Reticular-Activating System Case File

Reticular-Activating System Case File

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

CASE 34

A 36-year-old female presents to the clinic complaining of prolonged and extreme tiredness. She states that she has been suffering these symptoms for the past 6 months, and she feels just as tired after a full night’s sleep as she did when she went to bed. When she exerts herself physically, she is often overcome with a debilitating fatigue that leaves her bedridden for several days. A physical examination reveals that the woman has tender lymph nodes. The woman states that she was suffering from the flu just prior to the onset of the symptoms she described. She never fully recovered, and her flu symptoms eventually degenerated into her current illness. Based on this presentation, the patient is diagnosed with chronic fatigue syndrome (CFS).

• Damage to what structure in the brain is associated with sleepiness?
• Where is the affected brain structure located?

ANSWERS TO CASE 34: RETICULAR-ACTIVATING SYSTEM

Summary: A 36-year-old woman presents to clinic complaining of debilitating fatigue. She states that she had the flu just prior to onset of symptoms.

• Pathophysiology: It is believed that damage to the ascending reticularactivating system (RAS), an area in the brain that extends upward from the reticular formation and is associated with sleep function, may contribute to onset of CFS.
• Location of structure: Brainstem.

CLINICAL CORRELATION

CFS is a disorder marked by severe, chronic mental and physical exhaustion, among other symptoms, arising in a previously healthy and active person. It is a highly debilitating disorder of uncertain etiology. Most cases of CFS begin immediately following a period of stress. While some cases start gradually, the majority start suddenly, often triggered by a viral illness. In sudden onset cases, patients report a sudden, drastic start to their illness, some being able to specify the date or even hour of onset. Many people report having the flu, exposure to an allergen, or an infection such as bronchitis, from which they are never able to fully recover and which evolves into CFS. In some instances, patients claim that vaccination, particularly vaccinations against hepatitis B, is the cause of acute-onset CFS. Other patients suffer from Lyme disease before sinking into CFS. Patients who experience a gradual onset of CFS may not realize there is anything wrong for quite some time. These patients usually do not seek treatment until the condition is truly debilitating. Although CFS can affect people of any gender, age, race, or socioeconomic group, most patients diagnosed with CFS are 25-45 years old and female. Estimates of how many people are afflicted with CFS vary because of the similarity of CFS symptoms to other diseases and the difficulty in identifying it. The Centers for Disease Control and Prevention (CDC) has estimated that 4-10 people per 100,000 in the United States have CFS. According to the CFIDS Foundation, about 500,000 adults in the United States (0.3% of the population) have CFS. This probably is a low estimate since these figures do not include children and are based on the CDC definition of CFS, which is very strict for research purposes. While there is no known cause for CFS, many causes have been proposed. There is evidence that CFS may involve distinct neurological abnormalities, supporting many researchers’ classifications of CFS as a neurological illness. It is believed that damage to the ascending RAS, an area in the brain that extends upward from the reticular formation and is associated with sleep function, may contribute to onset of CFS. Imaging studies of CFS patients’ brains have shown metabolic abnormalities in the RAS, so it seems likely that damage to this area may be responsible for at lest some cases of CFS. This damage may be caused by bacterial or viral damage, or an autoimmune attack on the region. Because there is no one identifiable cause for CFS, there is also no one treatment protocol. Oftentimes, medications are administered to treat the symptoms of CFS. This includes antidepressants, hormones, and autonomic nervous system stimulants.

APPROACH TO RETICULAR-ACTIVATING SYSTEM

Objectives

1. Describe the anatomy of the RAS.
2. Describe the interaction between the RAS and the cortex.
3. Describe the function played by the RAS in REM sleep.

Definitions

Reticular Activating System: The area of the brain that plays a major role in arousal and attention. Located within the brainstem, lesions affecting this system lead to impairments in consciousness.

Pontine Tegmentum: Area of the brainstem located in the posterior aspect of the pons. This area houses the fibers and structures of the reticular activating system.

DISCUSSION

The RAS, composed of the reticular formation and its connections, is often called the attention center of the brain (see Figure 34-1). The reticular formation is one of the oldest systems in the nervous system. The brains of primitive vertebrates are almost exclusively made up of a reticular formation. Humans retained this formation over the course of evolution, as more organized components

of the nervous system appeared. The RAS plays several roles, including nonspecific arousal, cortical activation and tone, and regulating sleep and wakefulness. Injury to the reticular system can cause a change in the level of consciousness, ranging from sleepiness to coma. The medullary levels of the RAS control vital respiratory and cardiovascular centers. Defects in these areas can impair respiratory rate, heart rate, and blood pressure.

The RAS has a diffuse arrangement of both ascending and descending neurons that form a system of networks. It is connected at its base to the spinal cord, where it receives information projected from the ascending sensory tracts, and runs all the way up to the midbrain. As a result, the RAS is a very complex collection of neurons that serve as a point of convergence for signals from the external world and from interior environment.

The RAS is capable of generating dynamic effects on the activity of the cortex, including the frontal lobes, and the motor activity centers of the brain. The RAS acts as an information filter, managing what data to pass onto the cortex and what data to block. This function is vital, as there is too much competing information at any given time for the brain to process all at once. The RAS also plays a major role in mediating and filtering ascending and descending sensory and motor information. It is the center of balance for the other systems involved in learning, self-control or inhibition, and motivation. When functioning normally, it provides the neural connections that are needed for the processing and learning of information, and the ability to pay attention to the correct task.

Figure 34-1. Brainstem RAS and its ascending projections to the thalamus and cerebral hemispheres. (With permission from Aminoff ’s Clinical Neurology. 6th ed. Figure 7-6. Chapter 7.)

Researchers have hypothesized that the RAS also plays a role in anticipatory responding. It signals the cortex, alerting it to prepare to receive stimuli, allowing it to get into a heightened state of readiness. If the RAS fails to excite the neurons of the cortex as much as it should, the under-aroused cortex will result in difficulty learning, poor memory, little self-control, and so on. If the RAS fails completely to stimulate the cortex, the result would be a lack of consciousness. Injury of the RAS is directly associated with coma. In contrast, an overexcited RAS would arouse the cortex or other systems too much and cause restlessness and hyperactivity.

It is also evident that the RAS is the primary mechanism for turning REM sleep on and off. During wakefulness, the RAS maintains cortical arousal. The high activity in the ascending RAS stimulates the brain through projections into different neurological systems in the cortex. However, the midbrain reticular formation becomes activated immediately prior to REM sleep. At this time, the medullary reticular formation spurs a postsynaptic inhibition. This results in a loss of muscle tone.

The reticular formation in general decreases sensory input, and reduces motor output during REM sleep. REM sleep-on cells, located in the pontine tegmentum, are particularly active during REM sleep, and are probably responsible for its occurrence. The release of certain neurotransmitters, the monoamines (norepinephrine, serotonin, and histamine), is completely shut down during REM. This causes REM atonia, a state in which the motor neurons are not stimulated and thus the body’s muscles do not move. Lack of such REM atonia causes REM behavior disorder; sufferers act out the movements occurring in their dreams.

COMPREHENSION QUESTIONS

Refer to the following case scenario to answer questions 34.1-34.3:

A 35-year-old man is brought into the hospital following an industrial accident, where a large metal pipe fell and hit him in the back of the head. He is stabilized and placed in the ICU. Following treatment of his obvious traumatic injuries, his heart rate, respiratory drive, and blood pressure are all stable without medical intervention, but he remains unresponsive. An EEG demonstrates continuous slow-wave sleep.

[34.1] Based on these findings, where would the physician expect to find a lesion in this man?

A. Medullary tegmentum

B. Midbrain tegmentum

C. Cerebral cortex

D. Cerebellum

[34.2] In addition to maintenance of consciousness and arousal, in what other process does the ARAS participate in a normal brain?

A. Motor control

B. Sensory interpretation

C. Information filtering

D. Emotional regulation

[34.3] Along with its role in consciousness and attention, what role does the ARAS play in sleep?

A. Initiation of stage one sleep

B. Initiation of REM sleep

C. Inhibition of muscle tone during stage 4 sleep

D. Inhibition of thermoregulatory mechanisms during REM sleep

Answers

[34.1] B. Damage to the midbrain tegmentum will sever all connection between the cortex and the ARAS, resulting in a coma as is seen here. The ascending RAS is located in the tegmentum of the brainstem, from medulla to midbrain. Projections from the ARAS to the cortex are necessary for the maintenance of consciousness and awareness. This man has a defect in this system as evidenced by his persistent sleeplike state with slow-wave sleep waves on EEG. Damage to the medullary tegmentum, in addition to causing problems with arousal, would likely damage some part of the heart rate, blood pressure, or respiratory control centers that are part of the medullary ARAS. Since the patient is stable, this does not seem like the likely place for the lesion.

[34.2] C. The correct answer is information filtering. The ARAS sits at a very important point between the cortex which perceives and analyzes information, and the brainstem where a huge amount of sensory information, both about the external world and the internal body come in. There is far too much information sensed at a time for the cortex to be able to interpret, so this information must be filtered somehow. The ARAS is responsible to filtering this information, and depending on what information gets through, it plays a role in directing selected attention of the cortex.

[34.3] B. Several areas of the pontine tegmentum that are also part of the ARAS are thought to be involved in the initiation of REM sleep. This REM-on system utilizes excitatory acetylcholine projections to the thalamus and cortex to generate REM sleep. Other areas of the ARAS seem to be involved in the inhibition of muscle tone during REM sleep, but not during stage 4 sleep.

NEUROSCIENCE PEARLS ❖ RAS is known as the attention center of the brain; injury to the RAS can cause a change in the level of consciousness, ranging from sleepiness to coma. ❖ RAS is the primary mechanism for turning REM sleep on and off. ❖ Release of monoamine neurotransmitters (norepinephrine, serotonin, and histamine) is completely shut own during REM, resulting in REM atonia.

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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