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The Brain Set Free

Lifting neural constraints could turn back time, making way for youthful flexibility

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11:02am, July 27, 2012
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A baby’s brain is a thirsty sponge, slurping up words, figuring out faces and learning which foods are good and bad to eat. Information about the world flooding into a young brain begins to carve out traces, like rushing water over soft limestone. As the outside world sculpts the growing brain, important connections between nerve cells become strong rivers, while smaller unused tributaries quietly disappear.

In time, these brain connections crystallize, forming indelible patterns etched into marble. Impressionable brain systems that allowed a child to easily learn a language, for instance, go away, abandoned for the speed and strength that come with rigidity. In a fully set brain, signals fly around effortlessly, making common­place tasks short work. A master of efficiency, the adult brain loses the exuberance of childhood.

But the adult brain need not remain in this petrified state. In a feat of neural alchemy, the brain can morph from marble back to limestone.

The potential for this metamorphosis has galvanized scientists, who now talk about a mind with the power to remake itself. In the last few years, researchers have found ways to soften the stone, recapturing some of the lost magic of a young brain.

“There’s been a very, very significant change,” says Richard Davidson of the University of Wisconsin–Madison. “I don’t think the import of that basic fact has fully expressed itself.”

Though this research is still in its early stages, studies suggest techniques that dissolve structures that pin brain cells in place, interrupt molecular stop signals and tweak the rush of nerve cell activity can restore the brain’s youthful glow. Scientists are already attempting to reverse brain rigidity, boosting what’s known as “plasticity” in people with a vision disorder once thought to be irreversible in adults.

These efforts are not an exercise in neural vanity. A malleable brain, researchers hope, can heal after a stroke, combat the decline in vision that comes with old age and perhaps even repair a severed spinal cord. An end to childhood — and the prodigal learning that comes with it — does not need to eliminate the brain’s capacity for change. “There are still windows of opportunity out there,” says neuroscientist Daphné Bavelier of the University of Rochester in New York. “It may require a little more work to open them, though.”

Prying at windows

Research aimed at restoring the brain’s youthful flexibility is leading to a more nuanced view of findings from the 1960s. In experiments that won them the Nobel Prize in physiology or medicine, David Hubel and Torsten Wiesel discovered that sealing shut a kitten’s eye for a period during the early stage of life would leave the animal unable to see normally out of that eye. If the opposite eye were then patched, forcing the underdeveloped eye to work, the kitten could recover, scientists later discovered. This patch fix worked only on a young animal, suggesting there was a finite window of time during which the brain could rewire itself.

Humans have this window of opportunity, too. During what scientists call a “critical period,” nerve cells in the brain can forge new connections, sprouting tendrils that carry messages to other cells. Children with amblyopia, a condition in which one eye is weaker than the other, can be cured with a patch over the strong eye, which forces the brain to rewire incoming information from the stunted eye. In adulthood, the exact same treatment is useless. By figuring out why this period ends, and why other forms of flexibility are also lost, researchers think they might be able to bring the brain’s healing power back.

Some of the more obvious players ushering in an end to brain plasticity are structures that literally pin nerve cells in place. One is a tight mesh straitjacket — with the texture of cartilage — that surrounds a nerve cell and restricts the formation of new connections in the brain. Called perineuronal nets, these webs show up early in life to stabilize most nerve cells in the brain and spinal cord.

Manipulating these perineuronal nets might be a way to “return people to a childlike state,” in which rapid learning or recovery can happen, says neuroscientist James Fawcett of the University of Cambridge in England.

Unlike in Hubel and Wiesel’s animals, whose visual deficits were locked in once adulthood arrived, the visual systems of mice with abnormal or missing perineuronal nets retained the ability to be sculpted, Fawcett and colleagues have found. These nets may hem in neurons by calling in particular molecules, perhaps ones that stymie new nerve cell connections, Fawcett and Difei Wang, also at Cambridge, wrote in the July Cell and Tissue Research.

Another impediment to malleability comes from a fatty substance called myelin, which winds around neurons’ information-sending axons like insulation around an electrical wire, speeding messages along. With this speed comes less flexibility, as the myelin holds nerve cell fibers in place. Wresting myelin off of nerve cells restores plasticity in mice, neuroscientist Takao Hensch at Boston Children’s Hospital and colleagues have shown.

Besides its physical constraints, myelin also releases repressive signals. One, a protein called ephrin-B3, holds axons back, Stephen Strittmatter of Yale School of Medicine and colleagues reported in the March 27 Proceedings of the National Academy of Sciences. Removing ephrin-B3 allowed axons to grow much more than those in normal mice after an injury.

Other myelin-related proteins are known to squash new nerve cell connections. One is the downer protein NoGo. When a neuron detects NoGo, it kicks off a series of changes that prevent the growth of new connections. If NoGo detector proteins are eliminated, nerve cells become extra active and primed for growth.

Already, results from various studies have pushed scientists to stop talking about cut-and-dry “critical” periods, but rather, “sensitive” ones. The brain can be coaxed into changing, even in adulthood. 

Behavior revisited

While some researchers are overcoming physical barriers that swaddle nerve cells and stunt new growth, others recognize an easier path to malleability: manipulating nerve cell behavior to make cells more or less likely to fire off messages. “Changing the structure is hard, but changing function is possible,” says vision scientist Dennis Levi of the University of California, Berkeley.

Rather than relocating the concrete walls of a stone canal, the functional approach alters the speed of water moving through that canal. One architecture can sustain either a rushing stream or a trickle.

Hensch and his colleagues started with a hunt for substances in the brain that were scarce during early life but abundant as brain wiring windows closed. The protein lynx1 popped out. (Its molecular makeup resembles an active molecule in snake venom.) Mice genetically engineered to lack lynx1 spontaneously recover from early vision problems, retaining a malleable brain long into adulthood, Hensch and his team reported in Science in 2010.

Normally, lynx1 puts a damper on certain nerve cells’ excitability, a job that helps the brain maintain the proper flow rate of nerve cell activity. In a balancing act, the brain is poised between too much activity (excited) and too little (inhibited). By muffling certain cells, lynx1 holds the adult brain to a status quo, called the excitatory/inhibitory balance. But lose lynx1, and the brain shifts toward a more excited, and more malleable, state.

“You can pursue all of the molecules,” Hensch says. “What’s exciting is that they all converge on the excitatory/inhibitory balance.”

Neuroscientist Alessandro Sale of the Institute of Neuroscience CNR in Italy thinks that this balancing act may explain many of his team’s results in adult rats. Over the last several years, Sale and colleagues have reported a growing number of situations that can repattern the adult rat’s visual system: Exercise, living in a stimulating environment, starvation and even doses of Prozac, which caused certain nerve cells to become more active, all reinstated a brain with more youthful behavior.

“At the very beginning, I was surprised that many different noninvasive strategies were able to elicit plasticity in the adult brain in such a powerful way,” Sale says. But after looking closely, his team believes that the procedures all alter the flood of messages that nerve cells send.

Although many of these detailed experiments in animals test the visual system, the same general principles might underlie other brain systems, Sale says. Of course, the real goal of this work is not to make blind rats see again, but to help people retrain their brains.

Help for humans

Preliminary studies in people hint that the excitatory/inhibitory balance is important for many aspects of a healthy brain. People with Down syndrome, Alzheimer’s disease and even spinal cord injuries may have out-of-whack balances, studies suggest. Though there’s no really good way to see how nerve cells in a live human brain behave, some training techniques (like those used by Sale in rats) do appear to resculpt the adult mind.

In some ways, the idea that experiences shape the brain is obvious to anyone who has ever learned anything. Playing the guitar, leisurely swinging golf clubs and driving a taxi in London for years all mold the adult brain, some more dramatically than others. Just two hours of playing a racing video game changed the structure of volunteers’ brains, researchers reported in the March 22 Neuron. Similar processes are at the core of products that promise to boost cognitive powers (though many of these brain-training regimes have yet to be validated).

“We are continuously being exposed to the environment, and those things that impinge upon us are continuously shaping our brains,” Davidson says. So the question isn’t so much whether something can change the brain, but rather, how people can take charge of the process for a desired outcome.

Studies by Levi and his collaborators have found that a certain kind of vision practice can actually help adults see better. Hours of difficult vision training, in which people had to discern hazy lines, for instance, improved vision in people with amblyopia, normal vision and even normal age-related vision decline. People could see sharper images, detect contrasts better and even read small letters faster.

Older people’s eyes still sent blurry information to their brain, but the brains were better equipped to handle it, Levi and colleagues wrote in Scientific Reports. Levi believes that the improvement comes from a training-enhanced ability to pay attention to relevant information and ignore the blurred distractions.

There may be a more fun way. Data from Bavelier support a counterintuitive idea: Mindless video games actually make the brain sharper. Action-packed video games like Call of Duty 2 seem to enhance people’s perception, and not just in ways required to get a high score. “You get benefits that ripple,” Bavelier says.

After logging hours at the games, people were better at nimbly switching between two demanding jobs and quickly determining whether a number is even or odd. The results, reported in May in Computers in Human Behavior, suggest that this kind of brain training reopens a window. “What really changes is the ability to locate resources and ignore distractions,” Bavelier says.

Flexibility too far

Efforts toward restoring plasticity hold great promise, but only when targeted to hit particular brain systems. If not, the potential benefits come with some strong caveats. “I’m very scared of taking off the brakes,” Hensch says. “They’re there for a reason.”

Myelin insulation on nerve cells, for instance, is damaged in patients with multiple sclerosis. That damage affects the conduction of nerve impulses, leading to the hallmark symptoms of the disease.

In Hensch’s lab, the mice genetically engineered to lack lynx1 protein show dementia-like damage in their brains earlier than their normal counterparts. “After nine months, you see holes in cortex,” Hensch says. Parts of the brain that are damaged earliest are the most malleable throughout life. “Maybe the price we pay for plasticity is the susceptibility to neurodegeneration.”

Brakes may also help the brain know what not to learn. Extremely proficient musicians have reported a rare condition in which neural pathways become so shaped by playing music that the performers’ brains fuse the control regions for separate fingers, and the ability to cleanly pluck a single string is lost.

Likewise, too much malleability could play a role in inappropriate fear or anxiety. It would be bad if people learned to associate a strong emotional response with every negative situation encountered in daily life. “If our brains exhibited plasticity for all of those kinds of cues, it would likely elicit anxiety disorders in the entire population,” says Davidson.

Researchers attribute such concerns to what they call the double-edged sword of plasticity: “A system capable of such flexible reorganization harbors the risk of unwanted change,” Alvaro Pascual-Leone of Harvard Medical School and colleagues wrote in 2005 in Annual Reviews of Neuroscience.

For now, scientists are proceeding cautiously, still in the discovery phase. But their studies may ultimately lead to ways to let the right signals rush in and sculpt a readily accepting brain. For the first time, Davidson says, “we can actually take more responsibility for the shaping of our own brains.”

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