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

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

An increasing number of children are being diagnosed with ADHD, and the demand for ADHD medication has been rising. Although ADHD medication is often effective, this is unfortunately not the case for all children and adolescents with ADHD; furthermore, the majority of those who use the medication experience side effects of some kind. There are currently no known factors that are clearly linked to whether ADHD medications will be effective or cause significant side effects. The healthcare system therefore has limited ability to provide recommendations on ADHD medication at the individual level, which means that most children and adolescents with ADHD try medication. Studies show that 35% of children aged 4-11 and 53% of 12-17-year-olds discontinue ADHD medication within a year. Perhaps these children and adolescents could have avoided fruitless treatment attempts if the healthcare system had been able to provide better recommendations regarding when ADHD medications are most likely to be effective and tolerable treatment options. This, combined with reports of rising mental health issues and an avalanche-like increase in demand for child and adolescent psychiatric services, makes it particularly urgent to develop methods for offering effective interventions to the right patients as specifically as possible.

Previous studies have not consistently identified factors (neither genetic nor other factors such as gender, age, symptom severity, symptom profile, or comorbidities) that are linked to the efficacy or side effects of ADHD medications.

In this project, we will investigate whether the efficacy and side effects of ADHD medications are linked to eye movements or activity within the autonomic nervous system. The autonomic nervous system is the part of our nervous system that is not under our conscious control. It controls many bodily functions such as pupil size, heart rate, blood pressure, and reactions to stress.

Eye and pupil movements are measures of where an individual's attention is directed and how activated the brain is. ADHD is a condition in which the individual has difficulty regulating attention and activity. Therefore, there may be reason to believe that eye movements could be significant in the treatment of ADHD, even though this has never been studied before. Nor has the connection between the autonomic nervous system and the effects of ADHD medications been studied previously, even though changes in heart rate and blood pressure are among the common side effects of ADHD medications.

We will invite children and adolescents who are about to begin ADHD medication. Before they start taking the medication, we will measure eye movements, pupil dilation, and the pupil's reaction to light using so-called eye-tracking technology. This is done by having the child or adolescent look at a screen and follow certain instructions while the pupil's movements are measured. We will also measure heart rate variability, i.e., how much the pulse varies, which can be done by continuously measuring the pulse for 10 minutes. We will investigate whether there is a correlation between the characteristics of these eye movement, pupil, and heart factors before medication begins and the extent to which the medication produces effect and side effects. We will also analyze how these factors are affected by the medication.

The advantage of these factors is that they can be measured without causing pain. Furthermore, they are objective because they measure time and distance and are therefore not dependent on anyone's personal perceptions, as is so often the case with the rating scales otherwise used in psychiatry.

If we can identify correlations between eye movements and activity in the autonomic nervous system and how ADHD medications affect children and adolescents with ADHD, there is a possibility that this could be used to provide better recommendations regarding ADHD medication. Many children could then be recommended other interventions first and avoid unnecessary and unpleasant drug treatments.

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.

Inclusion Criteria:

• ages of 6 -17
• diagnosis of ADHD and agreed to medication administration in accordance with the clinic's procedures.

Exclusion Criteria:

• diagnoses of arrhythmia, cardiovascular disease, or current substance use
• concurrent use of non-steroidal asthma medications or beta-blockers
• the inability to complete study participation before the participant's 18th birthday.
• severe motor impairments and visual impairments that prevent participation in eye-tracking measurements.
• caffeine intake within 4 hours prior to HRV and eye-tracking measurements