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Published: January 11, 2018

Naomi Davis, Department of Psychiatry and Behavioral Sciences, School of Medicine, Duke University, Durham, North Carolina, United States of America.

Jeff Bower, Akili Interactive Labs, Inc., Boston, MA, United States of America

Scott Kollins, Department of Psychiatry and Behavioral Sciences, School of Medicine, Duke University, Durham, North Carolina, United States of America

PLoS ONE, https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0189749#references

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Naomi O. Davis,

Jeffrey Bower,

Scott H. Kollins

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Abstract

Objective

Pharmacological and behavioral therapies have limited impact on the distinct neurocognitive impairments associated with ADHD, and existing cognitive training programs have shown limited efficacy. This proof-of-concept study assessed treatment acceptability and explored outcomes for a novel digital treatment targeting cognitive processes implicated in ADHD.

Method

Participants included 40 children with ADHD and 40 children without ADHD. Following psychiatric screening, ADHD ratings, and baseline neuropsychological measures, participants completed 28-days of at-home treatment. Neuropsychological assessment was repeated at end-of-study along with treatment satisfaction measures.

Results

Eighty-four percent of treatment sessions were completed and ratings showed strong intervention appeal. Significant improvements were observed on a computerized attention task for the ADHD group and a highly impaired ADHD High Severity subgroup. There was no change for the non-ADHD group. Spatial working memory also improved for the ADHD group and the ADHD High Severity subgroup.

Conclusion

Findings provide preliminary support that this treatment may improve attention, working memory, and inhibition in children with ADHD. Future research requires larger-scale randomized controlled trials that also evaluate treatment impact on functional impairments.

Citation: Davis NO, Bower J, Kollins SH (2018) Proof-of-concept study of an at-home, engaging, digital intervention for pediatric ADHD. PLoS ONE 13(1): e0189749. https://doi.org/10.1371/journal.pone.0189749

Editor: Omid Beiki, Karolinska Institutet, SWEDEN

Received: February 16, 2017; Accepted: December 1, 2017; Published: January 11, 2018

Copyright: © 2018 Davis et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting Information files.

Funding: This study was funded by Akili Interactive Labs. As part of the sponsored clinical study conducted with Duke University, Akili provided financial support in the form of salaries that was used for partial salary support for two authors [SHK, NOD]. Akili also participated in study design, data analysis, decision to publish, and preparation of the manuscript, and Akili is employer for the third author [JB] who worked in this capacity. These contributions are articulated in the 'author contributions' section. No salary support was provided for preparation of this manuscript.

Competing interests: Jeffrey Bower is an employee of Akili Interactive Labs. Scott Kollins is an advisor to Akili. Naomi Davis is a Principal Investigator for another Akili study. In the past 2 years Dr. Davis has received research support and/or consulting fees from Akili Interactive Labs and Rhodes Pharmaceuticals. Dr. Kollins has received research support and/or consulting fees from the following commercial sources in the last 2 years: Purdue Canada, Akili Interactive Labs, Alcobra, Bose, Jazz, Ironshore, Medgenics. Sunovion, Rhodes, Shire, SK Life Sciences, KemPharm, and NLS Pharma. This commercial affiliation does not alter our adherence to PLOS ONE policies regarding sharing data and materials.

Introduction

Attention Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder characterized by symptoms of inattention, hyperactivity, and impulsivity that are elevated relative to developmental level and pervasive across settings and over time, often persisting from childhood into adulthood [ 1]. Although ADHD is diagnosed by examining behavioral symptoms and associated functional impairments, the disorder is associated with distinct structural and functional brain differences that subserve neurocognitive functioning [ 2, 3], including executive functioning, working memory, processing efficiency, as well as motivational systems that impact intrinsic motivation and sensitivity to rewards/punishments [ 4, 5]. These challenges to cognitive control influence the behavioral manifestations of ADHD and constitute key potential treatment targets.

Current evidence-based treatments for ADHD include medication and behavioral therapies involving the patient and/or family members [ 6, 7]. Despite significant research documenting its benefits, pharmacological treatment has limitations including unfavorable side effects for some patients [ 8], lack of normalization even in well-titrated doses [ 9], and lack of benefit when medication is not taken. Recent evidence also suggests that pharmacological treatment may not show optimal benefits in some neurocognitive domains [ 10, 11]. With respect to behavioral therapy, parent behavior management training and cognitive behavioral skills training for adolescent and adults with ADHD are effective treatments, in particular when provided in conjunction with medication, and optimal outcomes may result when behavioral therapy is initiated prior to pharmacological treatment [ 12]. However, effects of behavioral therapy are often not maintained outside the treatment period, treatment can be difficult to access, and a recent meta-analysis raised questions about its efficacy for improving ADHD symptoms [ 13, 14]. Critically, adherence and compliance to both pharmacological and behavioral treatment regimens is often quite poor [ 15].

Given the chronicity of ADHD and the challenges of achieving sustained treatment efficacy over time, the potential for directly impacting ADHD impairments through direct cognitive training has garnered widespread interest [ 16]. Indeed, current evidence-based treatments were not explicitly designed to address the underlying pathophysiology that is associated with ADHD, which may explain some of the limitations of existing pharmacological and behavioral treatments [ 17]. An array of cognitive training programs has been promoted to address the specific cognitive processes that are impaired in ADHD. To date, however, despite promising findings from individual studies of such methods, equivocal findings from meta-analyses have been reported, such as inadequate generalizability of effects outside of training and the limitations of addressing cognitive processes versus core symptoms [ 18- 20]. Lack of effects may also be attributed to the wide range of treatment targets, which may not address neurocognitive mechanisms that are specifically associated with impairment in ADHD [ 17].

Cognitive neuroscience research has the potential to inform the development of novel interventions for specific disorders, such as ADHD, by linking implicated brain systems with specifically-targeted digital interventions, which can be optimally designed to operate within game interfaces [ 21]. In a series of studies, Gazzaley and colleagues identified a critical neural process underlying cognitive control ability, and demonstrated that a game-like cognitive intervention built to specifically target this system can achieve cognitive remediation [ 22, 23]. Their therapeutic approach for cognitive remediation relied on improving management of "cognitive interference," which occurs when two or more tasks or goals compete for cognitive resources within the executive function system. Susceptibility to cognitive interference is a core limitation to cognitive control ability and underlies cognitive deficits in sustained attention, impulsivity and working memory. Susceptibility to cognitive interference was measured by comparing performance when tasks are performed in isolation to when they are performed simultaneously with other tasks. The team designed a video game-like computerized treatment deployed in a home setting, called Neuroracer, to measure and, over time, reduce susceptibility to cognitive interference among a population of older adults. Results of the study indicated that interference susceptibility was reduced and demonstrated that cognitive benefits transferred to performance on untrained tests of attention, impulsivity, and multitasking [ 23]. In addition, they showed that changes in EEG signals occurred at neurological loci associated with cognitive control after completing the prescribed therapeutic regimen. Improvements in multi-tasking were maintained in the treatment group after 6 months of no treatment, and this maintenance effect also correlated with the same EEG-based neurological changes.

Given that these cognitive processes-difficulty with sustained attention, impulsivity, and working memory-are similarly implicated in ADHD, the current study was designed to directly explore the feasibility of using an advanced version of the digital interference treatment with this population. Designed to achieve acceptability in this population, as well as to enable at-home engagement and high-compliance with the treatment regimen, Project: EVO (EVO) is a digital treatment based on the Neuroracer model that deploys the interference-based cognitive control-targeting mechanics in a high-quality action video game-like interface. The intervention was developed using high-quality graphics and reward loops designed to be engaging for children. Additionally, the intervention embeds algorithms that continuously adapt to cognitive control ability and provide feedback on progress and compliance.

A multi-site research program was undertaken to examine the cognitive mechanics of the EVO platform across ADHD and non-ADHD children to assess feasibility in multiple pediatric populations. Here, we report on the feasibility, safety, and effects of the EVO adaptive treatment as an at-home, non-physician-administered intervention in this population. Specifically, the objectives were: 1) To demonstrate treatment acceptability in an at-home intervention protocol, specifically addressing compliance with the protocol and qualitative feedback at the end of the study period; and 2) To explore whether participants demonstrate improvements in cognitive function (e.g., objective measures of attention and working memory) following the intervention period.

Methods

Participants

Participants were self-referred and were recruited from 3 U.S. sites (i.e., one university setting and two clinical research centers) between January 2014 and August 2014. Data collection was completed on-site. Participants included 40 children with a confirmed diagnosis of ADHD ( M = 10.3 years) and 40 age-matched children without ADHD or any psychiatric disorder ( M = 10.5 years) ( Table 1). Eligible participants were between the ages of 8-12 years and were able to follow verbal and written instructions in English. All participants were, in the opinion of the investigators, functioning within the normal range of intellectual functioning. Eligibility criteria for the ADHD cohort included the following: 1) confirmed DSM-IV diagnosis of ADHD (any subtype); 2) baseline ADHD-RS-IV score > = 24 (completed via a clinician-administered semi-structured interview with the participant's parent); and 3) off psychotropic medication to treat ADHD (i.e., stimulant medication) for at least one week prior to study enrollment. Participants who had previously taken medication were expected to have discontinued the use of ADHD medication prior to study recruitment and were not asked or encouraged to discontinue their ADHD treatment in order to participate in the study. Eligibility criteria for the non-ADHD cohort included an ADHD-RS-IV score < = 13. For both cohorts, additional eligibility criteria required the following: 1) consistently off any other psychotropic medication for the prior month; 2) no comorbid psychiatric diagnosis that was uncontrolled or may have confounded the study objectives, as assessed via the MINI-KID; 3) not entering or exiting behavioral therapy within the prior four weeks; and 4) no history of failure to respond to an adequate trial of two ADHD treatments. Written consent was obtained from parents/caregivers of all participants prior to completing study procedures. Given the open-label design, participants and study staff were not blinded to study condition. This study was reviewed and approved by the Copernicus Group IRB on 8/28/2013 (IRB Tracking #: AKI1-13-296). See Fig 1 for the CONSORT flow diagram.

A subset of participants from the ADHD group was subsequently selected via post-hoc statistical analyses to comprise the ADHD High Severity group. As described further below and characterized in Table 1, this subset of participants demonstrated a greater response to the intervention. The ADHD High Severity group was characterized by a baseline TOVA API score of less than or equal to -1.8 and an ADHD-RS score of greater than or equal to 30. Twenty-two of the 40 ADHD participants met these criteria.

Measures

Screening and selection measures.

MINI International Neuropsychiatric Interview for Children and Adolescents (MINI-KID) [ 24]. The MINI-KID is a structured diagnostic interview that assesses psychiatric disorders in children and adolescents. It has demonstrated concordance to other structured psychiatric interviews and can be implemented using parent report. For the present study, the MINI-KID was used to establish ADHD diagnosis and to rule out other exclusionary psychopathology.

ADHD-Rating Scale-4 th edition (ADHD-RS-IV) [ 25]. The ADHD-RS is an 18-item validated scale that is completed via semi-structured interview with the participant's parent to assess symptom severity. Each item corresponds to one of the DSM-IV diagnostic criteria for ADHD and is rated on a 4-point scale (0-3) based on frequency of symptoms, resulting in a range of scores from 0-54, with higher scores reflecting more significant symptomatology.

Columbia Suicide Severity Rating Scale (C-SSRS) [ 26]. The C-SSRS is a brief interview instrument that is used to assess suicidal ideation and suicidal behavior including severity, intensity, types of behaviors, and potential lethality of behaviors. It has been well-validated for use in clinical trials.

Safety and feasibility measures.

Adverse events. Parents were instructed to report any adverse events by phone to the study staff during the study period, and any adverse events that were spontaneously reported during study visits were recorded.

Compliance. The number of treatment sessions completed at home was divided by the number of prescribed sessions to calculate the proportion of required intervention sessions completed for each participant.

Questionnaire on intervention appeal. Questionnaires regarding treatment experience and satisfaction were administered at Screening (Day 0) and Post-Intervention (Day 28) visits and were used to assess product acceptance and tolerability. Parents completed a 14-item paper questionnaire about their child's experience, and study participants responded to 16 questions that were administered orally by study staff. Both Questionnaires were a mix of Likert scales, multiple choice, and open-ended questions. Descriptive statistics were calculated for Likert items while frequency of responses was totaled for multiple choice and open-ended questions.

Neurocognitive/attentional outcomes.

Test of Variables of Attention (TOVA, version 8) [ 27]. The TOVA is a computerized continuous performance test that objectively measures attention and impulsivity, comprising a target stimulus and a nontarget stimulus that are presented individually and randomly based on a predetermined ratio. Participants are instructed to press a button immediately after seeing a target but not to respond when a nontarget is presented. The TOVA provides numerous summary statistics of performance (e.g., average reaction time, reaction time standard deviation, omission errors, and commission errors) and generates an Attention Performance Index (API) score. The API is a composite of z-scores for reaction time, reaction time variability, and d' (sensitivity index) and includes scores typically ranging from -10 to 10. The threshold for typical performance on the API is set at zero, with most typically developing individuals performing above zero (i.e., between 0-10). The API score was used as the primary TOVA outcome for this study. In addition, all of the TOVA standardized scores were also examined as well as Exgaussian TAU, which is an experimental measure that is sensitive to the long reaction times that are observed among individuals with ADHD.

Behavior Rating Inventory of Executive Function (BRIEF)-Parent Form [ 28]. The BRIEF is an 86-item parent-completed questionnaire that assesses executive functioning behaviors of children in everyday life. Behaviors are rated on a 3-point scale based on frequency. The BRIEF's eight subscales are aggregated into two domains (Metacognition and Behavioral Regulation) and also yield one overall score (Global Executive Composite). Given the hypothesis that the intervention would directly affect executive measures in the attention, impulsivity, and working memory domains, we analyzed the Working Memory subscale (Metacognition domain) and the Inhibit subscale (Behavioral Regulation domain). Additional analyses were also conducted with the available summary scores (i.e., Metacognition, Behavioral Regulation, Global Executive Composite).

Cambridge Neuropsychological Test Automated Battery (CANTAB) is a computer-based cognitive assessment that measures neuropsychological functioning [ 29, 30]. The CANTAB cognitive tests used in this study were selected from tests that were relevant to ADHD and provide information on different cognitive domains fitting with our intended cognitive targets, including Spatial Working Memory (SWM), Rapid Visual Processing (RVP), and Delayed Match to Sample (DMS).

Procedure

The study involved three phases: a screening visit, an intervention period, and a post-intervention visit ( Fig 2). The screening visit (Day 0) was conducted to determine study eligibility and to collect baseline data before initiating the intervention period. Eligibility was determined by administration of the MINI-KID to establish or rule out a diagnosis of ADHD and other psychiatric conditions, and to determine the severity of any presenting ADHD symptoms. Following psychiatric screening, eligible participants completed laboratory baseline assessments (CANTAB, TOVA). After a short break, participants were instructed to engage with EVO for approximately 20 minutes to establish baseline performance and ensure that participants understood how to use with the intervention properly. This period included one EVO practice session, one diagnostic/assessment session, and one treatment session. Following EVO use, study staff recorded observations about the child's experience, and throughout the session any adverse events were captured by study staff. At the end of the screening visit, parents were given instructions for the at-home intervention period.

*All participants drop outs were due to noncompliance with the intervention.

During the intervention period (Days 1-27) participants were instructed to use the intervention at-home for approximately 30-45 minutes a day, 5 days a week. Each daily treatment period was accomplished by completing 7 consecutive EVO sessions, which consisted of either a four-minute dual-task intervention segment or an automatically triggered ten-minute dual-task evaluation segment that was used to recalibrate the cognitive skills difficulty for the next level. On each day of the intervention, EVO counts the number of sessions as they are completed and limits use for the remainder of any given day following 7 completed sessions. Compliance with treatment was monitored electronically and the parents of participants were notified by email if there was failure to use the intervention over a 48-hour period. Parents were also given a reminder phone call on day 21 to notify them that their child was entering the final week of the study.

Participants returned to the clinic on Day 28 for a final evaluation. Post-intervention data that were collected included the cognitive assessments (CANTAB, TOVA) and additional EVO cognitive metric and interaction data, as well as parent-completed questionnaires.

Digital treatment

The Project: EVO platform was designed to incorporate the fundamental features of Neuroracer [ 23] into a state-of-the-art mobile digital intervention platform that participants engage with through an action video game interface that deploys modern videogame graphics, engaging reward loops, and real-time adaptive mechanics to dynamically personalize difficulty based on the user's ability. Project: EVO employs a perceptual discrimination attention/memory task as well as a continuous visuomotor "driving" task. Performance is assessed on each task in isolation and when performed together to calculate a performance index for each individual user. A personalized multi-task intervention regimen is automatically configured and delivered to the user, and is optimized adaptively across both tasks to constantly increase multi-task performance. As patients/participants proceed through the treatment, periodic re-calibration occurs to maintain an optimal difficulty level. In addition, the mechanics are coded into a proprietary framework that utilizes real-time and between-session adaptation in order to tailor the treatment specifically to an individual automatically, without the need for any configuration or tuning by a clinician, thus allowing it to be deployed entirely remotely in the patient's home. This tailoring ensures that patients are consistently performing at a predefined level of difficulty that is challenging but also tolerable because of inherently rewarding videogame-like interaction mechanics.

Statistical analysis

Intervention safety and acceptability were examined by analyzing EVO data on compliance with intervention use, adverse events, and parent and child satisfaction ratings.

Analyses were also conducted to examine all cognitive/behavioral outcome measures that were administered in the pre- and post-intervention visits. Analyses were run separately for the ADHD and non-ADHD groups. The means of the pre-test scores were compared to the means of the post-test scores using a 2-tailed paired T-test. For the main neurocognitive outcome, TOVA API, a Shapiro-Wilk test for normality was performed. If the distribution of scores was found to deviate from normality at an alpha of less than 0.05, an equivalent Wilcoxon sign rank test was performed instead of a T-test. Due to the exploratory nature of these analyses, all results less than an alpha of 0.05 were considered statistically significant. For completeness we also report if the alpha levels meet significance under a Bonferroni correction within a statistical family. The outcome measures from the TOVA, CANTAB Spatial Working Memory, CANTAB Rapid Visual Processing, CANTAB Delayed Match to Sample, and BRIEF each measure distinct aspects of executive function and each will be treated as independent statistical families for Bonferroni adjustments. All analyses were conducted in the open source statistical package, R (v. 3.3.1). Only participants who completed the at-home period and completed the final assessments were included in the analysis, therefore no missing data was present. Completing the at-home period was defined by completion of 50% of the required treatment sessions. Treatment session data was uploaded electronically through WI-FI and processed through a cloud-based Application Programming Interface (API) to create a daily report to clinical site staff on participant treatment compliance. Clinical staff were instructed to reach out to the participants if there was no documented usage of the intervention for more than 24 hours. Participants that were dropped or did not complete the study were replaced and thus only participants without protocol deviations (a Per-Protocol analysis set) were included in analyses. Four participants from the non-ADHD group were dropped from the study for poor compliance, which represents a replacement rate of 5% of the total study final sample size. An Intent To Treat (ITT) analysis was not considered necessary due to the low drop rate.

In addition to these planned analyses, post-hoc analyses were also conducted to examine outcomes for the subset of the ADHD group with most impairment as defined by greater functional deficits and lower attentional performance. A cut-point analysis was performed [ 31] to find the optimal cut-points for baseline ADHD-RS and TOVA API scores that would define a subgroup of ADHD participants that showed maximum change on the TOVA API. Sub-samples were selected at combinations of baseline scores (cut-points) for the ADHD-RS (ADHD-RS score range, 24 to 41) with TOVA API (TOVA API score range -6 to 1). The results of this analysis indicated that the greatest change on TOVA API was observed with a sub-sample that had an ADHD-RS baseline score of > = 30 and a TOVA API < -1.8. This sub-sample had 22 participants (mean age = 10.2, 14 males and 8 females), and did not differ in terms of age or gender.

Given the exploratory nature of the study, the sample size was chosen to be sufficiently large to detect significant within subject effects of at least 0.45 (Cohen's D) for a 2-Tailed test, at anlpha-0.05 with a power of 80%.

Results

Participant flow

A total of 87 participants were screened for the study and a total of 3 participants were screen fails. During the intervention period, four participants from the non-ADHD group were dropped from the study for non-compliance with the at-home intervention use. These participants were replaced by recruiting additional participants. All of the ADHD group participants were compliant with the intervention and none of these participants were replaced during the study. A total of 40 ADHD and 40 non-ADHD participants completed the study. See Fig 2 for a graphical representation of the participant flow through the study.

Safety and acceptability

Across all participants, 84% of all prescribed in-home sessions were completed. This is equal to approximately 10.9 hours of total intervention time per child across the approximately 28-day intervention period. The ADHD group completed an average of 81% (10.8 hours of intervention), the ADHD High Severity subgroup completed an average of 86% (11.1 hours of intervention), while the non-ADHD group completed an average of 87% (11.5 hours of intervention) of the required at-home sessions. There were no significant differences found between the ADHD and non-ADHD groups (p = 0.20), the ADHD and ADHD High Severity subgroup (p = 0.38), or the non-ADHD and the ADHD High Severity subgroup (p = 0.30). Compliance was calculated based on number of exact days at home with the intervention, which varied slightly between groups based on each child's exit visit.

A total of 9 adverse events were reported over all study phases; however, none of those adverse events were judged by the PIs and site staff as related to EVO ( Table 2). None of the adverse events were reported during the practice session at the Screening Visit. Additionally, there were only 4 participants who dropped out of the study, and none of these participants were in the ADHD cohort.

Results from the questionnaire on intervention appeal showed an average participant-reported enjoyment rating for EVO treatment of 6.9 on a 1-10 scale (ADHD M = 6.93; ADHD High Severity subgroup M = 7.1; non-ADHD M = 6.85). Parent ratings of their child's enjoyment showed a similar pattern of overall enjoyment (ADHD M = 6.1; non-ADHD M = 6.6). See Table 3 for additional intervention appeal ratings.

Neurocognitive outcomes

Attentional functioning.

Significant improvements were observed on the TOVA primary composite measure, the Attention Performance Index (API) in the ADHD group (T-Test; N = 40, t = 2.21, p = 0.033, Effect Size (d) = 0.35, mean of differences = -1.43, 95%CI-Lower = -2.75, 95%CI-Upper = -0.12). In addition, a larger effect of the intervention was observed for the subset of ADHD participants with greater functional deficits and lower attentional performance (T-Test; N = 22, t = 3.33, p = 0.003, Effect Size (d) = 0.71, mean of differences = -3.05, 95%CI-Lower = -4.96, 95%CI-Upper = -1.15). There was no change in API scores for the non-ADHD group (T-Test; N = 40, t = 1.04, p = 0.30, Effect Size (d) = 0.17, mean of differences = -0.39, 95%CI-Lower = -1.16, 95%CI-Upper = 0.37). See Figs 3 and 4 for API results.

Several other standardized score measurements from the TOVA were examined. The ADHD High Severity subgroup, but not the full ADHD group, showed significant improvements on two indicators of ADHD severity: Reaction Time Mean Standard Score (T-Test; N = 22, t = 3.03, p = 0.006, Effect Size (d) = 0.65, mean of differences = -13.16, 95%CI-Lower = -22.19, 95%CI-Upper = -4.13), and Reaction Time Variability (Variance) Standard Score (T-Test; N = 22, t = 2.89, p = 0.009, Effect Size (d) = 0.62, mean of differences = -26.42, 95%CI-Lower = -45.42 95%CI-Upper = -7.43). Both the ADHD group (Wilcoxon; N = 40, z = 2.39, p = 0.016, Effect Size (r) = 0.38, mean of differences = 53.27, 95%CI-Lower = 3.34, 95%CI-Upper = 46.02) and the non-ADHD group (Wilcoxon; N = 40, z = 2.05, p = 0.040, Effect Size (r) = 0.32, mean of differences = 40.27, 95%CI-Lower = 0.32, 95%CI-Upper = 33.33) showed a decline in Omission Error Standard Score (i.e., missing targets). D-prime, a measure of signal detection sensitivity, remained relatively constant in both the ADHD group ( p = 0.718) and the ADHD High Severity subgroup ( p = 0.406). Analyses of the ExGaussian Tau, an experimental measure derived from the TOVA that may be a sensitive metric for attentional challenges, indicated significant improvement for both the ADHD group (T-Test; N = 40, t = 2.14, p = 0.039, Effect Size (d) = 0.34, mean of differences = 30.56, 95%CI-Lower = 1.7, 95%CI-Upper = 59.43) and the ADHD High Severity subgroup (T-Test; N = 22, t = 3.21, p = 0.004, Effect Size (d) = 0.69, mean of differences = 64.77, 95%CI-Lower = 22.85, 95%CI-Upper = 106.7) A complete table listing of TOVA standardized score results with Bonferroni corrections reported is found in S1 Table.

Working memory and other cognitive outcomes.

The ADHD group showed significant improvement (p < 0.05) on 8 of 12 variables within the CANTAB Spatial Working Memory (SWM) test, 3 of 10 variables within the Rapid Visual Processing (RVP) test, and 0 of 16 within the Delayed Match to Sample (DMS) test. Figs 5 and 6 demonstrate one such measure for demonstration purposes. The ADHD High Severity subgroup showed significant improvement (p < 0.05) on 8 of 12 variables within the SWM, 0 of 10 variables within the RVP, and 1 of 16 within the DMS. The non-ADHD group showed significant improvement (p < 0.05) on 5 of 12 variables within the SWM, 6 of 10 variables within the RVP, and 9 of 16 within the DMS. Overall, the results suggest an improvement for Spatial Working Memory (SWM) for the ADHD and ADHD High Severity subgroup and well as improvements for the non-ADHD group on Rapid Visual Processing (RVP) and Delayed Match to Sample (DMS). Please see S2- S4 Tables for a complete table listing of these CANTAB results with Bonferroni corrections reported.

Executive functioning.

On the Working Memory subscale, percentile scores for the ADHD group improved non-significantly but a trend-level effect was observed (Wilcoxon; N = 40, z = 1.81, p = 0.07, Effect Size (r) = 0.29, mean of differences = 2.48, 95%CI-Lower = 0.0, 95%CI-Upper = 5.5) ( Table 4). For the ADHD High Severity subgroup, percentile scores on Working Memory (Wilcoxon; N = 22, z = 2.40, p = 0.014, Effect Size (r) = 0.51, mean of differences = 3.23, 95%CI-Lower = 1, 95%CI-Upper = 7.5) and Inhibition (Wilcoxon; N = 22, z = 2.19, p = 0.027, Effect Size (r) = 0.47, mean of differences = 5.68, 95%CI-Lower = 1, 95%CI-Upper = 15.5) improved significantly. The Working Memory and Inhibit scores did not change significantly for the non-ADHD group. In addition, the BRIEF summary scores (i.e., Metacognition, Behavioral Regulation, Global Executive Composite) did not change significantly over time for any of the groups.

Discussion

The primary aim of this study was to explore the feasibility of using an at-home digital intervention with children diagnosed with ADHD. Project: EVO was well-tolerated by children with ADHD, was feasibly deployed in the home setting over a treatment period of four weeks, and resulted in positive ratings of acceptability by both parents and children. Notably, there was high compliance and no dropouts in the ADHD cohort. The lack of dropouts was particularly notable considering the time burden required, the fact that no physician or clinician was directly involved in the treatment protocol, and documented dropout rates of >10% in traditional treatment trials as well as real-world settings [ 15, 32]. Given the risks that must be considered regarding other treatment options for ADHD, this information is of high importance as a first step in developing innovative treatment for this chronic disorder. Specifically, given the high demands on parents' time and resources, it is critical that available treatments for ADHD can be reasonably incorporated into a daily routine, utilized consistently by children with ADHD, and most critically implemented without the need for a physician, therapist, or psychologist oversight. Furthermore, research on treatment acceptability suggests high acceptability ratings for behavioral as compared to pharmacological treatment [ 33, 34], yet access to behavioral treatments is limited when interventions can only be given by trained providers in a clinic setting.

Findings from the current study provide preliminary support that this digital therapy intervention may be effective for improving attention, working memory, and inhibition in pediatric ADHD, especially among children with greater symptom severity and impaired attention. As shown in prior work with Neuroracer, the platform upon which Project: EVO was developed, participants who received the digital intervention demonstrated improvements in attentional functioning and spatial working memory as measured by accepted computerized tests over the one-month intervention period. These improvements were observed on TOVA's composite Attention Performance Index and hallmark sub-component metrics such as reaction time and reaction time variability (variance), as well as a range of metrics on the CANTAB spatial working memory test. Interestingly, the ADHD groups' improved Attention Performance index and maintenance of D-prime, despite a decrease in the omission error standard score, may imply attentional improvements that accompany and are not compromised by a shift to a more cautious/withholding response profile.

Results of the study build upon those reported for other computerized cognitive training programs that have demonstrated positive outcomes on executive tasks that are similar to trained tasks but have shown limited generalization to other tasks [ 35, 36]. In the current work, findings suggest generalizability of benefits to outcome measures that are different in design and that tap domains that differ from the intervention itself. Engaging with Project: EVO's regimen was associated with statistically significant improvements in attention and impulsivity, as measured by TOVA API and other component TOVA metrics. Both Project: EVO and TOVA contain perceptual discrimination tasks where the participant must respond to a pre-indicated target and not respond to others. However, Project: EVO differs from the TOVA in several ways: 1) EVO contains both single and multitask conditions; 2) EVO's perceptual discrimination environment and rules change with increasingly complexity throughout treatment; and 3) EVO's tasks are embedded in a 'rich' virtual environment whereas the TOVA involves a uniform task with monochromatic, geometric stimuli. See Fig 7 for a graphic of a Project: EVO targeting task. Taken together, results from TOVA metrics support modest transfer of benefit effects given the noted differences in platforms. Study results also suggested more distal transfer of benefit on the CANTAB working memory test, since the task demands on the CANTAB (e.g., spatial working memory of geometric shapes) are unlike any of the types of perceptual demands in the EVO environment.

Additionally and uniquely, Project: EVO is designed to appeal to children through a consumer-grade videogame-like format and a user-friendly at-home intervention that can be self-administered, both of which may enhance motivation and acceptability in real-world treatment deployment. Indeed, qualitative ratings provided by parents suggest that the vast majority describe the intervention as having value, and a majority of parents believed it was worthwhile enough to report the desire for access to the intervention after the study period. Importantly, despite 80% of parents indicating that the intervention was somewhat or very worthwhile, 40% of parents did not indicate a desire to continue the intervention. These parent ratings may be influenced by children's perceptions that the intervention was challenging. As a therapeutic product, EVO attempts to balance children's experience of both fun and challenge with effective clinical outcomes. Overall, these satisfaction findings are still considered to be very good and are consistent with prior research that parent acceptability of ADHD treatment is influenced by multiple factors [ 37].

Results of the current study are particularly important given that medication management, the mostly commonly utilized treatment for ADHD, has a very significant effect on core symptoms of ADHD but only equivocal effects on specific executive functions [ 38- 40]. In addition, although the executive function profiles of individuals with ADHD are extremely heterogeneous, the presence of such deficits confers risk for more significant the impairment [ 41, 42]. Given the limitations of existing therapies in remediating these challenges, the current study demonstrates an important step toward increasing therapeutic options for children with ADHD and executive dysfunction. Specifically, Project: EVO was developed to address the underlying areas of neurocognitive functioning that are impacted in ADHD. In keeping with the guidelines outlined by the National Institutes of Mental Health experimental medicine initiative, treatments that directly address the underlying disease mechanism in psychiatric conditions are greatly needed [ 43]. Although our results are preliminary, they constitute a step in this direction.

A key part of the current proof-of-concept study was to gain an understanding of how clinically-relevant outcomes may be assessed using measures that have demonstrated utility in characterizing functioning in individuals with ADHD. For example, the BRIEF parent-report provides important clinical information about functional deficits associated with ADHD, and has been correlated with both neuroanatomy and performance on working memory measures [ 44, 45]. Although only a subset of BRIEF scales was examined in the current analyses, results suggest that this measure may provide a useful proxy for understanding the effects of EVO on aspects of executive functioning such as working memory and inhibition. At the same time, this parent-report measure may be less sensitive to effects of the intervention than the computer-based measures because the constructs are somewhat distinct. Similarly, deficits observed on the CANTAB among individuals with ADHD improve in the context of stimulant treatment, suggesting these are key targets for other novel interventions for this disorder [ 38]. The results of this study suggest that moderate improvements across a range of working memory and processing measurements on the CANTAB resulted from EVO treatment.

Several study limitations are important to note. The positive performance trajectories of children with ADHD and non-ADHD participants without ADHD were objectively demonstrated via several standardized outcome measures; however, next studies will need to include additional measures of real-world outcomes in order to determine if the cognitive improvements translate to everyday functioning. In addition, because the current study was an open-label, proof-of-concept trial, it is possible that any improvements observed via parent report were influenced by parent expectations of benefit that would be received from the intervention. However, research on cognitive training methods suggests a much smaller magnitude of improvement [ 46], and the TOVA test of attentional functioning has traditionally shown little to no placebo response [ 47], so it is likely that the current study reflects effects that are well above the impact of a placebo or expectation bias. In addition, study participants with ADHD represented a subset of the pediatric general population, but may not be representative of the entire general population of children with ADHD (e.g., not on medication, no significant co-morbid psychiatric disorders) which may affect the generalizability of these preliminary findings. Finally, given that the study's exploratory goals involved examining efficacy effects of many outcome measures across several domains of executive function, these is concern that some results may be a result of Type I error. The current study reports Bonferroni corrected significance values to address this concern; however, future studies will need to replicate the current findings with a priori hypotheses to confirm these exploratory findings.

Although medication is the front line treatment for children with ADHD, there remains a need for the development of alternative intervention modalities to optimize care for these patients. Delivery of a digital treatment intervention on a mobile device may increase access to treatment, reduce cost of care, and increase compliance by making the treatment enjoyable and comfortable for use in an at-home setting. Future research on Project: EVO will require larger-scale randomized controlled trials to better examine the efficacy of this digital treatment for children with ADHD. These trials will benefit from including outcomes to evaluate the impact of treatment not only on executive functioning tasks and ADHD symptoms but also on the functional impairments (e.g., academic, social) that impact these children in their day-to-day lives. Additional studies that examine the amount of therapy necessary to produce a meaningful effect (i.e., the appropriate "dose" in pharmacological terms) will also be important to identify the most optimal delivery of this intervention.

Acknowledgments

We would like to thank the children and families who participated in this research. We greatly appreciate the support and dedication of the clinicians and study staff at two clinical sites who made this research possible.

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Proof-of-concept study of an at-home, engaging, digital intervention for pediatric ADHD

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Objective Pharmacological and behavioral therapies have limited impact on the distinct neurocognitive impairments associated with ADHD, and existing cognitive training programs have shown limited efficacy. This proof-of-concept study assessed treatment acceptability and explored outcomes for a novel digital treatment targeting cognitive processes implicated in ADHD.

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Published: June 15, 2020

Laura Kurtzman, Senior public information representative, University of California San Fransisco

https://www.ucsf.edu/bio/laura-kurtzman

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Laura Kurtzman covers translational health research, including digital health and precision medicine, global health and infectious disease, women's reproductive health, health policy and medical and graduate education. She was a reporter for many years at the San Jose Mercury News, as well as the Associated Press and the Los Angeles Times.

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Published: February 14, 2022

Stephanie Sutton, Editor, The Medicine Maker

https://themedicinemaker.com/discovery-development/the-story-behind-an-fda-approved-video-game-treatment-for-adhd

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In June 2020, the FDA granted marketing authorization to EndeavorRx for children aged 8 to 12 years old with ADHD. New therapeutics are approved by the FDA all the time, but this one broke the mould. Rather than popping pills, patients race around alien worlds saving lifeforms from extinction...

But how can a video game ever work as well as a drug treatment that chemically or biologically elicits a therapeutic effect? First, the video game is just the way the medicine is delivered, like a capsule or syringe delivering a pharmaceutical API. Underneath the game are patented stimuli and algorithms designed to target the areas of the brain that play a role in attention function.

The game isn't intended to be a stand-alone therapeutic - and the company has stressed that it's not a substitute for a child's medication. But Akili Interactive, the company behind the innovation, has delivered compelling evidence that shows how EndeavorRx improves attention function in children with ADHD, as measured by the Test of Variables of Attention (an FDA-cleared objective test of attention), as well as other assessments such as reports from parents and physicians. Studies were conducted in more than 600 children - and, perhaps unsurprisingly, there were no serious side effects (although adverse events included frustration, headache, dizziness, emotional reaction, and aggression) (1).

Video games don't have the best reputation in certain circles. For as long as video games have been around, there have been concerns about how they impact children. But with video games continuing to increase in popularity, some researchers have started to focus on the positive side. Studies have emerged showing how video games can improve mental health; for example, a paper published in 2021 by researchers at the UK's University of Oxford claimed that video gameplay was positively correlated with mental health (2).

Also in 2021, scientists from UC San Francisco's Neuroscape translational neuroscience center reported that they had developed a virtual reality video game that could potentially help improve memory in healthy, older adults (3).

But the approval of EndeavorRx really takes the game to the next level. Here, I ask Anil Jina, Chief Medical Officer at Akili Interactive, how the approach works and why gaming should not be dismissed as a gimmick when it comes to neurological disorders.

It started when our co-founders, Adam Gazzaley (Chief Scientific Officer), Matt Omernick (Chief Creative Officer), and Eddie Martucci (CEO) found themselves thinking about the same problem - but from different angles. On the science side, Adam was (and still is) a neurologist with UC San Francisco. He heads up the university's translational neuroscience center, Neuroscape, and has written books around the cognition crisis. Our cognition is being bombarded and declining due to various intrinsic and extrinsic reasons. Adam wanted to find ways not only to assess this but also to improve cognition. Cognitive training does exist, but the tasks are usually delivered in a human way, on a one-to-one basis, and you cannot deliver multiple tasks simultaneously. Adam wanted to find ways to deliver different cognitive tasks together, but the only way to do this is to make it digital.

Adam then met Matt Omernick, who comes from the gaming world and has experience in big gaming houses on the west coast, including EA and Lucas. Matt explained that there was a trend in the tech sector exploring gaming for good, as well as interest in using video games to help improve generic cognition and attention. Eddie Martucci is a biologist by training and comes from the venture capitalist side in Boston; after seeing the research, he became very interested in the concept. And that's how the three of them linked up - and how Akili Interactive began.

To an extent, cognitive function is practiced almost daily. For example, I'm having to concentrate on this video call with you right now. I have to ignore my wife, who is on a Zoom call in the other room, and I have to ignore all of the things on my desk. There may be other things in the home that I have to ignore too. A more intense example? Consider playing a sport like soccer. You need to think about the ball, think about the other players, think about movement and space, think about how you handle the ball, how you position your hands and feet - all while abiding by the rules of the game.

In 2013, Adam co-authored a paper in Nature, which made the cover and distilled a lot of research about cognition, multitasking, and the potential of using a custom-made video game to enable cognitive training and improve multitasking performance (4). Ultimately, the paper showed that it was possible to formally embed cognitive tasks from the ground up in a video game. A custom designed game was used to assess the cognitive performance of players - and it showed a linear, age-related decline from 20 to 79 years of age. We all know that cognition declines with age - which is disappointing for everyone - but the game specifically showed that it was a steady decline.

The paper also showed that when the 60 plus age group was "treated" using a specially designed game for a month (about a half an hour a day; five days a week), their cognition improved and, crucially, was sustained for six months. This provides evidence of a neuroplastic effect - something happens in the brain cells and pathways that enables the cognitive training to embed itself, rather than just disappear. All of this is very different from drug development, where you have a molecule and receptor that bind together, exerting an effect that lasts until the drug is metabolized or actively released.

The researchers also looked at EEG data and saw that the brain activity promoted by gaming was in the prefrontal cortex - the location of the attention networks. After a month of playing, older adults showed a different picture of neurological activity compared with before playing. Notably, the activity was similar to that in the baseline 20-40 year old group. Players who received all the tasks at once - forcing them to multitask rather than playing different subsets of the game - saw the largest improvement.

All of this research fed into Akili's strategy. Gaming and medical specialists were hired to work together on the task of developing a game as a medical device. Here, I'd like to note that the development of the game followed the same rigorous development as a drug in terms of clinical trials with clinical endpoints.

In June of 2020, we obtained regulatory clearance from the FDA for EndeavorRx to be prescribed for children aged 8 to 12 years old with primarily inattentive or combined-type ADHD who have demonstrated an attention issue (5). This isn't meant to replace ADHD drugs that are working for some kids, but it's a great new option that parents can turn to as part of their child's treatment.

There was a lot of scepticism about using gaming in such a manner, but we were not deterred. Ultimately, no one fully understands how the brain works - we're only just scratching the surface of a lot of the functionality. Given our collective lack of knowledge in this area, it could be considered naïve to assume that a different approach is not viable. And to be blunt, if existing drug therapies are so good, why do we still have cognitive decline and so many neurological issues?

In my experience, there is scepticism or uncertainty around cognition in general. I am a trained physician, so I know that those studying medicine learn very little about the functional aspects of cognition - this is the realm of psychologists, cognitive scientists, and behavioral therapists. But when I worked as an anaesthetist, I often saw people coming out of anaesthesia with cognitive dysfunction - and it would commonly affect older people for longer. When I worked in the neuroscience space on schizophrenia, bipolar disorder, and depression, there was certainly an awareness of cognitive dysfunction - but because no treatment existed it was not a focus.

But the world is changing - and we're now seeing more acceptance of the cognitive deficits presented in many disorders. "Brain fog" is a term frequently used by patients to describe symptoms of various disorders - including those who have recovered from COVID-19. Here, perhaps some type of inflammatory or microvascular mechanism is causing cognitive function to be depleted. For most physicians, this brain fog or decline in cognitive performance becomes almost irrelevant compared with the immense physical impact of the original symptoms/disease. However, if many people in the general population are saying, "I'm not sick anymore, but I can't work or look after my children or go grocery shopping," the impact would be huge. We should not ignore those cases where an improvement in cognition lags behind physical improvement.

There is only so much that doctors can do, but I hope new approaches - for example, home-based cognitive training (potentially using gaming) that adapts to a patient's changing needs - will ultimately be able to help.

In short, it's truly new. I was super excited to join the company just over three years ago because it wasn't simply digitalizing an existing medical therapy (there are a lot of digital therapeutics out there that are digitizing traditional cognitive behavior therapy, standardizing and simplifying to improve access. Akili Interactive has created a new therapy that can only be delivered by this game. And nothing else like it exists on the planet!

The game incorporates multiple tasks that deliberately hit different aspects of attention including processing speed, sustained attention, divided attention, conflict resolution, focus, and interference processing. Cognitive scientists or therapists can measure these with different tests and offer certain therapies but they can't give you something that targets all of these at once. A game can. And it does this in a fun and engaging way that is also adaptive.

We looked at several diseases and disorders - and there are a number of areas where we believe our approach could have benefits; however, we had to keep in mind the scepticism we would undoubtedly encounter. We felt it was important to focus on an area where people might intuit that a game-based approach could work. We didn't want huge leaps of faith - we needed people to think, "Okay - yeah - that actually makes sense."

After much discussion, we settled on children with ADHD for two key reasons. First, children typically love games! And second, our game had been designed to focus on the attention networks of cognition, rather than something like memory. Attention is clearly a critical part of ADHD - and, importantly, established scales and clinical outcomes for ADHD already exist. In other words, if the game could boost the attention network in patients, we should be able to measure the improvement on the scale. In other disorders, such as schizophrenia, there are fewer scales that measure cognition, so it's more difficult to prove the benefits of therapy.

We met with the FDA to explain our approach and we also shared results from a pilot study. We discussed what could be improved and we agreed on endpoints that made sense from both an ADHD perspective and a regulatory perspective. We did the study and the results were positive. With data from five clinical studies in more than 600 kids with ADHD, the FDA approved the game in June 2020 as a class II medical device. It was such an amazing accomplishment. Sadly, we didn't get to have a celebration party because of pandemic lockdowns!

The meta story for the game is that the player is a space cadet who travels from world to world to participate in missions. Each world has a different landscape and there are certain tasks to accomplish. Often, the planet is collapsing and the player needs to save different alien creatures from extinction. The player must follow a meandering path - which could be a stream, lava, a road, or even just space, depending on the world - through the level and capture creatures to put in their space farm.

Ultimately, all of this world building is just a mask to disguise a set of challenging cognitive tasks...

The player's avatar rides a hover platform through the level. The road meanders randomly and the player steers by tilting their phone or iPad left and right to avoid hitting the edges. Depending on the level, there may be gates to pass through (like in ski racing) or barriers to avoid. This cognitive navigation task requires sustained, selective attention.

Gameplay also incorporates conflict resolution inhibition. As well as steering and avoiding or hitting certain obstacles, the player is tasked with capturing aliens. At the start of the level, players are shown the different alien creatures that inhabit the world - usually three, but it can increase on the harder levels. They are told to capture just one of them - perhaps the blue one, the spiky one, or whatever. As the player is steering through the level, alien creatures jump at the player from the side of the screen. The player must tap when they see the correct alien and suppress their urge to tap when they see the others. The game also draws on working memory requirements as the player needs to remember the type of alien they need to capture.

Because a multitude of cognitive tasks targeting the attention network come at the player simultaneously, the player cannot just focus on one aspect - steering or capturing aliens - they must divide their attention between both.

The team has also incorporated other aspects you would expect from a video game. For example, completing levels and tasks earns in-game currency that can be spent on different costumes. Players can also customize their spaceship and unlock additional missions.

Perhaps most importantly, the game constantly adapts and is personalized for each patient in terms of the speed, frequency of the gates and obstacles, and the targets coming at the player. This cognitive load is balanced in a staircase fashion on a second by second basis. If the level of cognitive stress on the attention is too much and the player makes too many mistakes, such as hitting the edges or catching the wrong alien, the speed is reduced. If they are steering really well, avoiding obstacles or hitting the gates correctly, and making the correct no/go decisions on the aliens, the game speeds up.

This is a big difference between EndeavorRx and most standard video games. In a regular game, all players start at level one and require the same level of aptitude to reach level two, level three, and so on. Because EndeavorRx adapts to the player's cognitive function, "level one" will vary from player to player. Some children with autism and ADHD may be at the lower end of the functional spectrum, but others can be highly functioning. Because the game adapts to ability, all kids can progress to levels that are relevant to them. Once the baseline is set, the game follows an algorithm that tries to challenge and push the player's cognitive function enough to stress - but not overstress. In other words, every child has a meaningful experience, regardless of their cognitive ability.

This "baselining" happens at the beginning of the game, but it also continues throughout the child's gameplay based on data that is collected second by second. The game tries to keep the player at the right level and will adapt if they start to find it too easy or too difficult.

Kids will be kids, and so a few have tried to "game" the game - purposely performing badly at the beginning so that they can start on an easy level and do better. But, like all good game designers, we already anticipated that behaviour, and EndeavorRx quickly adapts to their true ability!

In every patient population we have studied, we have seen cognitive improvements. The big challenge lies in answering two questions: Would the improvement be clinically meaningful? And would it last? I cannot answer these big questions right now because the studies haven't yet been conducted. My gut feeling is that it's worth trying.

Doctors keep asking us about Alzheimer's, and I think it would be great for us to expand into other areas. The indications we've studied the most are ADHD, multiple sclerosis, autism and depression - and we're starting to publish more scientific and medical data so that others can read and interrogate our findings (6). But I'd like to reiterate that the studies we do are rigorously designed to answer clinical questions - and they are just as robust as the type of studies I would have done in my previous roles at Pfizer, Sanofi, and Shire.

In gaming, this is known as the wellness space. And there are many companies who have developed consumer "brain-training" games, but they can't make claims from a disease perspective or they'll run afoul of advertising standards and regulatory bodies. For example, such companies cannot say, "This game can improve your cognition, which is important for diseases, such as Alzheimer's." When targeting the general wellness market, you can only talk about common or general health.

Interestingly, there are companies in the wellness space who, perhaps after seeing what we have done, are trying to develop a more regulated version of their product. Equally, there may be the potential to do the reverse too. Personally, I'm glad we've done the hard part first!

The great thing about games is the high safety and minimum side effects. Yes, there are still side effects, but things like frustration and headache - not in the same league as some drugs. From that perspective, games are well suited to be used as wellness products.

Some have recognized the potential of the space. Shire, for example, which does a lot of work in ADHD, was an early investor. We've also had interactions with pharma companies working in other disease areas.

But some pharma companies are very conservative and see products like ours as fitting in very differently to standard therapeutics. At a consumer electronics show a few years ago, our CEO stated that we are happy to talk with pharma companies but made it clear that we are not the toy in the Happy Meal. A great analogy! His point being that pharma companies make a lot of money on drugs and are always looking for other offerings that could help better position those drugs. We want our product to have the focus and respect that it deserves. We don't want to be a side giveaway to promote greater use of a company's drug.

Healthcare is now evolving beyond traditional providers, pharma companies, and device manufacturers. The likes of Amazon and Google have an interest in health too. I know one thing: this market is going to change. In the future, I hope - or even expect - to see a greater understanding of the scientific rigor behind products like ours.

When the game was in development, employees across the company were involved in "testing" But now that we have FDA approval, the game is classified as a medical device and is only available by prescription. If we were focused on diabetes, employees could not try out the insulin! In short, we have put restrictions in place.

1. H Kollins, D DeLoss, E Cañadas, J Lutz, R Findling, R Keefe, et al., The Lancet, e168-e178 (2020).

2. N Johannes, M Vuorre, AK Przybyski, Royal Society Open Science, 8 (2021).

3. PE Wais et al., Scientific Reports, 11 (2021).

4. JA Anguera et al., Nature, 501, 97-101 (2013).

5. FDA (2021). Available at: https://bit.ly/34jjYRb

6. Akili Interactive (2021). Available at: https://bit.ly/3KZUw43

Stephanie Sutton

Making great scientific magazines isn't just about delivering knowledge and high quality content; it's also about packaging these in the right words to ensure that someone is truly inspired by a topic. My passion is ensuring that our authors' expertise is presented as a seamless and enjoyable reading experience, whether in print, in digital or on social media. I've spent fourteen years writing and editing features for scientific and manufacturing publications, and in making this content engaging and accessible without sacrificing its scientific integrity. There is nothing better than a magazine with great content that feels great to read.

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The story behind an FDA-Approved Video Game Treatment for ADHD

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In June 2020, the FDA granted marketing authorization to EndeavorRx for children aged 8 to 12 years old with ADHD. New therapeutics are approved by the FDA all the time, but this one broke the mould. Rather than popping pills, patients race around alien worlds saving lifeforms from extinction...

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Many children are diagnosed with attention deficit hyperactivity disorder (ADHD) every year. These children struggle with focusing on everyday tasks, controlling their impulses, and managing their behaviors appropriately. The constant struggles that children with ADHD face affects every aspect of their lives. Which is why finding ways to manage the symptoms is so important. Kurtzman (2020), reports that “the United Stated Food and Drug Administration has approved the first video game therapeutic as a treatment for ADHD in children.” The game, called EndeavorRx, works by creating multi-task training targets geared at enhancing the neural network of the human brain in 8–12-year old’s diagnosed with ADHD. According to Sutton (2022), the game is designed to target multiple areas of attention, such as “processing speed, sustained attention, divided attention, conflict resolution, focus, and interference processing.” The story within the game features a space recruit that must travel through the different levels to save the planet and its inhabitants from destruction. “Because a multitude of cognitive tasks targeting the attention network come at the player simultaneously, the player cannot just focus on one aspect – steering or capturing aliens – they must divide their attention between both” (Sutton, 2022). A baseline is determined at the start of the game that allows each player to engage at their own cognitive level and advances them through the levels based on their current play abilities. Davis et al. (2018), explains that through numerous clinical trials, EndeavorRx has shown improvements in attentional functioning, working memory, rapid visual processing, and executive functioning.

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~ Non-pharmacologic
~ No serious adverse events or side effects
~ Easy to download
~ Portable
~ Fun
~ Individualized treatment
~ Time limited per "dosage" to ovoid over playing
~ Backed by research and clinical trials
~ High compliance
~ Increased access
~ Reduced cost of care
~ Improved brain function

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x Requires a prescription
x Expensive
x Only for 8-12 year olds
x Side effects: frustration, headache, emotional reactions
x Not meant to be used a sole treatment
x Social replacement
X Scepticism

# data[].attributes.body
In my opinion, the EndeavorRx prescription video game is a great idea for helping with the treatment of ADHD symptoms in children. It has the potential to completely change the way medical professionals think about neuro-developmental disorders, and can pave the way for new games and technology to be used in the future. Only time will tell how this technology can be adapted to help treat other diseases. This alternative to a medication only regime, is an accessible, more affordable, and fun way for kids to actively engage in their own treatment. Parents also get to monitor their progress, and see the difference in their every day interactions. Kurtzman (2020), noted that the results of playing the game show "evidence of a neuroplastic effect – something happens in the brain cells and pathways that enables the cognitive training to embed itself, rather than just disappear." This shows long term, and possibly permanent effects that can change the way children grow and develop. I firmly believe that digital therapies are the future of medical treatment and EndeavorRx is proving that they can work and make a difference in the lives of patients and families.

# data[].attributes.body
1. Deliberative
Being deliberative is an asset, as it will allow me to make good decisions while planning for any unexpected events that may arise during implementation.
2. Relator
Being a relator is an asset, as it will allow me to build relationships with the members of the team, and provide a sense of trust in the process and people involved.
3. Discipline
Being disciplined is an asset, as it will allow me to be organized, productive, and efficient, which will provide structure to the team and project as a whole.
4. Futuristic
Being futuristic is an asset, as it will allow me to constantly be thinking about the positive future impacts of implementing this technology, and motivate the team to strive for success.
5. Empathy
Being empathic is an asset, as it will allow me to be in tune with the feelings and emotions of all team members, and allow me to provide support to meet the needs of everyone involved.

# data[].attributes.body
1. Daisy -> Developer
Daisy would be a great addition to the team because, as a developer she will be able to mentor, teach, and motivate the other team members to put forth their best work in order to achieve our end goals.
2. Ivy -> Individualization
Ivy would be a great addition to the team because, as an individualizer she would be great at delegating tasks that fit the different qualities of individual team members and help the team come together to work productively, as one.
3. Rachel -> Restorative
Rachel would be a great addition to the team because, as someone with a restorative strength she would be able to help solve and work through any potential problems that may arise.
4. Abraham -> Arranger
Abraham would be a great addition to the team because, as an arranger Abraham possesses the organizational skills that allow him to get the job done, but also allows for flexibility to modify and change things as they no longer fit the goal.
5. Chelsea -> Command
Chelsea could be a great addition to the team because, as a commander she will be able to make quick, decisive decisions that will allow the team to get the job done in a timely and effective manner.

# data[].attributes.body
Davis, N. O., Bower, J., & Kollins. S. H. (2018). Proof-of-concept study of an at-home, engaging, digital intervention for pediatric ADHD. PLoS ONE 31(1), e0189749. https://doi.org/10.1371/journal.pone.0189749

EndeavorRx (2022). EndeavorRx Full Length Trailer [Video]. YouTube. https://youtu.be/vtCp7JrS9-w

Kurtzman, L. (2020). FDA approves video game based on UCSD brain research as ADHD therapy for kids. University of California San Francisco. https://www.ucsf.edu/news/2020/06/417841/fda-approves-video-game-based-ucsf-brain-research-adhd-therapy-kids

Sutton. S. (2022). The story behind Akili Interactive’s FDA- approved video game: How Akili won FDA approval for EndeavorRx - the first “game-based digital therapeutic” for children with ADHD. The Medicine Maker. https://themedicinemaker.com/discovery-development/the-story-behind-an-fda-approved-video-game-treatment-for-adhd