According to Ramachandran (1998), the implications to his investigation suggested that brain maps can change. In neuroscience, this is known as neuroplasticity. Ela

located) of our brain for adding, subtracting, multiplying and dividing? I think not. But clearly this region—the angular gyrus—is somehow necessary for numerical computational tasks but is not needed for other abilities such as short−term memory, language or humor. Nor, paradoxically, is it needed for understanding the numerical concepts underlying such computations. We do not yet know how this "arithmetic" circuit in the angular gyrus works, but at least we now know where to look.10

Many patients, like Bill, with dyscalculia also have an associated brain disorder called finger agnosia: They can no longer name which finger the neurologist is pointing to or touching. Is it a complete coincidence that both arithmetic operations and finger naming occupy adjacent brain regions, or does it have something to do with the fact that we all learn to count by using our fingers in early childhood? The observation that in some of these patients one function can be retained (naming fingers) while the other (adding and subtracting) is gone doesn't negate the argument that these two might be closely linked and occupy the same anatomical niche in the brain. It's possible, for instance, that the two functions are laid down in close proximity and were dependent on each other during the learning phase, but in the adult each function can survive without the other. In other words, a child may need to wiggle his or her fingers subconsciously while counting, whereas you and I may not need to do so.

These historical examples and case studies gleaned from my notes support the view that specialized circuits or modules do exist, and we shall encounter several additional examples in this book. But other equally interesting questions remain and we'll explore these as well. How do the modules actually work and how do they "talk to" each other to generate

conscious experience? To what extent is all this intricate circuitry in the brain innately specified by your genes or to what extent is it acquired gradually as the result of your early experiences, as an infant interacts with the world? (This is the ancient "nature versus nurture" debate, which has been going on for hundreds of years, yet we have barely scratched the surface in formulating an answer.) Even if certain circuits are hard−wired from birth, does it follow that they cannot be altered? How much of the adult brain is modifiable? To find out, let's meet Tom, one of the first people who helped me explore these larger questions.

CHAPTER 2

Knowing Where to Scratch

My intention is to tell of bodies changed to different forms.

The heavens and all below them, Earth and her creatures, All change,

And we, part of creation, Also must suffer change.

—Ovid

Tom Sorenson vividly recalls the horrifying circumstances that led to the loss of his arm. He was driving home from soccer practice, tired and hungry from the exercise, when a car in the opposite lane swerved in front of him. Brakes squealed, Tom's car spun out of control and he was thrown from the driver's seat onto the ice plant bordering the freeway. As he was hurled through the air, Tom looked back and saw that his hand was still in the car, "gripping" the seat cushion—severed from his body like a prop in a Freddy Krueger horror film.

As a result of this gruesome mishap, Tom lost his left arm just above the elbow. He was seventeen years old, with just three months to go until high school graduation.

21

In the weeks afterward, even though he knew that his arm was gone, Tom could still feel its ghostly presence below the elbow. He could wiggle each "finger," "reach out" and "grab" objects that were within

arm's reach. Indeed, his phantom arm seemed to be able to do anything that the real arm would have done automatically, such as warding off blows, breaking falls or patting his little brother on the back. Since Tom had been left−handed, his phantom would reach for the receiver whenever the telephone rang.

Tom was not crazy. His impression that his missing arm was still there is a classic example of a phantom limb—an arm or leg that lingers indefinitely in the minds of patients long after it has been lost in an accident or removed by a surgeon. Some wake up from anesthesia and are incredulous when told that their arm had to be sacrificed, because they still vividly feel its presence.1 Only when they look under the sheets do they come to the shocking realization that the limb is really gone. Moreover, some of these patients experience excruciating pain in the phantom arm, hand or fingers, so much so that they contemplate suicide. The pain is not only unrelenting, it's also untreatable; no one has the foggiest idea of how it arises or how to deal with it.

As a physician I was aware that phantom limb pain poses a serious clinical problem. Chronic pain in a real body part such as the joint aches of arthritis or lower backache is difficult enough to treat, but how do you treat pain in a nonexistent limb? As a scientist, I was also curious about why the phenomenon occurs in the first place: Why would an arm persist in the patient's mind long after it had been removed? Why doesn't the mind simply accept the loss and "reshape" the body image? To be sure, this does happen in a few patients, but it usually takes years or decades. Why decades—why not just a week or a day? A study of this phenomenon, I realized, might not only help us understand the question of how the brain copes with a sudden and massive loss, but also help address the more fundamental debate over nature versus nurture—the extent to which our body image, as well as other aspects of our minds, are laid down by genes and the extent to which they are modified by experience.

The persistence of sensation in limbs long after amputation had been noticed as far back as the sixteenth century by the French surgeon Am−broise Paré, and, not surprisingly, there is an elaborate folklore surrounding this phenomenon. After Lord Nelson lost his right arm during an unsuccessful attack on Santa Cruz de Tenerife, he experienced compelling phantom limb pains, including the unmistakable sensation of fingers digging into his phantom palm. The emergence of these ghostly sensations in his missing limb led the sea lord to proclaim that his phantom was "direct evidence for the existence of the soul." For if an arm can

exist after it is removed, why can't the whole person survive physical annihilation of the body? It is proof, Lord Nelson claimed, for the existence of the spirit long after it has cast off its attire.

The eminent Philadelphia physician Silas Weir Mitchell2 first coined the phrase "phantom limb" after the Civil War. In those preantibiotic days, gangrene was a common result of injuries and surgeons sawed infected limbs off thousands of wounded soldiers. They returned home with the phantoms, setting off new rounds of speculation about what might be causing them. Weir Mitchell himself was so surprised by the phenomenon that he published the first article on the subject under a pseudonym in a popular magazine called Lippincott's Journal rather than risk facing the ridicule from his colleagues that might have ensued had he published in a professional medical journal. Phantoms, when you think about it, are a rather spooky phenomenon.

Since Weir Mitchell's time there have been all kinds of speculations about phantoms, ranging from the sublime to the ridiculous. As recently as fifteen years ago, a paper in the Canadian Journal of Psychiatry stated that phantom limbs are merely the result of wishful thinking. The authors argued that the patient desperately wants his arm back and therefore experiences a phantom—in much the same way that a person may have recurring dreams or may even see "ghosts" of a recently deceased parent. This argument, as we

shall see, is utter nonsense.

A second, more popular explanation for phantoms is that the frayed and curled−up nerve endings in the stump (neuromas) that originally supplied the hand tend to become inflamed and irritated, thereby fooling higher brain centers into thinking that the missing limb is still there. Though there are far too many problems with this nerve irritation theory, because it's a simple and convenient explanation, most physicians still cling to it.

There are literally hundreds of fascinating case studies, which appear in the older medical journals. Some of the described phenomena have been confirmed repeatedly and still cry out for an explanation, whereas others seem like far−fetched products of the writer's own imagination. One of my favorites is about a patient who started experiencing a vivid phantom arm soon after amputation—nothing unusual so far—but after a few weeks developed a peculiar, gnawing sensation in his phantom. Naturally he was quite puzzled by the sudden emergence of these new sensations, but when he asked his physician why this was happening, the

doctor didn't know and couldn't help. Finally, out of curiosity, the fellow asked, "Whatever happened to my arm after you removed it?" "Good question," replied the doctor, "you need to ask the surgeon." So the fellow called the surgeon, who said, "Oh, we usually send the limbs to the morgue." So the man called the morgue and asked, "What do you do with amputated arms?" They replied, "We send them either to the incinerator or to pathology. Usually we incinerate them."

"Well, what did you do with this particular arm? With my arm?" They looked at their records and said, "You know, it's funny. We didn't incinerate it. We sent it to pathology."

The man called the pathology lab. "Where is my arm?" he asked again. They said, "Well, we had too many arms, so we just buried it in the garden, out behind the hospital."

They took him to the garden and showed him where the arm was buried. When he exhumed it, he found it was crawling with maggots and exclaimed, "Well, maybe that's why I'm feeling these bizarre sensations in my arm." So he took the limb and incinerated it. And from that day on, his phantom pain disappeared.

Such stories are fun to tell, especially around a campfire at night, but they do very little to dispel the real mystery of phantom limbs. Although patients with this syndrome have been studied extensively since the turn of the century, there's been a tendency among physicians to regard them as enigmatic, clinical curiosities and almost no experimental work has been done on them. One reason for this is that clinical neurology historically has been a descriptive rather than an experimental science. Neurologists of the nineteenth and early twentieth centuries were astute clinical observers, and many valuable lessons can be learned from reading their case reports. Oddly enough, however, they did not take the next obvious step of doing experiments to discover what might be going on in the brains of these patients; their science was Aristotelian rather than Galilean.3

Given how immensely successful the experimental method has been in almost every other science, isn't it high time we imported it into neurology?

Like most physicians, I was intrigued by phantoms the very first time I encountered them and have been puzzled by them ever since. In addition to phantom arms and legs—which are common among amputees—I had also encountered women with phantom breasts after radical mastectomy and even a patient with a phantom appendix: The characteristic spasmodic pain of appendicitis did not abate after surgical removal, so much so that the patient refused to believe that the surgeon

had cut it out! As a medical student, I was just as baffled as the patients themselves, and the textbooks I consulted only deepened the mystery. I read about a patient who experienced phantom erections after his penis had been amputated, a woman with phantom menstrual cramps following hysterectomy, and a gentleman who had a phantom nose and face after the trigeminal nerve innervating his face had been severed

/ – –

(a) (b)

in an accident.

All these clinical experiences lay tucked away in my brain, dormant, until about six years ago, when my interest was rekindled by a scientific paper published in 1991 by Dr. Tim Pons of the National Institutes of Health, a paper that propelled me into a whole new direction of research and eventually brought Tom into my laboratory. But before I continue with this part of the story, we need to look closely at the anatomy of the brain—particularly at how various body parts such as limbs are mapped onto the cerebral cortex, the great convoluted mantle on the surface of the brain. This will help you understand what Dr. Pons discovered and, in turn, how phantom limbs emerge.

Of the many strange images that have remained with me from my medical school days, perhaps none is more vivid than that of the deformed little man you see in Figure 2.1 draped across the surface of the cerebral cortex—the so−called Penfield homunculus. The homunculus is the artist's whimsical depiction of the manner in which different points on the body surface are mapped onto the surface of the brain—the grotesquely deformed features are an attempt to indicate that certain body parts such as the lips and tongue are grossly overrepresented.

The map was drawn from information gleaned from real human brains. During the 1940s and 1950s, the brilliant Canadian neurosurgeon Wilder Penfield performed extensive brain surgeries on patients under local anesthetic (there are no pain receptors in the brain, even though it is a mass of nerve tissue). Often, much of the brain was exposed during the operation and Penfield seized this opportunity to do experiments that had never been tried before. He stimulated specific regions of the patients' brains with an electrode and simply asked them what they felt. All kinds of sensations, images, and even memories were elicited by the electrode and the areas of the brain that were responsible could be mapped.

Among other things, Penfield found a narrow strip running from top to bottom down both sides of the brain where his electrode produced sensations localized in various parts of the body. Up at the top of the brain, in the crevice that separates the two hemispheres, electrical stimulation elicited sensations in the genitals. Nearby stimuli evoked sensa−

Figure 2.1 (a) The representation of the body surface on the surface of the human brain (as discovered by Wilder Penfield) behind the central sulcus. There are many such maps, but for clarity only one is shown here. The homunculus ("little man") is upside down for the most part, and his feet are tucked onto the medial surface (inner surface) of the parietal lobe near the very top, whereas the face is down near the bottom of the outer surface. The face and hand occupy a disproportionately large share of the map. Notice, also that the face area is below the hand area instead of being where it should—near the neck—and that the genitals are represented below the foot. Could this provide an anatomical explanation of foot fetishes'? (b) A whimsical

three−dimensional model of the Penfield homunculus—the little man in the brain—depicting the representation of body parts. Notice the gross overrepresentation of mouth and hands. Reprinted with permission from the British Museum, London.

tions in the feet. As Penfield followed this strip down from the top of the brain, he discovered areas that receive sensations from the legs and trunk, from the hand (a large region with a very prominent representation of the thumb), the face, the lips and finally the thorax and voicebox. This "sensory homunculus," as it is now called, forms a greatly distorted representation of the body on the surface of the brain, with the parts that are particularly important taking up disproportionately large areas. For example, the area involved with the lips or with the fingers takes up as much space as the area involved with the entire trunk of the body. This is presumably because your lips and fingers are highly sensitive to touch and are capable of very fine discrimination, whereas your trunk is considerably less sensitive, requiring less cortical space. For the most part, the map is orderly though upside down: The foot is represented at the top and the outstretched arms are at the bottom. However, upon close

examination, you will see that the map is not entirely continuous. The face is not near the neck, where it should be, but is below the hand. The genitals, instead of being between the thighs, are located below the foot.4

These areas can be mapped out with even greater precision in other animals, particularly in monkeys. The researcher inserts a long thin needle made of steel or tungsten into the monkey's somatosensory cortex—the strip of brain tissue described earlier. If the needle tip comes to lie right next to the cell body of a neuron and if that neuron is active, it will generate tiny electrical currents that are picked up by the needle electrode and amplified. The signal can be displayed on an oscilloscope, making it possible to monitor the activity of that neuron.

For example, if you put an electrode into the monkey's somatosensory cortex and touch the monkey on a specific part of its body, the cell will fire. Each cell has its territory on the body surface—its own small patch of skin, so to speak—to which it responds. We call this the cell's receptive field. A map of the entire body surface exists in the brain, with each half of the body mapped onto the opposite side of the brain.

While animals are logical experimental subjects in which to examine the detailed structure and function of the brain's sensory regions, they have one obvious problem: Monkeys can't talk. Therefore, they cannot tell the experimenter, as Penfield's patients could, what they are feeling. Thus a large and important dimension is lost when animals are used in such experiments.

But despite this obvious limitation, a great deal can be learned by doing the right kinds of experiments. For instance, as we've noted, one important question concerns nature versus nurture: Are these body maps on the surface of the brain fixed, or can they change with experience as we grow from newborns to infancy, through adolescence and into old age? And even if the maps are already there at birth, to what extent can they be modified in the adult?5

It was these questions that prompted Tim Pons and his colleagues to embark on their research. Their strategy was to record signals from the brains of monkeys who had undergone dorsal rhizotomy—a procedure in which all the nerve fibers carrying sensory information from one arm into the spinal cord are completely severed.6 Eleven years after the surgery, they anesthetized the animals, opened their skulls and recorded from the somatosensory map. Since the monkey's paralyzed arm was not sending messages to the brain, you would not expect to record any sig−

nals when you touch the monkey's useless hand and record from the "hand area" of the brain. There should be a big patch of silent cortex corresponding to the affected hand.

Indeed, when the researchers stroked the useless hand, there was no activity in this region. But to their amazement they found that when they touched the monkey's face, the cells in the brain corresponding to the "dead" hand started firing vigorously. (So did cells corresponding to the face, but those were expected to fire.) It appeared that sensory information from the monkey's face not only went to the face area of the cortex, as it would in a normal animal, but it had also invaded the territory of the paralyzed hand!

The implications of this finding are astonishing: It means that you can change the map; you can alter the brain circuitry of an adult animal, and connections can be modified over distances spanning a centimeter or more.

Upon reading Pons's paper, I thought, "My God! Might this be an explanation for phantom limbs?" What did the monkey actually "feel" when its face was being stroked? Since its "hand" cortex was also being excited, did it perceive sensations as arising from the useless hand as well as the face? Or would it use higher brain centers to reinterpret the sensations correctly as arising from the face alone? The monkey of course was silent on the subject.

It takes years to train a monkey to carry out even very simple tasks, let alone signal what part of its body is being touched. Then it occurred to me that you don't have to use a monkey. Why not answer the same question by touching the face of a human patient who has lost an arm? I telephoned my colleagues Dr. Mark Johnson and Dr. Rita Finkelstein in orthopedic surgery and asked, "Do you have any patients who have recently lost an arm?"

That is how I came to meet Tom. I called him up right away and asked whether he would like to participate in a study. Although initially shy and reticent in his mannerisms, Tom soon became eager to participate in our experiment. I was careful not to tell him what we hoped to find, so as not to bias his responses. Even though he was distressed by "itching" and painful sensations in his phantom fingers, he was cheerful, apparently pleased that he had survived the accident.

With Tom seated comfortably in my basement laboratory, I placed a blindfold over his eyes because I didn't want him to see where I was touching him. Then I took an ordinary Q−tip and started stroking various

parts of his body surface, asking him to tell me where he felt the sensations. (My graduate student, who was watching, thought I was crazy.)

I swabbed his cheek. "What do you feel?"

"You are touching my cheek."

"Anything else?"

"Hey, you know it's funny," said Tom. "You're touching my missing thumb, my phantom thumb."

I moved the Q−tip to his upper lip. "How about here?"

"You're touching my index finger. And my upper lip."

"Really? Are you sure?"

"Yes. I can feel it both places."

"How about here?" I stroked his lower jaw with the swab.

' ..

"That's my missing pinkie."

I soon found a complete map of Tom's phantom hand—on his face! I realized that what I was seeing was perhaps a direct perceptual correlate of the remapping that Tim Pons had seen in his monkeys. For there is no other way of explaining why touching an area so far away from the stump—namely, the face—should generate sensations in the phantom hand; the secret lies in the peculiar mapping of body parts in the brain, with the face lying right beside the hand.7

I continued this procedure until I had explored Tom's entire body surface. When I touched his chest, right shoulder, right leg or lower back, he felt sensations only in those places and not in the phantom. But I also found a second, beautifully laid out "map" of his missing hand— tucked onto his left upper arm a few inches above the line of amputation (Figure 2.2). Stroking the skin surface on this second map also evoked precisely localized sensations on the individual fingers: Touch here and he says, "Oh, that's my thumb," and so on.

Why were there two maps instead of just one? If you look again at the Penfield map, you'll see that the hand area in the brain is flanked below by the face area and above by the upper arm and shoulder area. Input from Tom's hand area was lost after the amputation, and consequently, the sensory fibers originating from Tom's face—which normally activate only the face area in his cortex—now invaded the vacated territory of the hand and began to drive the cells there. Therefore, when I touched Tom's face, he also felt sensations in his phantom hand. But if the invasion of the hand cortex also results from sensory fibers that normally innervate the brain region above the hand cortex (that is, fibers that originate in the upper arm and shoulder), then touching points on

Figure 2.2 Points on the body surface that yielded referred sensations in the phantom hand (this patient's left arm had been amputated ten years prior to our testing him). Notice that there is a complete map of all the fingers (labeled 1 to 5) on the face and a second map on the upper arm. The sensory input from these two patches of skin is now apparently activating the hand territory of the brain (either in the thalamus or in the cortex). So when these points are touched, the sensations are felt to arise from the missing hand as well.

the upper arm should also evoke sensations in the phantom hand. And indeed I was able to map out these points on the arm above Tom's stump. So, this sort of arrangement is precisely what one would expect: One

cluster of points on the face that evoke sensations in the phantom and a second cluster on the upper arm, corresponding to the two body parts that are represented on either side (above and below) of the hand representation in the brain.8

It's not often in science (especially neurology) that you can make a simple prediction like this and confirm it with a few minutes of exploration using a Q−tip. The existence of two clusters of points suggests strongly that remapping of the kind seen in Pons's monkeys also occurs in the human brain. But there was still a nagging doubt: How can we

"Knowing Where to Scratch" / 31

be sure that such changes are actually taking place—that the map is really changing in people like Tom? To obtain more direct proof, we took advantage of a modern neuroimaging technique called magnetoence−phalography (MEG), which relies on the principle that if you touch different body parts, the localized electrical activity evoked in the Penfield map can be measured as changes in magnetic fields on the scalp. The major advantage of the technique is that it is noninvasive; one does not have to open the patient's scalp to peer inside the brain.

Using MEG, it is relatively easy in just a two−hour session to map out the entire body surface on the brain surface of any person willing to sit under the magnet. Not surprisingly, the map that results is quite similar to the original Penfield homunculus map, and there is very little variation from person to person in the gross layout of the map. When we conducted MEGs on four arm amputees, however, we found that the maps had changed over large distances, just as we had predicted. For example, a glance at Figure 2.3 reveals that the hand area (hatched) is missing in the right hemisphere and has been invaded by the sensory input from the face (in white) and upper arm (in gray). These observations, which I made in collaboration with a medical student, Tony Yang, and the neurologists Chris Gallen and Floyd Bloom, were in fact the first direct demonstration that such large−scale changes in the organization of the brain could occur in adult humans.

The implications are staggering. First and foremost, they suggest that brain maps can change, sometimes with astonishing rapidity. This finding flatly contradicts one of the most widely accepted dogmas in neurology— the fixed nature of connections in the adult human brain. It had always been assumed that once this circuitry, including the Penfield map, has been laid down in fetal life or in early infancy, there is very little one can do to modify it in adulthood. Indeed, this presumed absence of plasticity in the adult brain is often invoked to explain why there is so little recovery of function after brain injury and why neurological ailments are so notoriously difficult to treat. But the evidence from Tom shows— contrary to what is taught in textbooks—that new, highly precise and functionally effective pathways can emerge in the adult brain as early as four weeks after injury. It certainly doesn't follow that revolutionary new treatments for neurological syndromes will emerge from this discovery right away, but it does provide some grounds for optimism.

Second, the findings may help explain the very existence of phantom limbs. The most popular medical explanation, noted earlier, is that nerves that once supplied the hand begin to innervate the stump. Moreover,

Figure 2.3 Magnetoencephalography (MEG) image superimposed on a magnetic resonance (MR) image of the brain in a patient whose right arm was amputated below the elbow. The brain is viewed from the top. The right hemisphere shows normal activation of the hand (hatched), face (black) and upper arm (white) areas of the cortex corresponding to the Penfield map. In the left hemisphere there is no activation corresponding to the missing right hand, but the activity from the face and upper arm has now "spread" to this area.

these frayed nerve endings form little clumps of scar tissue called neuromas, which can be very painful. When neuromas are irritated, the theory goes, they send impulses back to the original hand area in the brain so that the brain is "fooled" into thinking the hand is still there: hence the phantom limb and the notion that the accompanying pain arises because the neuromas are painful.

On the basis of this tenuous reasoning, surgeons have devised various treatments for phantom limb pain in which they cut and remove neuromas. Some patients experience temporary relief, but surprisingly, both the phantom and the associated pain usually return with a vengeance. To alleviate this problem, sometimes surgeons perform a second or even a third amputation (making the stump shorter and shorter), but when you think about this, it's logically absurd. Why would a second ampu−

tation help? You'd simply expect a second phantom, and indeed that's usually what happens; it's an endless regress problem.

Surgeons even perform dorsal rhizotomies to treat phantom limb pain, cutting the sensory nerves going into the spinal cord. Sometimes it works; sometimes it doesn't. Others try the even more drastic procedure of cutting the back of the spinal cord itself—a cordotomy—to prevent impulses from reaching the brain, but that, too, is often ineffective. Or they will go all the way into the thalamus, a brain relay station that processes signals before they are sent to the cortex, and again find that they have not helped the patient. They can chase the phantom farther and farther into the brain, but of course they'll never find it.

Why? One reason, surely, is that the phantom doesn't exist in any one of these areas; it exists in more central parts of the brain, where the remapping has occurred. To put it crudely, the phantom emerges not from the stump but from the face and jaw, because every time Tom smiles or moves his face and lips, the impulses activate the "hand" area of his cortex

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