Fragile Beginnings

by Adam Wolfberg, MD

  In another study,4 Saigal asked adolescents, some of whom had been born prematurely, and their parents, neonatologists, and neonatal nurses to rate the quality of life of a set of hypothetical disabled children. When Saigal looked at her data, she was surprised. Her adolescents had lots of different opinions about what kind of lives the hypothetical children led, but the answers had little to do with whether or not the adolescents surveyed were disabled or born prematurely. Parents also rated the quality of life of these hypothetical children more or less the same, irrespective of whether they were the parents of children born at term or born prematurely. The median utility score for Sandy for the parents was 0.25, the same as the median score given by the adolescents.

  In contrast, the physicians and nurses surveyed gave Sandy a median utility score of 0—equivalent to death. Health-care providers—the ones on the front lines fighting for the survival of the tiniest premature newborns, and the ones deciding whether or not to resuscitate these babies—uniformly rated the quality of life of Saigal’s hypothetical children lower than parents did, and lower than the adolescents did. The only exception was that the health-care providers thought the quality of life for the least impaired children was higher than the adolescents did, although lower than the parents did. Saigal doesn’t know why physicians are so pessimistic but wonders whether they bring their experience caring for very injured children to the experiments. “We look through different-colored lenses, I suppose,” she said.

  In a famous study conducted in the mid-1970s,5 researchers interviewed three groups of Illinois residents about their happiness. The members of one group had won between fifty thousand and a million dollars in the Illinois state lottery. The second group had been victims of accidents that left them paralyzed from either the waist or the neck down. The third group was a control group of approximately the same age and economic status as the other two groups.

  Not surprisingly, the lottery winners rated the experience of winning as highly positive, and the accident victims looked back on their injuries as negative events. But when asked about their current happiness, the lottery winners were about as happy as the control subjects (victims were less happy), and when asked how happy they would be in the future, all three groups believed they would be equally happy.

  Interestingly, when the lottery winners were asked how they enjoyed the daily pleasures of life—hearing a joke, reading, talking with friends—they reported less happiness than the control subjects did and about the same amount as the accident victims. Good fortune seems to have soured their day-to-day enjoyment of life.

  Like lottery winners and accident victims, parents of premature newborns cannot see beyond the overwhelming shock of the present to a time when the extreme situation becomes mundane, and the obvious differences routine. But this transition does inevitably occur, and whether it’s because of human resilience or adaptation or just the instinct to make lemonade when handed lemons, there’s a robust body of scientific literature that supports the old adage that happiness really doesn’t have a lot to do with the external conditions in life.

  Now, years later, Saigal feels she can answer the question that parents ask: “I can tell parents now that the children rate their quality of life fairly high, and that none have asked, ‘Why did you save me?’ And that is reassuring to parents.”

  Lying propped on her side in her incubator, her back against a towel roll, Larissa was beginning to thrive. There were no new surprises. Her oxygen demand dropped each day.

  However, movement impairment seemed certain. Would she walk? Would she use her right hand? Normal function was not going to happen. The question was how severe the impairment would be. But for Kelly and for me, the more agonizing uncertainty was the question about Larissa’s cognitive function. Would she read? Would she laugh at jokes? Would she tell them?

  The medical literature suggested Larissa’s prognosis was grim; the best pediatric neurologists in the world had hedged their bets, and Ringer had opined that Larissa looked like a good baby but admitted that his view was based on instinct, not clinical data.

  We had read dozens of published studies, talked to a host of experts, and agonized for countless hours. In the end, there was no decision. I walked into the living room one night where Kelly was attempting to distract herself by watching television. Standing in the doorway, I said, “I think we should hope for the best.”

  “So do I,” she said.

  Chapter 8. The Recovery Pathway

  Innumerable medical school essays recount the applicant’s volunteer experience with some highly empathetic medical group—the traveling troop of cataract surgeons in Guatemala, the health center in urban Baltimore, the emergency room doctors in Chicago—and identify the point when medicine became the applicant’s calling. Jason Carmel’s essay framed a hypothesis: that service requires both skill and compassion—alone, neither is sufficient.

  The hypothesis came from Carmel’s experience working at Camp Ramapo in New York’s Hudson Valley. The Carmel family had been involved with the camp for decades, and Jason and his brothers had been encouraged to get involved when they were old enough to be counselors.

  Ramapo took troubled children, mostly from urban environments, and created an atmosphere that provided a mainstream camp experience—but with the support and structure these kids needed. Whether the child had limited cognitive function, autism, or just severe behavioral challenges, Ramapo’s staff used the tools at their disposal to help these kids—who had failed so often at so many things—succeed.

  Carmel recognized that the formula for success wasn’t rocket science: a highly structured environment with no downtime during which kids could get into trouble; one-to-one supervision by college students like Carmel who attended a one-week boot camp prior to the start of the summer learning Ramapo’s time-perfected techniques; and nearly limitless encouragement and enthusiasm.

  “I tend to be a pretty optimistic and can-do type of person,” Carmel said, reflecting on the seven summers he spent at Ramapo beginning at the age of seventeen, “but having that kind of experience early on, where you see the impact you can have on another human being, is an important experience to have.”

  All three Carmel brothers spent summers at Ramapo. David, who shared Jason’s can-do attitude, had taken the lead while he was a student at Harvard and started a Ramapo-inspired mentoring program for children identified by their Head Start teachers as being at risk for behavioral and academic difficulties. The program, called Jumpstart, originated in New Haven and Boston but grew quickly, and today it operates on eighty college campuses and serves over nine thousand kids annually.

  Ramapo showed Jason Carmel what a thoughtfully designed curriculum combined with an enormous amount of compassion could do for a troubled child. He also learned what it could not do: it could not help the child who was hallucinating and needed medical care or the child with epilepsy who had difficulty learning and behaving in school because he kept seizing. To a can-do guy, these problems that could not be addressed by a structured curriculum were frustrating. They came to represent a challenge and informed the attitude toward service that he outlined in his medical-school-application essay.

  Three years after taking a “year off,” Carmel graduated from medical school at Columbia. With an MD and a neuroscience doctorate in hand, he had a new direction: understanding—and eventually repairing—spinal cord injury. He would do a residency in neurology, and because adult neurologists tended to focus on degenerative diseases, such as Parkinson’s and Alzheimer’s, and stroke, he chose pediatric neurology, which more closely aligned with his interest in repair and regeneration of damaged nerve structures.

  Columbia has one of the nation’s preeminent neuroscience research programs and includes among its faculty two Nobel Prize winners, but when Jason Carmel started his residency the next year, he aligned himself with Jack Martin, a lesser-known researcher who
had some innovative ideas about the brain. In an era when discovering molecular and genetic mechanisms for degenerative diseases won publicity and grant dollars, Martin was figuring out how the brain and spinal cord control movement.

  Experimenting with cats and rats, Jack Martin had built a career working out the structure and function of the corticospinal tract, the bunch of neurons connecting the brain and the spinal cord that is responsible for most voluntary movement of the arms and legs. At the time that Carmel came along looking for a research project, Martin was asking some fundamental questions about the spinal cord—how do animals learn how to move? how do they relearn how to move after injury?—and he was developing some intriguing hypotheses. For Carmel, a newly minted neuroscientist with a twin brother in a wheelchair, these questions held both intellectual and personal urgency.

  The cell bodies of corticospinal tract neurons are located under the surface of the cerebral cortex and serve a variety of functions, including movement planning, integration of sensation and action, and perhaps even processing of emotion and cognition. At least half of these cells are located deep inside the precentral gyrus of the cortex, approximately three inches above the ear. These are the neurons that constitute the homunculus, the odd map of the human body superimposed on the cortex that shows that more of the brain is devoted to highly innervated areas, such as the hand, than to less dexterous anatomy, such as the elbow.

  The long axons of these cells coalesce downward toward the brain stem and serve as the principal pathway for voluntary movement. At the brain stem, most cross over to the opposite side, which explains why the left side of the brain controls the right side of the body and vice versa, although a small number of cells send their projections down the same side of the brain stem. After they cross, the corticospinal tract axons descend down the brain stem in bundles reminiscent of pyramids, giving rise to their alternate name, the pyramidal tract. These cells continue down the spinal column and then connect at synapses with one or more lower motor neurons, which branch out into the body to control various muscles—for example, a portion of the muscle involved in rotating the palm of the hand toward the sky.

  Anatomically, the fact that some, but not all, axons—which are each as thick as a human hair and several feet long—cross from one side to the other is critically important. It explains why an injury to the left side of the brain, as happened in Larissa’s case, affects the right side of the body.

  The small set of nerve fibers that never cross influences the unpredictability of brain injury as well as the brain’s capacity for recovery, because this group of nerve fibers represents a direct connection between the right brain and the right side of the body.

  Early in their development, the corticospinal axons branch wildly at the level of the spinal cord where they end. None of the connections made by these branches is particularly strong or robust, and over time these branches are pruned back, leaving a few primary connections that grow in strength.

  What causes this to happen? Is it hardwired—some complex set of genetically programmed instructions relayed to the neurons by growth factors and neurotransmitters? Or is it plastic—that is, does it depend on the experience and external environment of the child?

  Martin had a theory; he thought that at birth each side of the brain was more or less able to control either side of the body—or both sides at once. He believed that the pruning of branches over time represented competition, one group of neurons beating another to set up productive connections. During the process of normal development, the corticospinal tract fibers that cross from the right brain to the left side of the spinal cord are more robust than the thin tract of neurons descending on the left side, so the right-side fibers outcompete the same-side fibers in making meaningful connections to the left hand and left leg.

  Evidence for his theory is in every newborn nursery: babies’ early movements are frequently mirrored—that is, the right side mirrors the left—and it is only over time that purposeful, single-side movements develop and are refined.

  In a series of experiments, Martin and his students set about proving his theory. They kept asking, “What is the exact pathway here?” Then they would arrange experiments to find the answers. Martin was also investigating connections, but his work focused not on the cortex, where the signal originated, or the insulating white-matter cells, whose failure was responsible for cerebral palsy, but rather on the wires of the corticospinal tract that carried signals from the cortex down the spinal cord.

  In one experiment using a cat, the researchers sent a mild electric current through the corticospinal axons as they passed through the cat’s brain stem and then measured the effect on the muscle innervated by that axon. They found that once muscle stimulation had occurred, it took less stimulation the next time to achieve the same effect. They used the neurology term facilitation to describe this process that really represented learning on a cellular level.

  Recall the example of learning to type. When I was learning to type, I formed, for instance, the image of an X in my mind. Then I looked at the keyboard and saw that the X required that I move the ring finger of my left hand down to the row below the home row, where my finger was poised above the S. So I moved that finger to strike the X. It was a slow process, requiring multiple steps and involving numerous errors. Over time I learned fluency, and the X became second nature, so that now as soon as I think about typing X, my finger goes there. This is oversimplified, because centers of language, memory, sensation, and motor activity all contribute to this process, as do a complex set of neurotransmitters and receptors. But part of that learning process was the strengthening of a connection between a corticospinal neuron and the lower motor neuron that linked to a muscle that flexed my ring finger. Over time the action became easier, and on a cellular level, it required less stimulation to achieve. The behavior had been learned.

  In another set of experiments quite similar to the Hubel and Wiesel research on kittens’ vision, Martin’s group temporarily knocked out function of the corticospinal tract on the right side of a rat brain by infusing muscimol, a medication that blocked all those nerve fibers’ activity, for two weeks during the critical time of development when refinement of the corticospinal tract normally takes place. (The human equivalent to this would be paralyzing one side of a child’s brain between the ages of four and fourteen and then allowing the brain to resume functioning.)

  Not surprisingly, the connections observed in the rat’s spinal cord on the left side, the side affected by the paralyzing infusion on the right, withered or failed to develop with the exuberance of the corticospinal connections originating in the unscathed left brain. A period of learning had been disrupted.

  Martin used a piece of software called Spaceballs, named after the Mel Brooks movie parody, that created a three-dimensional matrix of virtual spheres and then counted the number of axons that passed through each sphere.

  With the Spaceballs results in hand and screen projections of the fine, butterfly-shaped slices of spinal cord that showed the bright lines and dots of the fluorescent-dye-marked connections, the researchers noticed something unexpected: corticospinal connections from the unscathed, unblocked left side of the brain were particularly prominent on the left side of the spinal cord.

  Usually, these same-side neurons are relatively inactive, since they’re competitively overwhelmed by neurons from the larger and more prominent tract that crosses from the other side. But because the crossing neurons had been paralyzed during a critical period of development, the same-side neurons had blossomed and formed a robust set of connections in the atypical environment where they could compete and win.

  Martin’s papers were not going unnoticed by scientists who studied cerebral palsy. Researchers working with children who had CP had found that gentle stimulation of the injured side of the brain using a noninvasive technology called transcranial magnetic stimulation (TMS) elicited minimal resp
onse on the opposite side, owing to the injured brain tissue’s inability to communicate. However, in these same patients, TMS to the uninjured side caused both sides to respond—evidence that the uninjured side of the brain had developed the normal connections to the opposite side in addition to the unusual same-side connections.

  Other experiments showed that learning didn’t happen simply from the brain down; the experience of the limbs mattered too. When researchers injected botulinum toxin (Botox) into the paw of a kitten at the same critical point in development that Martin had paralyzed the rat brain, they saw the same absence of normal connections. Learning depended not only on the repetition of action but also on the receipt of feedback in the form of sensations each time the action was executed successfully. (Of course this is obvious: no one improves his tennis stroke merely by going over it in his mind. But science depends on breaking down results into mechanisms, so these experiments formed the foundation for the critical research that followed.)

  All of these experiments informed Martin’s hypothesis: neurons compete with one another to form connections, a competition that rewards activity and punishes both injury and paralysis. A sort of Darwinism of connections is at work, resulting in profound consequences for therapy.

  When an enthusiastic young resident with a doctorate in neuroscience walked into Martin’s lab looking for a project, Martin and his team were wondering how they could translate their understanding of corticospinal tract development into therapies to treat patients with cerebral palsy and other motor abnormalities.