Children with ADHD and EEG abnormalities at baseline assessment, risk of epileptic seizures and maintenance on methylphenidate three years later.

PURPOSE: This study aimed to assess the incidence of EEG abnormalities (EEG-ab) in children diagnosed with ADHD, investigate the risk of epileptic seizures (SZ) and maintenance on methylphenidate (MPH) over a three-year period. METHODS: A total of 517 ADHD children aged 6-14 years were included. Baseline assessments included the identification of EEG-ab, ADHD inattentive subtype (ADHD-I), comorbid epilepsy, the use of antiepileptic drugs (AEDs) and the use of MPH. At the 3-year follow-up, assessments included the presence of EEG-ab, maintenance on MPH, AED usage, SZ risk in cases with EEG-epileptiform abnormalities (EEG-epi-ab), compared with control ADHD cases without EEG-epi-ab matched for age and gender. RESULTS: EEG-ab were identified in 273 (52.8%) cases. No statistically significant differences were observed between the EEG-ab and EEG-non-ab groups in terms of age, gender, ADHD-I type or initial use of MPH. EEG non-epileptiform abnormalities (EEG-non-epi-ab) were found in 234 out of 478 (49%) cases without EEG-epi-ab. Notably, EEG-non-epi-ab occurred more frequently in the group of 39 cases with EEG-epi-ab (30/39 (76.9%) vs. 9/39, (21.3%), a subset selected for 3-year follow-up. At 3-year-follow-up no statistically significant difference was found in maintenance on MPH in ADHD cases with and without EEG-epi-ab. Nobody of ADHD cases without comorbid epilepsy or with comorbid epilepsy with achieved SZ freedom developed new SZ. Only 3 children with drug resistant epilepsy experienced SZs, without increase in SZ frequency. The disappearance rate of EEG-epi-ab was higher than that EEG-non-epi-ab (71.8% vs. 33.3%). CONCLUSIONS: Children with and without EEG-ab exhibited similar patterns of MPH use (initial use, positive response, and maintenance on MPH). The presence of comorbid epilepsy and EEG-ab, with or without EEG-epi-ab, was not associated with an increased risk of SZ despite the use of MPH.

Is Visual Prediction Impaired in Adolescents with Autism spectrum Disorder? Event-Related Potentials in a Cued Visual GO/NOGO Task.

Aim: Deviant visual processing has been observed in autism spectrum disorder (ASD), manifesting as decreased P1 and P2 components of visual event-related potentials (ERPs). Alterations have been attributed to a failure of Bayesian inference, characterized by hypo-activation of top-down predictive abilities. To test this hypothesis, we measured the visual negativity (vN) as an ERP index of visual preparation hypothesized to mirror predictive brain activity. Method: ERPs in a cued visual GO/NOGO task in 63 adolescents with ASD (IQ > 70, attention-deficit hyperactivity disorder excluded) were compared with ERPs in a sex- and age-matched group of 60 typically developing (TD) controls. Results: The behavioral variables (omissions, commissions, reaction time, and reaction time variability), as well as ERP components reflecting, among other processes, cognitive control (contingent negative variation, P3 GO, P3 NOGO, N2 NOGO) did not differ between the groups. There were group differences in visually based ERPs. Besides P1 and P2 differences, the vN component differentiated the 2 groups with the highest effect size (d = 0.74).Conclusion: This ERP study lends support to the hypothesis suggesting that a Bayesian hypo-prediction could underlie unique perceptual experiences in individuals with ASD. This could lead to a predisposition to perceive the world with reduced influence and modulation from contextual cues, prior experiences, and pre-existing expectations.

Verbal working memory and processing speed: Correlations with the severity of attention deficit and emotional dysregulation in adult ADHD.

OBJECTIVES: The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), emphasizes symptoms severity with regard to the diagnosis of attention deficit hyperactivity disorder (ADHD). Many clinicians use neuropsychological test results as objective measures of cognitive functions as part of the diagnostic work-up. The aim of this study was to investigate whether the psychometric test results regarding verbal working memory and processing speed are useful as indicators of the severity of attention deficits and emotional dysregulation in adults with ADHD. METHODS: This observational cross-sectional clinical study included 418 adults diagnosed with ADHD according to the DSM-5. Attention deficit severity was defined based on the inattentive subscale of the Adult ADHD Self-Report Scale. Emotional dysregulation was assessed with the Deficient Emotional Self-Regulation scale. Verbal working memory was measured with the Working Memory Index (WMI), and processing speed was measured with the Processing Speed Index (PSI) from the Wechsler Adult Intelligence Scale, third edition. RESULTS: The full-scale intelligence quotients of the participants were in the normal range, with expected reductions in verbal working memory and processing speed. Only processing speed was associated with attention deficits (ß = -.056, p = .003). The association between the psychometric test result for verbal working memory and processing speed and that between the severity of attention deficits and emotional dysregulation were weak (R2 < .1) and mostly non-significant. CONCLUSION: The psychometric index scores for verbal working memory (WMI) and processing speed (PSI) seem to have limited utility as indicators of the severity of attention deficits and emotional dysregulation in adult ADHD patients.

Event Related Potentials (ERPs) and other EEG Based Methods for Extracting Biomarkers of Brain Dysfunction: Examples from Pediatric Attention Deficit/Hyperactivity Disorder (ADHD).

Neuropsychiatric diagnoses like ADHD are based on subjective methods like interviews, rating scales and observations. There is a need for more brain-based supplements. Stimulant medication is the most common treatment for ADHD. Clinically useful predictors of response have so far not been reported. The aim of this paper is to describe the EEG based methods we apply to extract potential biomarkers for brain dysfunction. Examples relate to biomarkers for pediatric ADHD, and prediction of medication response. The main emphasis is on Event Related Potentials (ERPs). A nineteen channel EEG is recorded during a 3 min eyes-opened task, a 3 min eyes-closed task, and a 20 min cued visual GO/NOGO task (VCPT). ERPs are recorded during this task. The goal of the ERP protocol is to extract biomarkers of assumed brain dysfunctions that significantly differentiate between a patient group and healthy controls. The protocol includes recording during standard conditions and artifact correction. ERP waves can be used or transformed into latent components. The components of the patient group are compared with controls, empathizing components that, when compared, show relatively high effect sizes. Sub-groups of the patients are selected on the basis of the cluster analysis in the space of the components. Treatment procedure (such as medication, tDCS or neurofeedback protocol) can be applied and the changes in components related to treatment in the subgroups are observed, forming the basis for clinical recommendations. The methods described were applied in a study of 87 pediatric ADHD patients. The index of medication response discriminated significantly between responders and non-responders with a large, and clinically meaningful effect size (d = 1.84). In an ongoing study comparing ADHD children with matched controls, several variables discriminate significantly between patients and controls. The global index will exceed d = .8. The EEG based methods described here could be clinically meaningful.

Indexing Executive Functions with Test Scores, Parent Ratings and ERPs: How Do the Measures Relate in Children versus Adolescents with ADHD?

OBJECTIVE: Rating scales and neuropsychological tests including continuous performance tests (CPTs) are widely used to assess executive functions (EFs). Event-related potentials (ERPs) are also used to index certain EFs such as action preparation and inhibition. In this descriptive study, we examined the associations between results on an EF rating scale, a CPT and ERP components in ADHD as a function of age. METHODS: Fifty-nine patients with ADHD (and more often than not with comorbid disorders) in two age groups (9-12 years and 13-17 years) were assessed using EF ratings, a visual CPT and ERPs (CueP3, P3go and P3no-go). RESULTS: There were age related changes in the ERPs with the CueP3 amplitude being stronger in children, and the P3no-go amplitude stronger in adolescents. The associations between the EF measures were different in the two age groups. In particular, the P3no-go seemed to reflect different EF-related processes in children versus adolescents. CONCLUSION: Age group effects were seen on a selection of ERP amplitudes in this sample of patients with ADHD. Ratings, test scores and EF-related ERPs seem to capture different aspects of EF in ADHD, and the associations differed depending on age group. The results show that different measures of EF are not interchangeable and highlight the importance of age when interpreting ERPs.

Predicting Clinical Gains and Side Effects of Stimulant Medication in Pediatric Attention-Deficit/Hyperactivity Disorder by Combining Measures From qEEG and ERPs in a Cued GO/NOGO Task.

OBJECTIVES: The study aim was to develop 2 scales: predicting clinical gains and risk of acute side effects of stimulant medication in pediatric attention-deficit/hyperactivity disorder (ADHD), combining measures from EEG spectra, event-related potentials (ERPs), and a cued visual GO/NOGO task. METHODS: Based on 4-week systematic medication trials, 87 ADHD patients aged 8 to 17 years were classified as responders (REs, n = 62) or non-REs (n = 25), and belonging to the side effects (SEs, n = 42) or no-SEs (n = 45) groups. Before starting the trial, a 19-channel EEG was registered twice: Test 1 (T1) without medication and T2 on a single dose of stimulant medication a few days before the trial. EEG was registered T1 and T2: 3 minutes eyes-closed, 3 minutes eyes-open, and 20 minutes cued GO/NOGO. EEG spectra, ERPs, omissions, commissions, reaction time (RT), and RT variability were computed. Groups were compared at T1 and T2 on quantitative EEG (qEEG), ERPs and behavioral parameters; effect sizes ( d) were estimated. Variables with d > 0.5 were converted to quartiles, multiplied by corresponding d, and summed to obtain 2 global scales. RESULTS: Six variables differed significantly between REs and non-REs (T1: theta/alpha ratio, P3NOGO amplitude. Differences T2-T1: Omissions, RT variability, P3NOGO, contingent negative variation [CNV]). The global scale d was 1.86. Accuracy (receiver operating characteristic) was 0.92. SEs and no-SEs differed significantly on 4 variables. (T1: RT, T2: novelty component and alpha peak frequency, and RT changes. Global scale d = 1.08 and accuracy = 0.78. CONCLUSION: Gains and side effects of stimulants in pediatric ADHD can be predicted with high accuracy by combining EEG spectra, ERPs, and behavior from baseline and single-dose tests. ClinicalTrials.gov identifier: NCT02695355.

Methylphenidate selectively modulates one sub-component of the no-go P3 in pediatric ADHD medication responders.

Methylphenidate (MPH) has been shown to modulate the amplitude of the no-go P3 component of the event-related potential (ERP; Øgrim, Aasen, & Brunner, 2016). Using group independent component analysis, the no-go P3 from a cued go/no-go task has been separated into two sub-components (Brunner et al., 2013). This study investigated whether sub-components of the no-go P3 could be identified in children with ADHD, and how MPH modulates their amplitudes. ERPs were registered twice (on/off MPH) in 57 children with ADHD classified as medication responders in a four-week medication trial. Two no-go P3 sub-components were identified. In the MPH session, the amplitude of one sub-component, the IC P3no-goearly (mean latency 378 ms, with a central distribution), was significantly larger than at baseline, whereas the other sub-component, the IC P3no-golate (mean latency 428 ms, with a centro-frontal distribution), was not significantly affected. These results add to the literature documenting that the no-go P3 consists of two overlapping phenomena with different functional correlates.

Event-Related Potentials in a Cued Go-NoGo Task Associated with Executive Functions in Adolescents with Autism Spectrum Disorder; A Case-Control Study.

Executive functions are often affected in autism spectrum disorders (ASD). The underlying biology is however not well known. In the DSM-5, ASD is characterized by difficulties in two domains: Social Interaction and Repetitive and Restricted Behavior, RRB. Insistence of Sameness is part of RRB and has been reported related to executive functions. We aimed to identify differences between ASD and typically developing (TD) adolescents in Event Related Potentials (ERPs) associated with response preparation, conflict monitoring and response inhibition using a cued Go-NoGo paradigm. We also studied the effect of age and emotional content of paradigm related to these ERPs. We investigated 49 individuals with ASD and 49 TD aged 12-21 years, split into two groups below (young) and above (old) 16 years of age. ASD characteristics were quantified by the Social Communication Questionnaire (SCQ) and executive functions were assessed with the Behavior Rating Inventory of Executive Function (BRIEF), both parent-rated. Behavioral performance and ERPs were recorded during a cued visual Go-NoGo task which included neutral pictures (VCPT) and pictures of emotional faces (ECPT). The amplitudes of ERPs associated with response preparation, conflict monitoring, and response inhibition were analyzed. The ASD group showed markedly higher scores than TD in both SCQ and BRIEF. Behavioral data showed no case-control differences in either the VCPT or ECPT in the whole group. While there were no significant case-control differences in ERPs from the combined VCPT and ECPT in the whole sample, the Contingent Negative Variation (CNV) was significantly enhanced in the old ASD group (p = 0.017). When excluding ASD with comorbid ADHD we found a significantly increased N2 NoGo (p = 0.016) and N2-effect (p = 0.023) for the whole group. We found no case-control differences in the P3-components. Our findings suggest increased response preparation in adolescents with ASD older than 16 years and enhanced conflict monitoring in ASD without comorbid ADHD during a Go-NoGo task. The current findings may be related to Insistence of Sameness in ASD. The pathophysiological underpinnings of executive dysfunction should be further investigated to learn more about how this phenomenon is related to core characteristics of ASD.

Single-dose effects on the P3no-go ERP component predict clinical response to stimulants in pediatric ADHD.

OBJECTIVE: Approximately 30% of children and adolescents diagnosed with attention-deficit/hyperactivity disorder (ADHD) and treated with stimulants are considered non-responders (non-REs). Reliable predictors of response are missing. We examined changes in Event-Related Potentials (ERPs) induced by a single dose of stimulant medication in order to predict later clinical response. METHODS: ERPs were registered twice during performance of a visual cued go/no-go task in 87 ADHD patients (27 girls) aged 8-18years; the second recording on a single dose of stimulant medication, followed by a systematic medication trial lasting 4weeks. Based on the four-week trial, participants were categorized as responders (REs, N=62) or non-REs (N=25). Changes among REs and non-REs in ERP components (cueP3, CNV, P3go, N2no-go, P3no-go) and behavioral-test variables were then compared. RESULTS: REs and non-REs differed significantly in medication-induced changes in P3no-go, cue-P3, CNV, omission errors, reaction time, and reaction-time variability. The largest effect size was found for P3no-go amplitude (p<.001; d=1.76). Changes in P3no-go and omission errors correctly classified 90% of the REs and 76% of the non-REs, when controlling for the age of the participants. CONCLUSION: Clinical response to stimulants can be predicted by assessing single-dose changes in the P3no-go ERP component amplitude. SIGNIFICANCE: Changes in P3no-go may be a clinically useful marker of response to stimulants.

Predicting the clinical outcome of stimulant medication in pediatric attention-deficit/hyperactivity disorder: data from quantitative electroencephalography, event-related potentials, and a go/no-go test.

BACKGROUND: We searched for predictors of the clinical outcome of stimulant medication in pediatric attention-deficit/hyperactivity disorder (ADHD), emphasizing variables from quantitative electroencephalography, event-related potentials (ERPs), and behavioral data from a visual go/no-go test. METHODS: Nineteen-channel electroencephalography (EEG) was recorded during the resting state in eyes-open and eyes-closed conditions and during performance of the cued go/no-go task in 98 medication-naïve ADHD patients aged 7-17 years and in 90 controls with the same age and sex distribution as the patients. For patients, the recording was followed by a systematic trial on stimulant medication lasting at least 4 weeks. Based on data from rating scales and interviews, two psychologists who were blind to the electrophysiological results independently rated the patients as responders (REs) (N=74) or non-responders (non-REs) (N=24). Using a logistic regression model, comparisons were made between REs and non-REs on the EEG spectra, ERPs (cue P3, contingent negative variation, and P3 no-go of the ERP waves and independent components [ICs] extracted from these waves), reaction time, reaction time variability, number of commission and omission errors, intelligence quotient, age, sex, ADHD subtype, and comorbidities. RESULTS: The two groups differed significantly on eight of the variables, with effect sizes (Cohen's d) ranging from 0.49 to 0.76. In the multivariate logistic regression analysis, only three of these variables were significantly associated with clinical outcome. The amplitude of the IC cue P3, which has a parietal-occipital distribution, was normal in REs but significantly smaller in non-REs, whereas the centrally distributed IC P3 no-go early was smaller in REs than in non-REs and controls. In addition, the REs had more power in the EEG theta band. A quartile-based index was calculated using these three variables. The group with the lowest scores comprised only 36% REs; response rates in the three other groups were 83%, 86%, and 89%. CONCLUSION: The clinical outcome of stimulant medication was best predicted by electrophysiological parameters. The brain dysfunctions of the REs appear to be primarily associated with prefrontal lobe hypoactivation. The non-REs were deviant from the controls in parietal-occipital functions.

Predicting acute side effects of stimulant medication in pediatric attention deficit/hyperactivity disorder: data from quantitative electroencephalography, event-related potentials, and a continuous-performance test.

BACKGROUND: The aim of this study was to search for predictors of acute side effects of stimulant medication in pediatric attention deficit/hyperactivity disorder (ADHD), emphasizing variables from quantitative electroencephalography (QEEG), event-related potentials (ERPs), and behavior data from a visual continuous-performance test (VCPT). METHODS: Seventy medication-naïve ADHD patients aged 7-16 years were tested with QEEG, including a go/no-go task condition (VCPT) from which behavior data and ERPs were extracted, followed by a systematic trial on stimulant medication lasting at least 4 weeks. Based on data from rating scales and interviews, two psychologists who were blind to the QEEG/ERP test results independently rated the patients as having no or small side effects (n = 37) or troublesome side effects (n = 33). We determined if the side effects were related to sex, age, IQ, ADHD subtype, comorbidities, clinical outcome, and variables in QEEG, ERPs, and VCPT. RESULTS: There was a moderate negative correlation between clinical outcome and side effects. Three variables were significantly associated with side effects in a multivariate logistic regression analysis. In the ERP independent component - contingent negative variation - which reflected action preparation and time evaluation, patients with high amplitudes (close to normal values) experienced more side effects than patients with lower amplitudes. A faster-than-normal reaction time in VCPT was associated with side effects, as was a high amplitude in an early ERP component (early visual independent component), reported to be influenced by attention, perceptual sensitivity, and anxiety. CONCLUSION: The group with troublesome side effects had normal action-preparation electrical brain activity, a faster-than-normal reaction time, and an increased level of anxiety (measured by ERP) compared with the no side-effects group.

Effects of neurofeedback versus stimulant medication in attention-deficit/hyperactivity disorder: a randomized pilot study.

OBJECTIVE: The purpose of this pilot study was to compare the effects of 30 sessions of neurofeedback (NF) with stimulant medication on attention-deficit/hyperactivity disorder (ADHD) patients. METHODS: Thirty-two medication-naïve ADHD patients, ages 7-16, from a neuropsychiatric clinic, were randomized to NF (n=16) or drug treatment (n=16). Other actions, such as parent management training, information, or support in school were given as needed, with no differences between the groups. All participants were assessed before treatment on two rating scales, each with parent and teacher forms. In addition, quantitative electroencephalogram (QEEG) and event-related potentials (ERPs), which included behavioral data from a go/no go test were administered. NF training took place in the clinic over a period of 7-11 months, and was followed by a repeat of the same assessment tools. The mean time interval between pre- and postassesment was not significantly different in the two groups. The 18 symptoms of ADHD (American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV)) were used as the primary outcome measure. RESULTS: Analysis of covariance revealed a significant difference between the groups at evaluation in favor of medication, with a large effect size. This picture was confirmed by other outcome measures. The QEEG spectral power in the theta and beta bands did not change in either group. In ERP, the P3 no go component increased significantly in 8 of 12 patients who had a clinically relevant medication effect, but did not increase in the medication nonresponders or the NF group. CONCLUSIONS: Our study supports effects for stimulants, but not for NF. Effects of NF may require thorough patient selection, frequent training sessions, a system for excluding nonresponders, and active transfer training. The P3 no go ERP component may be a marker for treatment response.

The quantitative EEG theta/beta ratio in attention deficit/hyperactivity disorder and normal controls: sensitivity, specificity, and behavioral correlates.

The purpose of the present study was to determine if the theta/beta ratio, and theta and beta separately, correlate with behavioral parameters, and if these measures discriminate between children and adolescents with attention deficit/hyperactivity disorder (ADHD) and normal gender- and age-matched controls. Participants comprised 62 patients and 39 controls. A continuous performance test (CPT), a GO/NOGO test and two rating scales were used to measure behavior in the patient group. EEG spectra were analyzed in eyes-closed and eyes-opened conditions, and in a GO/NOGO task in both groups. Neither the theta/beta ratio at CZ, nor theta and beta separately, discriminated significantly between patients and controls. When each person was compared with the database, significant elevations of theta were found in 25.8% of the patients and in only one control subject (2.6%). In the ADHD group, theta at CZ was positively correlated with inattention and executive problems and negatively correlated with hyperactivity/impulsivity. Beta correlated with good attention level in the control group, but with ADHD symptoms in the patients. Omission errors in the GO/NOGO test discriminated between patients and controls with an accuracy of 85%. For theta at CZ, the accuracy was 62%. Significantly elevated theta characterized a subgroup of ADHD patients, and correlated with inattention and executive problems.