Review of Medical Physiology - William F. Ganong 2002

Functions of the Nervous System
Anxiety States, Sleep, and Electrical Activity of the Brain
Physiological Basis of the EEG, Consciousness, and Sleep

The EEG is a recording of the electrical activity of cortical neural units within a volume conductor (see Chapter 2). Because it is typically recorded from the scalp or cranium, its voltage is substantially lower than that of recordings obtained directly from the Cerebral Cortex. As noted above, recording from the cortical surface or scalp registers a positive wave when the current is directed toward the electrode, and a negative wave when the direction is away from the surface.

Class="center">

Fig. 11-5. Rabbit cortical EEG showing an arousal reaction induced by an olfactory stimulus.

Fig. 11-6. EEG and muscular activity during various stages of Sleep. EOG, electrooculogram recording Eye Movements; EMG, electromyogram recording Skeletal Muscle activity; CENTRAL, FRONTAL, OCCIPITAL locations of three EEG electrodes. Note the low muscle tone alongside extensive eye movements during REM sleep (reprinted with permission from Kales A et al: Sleep and dreams: Recent research on clinical aspects. Ann Intern Med. 1968;68:1078).

Cortical Dipoles

In all cases, the presence of waves on the EEG indicates that activity in the region of the cerebral cortex measured by the EEG alternates between increases and decreases. However, if this activity were chaotic, synchronous discharges and, consequently, waves would not emerge. The impact of these rhythms on behavioral states and even on consciousness remains elusive. At the same time, strong evidence suggests that these waves are driven by oscillatory activity within the cortex and fluctuations in thalamocortical feedback loops.

Cortical Cell dendrites are tree-like, uniformly oriented, densely packed units located in the superficial layers of the cerebral cortex (see Fig. 11-1). Propagated potentials can be generated in dendrites (see Chapter 4). In addition, recurrent axon collaterals terminate on dendrites in the superficial layers. Nevertheless, dendrites primarily serve as sites for non-propagating hypopolarizing local potentials. When excitatory and inhibitory endings on the dendrites of each cell become active, they act as sources or sinks for bioelectric currents relative to the rest of the dendritic arbor and The Cell body. Consequently, a constantly shifting bipolarity exists between the cell body and the dendrites. The flow of impulses within this dipole produces wave-like potential oscillations in the volume conductor (Fig. 11-7). If the overall dendritic activity is negative relative to the cell body, the cell becomes hypopolarized and hyperexcitable; if it is positive, the cell is hyperpolarized and less excitable. Two other Regions of the Central Nervous system containing abundant, complex, parallel dendritic arbors positioned beneath the pia mater over a layer of Cells are the CEREBRAL CORTEX AND the hippocampus. Both regions exhibit characteristic rhythmic fluctuations in surface potential similar to those observed in the cortical EEG.

Fig. 11-7. Schematic comparison of the electrical responses of an axon and the dendrites of a large cortical neuron. The flow of biopotentials through active synaptic boutons on dendrites produces wave activity, whereas all-or-none action potentials propagate along the axon.

Thalamocortical Oscillations

Another source of EEG waves is the reciprocal oscillatory activity between the midline thalamic nuclei and the cerebral cortex (Fig. 11-8). Thalamic Neurons are hyperpolarized and change their charge only in spindle-like phasic bursts during slow-wave sleep. In the conscious state, they are partially depolarized and tonically "fire" at a high rate, which is associated with a higher firing rate in cortical neurons.

The state of thalamic neurons transitions from hyperpolarized phasic "bursting" to depolarized tonic firing As a result of sensory stimulation, which produces arousal. Conversely, the transition from depolarization to hyperpolarization is triggered by stimulating sleep-promoting areas (see below). There is reason to believe that when neurons are hyperpolarized and fire only during phase bursts, thalamocortical oscillatory activity prevents cortical neurons from receiving or Processing specific incoming signals.

Mechanisms Underlying EEG Arousal

The replacement of rhythmic EEG patterns with low-voltage fast activity occurs as a result of stimulating specific Sensory systems up to the Midbrain level. At the same time, stimulation of these systems above the midbrain, irritation of specific sensory Relay nuclei of the thalamus, or stimulation of the receiving areas of the cortex itself does not elicit an arousal reaction. On the other hand, high-frequency stimulation of the midbrain reticular formation produces an EEG arousal reaction (Fig. 11-9) and awakens a sleeping animal. Significant bilateral lesions of the lateral and superior regions of the midbrain that interrupt the medial lemnisci and other ascending specific sensory systems do not prevent the "arousal" EEG response triggered by sensory stimuli; however, lesions in the midbrain tegmentum affecting the ARAS, while leaving specific systems intact, are associated with a slow-wave synchronized rhythm pattern that is unresponsive to sensory stimuli. Animals with the former type of lesion remain awake, whereas those with the latter remain in a coma for prolonged periods. Patients with lesions interrupting the ARAS also experience sleep or coma. Therefore, ascending activity responsible for the EEG arousal reaction due to sensory stimuli ascends via specific sensory systems to the midbrain, enters the ARAS through collaterals, and projects to the cerebral cortex via the intralaminar thalamic nuclei and the nonspecific thalamic projection system.

Fig. 11-8. Relationship between behavioral states, EEG, and cellular responses in the cerebral cortex and thalamus (modified and reprinted from McCormick DA: Are thalamocortical rhythms the Rosetta stone of a subset of neurological disorders? Nat Med. 1999; 12:1349).

Fig. 11-9. Simultaneous recordings of surface EEG, intracortical EEG at 1.2 mm, and cortical neuron responses recorded with an intracellular electrode in a lightly anesthetized cat. Stimulation of the midbrain reticular formation (MRF) at 300 Hz triggered an arousal reaction. Note that The rate of potential change in the intracortical neuron increases during and after stimulation (reprinted with permission from Steriade M, Amzica F, Contreras D: Synchronization of fast (30-40 Hz) spontaneous cortical rhythms during Brain activation. J Neurosci. 1996;16:392).

Origins of Slow-Wave Sleep

Slow waves on the EEG, their behavioral effects, and slow-wave sleep can be induced by stimulating at least three subcortical zones.

The diencephalic sleep zone is located in the posterior Hypothalamus and adjacent intralaminar and anterior thalamic nuclei. The stimulus frequency must be approximately 8 Hz; faster stimuli induce arousal. Notably, low- and high-frequency stimulation produce opposite reactions. Another area is the medullary synchronizing region within the reticular Formation of the Medulla Oblongata at the level of the Nucleus of the solitary tract. Stimulation of this area with low frequencies mimics the effects of diencephalic sleep zone stimulation and induces sleep, whereas high frequencies cause arousal. The underlying mechanisms remain unclear, though it is hypothesized that pathways leading to the thalamus are involved. A third synchronizing area is the basal Forebrain sleep zone. It encompasses the preoptic area and the diagonal band of Broca, differing from the other two in that stimulation of the basal forebrain zone induces slow waves and sleep regardless of stimulation frequency. Neurons in the ventrolateral preoptic area project to the mamillary body—part of the posterior hypothalamus involved in the diencephalic sleep zone.

Notably, stimulation of Skin mechanoreceptor afferents at a frequency of 10 Hz or less also induces sleep in animals, and humans are well known to fall asleep in response to regular, repetitive, monotonous stimuli.

On the other hand, slow-wave sleep is under robust circadian control. The Role of the suprachiasmatic nuclei of the hypothalamus in regulating sleep and other circadian rhythms is described in Chapter 14.

Intense debate once surrounded the role of serotonergic neurons in the brain (see Chapter 15) regarding sleep; however, it is now established that serotonin agonists suppress sleep, whereas the serotonin antagonist ritanserin enhances slow-wave sleep in humans. Adenosine concentration increases in cholinergic areas of the basal forebrain and mesopontine cholinergic nuclei (see below) during wakefulness and decreases during sleep. Because both of these regions are linked to sleep, adenosine may act as a sleep-promoting factor. This Conclusion does not contradict the well-known stimulatory effects of caffeine, which is an adenosine antagonist.

According to another hypothesis, the release of prostaglandin D₂ (PGD₂; see Chapter 17) in the medial preoptic area of the hypothalamus promotes slow-wave sleep and REM sleep, whereas PGE₂ promotes wakefulness. It is believed that this brain-derived lipid possesses sleep-inducing properties. Some researchers have argued that sleep is mediated by a brain-derived peptide. However, there is currently no consensus as to which specific peptide serves as this "sleep peptide" or what its physiological role might be, if any.

Factors Promoting Sleep During REM Sleep

Individuals awakened during a period when their EEG exhibits patterns characteristic of REM sleep almost invariably report having dreamed, whereas those awakened during slow-wave sleep do not. This observation, along with other evidence, suggests that REM sleep and dreaming are closely linked. Teeth grinding (bruxism), which occurs in some individuals, is also triggered by dreaming. REM sleep is characteristic of all studied species of mammals and birds, but it appears to be absent in other classes of organisms.

If individuals are awakened repeatedly every time they enter REM sleep and are subsequently allowed to sleep, the duration of REM sleep over the next few nights increases significantly compared to baseline. Conversely, prolonged deprivation of REM sleep does not produce the reverse physiological effect. However, experimental animals completely deprived of REM sleep for extended periods lose weight and ultimately die, suggesting that REM sleep plays an important, though not yet fully understood, homeostatic role. On the other hand, slow-wave sleep deprivation produces similar consequences, implying that these effects are not strictly unique to REM sleep.

THE ORIGIN OF REM Sleep

The low-voltage fast cortical rhythm observed during REM sleep resembles the EEG arousal response and is presumably generated in a similar manner. The main difference between REM sleep and the waking state is that dream consciousness is characterized by bizarre, imaginative, and illogical thoughts, and dreams are typically not remembered. The reason for this distinction remains unknown. However, PET scans of humans in REM sleep reveal increased activity in the pontine region, amygdala, and anterior cingulate gyrus, but decreased activity in the prefrontal and parietal cortices. Activity in visual association areas is elevated, whereas reduced activity is recorded in the primary visual cortex. All of this is consistent with heightened excitation and the operation of closed neuronal loops isolated from areas that connect brain activity to the outside world. The mechanisms responsible for triggering REM sleep are located in the reticular formation of the Pons. PGO waves originate in the lateral reticular tegmentum and correspond to shifts in the Membrane Potential of cholinergic neurons. It has been established that Changes in the polarization of noradrenergic neurons in the locus coeruleus and serotonergic neurons in the midbrain raphe induce insomnia, and that these neurons are inactive when cholinergic PGO waves trigger REM sleep. Reserpine, which depletes serotonin and catecholamines, blocks slow-wave sleep and certain aspects of REM sleep while enhancing PGO wave activity. Barbiturates reduce the duration of REM sleep.

Fig. 11-10. Normal sleep cycles across different age groups. REM sleep is indicated by darker shaded areas (Reproduced with permission from Kales AM, Kales JD: Sleep disorders. N Engl J Med. 1974;290:487).

Distribution of Sleep Stages

During a typical night's sleep, a young adult first enters NREM sleep, then transitions through stages 1 and 2, and within 70–100 minutes reaches stages 3 and 4. Afterward, sleep lightens and a period of REM sleep ensues. This cycle repeats at intervals of approximately 90 minutes throughout the night (Fig. 1-10). The cycles are largely similar, although closer to morning, stages 3 and 4 become shorter, while REM sleep grows longer. Consequently, there are four to six REM sleep periods over the course of the night. REM sleep accounts for 80% of total sleep time in premature infants (Fig. 11-11) and 50% in full-term infants. Subsequently, the percentage of REM sleep declines, stabilizes at around 25%, and decreases once more in old age. In children, total sleep duration and the duration of stage 4 sleep are longer than in adults.

Fig. 11-11. Age-related changes in human sleep. Each graph shows data for ages 6, 10, 21, 30, 69, and 84 years (Data from Kandel ER, Schwartz JH, Jessel TM [editors]: Principles of Neural Science, 3rd ed. McGraw-Hill Companies, Inc. 1991).

Fig. 11-12. Absence seizure (petit mal). Four-lead EEG recording in a 6-year-old boy during a seizure episode characterized by unresponsiveness and eye blinking. Time is indicated by the horizontal line (Reproduced with permission from Waxman SG: Correlative Neuroanatomy, 24th ed. McGraw-Hill, 2000).

Sleep Disorders

Insomnia, which can be defined as a subjective complaint of inadequate or non-restorative sleep despite adequate opportunity for sleep, affects almost all adults at some point. Chronic insomnia is caused by A wide variety of mental and medical conditions. It can be temporarily alleviated using sedatives, such as benzodiazepines. However, long-term use of any such medications is inadvisable because they also impair daytime functioning and lead to habituation.

Fatal familial insomnia is a progressive prion disease that occurs in both inherited and sporadic forms. It is characterized by progressive insomnia, autonomic and motor dysfunction, dementia, and death. Patients with this condition exhibit rapid neuronal loss and gliosis in the ventral and mediodorsal thalamic nuclei, the inferior olives, and the medulla oblongata. Prion diseases are transmissible spongiform encephalopathies that manifest in humans in several forms: Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome, and kuru, which is associated with ritualistic cannibalism.

Sleepwalking (somnambulism), nocturnal enuresis, and night terrors occur during arousal from slow-wave sleep. They are not associated with REM sleep. Sleepwalking episodes are more common in children than in adults, predominantly in males, and may last for several minutes. Somnambulists walk with their eyes open and navigate around obstacles in their path, yet if awakened, they cannot recall the sleepwalking episodes.

Narcolepsy is a disorder characterized by episodic, sudden losses of muscle tone (cataplexy) and an almost irresistible urge to sleep during the day. In some cases, it begins with sudden onsets of REM sleep. In healthy individuals, REM sleep almost never precedes slow-wave sleep. While hereditary forms of this condition in humans are rare, inherited forms in dogs are caused by a mutation in one of two receptors for orexin, a neuropeptide involved in The regulation of appetite (see Chapter 14).

Sleep apnea is caused by airway obstruction during inspiration, as detailed in Chapter 37. When this condition occurs repeatedly, as is common in the elderly, sleep loss leads to daytime fatigue and lethargy. This condition can be alleviated by training patients to avoid sleeping on their back, avoiding respiratory depressants, hypnotics, and alcohol, and, in severe cases, by applying continuous positive airway pressure (CPAP) during sleep.

REM sleep behavior disorder is a recently identified condition in which muscle atonia fails to develop during REM sleep. As a result, The behavior of these patients resembles that of cats with experimental lesions in the locus coeruleus—they "act out their dreams": they are restless and may even leap out of bed, ready to fight an imaginary adversary. This disorder is typically treated with benzodiazepines. Other specific sleep disorders are also described in clinical sleep Laboratory studies.

Clinical Applications of EEG

Electroencephalography (EEG) is occasionally useful for detecting pathological processes. If fluid accumulation blocks a region of the cerebral cortex, electrical activity over that area may be reduced, aiding in the Diagnosis and localization of subdural hematomas. Cortical lesions cause localized generation of irregular or slow waves that can be detected by EEG. Epileptogenic foci sometimes generate high-voltage spikes or waves that can likewise be identified.

Epilepsy is a syndrome that can arise from numerous causes. While certain forms exhibit a characteristic EEG pattern during seizures, these abnormalities are often difficult to detect during interictal periods. Seizures are broadly classified into those originating in a single cerebral hemisphere (partial or focal seizures) and those involving both hemispheres simultaneously (generalized seizures). Each category includes multiple subcategories. Tonic-clonic seizures (grand mal seizures) are accompanied by a sudden loss of consciousness. This is followed by a tonic phase involving sustained contraction of the limb Muscles, then a clonic phase characterized by symmetrical rhythmic jerking of the limbs resulting from alternating contraction and relaxation. EEG activity is high during the tonic phase. Each clonic jerk is accompanied by a slow wave followed by a spike. Slow waves persist for a short period following the seizure. Similar changes are observed in experimental animals during electroshock-induced convulsions. Absence seizures (petit mal) are a form of epilepsy marked by momentary lapses in responsiveness. They are characterized by a 3 Hz spike-and-wave discharge pattern (Fig. 11-12).