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William H. Calvin and George A. Ojemann, Inside the Brain:  Mapping the Cortex, Exploring the Neuron (New American Library, 1980), chapter 10. See also http://WilliamCalvin.com/
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copyright ©1980 by William H. Calvin and George A. Ojemann
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This 'tree' is really a pyramidal neuron of cerebral cortex.  The axon exiting at bottom goes long distances, eventually splitting up into 10,000 small branchlets to make synapses with other brain cells.
William H. Calvin

University of Washington
Seattle WA 98195-1800 USA






10

The Brain Controlling Itself: 
Loudness Adjustments in Sensation

 
copyright 
©1980 by 
William H. Calvin and 
George A. Ojemann




Switching different brain areas between internal and external stimuli is only part of the reticular activating system's role in selective. attention. Another aspect is regulating the flow of information into the brain. This is accomplished through a series of "downstream" connections that act as though they were adjusting the sensitivity of sensory systems up or down, depending on the novelty or irrelevance of a particular sensation. This system is one of the mechanisms that prevents the brain from being continuously bombarded by the touch sensations produced by our clothes, but still able to detect the new touch of a mosquito. It was, in fact, one of the earliest functions of the reticular activating system to be discovered.

This system regulates pain sensation as well as touch, so that one way to control severe pain would be to change the reticular activating system so that it turns down the sensitivity in pain pathways. Some painkilling drugs may act this way, turning down the central "pain loudness" control,' Electrical stimulation of part of the reticular activating system is another way to turn down the intensity of pain input. Indeed, stimulation of the tipper brain stem in animals seems to block pain completely. At least, the animals act as though they are not experiencing pain when their tails are shocked or overheated. Stimulation of this same area of brain stem has been used to treat a few difficult pain problems in man. In some of these patients, a few minutes of stimulation will lead to many hours of relief from chronic pain. In man, acute pain (as from a pinprick) is little altered by such brain-stem stimulation. Many treatments that work well for human acute pain, however, are of little value in chronic pain problems.

In both man and animals, the effects on pain from this electrical stimulation of the reticular activating system are blocked by the same drugs that block the function of opiates (morphine and its relatives). Stimulation locally releases substances with opiatelike properties. It has been suggested that these opiatelike substances are a class of neurotransmitters (endorphins, a word meant to suggest "internal morphine") which are used by the nerve cells in this system to control pain sensation. It has also been proposed that opiate drugs control pain through this same system.

Since the internal morphine pain control system can be stimulated electrically and by drugs, it can presumably be stimulated naturally by appropriate experiences. There are, for example, many war stories of soldiers who seem to feel no pain from a wound until after they have been evacuated from the battlefield. Many people who suffer from chronic pain disorders (as we discuss in Chapter 13) wish that they had a way of voluntarily activating this pain-control system. There is now evidence that the "power of suggestion" can act through this system. Physicians and faith healers alike have long known that for a certain percentage of pain sufferers, a confident attitude can alone 'work wonders ("Just take these pills and the pain will be gone tomorrow. You'll see!"). The "placebo" effect is very strong for chronic pain disorders; at least one-third of all patients will respond as well to a sugar pill as to narcotics, at least for a while.

When the evidence for an "internal morphine" system in the brain began to accumulate, several groups of researchers designed experiments around placebos, to see if the placebo activated the "internal morphine" and hence suppressed the pain. One approach was to see if morphine-blocking drugs also blocked the placebo responses. In one experiment, dental patients were used; they were forewarned that "experimental drugs" were being used which might or might not help their pain, and they consented to the experiment on. them. These dental patients had just had an impacted wisdom tooth extracted, a procedure which predictably causes postoperative pain for some time. After their local anesthetics had worn off and the period of postoperative pain had started, the patients were given two injections, some hours apart. Some of the patients ("placebo responders") got pain relief from the first injection, even though it was really nothing bitt water, The second injection was really a morphine antagonist called naloxone (typically used to treat heroin overdoses); it is the "wrong key," whose molecules plug up the "keyholes" on which opiate drugs (morphine, heroin, Methadone, Demerol) act. After this dose of naloxone, the placebo-responders again felt their pain. This result strongly suggests that the "power of suggestion" was acting by releasing an internal morphine. Yet naloxone does not affect some other kinds of experimental pain.

A different type of pain problem looks as if it may be due to excessive amp] Ification I n pathways that convey sensation from transducers to the brain. What happens then is much likq turning an audio amplifier gain up full-blast; the sensations that come through are distorted and unpleasant. Light touch feels like burning or an electric shock. This excessive amplification seems to occur when pathways for sensation from the body are damaged in the brain. Less sensation seems to reach the cortex, which may in turn ask the reticular activating system to turn up the amplifier full-blast. This is one possibility for what is wrong with the following patient.

It took about three months after her stroke for Edith to regain full function in her paralyzed left hand. Even when it moved well, the hand felt numb, as did the rest of her left side. Six months later, a pain problem had developed. The lightest touch caused her hand to bum and tingle. She couldn't even put the hand in her pocket, the touch of the fabric was so unpleasant. When the neurologist touched her left side with a pin, she felt it only when the pin was pushed hard, and then only after a delay. But when she did feel the sensation, it was awful; like a painful burning shock. The neurologist gave her a prescription that helped the pain somewhat, but then she developed a severe skin rash and had to stop taking the medicine. After that the pain was as bad as ever. No other medicines helped.

Three years later, an operation was done where an electrode was placed in her right brain in a part of the white matter which the surgeon called the "internal capsule," a main sensory pathway carrying body sensation to the cortex. When that electrode was stimulated, she felt a moderate tingling in the left side of her body. After a few days of nearly continuous stimulation, the pain faded away. The surgeon fixed the electrode so that she could turn it on and off through her skin, using a control like a miniature radio transmitter. She really didn't understand much about that, but she knew that if she occasionally used it during the day, her left hand would stop hurting, would not "burn" when touched, felt warm again, and that she could use her hand for most things.

 

Edith developed what is known as the "thalamic" syndrome after her stroke, so named because a stroke damaging the sensory pathways in the thalamus is one cause of this pain. condition (it was once thought to be the only one; now we know that damage to sensory pathways almost anywhere in the brain can produce the same pain symptoms). With damage to the sensory pathways, the amplifier seems to be turned up so that when sensation does get through, it is too intense: burning, shocking. One way of treating this particular kind of pain, turning the amplifier setting of the sensory system down toward normal, is to increase the other sensations reaching the cortex. It is thought that the stimulating electrode in the internal capsule does this by artificially activating the axons that normally carry sensation through the internal capsule to the sensory cortex. This, then, could change the setting of the amplifier part of the reticular activating system indirectly, by altering the reports given it by other brain areas on the level of sensation they are receiving. Modern technology allows such an electrode to be activated by a radio receiver implanted beneath the skin; the receiver in turn is activated by a small radio transmitter whose antenna is placed on the skin over the receiver.

Problems like Edith's with the "volume control" in sensory systems represent only a very small percentage of the cases of chronic pain. Manipulation of this amplifier-sctting system by stimulation is a method of treatment still undergoing evaluation; it seems to be of value for only a few pain problems. We will return later to more common causes of persisting pain in which the amplifiers are set normally, such as those in which seemingly normal pain -signals are continuously generated by damage to peripheral nerves.

The ability to discriminate novel from repetitious sensations is so important that the amplifier controls in the reticular activating system are not the only mechanism in the nervous system entrusted with this job. Mechanisms which minimize repetitive sensations exist at many levels, beginning with mechanisms built into single nerve cells. As someone once noted: "Big brains, like big governments, do not do simple things in simple ways."

How do individual neurons detect the novel and ignore the mundane? An external stimulus starts up neural signals in a transducer neuron by producing a voltage change proportional to the stimulus strength. This transducer voltage may sag with time, becoming only half as big after a second or two, even though the stimulus strength is being held constant. In some transducers, this sag is dramatic: bending a hair on your skin produces a transducer voltage for only a few seconds. In other transducers, such as those in muscles and joints, the sag (or adaptation, as it is formally called) is less than 50 percent and also takes longer to occur.

A second opportunity for reducing the intensity of the neural message sent occurs when the transducer voltage produces impulses at the beginning of the transducer neuron's axon. The rate at which impulses are produced is often proportional to the transducer voltage, although there is a minimum level (or threshold) for impulse production. This impulse production rate may also sag, even if the transducer voltage is constant. Thus there are two opportunities for reducing the message sent (the impulse train), even before the message reaches the spinal cord or brain . Changes in such mechanisms occur in inflammation, when transducer neurons in the skin adjacent to an injury become more sensitive, producing impulse trains more easily and for longer times than normal.

When each impulse reaches the spinal cord (or an analogous part of the brain stem), it releases a packet of neurotransmitter molecules onto another neuron, the second neuron in the sensory chain. During a long train of impulses, the amount of neurotransmitter released per impulse may change. In some cases, it goes up (facilitation or potentiation); in other cases, it goes down (antifacilitation, sometimes called synaptic depression) .3 In some cases, the amount of neurotransmitter released per impulse is simply under the control of the historical factors within the axon terminal itself, such as fatigue. In other cases, there is regulation of the synaptic transmission between two neurons by a third neuron.

An excellent example of the regulatory processes has been studied in a group of neurons fn the sea slug Aplysia. This animal has a simple withdrawal reflex, quite analogous to the one humans use to lift a foot after encountering a thumbtack. The gill will be withdrawn if some adjacent skin is touched. If the skin is repeatedly touched every twenty seconds, the animal will cease withdrawing its gill so vigorously. This decline in the response to a repeated stimulus is called "habituation" when it can be reversed by presenting a novel stimulus, such as touching the animal's head. Following that novel stimulus elsewhere, the gill-withdrawal reflex will be restored to its original vigor.

The decline in the effectiveness of the skin stimulus occurs because, after a number of stimuli, the transducer neuron's axon terminals release less and less neurotransmitter per impulse. The novel stimulus to the head does not stimulate the skin transducer neurons involved in the gill-withdrawal reflex; how then is the reset message delivered to their axon terminals, that something has touched the head? The answer is thought to involve an interneuron, which receives the information from the head but which regulates the synaptic transmission from the transducer neuron to the second neuron of the reflex chain (which is the motor neuron activating the gill muscles). This interneuron affects the axon terminal of the transducer neuron, changing the amount of calcium which enters the terminal upon the next arrival of an impulse from the transducer. More calcium causes more transmitter to be released; since calcium entry declines during habituation, this reverses the habituation.

Another use of an interneuron is involved in "presetting" an axon to release less neurotransmitter when an impulse arrives; this interneuron seems to make a connection to the axon terminals of the transducer neuron and has the action of reducing the neurotransmitter released by an impulse when one arrives. This is called "presynaptic inhibition." Its effect is to reduce the transmitter released by an impulse by a certain percentage, so it is analogous to division (in contrast to postsynaptic inhibition, which is analogous to subtraction).

The anatomical and physiological aspects of presynaptic inhibition have been studied in many types of animals. This interneuron regulation of impulse-evoked neurotransmitter release seems to be a widespread principle of the organization of nervous systems. Whether or not habituation, or perhaps learning, is also mediated through such presynaptic regulation is not yet known in many cases. Like the simpler adaptation, habituation may occur at many stages of the neuron chain, perhaps using multiple mechanisms.

 

Interneuron regulation of sensory messages. Transducer neurons in the hand send their axons to second-order neurons which are located at the base of the brain, near its junction with the spinal cord. Their axon terminals make synapses onto a second-order neuron whose axon, in turn, ascends toward the thalamus. This synaptic transmission is regulated by other neurons ("interneurons") whose axons end upon the transducer axon's terminals to produce presynaptic inhibition. The regulating interneurons are activated by inputs descending from the cerebral cortex (such as from the sensory and motor strips). Other interneurons produce postsynaptic inhibition and excitation directly upon the second-order neuron. Commands descending from cortex determine the intensity with which sensory messages are relayed onward to the thalamus and cortex; they also regulate how large an area of skin will activate a given second-order neuron (diagram modified from Walberg, 1965).

Thus, not only do "loudness controls" exist within single neurons, but there are also systems of neurons which may regulate the internal settings. A similar scheme has been hypothesized for learning: if synapses (or other aspects of neurons) are to modify themselves with use, surely there will exist systems of neurons which will regulate this plasticity, which will permit or prohibit plasticity under varying circumstances. For example, one role of the hippocampus in short-term memory might be to regulate the facilitation properties of synapses elsewhere in the brain; with destruction of the hippocampus, the synapses elsewhere might fail to receive the necessary permission to be modified by use, and thus a new memory trace could not be established.


Continue to CHAPTER 11

Notes and References for this chapter  
Book's Table of Contents  

Copyright 1980 by
William H. Calvin and George A. Ojemann

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