Fragile Beginnings

by Adam Wolfberg, MD

  When I visited recently, Sarah was dropped off by the school bus and came in the door, taking deliberate, stilted steps. Now seven, she had walked without help for just over a year. A smiling and happy child with short brown hair, Sarah had made significant gains.

  “Did you have a good day at school?” David asked.

  “Yes,” Sarah said, drawing out the final s.

  “Did you do math today?”

  “Yes.”

  “Did you count by ones?”

  “Yes.”

  “What other numbers did you count by?”

  “Yes.”

  Sarah had recently gotten a communication device that spoke when she pushed a button on a console coded with bright images of everyday objects. Kim and David hoped this would help her “speak,” but they realized that although the device would help Sarah overcome the difficulty of speech, it wouldn’t help with the challenges of language.

  Because Sarah’s vision was limited and her ability to speak complicated by her cerebral palsy, Kim wasn’t entirely sure of the extent of her daughter’s intellectual capacity or of her specific limitations. Sarah knew all of her letters and numbers, but Kim admitted, “Cognitively, it’s hard to tell where she’s at.”

  In the mainstream school where Sarah went to first grade, she had a full-time one-on-one aide, but sometimes the help Sarah got was baffling. Schoolwork came home printed in a tiny font obviously too small for Sarah to see. Drawings showed evidence of the aide’s coloring, not necessarily Sarah’s, and Kim heard that Sarah wasn’t allowed to move around the classroom or interact with the other children—the school administrators were afraid she would fall and hurt herself.

  Relatively insulated from the outside world, Kim saw significant progress on a daily and weekly basis as her daughter gained strength and skills and learned new things. “It’s only when you see her with other children her own age that you realize how far behind she is,” Kim said.

  What’s entirely impossible to understand is how Sarah perceives the world around her. “We were on a train at this park up in Vermont,” recounted David. “Sarah likes trains a lot, and she started making this sound that she often makes, ‘Aah-aah,’ while rocking her head back and forth. It’s just something that she does.” A father sitting nearby with his kids picked his kids up and moved them to the other side of the train, as far from Sarah as he could get.

  “Sarah doesn’t notice,” David said. “At least I don’t think she does.”

  David worries about what will happen when Sarah is older and notices that people move away from her or don’t want to play with her. “Right now, at her developmental stage, it’s not a big deal. But as she gets older, the impact on her self-esteem worries me,” he said. Of course one of the problems is that they don’t know exactly where Sarah is developmentally.

  “We haven’t had her tested,” Kim said. “She knows her address, and she can count to thirty.”

  “She can count by tens to a hundred,” David offered.

  “I’d say she’s probably about four or five,” Kim guessed. “But she doesn’t grasp cause and effect,” she added. “If she wants to pick something up, she often doesn’t realize she has to put what’s in her hand down to pick up the next thing. In some areas she’s very advanced, but in other areas she’s very far behind.”

  Sarah came into the kitchen. “Du,” she said, her way of saying that the television show was over. “Ju?” she asked. “Ju?” And Kim made her a sippy cup of juice.

  “You did a good job,” she told Sarah.

  Chapter 11. The Plasticity Treadmill

  Jason Carmel took over a lab bench in Jack Martin’s lab, a warren of small rooms packed with equipment on the ninth floor of an aging City College building on the West Side of New York City. Looking through dirty panes, Carmel could see across Manhattan to the East River and Queens. He was working on the building blocks of his theory: well-defined animal experiments that would prove—or refute—his overall hypothesis that same-side neurons could develop into a viable system of control for parts of the body abandoned by injured neurons. What if, Carmel thought, he could reverse the process that led to opposite-side control and recruit the frail same-side neurons to action? Could the right brain be convinced to control both the right and left sides of the body after an injury to the left brain? In Larissa’s case, could her right brain be made to control her right side after her left-brain injury at birth had abandoned the right side of her body?

  The theory was radical because it contradicted conventional wisdom about treating stroke and cerebral palsy, which focused on rehabilitating injured brain, not recruiting healthy brain to take on a new and unexpected task.

  Although he didn’t know Larissa, Carmel’s idea would translate to her situation like this: because of the injury to the left side of Larissa’s brain, the dominant corticospinal tract fibers that typically control the right side of the body are underdeveloped, and this may have allowed greater-than-normal development of those few corticospinal fibers that ran from the right side of Larissa’s brain to the right side of her body. Maybe, thought Carmel, he could harness the innate plasticity of these same-side neurons and coax extraordinary function out of their narrow axons.

  Ignoring decades of research that held that the best way to help a patient regain function after a brain injury was to focus on rehabilitation of the injured brain cells, Carmel decided to see if a bold approach leveraging an arsenal of therapies could teach the uninjured side of the brain to control both sides of the body. “Our goal is to drive bilateral control from one side of the cortex,” Carmel explained, “by activating the long-dormant ipsilateral [same-side] fibers.”

  The potential side effects of this approach were not trivial. Patients with spinal cord injuries worked hard to strengthen and regenerate synapses only to develop excruciating pain syndromes linked to the new connections they had formed. A few researchers even thought that after a stroke, developing the same-side neurons actually impeded the rehabilitation of the injured brain cells and the relearning of the cells with connections that crossed over.

  The biggest uncertainty, from the perspective of Carmel and his new research mentor Jack Martin, was the extraordinary complexity of the brain itself. It’s one thing to stimulate the brain of a rat in a particularly well-known region of the motor cortex and observe the expected twitching of the paw, but that doesn’t mean that there aren’t other ways for a signal to go from the motor cortex to the paw, or that a host of other circuits don’t modify and influence the action between the initiating cell in the motor cortex and the muscle fiber. With his years of experience methodically piecing together the anatomy and function of the corticospinal tract, Martin cautioned Carmel that circuits they hadn’t yet considered could torpedo the ambitious plan.

  While building the foundation of a research program in Jack Martin’s lab, Jason and Amanda Carmel had bought a condominium in a newly renovated building in South Harlem, close to work and to Central Park, and they’d started a family. Like any dual-career couple, they struggled to balance their jobs with their family’s needs, and except for their own sleep requirements, they managed to meet the needs of their family and their jobs.

  One hundred blocks to the south, David had returned from the West Coast and had also married and had children. The Carmel brothers got together regularly, now with their small children in tow.

  On a recent winter night, Jason Carmel finished up an experiment, took the rats back to the animal facility, bundled up against the cold, and made his way out into the New York twilight. It was a fifteen-minute walk to his condo, dodging road construction and passing low-rise housing developments built in the 1950s.

  His apartment building appealed to young families, and evidence of children was everywhere; strollers and trikes competed for space. He went up an elevator and turned his key in the lock, and th
e warmth of home spilled into the hallway. Two children came running, a third crawling, and their nanny smiled in the background. In the suburbs there would be space for a playroom, but in the city, it was the living room that had a miniature play structure and the remnants of a pillow-and-blanket fort. Amanda’s clinic ran late that evening, so Carmel was on his own for a while. Sometimes he marveled at the innate ability of his children, like most children, to learn complex tasks that combine curiosity with intricate movements. Most of the time, he left work behind and just enjoyed the simple, satisfying time with his kids.

  In the lab, the tools available to Carmel were somewhat crude: electrical stimulation; systems of restraint, like the cast Larissa wore for a month in Birmingham; and planned activity for the impaired limb. Success would depend on two things: the validity of Carmel’s hypothesis and his creativity with the tools available to him.

  With some funding from Martin, and later a small grant from the foundation set up by actor Christopher Reeve after he suffered a catastrophic spinal cord injury while horseback riding, Carmel set up his experiments and got to work.

  Because in science nothing can be taken for granted, Carmel’s initial experiment had three objectives. First, confirm what everyone knows is true—that after an injury to the corticospinal tract, a rat can be taught to regain much of the motor control it lost through injury. Second, explain the circuits of neurons that allow for recovery of function—in essence, understand the anatomy of plasticity. And third, use activity to strengthen those circuits.

  Carmel’s rats were white and six inches long, and they had beady red eyes. It turned out that their eyesight was very poor, so they depended on the sensory input from their whiskers to navigate the world.

  For this experiment, the rats spent eight weeks learning to walk across a ladder. Carmel fashioned the ladder with high walls made of clear Plexiglas (so Carmel could watch the rat on the ladder, but the rat couldn’t jump off the side) and rungs that could be moved or taken out so that they were unpredictable—the rat had to use its eyesight and whiskers to sense where it was and to put its paws down in the correct place, not just memorize the distance between regularly spaced rungs.

  For the rat, training involved being picked up and put on a short chute that led to the ladder and then running across to the other side, where a Q-tip dipped in sugar water awaited as a treat. Next to the ladder, a video camera recorded it all.

  Carmel’s assistant, Lauren, who had had a career as a personal injury lawyer before taking a job in the lab so she could work her way through her pre-med courses, had become something of a professional rat trainer. A rat ran ten times one way across the ladder, and then ten times in the opposite direction. Then Lauren changed the rung pattern and started over.

  Rewarded after each trip across the ladder, the rat was cooperative and fast, its feet scurrying across the twenty rungs with seemingly perfect accuracy.

  Halfway through one set of exercises she called to another research assistant in the next room. “Can you get me another Q-tip? The rat ate this one.”

  When the training exercise was over, she stopped the video and downloaded the data into the iMovie software on her Macintosh computer. In real time, the rat moved much too quickly for Lauren to assess the accuracy of its paws on the rungs of the ladder, which was the purpose of this exercise. But looking frame by frame on the computer, Lauren could assess each step and determine whether the rat put its paw down directly on the rung or overstepped slightly so the rung hit the wrist. Understeps were easy to detect, as the paw missed the rung entirely and the rat had to catch itself so it didn’t stumble. By the eighth week, the rats ran across the ladder flawlessly.

  Then it was time for surgery. Anesthesia was injected, and the skin at the front of the neck incised. Looking through a microscope and using a fine set of scissors, Carmel dissected the neck, gently pushing aside the trachea and passing between the carotid arteries until he found the base of the skull. He drilled a tiny hole in the skull and then used the scissors to slice through the dura mater that formed the protective layer around the brain and spinal cord; he identified the dual pyramids of the corticospinal tract just below the area where they crossed and cut through the left pyramid, severing connections between the right motor cortex and the left side of the body. Then he closed the skin with tiny surgical staples and waited for the rat to wake up.

  A day or two later the testing began. The rat was run across the ladder just as before—ten times in one direction; ten times in the reverse direction. Lauren could see the impairment just by watching the rat, but when she sat down at her Mac and slowed the video, it was really apparent: the left foot kept missing the rungs—overstepping and landing on the wrist, or understepping and stumbling.

  But over several days, the left paw got markedly better. The rat was never as accurate with its left foot as it was with its unimpaired right, but the left paw regained significant accuracy.

  The challenge for Carmel was understanding the mechanism of learning that allowed the rat to improve its ladder run after the injury to its corticospinal tract. Prior research had demonstrated that once severed, the corticospinal tract did not repair itself. So did the same-side tract rise to the occasion, as Carmel had hoped, or was it some other mechanism at work? It was time to find out.

  Back under the dissecting microscope, Carmel consulted an atlas of rat-brain anatomy to make sure he was in precisely the right spot. He identified the motor cortex on the rat’s right side—the side that had been disconnected from the left side of the body when the corticospinal tract was severed weeks earlier.

  Now, he injected a tiny amount of a special tracer into the cortex. He finished the surgery: cement went on in place of the skull and skin, and the rat was again awakened and allowed to recover before facing the ladder in the days that followed.

  Unbeknownst to the rat, the injected dye—which traveled from cell body to axon only and never in the reverse direction—was making its way down the intact corticospinal neurons. Over a period of several days, the dye came to occupy the nerve axons of intact corticospinal tract neurons.

  After the tracer dye had been given enough time to fully color the intact neurons (the dye could not cross the site of injury, so injured neurons would not absorb the dye), training ended, and it was time to see if Carmel’s hypothesis was right.

  After a purposeful overdose of anesthesia, Carmel made cross-sections of spinal cord a few microns thick and affixed the slices to slides that he could examine under the microscope.

  Using a chemical that turned the axons black, Carmel looked for the tracer that marked the axons of corticospinal tract neurons. Bright black dots for axons passing perpendicularly through the slice on the slide; short lines for axons traveling parallel along the plane of the slice.

  He compared the results to a set of spinal cord slices made from control rats, those who hadn’t participated in the training regimen.

  In the butterfly-shaped cross-section of the spinal cord, Carmel saw a collection of black on the impaired side in the middle—much more dense than what was seen on the brain slices of the control animals. These were the same-side corticospinal tract connections. And on the unimpaired side, he saw nothing. His hypothesis was correct: by the process of plasticity, these same-side neurons had come to the rescue of the obliterated neurons.

  This was good news, but hardly a breakthrough. Anyone with a brain injury will say that although some skills are regained over time, physical and occupational therapy alone—the human equivalent of ladder running—does not restore normal function. Given what Carmel knew about the significant improvement in his rats’ function but the only minimal improvement in the function of humans who had the equivalent injury, there was more research to be done.

  He embarked on a series of experiments to see whether he could enhance the process of plasticity. By infusing a temporary paralytic into the a
rea over the motor cortex, he learned about the long-term effects of brain injury on development—those rats who were temporarily paralyzed early in life never caught up, even after the paralytic infusion ended.

  In another set of experiments, he implanted a tiny electrode directly into the rat’s left motor cortex, the side of the brain that remained connected to the right side of the body through the neurons that crossed over. Peering through the dissecting microscope and watching for the front paw to respond when a tiny stimulation was given through the electrode, Carmel pinpointed the exact location where the electrode should sit. This experiment was somewhat counterintuitive, given the years of research that focused on using electrical stimulation to the injured side (in this case, the rat’s right motor cortex that had been disconnected from the rat’s left side).

  After the electrode was implanted, Carmel secured it with the cement, and over a period of weeks, he provided a low-level stimulation while the training with the ladder was ongoing.

  Finally, Carmel was getting impressive results: the density of the same-side neurons labeled with the tracer dye increased with each new tactic. Other researchers had shown that exercise was better than no exercise. Carmel now demonstrated that electrical stimulation was better than no stimulation. And electrical stimulation in addition to exercise was best of all. And of critical significance to Carmel and Martin, who had spent so much time understanding the circuitry, when they looked at slices of spinal cord under the microscope, the stimulation created connections that explained the improved function they saw on the ladder.

  Martin and Carmel were proving their hypothesis, at least in rats, experiment by experiment. Injury reignited competition between the injured side of the brain and the intact side of the brain for control of the abandoned side of the body, and the two neuroscientists had proven that exercise and electrical stimulation could help the same-side fibers outcompete for control. They had ladder-running data to prove it, and they had fluorescent Spaceballs data from the slices of spinal cord.1