Evaluation of the Relationship Between Medication, Eye Movements, and Autonomic Nervous System (ANS) Functions in Children and Adolescents With ADHD

Purpose and aims:

How objective measures such as measures of the autonomic nervous system (ANS) and eye movements are related to ADHD is insufficiently studied. Further, it is largely unknown how ADHD medication affects these biomarkers. The overarching purpose of the proposed study is to increase the understanding of mechanisms underpinning effects (symptom reduction, as well as side effects) of medication in children and adolescents with ADHD.

Specifically, we aim to examine the following research questions (RQs):

RQ1) Are there associations between:

1. symptom level and eye movement measures?
2. medication and changes in eye movement measures?
3. eye movement measures and symptom level changes?
4. eye movement measures and side effects?

RQ2) Are there associations between:

1. symptom level and pupil dilation?
2. medication and changes in pupil dilation?
3. pupil dilation and symptom level changes?
4. pupil dilation and side effects?

RQ3) Are there associations between:

1. symptom level and pupillary light reflex?
2. medication and changes in pupillary light reflex?
3. pupillary light reflex and symptom level changes?
4. pupillary light reflex and side effects?

RQ4) Are there associations between:

1. symptom level and heart rate variability (HRV)?
2. medication and changes in HRV?
3. HRV and symptom level changes?
4. HRV and side effects?

Theory and method

The study has a quasi-experimental pretest posttest design that will be performed within child and adolescent psychiatry (CAP) in Västerbotten. At least n=150 individuals aged 6-17 years diagnosed with ADHD will be invited to participate in the study. Power analyses accounting for the hierarchical nature of the data (with variation within and across individuals) were conducted using Monte Carlo simulations using the simr package (Green \& MacLeod, 2016) implemented in R (R Core Team, 2013). These analyses were conducted based on observed covariances between trials from the same individuals (random effect covariances) from eye tracking studies in children of similar ages conducted by collaborators (e.g., Kleberg et al., 2021a; Kleberg et al., 2021b). Based on previous data collected by the applicant (Lilja et al., 2025), it was assumed that 1/3 of participants could be categorized as responders. Based on these assumptions, the study has 96% power to detect moderate effects (Cohen's f2 > 0.15) at a sample size of 175, 85% with a sample size of 150, 84% with n = 125, and even 73% with a small sample size of n = 100. Exclusion criteria will be diagnoses of arrythmia, cardiovascular disease, or ongoing substance abuse, concomitant use of non-steroid asthma medications or beta-blockers, and the inability to fulfill the study participation before the participant´s 18th birthday. No caffeine intake will be allowed 4 h prior to ANS and eye tracking measurements.

Data collection:

Eye movement and ANS measureswill be collected before medication startand at a follow-up measurement approximately 2-3 months after the first measurement. Symptom screenings, and screening of side effects will be collected before the first measure, and at the follow-up. For a subset of children the eye movement and ANS measurements will be made before and after the intake of ADHD medication, both at baseline and at the follow-up.

Assessment:

Rating scales SNAP-IV-parent- and teacher-rated (Bussing et al., 2008), and the World Health Organization Adult ADHD Self-Report Scale for adolescents (Sonnby et al., 2015) will be used to measure ADHD symptoms. The Pediatric side-effects checklist (P-SEC) will be used to screen for side effects To measure other psychiatric symptoms we will use SCAS, ASSQ, SDQ-Sve, ACE-Q SE, and ARI.

Equipment ATobii Pro Spectrum 1200 HZ eye tracker (Tobii, Stockholm, Sweden) will be used to measure eye movements, pupil dilatation and the pupillary light reflex.

Bio-tracer NeXus 10 device with bipolar ECG channels (MindMedia, Herten, the Netherlands) will be used to measure HRV with 10 min baseline registration with no intervention in supine position, after 15 min rest.

Analyses:

To judge if the child is a responder to ADHD medication the SNAP-IV rating of ADHD symptoms (before and at three-month follow-up after medication start) is used. Children, who at three months have a minimum of 40% reduction in SNAP-IV score, are classified as "responders" According to previous studies, 40% threshold has shown well coherence with the degree of change in the SNAP-IV rating scale score that predominantly correspond to a substantial clinical effect, in regards of ADHD characteristic symptoms (Newcorn et al., 2008; Newcorn et al., 2009). Those who have a smaller than 20% change in SNAP-IV score are classified as "non-responders".

1. The associations between ADHD symptoms and the ANS and eye movement measures will be explored with linear regression models with ADHD symptom load as independent variable, and the ANS or eye movement measures as dependent variables.
2. The associations between medication and changes in the ANS or eye movement measures will be measured with linear regression models with the time-point as independent variable and the change in the measure as independent variable
3. The associations between the ANS or eye movement measure changes and ADHD symptom changes will be explored both with logistic regression (for the primary outcome of the study) with the ANS or eye movement measures as independent variables and medication responder status as dependent variable, as well as with linear regression with the ANS or eye movement measures as independent variables and the change in ADHD symptoms as dependent variable after correction for symptoms at baseline.
4. The associations between the ANS or eye movement measure changes, and side effects, will be explored with logistic regression with the ANS or eye-tracking measures as independent variables and side-effects as the dependent variable.