Sleep EEG slow-wave activity in medicated and unmedicated children and adolescents with attention-deficit/hyperactivity disorder

Slow waves (1–4.5 Hz) are the most characteristic oscillations of deep non-rapid eye movement sleep. The EEG power in this frequency range (slow-wave activity, SWA) parallels changes in

cortical connectivity (i.e., synaptic density) during development. In patients with attention-deficit/hyperactivity disorder (ADHD), prefrontal cortical development was shown to be delayed

and global gray matter volumes to be smaller compared to healthy controls. Using data of all-night recordings assessed with high-density sleep EEG of 50 children and adolescents with ADHD

(mean age: 12.2 years, range: 8–16 years, 13 female) and 86 age- and sex-matched healthy controls (mean age: 12.2 years, range: 8–16 years, 23 female), we investigated if ADHD patients

differ in the level of SWA. Furthermore, we examined the effect of stimulant medication. ADHD patients showed a reduction in SWA across the whole brain (−20.5%) compared to healthy controls.

A subgroup analysis revealed that this decrease was not significant in patients who were taking stimulant medication on a regular basis at the time of their participation in the study.

Assuming that SWA directly reflects synaptic density, the present findings are in line with previous data of neuroimaging studies showing smaller gray matter volumes in ADHD patients and its

normalization with stimulant medication.

Despite attention-deficit/hyperactivity disorder (ADHD) is one of the most studied developmental disorders from child- to adulthood, the genetic and neuronal factors underlying the

development of ADHD are not fully understood1. Yet, a wide range of neuroimaging studies revealed that lower gray matter volumes in different brain regions, e.g. the basal ganglia2,3, and

lower cortical thickness4,5 are associated with the disorder. According to longitudinal magnetic resonance imaging (MRI) data, there is evidence that a delay in brain maturation underlies

these differences5,6,7,8.

In recent years, a new imaging modality proved useful in tracking brain maturation in humans, i.e. high-density electroencephalography (hd EEG) recordings during sleep9. Using this

technique, studying sleep EEG slow waves, oscillations of about 1–4.5 Hz characterizing deep non-rapid eye movement (NREM) sleep, offer a promising readout of the functional output of

neuronal connectivity10,11. Slow-wave activity (SWA) is defined as the EEG power in the slow wave frequency band. During the first two decades of life, SWA follows an inverted U-shaped

curve10,12, similar to gray matter development. Moreover, the predominant location of SWA undergoes a posterior–anterior shift across the scalp from early childhood to late adolescence13,

which again parallels cortical maturation14,15. In children with ADHD, SWA was shown to be relatively increased over central brain regions16. Since this pattern resembles that of healthy

children of younger age, it supports the assumption that ADHD is characterized by a delay in cortical maturation. Apart from this study, little is known about ADHD-related topographical

alterations in SWA during sleep.

In the present study, we included data of all-night recordings assessed with high spatial resolution sleep hd EEG of 50 children and adolescents with ADHD and 86 age- and sex- matched

healthy controls. Our aim was to investigate whether ADHD patients differ from healthy controls in terms of sleep SWA across the cortex. Additionally, we aimed to assess the effects of

psychostimulants on SWA, because standard prescribed drugs, i.e. psychostimulants, not only improve specific and broader clinical symptoms, but also seem to normalize gray matter

maturation3,17,18.

Fifty patients (13 female) between 8 and 16 years (mean: 12.2 years) diagnosed with ADHD (33 combined type, 14 predominantly inattentive type, 3 unknown) were included in the analysis (Table

1). Fifteen were recruited from the Department for Child and Adolescent Psychiatry at the University of Zurich (14 diagnosed according to DSM-IV criteria and 1 according to DSM-V criteria)

and 27 from a private children’s practice in Zurich Oerlikon (all diagnosed according to DSM-IV criteria). For 8 participants the information about what diagnostic criteria were applied was

not available. Diagnoses were not verified. All subjects participated in one of three studies performed between 2010–2012 (data of 9 participants published in ref. 16), 2013 (unpublished)

and 2017 (unpublished), respectively. 10 ADHD patients (10–16 years, mean: 12.8 years, 2 female) reported regular intake of stimulant medication for the treatment of ADHD (methylphenidate,

18–80 mg/day, mean: 42 mg/day) including the morning of measurement. Another 18 patients (8–16 years, mean: 12.2 years, 5 female) reported regular intake of psychostimulants but refrained

from medication during the 24 h before the evening of the night measurement. Sixteen of them received methylphenidate (Concerta®, Ritalin®, Ritalin LA®, Medikinet®) with dosages ranging from

10 to 46 mg per day (mean: 28 mg/day) and two lisdexamphetamine (Elvanse®, both 30 mg/day). According to personal reports, medication was usually taken five (workdays) to seven days per

week. However, we did not use a standardized drug diary in the weeks before the experimental night. Five patients were medicated with methylphenidate during the time of measurement, but

details on the concentration and last time of drug intake before the sleep assessment were not assessed. Six patients (9–14 years, mean: 12.7 years, 1 female) received psychostimulant

medication in the past but had stopped medical treatment before the start of the study (from several weeks up to 2 years) and did no longer receive stimulant drugs, and 11 were drug-naïve

(9–15 years, mean: 11.6 years, 2 female). Details of diagnosis across these medication subgroups can be found in Table 1.

Eighty-six sex- and age-matched healthy control participants (mean age: 12.2 years, range: 8–16 years, 23 female) who were never diagnosed with a psychiatric disorder were included in the

analysis. Matching of the control group was done as follows: all children in the same age range as the ADHD patients (8–16 years) were selected from three studies that were performed in

2008–201313,19,20 and from a study conducted in 2017 (unpublished), resulting in 121 possible healthy control participants. From this pool, the maximal amount of participants was chosen such

that their age (mean and standard deviation) as well as the proportion of sexes precisely matched the ADHD group, leading to a sample size of n = 86. Recruitment of control participants was

done via local schools, advertisements and social media.

Of note: both, in the patient and control group, subjects were pooled from several, independent studies. All studies were performed in the same rooms, with the same equipment (EEG-system,

electrodes etc.), followed the same general procedure and the experimenters were always master- or PhD students of the same research group. Furthermore, none of the participants reported to

suffer from a diagnosed sleep disorder at the time of measurement.

To evaluate overall cognitive differences between the groups, the intelligence quotient (IQ) was estimated from either German (short-) versions of the WISC-III or WISC-IV intelligence

test21,22 (59 controls, 27 ADHD patients) or from the TONI-423 (16 controls). No differences in IQ were found between the control group and any of the ADHD subgroups. Within the ADHD

subgroups, IQ was significantly lower in patients who were medicated in the past as compared to unmedicated patients (p