December 15, 2008
Carl Zimmer

My computer chirps. A new message has arrived. When I click on it, my monitor fills with a picture of my brain. It is cut into 36 horizontal layers, as if someone has run my head through a deli slicer. I study the dark hollow spaces formed by the ventricles, and the furrowed outer edges of the brain, the rind known as the cerebral cortex. For the first time in my life, I can see the billions of neurons in my own brain. I can also see them in action. Each time a neuron unleashes its tiny jolt, it needs to replenish its stores of energy for the next spark. Microscopic blood vessels woven throughout the brain deliver oxygen and nutrients to neurons in need. In the picture on my computer screen, some of those clumps of busy, hungry neurons glow red or yellow. In other words, this is not just a picture of my brain. It is also a picture, of sorts, of my thoughts.

Randy Buckner, PhD, a cognitive neuroscientist at Harvard had e-mailed the picture to me. Four days earlier, I heard Buckner’s voice through an intercom while I lay on a slab, dressed in hospital scrubs, with my body lodged inside a functional magnetic resonance image (fMRI) scanner. A small cage was wrapped around my face, and through the bars I could see a mirror, which reflected a computer monitor at the far end of the shaft. My head was gently held in place by a soft vise. Earplugs blocked some of the hammering and beeping of the machine. It was shooting radio waves through my head to detect the surge of blood flowing inside my brain, feeding the hungry neurons.

I went to Buckner’s lab to get a glimpse of my aging brain. At 42, I can see the outward signs of time in my graying hair and my crow’s-feet, and I know age-related cognitive decline starts in the forties, but it’s hard for me to know what’s going on inside my head. Are my neurons dying off? Is there fraying in the fibers of white matter that connect the different regions of my brain? Are my neurotransmitters failing to swim from neuron to neuron so that I lose thoughts like dropped calls on my cell phone? I do know that names sometimes take longer to come to mind and I can’t work late into the night the way I used to. I wonder if the cognitive fog that comes with age is closing in and if there is anything I can do to prevent it?

Up until recently, the march of neurological time seemed beyond the control of doctors. But that’s beginning to change for two reasons: Neuroscientists recently discovered, to their surprise, that neurons in the adult brain can still grow (a process known as neurogenesis) and that by thinking, learning, and acting, the brain can restructure both its anatomy and physiology (a concept called neuroplasticity). “The discovery that the brain is not a machine, as was thought, but that it is neuroplastic is the most important change in our understanding of the brain in 400 years,” says Norman Doidge, MD, author of The Brain That Changes Itself and a member of the research faculty at the Columbia University Center for Psychoanalytic Training and Research. Furthermore, there is an emerging understanding of how the brain ages, and in particular, how mental sharpness has more to do with how regions of the brain are linked together in circuits than how well the individual parts work. Some observers believe we’re on the cusp of a revolution in brain health similar to the fitness awakening that took place in the 1970s regarding the benefits of running and aerobics.

Neuro-enhancing treatments (drugs, diets, training programs, and workouts) are rapidly becoming mainstream. The demand for brain-stimulation products is sky-rocketing, with sales doubling from $100 million in 2005 to $225 million in 2007. In a recent survey in the journal Nature, 20 percent of scientists said they already take cognitive-boosting drugs such as Provigil (a stimulant created to treat narcolepsy) and Ritalin (a stimulant designed to treat ADHD), not to treat medical conditions, but to help them work more effectively. “It’s a very promising time,” says P. Murali Doraiswamy, MD, chief of the biological psychiatry division at Duke University and author of The Alzheimer’s Action Plan, a memory-fitness guide for the 40-plus man, “but we need to see more clinical evidence that demonstrates the benefits and safety of these kinds of treatments on everyday brain function.” The next generation of cognitive drugs may turn out to be much more powerful because Buckner and other neuroscientists are, for the first time, seeing the brain changes that cause our minds to age. “Randy Buckner’s work is providing critical insights into how brain systems change with aging and disease,” says Daniel Schacter, PhD, a Harvard psychologist and author of The Seven Sins of Memory: How the Mind Forgets and Remembers. Buckner’s work could help lay the foundation for a new kind of treatmentsfor the brain that makes today’s approach look as quaint as a 19th-century leech.

All right, Carl,” says Buckner. His deep voice is rendered faint and crackling by the intercom. He speaks to me from an adjoining room. “I am going to show you a crosshair, and you’re going to stare at it. Try to relax and not think of anything. Keep your head as still as possible. It will only be for six or seven minutes, but it’s going to feel like a long time.” Indeed. I listen to the low thunk of the scanner’s cooling pumps and the alarm-clock whine of coil. The noise pushes through my earplugs like some industrial-rock soundtrack. As I stare at the crosshair, my thoughts drift like flotsam. I run through the questions I want to ask Buckner. I think about the salt marshes and strip malls that flew past my train window that morning. I think about a prospector I once met in Rwanda, holding a nugget of gold he had sieved out of a river. I think of how long six minutes can be.

It might seem like a waste of time for Buckner to take a picture of my brain while I’m not thinking of anything in particular. Shouldn’t I be putting my brain to the test, trying to solve some calculus equation or recall a Shakespearean-sonnet? It turns out that wandering thoughts reveal profound clues about how we age. Buckner and other researchers have found that in our daydreams and downtime, certain parts of our brains are working very hard. This remarkable network helps gives us a sense of who we are, of our past and our future. And as we age, this network deteriorates.

Buckner has scanned his own brain dozens of times. He started scanning his brain when he was 20 years old and designing experiments for his PhD at Washington University in St. Louis. Today, at the age of 38, he has a sobering series of portraits. “I can already see the difference between my brain now and when I started more than 15 years ago,” he tells me after I emerge from the scanner.

Buckner’s brain has visibly shrunk, he explains, but there is nothing wrong with him: Everyone’s brain begins to shrink about 0.2 percent a year starting in his or her early twenties. “These are just normal changes,” says Buckner. He originally became a brain scanner in order to understand memories. He pioneered a new method of capturing snapshots of people’s brains as they thought back to the past. “It allows us to isolate those moments when people are recollecting events from their past,” says Buckner. He and his colleagues went on to show that no one part of the brain is responsible for memory. “You find a very specific network that becomes active when you succeed in remembering something,” says Buckner. “The network is made up of isolated patches of brain scattered from the back of the head to the front. They can work together to summon memories because they are linked by long fibers known as white matter, like computers joined in a high-speed network.”

Buckner soon began to see the memory net-work turn up in other experiments, ones that didn’t seem at first to require people to remember anything. For instance, Schacter and his team asked people to think about things that were going to happen in the future, such as an upcoming graduation. When the people in the study thought ahead, their memory networks lit up. “We do not use our memory systems to think about the past as much as we use them to build models of the future,” says Buckner. “We’re walking prediction machines.”

The same memory network lit up in experiments in which people were asked to think about what other people felt or knew. And most surprisingly, it also became active when people weren’t asked to think about anything at all. When Buckner asked me to stare at the crosshair in his scanner, this same network came to life. “It’s the network we use to think to ourselves,” he says. Scientists now call this network the default network; it’s active when we are not doing something else. “This costs a great deal metabolically,” says Buckner. That cost suggests to Buckner that the default network is doing something very important. “It’s probably one factor that allowed our species to succeed,” he says. “We have this amazing capacity to think of alternatives to what is happening right now. The problem is that you can’t turn it off.”

As Buckner learned more about memories, he turned his attention to the mystery of how we lose them. He was driven by scientific curiosity. . .and self-interest: Alzheimer’s disease runs in his family. An estimated 5.2 million Americans suffer from Alzheimer’s disease, which gradually slows the brain’s processing ability with tangled proteins. Buckner and his colleagues found that these tangled proteins, called amyloid plaques, begin their attacks on the brain within the same default network Buckner’s research identified as being so important to our sense of self. Buckner suspects that the default network becomes vulnerable to plaques because it works so hard. The more a neuron processes signals, the more proteins it has to make. And the more proteins it makes, the more likely it is to make a few defective ones.

Buckner is now trying to tell the difference between normal aging brains and those in the early stages of Alzheimer’s. In a recent experiment, he and his colleagues scanned the healthy brains of people in their early twenties, as well as people in their sixties who have no plaques in their brains and no signs of any sort of dementia. As Buckner and his colleagues reported in the journal Neuron, they found some stark differences between the young brains and the old ones. In young people, all of these networks tend to work together in a tight synchrony. When one part of the network is active, the other parts usually are too. In an older brain, the visual network is still tightly connected, but the default network and the attention network are frayed. If one part of these networks is active, the other parts may be shut down.

“We know that these parts of the brain are not severed; they are talking to one another,” Buckner says. So why aren’t they in sync anymore? Buckner’s research suggests that the white matter that links distant regions of the brain (like the ones in the default network) gradually becomes damaged and can’t relay signals as well. “We’ve identified changes in aging brains that are not on the road to Alzheimer’s. There are separate kinds of deterioration.”

This is an important new insight. A sharp mind is more than just a certain number of neurons; it’s how the neurons work together. If you look at each region in a person’s brain on its own, it may seem in good shape. But those regions have a harder time working together as we get older. Remarkably, though, our brains have the ability to rewire their own networks. When a person loses his eyesight, for example, his brain will connect the visual processing center of the brain to neurons -carrying information from other senses. And Buckner’s own research shows that many people reorganize their brain networks to cope with aging. Just as older athletes use experience and technique to maintain a high level of performance, so the aging brain can be trained to function more efficiently even as it deteriorates physically.

After my scan is finished and I join Buckner, he asks a graduate student, Fenna Krienen, to pull up the previous morning’s scan. It shows the brain of a 60-year-old man. His brain has shrunk so much that I can see a thick black band separating it from the inside of his skull.

“But you know what?” says Buckner. “This guy is still doing very well.”

It’s possible, Buckner speculates, that people who age gracefully have unknowingly reorganized their brain networks. A life of learning–of challenging ourselves to take on new skills, to understand new ideas, to take another small bite of our own ignorance–may encourage this flexibility. Renaissance men had it right. Buckner goes as far as suggesting that 40-year-olds take university courses to fight the effects of aging. Most of us spend our middle years replaying already mastered skills, so we never pay as close attention as we did when we were in middle school trying to learn French vocabulary. The key is to engage the brain in learning activities that demand an intense attention to detail. Like many neuroscientists, he also recommends cardiovascular exercise. People in very good physical shape tend to suffer less effects in their brains from aging, and Buckner thinks he knows why: They can give their brains a greater blood supply, which can shield white matter from damage. As a result, fit people keep their networks more connected. “Having a healthy heart provides support for the brain,” says Buckner.

In years to come, Buckner expects that the research he and others are doing, both in diagnosing and treating the aging brain, will lead to a new era in brain health. Dr. Doraiswamy expects fMRI scans to rate neural networks, and PET scans, which map the buildup of Alzheimer’s-related beta-amyloid plaques in the brain, to become more prevalent within a couple of years. “Initially, they will be for patients with serious memory problems,” he says. “The technology will trickle down in a similar way to how colonoscopies originally were done only on people in their seventies, then in their sixties and fifties, and now they’re done on people in their forties.” Regular fMRI scans may allow doctors to see whether a patient’s brain is experiencing ordinary aging or showing early signs of disease. Dr. Doraiswamy also predicts that doctors will scan the genomes of their patients for genes that make them susceptible to cognitive decline. All this information will help doctors tailor medications to the specific needs of their patients, instead of taking a one-size-fits-all approach.

Dr. Doraiswamy says it’s difficult for pharmacological companies to bring to market drugs that will be used by healthy people (such as cognitive boosters) because of the difficulties in clinically proving how effective the drugs are and the requirements for very low risk. That’s why there is a greater focus on developing drugs to treat Alzheimer’s and its precursor, mild cognitive impairment (MCI). He recently published a review that details how more than 50 proprietary pharmacological products are being developed to treat Alzheimer’s. Simplified somewhat, they break down into two types: drugs that decelerate the pathology of MCI and Alzheimer’s, and drugs that stimulate neurotransmitters.

“There are several plaque-busting anti-amyloid drugs in clinical trials, as well as a couple of anti-tau drugs, which target Alzheimer’s-related tangles,” he says. “If proved effective, these drugs could be prescribed in a similar way to statins, initially to patients with superhigh cholesterol, but eventually to a broader population.”

One biotech company is approaching this problem from a different angle. Accera’s drug Axona is expected to be released as a “medical food” in the spring of 2009. It’s a product that does not occur naturally, manages a disease through diet, and is available by prescription only. Brains suffering from age-associated memory impairment (AAMI) and Alzheimer’s do not effectively metabolize glucose (the brain’s main energy source), resulting in the buildup of plaques. Axona, a first-in-its-class drug, delivers an alternative energy source (in the form of ketones) that the brain can process. It had a positive and clinically meaningful effect on memory in people with AAMI and Alzheimer’s in a 2007 clinical trial. Dr. Doraiswamy expects to see more advanced versions of drugs that stimulate the neurotransmitters in the brain, such as acetylcholine, dopamine, norepinephrine, and glutamate, which could enhance memory and attention. He’s most excited about a third class of drugs called neurotrophics, which mimic the substance in the brain that allows brain cells and networks to flourish. “They’re like fertilizers for the brain,” he says. “The drug companies think neurotrophics could be to the brain what Botox is to the skin, but we’re looking at least 10 years into the future for FDA approval.”

A brain scan like the kind Buckner takes comes in two parts. The first part is quick. The fMRI takes a highly detailed picture of a person’s brain. By the time I’ve finished the tests, put my clothes back on, and joined Buckner and his grad student at the computer, the anatomical scan is done.

“We’re connoisseurs of brains here,” Buckner says jokingly as he inspects the picture. “That’s a good-looking brain.” I don’t take the compliment too much to heart though. Thanks to Buckner, I know there is more to a brain than good looks. I want to know how it works. But in order to add the default network to the picture, Buckner has to finish the second part of the scan. He needs time for his computer to process the data he has just collected. He promises to send me the results within a few days.

I step onto the train at Boston’s South Station and head home. I start thinking about my “good-looking” brain. I’ve tried, with mixed success, to stay physically fit, but I’ve never thought about keeping my brain in shape. I just assumed I was stuck with the particular batch of neurons that fate had put in my head. That resignation was comforting too–who wants responsibility for his own soul, after all? But on the train, I begin to use my brain to wonder how I will take care of my brain. For starters, I’ll run more. And maybe I’ll take a class on statistics, reorganizing my brain to work efficiently as I finally try to understand correlation coefficients and time-series analysis. Years ago, I tried learning Spanish, but somehow I felt as if there were no room left in my head for hundreds of new words. Maybe it’s time to create some room.

The functional images come by e-mail a few days later. “Here are the results of your brain scan,” writes Buckner. “I seeded the posterior core of the default network and, as expected, the anterior portions of the default network are correlated.” In other words, my default network is still tightly linked, like a young brain should be.

The message is a relief, but as I gaze at the slices of my brain, I wonder about the future. Obviously, I hope I never suffer from Alzheimer’s. But if I suffer a gentler decline, should I just chalk it up to being human? Scientists are racing to create drugs that precisely target the default network, keeping it in good working order. Would I take one?

“I certainly would,” Buckner had said to me. “Wouldn’t you?” Buckner’s question led me to contact Judith Illes, a leading thinker in the new field of neuroethics at the University of British Columbia. She warns that we should think very carefully before making brain drugs as regular a part of our lives as vitamins.

“What will be the effect on an older person’s employability?” she asks. Will your boss be able to fire you if you’re over 50 and can’t afford to take mind-enhancing pills? Illes also wonders if we’ll really want to trade the wisdom of old age for a mind on overdrive. “Not remembering is sometimes very adaptive,” she says.

Buckner isn’t so troubled.

“I don’t think there’s an ethical question,” he says. “This is damage to the brain that can be avoided. If we can safely treat these changes, I think we’ll want to. Because it could let us live well and think clearly into our nineties.”

I’m not so sure. Somehow, taking a pill seems like cheating. It’s like using electrodes to build up your muscles as you lie in bed, rather than working out with real weights. It’s bad enough to cheat with your body; to cheat with your mind seems far worse. Of course, I have to admit that I cheat every morning when I drain my bowl-size cup of coffee, infusing my brain with mind-altering caffeine. Perhaps, as brain drugs become more familiar, they won’t bother me either. Maybe if I find out Buckner is living well with a prescription, I’ll find out what that prescription is. In the meantime, I’ll lace up my running shoes and head outside to clear my head–and strengthen my brain.