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EXERCISE AND THE BRAIN

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Prescribing Exercise to Treat DepressionBy GRETCHEN REYNOLDS

August 31, 2011

Can a stroll help ease depression? That question preoccupied Dr. Madhukar H. Trivedi, a

professor of psychiatry at the University of Texas Southwestern Medical Center in Dallas,

after several of his patients, all suffering from serious depression, mentioned that they felt

happier if they went for a walk. The patients in question were taking the widely

prescribed antidepressants known as S.S.R.I.’s, for selective serotonin reuptake

inhibitors, but not responding fully. They remained, by clinical standards, depressed. Dr.

Trivedi and his colleagues began to wonder if adding a formal “dose” of exercise would

increase their chances of getting better.

Certainly the possibility was worth investigating. Clinical depression, as anyone

who has experienced or watched a loved one struggle with the condition knows, can be

stubbornly intractable. Even if patients have been taking an antidepressant for months,

recovery rates tend to hover below 50 percent.

In order to increase the odds of improvement, doctors frequently add a second

treatment — often another drug, like lithium or an antipsychotic — to the S.S.R.I.

regimen at some point, Dr. Trivedi said. Most patients ultimately require at least two

concurrent treatments to achieve remission of their depression, he said. Studies have

shown that these secondary drug treatments help an additional 20 to 30 percent of

depressed patients to improve, but the medications can be expensive and have unpleasant

side effects.

Which prompted Dr. Trivedi to look to exercise. His investigation joins a growing

movement among some physiologists and doctors to consider and study exercise as a

formal medicine, with patients given a prescription and their progress monitored, as it

would be if they were prescribed a pill.

In this case, Dr. Trivedi and his collaborators, who included researchers at the

Cooper Institute in Dallas, the Pennington Biomedical Research Center in Louisiana and

other institutions, recruited 126 people with depression who had been using S.S.R.I.’s for

a minimum of two months, without achieving remission. None of the patients exercised.

Dr. Trivedi and his colleagues divided these volunteers into two groups. One began

a gentle aerobic exercise routine, under the tutelage of Cooper Institute researchers,

which required them to burn a certain amount of calories per session, depending on their

weight. How the subjects expended the energy was up to them. Some walked for about 10

minutes a day, on a treadmill or by strolling around the block, at a pace of three miles an

hour. Others chose an equivalent easy cycling workout.

The second group was more energetic, walking briskly for about 30 minutes a day at

a pace of four miles an hour, or the cycling equivalent, a regimen that meets the current

exercise recommendations from the American College of Sports Medicine.

Each volunteer exercised for four months, while continuing to take an

antidepressant. At the end of that time, according to the study published recently in The

Journal of Clinical Psychiatry, 29.5 percent had achieved remission, “which is a very

robust result,” Dr. Trivedi said, equal to or better than the remission rates achieved using

drugs as a back-up treatment. “I think that our results indicate that exercise is a very valid

treatment option” for people whose depression hasn’t yielded to S.S.R.I.’s, he said.

As with most scientific findings, though, there are caveats.

One is practical. More patients improved in the group that completed the longer,

brisker workouts than in the group assigned the easier exercise, but more of them also

dropped out of the study. “We need to find ways to support people’s efforts to exercise,”

Dr. Trivedi said. “It’s not going to be enough to casually say, ‘Go for a walk.’” Exercise,

if it’s to be medicinal in depression treatments, will have to be monitored, he said, so it

can’t be shrugged off.

Even then, many people will not respond. Almost 70 percent of the volunteers in

this study did not achieve full remission. Failure rates were particularly high for women

with a family history of depression, perhaps as a result of some as yet unknown genetic

quirk. And women in that group who did recover were more likely to succeed using the

lighter exercise program than the more strenuous routine.

Then there is the issue of a control group, whose members would have continued

with their S.S.R.I.’s but not exercised. This study did not have one, making interpreting

the results tricky, said James A. Blumenthal, a professor of psychology and neuroscience

at Duke University who was not involved with this study but who has written extensively

about exercise and depression. Perhaps four additional months of S.S.R.I. treatment

raised people’s moods, and the exercise was incidental. “Evidence is accumulating that

exercise may be an effective treatment for depressed patients who are receptive to

exercise as a possible treatment and who are able to safely engage in exercise,” he said.

But the evidence is by no means definitive.

Still, Dr. Trivedi said, although additional studies certainly are needed, there’s no

reason for people with unyielding depression not to talk now with their doctors about

exercise as a treatment option. “Side effects are almost nonexistent,” he said, “while you

get additional benefits, in terms of improvements in cardiovascular health and reductions

in other disease risks,” things antidepressant drugs do not provide. “Plus,” he pointed out,

“the cost profile is very favorable.” Exercise, as medicines go, is cheap.

How Exercise Can Strengthen the BrainBy GRETCHEN REYNOLDS

September 28, 2011

Can exercise make the brain more fit? That absorbing question inspired a new study at

the University of South Carolina during which scientists assembled mice and assigned

half to run for an hour a day on little treadmills, while the rest lounged in their cages

without exercising.

Earlier studies have shown that exercise sparks neurogenesis, or the creation of

entirely new brain cells. But the South Carolina scientists were not looking for new cells.

They were looking inside existing ones to see if exercise was whipping those cells into

shape, similar to the way that exercise strengthens muscle.

For centuries, people have known that exercise remodels muscles, rendering them

more durable and fatigue-resistant. In part, that process involves an increase in the

number of muscle mitochondria, the tiny organelles that float around a cell’s nucleus and

act as biological powerhouses, helping to create the energy that fuels almost all cellular

activity. The greater the mitochondrial density in a cell, the greater its vitality.

Past experiments have shown persuasively that exercise spurs the birth of new

mitochondria in muscle cells and improves the vigor of the existing organelles. This

upsurge in mitochondria, in turn, has been linked not only to improvements in exercise

endurance but to increased longevity in animals and reduced risk for obesity, diabetes and

heart disease in people. It is a very potent cellular reaction.

Brain cells are also fueled by mitochondria. But until now, no one has known if a

similar response to exercise occurs in the brain.

Like muscles, many parts of the brain get a robust physiological workout during

exercise. “The brain has to work hard to keep the muscles moving” and all of the bodily

systems in sync, says J. Mark Davis, a professor of exercise science at the Arnold School

of Public Health at the University of South Carolina and senior author of the new mouse

study, which was published last month in The Journal of Applied Physiology. Scans have

shown that metabolic activity in many parts of the brain surges during workouts, but it

was unknown whether those active brain cells were actually adapting and changing.

To see, the South Carolina scientists exercised their mice for eight weeks. The

sedentary control animals were housed in the same laboratory as the runners to ensure

that, except for the treadmill sessions, the two groups shared the same environment and

routine.

At the end of the two months, the researchers had both groups complete a run to

exhaustion on the treadmill. Not surprisingly, the running mice displayed much greater

endurance than the loungers. They lasted on the treadmills for an average of 126 minutes,

versus 74 minutes for the unexercised animals.

More interesting, though, was what was happening inside their brain cells. When the

scientists examined tissue samples from different portions of the exercised animals’

brains, they found markers of upwelling mitochondrial development in all of the tissues.

Some parts of their brains showed more activity than others, but in each of the samples,

the brain cells held newborn mitochondria.

There was no comparable activity in brain cells from the sedentary mice.

This is the first report to show that, in mice at least, two months of exercise training

“is sufficient stimulus to increase mitochondrial biogenesis,” Dr. Davis and his co-

authors write in the study.

The finding is an important “piece in the puzzle implying that exercise can lead to

mitochondrial biogenesis in tissues other than muscle,” says Dr. Mark Tarnopolsky, a

professor of medicine at McMaster Children’s Hospital, who was not involved with this

experiment but has conducted many exercise studies.

The mitochondrial proliferation in the animals’ brains has implications that are

wide-ranging and heartening. “There is evidence” from other studies “that mitochondrial

deficits in the brain may play a role in the development of neurodegenerative diseases,”

including Alzheimer’s and Parkinson’s diseases, Dr. Davis says. Having a larger reservoir

of mitochondria in your brain cells could provide some buffer against those conditions, he

says.

Dr. Tarnopolsky agrees. “Epidemiological studies show that long-term runners have

a lower risk of neurological disease,” he points out.

More immediately, Dr. Davis speculates, re-energized brain cells could behave like

mitochondrial-drenched muscle cells, becoming more resistant to fatigue and, since

bodily fatigue is partly mediated by signals from the brain, allowing you to withstand

more exercise. In effect, exercising the body may train the brain to allow you to exercise

more, amplifying the benefits.

Revitalized brain cells also, at least potentially, could reduce mental fatigue and

sharpen your thinking “even when you’re not exercising,” Dr. Davis says.

Of course, this experiment was conducted with animals, and “mouse brains are not

human brains,” Dr. Davis says. “But,” he continues, “since mitochondrial biogenesis has

been shown to occur in human muscles, just as it does in animal muscles, it is a

reasonable supposition that it occurs in human brains.”

Best of all, the effort required to round your brain cells into shape is not daunting. A

30-minute jog, Dr. Davis says, is probably a good human equivalent of the workout that

the mice completed.

How Exercise Benefits the BrainBy GRETCHEN REYNOLDS

November 30, 2011

To learn more about how exercise affects the brain, scientists in Ireland recently asked a

group of sedentary male college students to take part in a memory test followed by

strenuous exercise.

First, the young men watched a rapid-fire lineup of photos with the faces and names

of strangers. After a break, they tried to recall the names they had just seen as the photos

again zipped across a computer screen.

Afterward, half of the students rode a stationary bicycle, at an increasingly strenuous

pace, until they were exhausted. The others sat quietly for 30 minutes. Then both groups

took the brain-teaser test again.

Notably, the exercised volunteers performed significantly better on the memory test

than they had on their first try, while the volunteers who had rested did not improve.

Meanwhile, blood samples taken throughout the experiment offered a biological

explanation for the boost in memory among the exercisers. Immediately after the

strenuous activity, the cyclists had significantly higher levels of a protein known as brain-

derived neurotrophic factor, or BDNF, which is known to promote the health of nerve

cells. The men who had sat quietly showed no comparable change in BDNF levels.

For some time, scientists have believed that BDNF helps explain why mental

functioning appears to improve with exercise. However, they haven’t fully understood

which parts of the brain are affected or how those effects influence thinking. The Irish

study suggests that the increases in BDNF prompted by exercise may play a particular

role in improving memory and recall.

Other new studies have reached similar conclusions, among both people and

animals, young and old. In one interesting experiment published last month, Brazilian

scientists found that after sedentary elderly rats ran for a mere five minutes or so several

days a week for five weeks, a cascade of biochemical processes ignited in the memory

center of their brains, culminating in increased production of BDNF molecules there. The

old, exercised animals then performed almost as well as much younger rats on rodent

memory tests.

Another animal study, this one performed by researchers in the Brain Injury

Research Center at the University of California, Los Angeles, and published in September

in the journal Neuroscience, showed that if adult rats were allowed to run at will for a

week, the memory center of their brains afterward contained more BDNF molecules than

in sedentary rats, and teemed with a new population of precursor molecules that

presumably would soon develop into fully functioning BDNF molecules.

Perhaps the most inspiring of the recent experiments is one involving aging human

pilots. For the experiment, published last month in the journal Translational Psychiatry,

scientists at Stanford University School of Medicine asked 144 experienced pilots ages 40

to 65 to operate a cockpit simulator three separate times over the course of two years.

For all of the pilots, performance declined somewhat as the years passed. A similar

decline with age is common in all of us.

Many people find it more difficult to perform skilled tasks — driving an

automobile, for instance — as they grow older, says Dr. Ahmad Salehi, an associate

professor of psychiatry and behavioral sciences at Stanford and lead author of the study.

But in this case, the decline was especially striking among one particular group of

men. These aging pilots carried a common genetic variation that is believed to reduce

BDNF activity in their brains. The men with a genetic tendency toward lower BDNF

levels seemed to lose their ability to perform complicated tasks at almost double the rate

of the men without the variation.

While the pilot experiment wasn’t an exercise study, it does raise the question of

whether strenuous exercise could slow such declines by raising BDNF levels, thereby

salvaging our ability to perform skilled manual tasks well past middle age.

“So many studies have shown that exercise increases levels of BDNF,” says Dr.

Salehi. While he notes that other growth factors and body chemicals are “upregulated” by

exercise, he believes BDNF holds the most promise.

“The one factor that shows the fastest, most consistent and greatest response is

BDNF,” he says. “It seems to be key to maintaining not just memory but skilled task

performance.”

Dr. Salehi plans next to examine the exercise histories of the pilots, to see whether

those with the gene variant, which is common among people of European or Asian

backgrounds, respond differently to workouts.

In people who have the variant and less BDNF activity, “exercise is probably even

more important,” he says. “But for everyone, the evidence is very, very strong that

physical activity will increase BDNF levels and improve cognitive health.”

Exercising an Aging BrainBy DENISE GRADY

March 7, 2012

More and more retired people are heading back to the nearest classroom — as students

and, in some cases, teachers — and they are finding out that school can be lovelier the

second time around. Some may be thinking of second careers, but most just want to keep

their minds stimulated, learn something new or catch up with a subject they were always

curious about but never had time for.

For many, at least part of the motivation is based on widespread reports that

exercising the brain may preserve it, forestalling mental decline and maybe even

Alzheimer’s disease and other types of dementia.

Is there any truth to it? And if there is, what type of learning is best suited to the

older brain?

Many studies do find that being mentally active is associated with a lower risk of

Alzheimer’s disease. But the standard caveat applies: association does not prove cause

and effect, and there is always the chance that the mentally active people who never got

Alzheimer’s simply had healthier brains to begin with.

Even, so, researchers say, there is no harm in telling people to try to stay engaged.

“When you and I are having this conversation, you’re taking notes, thinking,

remembering pieces of it, trying to relate it to other things,” said Arthur Toga, a professor

of neurology and director of the laboratory of neuroimaging at the University of

California, Los Angeles. “You’re changing the circuitry in your brain. That is because

you have changed something in your brain to retain that memory.”

Dr. Toga elaborated: “The conversation requires nerve cells in the brain to fire, and

when they fire they are using energy. More oxygen and sugar must be delivered, by

increased blood flow to those regions.

“Why would that be good? If you are vasodilating, delivering more blood to certain

regions of the brain, that is important. It increases the longevity and the health of those

circuits. In adults, if I ask you to perform tasks you’ve never done before, the amount of

brain it takes for you to try and do it is far greater than the amount of brain it takes for

you to do something you’re already good at. So yes, exercising the brain is good.”

Playing video games probably qualifies as a type of brain exercise, he said, though older

people might not sharpen their skills as fast as younger ones do.

But Dr. Toga warned that while using the brain might help avert some of the mental

slowing that normally comes with aging, it had its limits. “I do not believe that it

forestalls degenerative disease, however,” he said. “That’s a different process.” There is a

“little bit of snake oil,” he added, in the various products and programs that are being

marketed with the implied promise that they will ward off Alzheimer’s disease.

But research continues. Dr. William Jagust, a professor of public health and

neuroscience at the University of California, Berkeley, said there were two main theories

that tried to explain why exercising the brain might make it more resistant to disease.

One is the “cognitive reserve” theory, which says that if the brain is in the best

possible shape with extensive neuronal connections from being used a lot, it may be able

to withstand the onset of Alzheimer’s disease for a while and symptoms may take longer

to develop.

A hallmark of Alzheimer’s is deposits in the brain of an abnormal form of a protein

called amyloid.

“A paper we published showed that people who were more cognitively active over

their whole life span had less amyloid,” Dr. Jagust said.

Animal research, he said, shows that neural activity actually releases amyloid into

the brain. How, then, could mentally active people have less amyloid?

“My interpretation is that people who are more cognitively active have more

efficient brains,” Dr. Jagust said. “What seems to happen in aging is that older people

seem to have less efficient brains.” A scan of brain activity on a 20-year-old being asked

to remember something will show less activity needed than in an 80-year-old asked to

perform the same task.

“Older people seem to activate or bring on line brain areas that young people don’t

use,” Dr. Jagust said. “They have to work their brains harder. So people who stay

cognitively active may use their brains more efficiently.”

That way, they may generate fewer amyloid deposits. But he emphasized that being

mentally active throughout life — not just in old age — was what mattered.

“It has to do with lifelong patterns of behavior,” Dr. Jagust said. “We tend to focus

on what people do at 75 in terms of dementia. But there is more evidence that what you

do in your life, at 40 or 50, is probably more important.”

Nonetheless, Dr. Jagust acknowledged, “this is all theoretical.”

As to what kinds of things older people tend to be best at learning, the researchers

said there were no hard and fast rules. Memory usually does diminish, even in people

who do not have dementia, and reaction time slows.

“You’re not going to learn to hit a fastball,” Dr. Jagust said.

Over time, he said, the best-preserved abilities seem to involve vocabulary and

knowledge about the world, what researchers call “crystallized intelligence.” Problem-

solving and math ability, part of “fluid intelligence,” do not seem to stick as well.

The slippage in memory may make it tough to learn a new language. But people

who already know more than one language may be more adept than others, because the

process of learning different rules of syntax and grammar, especially early in life, seems

to program extra skills into the brain, ones that people appear to retain.

Dr. Toga said that the sensorimotor parts of the brain that control the senses and

muscle movement did not tend to shrink later in life the way the cognitive centers did. So

in theory, learning physical skills like dancing ought to come easily. But nature can be

cruel: where the brain is strong, the flesh may be weak. Failing eyesight and hearing,

weakened muscles and stiff joints may all sabotage the signals the brain needs to

choreograph smooth moves on the dance floor.

“Everything is sliding downward, unfortunately,” he said, laughing.

But it is still a good idea to try something new.

“A variety of things is important,” Dr. Toga said. “We try to encourage people to do

certain things because it couldn’t hurt and may be good. Retaining lots of social

interaction is really important. It involves so much of the brain. You have to interpret

facial expressions and understand new concepts. If you want to learn to ride a monocycle

or do acrobatics at 75, it’s probably not a good idea. But exercising more geography in

the brain, I think that’s important.”

Columbia University has had a program for “lifelong learners” since 1986. About

200 participants take regular Columbia courses. They are expected to keep up with the

reading, but there are no term papers, homework, exams or grades.

The older students tend toward history courses, renowned professors and language

classes that they hope will help in their travels.

“A lot of the time, when seniors are in history classes, specially if it’s relevant to the

topic, they are often used by professors as sort of experts to give testimony to events that

actually occurred during a certain period,” said Kristine Billmyer, the dean and a

professor at Columbia’s school of continuing education. “That’s pretty cool, and I think

it’s something that’s highly valued by the students as well as the faculty.”

Programs geared to older people also exist at many other colleges and universities.

An organization based in California, the Bernard Osher Foundation, supports lifelong

learning programs at 117 colleges and universities, at least one in every state, based on

the idea that many older students go back to school for the joy of learning.

One of the largest programs for retirees is at the University of Wisconsin, Green

Bay (it is not associated with Osher). Called Learning in Retirement, it is sponsored by

the university, with more than 1,000 members and more than 240 courses a year. Classes

— mostly short, a few two-hour sessions — include painting, jazz, travel, eBay,

osteoarthritis, Zumba, the periodic table, the history of the earth, building with straw

bales and “motorcycling and aging awareness.” Most require no outside reading,

homework or exams. Some are taught by college faculty, some by members of the group

or others in the community.

Michael W. Murphy, who spent more than 30 years as an English professor, said

this program had brought him some of the greatest joy he had experienced in the

classroom. Since 2001, when he stepped down from his post as acting dean at the

university, he has been teaching poetry and other subjects to Learning in Retirement

members. It is an unpaid position.

“I’ve always enjoyed teaching, and the idea of teaching without having to read

papers, correct tests and worst of all, give out grades, was really appealing,” Dr. Murphy

said.

To his delight, the students actually want to be there. They take the time to tell him

how much they appreciate him and sometimes even break into applause after his lectures.

One of his courses filled a hall with seats for 120 and had 130 more people on the waiting

list. The students include doctors, lawyers, professors and high-school dropouts, who

have all been around the block a few times, and every so often someone challenges him

— a kind of mental jousting he enjoys.

“The biggest problem I had teaching 18-year-olds was a kind of general apathy,” Dr.

Murphy said. “They were looking forward to a career in high finance and I was trying to

teach them to appreciate Tennyson. The fact that these people show up, and toddle in or

waddle in, some with their walkers or wheelchairs, it’s heartwarming.”

How Exercise Could Lead to a BetterBrainBy GRETCHEN REYNOLDS

April 18, 2012

The value of mental-training games may be speculative, as Dan Hurley writes in his

article on the quest to make ourselves smarter, but there is another, easy-to-achieve,

scientifically proven way to make yourself smarter. Go for a walk or a swim. For more

than a decade, neuroscientists and physiologists have been gathering evidence of the

beneficial relationship between exercise and brainpower. But the newest findings make it

clear that this isn’t just a relationship; it is the relationship. Using sophisticated

technologies to examine the workings of individual neurons — and the makeup of brain

matter itself — scientists in just the past few months have discovered that exercise

appears to build a brain that resists physical shrinkage and enhance cognitive flexibility.

Exercise, the latest neuroscience suggests, does more to bolster thinking than thinking

does.

The most persuasive evidence comes from several new studies of lab animals living

in busy, exciting cages. It has long been known that so-called “enriched” environments

— homes filled with toys and engaging, novel tasks — lead to improvements in the

brainpower of lab animals. In most instances, such environmental enrichment also

includes a running wheel, because mice and rats generally enjoy running. Until recently,

there was little research done to tease out the particular effects of running versus those of

playing with new toys or engaging the mind in other ways that don’t increase the heart

rate.

So, last year a team of researchers led by Justin S. Rhodes, a psychology professor

at the Beckman Institute for Advanced Science and Technology at the University of

Illinois, gathered four groups of mice and set them into four distinct living arrangements.

One group lived in a world of sensual and gustatory plenty, dining on nuts, fruits and

cheeses, their food occasionally dusted with cinnamon, all of it washed down with

variously flavored waters. Their “beds” were colorful plastic igloos occupying one corner

of the cage. Neon-hued balls, plastic tunnels, nibble-able blocks, mirrors and seesaws

filled other parts of the cage. Group 2 had access to all of these pleasures, plus they had

small disc-shaped running wheels in their cages. A third group’s cages held no

embellishments, and they received standard, dull kibble. And the fourth group’s homes

contained the running wheels but no other toys or treats.

All the animals completed a series of cognitive tests at the start of the study and

were injected with a substance that allows scientists to track changes in their brain

structures. Then they ran, played or, if their environment was unenriched, lolled about in

their cages for several months.

Afterward, Rhodes’s team put the mice through the same cognitive tests and

examined brain tissues. It turned out that the toys and tastes, no matter how stimulating,

had not improved the animals’ brains.

“Only one thing had mattered,” Rhodes says, “and that’s whether they had a running

wheel.” Animals that exercised, whether or not they had any other enrichments in their

cages, had healthier brains and performed significantly better on cognitive tests than the

other mice. Animals that didn’t run, no matter how enriched their world was otherwise,

did not improve their brainpower in the complex, lasting ways that Rhodes’s team was

studying. “They loved the toys,” Rhodes says, and the mice rarely ventured into the

empty, quieter portions of their cages. But unless they also exercised, they did not

become smarter.

Why would exercise build brainpower in ways that thinking might not? The brain,

like all muscles and organs, is a tissue, and its function declines with underuse and age.

Beginning in our late 20s, most of us will lose about 1 percent annually of the volume of

the hippocampus, a key portion of the brain related to memory and certain types of

learning.

Exercise though seems to slow or reverse the brain’s physical decay, much as it does

with muscles. Although scientists thought until recently that humans were born with a

certain number of brain cells and would never generate more, they now know better. In

the 1990s, using a technique that marks newborn cells, researchers determined during

autopsies that adult human brains contained quite a few new neurons. Fresh cells were

especially prevalent in the hippocampus, indicating that neurogenesis — or the creation

of new brain cells — was primarily occurring there. Even more heartening, scientists

found that exercise jump-starts neurogenesis. Mice and rats that ran for a few weeks

generally had about twice as many new neurons in their hippocampi as sedentary animals.

Their brains, like other muscles, were bulking up.

But it was the ineffable effect that exercise had on the functioning of the newly

formed neurons that was most startling. Brain cells can improve intellect only if they join

the existing neural network, and many do not, instead rattling aimlessly around in the

brain for a while before dying.

One way to pull neurons into the network, however, is to learn something. In a 2007

study, new brain cells in mice became looped into the animals’ neural networks if the

mice learned to navigate a water maze, a task that is cognitively but not physically taxing.

But these brain cells were very limited in what they could do. When the researchers

studied brain activity afterward, they found that the newly wired cells fired only when the

animals navigated the maze again, not when they practiced other cognitive tasks. The

learning encoded in those cells did not transfer to other types of rodent thinking.

Exercise, on the other hand, seems to make neurons nimble. When researchers in a

separate study had mice run, the animals’ brains readily wired many new neurons into the

neural network. But those neurons didn’t fire later only during running. They also lighted

up when the animals practiced cognitive skills, like exploring unfamiliar environments. In

the mice, running, unlike learning, had created brain cells that could multitask.

Just how exercise remakes minds on a molecular level is not yet fully understood,

but research suggests that exercise prompts increases in something called brain-derived

neurotropic factor, or B.D.N.F., a substance that strengthens cells and axons, fortifies the

connections among neurons and sparks neurogenesis. Scientists can’t directly study

similar effects in human brains, but they have found that after workouts, most people

display higher B.D.N.F. levels in their bloodstreams.

Few if any researchers think that more B.D.N.F. explains all of the brain changes

associated with exercise. The full process almost certainly involves multiple complex

biochemical and genetic cascades. A recent study of the brains of elderly mice, for

instance, found 117 genes that were expressed differently in the brains of animals that

began a program of running, compared with those that remained sedentary, and the

scientists were looking at only a small portion of the many genes that might be expressed

differently in the brain by exercise.

Whether any type of exercise will produce these desirable effects is another

unanswered and intriguing issue. “It’s not clear if the activity has to be endurance

exercise,” says the psychologist and neuroscientist Arthur F. Kramer, director of the

Beckman Institute at the University of Illinois and a pre-eminent expert on exercise and

the brain. A limited number of studies in the past several years have found cognitive

benefits among older people who lifted weights for a year and did not otherwise exercise.

But most studies to date, and all animal experiments, have involved running or other

aerobic activities.

Whatever the activity, though, an emerging message from the most recent science is

that exercise needn’t be exhausting to be effective for the brain. When a group of 120

older men and women were assigned to walking or stretching programs for a major 2011

study, the walkers wound up with larger hippocampi after a year. Meanwhile, the

stretchers lost volume to normal atrophy. The walkers also displayed higher levels of

B.D.N.F. in their bloodstreams than the stretching group and performed better on

cognitive tests.

In effect, the researchers concluded, the walkers had regained two years or more of

hippocampal youth. Sixty-five-year-olds had achieved the brains of 63-year-olds simply

by walking, which is encouraging news for anyone worried that what we’re all facing as

we move into our later years is a life of slow (or not so slow) mental decline.

How Working the Muscles May BoostBrainpowerBy GRETCHEN REYNOLDS

May 9, 2012

Upending the cliché of muscleheads, scientists at the Laboratory of Neuroscience at the

National Institute on Aging recently set out to examine whether changes in muscles

prompted by exercise might subsequently affect and improve the brain’s ability to think.

Lab animals and people generally perform better on tests of cognition after several

weeks of exercise training, and studies have shown that over time, running and other

types of endurance exercise increase the number of neurons in portions of the brain

devoted to memory and learning. But the mechanisms that underlie this process remain

fairly mysterious. Do they start within the brain itself? Or do messages arrive from

elsewhere in the body to jump-start the process?

The researchers were especially interested in the possibility that the action starts

outside the brain — and specifically in the muscles. “We wondered whether peripheral

triggers might be activating the cellular and molecular cascades in the brain that led to

improvements in cognition,” says Henriette van Praag, the investigator at the National

Institute on Aging who led the study.

Muscles are, of course, greatly influenced by exercise. Muscle cells respond to

exercise by pumping out a variety of substances that result in larger, stronger muscles.

Some of those compounds might be entering the bloodstream and traveling to the brain,

Dr. van Praag says.

The problem is that exercise is such a complicated physiological stimulus that it’s

very difficult to isolate which compounds are involved and what their effects might be.

So she and her colleagues decided to study “fake” exercise instead, using two specialized

drugs that had been tested several years ago by scientists at the Salk Institute in San

Diego. The drugs had been shown to induce the same kinds of changes in sedentary

animals’ muscles that exercise would cause, so that even though the mice didn’t exercise,

they physiologically responded as if they had.

One of the drugs that they used, known as Aicar, increases the muscles’ output of

AMPK, an enzyme that affects cellular energy and metabolism. Regular endurance

exercise, like running or cycling, increases the muscles’ production of this enzyme. In the

Salk experiments, Aicar enabled untrained mice to run 44 percent farther during treadmill

tests than other, sedentary animals that hadn’t received the drug.

The second compound, GW1516, a cholesterol drug, also stimulates biochemical

changes in muscle cells like those caused by endurance exercise. But in the Salk studies,

it had amplified endurance primarily in animals that also ran, allowing them to run farther

than another set of running mice that didn’t get the drug. But it hadn’t done much muscle-

wise for animals that remained sedentary.

By using these drugs in unexercised animals under well-controlled conditions, the

scientists from the National Institute on Aging sought to determine whether changes in

muscles then initiated changes in the brain.

And as it turned out, muscles did affect the mind. After a week of receiving either of

the two drugs (and not exercising), the mice performed significantly better on tests of

memory and learning than control animals that had simply remained quiet in their cages.

The effects were especially pronounced for the animals taking Aicar.

The results, published in the journal Learning and Memory, showed that the

drugged animals’ brains also contained far more new neurons in brain areas central to

learning and memory than the brains of the control mice, an effect found by microscopic

examination.

Because the two drugs “don’t cross the blood-brain barrier much, if at all,” Dr. van

Praag says, “we could be fairly confident that the changes we were seeing were related to

an exercise-type reaction in the muscles” and not to brain responses to the drugs.

The message of this finding, she continues, is that “improvements in cognition” that

follow exercise “would seem to involve changes throughout the body and not just in the

brain.”

Although the exact process isn’t clear, Dr. van Praag speculates that some of the

AMPK enzyme created during exercise enters the bloodstream and travels to the brain,

setting off a series of new reactions there.

The implication, she continues, is that exercise may need to be aerobic if it’s going

to substantially affect the brain. “You probably need to increase blood flow, which

mostly occurs during endurance training,” she says. Also, in animal studies, AMPK

production has been found to increase principally after running. Of course, “it’s very hard

for us to study weight lifting in mice,” Dr. van Praag says, so it’s possible that other types

of exercise might improve AMPK production and cognition too, she says.

Interestingly, when the scientists continued injecting mice with Aicar for an

additional week, the animals’ brains stopped responding. They actually began losing their

augmented ability to learn, compared with the control animals, a finding that suggests,

Dr. van Praag says, that drugs may be an unsatisfactory — and potentially detrimental —

way to emulate the effects of exercise.

Exercise, on the other hand, is generally safe. “And the scientific evidence,

including ours,” she says, “is strong and growing that it is very good for the muscles —

and for the brain.”

How Exercise Can Jog the MemoryBy GRETCHEN REYNOLDS

May 30, 2012

It’s well established that exercise substantially changes the human brain, affecting both

thinking and emotions. But a sophisticated, multifaceted new study suggests that the

effects may be more nuanced than many scientists previously believed. Whether you gain

all of the potential cognitive and mood benefits from exercise may depend on when and

how often you work out, as well as on the genetic makeup of your brain.

For the experiment, published last month in Neuroscience, researchers in the

department of psychology and neuroscience at Dartmouth College in Hanover, N.H.,

recruited 54 adults, ages 18 to 36, from the college and the surrounding community. The

volunteers were healthy but generally sedentary; none exercised regularly.

During their first visit to the lab, they completed a series of questionnaires about

their health and mood, including how anxious they were both at that moment and in

general.

They also gave blood for genetic testing. Earlier studies had shown that exercise can

increase levels of a protein called brain-derived neurotropic factor, or BDNF, which is

thought to play a role in the positive effects of exercise on thinking. But some people

produce less BDNF after exercise than others because they have a variation in the gene

that controls BDNF production, though it’s unknown whether they derive less cognitive

benefit from exercise as a result. So the scientists wanted to determine each volunteer’s

BDNF gene status.

Then the group submitted to a memory test, consisting of pictures of objects flashed

across a computer screen. Soon after, another set of pictures appeared, and the volunteers

were asked to note, with keystrokes, whether they’d seen each particular image before.

This task involves a different part of the brain from the one most often focused on in

studies of exercise and memory, says David Bucci, an associate professor of psychology

and brain science at Dartmouth, who oversaw the study. Other experiments typically

examine the effect of exercise on the hippocampus, the brain’s primary memory center,

he says, but the object-recognition task involves activity in the perirhinal cortex, a portion

of the brain essential to remembering particular things or objects and whether they

happen to be new in your experience. Without a healthy perirhinal cortex, you might

recall where you’ve put your car keys (a hippocampal memory task), but not what car

keys are.

Finally, after completing the tests, the volunteers were randomly assigned to

exercise or not during the next four weeks. Half began a supervised program of walking

or jogging four times a week for at least 30 minutes. The other half remained sedentary.

After a month, the volunteers returned to the lab for retesting. But first, some

exercised. Half of the exercising group walked or jogged before the testing; half did not.

Ditto for the sedentary group: Half exercised that day for the first time since the start of

the study; the rest did not.

The earlier tests of memory and mood were repeated.

The results were, in certain aspects, a surprise. As expected, many of the volunteers

who’d been exercising for the past month significantly improved their scores on the

memory and mood tests. But not all of them did. In general, those volunteers who had

exercised for the past month and who worked out on the day of retesting performed the

best on the memory exam. They also tended to report less anxiety than other volunteers.

Those who had exercised during the preceding month but not on the day of testing

generally did better on the memory test than those who had been sedentary, but did not

perform nearly as well as those who had worked out that morning.

Interestingly, while exercising before the test didn’t improve the memory scores of

those who’d remained sedentary for the past month, it did increase their self-reported

anxiety levels. They were more jittery than they had been on the first lab visit.

Perhaps most intriguing, though, was what the researchers discovered when they

compared the volunteers’ BDNF gene variants and their scores on the memory test. They

found that those with the variant that blunts BDNF production after exercise — a fairly

common variation, existing in about 30 percent of people of European Caucasian heritage

— did not improve their memories, even if they exercised regularly. (No consumer test

exists to check for the variant.)

What all of this means for people who are hoping that exercise will improve their

minds is unclear, Dr. Bucci says, but it does suggest that the interplay of physical activity

and brainpower is more complex than we have perhaps yet acknowledged.

Some people’s ability to recall objects, for instance, “may respond less robustly” to

exercise than other people’s, he says, if their genetic makeup doesn’t promote the release

of BDNF.

But the overall message of this study and of ongoing research in his lab, Dr. Bucci

adds, is that exercise generally enhances the ability to remember. The people who did

improve their memory test scores, he points out, were invariably those who’d exercised

throughout the previous month and again the morning of the testing, suggesting a

powerful cumulative effect from the exercise sessions, he says.

More generally, Dr. Bucci says, there are many types of memory involving many

different areas within the brain, and few seem unaffected by regular, moderate exercise,

although the effects may be inconsistent from person to person.

“The current data strongly suggests that people should be physically active” if they

wish to enjoy a sturdy, unporous memory in the long term, Dr. Bucci says. Walk or jog

regularly, in other words, and most of us can expect to continue recognizing our keys as

keys.

Exercise May Ease Depression in HeartFailure PatientsBy ANAHAD O’CONNOR

July 31, 2012

Heart failure can take a heavy psychological toll, with many patients developing

symptoms of depression. But a new study suggests that an exercise plan can ease the

melancholy, creating improvements in mood that are comparable to the effects seen with

medication.

For roughly a year, researchers followed more than 2,000 people treated for

congestive heart failure at 82 medical centers in the United States, France and Canada.

Those who were assigned to a moderate aerobic exercise program — about 90 to 120

minutes a week — saw greater reductions in symptoms of depression than those who

were not enrolled in such a program.

“I think this shows that for patients who have heart failure, exercise is certainly an

excellent treatment,” said Dr. James A. Blumenthal, a professor of medical psychology at

Duke University Medical Center and the lead author of the study, which was published in

the Journal of the American Medical Association. “It’s something that most patients can

engage in. It results in improved cardiorespiratory fitness, they have more stamina, and

now we see that not only do they derive these physical benefits, but they also derive

psychological benefits as well.”

An estimated five million Americans are living with heart failure, with more than

half a million new cases diagnosed each year. Patients often experience a drastic decline

in their physical abilities, and with it a blow to their mental health. Up to 75 percent of

patients develop some symptoms of depression, with about 40 percent suffering from

full-blown clinical depression, which can worsen their overall prognosis.

Building on a growing body of research suggesting that aerobic exercise can elevate

mood surprisingly well in people who have depression, Dr. Blumenthal and his

colleagues set out to determine whether regular activity might have similar benefits in

depressed heart failure patients. They began by assessing their subjects, whose average

age was about 60, with a standard questionnaire called the Beck Depression Inventory II

that rates depressive symptoms on a scale from 0 to 59. Higher scores indicate greater

severity of depression, with a score of 14 or more generally considered to represent

clinically significant depression.

At the beginning of the study, the median score of the participants was about 8,

though about a third had a score of 14 or more.

The researchers then randomly assigned patients to one of two groups. Those in the

first group completed three supervised exercise sessions a week for three months,

typically at a cardiac rehab center, followed by 120 minutes a week of home exercise for

another nine months. The patients primarily used treadmills and stationary bikes.

Those in the second group, meanwhile, received what the researchers called “usual

care.” They did not receive any formal exercise instructions, only traditional

recommendations to get about 30 minutes of activity most days of the week, in line with

American Heart Association guidelines. Like those in the exercise group, they were also

given detailed educational materials with information on things like medication and

sodium intake.

As the researchers checked in at regular intervals, they found that the depression

scores in the exercise group were consistently lower than in the control group — by about

a point, which was a modest reduction. Patients who reported greater adherence to the

exercise program had the most significant reductions in depressive symptoms.

For those who made up the subset of patients with the most severe symptoms — a

depression score of 14 or greater — the difference between the exercise group and the

control group was greater, with a reduction of about two points. Dr. Blumenthal said this

magnitude of difference was similar to what has been shown in studies that have

compared antidepressant use with placebo.

At the start of the study, one of the questions for the research team was whether

heart failure patients could even exercise without hazard, which is why the first three

months of exercise were supervised.

“I think historically, physicians have been very cautious about recommending

exercise for these patients because it wasn’t clear that it was safe or that they would even

derive the same benefits that other people derive,” said Dr. Blumenthal.

But it’s now clear that they do benefit in terms of aerobic capacity, he said, and that

a moderate exercise program can be safe.

As for why exercise would provide psychological benefits, Dr. Blumenthal said he

could only speculate.

“When you have a debilitating condition like this, there’s a tendency to feel you

don’t have a lot of control over your health,” he said. “But I think for a lot of patients in

this study, they felt like they were doing something positive for themselves, and they had

an enhanced sense of self confidence. They could do more, they increased their strength

and stamina, and I think that really served to improve their moods.”

Changing Our Tune on ExerciseBy JANE E. BRODY

August 27, 2012

What would it take to persuade you to exercise?

A desire to lose weight or improve your figure? To keep heart disease, cancer or

diabetes at bay? To lower your blood pressure or cholesterol? To protect your bones? To

live to a healthy old age?

You’d think any of those reasons would be sufficient to get Americans exercising,

but scores of studies have shown otherwise. It seems that public health experts, doctors

and exercise devotees in the media — like me — have been using ineffective tactics to

entice sedentary people to become, and remain, physically active.

For decades, people have been bombarded with messages that regular exercise is

necessary to lose weight, prevent serious disease and foster healthy aging. And yes, most

people say they value these goals. Yet a vast majority of Americans — two-thirds of

whom are overweight or obese — have thus far failed to swallow the “exercise pill.”

Now research by psychologists strongly suggests it’s time to stop thinking of future

health, weight loss and body image as motivators for exercise. Instead, these experts

recommend a strategy marketers use to sell products: portray physical activity as a way to

enhance current well-being and happiness.

“We need to make exercise relevant to people’s daily lives,” Michelle L. Segar, a

research investigator at the Institute for Research on Women and Gender at the University

of Michigan, said in an interview. “Everyone’s schedule is packed with nonstop to-do’s.

We can only fit in what’s essential.”

Dr. Segar is among the experts who believe that people will not commit to exercise

if they see its benefits as distant or theoretical.

“It has to be portrayed as a compelling behavior that can benefit us today,” she said.

“People who say they exercise for its benefits to quality of life exercise more over the

course of a year than those who say they value exercise for its health benefits.”

Her idea for a public service advertisement to promote exercise for working women

with families: A woman is shown walking around the block after dinner with her children

and says, “This is great. I can fit in fitness, spend quality time with my kids, and at the

same time teach them how important exercise is.”

Based on studies of what motivates people to adopt and sustain physical activity, Dr.

Segar is urging that experts stop framing moderate exercise as a medical prescription that

requires 150 minutes of aerobic effort each week. Instead, public health officials must

begin to address “the emotional hooks that make it essential for people to fit it into their

hectic lives.”

“Immediate rewards are more motivating than distant ones,” she added. “Feeling

happy and less stressed is more motivating than not getting heart disease or cancer,

maybe, someday in the future.”

In a study of 252 office workers, David K. Ingledew and David Markland,

psychologists at the University of Wales, found that while many began to exercise as way

to lose weight and improve their appearance, these motivations did not keep them

exercising in the long term. “The well-being and enjoyment benefits of exercise should be

emphasized,” the researchers concluded.

Dr. Segar put it this way: “Physical activity is an elixir of life, but we’re not

teaching people that. We’re telling them it’s a pill to take or a punishment for bad

numbers on the scale. Sustaining physical activity is a motivational and emotional issue,

not a medical one.”

Other studies have shown that what gets people off their duffs and keeps them

moving depends on age, gender, life circumstances and even ethnicity. For those of

college age, for example, physical attractiveness typically heads the list of reasons to

begin exercising, although what keeps them going seems to be the stress relief that a

regular exercise program provides.

The elderly, on the other hand, may get started because of health concerns. But often

what keeps them exercising are the friendships, sense of community and camaraderie that

may otherwise be missing from their lives — easily seen among the gray-haired women

who faithfully attend water exercise classes at my local YMCA.

In a recent study of 1,690 overweight or obese middle-aged men and women, Dr.

Segar found that enhancing daily well-being was the most influential factor for the

women in the study. Men indicated they were motivated by more distant health benefits,

although Dr. Segar suspects this may be because men feel less comfortable discussing

their mental health needs.

“What sustains us, we sustain,” Dr. Segar said. “We need to promote what

marketers call ‘customer loyalty.’ We need to help people stay engaged with movement

by teaching them how it can help sustain them in their lives.”

Many, if not most, people start exercising because they want to lose weight. But

very often they abandon exercise when the expected pounds fail to fall off. Study after

study has found that, without major changes in eating habits, increasing physical activity

is only somewhat effective for losing weight, though it helps people maintain weight loss

and shedding even a few pounds, especially around one’s middle, can improve health.

For example, researchers in Brisbane, Australia, and in Leeds, England, studied 58

sedentary overweight or obese men and women who participated in a closely monitored

12-week aerobic exercise program. Weight loss was minimal, but nonetheless the

participants’ waistlines shrunk, their blood pressure and resting heart rate dropped, and

their aerobic capacity and mood improved.

“Exercise should be encouraged and the emphasis on weight loss reduced,” the

researchers concluded. “Disappointment and low self-esteem associated with poor weight

loss could lead to low exercise adherence and a general perception that exercise is futile

and not beneficial.”

I walk three miles daily, or bike ten miles and swim three-quarters of a mile. If you

ask me why, weight control may be my first answer, followed by a desire to live long and

well. But that’s not what gets me out of bed before dawn to join friends on a morning

walk and then bike to the Y for my swim.

It’s how these activities make me feel: more energized, less stressed, more

productive, more engaged and, yes, happier — better able to smell the roses and cope

with the inevitable frustrations of daily life.

How Testosterone May Alter the BrainAfter ExerciseBy GRETCHEN REYNOLDS

September 12, 2012

It’s widely accepted among scientists that regular exercise transforms the brain,

improving the ability to remember and think. And a growing and very appealing body of

science has established that exercise spurs the creation of new brain cells, a process

known as neurogenesis. But just how jogging or other workouts affect the structure of the

brain has remained enigmatic, with many steps in the process unexplained.

A new study published last month in Proceedings of the National Academy of

Sciences may fill in one piece of the puzzle, by showing that male sex hormones surge in

the brain after exercise and could be helping to remodel the mind. The research was

conducted on young, healthy and exclusively male rats — but scientists believe it applies

to female rats, too, as well as other mammals, including humans.

The decision to use only males was carefully considered. “We’ve known for a while

that estrogen,” the female sex hormone, “is produced in the brain” not just of female

animals but also, to some degree, in males, says Bruce S. McEwen, the director of the

Laboratory of Neuroendocrinology at Rockefeller University in New York and an author

of the study, which also involved scientists from the University of Tsukuba in Japan and

other institutions. Estrogen has been well studied and has many effects, he said,

including, scientists suspect, new brain cell growth.

But far less has been known about the role of male sex hormones in mammalian

brains, particularly after exercise.

While both sexes produce male sex hormones, males produce far more of it —

mostly in the gonads but, the researchers suspected, also in the brain.

The only way to know for sure if the hormones were being synthesized in the brain

would be to shut off production in the testes, to guarantee that hormones from that site

wouldn’t migrate to the brain. So some of the rats in the experiment were surgically

castrated. The rest underwent a sham operation, in which nothing was removed. That

procedure ensures that stress from the operation won’t skew results; all animals will have

had the same unpleasant experience.

Separately, some of the animals also were injected with a drug that blocks the ability

of male sex hormones to bind to receptors in the brain. Those animals might be able to

produce the hormones, but they wouldn’t have any effects on the brain.

After recovery, most of the rats ran for two weeks on treadmills set at a leisurely

jogging pace. Some remained sedentary.

Then the scientists examined all of the animals’ brains. They found that, compared

with the sedentary animals, the running rats had significantly more of a potent

testosterone derivative called dihydrotestosterone, or DHT, in their brains. Even the

brains of rats that had been castrated sloshed with DHT.

So the exercise had prompted increased production of the hormone.

Most of the animals also had a plethora of new neurons in the hippocampus, a

portion of the brain associated with learning and memory. Unexpectedly, however, the

animals in this experiment that could not use the DHT in their brains did not experience

enhanced neurogenesis. They exercised just as the other animals did, but their brains did

not benefit in the same way.

This tells us that the uptake of DHT in the brain after exercise “appears to be a

necessary step in achieving adult hippocampal neurogenesis,” Dr. McEwen says.

In essence, exercise prompts the production of more DHT. And more DHT helps to

create more new brain cells.

But while those findings may be salutary for men who are active and fit, or planning

to become so, they seem potentially troubling for those of us without testes. If DHT is

necessary for neurogenesis after exercise and women produce far less of it than men, do

women gain less brain benefit from exercise than men?

“It’s unlikely,” Dr. McEwen says. One reason that early experiments into exercise

and neurogenesis tended to be performed in female rats was that “in rats, females exercise

more than the males,” he said. “They’ll run for hours and keep running, even when

they’re old.” Elderly males, in contrast, willingly quit working out. In those experiments,

neurogenesis was plentiful in the female brains.

“It’s very probable that estrogen plays a role” like that of DHT in the female brain

after exercise, Dr. McEwen says. Meanwhile, female brains also produce varying

amounts of male hormones. So there may be some as-yet-undiscovered interactions

between the male and female hormones in the brain that mesh after jogging to increase

brain cell numbers and improve the ability to think.

But for the moment, the full effects of exercise and sex hormones on the brain are

still being teased out.

But one aspect of the new experiment is already resoundingly clear and reassuring,

Dr. McEwen points out. “The exercise in this experiment was quite mild,” he says — the

equivalent of jogging at a pace at which someone could speak (or squeak) to a

companion. “That’s achievable for most people,” he concludes, “and the evidence

suggests that it will improve brain health.”

How Exercise Can Help You MasterNew SkillsBy GRETCHEN REYNOLDS

September 26, 2012

Can you improve your body’s ability to remember by making it move? That rather odd-

seeming question stimulated researchers at the University of Copenhagen to undertake a

reverberant new examination of just how the body creates specific muscle memories and

what role, if any, exercise plays in the process.

To do so, they first asked a group of young, healthy right-handed men to master a

complicated tracking skill on a computer. Sitting before the screen with their right arm on

an armrest and a controller similar to a joystick in their right hand, the men watched a red

line squiggle across the screen and had to use the controller to trace the same line with a

white cursor. Their aim was to remain as close to the red squiggle as possible, a task that

required input from both the muscles and the mind.

The men repeated the task multiple times, until the motion necessary to track the red

line became ingrained, almost automatic. They were creating a short-term muscle

memory.

The term “muscle memory” is, of course, something of a misnomer. Muscles don’t

make or store memories. They respond to signals from the brain, where the actual

memories of any particular movement are formed and filed away.

But muscle memory — or “motor memory,” as it is more correctly referred to

among scientists — exists and can be quite potent. Learn to ride a bicycle as a youngster,

abandon the pastime and, 20 years later, you’ll be able to hop on a bicycle and pedal off.

To date, most studies of the effect of exercise on memory have looked at more

intellectual tasks, like memorizing lists of words. In those cases, regular exercise appears

to improve the brain’s general ability to remember.

But the Copenhagen scientists wanted to see how exercise influences the

development and consolidation of physical memories. So before having their volunteers

master the squiggle test, they first had a third of the group ride a bicycle at an intense but

not exhausting pace for 15 minutes. The other two-thirds of the group rested quietly

during this time.

Then, after the computer motor-skill testing, a third of those who’d previously rested

completed the same strenuous 15-minute bike ride. The others rested.

All of the volunteers then repeated the follow-that-squiggle test after an hour, a day

and a week, to see how well they’d learned and remembered that particular skill.

Their scores for speed and accuracy of squiggle shadowing were almost identical at

the one-hour point, although the group that had ridden the bicycle after the first computer

practice session was a bit less accurate.

After a week, though, things looked different. The men who had exercised just after

first learning the motor skill were noticeably better at remembering the task, with their

tracing of the red line on the computer more agile and accurate. The men who’d exercised

before learning the new skill were not quite as adept now, although they were better than

those in the group that hadn’t exercised at all.

What this result suggests, says Marc Roig, a postdoctoral researcher at the

University of Copenhagen who led the study with his colleague Kasper Skriver, is that

physical exercise may help the brain to consolidate and store physical or motor memories.

Consolidating a memory is not instantaneous, after all, or even inevitable. Every

memory must be encoded and moved from short-term to long-term storage. Some of

those memories are, for whatever reason, more vividly imprinted than others.

It may be that physical, aerobic exercise performed right after a memory has been

formed intensifies the imprinting, Dr. Roig says. It makes the memory stronger.

In the short term, though, exercise may leave the brain overstimulated, he continues,

making it less able to pinpoint and access new memories. That may be why men who had

exercised after learning the new skill performed worst during the first motor-memory

recall test.

But they performed better in the long term, because their memory of the new skill

was, it would seem, sturdier.

How a single workout can strengthen a particular memory is uncertain, Dr. Roig

acknowledges, but he suspects biochemistry. “There is evidence that aerobic exercise

produces substances” in the brain, like brain-derived neurotropic factor and

noradrenaline, that drive memory consolidation and learning, he says.

Ultimately, how exercise operates in this context may be less significant for most of

us than when. The “timing of the exercise is critical,” Dr. Roig says. To be maximally

effective, it needs to be performed “right after exposure to the information to be

remembered.”

Want to remember how to ride that bike, in other words? Then ride it as soon as you

have managed to stop wobbling. The exercise seems able then to cement the memory of

how to ride. Ditto if you’ve just perfected the snap of your tennis serve or the spin on

your soccer kick. Go for a run immediately afterward, and your body may later better

remember.

Whether that same run will strengthen the creation and storage of more intellectual

memories remains to be seen, although Dr. Roig is optimistic. He and his colleagues are

working with schoolchildren in Copenhagen to determine whether having the youngsters

run about or otherwise exercise immediately after being taught a new concept improves

their later test scores in that subject. Early results are promising, and could make the

mastering of algebra almost invigorating.

Exercise May Protect Against BrainShrinkageBy ANAHAD O’CONNOR

October 26, 2012

Remaining physically active as you age, a new study shows, may help protect parts of

your brain from shrinking, a process that has been linked to declines in thinking and

memory skills. Physical exercise not only protected against such age-related brain

changes, but also had more of an effect than mentally and socially stimulating activities.

In the new report, published in the journal Neurology, a team at the University of

Edinburgh followed more than 600 people, starting at age 70. The subjects provided

details on their daily physical, mental and social activities.

Three years later, using imaging scans, the scientists found that the subjects who

engaged in the most physical exercise, including walking several times a week, had less

shrinkage and damage in the brain’s white matter, which is considered the “wiring” of the

brain’s communication system. The relationship remained even after the researchers

controlled for things like age, health status, social class and I.Q.

As far as mental exercise, “we can only say we found no benefit in our sample,” said

Dr. Alan J. Gow, an author of the study and a senior research fellow at Edinburgh. He

added: “There might be associations earlier in the life course. Such activities also have

important associations with well-being and quality of life, so we would certainly agree it

is important for older adults to continue to pursue them.”

Because the findings showed only an association, not a causal relationship, the

authors could not rule out the possibility that people with less deterioration in their brains

were simply more likely to be physically active. But they said that based on their

findings, they would advise that people take up physical exercise “whatever their age.”

Can Exercise Protect the Brain FromFatty Foods?By GRETCHEN REYNOLDS

November 7, 2012

In recent years, some research has suggested that a high-fat diet may be bad for the brain,

at least in lab animals. Can exercise protect against such damage? That question may

have particular relevance now, with the butter-and cream-laden holidays fast

approaching. And it has prompted several new and important studies.

The most captivating of these, presented last month at the annual meeting of the

Society for Neuroscience in New Orleans, began with scientists at the University of

Minnesota teaching a group of rats to scamper from one chamber to another when they

heard a musical tone, an accepted measure of the animals’ ability to learn and remember.

For the next four months, half of the rats ate normal chow. The others happily

consumed a much greasier diet, consisting of at least 40 percent fat. Total calories were

the same in both diets.

After four months, the animals repeated the memory test. Those on a normal diet

performed about the same as they had before; their cognitive ability was the same. The

high-fat eaters, though, did much worse.

Then, half of the animals in each group were given access to running wheels. Their

diets didn’t change. So, some of the rats on the high-fat diet were now exercising. Some

were not. Ditto for the animals eating the normal diet.

For the next seven weeks, the memory test was repeated weekly in all of the groups.

During that time, the performance of the rats eating a high-fat diet continued to decline so

long as they didn’t exercise.

But those animals that were running, even if they were eating lots of fat, showed

notable improvements in their ability to think and remember.

After seven weeks, the animals on the high-fat diet that exercised were scoring as

well on the memory test as they had at the start of the experiment.

Exercise, in other words, had “reversed the high-fat diet-induced cognitive decline,”

the study’s authors concluded.

That finding echoes those of another study presented last month at the Society for

Neuroscience meeting. In it, researchers at Kyoto University in Japan gathered a group of

mice bred to have a predisposition to developing a rodent version of Alzheimer’s disease

and its profound memory loss.

Earlier studies by the same scientists had shown that a high-fat diet exacerbated the

animals’ progression to full-blown dementia, and that both a low-fat diet and exercise

slowed the animals’ mental decline.

But it hadn’t been clear in these earlier experiments which was more effective at

halting the loss of memory, a leaner diet or regular rodent workouts.

So the scientists set out now to tease out the effects of each intervention by first

feeding all of their mice a high-fat diet for 10 weeks, then switching some of them to low-

fat kibble, while moving others to cages equipped with running wheels.

A third group began both a low-fat diet and an exercise routine, while the remainder

of the mice continued to eat the high-fat diet and didn’t exercise.

After an additional 10 weeks, this last group, the animals that ate lots of fat and

lounged around their cages, had developed far more deposits of the particular brain

plaques associated with Alzheimer’s disease than the other mice. They also performed

much more poorly on memory tests.

The mice that had been switched to a low-fat diet had fewer plaques and better

memories than the control group.

But the mice that were exercising had even healthier brains and better memory

scores than the low-fat group — even if they had remained on a high-fat diet. In other

words, exercise was “more effective than diet control in preventing high-fat diet-induced

Alzheimer’s disease development,” the authors write.

Just why high-fat diets might affect the brain and how exercise undoes the damage

is not yet clear. “Our research suggests that free fatty acids” from high-fat foods may

actually infiltrate the brain, says Vijayakumar Mavanji, a research scientist at the

Minnesota VA Medical Center at the University of Minnesota, who, with his colleagues

Catherine M. Kotz, Dr. Charles J. Billington, and Dr. Chuan Feng Wang, conducted the

rat study. The fatty acids may then jump-start a process that leads to cellular damage in

portions of the brain that control memory and learning, he says.

Exercise, on the other hand, seems to stimulate the production of specific

biochemical substances in the brain that fight that process, he says.

In the Japanese study, for instance, the brains of the exercised animals teemed with

high levels of an enzyme that is known to degrade the plaques associated with

Alzheimer’s disease.

Of course, lab animals are not people, Dr. Mavanji cautions, and it’s not known if

exercise might protect our brains in the same manner as it does in mice and rats.

Still, he says, there’s enough accumulating evidence about the potential cognitive

risks of high-fat foods and the countervailing benefits from physical activity to

recommend that “people exercise moderately,” he says, particularly during periods of

repeated exposure to alluring, fatty holiday buffets.

The amount of exercise required to potentially protect our brains from the possible

depredations of marbled beef and cheesecake isn’t excessive, after all, he continues. His

rats were running for the human equivalent of about a daily 30-minute jog. So if you

can’t walk away from the buffet table, be sure to at least take a walk afterward.

Exercise and the Ever-Smarter HumanBrainBy GRETCHEN REYNOLDS

December 26, 2012

Anyone whose resolve to exercise in 2013 is a bit shaky might want to consider an

emerging scientific view of human evolution. It suggests that we are clever today in part

because a million years ago, we could outrun and outwalk most other mammals over long

distances. Our brains were shaped and sharpened by movement, the idea goes, and we

continue to require regular physical activity in order for our brains to function optimally.

The role of physical endurance in shaping humankind has intrigued anthropologists

and gripped the popular imagination for some time. In 2004, the evolutionary biologists

Daniel E. Lieberman of Harvard and Dennis M. Bramble of the University of Utah

published a seminal article in the journal Nature titled “Endurance Running and the

Evolution of Homo,” in which they posited that our bipedal ancestors survived by

becoming endurance athletes, able to bring down swifter prey through sheer doggedness,

jogging and plodding along behind them until the animals dropped.

Endurance produced meals, which provided energy for mating, which meant that

adept early joggers passed along their genes. In this way, natural selection drove early

humans to become even more athletic, Dr. Lieberman and other scientists have written,

their bodies developing longer legs, shorter toes, less hair and complicated inner-ear

mechanisms to maintain balance and stability during upright ambulation. Movement

shaped the human body.

But simultaneously, in a development that until recently many scientists viewed as

unrelated, humans were becoming smarter. Their brains were increasing rapidly in size.

Today, humans have a brain that is about three times the size that would be

expected, anthropologists say, given our species’ body size in comparison with that of

other mammals.

To explain those outsized brains, evolutionary scientists have pointed to such

occurrences as meat eating and, perhaps most determinatively, our early ancestors’ need

for social interaction. Early humans had to plan and execute hunts as a group, which

required complicated thinking patterns and, it’s been thought, rewarded the social and

brainy with evolutionary success. According to that hypothesis, the evolution of the brain

was driven by the need to think.

But now some scientists are suggesting that physical activity also played a critical

role in making our brains larger.

To reach that conclusion, anthropologists began by looking at existing data about

brain size and endurance capacity in a variety of mammals, including dogs, guinea pigs,

foxes, mice, wolves, rats, civet cats, antelope, mongooses, goats, sheep and elands. They

found a notable pattern. Species like dogs and rats that had a high innate endurance

capacity, which presumably had evolved over millenniums, also had large brain volumes

relative to their body size.

The researchers also looked at recent experiments in which mice and rats were

systematically bred to be marathon runners. Lab animals that willingly put in the most

miles on running wheels were interbred, resulting in the creation of a line of lab animals

that excelled at running.

Interestingly, after multiple generations, these animals began to develop innately

high levels of substances that promote tissue growth and health, including a protein called

brain-derived neurotrophic factor, or BDNF. These substances are important for

endurance performance. They also are known to drive brain growth.

What all of this means, says David A. Raichlen, an anthropologist at the University

of Arizona and an author of a new article about the evolution of human brains appearing

in the January issue of Proceedings of the Royal Society B, is that physical activity may

have helped to make early humans smarter.

“We think that what happened” in our early hunter-gatherer ancestors, he says, is

that the more athletic and active survived and, as with the lab mice, passed along

physiological characteristics that improved their endurance, including elevated levels of

BDNF. Eventually, these early athletes had enough BDNF coursing through their bodies

that some could migrate from the muscles to the brain, where it nudged the growth of

brain tissue.

Those particular early humans then applied their growing ability to think and reason

toward better tracking prey, becoming the best-fed and most successful from an

evolutionary standpoint. Being in motion made them smarter, and being smarter now

allowed them to move more efficiently.

And out of all of this came, eventually, an ability to understand higher math and

invent iPads. But that was some time later.

The broad point of this new notion is that if physical activity helped to mold the

structure of our brains, then it most likely remains essential to brain health today, says

John D. Polk, an associate professor of anthropology at the University of Illinois at

Urbana-Champaign, and co-author, with Dr. Raichlen, of the new article.

And there is scientific support for that idea. Recent studies have shown, he says, that

“regular exercise, even walking,” leads to more robust mental abilities, “beginning in

childhood and continuing into old age.”

Of course, the hypothesis that jogging after prey helped to drive human brain

evolution is just a hypothesis, Dr. Raichlen says, and almost unprovable.

But it is compelling, says Harvard’s Dr. Lieberman, who has worked with the

authors of the new article. “I fundamentally agree that there is a deep evolutionary basis

for the relationship between a healthy body and a healthy mind,” he says, a relationship

that makes the term “jogging your memory” more literal than most of us might have

expected and provides a powerful incentive to be active in 2013.

Do the Brain Benefits of Exercise Last?By GRETCHEN REYNOLDS

January 9, 2013

It is well established that exercise bolsters the structure and function of the brain.

Multiple animal and human studies have shown that a few months of moderate exercise

can create new neurons, lift mood and hone memory and thinking.

But few studies have gone on to examine what happens next. Are these desirable

brain changes permanent? Or, if someone begins exercising but then stops, does the brain

revert to its former state, much like unused muscles slacken?

The question may be particularly relevant at this time of year, when so many people

start new exercise programs. Helpfully, two recent animal studies that were presented at

the 2012 annual meeting of the Society for Neuroscience in New Orleans have taken on

the issue and may have relevance for people, though the results are disquieting.

Of the two experiments, the more dramatic looked at what happens to the brain’s

memory center when exercise is stopped.

Researchers from the University of Sao Paulo in Brazil began by allowing half of a

group of healthy, adult rats to run at will on running wheels. Rats enjoy that activity and,

for a week, they enthusiastically skittered on their wheels. The animals were also injected

with a substance that marks newborn neurons in the hippocampus, or memory center of

the brain, so that the scientists would be able to track how many cells had been created.

Inactive animals, including people, create new brain cells, but exercise is known to spark

the creation of two or three times as many new hippocampal neurons.

A separate control group was housed in cages with locked wheels, so that they

remained sedentary. They were also monitored for new brain cell growth.

After a week, the runners’ wheels were locked and they, too, became inactive.

A week later, some of the exercised and control rats completed memory testing that

required them to find, then remember, the location of a platform placed along the wall of

a small swimming pool. (Rats aren’t fond of being in the water, and the platform allowed

them to clamber out.) Those with better memories remembered and paddled to the

platform more quickly.

The remaining animals completed the same memory test after either three weeks or

six weeks of inactivity.

Afterward, the researchers compared the animals’ performance on the memory test,

as well as the number of new brain cells in the hippocampus of each group of rats.

They found that, after only a week of inactivity, the rats that had run were much

faster on the water maze test than the control animals. They also had at least twice as

many newborn neurons in the hippocampus.

But those advantages faded after several more weeks of not running. The brains of

the animals that had been inactive for three weeks contained far fewer newborn neurons

than the brains of the animals that had rested for only one week. The brains of the animals

that had been inactive for six weeks had fewer still.

The animals inactive for three or six weeks also performed far worse on the water

maze test than the animals that had been inactive for only a single week. In fact, their

memories were about as porous of those of the control animals, “indicating,” the authors

write, “that the exercise-induced benefits may be transient.”

The other new study of exercise-induced brain changes found that they were

similarly fragile, although this study explored the impacts of exercise on mood.

In earlier experiments by the same group of scientists, from McMaster University in

Hamilton, Ontario, rats given access to a running wheel, toys and other types of

environmental enrichment were able to use serotonin, a neurotransmitter involved in

anxiety and other moods, more efficiently. After several months of exercise, the exercised

animals became noticeably less anxious and more resilient to stress during behavioral

testing. But that savoir-faire dissipated rapidly if they were removed from the cages with

running wheels and toys.

In their latest experiment, also presented at the Society for Neuroscience meeting,

the researchers reported that after 10 weeks of running, followed by three weeks of

inactivity, the running rats’ brains were almost indistinguishable from those of animals

that had never exercised. They had almost comparable levels of an enzyme in the brain

that affects the synthesis and uptake of serotonin. It was as if they had never run.

In other words, the brain benefits “wear off quickly,” said Dr. Michael Mazurek, a

professor of neurology at McMaster, who oversaw the study. “This is analogous to what

happens to muscle bulk or heart rate following exercise withdrawal.”

Gilberto Xavier, a professor of psychology at the University of Sao Paulo and senior

author of the study of hippocampal neurons, agrees. “Brain changes are not maintained

when regular physical exercise is interrupted,” he said, adding that, “though our

observations are restricted to rats, indirect evidence suggests that the same phenomenon

occurs in human beings.”

Meaning that the lessons of both studies point in the same direction. For the ongoing

health of our minds, as well as for the plentiful other health benefits of exercise, it might

be wise to stick to those New Year’s exercise resolutions.

How Exercise May Keep Alzheimer's atBayBy GRETCHEN REYNOLDS

January 18, 2012

Alzheimer’s disease, with its inexorable loss of memory and self, understandably alarms

most of us. This is especially so since, at the moment, there are no cures for the condition

and few promising drug treatments. But a cautiously encouraging new study from The

Archives of Neurology suggests that for some people, a daily walk or jog could alter the

risk of developing Alzheimer’s or change the course of the disease if it begins.

For the experiment, researchers at Washington University in St. Louis recruited 201

adults, ages 45 to 88, who were part of a continuing study at the university’s Knight

Alzheimer’s Disease Research Center. Some of the participants had a family history of

Alzheimer’s, but none, as the study began, showed clinical symptoms of the disease.

They performed well on tests of memory and thinking. “They were, as far as we could

determine, cognitively normal,” says Denise Head, an associate professor of psychology

at Washington University who led the study.

The volunteers had not had their brains scanned, however, so the Washington

University scientists began their experiment by using positron emission tomography, an

advanced scanning technique, to look inside the volunteers’ brains for signs of amyloid

plaques, the deposits that are a hallmark of Alzheimer’s. People with a lot of plaque tend

to have more memory loss, though the relation is complex.

Next they genetically typed their volunteers for APOE, a gene involved in

cholesterol metabolism. Everyone carries the APOE gene, but scientists have determined

that those who have a particular variation of the gene known as e4 are at 15 times the risk

of developing Alzheimer’s compared with those who do not carry the variant. The report

also noted that carriers tend to show symptoms of dementia at a younger age, beginning

in their late 60s, on average, instead of in their early 80s for people without the variant.

Fifty-six of the volunteers, of various ages and both sexes, turned out to be positive

for APOE-e4. (A family history of Alzheimer’s may suggest that someone is a carrier for

the e4 variant, Dr. Head says, but it also may not; there are probably many other, still-

unknown genetic causes of the disease, she says.)

Finally, the scientists asked the volunteers to fill out detailed questionnaires about

their exercise habits during the past 10 years. Recently, many studies have looked at

whether being active can lessen someone’s risk for Alzheimer’s, but the results have been

inconsistent, with some studies, in both animals and people, suggesting that regular

exercise has a protective effect and others finding little discernible benefit.

One reason for the inconsistency, Dr. Head suspected, might be that many earlier

studies did not differentiate between people with the e4 variant and those without, and

each group, at least potentially, could respond differently to exercise.

And that certainly proved to be the case in this study. For the group as a whole,

exercise provided marginal benefits. The volunteers who reported walking or jogging

often — meeting (or, in rare instances, exceeding) the American Heart Association’s

exercise recommendation of 30 minutes of moderate or vigorous activity five times a

week — had fewer amyloid plaques than the volunteers who reported almost never

exercising. But the preventive value of the exercise was small, barely reaching the level

of statistical significance.

That situation changed, however, when the scientists examined the results for people

with the e4 gene variant. Most of those who carried the APOE-e4 gene displayed much

larger accumulations of amyloid plaques than those without it.

Unless they exercised. The carriers of the gene who reported walking or jogging for

at least 30 minutes five times a week had plaque accumulation similar to that of

volunteers who were e4-negative. In essence, the APOE-e4 gene carriers mitigated their

inherited risk for developing Alzheimer’s by working out. Or, as the study authors wrote,

a “physically active lifestyle may allow e4 carriers to experience brain amyloid levels

equivalent to e4-negative individuals.”

“The good news is that we found that activity levels, which are potentially

modifiable, could have an impact” on plaque accumulation — and presumably on the

course of Alzheimer’s — in people with a genetic predisposition to the condition, Dr.

Head says.

But the findings came with a downside, too. An overwhelming majority of the

people in the study were sedentary, and for them, an inactive lifestyle seemed to be

accelerating the accumulation of amyloid plaques. Those with the e4 variant who rarely

or never exercised had the most plaques, putting them at heightened risk for the memory

loss of Alzheimer’s in the years to come.

At the moment, it’s not known whether beginning to exercise after plaques have

started to build up might alter that outcome, Dr. Head says. But, she continues,

experiments in mice bred to develop memory loss “have shown that elderly animals that

began a running program benefited.” They experienced less dementia than mice that

didn’t run.

Still, countless questions remain about the interactions of exercise, genetics and

Alzheimer’s, including why the protective benefits of exercise in this study seemed

substantial only for those with the gene variant. “It is looking as if there is some still-

unexplained biochemical interplay between being e4-positive and inactive,” Dr. Head

says, “which heightens risk” for the disease.

“But that doesn’t mean that everyone shouldn’t exercise,” she continues, regardless

of whether they suspect they have a genetic risk for dementia. “There are so many

benefits to exercise,” she says, “and one may be that it helps the brain” to defend itself

against the slow leaking away of memory.

Fitness May Lower Dementia RiskBy NICHOLAS BAKALAR

February 11, 2013

Being physically fit in midlife is associated with a lower risk of dementia in old age, a

new study reports.

Between 1971 and 2009, 19,458 healthy adults younger than age 65 took a treadmill

fitness test as part of a broader health examination. Researchers followed the subjects

through their Medicare records for an average of 24 years.

After adjusting for age, smoking, diabetes, cholesterol and other health factors, the

researchers found that compared with those in the lowest 20 percent for fitness in midlife,

those in the highest 20 percent had a 36 percent reduced risk of dementia.

The reason for the association is unclear, but it was independent of cardiovascular

and cerebrovascular risk factors for dementia, suggesting that both vascular and

nonvascular mechanisms may be involved.

“Dementia is a disease with no cure and no good therapies,” said the lead author, Dr.

Laura F. DeFina, the interim chief scientific officer at the Cooper Institute in Dallas.

Physical activity may be “a preventive way to address dementia instead of addressing the

costs of a disabled elder.”

The study population was largely white and highly educated, and the researchers

acknowledge that their findings, published last week in The Annals of Internal Medicine,

cannot be generalized to other populations. They emphasize that the study is

observational and does not prove causation.

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