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OBJECTIVE: ADHD is a prevalent neurodevelopmental disorder characterized by symptoms of inattention and hyperactivity-impulsivity. Impairments in executive functioning (EF) are central to models of ADHD, while alpha-band spectral power event-related decreases (ERD) have emerged as a putative electroencephalography (EEG) biomarker of EF in ADHD. Little is known about the roles of EF and alpha ERD and their interactions with symptoms of ADHD. METHOD: We estimated network models of ADHD symptoms and integrated alpha ERD measures into the symptom network. RESULTS: EF emerges as a bridge network node connecting alpha ERD and the hyperactivity/impulsivity and inattention symptoms. We found that EF most closely relates to a subset of symptoms, namely the motoric symptoms, seat (difficulty staying seated), and runs (running or climbing excessively). CONCLUSIONS: EF functions as a bridge node connecting alpha ERD and the ADHD symptom network. Motoric-type symptoms and EF deficits may constitute important nodes in the interplay between behavior/symptoms, cognition, and neurophysiological markers of ADHD.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) remains underdiagnosed and undertreated in girls. Inattentive symptoms, often predominant in girls with ADHD, represent a key driver of impairment and often persist into adulthood. AKL-T01 is a regulated digital therapeutic targeting inattention. We examined potential sex differences in the efficacy of AKL-T01 in three separate trials for 1) children, 2) adolescents, and 3) adults. METHODS: We conducted secondary analyses of clinical outcomes by sex in three AKL-T01 randomized clinical trials in ADHD (n1 = 180 children 30.6% female, M(SD) age = 9.71 (1.32); n2 = 146 adolescents; 41.1% female, M(SD) age = 14.34 (1.26); n3 = 153 adults; 69.9% female, M(SD) age = 39.86 (12.84)). Active treatment participants used AKL-T01 for 25 min/day over 4-6 weeks. Primary outcomes included change in attention on the Test of Variables of Attention (TOVA) and symptom change on the clinician-rated ADHD Rating Scale (ADHD-RS). To evaluate study hypotheses, we conducted a series of robust linear regressions of TOVA and ADHD-RS change scores by sex, adjusting for baseline scores. RESULTS: In children, girls demonstrated greater improvement in objective attention relative to boys following AKL-T01 (TOVA Attentional Composite Score; Cohens d = .36 and Reaction Time Mean Half; Cohens d = .54), but no significant sex differences in ADHD rating scale change. We did not observe significant sex differences in outcomes in the adolescent or adult trials. Limitations include binary sex categorization and slight study design variation across the three samples. CONCLUSION: AKL-T01 might notably improve attentional functioning in girls with ADHD relative to boys. Objective attention measures may be particularly important in the assessment of attentional improvement in childhood, given known gender biases in ADHD symptom reporting. We emphasize the importance of considering sex and gender-specific factors in ADHD treatment evaluation. TRIAL REGISTRATIONS: STARS ADHD CHILD: ClinicalTrials.gov ID NCT03649074; STARS ADHD ADOLESCENT: ClinicalTrials.gov ID NCT04897074; STARS ADHD ADULT: ClinicalTrials.gov ID NCT05183919.

Multiple pathway models propose that attention deficit hyperactivity disorder (ADHD) arises from dysfunction in separate systems comprised of a "cool" or cognitive pathway versus a "hot" or emotional/reward pathway. Interactions between these pathways and the degree of maturation may further determine functional outcomes for adolescents ranging from those diagnosed with ADHD to typical development (TD). We used a latent profile analysis on rating scales and behavioral task performance assessing emotion, irritability, impulsivity, risk-taking, future orientation, and processing speed (PS) to identify subgroups of TD adolescents and adolescents with ADHD (N = 152) based on the hot and cool pathway model. We identified four classes: 1) High-Complex Challenges; 2) Moderate-Mixed Challenges; 3) Non-Emotive Impulsivity; and 4) High Regulation and Control. A multiple pathway model of ADHD is supported with classes differing in degree of emotional lability and irritability, types of impulsivity, and ability to use future consequences to modulate impulsivity and PS. The classes differed regarding functional behavior, with the High-Complex class demonstrating the most severe functional challenges in academic-related functioning. The Moderate-Mixed class also displayed significant functional challenges but with moderate emotional lability and irritability ratings. The Non-Emotive Impulsivity class exhibited low emotionality and low irritability, yet high impulsivity with limited negative functional consequences, and was composed of a mix of ADHD and TD adolescents. Differences between classes suggest ADHD symptomatology may represent both categorical and dimensional differences. Precision health interventions may be more effective in addressing the specific challenges associated with the classes rather than a one-size-fits-all approach to treating ADHD.