Video games that can affect the brain have been in existence for some time, but only in the last several years has the concept of measuring those effects or using those problem-solving skills been applied to the drug development process. 

This concept, known as gamification, has permeated the life sciences industry over the last few years, starting as a way to entice online gamers to become “citizen scientists,” helping to solve complex scientific problems such as protein folding or creating a virtual map of the eye, while playing a video game online.

Now, gamification has moved into healthcare, offering patients incentives to comply with their medical regimens through mobile gaming systems that reward adherence, helping diagnose illnesses, explaining clinical trials and recruiting patients.

“Gamification works because our response to games is deeply hard-wired into our psychology,” Kevin Werbach, associate professor of legal studies and business ethics at the Wharton School at the University of Pennsylvania, wrote in the journal The Conversation. “Game design techniques can activate our innate desires to recognize patterns, solve puzzles, master challenges, collaborate with others and be in the driver’s seat when experiencing the world around us. They also can create a safer space for experimentation and learning. The surface dimension is motivation through rewards.”

Some of the most basic health e-games range from Destination Discovery, a lighthearted video board game on Eli Lilly’s web site that teaches about drug development by asking players a series of questions about the research process, to Pain Squad, which integrates a criminal investigation game to encourage kids with cancer who still are weak from chemotherapy treatments to fill out their pain diaries twice a week.   

In clinical trials, Patient Partner has been used to improve medication adherence, and The Paper Kingdom helps children ages eight to 14 confront and eliminate common misconceptions about trial participation.

Patient diagnosis

One key growth area in medical gamification is helping diagnose patients with early signs of diseases. Pfizer has partnered with and recently invested in Boston-based Akili Interactive Labs, whose video game Evo Challenge is designed to detect early signs of Alzheimer’s disease in healthy individuals. Players have to navigate obstacles, responding to targets by tapping on objects that pop up and are a certain color, based on game instructions. 

Evo Challenge also keeps track of movements every 30 milliseconds and can monitor the user’s behavior, quickly adapting the game level to that player. The game determines how well users pay attention and make decisions amid a series of distractions.

“In Alzheimer’s, there is a big unmet need in trying to identify individuals who are at risk of developing the disease before major symptoms occur,” said Eddie Martucci, Akili’s president. “Right now there is no simple cognitive way to do that. Drug companies want earlier disease signs before the typical symptoms, and one way to do that is with very expensive PET scans [positron emission tomography—an imaging test that uses a radioactive substance to look for disease in the body] or MRIs [magnetic resonance imaging—an imaging technique used to investigate the anatomy and physiology of  the body].”

Pfizer was looking for a less cumbersome way to identify early stages of Alzheimer’s, possibly through a downloadable video game that is both cheaper and more accessible. Now, Akili is working with Pfizer on an early stage clinical trial recruiting 100 healthy people in Florida and Michigan, 50% of them with abnormal deposits of amyloid, a protein associated with Alzheimer’s and linked to increased risk of developing symptoms of the disease. All trial participants will receive an iPad on which to play Evo Challenge, which features cutting-edge graphics, bright colors and modern dance-beat music, with an older doctor character who serves as the player’s mentor.

Researchers will analyze each participant’s game performance to determine if they can differentiate between the two groups of volunteers. Akili’s technology will be used as a “biomarker” to detect early signs of Alzheimer’s—and as a way for Pfizer to assess and select clinical trial patients, said Martucci.

The Evo Challenge is part of a series of recent and ongoing studies based on the research of Adam Gazzaley, a co-founder of Akili, and his scientific group at the University of California, San Francisco. Nearly 20 months ago, Gazzaley’s team wrote a paper in the journal Nature concluding that video game training can improve multitasking, attention and memory function in older adults. It said after four weeks of training on a three-dimensional driving and multitasking video game (one hour, three days a week), older Americans had better brain performance and neural activity, which lasted six months without further game practice.

“Our technology provides us with a nice edge in multiple patient populations and multiple uses,” said Martucci, adding the company also is using EVO in smaller clinical trials, including a recently completed trial with Duke University to test the game’s effectiveness in improving function in children with Attention Deficit Hyperactivity Disorders (ADHD), one of the most common childhood disorders that can continue through adolescence and adulthood. Symptoms include difficulty staying focused and paying attention, difficulty controlling behavior and hyperactivity. Additional trials have been conducted for both children and college students with autism spectrum disorders, and in patients with depression.   

Akili is seeking FDA approval for the Alzheimer’s game as a medical device. The game, according to The New York Times, could “become a sort of cognitive Lipitor or Viagra, a game that your doctor might prescribe for your aging mind.”

Focusing on ADHD

Also on the FDA device regulatory pathway is CogCubed, a Minneapolis-based company focused on using video games to diagnose children and adults with ADHD. However, unlike Akili and others developing ADHD cognitive games, CogCubed uses Sifteo Cubes, an interactive game system developed at MIT in 2011. These small, white, high-tech cubes with touch screens look like tiny TVs. Aimed at an older group with Attention Deficit Disorder (ADD), the game requires a person to move, stack or tap the multiple sensors in the cubes, which have built-in accelerometers to measure any kind of movement.

With each touch, the cubes communicate wirelessly and the image on the screen responds to the change, which helps measure player behavior. The company’s technology focuses on players’ actions: Can they inhibit the impulse to grab the wrong cube when it makes a noise?

This interaction with the cubes provides a tangible user interface and is more engaging for both children and adults than a keyboard, mouse or other controller, according to Kurt Roots, CogCubed co-founder. He says the tactile experience of the cubes is easier to learn than the traditional graphic user interface system and enables players to increase problem-solving behavior and improve spatial cognition.

“We think cubes can become an attractive platform for therapeutic games, and using them in a game tells us a lot about the people who play them,” said Roots.

A second game, called Groundskeeper, resembles the old arcade game Whack-a-Mole, in which players must ignore distractions such as tweeting birds or a squirrel popping up to win. The focus is on reaction times. The company holds several patents for the capture and analysis of behavioral information while players are interacting with the game system. Roots cited a pilot study with students at the University of Minnesota, in which the game showed surprising power to diagnose ADHD as they played.

“The game could detect ADHD more than 75% of the time, which is an improvement over other current methods,” said Roots. “For us, as researchers, we hope these kinds of games can train the brain to improve being mindful, aware and alert. Shared among developers is making a positive and rewarding experience through good thought patterns and sharp cognitive functions, rather than creating games that just provide shooting skills or the ability to steal cars. The way a person uses the digital blocks tells us about that person,” said Roots.

The company also is pursuing FDA medical device approval for diagnosing and, eventually, treating other conditions in the brain, notably anxiety, depression and traumatic brain injuries.

In the earlier model that used citizen scientists to help solve complex problems, online game FoldIt, developed by a team at the University of Washington in Seattle, allowed players to fiddle at folding proteins on their home computers in search of the best-scoring (lowest-energy) configurations. More than 250,000 users have participated, including 57,000 who were credited in Nature for finding the most optimal folding scheme, most of them with no background in biochemistry.

A similar video game, EyeWire, developed by a team at MIT, also hoped to get a community of untrained people to virtually map the eye to learn more about the eye’s transmission of data to the brain. Starting in 2013, 120,000 people responded, and now a 3D model of how retinal neurons sense motion is complete.

Using e-formulations

In the patient-focused role of gamification, Pear Therapeutics has a different approach—and business model—for developing its games, pairing game developers with brand name and generic drug makers and nutritional supplement companies to create a combination of drug/supplement-software “e-formulations.” If successful, patients picking up medication at the pharmacy would find a software code on the package directing them to a complementary game.

“We know of some 30 combinations in which drugs with software apps have a chance to make the drugs more effective, starting with anxiety,” said Corey McCann, Pear’s founder and CEO. “With anxiety disorder, the game encourages people to breath in a rhythmic pattern to stimulate the vagus nerve in the brain, along with meditation.  If, after using the deep breathing app, you do not get the expected relief, you can take the packaged drug, benzodiazepine, and record your symptoms using your smartphone, and then have a follow-up conversation with your therapist or doctor.”

McCann also sees pairing a role-playing game with an antidepressant medication, such as Prozac, and tailoring parts of the game content to specific stages of therapy. The company, which plans to file its first e-formulation plans with the FDA for general anxiety with a generic drug, hopes to receive regulatory approval by early 2016. McCann also is looking to offer drug-game software combinations for Post Traumatic Stress Disorder (PTSD), pediatric refractory depression and insomnia.

E-formulations also could provide new financial opportunities for drug companies, which could boost their bottom lines and qualify as new formulations, possibly extending their patent protection.

“We have a lot of interest from pharmaceutical companies in the early stages of validating this model, and we can demonstrate to payers better efficacy and no major safety risks,” said McCann. “Gamification is incredibly different for us, as it drives the dose of different therapeutic interventions.” 

Looking ahead

Exactly how some of these games—particularly those designed to provide a diagnosis and are FDA-approved as medical devices—will fit into standard clinical trials is unclear.

CogCubed’s Groundskeeper game, designed to provide accurate measurements of behavior as a patient plays that then can be analyzed to determine ADD impairment, is aiming for regulatory approval by 2017.

“We think consumers will be interested in Groundskeeper as a tool, but not yet,” said Roots.

Other video games that don’t elicit specific diagnostic information may not require regulatory approval. Nonetheless, some early evaluations show gamification in a web-based medium is more popular with younger patient populations, which may pose challenges for clinical trials that target older patients.

As clinical trials seek the participation of growing numbers of millennials, gamification initiatives may play an important role in recruitment and retention. Study staff will need to become proficient at integrating these initiatives into study conduct activity and at providing responsive support when there are technical difficulties.

Others insist cognitive games in clinical trials still are in the early stages, with limited involvement from sites. Simply applying a blanket tracking tool to an already existing game is not going to provide any meaningful medical answers, say game developers. To be successful, they stress comprehensive user research to understand the needs of the audience and the relevant medical condition.

“For use in clinical trials, we are still at the dawn,” said Jim Gearhart, a director at Quorum Review IRB. “There is still a lot of skepticism about video games providing solid information. Sites can explain [to patients] the use of games and how they work with a computer, a tablet and maybe an iPhone, showing how they can track patients’ progress. But practically, there is a hardware compatibility question of presenting a video game on all platforms.”

“A lot of people seem to be saying there is great potential to these games in clinical trials,” he said. “But there is still a ways to go—including validation and acceptance.” 

Email comments to Ronald at ronald.rosenberg@centerwatch.com. Follow @RonRCW

This article was reprinted from Volume 22, Issue 02, of The CenterWatch Monthly, an industry leading publication providing hard-hitting, authoritative business and financial coverage of the clinical research space. Subscribe >>