Fragile Beginnings

by Adam Wolfberg, MD

  For Larissa, the goal would not be to reassign neurons to do the work previously done by her destroyed brain cells. Rather, she would depend on that plasticity from the very start, relying on completely new organizations and neural connections to operate her right arm and right leg and do the complex and subtle tasks involved in cognition.

  The neurologists at Children’s argued a bit over how to frame their prediction. They knew we were looking for certainty, and they knew there was none to be had. Even so, as du Plessis liked to say, “There’s no gold medal for identifying things you can do nothing about.”

  Eventually the troop of neurologists in white coats came back to the Brigham NICU. The attending led the way to Larissa’s bedside, and they all stood in a semicircle while he wrote a note in the chart.

  As doctors tend to do, the attending neurologist briefly restated her injury and noted the imaging that had been done.

  Then he wrote two lines under the heading of Prognosis.

  Chance of movement impairment on the right side is 100%—degree of impairment is difficult to predict.

  Chance of normal cognitive function (IQ greater than 70): 50%.

  Chapter 5. Injury, and What Follows

  Review books and index cards piled around him, Jason Carmel was deep into the rite of passage familiar to every medical student—studying for Step 1 of the United States Medical Licensing Examination. The anatomy of the inner ear and the biochemistry of the renal collecting system were swirling around in his head when his cell phone rang.

  His twin brother, David, was traveling with friends in Puerto Vallarta, Mexico. He’d been playing soccer on the beach when the group decided to go swimming to cool off. David ran into the surf until the water got too deep, and then he dove in, ramming headfirst into a sandbar that lay hidden beneath the waves.

  Information was sketchy at first: He had fallen and hit his head. He had fallen and couldn’t move his legs. Throughout the day, phone calls flew back and forth between David’s friends, who were with him, and David’s family on the East Coast, particularly from the twins’ father, a neurosurgeon. At the end of the day, David was airlifted to San Diego to undergo emergency surgery to stabilize his spine fracture.

  The next morning, Jason Carmel sat next to his father on a cross-country flight with his anatomy atlas in his lap, trying to understand the prognosis of his brother’s injury. “I was a second-year medical student,” Jason remembered. “I knew it was serious, but I didn’t understand what serious meant.”

  In the intensive care unit, Jason began to comprehend the consequences of his brother’s injury. David had suffered a burst fracture of the sixth cervical vertebra, and the bone fragments had injured his spinal cord. Because the neurons in the brain control movement through the corticospinal tract; that tract had been injured, so communication that orchestrates movement at the site of injury and below had largely ceased. David was paralyzed below the chest; he could lift his arms, but he had only minimal movement in his hands. When David arrived in San Diego, surgeons had removed the shattered vertebra and installed screws to support his spine. Over the next week X-rays, MRIs, and an additional surgery followed in rapid succession.

  “I remember sleeping in a motel near the hospital, and it didn’t feel right,” Jason recalled. “I was lying down in a soft bed while David was immobilized in a hard collar in the ICU.”

  Eventually, David was discharged from the ICU and flown home to begin inpatient rehabilitation at Mount Sinai Medical Center in New York.

  Jason Carmel finished studying for his exam, splitting his time between his apartment and the medical library at Mount Sinai, which was downstairs from his brother’s room. Then he started his third year of medical school at Columbia and began the series of required rotations that teach students the basics of a wide variety of medical specialties—from internal medicine to surgery, psychiatry to obstetrics—and help them decide what they want to specialize in when they graduate.

  But he found himself unable to focus. “I was directionless that year,” Jason remembered. “The normal energy that people apply to figuring out their lives, I lost in my distraction with David’s injury. I didn’t know what I wanted to do.”

  Jason and David Carmel, and their older brother, Jonathan, had grown up surrounded by doctors; their father was a pediatric neurosurgeon, and both of their grandfathers were physicians. Jason knew he wanted to be a doctor, but unlike many of his classmates, who one day realized that they were destined to be gastroenterologists (or otolaryngologists, or family practice doctors), Jason Carmel had no epiphany that revealed his future specialty.

  One afternoon Jason was visiting David when Wise Young, an eminent researcher in spinal cord injury and a longtime acquaintance of their dad, stopped by the drab room at Mount Sinai. “Here was this bearded Asian guy,” Jason recalled, “who came into the hospital room and sat down and held David’s hand and talked about spinal cord injury and what he was trying to do in his lab. He was warm and caring and showed enormous empathy.”

  Young was also brilliant and successful. He had gone to medical school and trained for two years as a neurosurgeon before leaving the OR for the lab. Listening from across the room as Young talked about his research in understanding and treating spinal cord injury, Jason found himself transfixed. “It seemed there was energy and promise in this field of research, and I suddenly felt like I wanted to participate in that.”

  Jason Carmel took a year off from medical school to do research and convinced Young to let him work in his Rutgers University lab. New to basic science, Carmel hurried to learn pipetting and sample preparation from graduate students and research assistants in the lab.

  That summer, the lab was enamored of a new technology that had the remarkable capacity to evaluate the function of dozens of genes simultaneously.

  In one experiment, Carmel simulated human spinal cord injury in a rat: he dropped a half-ounce metal rod from a height of precisely one inch onto the rat’s exposed spinal cord, and then he used the GeneChip to see what happened to the function of spinal cord genes below the site of injury.

  There was so much data about so many genes that Carmel and his colleagues had trouble figuring out what the results meant; they didn’t know what to do with the information other than publish a long paper. Although the practical benefit of all that knowledge seemed elusive, the research was a starting point for the young investigators.

  Carmel’s year in the lab flew by, and his team began to focus on a specific question: Why can injured neurons regenerate in some parts of the body but not in others? They teamed up with another lab that had concocted a compound that allowed neurons to grow anywhere, even in parts of the body where they were usually dormant. The researchers applied the compound to neurons, then used the GeneChips to see what genes were expressed in the neurons after the growth treatment; they found a number of genes had been turned on by the treatment. (All genes are present in all cells all the time, but only a fraction of genes are functional, or expressed.) This new research had the potential for useful therapy: in areas where injured neurons did not heal themselves, such as the spinal cord, the growth compound could turn on genes that were not typically expressed and possibly lead to nerve regeneration. To Carmel, working in the lab felt like pushing the bounds of what was possible in a way that clinical rotations had not.

  Three months after entering Mount Sinai, David was discharged, and he settled into a routine as he adapted to his post-injury life. In time, he learned to be largely independent. An aide came in each morning to help him bathe and dress, but once he was in his wheelchair, he could navigate the world on his own.

  At the time he was injured, he’d been about to start at the Stanford Graduate School of Business; a year after his injury, he was ready to get on with his life, and David moved out to the West Coast.

  In Wise Young’s Rutgers lab, a year o
f research turned into two as Jason’s interest in spinal cord injury deepened and focused. “I didn’t have any illusions that I would be the one that got my brother more sensation or more movement,” Carmel said, but he acknowledged that the symmetry between David’s injury and his research path wasn’t accidental.

  Jason learned techniques and ran statistics on the GeneChip results for the lab’s research on the genetics of spinal cord injury, but he found himself inexorably drawn to research directed at protecting the spinal cord from injury or, better yet, regenerating it after injury.

  Jason found his social calendar disturbingly empty after David left New York. He finally got around to calling the daughter of a family friend who had started medical school at Columbia a few years after Jason. It was meant to be: in 2005 Amanda and Jason were married.

  Plasticity is the ability to change, and we are all plastic to the extent that we learn from experiences and adapt. Neuroplasticity is the adaptation of neurons and the connections they make with one another in response to experience.

  In his 1890 classic The Principles of Psychology, William James proposed the theory of neuroplasticity. In subsequent decades, a few researchers published papers providing evidence for neuroplasticity. But in the 1930s, the neurosurgeon Wilder Penfield used mild electric stimulation to identify the location in the brain where intractable seizure activity originated. In the process, he created detailed anatomic maps that linked specific locations in the brain to motion and sensation in specific parts of the body. The combined information of these maps was published as the homunculus, and it remains essentially uncorrected to the present day. The illustration fed a popular fascination with the elegant and logical layout of the brain and the concept that specific cortical real estate was assigned to specific anatomic structures. An age of locationism set in and lasted about fifty years; the earlier literature was largely ignored, and researchers came to the conclusion that the homunculus was not plastic and that brain injury led to permanent loss of function in the part of the body that had been unlucky enough to be wired to the injured section of the cortex.

  It became dogma that after childhood, the structure of the neurons and white-matter cells that made up the brain—the brain stem, the midbrain, and the cortex—was essentially fixed. The two exceptions were the areas that housed memories—the hippocampus and the dentate gyrus—which continued to grow new neurons into adulthood.

  Research into neuroplasticity began with the map. In the 1970s and 1980s, it was discovered that if the input going to a part of the map was removed—for example, if information from the middle finger stopped arriving—the area of the cortex that had been assigned to the middle finger did not lie dormant but rather began to participate in the coordination of other structures, typically nearby structures, such as, in this case, the second and fourth fingers. Conversely, if a tiny stroke obliterated the area of the cortex devoted to the middle finger, adjacent areas rapidly took up control of the middle finger and restored its function. This research was expanded through experiments using fine electrodes inserted into precisely mapped spots on the cortex and showed that the area of cortex dedicated to a specific anatomic location would increase if that part of the anatomy was used and stimulated extensively and became important from the perspective of the animal being studied.

  The ability of the brain to reorganize confounded scientists’ efforts to trick it. When neuroplasticity pioneer Michael Merzenich cut a peripheral nerve in a monkey and sewed it to an adjacent nerve, he expected the experiment to utterly confuse the monkey’s brain. But when he mapped the monkey’s cortex after a period of adjustment, he found the monkey’s brain had rectified the map, accommodating the nerve change by reorganizing inputs.

  Plasticity was enhanced when the desired movement was rewarded, as is often the case in psychological experiments. The behavior being studied developed more quickly and the area of the brain devoted to it got larger when rewards were given than when they weren’t.

  Maybe the most innovative neuroplasticity research was done by Paul Bach-y-Rita, who developed ingenious devices that leveraged neuroplasticity to overcome catastrophic impairments. For one woman, who’d been incapacitated by unremitting vertigo after the collapse of her vestibular system—the balance equilibrium system in the inner ear—Bach-y-Rita developed an external balancing device that utilized tiny shocks to the woman’s tongue to provide equilibrium input. Over a period of months, the device allowed the woman to regain her balance, proving that the brain can receive information about balance from the tongue as well as the vestibular system. Eventually, she even outgrew the need for the device.

  Another of Bach-y-Rita’s inventions was a camera that converted its video input into mechanical vibrations using stimulators connected to a chair. Over time, a research subject born blind gained the capacity to “see” by sitting in the chair and feeling the inputs against his skin; he was able to distinguish forms and pictures placed in front of the camera by way of the vibrations. Although Bach-y-Rita did not map the part of the brain that was processing the input from his chair, he proved that even in someone who had never seen, the brain could process images from an unlikely source of sensory stimulation—the skin.

  It is interesting to note that the research on the development of vision in kittens, one of the key series of experiments that explained neuroplasticity, was partly wrong. David Hubel and Torsten Wiesel showed that if one of a kitten’s eyelids was sewed closed soon after birth, the part of the visual cortex usually assigned to that eye learned to process visual information from the opened eye, and it continued to do so even when the sutures were later removed from the closed eyelid. The previously closed eye did not regain sight, and the researchers believed this was evidence that there was a critical period during which plasticity exists, and that, at the end of this period, plasticity ends (or is greatly diminished). In fact, this experiment may better represent evidence of learned nonuse. For the kitten, it was just plain easier to use the eye it had always used than to learn how to see out of the other eye.

  This same principle applies to motor connections that are disrupted early in life. An animal—or child—will use the limb that works the best; sparse connections can be forced to develop only if the subject is constantly encouraged to use the injured or affected limb.

  I met Sarah Habib in her comfortable New Hampshire home when she was five years old. Sarah was born fifteen weeks early, and her birth had all of the drama of Larissa’s: Sarah’s mom, Kim, had felt sick all weekend but chalked it up to a stomach virus. Monday morning Sarah’s father, David, left for Memphis on a business trip, and the next day Kim’s water broke and she rapidly went into labor. Sarah arrived feet first at a community hospital, and she was placed into an incubator and put in an ambulance that got her to the NICU at Tufts Medical Center in Boston in forty-five minutes.

  As rocky as Larissa’s initial days in the NICU were, Sarah’s were even bumpier. She had hemorrhages on both sides of her brain, and the doctors struggled to move oxygen from the ventilator through her lungs and into her bloodstream. They turned up the oxygen setting on the ventilator, knowing it might cause blindness but realizing that they had no alternative. Finally they brought in the ventilator of last resort, a machine often referred to as the jet because of the sound it makes; it got oxygen into Sarah’s lungs but made Sarah vibrate with each of the hundreds of tiny puffs of air a minute it sent into her lungs.

  One night after Kim and David had made the eighty-minute drive home to New Hampshire, the phone rang and the doctor on the other end of the line told them in a grave voice that they had better return to Tufts. Weary beyond speaking, they drove the abandoned highway back into Boston, where, afraid that Kim and David might arrive too late, the nurses had taken some photos of Sarah, just in case.

  It was the whole nightmare: intraventricular hemorrhages, lung failure, and now trouble maintaining Sarah’s blood pressure. Her doctors
came to Kim and David and suggested that they sign a do-not-resuscitate order so that in the event that Sarah’s heart stopped beating, the pediatricians wouldn’t be compelled to perform heroic measures on this baby who seemed so fragile and whose outcome was so uncertain. Kim and David signed the order.

  But over the next several days, Kim and David marveled at how their tiny newborn—their only child—hit obstacle after obstacle, complication after complication, and yet managed to survive.

  “We decided that if she was going to fight, then we would fight with her,” Kim said. The next day they rescinded the DNR order.

  Meanwhile, David was online looking for hope. He tracked down doctors around the world who had taken care of premature newborns with severe neurologic injury and had seen miracles. He read research on novel ways of encouraging development. “I was e-mailing with a doctor in the UK about therapies that could rewire the brain,” he recalled. “They had done some research, and maybe it was really new, but it made me optimistic.”

  Their Tufts neurologist was circumspect. “Well, you know,” was all he would say when David mentioned his far-flung communications.

  David wasn’t ready to accept less than normal. “I did not believe it,” he said. “I still believed that given the right opportunities, this kid could do whatever she wanted to in life.”

  Ever on the lookout for hopeful signs, Kim found one on the wall of the subway station below the hospital. LOVE CONQUERS ALL, it said—it was an advertisement for something, but to Kim it was a message aimed at her and Sarah.

  Chapter 6. Whose Choice?

  Wrapped in her blanket inside the warm and humidified incubator, Larissa was beginning to grow. Her demands on the NICU staff diminished each day. Whereas she had once required the ventilator, now she needed only a whiff of oxygen under her nose. Her blood count was stable, and the antibiotics that were being infused to ward off an infection seemed like overkill. Though, to be sure, she still needed formula dripped through a tube into her stomach and the warmth and protection that the incubator provided.