Sleep and Limbic System Case File

Sleep and Limbic System Case File

EUGENE C.TOY, MD, RAHUL JANDIAL, MD, PhD, EVAN YALE SNYDER, MD, PhD, MARTIN T. PAUKERT, MD

CASE 33

An 18-year-old Japanese woman presents to a medical clinic complaining of excessive sleepiness. Although she sleeps approximately 8 hours a night, she is constantly fatigued and sleepy during the day. Sleeping more during the night does not help. She also reports of waking up to find she has completed tasks which she has no recollection of completing. Additionally, she has been experiencing sudden bouts of muscular weakness, including slurred speech, weakened eyesight, and weakness at the knees. She notes that these experiences occur especially after laughing. After taking a polysomnogram to confirm the diagnosis, she is diagnosed with narcolepsy.

• What are common symptoms of narcolepsy?
• On what chromosome is the human leukocyte antigen (HLA) complex found?
• Which three major brain structures make up the limbic system?

ANSWERS TO CASE 33: SLEEP AND LIMBIC SYSTEM

Summary: An 18-year-old Japanese woman complaining of excessive sleepiness during the day even after sufficient nighttime sleep and muscular weakness after laughing.

• Symptoms: Excessive daytime sleepiness (EDS), cataplexy, slurred speech, impaired vision, weakness of facial and limb muscles, hypnagogic hallucinations, and sleep paralysis are common symptoms of patients with narcolepsy.
• Chromosome: The HLA complex is found on chromosome 6.
• Limbic system: The limbic system is composed of the hippocampus, amygdala, and hypothalamus among numerous other brain structures.

CLINICAL CORRELATION

Narcolepsy is a neurological condition characterized by EDS, often with episodes of muscular weakness known as cataplexy. Persons with narcolepsy tend to feel sleepy whenever they are awake, and often unable to keep themselves awake for long periods of time, even after adequate nighttime sleep. Cataplexy, which has been found to occur in nearly 75% of narcoleptic patients, is described as temporary muscular weakness or paralysis without loss of consciousness evoked by sudden emotional reactions, especially laughter. Other evoking emotions include anger, joy, fear, and surprise. Usually speech is slurred and vision is impaired, along with weakness of the face muscles and/or limbs. Narcoleptics also experience automatic behavior, meaning that they continue to function during sleep episodes, but awake with no recollection of what they have done. Approximately 40% of narcoleptics experience this. Other common symptoms include sleep paralysis (temporary inability to move or talk when waking up) and hypnagogic hallucinations (vivid, often frightening dreamlike episodes that occur when falling asleep and/or waking up). Narcolepsy can be diagnosed with the help of a polysomnogram or multiple sleep latency test. A polysomnogram involves continuous recording of brain waves and nerve and muscle functions during sleep. Narcoleptics fall asleep and enter REM sleep quickly, and may wake oftentimes during the night. In a multiple sleep latency test, the patient is allowed to sleep every 2 hours while observations of sleepiness and amount of time needed to reach various sleep stages are continuously taken. While true prevalence of narcolepsy is significantly underreported, the reported prevalence ranges from about 5 in 10,000 for North American and European populations, to 16 in 10,000 in Japan. While there seems to be no significant difference between men and women, there does seem to be a strong genetic link. One factor which may predispose an individual to narcolepsy is the HLA complex of chromosome 6. Though not specifically defined, there appears to be a correlation between certain variations in HLA genes and narcolepsy. Recently, it has been discovered that narcolepsy is specifically related to the hypothalamus. Brain cells which contain the chemical hypocretin and originate in the hypothalamus are found to be reduced by 85%–95% in people with narcolepsy. Scar tissue was present in hypothalamic regions where hypocretin brain cells used to be, indicating the cells were present at birth but later died. It is thought that certain variations in the HLA complex increase the risk of an autoimmune response to hypocretin.

In terms of treatment, the common symptoms of EDS and cataplexy must be treated separately. EDS can be treated with amphetamine-like stimulants such as dextroamphetamine, or with modafinil, another type of CNS stimulant known as a “wake promoter.” Cataplexy, sleep paralysis, and hypnagogic hallucinations can be treated using antidepressant compounds.

APPROACH TO SLEEP AND LIMBIC SYSTEM

Objectives

1. Know the signs and symptoms of narcolepsy.
2. Know the methods of treatment for EDS and cataplexy.

Definitions

Vegetative functions: Body regulatory functions.

Thermoreceptor: A sensory receptor that responds to heat and cold.

Osmoreceptor: A receptor sensitive to plasma osmolality that exists in the brain to regulate water balance in the body by controlling thirst and the release of vasopressin.

Antidiuretic hormone (ADH): Hormone secreted by the posterior pituitary gland and also by nerve endings in the hypothalamus; affects blood pressure by stimulating capillary muscles and reduces urine flow by affecting reabsorption of water by kidney tubules.

Oxytocin: A short polypeptide hormone released from the posterior lobe of the pituitary gland, which stimulates the contraction of smooth muscle of the uterus during labor and facilitates ejection of milk from the breast during nursing.

DISCUSSION

One of the oldest systems in the brain, the limbic system is involved in emotion and memory as well as numerous body regulatory functions collectively known as vegetative functions. While this system is composed of many structures, there are three main ones: the hippocampus, amygdala, and hypothalamus.

Hippocampus

The hippocampi are found bilaterally deep in the medial temporal lobe, and play a role in long-term memory and spatial navigation. Because the hippocampus is involved in transferring short-term memory to long-term memory, damage to this structure most commonly results in the inability to lay down new memories (anterograde amnesia).

Amygdala

Above the hippocampi lie the two almond-shaped neuron masses known as the amygdalae. The amygdala is involved in monitoring the environment for survival management and responds specifically to the stimuli of fear. The amygdalae sends output to several structures involved in the response to fear including (1) the hypothalamus to activate the sympathetic nervous system, (2) the reticular nucleus to increase reflexes, (3) the nuclei of trigeminal and facial nerves to modulate facial expressions, and to various areas (ie, ventral tegmental area and locus ceruleus) which result in increased release of dopamine, norepinephrine, and epinephrine. The amygdala also contains receptors for estrogen and androgens, suggesting a role in sexuality. A bilateral lesion of the amygdalae results in the Kluver-Bucy syndrome, characterized by loss of fear, hypersexuality, hyperorality, and emotional blunting.

Hypothalamus

Though extremely small, the hypothalamus is perhaps the most important structure of the limbic system. Its key central position in relation to the other limbic structures facilitates its two-way communication with all levels of the limbic system. Specifically the hypothalamus sends signals in three directions: up toward the higher areas of the diencephalon and cerebrum, down to the brainstem, and into the hypothalamic infundibulum to control hormonal secretion of the anterior and posterior pituitaries. With the help of the rest of the limbic system the hypothalamus controls numerous aspects of emotional behavior and most of the bodily vegetative functions, as explained next.

Cardiovascular Regulation

Stimulation of different regions of the hypothalamus is known to have different neurogenic effects on the cardiovascular system. For example, stimulation of the posterior and lateral hypothalamus (which is involved in sympathetic stimulation) increases heart rate and arterial pressure. On the other hand, stimulation of the preoptic area found in the anterior hypothalamus (which is involved in parasympathetic stimulation) causes a decrease in arterial pressure and heart rate. The specific cardiovascular control centers are found in the reticular regions of the brainstem, particularly the medulla and pons.

Regulation of Body Temperature

As discussed earlier in this book, the hypothalamus is involved in thermoregulation. The thermostatic center is located in the preoptic area, and thermoreceptors in the region are involved in monitoring the rise and fall of blood temperature. Increased blood temperature increases the activity of these thermoreceptors, while decreased blood temperature decreases their activity. The activity and signals from these receptors control a variety of thermoregulatory mechanisms, which are discussed in further detail in the case on thermoregulation.

Regulation of Body Water

The hypothalamus is also involved with the regulation of body water. Water homeostasis in controlled by two hypothalamic mechanisms: the osmoreceptor-ADH feedback system, and the thirst mechanism. The osmoreceptor-ADH feedback system regulates the amount of water absorbed in the kidney and excreted in the urine, while the thirst mechanism induces water drinking behavior whenever necessary. Special receptors known as osmoreceptors located in the supraoptic nucleus region are stimulated by changes in plasma sodium concentration. In turn, these osmoreceptors stimulate the secretion of ADH at nerve endings in the posterior pituitary. ADH acts on the collecting ducts of the kidney, causing increased water absorption. The thirst mechanism is controlled by the thirst center, composed of the AV3V region and a specialized area near the preoptic nucleus. When blood osmolarity rises above normal levels, this center stimulates a thirst sensation which greatly increases an organism’s desire to drink water.

Regulation of Uterine Contractility and of Milk Ejection from the Breasts

Stimulation of the paraventricular nucleus in the anterior hypothalamus induces secretion of oxytocin. In females oxytocin increases contractility of the uterus and myoepithelial cells that surround the breast alveoli. It is released mainly after distension of the cervix and vagina during labor and after stimulation of the nipples, thereby stimulating childbirth and breastfeeding respectively. A baby’s sucking on the mother’s nipple stimulates a reflex signal from the nipple to the posterior hypothalamus, and induces release of oxytocin, which then causes contraction of the breast milk ductules. Oxytocin is also known to play a role in circadian homeostasis, helping regulate body activity level and wakefulness.

Gastrointestinal and Feeding Regulation

Hunger and appetite stimulation is controlled by several areas of the hypothalamus. The area most involved with stimulation of the hunger sensation, large appetite, and food-seeking behavior is the lateral hypothalamic area.

Damage to this area can lead to starvation. On the other hand, the satiety center, which is located in the ventromedial nucleus, is involved in opposing the desire for food. When stimulated, this center causes an organism to lose interest in its food and stop eating. Damage to the satiety center can result in overeating and consequently obesity. Important hormones involved include leptin, which signals satiety; ghrelin, which signals hunger; and insulin, which signals satiety and subsequent glucose storage. Additionally, the mammillary bodies in the posterior hypothalamus are involved in controlling feeding reflexes, such as licking the lips and swallowing.

Behavioral Functions

Stimulation of different parts of the hypothalamus also affects behavior. For example, stimulation of the lateral hypothalamus increases the organism’s general activity level, in addition to causing thirst and hunger as explained in the previous section. Conversely, stimulation in the ventromedial nucleus leads to satiety and tranquility. Stimulation of a thin area of the periventricular nuclei near the third ventricle can lead to fear and punishment reactions. Additionally, several areas, especially those found in the most posterior and anterior regions of the hypothalamus are involved with stimulating sexual drive.

COMPREHENSION QUESTIONS

[33.1] A 55-year-old man comes into the clinic for a routine checkup, the first he has had in many years. You perform the usual history and physical examination, and note that his blood pressure (BP) is 165/94. In order to better assess this abnormality, you have him return several times over the next few weeks for BP checks, and each time it is a similar value. You diagnose him with hypertension and begin treatment. If this man’s hypertension is because of hyperactivity of a hypothalamic nucleus, which nucleus is most likely affected?

A. Anterior nucleus

B. Arcuate nucleus

C. Posterior nucleus

D. Ventromedial nucleus

[33.2] A 33-year-old woman is involved in an automobile accident, and suffers a head injury. When she regains consciousness after 2 weeks in the ICU, she is not interested in eating at all. She says that she simply isn’t hungry or interested in food in the least. If this lack of appetite is caused by a hypothalamic lesion, where would it most likely be?

A. Anterior hypothalamus

B. Lateral hypothalamus

C. Ventromedial hypothalamus

D. Dorsomedial hypothalamus

[33.3] A 27-year-old woman is in labor with her first child, and you are supervising her care. After several hours of laboring, it is apparent that she is not progressing appropriately. You decide to augment her labor by starting her on pitocin, a synthetic form of oxytocin. From what hypothalamic nucleus is oxytocin normally secreted?

A. Paraventricular nucleus

B. Arcuate nucleus

C. Preoptic nucleus

D. Suprachiasmatic nucleus

Answers

[33.1] C. The posterior and lateral nuclei of the hypothalamus have been associated with increased heart rate and arterial blood pressure. The anterior nucleus has been associated with decreased heart rate and blood pressure, the arcuate nucleus is involved in endocrine regulation, and the ventromedial nucleus is thought to be the satiety center.

[33.2] B. The lateral hypothalamus has been associated with hunger, appetite, and food-seeking behavior. Bilateral lesions to this area in experimental animals have caused them to starve to death despite the presence of food. While it is highly unlikely that a person could suffer isolated bilateral lesions to a single hypothalamic nucleus, if it were to occur, this would likely be the result. The ventromedial nucleus is the satiety center, and a lesion to it would cause the opposite symptoms: overeating and obesity.

[33.3] A. The paraventricular hypothalamic nucleus produces oxytocin, which is then transported in its axons down the pituitary stalk to the posterior pituitary where it is secreted into the bloodstream when the appropriate stimulus is present. The arcuate nucleus in involved in anterior pituitary endocrine control, the preoptic nucleus is involved in temperature regulation, and the suprachiasmatic nucleus helps regulate circadian rhythm.

NEUROSCIENCE PEARLS ❖ The limbic system is involved in emotion and memory and consists of the hippocampus, amygdala, and hypothalamus. ❖ The hippocampus plays role in long-term memory and spatial navigation. ❖ A bilateral lesion of the amygdalae results in the Kluver-Bucy syndrome, characterized by loss of fear, hypersexuality, hyperorality, and emotional blunting. ❖ The hypothalamus sends signals in three directions: up toward the higher areas of the diencephalon and cerebrum, down to the brainstem, and into the hypothalamic infundibulum to regulate the anterior and posterior pituitaries. ❖ In females, oxytocin increases uterine contractions and secretion of milk from breast ductules. ❖ Damage to the lateral hypothalamic area leads to decreased appetite (lesion of lateral = less eating) while damage to the ventromedial hypothalamic area leads to increased appetite (lesion of medial = more eating). ❖ Leptin signals satiety while ghrelin signals hunger.

REFERENCES

Bear MF, Connors B, Paradiso M, eds. Neuroscience: Exploring the Brain. 3rd ed. Baltimore, MD: Lippincott Williams & Wilkins; 2006. 

Purves D, Augustine GJ, Fitzpatrick D, et al, eds. Neuroscience. 3rd ed. Sunderland, MA: Sinauer Associates, Inc.; 2004. 

Zigmond MJ, Squire LR, Bloom FE, Landis SC, Roberts JL, eds. Fundamental Neuroscience. 2nd ed. San Diego, CA: Academic Press; 1999.

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