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Brain Training—Plain Gaming, or a New Vein for Preclinical Research?

If you listen to National Public Radio, watch TV, or surf the Web, chances are you have come across commercials enticing you to “improve your memory” and “unlock your inner genius” with “brain training developed by neuroscientists.”  In search of solid evidence for these claims, Alzforum came across a new research use for the data generated as millions of people are playing online while being tracked. Scientists are mining databases for clues that people might be sliding toward dementia, and become candidates for therapeutic prevention trials. Read Jessica Shugart’s two-part story.

Is Brain Training More Than Just Fun and Games?

Taking your brain to the gym has become more popular than ever. As evident from the NeuroGaming Conference and Expo held in San Francisco May 7-8, companies such as Lumosity claim that pushing your brain’s cognitive limits with computer games will boost its performance. However, carefully controlled studies are lacking, and evidence that brain-training skills transfer to other, more practical aspects of life has yet to materialize. While the jury is out on that, a new appreciation is emerging that the games might be useful to researchers in other ways. Some researchers hope to extract data from Lumosity’s gigantic, 60 million user-strong database to learn more about how cognition wanes with age and disease. Others predict the games may serve as sensitive, widely distributed tools to flag people in cognitive decline and guide them toward clinical trials, or to measure the effects of therapeutic interventions on the brain (see Part 2 of this two-part story). 

The potential benefits of cognitive training are based on the concept of neuroplasticity—the idea that the brain’s networks of cells, signals, and chemicals adapt when called into action. “That idea really drives this whole field,” said Adam Gazzaley of the University of California, San Francisco. “Games are a vehicle to deliver a targeted interaction that challenges the brain, and if that interaction is done is a way that is adaptive and facilitates learning, you’ll get benefits that go beyond performance on the game itself,” he said. Gazzaley has no relationship to Lumosity.

Brain Training or Just Plain Gaming? 
Neuroplasticity was certainly a buzzword at the NeuroGaming conference. Gaming companies and researchers who hope to use games to enhance mood, boost cognition, relieve the symptoms of PTSD, or just entertain, attended this second annual meeting. A key burden of proof that scientists demand from brain trainers is the demonstration that cognitive benefits transfer to realms beyond improving at the game itself. Pressed by an audience question about this transfer, Lumosity’s Joe Hardy acknowledged its importance during a panel discussion and said his company was working on creating reliable cognitive tests to measure it. “That’s what I’m spending most of my time thinking about these days,” he said. 

A Balanced Workout.

Lumosity claims its games target and strengthen key aspects of cognition that could lead to improvements in aspects of daily life. Researchers remain skeptical about how well the games deliver. Image courtesy of Lumosity.

Lumosity was co-founded in 2005 by Michael Scanlon, who left his Ph.D. studies in neuroscience at Stanford behind to start the company. The website went online in 2007 and to date has been backed by $67.5 million in venture capital investment, according to the company. Lumosity charges users a subscription fee to gain access to its full suite of games and cognitive tracking services, but declined to disclose how many initial users become subscribers. Hardy is the company’s vice president of research and development.

In an interview with Alzforum, Hardy cited the Advanced Cognitive Training for Independent and Vital Elderly trial as one that convinced him that brain training held promise for seniors. ACTIVE measured the effects of computerized brain training (from the company Posit Science) on nearly 3,000 healthy older adults, who played games designed to strengthen either reasoning, processing speed, or memory. Over five to 10 years, participants who played the games were modestly protected from declines in reported performance on activities of everyday living, such as preparing meals, keeping up with finances, and doing housework (see Rebok et al., 2014, and Dec 2006 news story). A decade after playing the games, participants in the reasoning and processing speed groups, though not the memory group, continued to show benefits of training based on cognitive tests designed to measure these skills.

Hardy also pointed to the Human Cognition Project, an ongoing collaboration between Lumosity and scientists around the globe. Adding to the company’s in-house studies, researchers involved in the project either use Lumosity’s games in their own studies or tap into the company’s 1.5 billion recorded game sessions in search of patterns that could reveal factors affecting cognition. Many of the project’s investigations test whether Lumosity’s brain games improve cognitive function in vulnerable populations, including children with attention deficit hyperactivity disorder, cancer survivors suffering from aftereffects of chemotherapy, and people with psychiatric disorders such as depression or schizophrenia. Some investigations focus on older people who could be in the preclinical phase of neurodegenerative diseases such as Alzheimer’s. 

Of the 47 posters, presentations, and publications listed on Lumosity’s HCP website, 11 have been published in peer-reviewed journals, and three of these dealt with cognitive impairment in the aging population. A pilot study led by Skye McDonald at the University of New South Wales in Kensington, Australia, looked at whether Lumosity games would improve cognition in 16 people with mild cognitive impairment (MCI). Those who participated in daily Lumosity training improved their performance on the games. However, they improved on only one of six measures—visual attention—of the Cambridge Neuropsychological Test Automated Battery (CANTAB), and this effect was partly due to a decrease in performance within the control group, who did not play games or participate in cognitive activities of any kind (see Finn and McDonald, 2011). After 30 training sessions spanning nearly 12 weeks, none of the participants reported improvements in daily functioning or boosts in memory, first author Maurice Finn told Alzforum. “The results weren’t convincing enough for us to pursue the Lumosity software further,” he said.

Another small study tested whether playing Lumosity games would improve attention and alertness in healthy older adults (see Mayas et al., 2014). Fifteen seniors each logged 20 one-hour Lumosity game sessions over 10 to 12 weeks, while a control group of 12 people met three times to chat about aging issues over coffee. After the trial, all were tested on a separate measure of distractibility in which they had to distinguish between odd and even numbers from a list while being distracted by unfamiliar sounds. Before the intervention, these distracting sounds slowed down response times by about 40 milliseconds in both groups. Following the intervention, those who played Lumosity’s games lowered that distraction penalty by an average of 12 milliseconds, while those in the control group stayed the same. The study also reported a small but significant improvement in a measure of alertness in the experimental group. The study did not test whether the benefit endured or translated to everyday tasks. For context, a blink of the human eye is 100 to 300 milliseconds long; the average driver’s reaction time is around .75 seconds, according to the Delaware Department of Motor Vehicles.

Thomas Dannhauser of St. Margaret’s Hospital in Epping, England, tested whether Lumosity’s brain games, when administered along with stimulating activities and physical exercise, could boost cognition in people with mild cognitive impairment (see Dannhauser et al., 2014). The researchers measured cognition in 67 people who received three interventions: learning new group activities, such as tap dancing, pottery, and photography; physical exercise; and individual cognitive training on Lumosity’s games. After 12 weeks, the participants showed improvement in working memory, which was one of six cognitive tests they took. They also improved in measures of physical health and fitness. Dannhauser said he hopes to conduct larger trials to parse out which of the three interventions each participant received was responsible for the cognitive benefit. Physical exercise has been reported in randomized controlled clinical trials to improve cognition in people with mild cognitive impairment (see Sep 2008 news story and Suzuki et al., 2012). For future studies, Dannhauser plans to use the Einstein Brain Trainer, another cognitive training program, because it is less expensive than a Lumosity subscription, he said. Dannhauser thinks the act of learning and participating in novel activities, whether computer brain training games or a new craft, is what may ultimately boost cognition.

Denise Park of the University of Texas in Dallas agrees. Park studies aging, and she recently reported that learning quilting, digital photography, or both (as opposed to playing word games, reading informative magazines such as National Geographic, or socializing) over 14 weeks improved cognitive function in healthy seniors (see Park et al., 2014). “This study tells us that you can probably maintain function of your mind longer if you stay mentally engaged and consistently challenge yourself,” said Park. “I don’t think it’s important what the activity is, but more that it be novel and hard enough to require mental effort,” she said. As to whether brain-training games such as Lumosity’s fit the bill for such challenging activities, Park said she considers their effectiveness yet to be determined.

John Harrison of Metis Cognition in Warminster, England, told Alzforum that based on available evidence, he remains agnostic whether or not brain training works. Many people in the field do not share his doubt, Harrison said, noting, “Views on whether brain training works seem to be very visceral.” Harrison consults for pharmaceutical companies looking to design cognitive tests that measure the effect of drugs. He also consults for companies that make brain-training games, such as the London-based MyCognition, which designs games to improve productivity at school or work, and to stave off cognitive decline. At present, MyCognition is still validating whether players of its game, called Monster Valley, even improve at the game as they play, Harrison said. Next will come the more important and challenging task: showing that the game improves cognitive function on separate neuropsychological tests or in everyday life.

Even for studies that appear to indicate a cognitive boost from brain training, interpretation of the results can be clouded by caveats, according to Daniel Simons of the University of Illinois in Urbana-Champaign. One pitfall is the placebo effect. This manifests in the form of expectations of better cognitive performance in members of the experimental group, Simons told Alzforum. Therefore, especially with studies that rely on groups of controls who do nothing or participate in activities that would not be expected to confer a cognitive benefit, the results should be taken with dose of skepticism, he said.

Racing Against Decline.

UCSF’s Adam Gazzaley looks on as a woman plays NeuroRacer, a game he designed to boost multitasking skills. Image courtesy of Adam Gazzaley, UCSF.

Some studies do include relevant control groups. In a recent trial, Gazzaley included an active control group that played a version of the driving game his lab developed, called NeuroRacer, without distractions from road signs. The experimental group, on the other hand, drove the digital car while also responding to the signs, a task the researchers hoped would improve multitasking. The experimental group did show gains in measures of attention and working memory, as compared with the active control group. The gains lasted up to six months and correlated with changes in brain-wave patterns (see Sep 2013 news story).

However, Simons counters that even in NeuroRacer, participants may still have a keen sense of exactly which skills they are being trained in, voiding the placebo control. Simons co-authored a survey in which researchers polled volunteers about their expectations for cognitive improvement from playing Tetris or an action video game, and found that participants expected the action video game (but not Tetris) would help them improve on visual and attention tasks (see Boot et al., 2013). Simons thinks researchers would be well advised to at least poll participants about their expectations to aid in the interpretation of results as well the development of well-designed controls.

Gazzaley’s study was featured in the general media, including The New York Times. It came on the heels of reports that improvements on game performance failed to transfer to related skills or to tasks of everyday life (see Redick et al, 2013, and Owen et al., 2010).—Jessica Shugart

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References

News Citations

  1. Brain Training Database: Treasure Trove for Preclinical Alzheimer’s Research?
  2. The ACTIVE Trial—Long-Term Effects of Cognitive Training
  3. Work Up a Sweat to Stay Sharp, Randomized Trial Suggests
  4. In Small Study, Brain Training Benefits Healthy Seniors

Paper Citations

  1. . Ten-Year Effects of the Advanced Cognitive Training for Independent and Vital Elderly Cognitive Training Trial on Cognition and Everyday Functioning in Older Adults. J Am Geriatr Soc. 2014 Jan 13; PubMed.
  2. . Computerised Cognitive Training for Older Persons With Mild Cognitive Impairment: A Pilot Study Using a Randomised Controlled Trial Design. Brain Impairment, Volume 12, Issue 03, December 2011, pp 187-199
  3. . Plasticity of attentional functions in older adults after non-action video game training: a randomized controlled trial. PLoS One. 2014;9(3):e92269. Epub 2014 Mar 19 PubMed.
  4. . A complex multimodal activity intervention to reduce the risk of dementia in mild cognitive impairment--ThinkingFit: pilot and feasibility study for a randomized controlled trial. BMC Psychiatry. 2014 May 5;14:129. PubMed.
  5. . Effects of multicomponent exercise on cognitive function in older adults with amnestic mild cognitive impairment: a randomized controlled trial. BMC Neurol. 2012 Oct 31;12:128. PubMed.
  6. . The impact of sustained engagement on cognitive function in older adults: the Synapse Project. Psychol Sci. 2014 Jan;25(1):103-12. Epub 2013 Nov 8 PubMed.
  7. . The Pervasive Problem With Placebos in Psychology: Why Active Control Groups Are Not Sufficient to Rule Out Placebo Effects. Perspectives on Psychological Science July 2013 vol. 8 no. 4 445-454
  8. . No evidence of intelligence improvement after working memory training: a randomized, placebo-controlled study. J Exp Psychol Gen. 2013 May;142(2):359-79. Epub 2012 Jun 18 PubMed.
  9. . Putting brain training to the test. Nature. 2010 Jun 10;465(7299):775-8. PubMed.

External Citations

  1. Department of Motor Vehicles
  2. The New York Times

Further Reading

Brain Training Database: Treasure Trove for Preclinical Alzheimer’s Research?

Whether or not researchers believe that brain training with computer games improves cognition, some have discovered a way to mine this vein for clinical research. Lumosity, the most prominent of the brain-training companies, has opened its gaming database to researchers as part of what it calls the Human Cognition Project. The database contains records of every mouse click from the 1.5 billion game sessions logged by the company’s 60 million users. Researchers from around the globe are sifting through it in search of patterns that may illuminate how aging, stress, sleep, and other lifestyle factors affect cognition. In particular, some scientists are panning the database for signatures of early decline that may flag people for prevention trials. Some researchers think brain games in general—which adapt to each user’s cognitive ability—may one day serve as cognitive diagnostics to monitor progression or help enroll clinical trials. Whether brain training boosts brain performance remains unclear (see Part 1 of the series), but in the meantime researchers are moving ahead to put the game data to some serious use.

Michael Weiner of the University of California, San Francisco, hopes to use the game data to identify people who show signs of cognitive decline and may make good candidates for AD prevention trials. Weiner will present initial results at the Alzheimer’s Association International Conference in Copenhagen, Denmark, in July. He told Alzforum that preliminary findings suggest that game performance slips with age, and that this is more severe in some people than others. Alas, navigating the data was no small task, Weiner said. “The data has a lot of variability. People are gaming in an unsupervised setting, and there are many factors that affect game performance,” he said. While Weiner hopes the game data will be useful, “we are just at the beginning of the beginning,” he said.

The Lumosity database offers the advantage of a historical record of cognitive function, noted Weiner. “When you enroll people in clinical trials, you have very little history about them,” he said. “Having some kind of objective, longitudinal data, even if it’s not perfect, can potentially identify people who are at risk for future cognitive decline and AD.” As therapeutic trials targeting preclinical Alzheimer’s are gearing up, they are facing the challenge of identifying people who are sliding toward Alzheimer’s dementia but are not showing up in doctors’ offices yet. At present these trials use various combinations of genetic and fluid and imaging biomarkers to find the right trial participants. If valid cognitive performance predictors can be found in the Lumosity database, then in theory the portion of its membership older than 50 might provide the necessary cohorts for some of those trials. Lumosity declined to share how many of its users are over 50, except to state that its user demographic is “similar to the demographic of the Internet.” According to the Pew Research Internet Project, 88 percent of people over 50 and 57 percent of people 65 and older used the Internet in 2014.

Murali Doraiswamy of Duke University in Durham, North Carolina, was one of the first researchers to partner with Lumosity. His work took a different tack. In a study that incorporated the cognitive performance of more than 100,000 Lumosity gamers per experimental group, Doraiswamy and Lumosity researchers reported that people who get seven hours of sleep per night perform optimally on the games, and that people who indulge in one to two alcoholic drinks per day outperform those who have more drinks or none (see Sternberg et al., 2013). These findings fall in line with previous studies that used cognitive tests, rather than games, to measure similar factors. Research on sleep and cognitive decline in aging reported seven hours of sleep to be ideal (Devore et al., 2014), and the finding that one or two alcoholic drinks, but not more or none, are relatively protective, is confirmed by meta-analysis (see AlzRisk).

While some researchers argue that the data from cognitive tests taken in uncontrolled settings is contaminated by uncertainties, Doraiswamy considers the home setting to be closer to reality than what researchers see in the clinic. “The Holy Grail in assessing cognitive problems, or assessing whether a person is showing early signs of AD, is to judge them in the settings where they are having problems,” Doraiswamy said. “That’s the real world.” On that, Weiner agrees. “We will present data at AAIC supporting the view that at home unsupervised tests are pretty good,” he said.

Even so, Weiner sees the Internet as a cost-efficient recruitment aid for clinical trials. He recently kicked off the Brain Health Registry, a UCSF-run website that collects demographic and longitudinal cognitive data on people of all ages who sign up to join in the research effort. The registrants answer questions about their mental and physical health, then take cognitive tests every six months. Rather than using games to assess cognitive function, this registry employs the CogState Brief Battery, which measures working memory, attention, and processing speed. The Brain Health Registry also uses the Brain Performance test from Lumosity, which advertises this registry on its own website.

Weiner plans to present the initial findings from the registry in Copenhagen as well, but told Alzforum he is elated by the speed of enrollment and how well the online cognitive test data seems to match up with similar data collected in a clinical setting. “We’ve had an unbelievably phenomenal success. Seven thousand people enrolled in three months, and more than half took the CogState battery.” Academic institutions and pharmaceutical companies can tap the registry for potential study enrollees, Weiner said. He added that the online tests do not replace conventional testing done by neuropsychologists. Instead they can serve as an efficient screen and offer an unprecedented level of longitudinal monitoring. “The question is, how can the Internet help us get to a cure more rapidly?” Weiner asked. “I think there are many ways to use it, and this is one.”

Putting Games to the Test
Apart from their potential roles in boosting cognition or flagging people in cognitive decline, some researchers propose that brain-training games may also serve as sensitive cognitive tests in their own right. Cognitive tests used in AD clinical trials, such as the MMSE, CogState, and batteries such as the ADAS-Cog, are highly validated and administered under the supervision of a neuropsychologist.  Advances are being made in putting together computerized composites, which researchers hope will be sensitive enough to detect people in earlier stages of cognitive decline (see Jun 2014 news story, Nov 2013 news story, and Alzforum Webinar).

However, unlike games, current tests used in clinical trials are not adaptive, meaning they do not adjust their difficulty in real time based on how well a person performs. This leads to varying amounts of effort and frustration on the part of people taking the test. It also leads to “ceiling” and “floor” effects, where the tests are either too easy or too hard to detect change in some people. “There are many tools that have been well established in AD, but a lot of them are too easy for people with MCI,” said Veronika Logovinsky of Eisai, Inc. in Woodcliff Lake, New Jersey. However, while Logovinsky thinks adaptive tests are likely to become the norm someday, she said implementing an adaptive test or game as a cognitive measure in a trial is an uphill battle. “Trials are a very tricky business, so if you introduce something new, you have to convince regulators that it provides valid results,” she said. “Right now, it’s clearly easier to just give the same test for everybody.”

Despite the potential for regulatory hurdles, Adam Gazzaley of the University of California, San Francisco, thinks cognitive tests based on adaptive games may one day prove themselves exquisitely sensitive. “We call it a game, but when you distill it down to its active ingredients, it’s a carefully calibrated cognitive test, and the adaptivity element helps to make it that way,” Gazzaley said.

Keith Wesnes of Wesnes Cognition Ltd. in Streatley on Thames, England, is an expert on the use of cognitive testing in dementia trials (e.g., Wesnes et al., 2013). He agreed that carefully designed computerized games could hold potential as tests. “It’s not far-fetched to believe that you could have a game that measures your cognitive function,” Wesnes said. “The game could be used as a way to measure someone’s cognitive changes over time.”

Screenshot of Akili's clinical product Project: EVO. Pfizer is collaborating with Akili to find out if the game can be used to flag people with prodromal AD. © Akili Interactive Labs 2014.

At least one company is hoping the games will win the hearts and minds of regulators and pharmaceutical companies seeking to detect subtle changes in cognition in response to drugs, or to pick out participants for such trials. Gazzaley co-founded the Boston-based company Akili Interactive Labs. This startup is developing a revved-up version of Gazzaley’s NeuroRacer game, called Project Evo, for cognitive training as well as diagnostic purposes. In collaboration with Pfizer, Akili plans to enroll 100 people who have subjective memory complaints that fall short of cognitive impairment measurable by the Mini Mental State Exam or ADAS-Cog. The participants will play the game regularly at home over the course of a month, while researchers monitor their every move from afar. The goal of the study is to determine whether a participant’s low performance and learning of the game correlates with positive AD biomarkers such as PET scans for amyloid, MRI for cortical thinning, and blood and genetic biomarkers. “If it works, then you have a cheap, at-home segmentation tool to refer people to clinical trials or to start taking early interventions,” Eddie Martucci of Akili told Alzforum at the NeuroGaming conference. The study is set to begin within the coming months, Martucci said.—Jessica Shugart 

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References

News Citations

  1. Is Brain Training More Than Just Fun and Games?
  2. Test Battery Picks Up Cognitive Decline in Normal Populations
  3. Are New Cognitive Tests Ready For Preclinical Trials?

Webinar Citations

  1. New Frontier: Developing Outcome Measures for Pre-dementia Trials

Paper Citations

  1. . The largest human cognitive performance dataset reveals insights into the effects of lifestyle factors and aging. Front Hum Neurosci. 2013;7:292. Epub 2013 Jun 20 PubMed.
  2. . Sleep duration in midlife and later life in relation to cognition. J Am Geriatr Soc. 2014 Jun;62(6):1073-81. Epub 2014 May 1 PubMed.
  3. . The role of human cognitive neuroscience in drug discovery for the dementias. Curr Opin Pharmacol. 2014 Feb;14:62-73. Epub 2013 Dec 22 PubMed.

External Citations

  1. Pew Research Internet Project
  2. AlzRisk
  3. Brain Health Registry

Further Reading

No Available Further Reading