Using transcranial oscillating direct current stimulation (toDCS) at 0.75 Hz, we investigated whether an externally triggered increase in slow oscillations during early SWS elevates memory performance in children with ADHD. Methods: 12 children with ADHD underwent a toDCS and a sham condition in a double-blind crossover study design conducted in a sleep laboratory. Memory was tested using a 2D object-location task. In addition, 12 healthy children performed the same memory task in their home environment.

We observed that young patients with ADHD displayed deficits with respect to the sleep-dependent consolidation of declarative memory which was associated with dysfunctional SO activity during early non-rapid eye movement sleep []. As recently shown, slow wave activity (SWA, 1–4.5 Hz) during SWS is altered in children suffering from ADHD: while over central positions the SWA was enhanced, it was attenuated by trend over frontal positions []. Our previous studies pointed to a reduced frontal brain function as the cause of the impaired memory consolidation during sleep in ADHD []. Therefore, the aim of the present study was to show that an enhancement of frontal SO activity at 0.75 Hz by toDCS during sleep enhances declarative memory consolidation in ADHD to a level comparable to that of healthy controls.

Sleep does not only restore cognitive capacity but also supports the consolidation in various memory systems in healthy children and adults []. There is increasing evidence that declarative (i.e. hippocampus-dependent) memory benefits particularly from slow wave sleep (SWS) which is characterized electrophysiologically by slow oscillations (∼0.8 Hz) occurring during slow wave activity (.5–5 Hz) []. These slow oscillations (SO) originate mainly over frontal brain regions [] and orchestrate hippocampal activity during SWS. Hereby, newly encoded declarative memory representations are reactivated, resulting in strengthened memory consolidation during sleep []. By using transcranial oscillating direct current stimulation (toDCS) at 0.75 Hz during SWS in young healthy adults, Marshall and colleagues increased SO power, resulting in boosted sleep-dependent consolidation of declarative memory [].

With a prevalence of 5–7%, attention-deficit/hyperactivity disorder (ADHD) is one of the most commonly diagnosed childhood disorders [], characterized by the cardinal symptoms of reduced attention, hyperactivity, and impulsiveness []. Imaging studies revealed that neuropsychological deficits in ADHD are predominantly caused by dysfunctions in frontal brain regions, the striatum, and the cerebellum []. Besides the core symptoms, ADHD is often accompanied by memory deficits [], which are likewise caused or at least exacerbated by reduced frontal brain functions (e.g. reduced attention, enhanced distractibility, deficits in buffering information) []. At the same time, frontal brain functions are susceptible to sleep deprivation [], and there is a whole body of research linking the often reported sleep problems to neuropsychological deficits in ADHD [].

Materials and methods

38 Delmo C.

Weiffenbach O.

Gabriel M.

Bölte S.

Marchio E.

Poustka F. Fragebogen für affektive störungen und schizophrenie für kinder im schulalter (6–18 jahre). 39 Kaufman J.

Birmaher B.

Brent D.

et al. Schedule for affective disorders and schizophrenia for school-age children - present and lifetime version (k-sads-pl): Initial reliability and validity data. 40 Achenbach T.M. Manual for the child behavior checklist/4-18 and 1991 profile. 41 Weiß R.H. Grundintelligenztest skala 2 revision, cft 20-r. 42 Lamberti G.

Weidlich S. Dcs - a visual learning and memory test for neuropsychological assessment. Table 1 Participant characteristics. ADHD Controls ADHD vs. controls Mean (SD) Mean (SD) P Age 12.1 (1.4) 11.9 (1.4) .678 IQ 105 (7.0) 105 (8.1) .915 Figural memory 65.4 (24.4) 75.7 (19.4) .267 Attention problems (CBCL) 68.6 (7.9) 50.4 (1.4) <.001 SD, standard deviation; CBCL, child behavior checklist. Twelve male children suffering from ADHD (mean age 12.1 yrs, range 10–14 yrs) and 12 healthy boys (mean age 11.9 yrs, range 9–14 yrs) participated in this study. Patients and controls did not differ with respect to age, IQ, or basic memory skills (all P-values >.2; see also Table 1 ). All children and their parents were interviewed using a German translation of the Revised Schedule for Affective Disorders and Schizophrenia for School-Age Children: Present and Lifetime Version (K-SADS-PL) []. A standard questionnaire, the Child Behavior Checklist (CBCL) [], was filled out by parents to assess any psychiatric symptoms of their children. ADHD patients were excluded, if they displayed any comorbidity apart from oppositional defiant disorder or conduct disorder. Controls were excluded if they displayed any psychiatric abnormalities. Further exclusion criteria for all participants were: below-average intelligence quotient (IQ < 85), as measured by the Culture Fair Intelligence Test 20-Revised Version (CFT 20-R) []; profound memory impairment as measured by a figural learning test to assess cerebral dysfunctions (Diagnosticum für Cerebralschädigung, DCS; cut-off score: 16th percentile of the reference sample) []; or self-reported sleep-disturbances, as measured by the Sleep-Self-Report questionnaire (SSR, cut-off score: 24).

3 American Psychiatric Association

Diagnostic and statistical manual of mental disorders. All participants had normal or corrected-to-normal vision. Patients met the criteria for ADHD according to DSM IV–TR []; four suffered from the inattentive type and another eight from the combined type. Three patients with ADHD additionally exhibited an oppositional defiant disorder (ODD) and another two were additionally diagnosed with conduct disorder. According to self-reports all participants were free of any neurological, immunological, or endocrinological disease. Parental reports revealed no significant sleep problems in their children, and no healthy participant took any medication. ADHD patients only took methylphenidate but discontinued medication 48 h (approximately twelve half-lives) prior to each experimental condition. According to self-reports none of them needed daytime naps.

All participating children and their parents gave written informed consent and were reimbursed with a voucher for their participation. The study was approved by the ethics committee of the medical faculty of the University of Kiel and followed the ethical standards of the Helsinki Declaration. The ethic committee, however, recommended not applying toDCS in healthy children, and we followed their advice.

Memory task Declarative memory was assessed by a computer version of the well-known card game “Concentration” or “Memory” (created with E-Prime 2.1, Psychology Software Tools, USA) which consisted of a configuration of 15 card pairs (6 columns, 5 rows; motives were cartoon animals and everyday items). In the beginning of the encoding session, one pair after the other was displayed faceup by the computer for 2 s and then facedown again. Participants were instructed to memorize as many card locations as possible. After all pairs were shown faceup once, the procedure was repeated a second time. Then, one card (cue) of a pair was shown faceup by the computer and participants were asked to choose the corresponding second card (target) by using the computer mouse. If the decision was correct, a green checkmark appeared on the chosen position, and the next card was turned over by the computer. If the choice was wrong, then a red X appeared on the chosen card and the card's correct location was displayed. This encoding procedure was repeated until participants made at least nine correct choices (60%). During the retrieval sessions, participants were presented with the same configuration; one cue card was displayed faceup and the target card had to be found using the computer mouse. After all 15 cue cards were presented once, the retrieval session was finished. Two sets of pictures with different positions were used, and their usage was counterbalanced over the experimental conditions. Although healthy children were confronted with only one experimental condition, half of them were confronted with the test material at the end of the diagnostic session. We did this in order to induce a comparable session effect in healthy controls as it might have been for patients. Dependent data were the percent of correctly identified positions. Memory performance was calculated as the difference between correctly identified card locations (in %) in the last round during the encoding phase (baseline) and the retrieval phase in the next morning (in %).

Transcranial oscillating direct current stimulation in ADHD 2 contact area) were applied bilaterally at frontolateral locations (F3 and F4 of the international 10:20 system, see also 2 (250 μA/0.503 cm2). Stimulation started 4 min after patients had entered non-REM sleep stage 2 for the first time over a period of 5 × 5 min separated by 1 min intervals free of stimulation. In the sham control session, the electrodes were applied as in the stimulation sessions, but the stimulator remained off. Stimulation was not felt by the participants. After each application, electrodes were cleaned, chlorinated, and the conductivity was checked. If the quality of electrodes was compromised, then they were replaced by new ones; otherwise they were reused. For ethical reasons, toDCS was not applied in the healthy children's group. Figure 1 Sinusoidal toDCS of 0.75 Hz started 4 min after patients had entered non-REM sleep stage 2 for the first time (upper panel); stimulation units (5 × 5 min) were separated by 1-min stimulation-free intervals; while anodal electrodes were fixed over F3 and F4 (arrows), cathodal electrodes were placed over ipsilateral mastoids (M1 and M2; lower panel); REM, rapid eye movement. According to Marshall and colleagues, we employed the following toDCS protocol: two Ag/AgCl sintered skin electrodes (13 mm outer diameter; 8 mm inner diameter: 0.503 cmcontact area) were applied bilaterally at frontolateral locations (F3 and F4 of the international 10:20 system, see also Fig. 1 ). Two further electrodes of the same kind were used as ipsilateral references, one placed at the left and one placed at right mastoid (M1 and M2). While frontal electrodes were affixed by adhesive EC2 paste (Grass, USA), mastoid electrodes were filled with chloride, abrasive electrolyte paste and affixed by adhesive washers (Easycap, Germany). The resistance of all electrodes was below 5 kΩ. Anodal toDCS (i.e., positive polarity at both frontal sites) was applied by two battery-driven constant-current stimulators (neuroconn, Germany). Both stimulators (one for the left and one for the right hemisphere, F3-M1, F4-M2) were synchronized by a common trigger. The current strength of each anodal electrode ranged from 0 to 250 μA at a frequency of 0.75 Hz. The monophasic stimulation was sinusoidal, and the maximum current density per anodal electrode was 0.497 mA/cm(250 μA/0.503 cm). Stimulation started 4 min after patients had entered non-REM sleep stage 2 for the first time over a period of 5 × 5 min separated by 1 min intervals free of stimulation. In the sham control session, the electrodes were applied as in the stimulation sessions, but the stimulator remained off. Stimulation was not felt by the participants. After each application, electrodes were cleaned, chlorinated, and the conductivity was checked. If the quality of electrodes was compromised, then they were replaced by new ones; otherwise they were reused. For ethical reasons, toDCS was not applied in the healthy children's group.

Sleep recordings 43 Rechtschaffen A.

Kales A. A manual of standardized terminology, techniques and scoring system for sleep stages in human subject. ADHD patients spent three nights in the sleep laboratory. The first night was used for adaptation and diagnostic purposes. Here a standard polysomnogram (PSG) was recorded using a 16-channel PSG system (Somnomedics, Germany). EEG was recorded at a 256 Hz sampling rate with band-pass filter (0.2–35 Hz) according to the International 10–20 system from Fz, C3, Cz, C4, P3, Pz, P4, Oz and referenced to the tip of the nose with a ground placed at AFz. Diagonal EOG (sampling rate: 256 Hz, band-pass filter: 0.2–10 Hz) was recorded from the lower right and upper left canthi. EMG was recorded from the chin and from the left and right lower legs at 256 Hz with a high-pass filter set to 10 Hz. A thermistor (for monitoring nasal air flow), a nasal air pressure monitor, and a piezoelectric band (for determining thoracic wall motion) were also attached to the patients. During the experimental nights (stimulation and sham), only EEG, EOG, and EMG (chin) were recorded, and the following macro sleep parameters were obtained: time in bed (TIB), sleep onset latency (time in minutes from lights off to the first epoch of sleep stage 2), total sleep time, sleep efficiency (ratio of total sleep time to time in bed), number of awakenings, duration of wakefulness after sleep onset, sleep stages 1–4 and REM sleep (in minutes), and sleep stage change index (number of sleep stage changes per hour of sleep). Sleep stages were visually scored according to standard criteria [] by a trained rater. Oscillatory EEG activity was obtained and analyzed from Fz, C3, Cz, C4, P3, Pz, P4, and Oz. The fast Fourier transform (FFT) algorithm was performed using Brain Vision Analyzer 2.0.4 (Brain Products, Germany). SO activity (0.6–1.1 Hz) was calculated during the five 1-min intervals after stimulation intervals. Only artifact-free epochs of 8-sec. duration were analyzed, and the truncating error was reduced by a Hanning window. The log-transformed absolute power values for SO were used for further analyzes. To reliably estimate differences in sleep stages and oscillatory activity between nights with stimulation and sham nights, all EEG epochs with distortion caused by toDCS in the stimulation night were correspondingly deleted from the sham night EEG after recording. For this purpose, we marked five intervals (each lasting 5 min) starting 4 min after patients had entered non-REM sleep stage 2. Intervals were separated by a 1-min break. Comparable to the stimulation night, we analyzed SO activity during these 1-min intervals after simulated stimulation. Healthy controls slept at home. Here, two consecutive nights were used. In the first night, children were familiarized with the EEG recording system by sleeping with a dummy device. The following night was the experimental night where EEG signals from only one position (F4 referenced to M1 with a ground electrode placed at AFz) were recorded by a 3-channel Somnowatch plus system (Somnomedics, Germany). This setup was used to screen for TIB, sleep onset latency, total sleep time, and non-REM sleep duration in minutes; a more detailed analysis of the EEG data was not possible.

Procedure ADHD patients 44 Wechsler D. Wechsler intelligence scale for children – fourth edition (wisc-iv). Electrodes were affixed prior to each experimental night at 7 p.m. Thereafter, patients were asked to rate their emotional state using the SAM scales of valence, arousal, and dominance and their current tiredness using a visual analog scale (ranging from 0 “not at all” to 10 “completely exhausted”). Moreover, the subtest digit-span (forward and backward) from the Wechsler Intelligence Scale for Children [] was conducted to assess the current working memory capacity. At 8 p.m., the memory encoding session took place. After reaching the criterion (at least 60% correctly identified pairs), patients were sent to bed at approximately 9 p.m. After children fell asleep, the investigator left the sleep laboratory. Unknown to the patients and the investigator, either a toDCS or a sham treatment was conducted by a briefed medical doctor. Patients were woken up by the blinded investigator at 7 a.m. After breakfast, patients were asked to rate their emotional state and their current tiredness and to work on the digit-span task before the retrieval session was carried out at 8 a.m. The order of conditions (stimulation/sham; each being conducted at least one week apart) and picture sets were counterbalanced across patients. Healthy controls Comparable to patients, electrodes were affixed in the beginning of the encoding session and children were asked to rate their emotional state and current tiredness using the same instruments as mentioned above. Then, at 8 p.m. the memory encoding phase began, and children were sent to bed after reaching the criterion of 60%. Children were woken up at 7 a.m. by their parents and the retrieval session took place at 8 a.m. To control for possible session effects that might have taken place in ADHD patients, half of the healthy children (randomly chosen) were familiarized with the parallel version of the memory task at the end of the diagnostic session. The other half was naïve to the memory task until the encoding session was conducted.