Review
Sensory processing and P300 event-related potential correlates of stimulant response in children with attention-deficit/hyperactivity disorder: A critical review

https://doi.org/10.1016/j.clinph.2021.01.015Get rights and content

Highlights

  • There are individual differences in stimulant response among children with attention-deficit/hyperactivity disorder (ADHD).

  • Scalp electrophysiology may be used to predict ADHD treatment response.

  • Stimulants appear to normalize the action preparation phase of attention processing.

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder associated with considerable impairment in psychiatric and functional domains. Although stimulant medication can reduce core symptoms of inattention, hyperactivity, and impulsivity, a subgroup of patients does not respond to this intervention. A precision medicine approach has been proposed, whereby biomarkers are used to identify an effective treatment approach for a given individual. This review synthesizes the existing literature on event-related potential (ERP) correlates of stimulant response in children diagnosed with ADHD, with the goal of evaluating the potential for ERP to inform precision medicine care in this population. Forty-three articles were examined and results tentatively suggest that stimulant medications normalize the amplitude of the P300 component, and this is also associated with behavioral improvement. In contrast, results generally indicate that stimulants do not significantly alter early processing components, although there are some exceptions to this finding. Implications for research, theory, and clinical work are considered and concrete recommendations for future directions are provided. While recognizing limitations of existing literature (e.g., homogenous samples, variable methodologies), we conclude that ERP methods represent a promising approach for precision medicine care of patients with ADHD.

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.

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