Many investigators have attempted to show that using intensive cognitive training to increase Attention- Deficit/Hyperactivity Disorder (ADHD) patients’ capacity to store information within WM might also reduce symptom severity or functional impairment. Those studies were based on strong evidence for WM behavioral and neural dysfunction in ADHD, a widely-held belief that WM-related brain dysfunction is etiologically significant, and arguments that impaired WM contributes to the maintenance of the disorder. But despite promising early evidence for WM storage training potential efficacy, a decade of equivocal and negative outcomes from several well-designed randomized clinical trials have left investigators wondering why meaningful, replicable ADHD clinical improvements are not always achieved when WM storage capacity is reliably enhanced. Because few investigators want to mistakenly abandon such a promising intervention premise, there is a search for novel working memory-related treatment targets that focus on something other than simple WM storage capacity. In this R61/R33 proposal, we synthesize published findings and provide our own pilot neuroimaging evidence to argue that a better WM training target might be brain regions that specifically underlie the executive aspects of WM. Such executive working (EWM) memory operations represent patients’ ability to effectively use the information represented in WM for behavioral and cognitive control. These abilities likely are more meaningful to ADHD behavioral impairment than merely how large patients’ general WM storage capacity is. An extensive theoretical framework supports that the ‘working’ part of WM involves a small handful of discrete cognitive operations that flexibly manipulate information within WM, or stabilize WM representations in the face of different types of environmental distraction. Dozens of prior fMRI studies reliably link the four primary types of these EWM operations to activity within specific brain regions – the superior frontal sulcus and mid- lateral prefrontal cortex. Converging evidence including our pilot evidence shows these regions function abnormally in ADHD, predict ADHD symptom severity, and can be enhanced by practicing EWM tasks. NIMH’s R61/R33 experimental therapeutics mechanism is ideal to learn if a typical 5-week, course of intensive training that uses these EWM exercises can engage the proposed brain targets linked to both EWM ability and to ADHD dysfunction. If this neuroscience-guided, initial 2-year R61 study phase achieves its milestones, a subsequent R33 study phase will seek to replicate, and then show the relevance of target engagement to ADHD clinical function. If both R61/R33 aims are achieved, a series of secondary analyses will re-examine the trial outcome data. These efforts will inform the design of any subsequent preliminary efficacy study, facilitating a rapid transition into larger-scale efficacy testing.

This R61/R33 proposal is based on converging evidence that suggests prior ADHD working memory training studies might have produced lackluster clinical outcomes because they focused on enhancing the wrong cognitive and neurobiological targets. The proposed studies will assess whether or not a novel executive working memory training intervention for Attention-Deficit/Hyperactivity Disorder can engage frontoparietal brain network treatment targets and behavioral performance (R61), then replicate target engagement while also determining if it correlates with clinically meaningful improvements in ADHD dysfunction (R33). The project was designed so that if the R61/R33 aims are successful, the data we obtain will be adequate to support a future preliminary efficacy clinical trial.