousal. This finding need not be confusing; the important point is that low- frequency stimulation produces one response, whereas high-frequency stimulation produces another. II. The second zone is the medullary synchronizing zone in the reticular formation of the medulla oblongata at the level of the nucleus of the tractus solitarius. Stimulation of this zone, like stimulation of the diencephalic sleep zone, produces sleep if the frequency is low but arousal if the frequency is high. III. The third synchronizing region is the basal forebrain sleep zone. This zone includes the preoptic area and the diagonal band of Broca. It differs from the other two zones in that stimulation of the basal forebrain zone produces slow waves and sleep whether the stimulating frequency is high or low. Neurons in the ventrolateral part of the preoptic area project to the tuberomamillary nucleus, part of the posterior hypothalamus that is in the diencephalic sleep zone. It is worth noting that stimulation of afferents from mechanoreceptors in the skin at rates of 10 Hz or less also produces sleep in animals, apparently via the brain stem, and it is of course common knowledge that regularly repeated monotonous stimuli put humans to sleep. On the other hand, slow-wave sleep is under marked circadian control. Serotonin agonists suppress sleep and that the serotonin antagonist ritanserin increases slow-wave sleep in humans. The concentration of adenosine increases in the cholinergic areas of the basal forebrain and the mesopontine cholinergic nuclei during wakefulness and declines during sleep. Both of these areas are concerned with sleep, so adenosine may be a sleep-producing factor. This is consistent with the well-known alerting effects of caffeine, which is an adenosine antagonist. Another hypothesis holds that release of prostaglandin D2 (PGD2) in the medial preoptic area of the hypothalamus causes increased slow-wave sleep and REM sleep whereas release of PGE2 causes wakefulness. A lipid produced by the brain is said to have sleep-inducing properties. Several investigators have argued that a peptide produced in the brain is responsible for sleep. Concomitants of REM sleep

 Humans aroused at a time when they show the EEG characteristics of REM sleep generally report that they were dreaming, whereas individuals awakened from slow-wave sleep do not. This observation and other evidence indicate that REM sleep and dreaming are closely associated. The tooth-grinding (bruxism) that occurs in some individuals is also associated with dreaming. If humans are awakened every time they show REM sleep, and then permitted to sleep without interruption, they show a great deal more than the normal amount of REM sleep for a few nights. However, experimental animals completely deprived of REM sleep for long periods lose weight in spite of increased caloric intake and eventually die, indicating that REM sleep has some not yet understood but important homeostatic role. On the other hand, deprivation of slow-wave sleep produces similar changes, so they may not be specifically related to REM sleep. Genesis of REM sleep The main difference between REM sleep and wakefulness is that dream consciousness is characterized by bizarre imagery and illogical thoughts, and dreams are generally not stored in memory. However, PET scanning of humans in REM sleep shows increased activity in the pontine area, the amygdalas, and the anterior cingulate gyrus but decreased activity in the prefrontal and parietal cortex. Activity in visual association areas is increased, but there is a decrease in the primary visual cortex. This is consistent with increased emotion and operation of a closed neural system cut off from the areas that relate brain activity to the external world. The mechanism that triggers REM sleep is located in the pontine reticular formation. PGO spikes originate in the lateral pontine tegmentum. The spikes are due to discharge of cholinergic neurons. It now appears that discharge of noradrenergic neurons in the locus ceruleus and serotonergic neurons in the midbrain raphe contributes to wakefulness and that these neurons are silent when cholinergic PGO spike discharge initiates REM sleep. Reserpine, which depletes serotonin and catecholamines, blocks slow-wave sleep and some aspects of REM sleep but increases PGO spike activity. Barbiturates decrease the amount of REM sleep. Distribution of Sleep Stages In a typical night of sleep, a young adult first enters NREM sleep, passes through stages 1 and 2, and spends 70-100 minutes in stages 3 and 4. Sleep then lightens, and an REM period follows. This cycle is repeated at intervals of about 90 minutes throughout the night. The cycles are similar, though there is less stage 3 and 4 sleep and more REM sleep toward morning. Thus, there are four to six REM periods per night. REM sleep occupies 80% of total sleep time in premature infants and 50% in full-term neonates. Thereafter, the proportion of REM sleep falls rapidly and plateaus at about 25% until it falls further in old age. Children have more total sleep time and stage 4 sleep than adults.