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Using pre-treatment biomarkers to guide patients to the preferred antidepressant medication treatment could be a promising approach to enhance its current modest response and remission rates. This open-label prospective study assessed the feasibility of using such pre-treatment biomarkers, by using previously identified EEG features (paroxysmal activity; alpha peak frequency; frontal alpha asymmetry) to inform the clinician in selecting among three different antidepressants (ADs; escitalopram, sertraline, venlafaxine) as compared to Treatment As Usual (TAU). EEG data were obtained from 195 outpatients with major depressive disorder prior to eight weeks of AD treatment. Primary outcome measure was the percentage change between before and after treatment on the Beck Depression Inventory-II (BDI-II). We compared TAU and EEG-informed prescription through AN(C)OVAs. Recruitment started with patients receiving TAU to establish baseline effectiveness, after which we recruited patients receiving EEG-informed prescription. 108 patients received EEG-informed prescription and 87 patients received TAU. Clinicians and patients were satisfied with the protocol. Overall, 70 (65%) of the EEG-informed clinicians followed recommendations (compared to 52 (60%) following prescriptions in the TAU group), establishing feasibility. We here confirm that treatment allocation informed by EEG variables previously reported in correlational studies, was feasible.

Background MDD patients with abnormal EEG patterns seem more likely to be non-responsive to the antidepressants escitalopram and venlafaxine, but not sertraline, than patients without EEG abnormalities. This finding suggests that patients with both MDD and abnormal EEGs may differentially respond to antidepressant treatment. In the current study, we investigated whether depressed patients with an abnormal EEG show a normalization of the EEG related to antidepressant treatment and response and whether such effect is drug specific, and whether having had early life stress (ELS) increases the chance of abnormal activity. Methods Baseline and week 8 EEGs and depression symptoms were extracted from a large multicenter study (iSPOT-D, n = 1008) where depressed patients were randomized to escitalopram, sertraline, or venlafaxine-XR treatment. We calculated Odds Ratios of EEG normalization and depression response in patients with an abnormal EEG at baseline, comparing sertraline versus other antidepressants. Results Fifty seven patients with abnormal EEGs were included. EEGs did not normalize significantly more with sertraline compared to other antidepressants (OR = 1.9, p = .280). However, patients with a normalized EEG taking sertraline were 5.2 times more likely to respond than subjects taking other antidepressants (p = .019). ELS was not significantly related to abnormal activity. Limitations Neurophysiological recordings were limited in time (two times 2-minute EEGs) and statistical power (n = 57 abnormal EEGs). Conclusions Response rates in patients with normalized EEG taking sertraline were significantly larger than in subjects treated with escitalopram/venlafaxine. This adds to personalized medicine and suggests a possible drug repurposing for sertraline.

Attention-deficit/hyperactivity disorder (ADHD) is highly associated with the delayed sleep phase disorder, a circadian rhythm sleep–wake disorder, which is prevalent in 73–78% of children and adults with ADHD. Besides the delayed sleep phase disorder, various other sleep disorders accompany ADHD, both in children and in adults. ADHD is either the cause or the consequence of sleep disturbances, or they may have a shared etiological and genetic background. In this review, we present an overview of the current knowledge on the relationship between the circadian rhythm, sleep disorders, and ADHD. We also discuss the various pathways explaining the connection between ADHD symptoms and delayed sleep, ranging from genetics, behavioral aspects, daylight exposure, to the functioning of the eye. The treatment options discussed are focused on improvement of sleep quality, quantity, and phase-resetting, by means of improving sleep hygiene, chronotherapy, treatment of specific sleep disorders, and by strengthening certain neuronal networks involved in sleep, e.g., by sensorimotor rhythm neurofeedback. Ultimately, the main question is addressed: whether ADHD needs to be redefined. We propose a novel view on ADHD, where a part of the ADHD symptoms are the result of chronic sleep disorders, with most evidence for the delayed circadian rhythm as the underlying mechanism. This substantial subgroup should receive treatment of the sleep disorder in addition to ADHD symptom treatment.

Daylight is the strongest synchronizer of human circadian rhythms. The circadian pathway hypothesis posits that synchrony between daylight and the circadian system relates to (in)attention. The dopamine neurotransmitter system is implicated in regulating the circadian system as well as in (attention)-deficit hyperactivity disorder [ADHD]. We studied the role of functional genetic variation in the gene encoding of dopamine-receptor-D4 (DRD4) in the relationship between inattention and seasonal daylight (changes). Gene-by-environment (GxE) mega-analyses were performed across eight studies including 3757 adult participants (with and without ADHD). We tested 1) theSpring-focus hypothesis, in which attention in 7R-carriers normalizes with increasing daylight levels preceding measurement, 2) theSummer-born ADHD hypothesis, in which 7R-carriers report more inattention when born in spring/summer than in autumn/winter, 3) theWinter-born ADHD hypothesis, opposing the second hypothesis. TheSpring-focus hypothesiswas upheld (1386 ADHD, 760 controls;d=-0.16 between periods); 7R-carriers reported evenlessinattention than 7R-non-carriers after winter solstice (d=0.27 between genotype-groups). Results were diagnosis-independent. Sensitivity analyses at individual study level confirmed the circannual patterns for 7R-carriers. Incorporating geographic changes into the independent measure, we also calculated changes in sunlight levels. This approach likewise showed that inattention correlated negatively with increasing light levels in 7R-carriers (r=-.135). Results emphasize peripheral effects of dopamine and the effects of (seasonal) daylight changes on cognition.

Low heart rate variability (HRV) has strongly been associated with an increased risk for cardiovascular disease. With cardiovascular disease being the number one cause of global deaths, factors that influence its development are relevant to understand. Season of birth has been suggested as one of the factors influencing the development of HRV. The current study was set up to replicate the finding that men born in winter have higher HRV later in life compared to those born in other seasons. To this end, we studied a sample of 1,871 healthy participants from the Brain Resource International Database during rest and during task. Furthermore, sex and age differences and associations with personality traits and psychiatric symptoms were explored. We replicated the earlier finding that men born in winter have a lower ratio of low frequency (LF) power to high frequency (HF) power during rest compared to summer and fall, and, although less pronounced, higher HF compared to summer. A difference between summer and winter for LF/HF in men was internally replicated using data recorded during task. Additionally, for both sexes, LF/HF ratio increased with age, and LF and HF both decreased. In general, LF/HF was lower in women, but heart rate was higher. In men, low HRV was associated with depression and the personality trait openness. In conclusion, results from a large multicenter data set covering the entire lifespan demonstrate that HRV changes with age in both sexes and confirm that season of birth influences HRV later in life in men., This is a replication study, showing heart rate variability (HRV) to vary with season of birth (SoB). Since both HRV and SoB have been related to cardiovascular disease, the relationship is relevant to understand. We used an almost five times larger sample than the original sample, covering wider geographic areas and the full lifespan. Additionally, age and sex differences in HRV were found. Replicating earlier findings provides solid evidence for a relationship between SoB and HRV later in life, thereby providing insights on how HRV develops and ultimately how increased risk for cardiovascular disease can be reduced.

Objective: A circadian pathway has been proposed where artificial blue light exposure in the evening delays sleep onset, thereby reducing sleep duration, which, in turn, results in increased symptoms of inattention. Hyperactivity, on the other hand, may be part of a different pathway, where symptoms of disordered breathing in sleep (DBS) result in increased hyperactivity/impulsivity symptoms (DBS pathway). The current study aimed to investigate the separate components described within the proposed pathways. Method: Data from 143 children with ADHD from a multicenter study were available for DBS pathway analyses and a subset (N=114) for circadian pathway analyses. Results: Each hypothesized step of both pathways was in accordance with the data when analyzing teacher- but not parent-rated symptoms.Conclusion: Relationships within the circadian and DBS pathways that were previously established in separate studies using separate samples were now reproduced in one sample, albeit only for teacher-rated symptoms of primary school-aged children.

Item does not contain fulltext Studies have shown that specific networks (default mode network [DMN] and task positive network [TPN]) activate in an anticorrelated manner when sustaining attention. Related EEG studies are scarce and often lack behavioral validation. We performed independent component analysis (ICA) across different frequencies (source-level), using eLORETA-ICA, to extract brain-network activity during resting-state and sustained attention. We applied ICA to the voxel domain, similar to functional magnetic resonance imaging methods of analyses. The obtained components were contrasted and correlated to attentional performance (omission errors) in a large sample of healthy subjects (N = 1397). We identified one component that robustly correlated with inattention and reflected an anticorrelation of delta activity in the anterior cingulate and precuneus, and delta and theta activity in the medial prefrontal cortex and with alpha and gamma activity in medial frontal regions. We then compared this component between optimal and suboptimal attentional performers. For the latter group, we observed a greater change in component loading between resting-state and sustained attention than for the optimal performers. Following the National Institute of Mental Health Research Domain Criteria (RDoC) approach, we prospectively replicated and validated these findings in subjects with attention deficit/hyperactivity disorder. Our results provide further support for the "default mode interference hypothesis". 9 p.

Highlights • Frontal alpha asymmetry (FAA) is moderately stable over time. • Antidepressant response prediction with FAA remains consistent, even after 8 weeks of treatment. • FAA is a differential predictor of antidepressant response robust to state and drug effects., Introduction Frontal alpha asymmetry (FAA) is a proposed prognostic biomarker in major depressive disorder (MDD), conventionally acquired with electroencephalography (EEG). Although small studies attributed trait-like properties to FAA, a larger sample is needed to reliably asses this characteristic. Furthermore, to use FAA to predict treatment response, determining its stability, including the potential dependency on depressive state or medication, is essential. Methods In the international Study to Predict Optimized Treatment in Depression (iSPOT-D), a multi-center, randomized, prospective open-label trial, 1008 MDD participants were randomized to treatment with escitalopram, sertraline or venlafaxine-extended release. Treatment response was established eight weeks after treatment initiation and resting state EEG was measured both at baseline and after eight weeks (n = 453). Results FAA did not change significantly after eight weeks of treatment (n = 453, p = .234), nor did we find associations with age, sex, depression severity, or change in depression severity. After randomizing females to escitalopram or sertraline, for whom treatment response could be predicted in an earlier study, FAA after eight weeks resulted in equivalent response prediction as baseline FAA (one tailed p = .028). Conclusion We demonstrate that FAA is a stable trait, robust to time, state and pharmacological status. This confirms FAA stability. Furthermore, as prediction of treatment response is irrespective of moment of measurement and use of medication, FAA can be used as a state-invariant prognostic biomarker with promise to optimize MDD treatments.

Contains fulltext : 158855.pdf (Publisher’s version ) (Closed access) OBJECTIVE: This study aimed to characterize alpha modulations in children with ADHD in relation to their attentional performance. METHODS: The posterior alpha activity (8-12Hz) was measured in 30 typically developing children and 30 children with ADHD aged 7-10years, using EEG while they performed a visuospatial covert attention task. We focused the analyses on typically developing boys (N=9) and boys with ADHD (N=17). RESULTS: Alpha activity in typically developing boys was similar to previous results of healthy adults: it decreased in the hemisphere contralateral to the attended hemifield, whereas it relatively increased in the other hemisphere. However, in boys with ADHD this hemispheric lateralization in the alpha band was not obvious (group contrast, p=.018). A robust relation with behavioral performance was lacking in both groups. CONCLUSIONS: The ability to modulate alpha oscillations in visual regions with the allocation of spatial attention was clearly present in typically developing boys, but not in boys with ADHD. SIGNIFICANCE: These results open up the possibility to further study the underlying mechanisms of ADHD by examining how differences in the fronto-striatal network might explain different abilities in modulating the alpha band activity. 10 p.

OBJECTIVE: Although poor sleep is often reported in adolescents with attention-deficit/hyperactivity disorder (ADHD), prior studies have been correlational. This study investigated whether sleep duration is causally linked to sleepiness, inattention, and behavioral functioning in adolescents with ADHD. METHOD: Seventy-two adolescents (ages 14–17 years) entered a three-week sleep protocol using an experimental crossover design. The protocol included a phase stabilization week, followed in randomized counterbalanced order by 1 week of sleep restriction (6.5 hours) and 1 week of sleep extension (9.5 hours). Sleep was monitored with actigraphy and daily sleep diaries, with laboratory visits at the end of each week. Analyses included 48 adolescents who had complete actigraphy data and successfully completed the sleep protocol (defined a priori as obtaining ≥1 hour actigraphy-measured sleep duration during extension compared to restriction). Parent and adolescent ratings of daytime sleepiness, ADHD symptoms, sluggish cognitive tempo (SCT), and oppositional behaviors were the primary measures. The A-X Continuous Performance Test (CPT) was a secondary measure. RESULTS: Compared to the extended sleep week, parents reported more inattentive and oppositional symptoms during the restricted sleep week. Both parents and adolescents reported more SCT symptoms and greater daytime sleepiness during restriction compared to extension. Adolescents reported less hyperactivity-impulsivity during sleep restriction than extension. No effects were found for parent-reported hyperactivity-impulsivity, adolescent-reported ADHD inattention, or CPT performance. CONCLUSION: This study provides the first evidence that sleep duration is a causal contributor to daytime behaviors in adolescents with ADHD. Sleep may be an important target for intervention in adolescents with ADHD.

Attention-deficit/hyperactivity disorder (ADHD) has been associated with an elevated resting-state theta/beta power ratio and elevated theta power. However, the potential confounding effect of a low individual alpha peak frequency (IAPF) on the theta-power estimate has often been disregarded when studying the relationship between ADHD and the theta/beta power ratio or theta power alone. The aim of the present study was to assess whether the theta/beta power ratio and relative theta power are correlated with behavioral functioning in children with ADHD, as expected from previous studies. Subsequently, the influence of IAPF and the amount of supposed overlap between the individually determined alpha-band and the fixed theta-band were studied. For 38 children (aged 8-15 years), electroencephalographic (EEG) and investigator-scored ADHD Rating Scale IV data were available. Additional neurocognitive data were available for 32 children. As expected, the theta/beta power ratio and theta were positively related to the ADHD core symptoms. This relationship strengthened when controlling for IAPF, although correlations did not significantly differ from one another. Eight of 38 children (21%) showed a supposed overlap between their individually determined alpha band and the theta band. Neurocognitive performance did not show any relationship with the theta/beta power ratio or theta. The results of this study confirm that the theta/beta power ratio and theta power are indeed correlated with behavioral symptoms in children with ADHD and underscore the relevance of taking the IAPF into account.

Item does not contain fulltext OBJECTIVE: A double-blind, randomized, placebo-controlled study was designed to assess the efficacy and safety of electroencephalographic (EEG) neurofeedback in children with attention-deficit/hyperactivity disorder (ADHD). The study started in August 2008 and ended in July 2012 and was conducted at Karakter Child and Adolescent Psychiatry University Centre in Nijmegen, The Netherlands. METHOD: Forty-one children (aged 8-15 years) with a DSM-IV-TR diagnosis of ADHD were randomly assigned to treatment with either EEG neurofeedback (n = 22) or placebo neurofeedback (n = 19) for 30 sessions, given as 2 sessions per week. The children were stratified by age, electrophysiologic state of arousal, and medication use. Everyone involved in the study, except the neurofeedback therapist and the principal investigator, was blinded to treatment assignment. The primary outcome was severity of ADHD symptoms on the ADHD Rating Scale IV, scored at baseline, during treatment, and at study end. Clinical improvement as measured by the Clinical Global Impressions-Improvement scale (CGI-I) was a secondary outcome. RESULTS: While total ADHD symptoms improved over time in both groups (F1,39 = 26.56, P < .001), there was no significant treatment effect, ie, group x time interaction (F1,39 = 0.36, P = .554); the same was true for clinical improvement as measured by the CGI-I (P = .092). No clinically relevant side effects were observed. Among the children and their parents, guessing treatment assignment was not better than chance level (P = .224 for children, P = .643 for parents). CONCLUSION: EEG neurofeedback was not superior to placebo neurofeedback in improving ADHD symptoms in children with ADHD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00723684.

Contains fulltext : 149200.pdf (Publisher’s version ) (Closed access) The evidence for a functionally inhibitory role of alpha oscillations is growing stronger, mostly derived from studies in healthy adults investigating spatial attention. It remains unexplored if the modulation of alpha band oscillations plays a similar functional role in typically developing children. The aim of this study was to characterize alpha modulations in children in relation to attentional performance. To this end, the posterior alpha activity (8-12Hz) in children between 7 and 10years old was measured using EEG while they performed a visuospatial covert attention task. We found that the alpha activity decreased in the hemisphere contralateral to the attended hemifield, whereas it relatively increased in the other hemisphere. In addition, we found that the degree of lateralized alpha modulation predicted performance on the attention task by negatively predicting the response time on invalid trials. Of note, children who were behaviorally less influenced by spatial cueing also were children with a clear lateralized alpha modulation pattern, with a significantly stronger alpha lateralization in the left hemisphere than children who were influenced more by spatial cueing. In addition, a bias to the right visual field such as that commonly observed in children, was significantly smaller or absent in the children influenced least by spatial cueing. Among all children, the magnitude of this visual field bias was positively related to the ability to modulate alpha activity. In conclusion, we have shown that the pattern of alpha oscillations modulated by attention is already present in 7-10year old typically developing children. Although a similar pattern is observed in adults, the consequences for behavior are different. The fact that alpha modulation is already present at this age opens up the possibility of using hemispheric alpha lateralization as a tool to study the physiological basis of attention deficits in clinical disorders such as ADHD. 8 p.

Item does not contain fulltext BACKGROUND: The number of placebo-controlled randomized studies relating to EEG-neurofeedback and its effect on neurocognition in attention-deficient/hyperactivity disorder (ADHD) is limited. For this reason, a double blind, randomized, placebo-controlled study was designed to assess the effects of EEG-neurofeedback on neurocognitive functioning in children with ADHD, and a systematic review on this topic was performed. METHODS: Forty-one children (8-15 years) with a DSM-IV-TR diagnosis of ADHD were randomly allocated to EEG-neurofeedback or placebo-neurofeedback treatment for 30 sessions, twice a week. Children were stratified by age, electrophysiological state of arousal, and medication use. Neurocognitive tests of attention, executive functioning, working memory, and time processing were administered before and after treatment. Researchers, teachers, children and their parents, with the exception of the neurofeedback-therapist, were all blind to treatment assignment. Outcome measures were the changes in neurocognitive performance before and after treatment. Clinical trial registration: www.clinicaltrials.gov: NCT00723684. RESULTS: No significant treatment effect on any of the neurocognitive variables was found. A systematic review of the current literature also did not find any systematic beneficial effect of EEG-neurofeedback on neurocognitive functioning. CONCLUSION: Overall, the existing literature and this study fail to support any benefit of neurofeedback on neurocognitive functioning in ADHD, possibly due to small sample sizes and other study limitations.

Item does not contain fulltext BACKGROUND: Until now, working memory training has not reached sufficient evidence as effective treatment for ADHD core symptoms in children with ADHD; for young children with ADHD, no studies are available. To this end, a triple-blind, randomized, placebo-controlled study was designed to assess the efficacy of Cogmed Working Memory Training (CWMT) in young children with ADHD. METHODS: Fifty-one children (5-7 years) with a DSM-IV-TR diagnosis of ADHD (without current psychotropic medication) were randomly assigned to the active (adaptive) or placebo (nonadaptive) training condition for 25 sessions during 5 weeks. The compliance criterion (>20 sessions) was met for 47 children. The primary outcome measure concerned the core behavioural symptoms of ADHD, measured with the ADHD Rating Scale IV (ADHD-RS). Secondary outcome measures were neurocognitive functioning, daily executive functioning, and global clinical functioning. The influence of the increase in difficulty level (Index-Improvement) for the treatment group was also analysed. Clinical trial registration information - 'Working Memory Training in Young ADHD Children'; www.clinicaltrials.gov; NCT00819611. RESULTS: A significant improvement in favour of the active condition was found on a verbal working memory task (p = .041; adapted Digit Span WISC-III, backward condition). However, it did not survive correction for multiple testing. No significant treatment effect on any of the primary or other secondary outcome measurements was found. The Index-Improvement significantly contributed to ADHD-RS and the Behavior Rating Inventory of Executive Function, both rated by the teacher, but revealed no significant group difference. CONCLUSIONS: This study failed to find robust evidence for benefits of CMWT over the placebo training on behavioural symptoms, neurocognitive, daily executive, and global clinical functioning in young children with ADHD.