Wednesday, October 01, 2014

Exercise Is Good for Your Brain

Two new studies demonstrate the power of exercise to heal our brains, or to prevent illness in the first place. One study (Cell, Sept 25) showed that a muscle gene activated by physical exercise protects the brains of mice from stress-induced depression. The other study (Pediatrics, Sept. 29) showed that kids who participate in regular physical activity showed enhancement of cognitive performance and brain function (executive control).

Here are summaries of each study, along with the abstract. The Pediatrics article is actually open access for those who want to read it.

Muscle to Mind

Exercise-induced muscle metabolites protect the brain from stress-induced depression in a mouse model.

By Jyoti Madhusoodanan | September 25, 2014


A muscle gene activated by physical exercise protects the brains of mice from stress-induced depression, according to results published today (September 25) in Cell. Triggering this gene, PGC-1α1, blocks the transport of a metabolite that, within the brain, may cause inflammation that leads to depression. Understanding the biochemical reason why exercise improves symptoms in some patients with depression “opens up a very interesting therapeutic future,” said study coauthor Jorge Ruas of the Karolinska Institute in Sweden.

Previous studies have shown that physical exercise can prevent or improve the condition of many diseases, ranging from diabetes and obesity to mood disorders and depression. But whether the improvement stems from cardiovascular effects, muscle conditioning, or psychosocial benefits has been unclear.

In 2012, Ruas and his colleagues found that different forms of the skeletal muscle PGC-1α gene responded to different kinds of exercise. The gene could be transcribed from two different promoters: one version was responsive to resistance training, such as lifting weights, while the other, PGC-1α1, responded to endurance activity. To understand the different variants of the gene, the researchers created various mouse models that constitutively expressed different forms of these genes at high levels, as well as knockout lines. The animal models also offered a means to separate the biochemical effects of exercise from less tangible psychosocial effects, Ruas explained.

In the new study, Ruas and his coauthors subjected transgenic PGC-1α1-expressing mice and control animals to chronic mild stress to mimic one trigger of human depression. After five weeks, the control animals showed behavioral signs of anhedonia and despair, such as failing to exert themselves during a forced swim test. Their brains also revealed changes that included decreased synaptic plasticity, imbalances in glutamate metabolism, and lower levels of neurotrophic factors. The transgenic mice, however, showed neither behavioral nor anatomical signs of depression.

Analyzing metabolic differences in the animals revealed differences in tryptophan metabolism, said Ruas. “From a brain perspective it made sense that tryptophan metabolism because it’s used by the brain to make serotonin,” he said, “but for the skeletal muscle it made less sense.”

Digging deeper, they found that the PGC-1α1 gene controls a step in muscle metabolism of tryptophan where one metabolite, kynurenine (KYN), is converted to a different form, kynurenic acid (KA). Previous studies have linked KYN within the brain to inflammation, which is correlated to depression and schizophrenia-like symptoms. Outside the brain, the liver converts more tryptophan to KYN in times of stress, and KYN can cross the blood-brain barrier to trigger an inflammatory response.

In mouse muscle, increased PGC-1α1 levels—such as those induced by exercise—converted more KYN to KA, which cannot cross the blood-brain barrier. To test whether the depression-like symptoms seen in their experiments were indeed mediated by KYN, the researchers administered KYN to both control and transgenic mice; only the former group showed gene expression and behavioral changes linked to depression.

The conversion of KYN to KA by PGC-1α1 may be a key metabolic step in linking stress-induced inflammation and depression, the results suggest.

“It is important to remember that ‘stress’ is not only having a stressful everyday life —but outside events that activates [the cellular] stress-response,” coauthor Maria Lindskog told The Scientist in an e-mail.

When control mice were put through an eight-week exercise regimen, skeletal muscle expression of the PGC-1α1 gene increased. Similar results were seen in healthy human adults after a three-week training program. Collectively, the results show that “exercised muscle acquires a detoxification role in stressful conditions that have not been described before,” said Ruas. “I don’t think anyone had previously thought of correlating muscle changes with inflammation [in the brain].”

“This is a very interesting study about the non-pharmacologic mechanisms of antidepressant action, a topic that’s not addressed very much,” said neuroscientist Michael Lutter of the University of Iowa who was not involved in the work.

Behavioral immunologist Andrew Miller of Emory University added that exercise, or drugs that target PGC-1α1, would likely be effective only in depressed patients who also had signs of inflammation and elevated KYN, such as those with early life stress, obesity, cancer, or other diseases. In physically healthy patients, brain levels of KYN are not clearly correlated to symptoms of depression. “Exercise may be especially relevant to those depressed patients who have increased inflammation,” said Miller, who was not involved with this study. These results “allow us to target therapies like exercise to select populations of individuals,” he added.

“Finding that certain aspects of muscle metabolism may be associated with the development of mood disorders adds to [an emerging] theme,” said Lutter. “There’s a much more intimate connection between the mind and body than was previously appreciated.”

L.Z. Agudelo et al. (2014, Sep 25). Skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. Cell; 159(1): 33–45. doi:10.1016/j.cell.2014.07.051, 2014.

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Skeletal Muscle PGC-1α1 Modulates Kynurenine Metabolism and Mediates Resilience to Stress-Induced Depression

Leandro Z. Agudelo, Teresa Femenía, Funda Orhan, Margareta Porsmyr-Palmertz, Michel Goiny, Vicente Martinez-Redondo, Jorge C. Correia, Manizheh Izadi, Maria Bhat, Ina Schuppe-Koistinen, Amanda T. Pettersson, Duarte M.S. Ferreira, Anna Krook, Romain Barres, Juleen R. Zierath, Sophie Erhardt, Maria Lindskog, Jorge L. Ruas

  • Skeletal muscle-PGC-1α1 transgenic mice are resilient to stress-induced depression
  • PGC-1α1 induces skeletal muscle kynurenine aminotransferase (KAT) expression
  • Skeletal muscle PGC-1α1 controls plasma and brain kynurenine/kynurenic acid balance
  • Exercise training activates PGC-1α1:PPARα/δ:KAT in mouse and human skeletal muscle


Depression is a debilitating condition with a profound impact on quality of life for millions of people worldwide. Physical exercise is used as a treatment strategy for many patients, but the mechanisms that underlie its beneficial effects remain unknown. Here, we describe a mechanism by which skeletal muscle PGC-1α1 induced by exercise training changes kynurenine metabolism and protects from stress-induced depression. Activation of the PGC-1α1-PPARα/δ pathway increases skeletal muscle expression of kynurenine aminotransferases, thus enhancing the conversion of kynurenine into kynurenic acid, a metabolite unable to cross the blood-brain barrier. Reducing plasma kynurenine protects the brain from stress-induced changes associated with depression and renders skeletal muscle-specific PGC-1α1 transgenic mice resistant to depression induced by chronic mild stress or direct kynurenine administration. This study opens therapeutic avenues for the treatment of depression by targeting the PGC-1α1-PPAR axis in skeletal muscle, without the need to cross the blood-brain barrier.

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Electrophysiological plots representing brain processing capacity and mental workload (P3 amplitude) during cognitive tasks that require executive control in children in the experiment and control groups. Red represents the greatest amplitude, and blue the lowest. (Hillman et al, Pediatrics/The Atlantic)

Mental exercises to build (or rebuild) attention span have shown promise recently as adjuncts or alternatives to amphetamines in addressing symptoms common to Attention Deficit Hyperactivity Disorder (ADHD). Building cognitive control, to be better able to focus on just one thing, or single-task, might involve regular practice with a specialized video game that reinforces "top-down" cognitive modulation, as was the case in a popular paper in Nature last year. Cool but still notional. More insipid but also more clearly critical to addressing what's being called the ADHD epidemic is plain old physical activity.

This morning the medical journal Pediatrics published research that found kids who took part in a regular physical activity program showed important enhancement of cognitive performance and brain function. The findings, according to University of Illinois professor Charles Hillman and colleagues, "demonstrate a causal effect of a physical program on executive control, and provide support for physical activity for improving childhood cognition and brain health." If it seems odd that this is something that still needs support, that's because it is odd, yes. Physical activity is clearly a high, high-yield investment for all kids, but especially those attentive or hyperactive. This brand of research is still published and written about as though it were a novel finding, in part because exercise programs for kids remain underfunded and underprioritized in many school curricula, even though exercise is clearly integral to maximizing the utility of time spent in class.

The improvements in this case came in executive control, which consists of inhibition (resisting distraction, maintaining focus), working memory, and cognitive flexibility (switching between tasks). The images above show the brain activity in the group of kids who did the program as opposed to the group that didn't. It's the kind of difference that's so dramatic it's a little unsettling. The study only lasted nine months, but when you're only seven years old, nine months is a long time to be sitting in class with a blue head. It may potentially be advisable to consider possibly implementing more exercise opportunities for kids.

Earlier this month, another study found that a 12-week exercise program improved math and reading test scores in all kids, but especially in those with signs of ADHD. (Executive functioning is impaired in ADHD, and tied to performance in math and reading.) Lead researcher Alan Smith, chair of the department of kinesiology at Michigan State, went out on no limb at all in a press statement at the time, saying, "Early studies suggest that physical activity can have a positive effect on children who suffer from ADHD."

Last year a very similar study in the Journal of Attention Disorders found that just 26 minutes of daily physical activity for eight weeks significantly allayed ADHD symptoms in grade-school kids. The modest conclusion of the study was that "physical activity shows promise for addressing ADHD symptoms in young children." The researchers went on to write that this finding should be "carefully explored with further studies."

"If physical activity is established as an effective intervention for ADHD," they continued, "it will also be important to address possible complementary effects of physical activity and existing treatment strategies ..." Which is a kind of phenomenal degree of reservation compared to the haste with which millions of kids have been introduced to amphetamines and other stimulants to address said ADHD. The number of prescriptions increased from 34.8 to 48.4 million between 2007 and 2011 alone. The pharmaceutical market around the disorder has grown to several billion dollars in recent years while school exercise initiatives have enjoyed no such spoils of entrepreneurialism. But, you know, once there is more research, it may potentially be advisable to consider possibly implementing more exercise opportunities for kids.


Children in the Illinois after-school physical activity program
(L. Brian Stauffer)

Over all, the pandemic of physical inactivity, as Hillman and colleagues put it in their Pediatrics journal article today, is "a serious threat to global health" responsible for around 10 percent of premature deaths from noncommincable diseases. But it clearly manifests in ways more subtle than deaths, including scholastic performance, which we're continuously learning. I talked last week with Paul Nystedt, an associate professor of economics and finance at Jönköping University in Sweden, who just published a multi-country study that found that obese teenagers go on to earn 18 percent less money as adults than their peers, even if they are no longer obese. He believes that's most likely because of the adversity that obese kids experience from classmates and teachers, which leads to both cognitive and noncognitive disparities between obese and non-obese kids. Because obese children are more likely to come from low-income homes to begin with, that only perpetuates wealth gaps and stifles mobility. Nystedt and his coauthors conclude, "The rapid increase in childhood and adolescent obesity could have long-lasting effects on the economic growth and productivity of nations."

John Ratey, an associate professor of psychiatry at Harvard, suggests that people think of exercise as medication for ADHD. Even very light physical activity improves mood and cognitive performance by triggering the brain to release dopamine and serotonin, similar to the way that stimulant medications like Adderall do. In a 2012 TED talk, Ratey argued that physical exercise "is really for our brains." He likened it to taking "a little bit of Prozac and a little bit of Ritalin." As a rule, I say never trust anyone who has given a TED talk. But maybe in this case that's a constructive way to think about moving one's body. But not the inverse, where taking Ritalin counts as exercise.
Hillman, CH, et al. (2014, Sep 29). Effects of the FITKids Randomized Controlled Trial on Executive Control and Brain Function. Pediatrics; doi: 10.1542/peds.2013-3219

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Effects of the FITKids Randomized Controlled Trial on Executive Control and Brain Function

Charles H. Hillman, PhD, Matthew B. Pontifex, PhD, Darla M. Castelli, PhD, Naiman A. Khan, PhD, RD, Lauren B. Raine, BS, Mark R. Scudder, BS, Eric S. Drollette, BS, Robert D. Moore, MS, Chien-Ting Wu, PhD, and Keita Kamijo, PhD

OBJECTIVE: To assess the effect of a physical activity (PA) intervention on brain and behavioral indices of executive control in preadolescent children.

METHODS: Two hundred twenty-one children (7–9 years) were randomly assigned to a 9-month afterschool PA program or a wait-list control. In addition to changes in fitness (maximal oxygen consumption), electrical activity in the brain (P3-ERP) and behavioral measures (accuracy, reaction time) of executive control were collected by using tasks that modulated attentional inhibition and cognitive flexibility.  
RESULTS: Fitness improved more among intervention participants from pretest to posttest compared with the wait-list control (1.3 mL/kg per minute, 95% confidence interval [CI]: 0.3 to 2.4; d = 0.34 for group difference in pre-to-post change score). Intervention participants exhibited greater improvements from pretest to posttest in inhibition (3.2%, 95% CI: 0.0 to 6.5; d = 0.27) and cognitive flexibility (4.8%, 95% CI: 1.1 to 8.4; d = 0.35 for group difference in pre-to-post change score) compared with control. Only the intervention group increased attentional resources from pretest to posttest during tasks requiring increased inhibition (1.4 µV, 95% CI: 0.3 to 2.6; d = 0.34) and cognitive flexibility (1.5 µV, 95% CI: 0.6 to 2.5; d = 0.43). Finally, improvements in brain function on the inhibition task (r = 0.22) and performance on the flexibility task correlated with intervention attendance (r = 0.24).  
CONCLUSIONS: The intervention enhanced cognitive performance and brain function during tasks requiring greater executive control. These findings demonstrate a causal effect of a PA program on executive control, and provide support for PA for improving childhood cognition and brain health.

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