The EndeavorRx Videogame – A Novel Digital Therapy for ADHD in Children

ADHD is characterised by a considerable variation in the degree of behavioural and cognitive dysfunction [Steinhousen 2009]. In addition to its core symptoms of inattentiveness and impulsivity, research has shown that ADHD affects sensory processing and sensory modulation. [Yochman et al. 2004]

Sensory Processing

• The manner in which the CNS assimilates, processes, and organises responses to information.

Sensory Modulation: 

• The ability to regulate the degree, intensity, and nature of that response to sensory input.

In patients with ADHD, it has long been shown that there are patterns in sensory processing and integration that are suggestive of not receiving informational input properly; as a result, these patients have difficulty producing appropriate adaptive responses, such as the impaired processing of auditory, touch, emotional, and social responses. [Scheerer et al, 2022], [Mulligan 1996]; [Dunn and Bennett 2002]

Neurobiology of Attention Deficit Hyperactivity Disorder (ADHD) – A Primer

Diagnosis and Management of Attention Deficit Hyperactivity Disorder (ADHD) – Focus on Adult ADHD

In 2013, Anguera et al. reported positive effects on cognitive control abilities when using a custom-built 3D video game and assessing multitasking performance (NeuroRacer, Akili Interactive Labs). Furthermore, they also reported a degree of transfer to untrained cognitive control abilities such as attention and working memory. [Anguera et al. 2013]

• In video game-based digital therapeutics, attentional control is measured using midline frontal theta (MFT) or Frontal Midline Theta (FMθ), a critical neural marker of attention. [Cavanagh and Frank 2014]
• Frontal Midline Theta (FMθ) activities are recorded from sensors overlying the medial prefrontal cortex (mPFC). These FMθ reflect mPFC-related control processes as part of top-down control across broad networks (cognitive control).
• Anguera et al. showed notable increases in MFT power, which was predictive of sustained attention and multitasking improvement.

Anguera et al. have since gone on to develop new software and a mobile app – EVO, by Akili Interactive Labs – that utilizes the underlying principles of the NeuroRacer intervention. [Anguera et al. 2017]

Project EVO was built to look like a consumer-grade video game, with a rich virtual environment and engaging visual and auditory feedback.

• EVO was piloted in children with ADHD and comorbid Sensory Processing Dysfunction (SPD) with an atypical response to sensory input and deficits in selective attention.
• In the DSM-5, SPD is not included as part of ADHD diagnosis. However, it is recognised that both commonly co-occur.
• Following 4 weeks of at-home training sessions with EVO, children with comorbid ADHD and SPD had significant improvements in attentional deficiencies that persisted for at least 9 months.
• A 3-year follow-up study then showed sustained benefits on inattention, with 54% of participants no longer meeting the criteria for ADHD. [Jurigova et al 2021]

A subsequent proof-of-concept study followed this pilot study by Anguera et al. in children aged 8–12 years with a confirmed diagnosis of ADHD. [Davis et al. 2018]

This study enrolled 40 children to complete the same study design of 4 weeks of 25 minutes per day at home, 5 days per week.

• This study reported significant improvements in the Test of Variables of Attention (TOVA) Attention Performance Index (1.43 versus 0.39; p=0.03).
• The ADHD group also showed significant improvements in 8 (of 12) variables in the CANTAB Spatial Working Memory Test (p<0.05)
• In addition, an ADHD high-severity subgroup showed significant improvements in their Reaction Time Mean Standard Score (0.65; p=0.006) and Reaction Time Variability Standard Score (0.62; p=0.009), both of which are indicators of ADHD severity.

Project EVO had since gone on to become EndeavorRx – a prescription-only game-based device to improve attention function in children with ADHD. It is considered a digital therapeutic device for primarily inattentive or combined-type ADHD who have attention issues.

EndeavorRx has demonstrated improvements in sustained and selective attention and has been designed to provide therapy as an adjunct to clinician-supervised treatment. In 2020, The US FDA permitted the marketing of EndeavorRx, the first therapeutic videogame (EndeavorRx, Akili Interactive Labs), for ADHD patients aged 8–12 years. [FDA news release 2020]

The EndeavorRx FDA authorization was based on successful trials, including the previously-described SPD+ADHD pilot [Anguera et al. 2017], the ADHD proof-of-concept study [Davis et al. 2018], and the STARS-ADHD and STARS-Adjunct clinical studies.

2020 STARS-ADHD:

• A multicentre randomised controlled trial that tested EndeavourRx in 348 children with ADHD.
• The TOVA Attention Performance Index significantly improved from baseline compared with the digital control (0.93 versus 0.03; p=0.006).
• Treatment-related AEs included decreased frustration tolerance (2.8%), headache (1.7%), and emotional reaction (1.1 %); however, no AE resulted in discontinuation. [Kollins et al. 2020]

2021 STARS-Adjunct:

• A multicentre open-label study enrolled children with ADHD who were either on or off stimulant medication. Children used EndeavourRx for 1 month, followed by 1 month of no use, and then a second 1-month of use.
• After 1 month, ADHD impairment significantly improved in both groups, persisted after the 1-month treatment pause, and improved further after the second treatment month. [Kollins et al. 2021]

EndeavourRx in adolescents with co-occurring ADHD and autism spectrum disorder: 

• This pilot study enrolled 19 adolescents aged 9–15 who were to complete 20 x 25-minute sessions (5 times per week for 4 weeks).
• Although EndeavourRx therapy resulted in a medium-to-large effect size on the TOVA Attention Performance Index, it did not reach statistical significance over the educational treatment group. [Yerys et al. 2019]
• However, secondary outcomes such as the parent-report measure ADHD Rating Scale IV: Home and the Behaviour Regulation Inventory of Executive Function (BRIEF-2) did show significant reductions compared with the educational treatment group.

The STARS trials showed significant improvements in attention performance, with minimal adverse effects. They also confirmed that EndeavorRx could be effective alongside or independent of stimulant medication, with lasting improvements in ADHD symptoms. According to the FDA, EndeavorRx should be considered as part of a therapeutic program that may include clinician-directed therapy, medication, and/or educational programs that further address symptoms of the disorder.

In 2023, Akili Interactive released a version of EndeavorRx for adults, called EndeavorOTC. It is currently available in the US for Android and Apple users.

Like EndeavorRx, EndeavorOTC promises to improve attention in adults with ADHD. Their website mentions an improvement in users who have played for at least 6 weeks, 70+ minutes a week.

EndeavorOTC also underwent a clinical study to assess efficacy, called A Single-Arm Pivotal Trial to Assess the Efficacy of Akl-T01, a Novel Digital Intervention for Attention, in Adults Diagnosed With ADHD, s. [Stamatis et al. 2023]

The study was a multicenter, single-arm trial at 14 US sites. Enrolled patients were 18 or older, had a diagnosis of ADHD (combined or inattentive), and demonstrated attentional impairment with a Test of Variables of Attention (TOVA) Attention Comparison Score (ACS) ≤ -1.8. The treatment involved using AKL-T01 at home 25 minutes per day, 5 days a week, for 6 weeks.

221 participants were enrolled, and 153 participants (M age = 39.9; 70% female; 39% current stimulant use) had sufficient data for analysis. TOVA-ACS significantly improved from baseline to study day 42 (M change = 6.46, SD = 6.95; t₁₅₂ = 11.49; p < .0001). There was significant improvement across all secondary endpoints (all p <.0001). In exploratory responder analyses, 36.6% moved into the normative range on TOVA (ACS > 0), and 27.1% had ADHD-RS-IV improvement ≥30%. The treatment was well-tolerated (5% reported adverse drug events [ADEs]; none serious), and compliance was high (M = 81.1%).

From the EndeavorOTC website, they also report the following results from the study:

• 73% of participants reported quality of life improvement
• 60% were better able to complete projects on time
• 78% reported increased productivity
• 54% were better able to keep track of important items such as their keys and wallet
• 50% were better able to pay attention when interacting with others

EndeavourRx is a first-of-its-kind digital therapeutic that has been shown to improve attentional functioning in children with ADHD significantly.

It has a videogame interface that targets attention and cognitive control for at-home play; with minimal AEs reported and an easily accessible format, EndeavourRx has tremendous potential to benefit populations without access to non-pharmacological interventions.

EndeavorRx reviews and testimonials are available in the EndeavorRx official website.