Looking into the eye of ADHD. Investigating the relationship between ADHD, the delayed circadian rhythm and the functioning of the eye.

The visual system may be affected in Attention-Deficit/Hyperactivity Disorder
(ADHD). As much as 70-80% children with ADHD have ophthalmologic deficiencies
including near- and farsightedness, cylindrical errors, cross-eyedness, depth
detection problems, convergence insufficiency, and deviant optic disc size [1,
2]. Adults with ADHD have problems with depth and blue-spectrum colour
perception, visual search and processing, and peripheral vision [3]. Moreover,
visual problems in ADHD can be reduced with ADHD-medications [4]. The visual
system deficiencies in individuals with ADHD may be related to a delayed
circadian rhythm, which is already apparent in childhood ADHD [5], and is
prevalent in 78% of adults with ADHD [6]. The circadian rhythm is orchestrated
by the suprachiasmatic nuclei (SCN) in the brain, that receive input a.o. from
the intrinsically photosensitive retinal ganglion cells (ipRGCs) in the retina.
The ipRGC system responds to light intensity, especially blue wavelengths, and
modulates a.o. the pupillary reflex and melatonin (*sleep hormone*) release
[7]. We found an increased prevalence of oversensitivity to light in adults
with ADHD as compared to controls [8], an indication for a deficiency of the
ipRGC system in ADHD. In order to study the role of the ipRGCs and the visual
system functioning in ADHD and healthy controls, we will measure the pupillary
reflex, conduct ophthalmologic assessments, and objective eye functioning
tests. We will determine the prevalence and type of visual system deficiencies,
and their relationship with circadian rhythm, ADHD symptoms, and comorbid
psychiatric disorders. The effects of a single-dose and a 3-week intervention
of commonly used treatments in adults with ADHD and delayed sleep on the visual
system functioning will be evaluated. Results give us insight into the
relationship between ADHD, visual system functioning, and circadian rhythm, all
by looking into the eye of ADHD. This may lead to a new and simple test for
ADHD.

REFERENCES
1. Mezer E, Wygnanski-Jaffe T. Do children and adolescents with attention
deficit hyperactivity disorder have ocular abnormalities? European journal of
ophthalmology 2012:0.
2. Gronlund MA, Aring E, Landgren M, Hellstrom A. Visual function and ocular
features in children and adolescents with attention deficit hyperactivity
disorder, with and without treatment with stimulants. Eye 2007;21:494-502.
3. Kim S, Chen S, Tannock R. Visual function and color vision in adults with
Attention-Deficit/Hyperactivity Disorder. Journal of Optometry 2013.
4. Martin L, Aring E, Landgren M, Hellstrom A, Andersson Gronlund M. Visual
fields in children with attention-deficit / hyperactivity disorder before and
after treatment with stimulants. Acta Ophthalmol (Oxf) 2008;86:259-64.
5. Van der Heijden KB, Smits MG, Van Someren EJ, Gunning WB. Idiopathic chronic
sleep onset insomnia in attention-deficit/hyperactivity disorder: a circadian
rhythm sleep disorder. Chronobiol Int 2005;22:559-70.
6. Van Veen MM, Kooij JJ, Boonstra AM, Gordijn MC, Van Someren EJ. Delayed
circadian rhythm in adults with attention-deficit/hyperactivity disorder and
chronic sleep-onset insomnia. Biol Psychiatry 2010;67:1091-6.
7. Schmidt TM, Kofuji P. Functional and morphological differences among
intrinsically photosensitive retinal ganglion cells. The Journal of
neuroscience : the official journal of the Society for Neuroscience
2009;29:476-82.
8. Kooij JJ, Bijlenga D. High prevalence of photophobia in ADHD. Submitted.

The aim of this project is to investigate associations between visual system
functioning, ADHD, and the circadian rhythm. We will also investigate the
effects on the functioning of the visual system of commonly used treatments for
ADHD and related disorders: methylphenidate and light therapy. In case we find
visual system deficiencies that are specific to ADHD, the development of an
objective diagnostic test for ADHD will come closer.

The following objectives and hypotheses are formulated:
Objective 1: To determine the prevalence and type of visual system deficiencies
in adults with ADHD and in healthy controls.
Hypothesis 1: Adults with ADHD will have more visual system deficiencies.

Objective 2: To study the relationship between visual system deficiencies, ADHD
symptoms, executive functioning, circadian rhythm, and comorbid psychiatric
disorders.
Hypothesis 2: Any relationship between visual system deficiencies and ADHD will
be mediated by a circadian rhythm disturbance.

Objective 3: To evaluate the single-dose effect of methylphenidate and bright
light on the visual system functioning in adults with ADHD.
Hypothesis 3: These single-dose interventions will lead to changes in visual
functioning.

Objective 4: To evaluate the effect of a 3-week treatment with these agents on
the visual system functioning in adults with ADHD.
Hypothesis 4: Longer duration of treatment will result in larger effects on the
functioning of the visual system.

The study consists of two phases, (1) exploring eye functioning in ADHD and
healthy controls in an observational case-control design, and (2) an
experimental randomized controlled trial on the effect of a single dose and a
3-week treatment period of these commonly used treatments on eye functioning.

Phase 1: Exploring eye functioning in ADHD and healthy controls

- Meeting objective 1: To determine the prevalence and type of visual system
deficiencies in adults with ADHD and in healthy controls.
- Meeting objective 2: To study the relationship between visual system
deficiencies, ADHD symptoms, circadian rhythm, and comorbid psychiatric
disorders.
In Phase 1, the prevalences of eye abnormalities and characteristics of the
visual system will be explored in ADHD patients (n=41) and in healthy controls
(n=41), using the full battery of assessments (total N=82), which are summed in
paragraph E4.

Phase 2: Effect evaluation of a single dose and a 3-week treatment period of
these commonly used treatments on retinal functioning

- Meeting objective 3: To evaluate the single-dose effect of methylphenidate
and bright white light on the visual system functioning in adults with ADHD.
- Meeting objective 4: To evaluate the effect of a 3-week treatment with these
agents on the visual system functioning in adults with ADHD.
ADHD patients that have participated in Phase 1 will be randomized for any of
the interventions or for a placebo condition (as a control condition for Mph)
or for a waiting list group (as a control condition for LT). Participants that
have already participated in Phase 1, with major substance abuse, or any
contra-indication for the interventions will be excluded. Each group will have
n=20 participants per group. All conditions and medication intake schedules are
designed according usual treatment regimes.
There will be a placebo condition for Mph, and a waiting list group as a
control condition for LT. Thus, in this example the following conditions will
be evaluated, N=40:

i. Methylphenidate vs. placebo: Randomization is double blind.
- 1A) Mph, 3 x 20 mg/day at 8 AM, 12 PM and 4 PM during 3 weeks, n=10
- 1B) Placebo, 3 x 20mg/day at 8 AM, 12 PM and 4 PM during 3 weeks, n=10

ii. Light Therapy vs. waiting list: Randomization is open because there is no
alternative good control condition for LT.
- 2A) LT, 30 minutes/day in the morning during 3 weeks, n=10
- 2B) Waiting list during 3 weeks, n=10


After a single dose, the PIPR will be re-assessed. After the 3-week
intervention period, the total assessment battery (see paragraph E4) will be
re-assessed. The intra-individual change of the outcomes between the Phase 1
and the Phase 2 measurements will be compared between the Mph and the placebo
group, and between the LT and waiting list group.

In Phase 2:
- 3 x daily 40 mg immediate release Methylphenidate (Ritalin) at 8 AM, 12 PM,
and 4 PM
- once daily 30 minutes of bright light therapy (10.000 lux at 20 cm from the
eyes) between 7 and 10 AM

The time needed to test one individual is estimated at 2.5 hours, of which 1.5h
for eye functioning assessments. If an individual is tested twice, the total
duration of the assessments is 5 hours. The eye assessments may lead to tired
eyes. Wearing an actiwatch is deemed minimally burdening. The questionnaires
are in nature not burdening to the participants. In Phase 2, the participant
will get a 3-week intervention period of placebo or methylphenidate, or has a
half hour of bright light therapy. These interventions are very common in
adults with ADHD.