ReviewSensory processing and P300 event-related potential correlates of stimulant response in children with attention-deficit/hyperactivity disorder: A critical review
Introduction
Attention-Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder that affects about 7% of children under the age of 18 years (Thomas et al., 2015). Children diagnosed with ADHD present with inattention, hyperactivity, and/or impulsivity (American Psychiatric Association, 2013). This clinical population often experiences functional impairment across several domains (e.g., academic, occupational, social) as well as elevated risk for anxiety, depression, and substance abuse in later life (Brown et al., 2001, Sibley et al., 2010, Sobanski et al., 2007). In 2017, the estimated cost to society of childhood and adolescent ADHD in the United States exceeded 124 billion dollars (Zhao et al., 2019). These data highlight the need to develop effective treatments for children and adolescents diagnosed with ADHD.
There are several evidence-based treatments for ADHD, including pharmacotherapy (e.g., stimulant medication) and behavior therapy (Hoza et al., 2008). A hallmark study on treatments for children with ADHD found that pharmacotherapy alone showed comparable improvements in core ADHD symptoms as the combined treatment of pharmacotherapy and behavior therapy, while both treatment arms outperformed behavior therapy alone (Group, M.C., 2004). Stimulant medications, including methylphenidate and amphetamines derivatives, are the most commonly prescribed pharmacological interventions for ADHD (Burcu et al., 2016) and function by increasing pre-synaptic levels of dopamine and norepinephrine in the brain. Positive effects of stimulant medications are reported in a majority (i.e., 60–75%) of children who receive this treatment (Stein et al., 2003, Swanson et al., 1993). However, these statistics are based on group averages and highlight the existence of a subgroup of patients for whom stimulant medications do not significantly reduce ADHD symptoms.
Individual differences in stimulant response may, at least partially, be accounted for by the neurobiological heterogeneity underlying ADHD (Arns and Olbrich, 2014). Consequently, in the past two decades, there has been an increased focus on identifying biomarkers that can inform precision medicine care (i.e., identifying the right treatment for the right person at the right time) for individuals with ADHD (Arns, 2012). Clinical decision-making could, for example, be guided by biomarkers or endophenotypes using ‘pharmaco-electroencephalography’ (EEG; Konopka and Zimmerman, 2014). In particular, the amplitude and latency of EEG-acquired event-related potentials (ERPs) have been discussed as promising biomarkers in research on pharmacological treatments for children diagnosed with ADHD (Konopka and Zimmerman, 2014, Luck, 2014). ERPs could be used in “preclinical research to define potential treatment targets” (Luck et al., 2011, p. 29). Notable benefits of EEG as a biomarker measurement tool include the fact that it is non-invasive and low-cost.
The aim of this review is to summarize the literature on ERP correlates of stimulant response in children diagnosed with ADHD and evaluate the potential for ERP metrics to inform precision medicine care in this population. We start by providing a basic overview of EEG and ERP methods and summarize how these have been applied to research on ADHD. Next, we present what is known about ERP correlates of stimulant response in children with ADHD, with a focus on early sensory processing (i.e., N1, P1, P2) and later attentional processing (i.e., P3a and P3b) components. We conclude with a discussion of major themes in the extant literature, implications for neuroscience theory, research, and clinical practice. We also identify limitations and strengths of the existing research and provide concrete recommendations for future work.
EEG is a noninvasive, cost-effective measurement technique that captures electrical fluctuations in the cortex with high temporal precision (Nunez and Srinivasan, 2006). Specifically, electrical field activity within the brain is measured as ions move across cell membranes (Niedermeyer and da Silva, 2005). EEG methods have been used to examine cortical brain activity within ADHD populations since the late 1930 s (Lenartowicz and Loo, 2014); results from such EEG research consistently demonstrate neural oscillatory differences in individuals diagnosed with ADHD (Loo and Makeig, 2012). Although some research has suggested the potential use of spectral EEG to identify biomarkers of ADHD (e.g., theta/beta ratio; Lubar, 1991), heterogeneity in the disorder and in control samples has hindered meaningful progress in this area (Clarke et al., 2001, Loo et al., 2018).
ERPs are stimulus-locked electric potentials captured through EEG (Woodman, 2010; see Fig. 1). ERPs reflect cortical responses to external stimuli or cognitive, sensory, or motor events (Blackwood and Muir, 1990). Components of the ERP are characterized by their relative latencies and positive or negative polarity, denoted by a P (positive) or N (negative), respectively (Woodman, 2010). ERP components are often categorized as relatively “early” and “late” processes, although most components of interest peak within the first 500 milliseconds following stimulus presentation (M. J. Taylor and Baldeweg, 2002). Early components are believed to reflect neuronal sensory processing and categorization and include P1, N1, P2 and N2 components (Woodman, 2010). Later components are believed to reflect cognitive attention and executive control processes and include the P3a and P3b components, or if measured through latency, the P300 waveform (Woodman, 2010). This review will focus on both early and late processing components and the extent to which their amplitudes (i.e., magnitude of positive or negative polarity) and latencies (timing of peak amplitude) are impacted by stimulant medications. Whenever possible, we will also consider whether stimulant-associated ERP changes correspond to behavioral improvements.
Both auditory and visual performance tasks elicit ERPs. One of the most common auditory paradigms is the auditory oddball task (Squires et al., 1975), in which the participant is presented with repetitive auditory stimuli, with a deviant auditory stimulus randomly interspersed. Visual paradigms include visual oddball tasks, working memory tasks, the Stroop task (Stroop, 1935), the Go/No Go task (GNG Donders, 1969), and variations of the continuous performance task (CPT; for additional review on variations see Riccio et al., 2002). Working memory tasks include lexical or pictorial stimuli n-backs. Each of these tasks targets unique neurocognitive processes, such as inhibitory control or novelty detection, as well as shared processes, such as attention maintenance and executive control. As such, all tasks elicit similar ERP waveforms with early components reflecting visual and auditory recognition and later components reflecting action preparation, task execution, and attention maintenance.
ERP differences among individuals with ADHD have been examined extensively. A recent meta-analysis of 52 articles including children and adults with ADHD (n = 1576) and without ADHD (n = 1794) found a moderate effect size for shorter Go-P100 latencies among individuals diagnosed with ADHD relative to non-ADHD participants (d = −0.33; Kaiser et al., 2020). In contrast to early processing, stronger group differences emerged for later ERP components (Kaiser et al., 2020). Specifically, ADHD was associated with smaller cue-P300 amplitudes, longer Go-P300 latencies, smaller NoGo-P300-amplitudes, and longer NoGo-P300 latencies (absolute d range = 0.35–0.56; Kaiser et al., 2020). These results are consistent with the hypothesis that neurocognitive deficits in ADHD are most apparent during action-execution attention processing phases, as opposed to basic sensory processing and categorization. Thus, in the current review we expected that stimulant effects would likewise be greatest for the P300 as compared to earlier ERP components.
Section snippets
Methods
To identify studies relevant to this review, we conducted a Boolean search of multiple databases (PsychINFO, PubMed, Science Direct, Google Scholar), using keywords “ADHD, EEG, ERP, stimulants, pediatric, child” with operators “and” and “or.” Additionally, we cross-referenced the bibliographies of identified studies for additional publications. Inclusion criteria were publication in the English language, pediatric sample (<18 years), administration of stimulant medications, and investigation of
Sensory ERP components
Within the first 300 milliseconds (ms) after stimulus onset, a series of early ERP components are visible in the ERP waveform. Typically, these include a temporal order of the P1 (100 ms), the N1 (150 ms), P2 (200 ms), and N2 (250 ms). The P1 is evoked via visual stimuli and is associated with basic sensory processing in the visual field (Hillyard and Anllo-Vento, 1998). The N1 wave consists of a negatively valanced amplitude and is thought to indicate information extraction from presented
Theoretical implications
When considered together, results from early sensory and later attention processing ERP components inform theoretical models of ADHD. Specifically, differences between ERP profiles among ADHD as compared to TD patients at baseline and following administration of stimulant medications contribute to our understanding of underlying pathophysiology in ADHD. Although some studies reported a significant effect of stimulant medications on early sensory processing components (e.g., N1), the most robust
Funding sources
This work was supported in part by grants from the National Institute of Mental Health (K99MH116064 to A.B.A.) and the Klingenstein Third Generation Foundation (ADHD Fellowship to A.B.A.).
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
References (106)
- et al.
Methylphenidate selectively modulates one sub-component of the no-go P3 in pediatric ADHD medication responders
Biol Psychol
(2018) - et al.
A review of electrophysiology in attention-deficit/hyperactivity disorder: I Qualitative and quantitative electroencephalography
Clin Neurophysiol
(2003) - et al.
A review of electrophysiology in attention-deficit/hyperactivity disorder: II. Event-related potentials
Clin Neurophysiol
(2003) - et al.
The effect of methylphenidate on response inhibition and the event-related potential of children with attention deficit/hyperactivity disorder
Int J Psychophysiol
(2005) - et al.
EEG-defined subtypes of children with attention-deficit/hyperactivity disorder
Clin Neurophysiol
(2001) - et al.
Effects of methylphenidate on adolescents with a childhood history of attention deficit disorder: II. Information processing
J Am Acad Child Psy
(1987) - et al.
Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis
Lancet Psychiatry
(2018) On the speed of mental processes
Acta Psychol
(1969)- et al.
Effects of sustained-release and standard preparations of methylphenidate on attention deficit disorder
J Am Acad Child Psy
(1992) - et al.
Electrophysiological evidence of enhanced distractibility in ADHD children
Neurosci Lett
(2005)
Responses to methylphenidate in adolescent AD/HD: evidence from concurrently recorded autonomic (EDA) and central (EEG and ERP) measures
Int J Psychophysiol
Event-related potentials and performance of attention-deficit hyperactivity disorder: children and normal controls in auditory and visual selective attention tasks
Biol Psychiatry
Earlier versus later cognitive event-related potentials (ERPs) in attention-deficit/hyperactivity disorder (ADHD): A meta-analysis
Neurosci Biobehav Rev
Neurofeedback and Psychopharmacology: Designing Effective Treatment Based on Cognitive and EEG Effects of Medications
Clin Neurotherapy Elsevier
Abnormal brain activity related to performance monitoring and error detection in children with ADHD
Cortex
Clinical utility of EEG in attention-deficit/hyperactivity disorder: a research update
Neurotherapeutics
An event-related potential investigation of the acute effects of aerobic and coordinative exercise on inhibitory control in children with ADHD
Dev Cog Neurosci
A roadmap for the development and validation of event-related potential biomarkers in schizophrenia research
Biol Psychiat
Effect of methylphenidate on auditory event related potential in boys with attention deficit hyperactivity disorder
Int J Pediatr Otorhinolaryngol
Attention, probability, and task demands as determinants of P300 latency from auditory stimuli
Electroencephalogr Clin Neurophysiol
Cognitive and biological determinants of P300: an integrative review
Biol Psychol
The continuous performance test: a window on the neural substrates for attention?
Arch Clin Neuropsychol
Attention-deficit/hyperactivity disorder: cognitive evoked potential (P300) topography predicts treatment response to methylphenidate
Clin Neurophysiol
Attention-deficit/hyperactivity disorder: use of cognitive evoked potential (P300) to predict treatment response
Clin Neurophysiol
Ontogeny of selective attention effects on event-related potentials in attention-deficit hyperactivity disorder and normal boys
Biol Psychiatry
Stimulant treatment history predicts frontal-striatal structural connectivity in adolescents with attention-deficit/hyperactivity disorder
Eur Neuropsychopharmacol
Two varieties of long-latency positive waves evoked by unpredictable auditory stimuli in man
Electroencephalogr Clin Neurophysiol
Effect of methylphenidate on attention in children with attention deficit hyperactivity disorder (ADHD): ERP evidence
Neuropsychopharmacology
Changes in event-related potentials with stimulant medication in children with attention deficit hyperactivity disorder
Biol Psychol
EEG-based personalized medicine in ADHD: Individual alpha peak frequency as an endophenotype associated with nonresponse
J Neurother
Personalized medicine in ADHD and depression: use of pharmaco-EEG
Association of ADHD and conduct disorder–brain electrical evidence for the existence of a distinct subtype
J. Child Psychol Psychiatry
Society for Developmental and Behavioral Pediatrics Clinical Practice Guideline for the Assessment and Treatment of Children and Adolescents with Complex Attention-Deficit/Hyperactivity Disorder
J Dev Behav Pediatr
Cognitive brain potentials and their application
Br J Psychiatry Suppl
Prevalence and assessment of attention-deficit/hyperactivity disorder in primary care settings
Pediatrics
Trends in stimulant medication use in commercially insured youths and adults, 2010–2014
JAMA Psychiatry
Effects of methylphenidate treatment in children with ADHD: a multimodal EEG/fNIRS approach
Psychiatr Clin Psychopharmacol
Young Psychophysiologist Award Address, 1980: P300 Latency: A New Metric of Information Processing
Psychophysiology
On quantifying surprise: The variation of event-related potentials with subjective probability
Psychophysiology
ADHD characteristics: I. Concurrent co-morbidity patterns in children & adolescents
Child Adolesc Psychiatry Ment Health
Visual event related potentials after methylphenidate and sodium valproate in children with attention deficit hyperactivity disorder
Clin EEG Neurosci
Meta-analysis of structural MRI studies in children and adults with attention deficit hyperactivity disorder indicates treatment effects
Acta Psychiatr Scand
Adverse effects of pharmacotherapies for attention-deficit hyperactivity disorder: epidemiology, prevention and management
CNS Drugs
Motivational incentives and methylphenidate enhance electrophysiological correlates of error monitoring in children with attention deficit/hyperactivity disorder
J Child Psychol Psychiatry
Event-related brain potentials in the study of visual selective attention
PNAS
Evidence-based treatments for attention-deficit/hyperactivity disorder (ADHD)
The event related brain potential as a selective index of display monitoring load
Hum Factors
A randomized controlled trial investigating the effects of neurofeedback, methylphenidate, and physical activity on event-related potentials in children with attention-deficit/hyperactivity disorder
J Child Adolesc Psychopharmacol
Cited by (16)
P3b correlates of inspection time
2024, IBRO Neuroscience ReportsEnhancement of visual dominance effects at the response level in children with attention-deficit/hyperactivity disorder
2024, Journal of Experimental Child PsychologyEvaluation of p300 and spectral resolution in children with attention deficit hyperactivity disorder and specific learning disorder
2023, Psychiatry Research - NeuroimagingMultiple mechanisms regulate statistical learning of orthographic regularities in school-age children: Neurophysiological evidence
2023, Developmental Cognitive Neuroscience