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Precision Medicine Care in ADHD: the Case for Neural Excitation and Inhibition

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Precision Medicine Care in ADHD: the Case for Neural Excitation and Inhibition brain sciences Perspective Precision Medicine Care in ADHD: The Case for Neural Excitation and Inhibition Ping C. Mamiya 1,*,†, Anne B. Arnett 2,† and Mark A. Stein 2 1 Institute for Learning and Brain Sciences, University of Washington, Seattle, WA 98195, USA 2 Department of Psychiatry & Behavioral Sciences, University of Washington, Seattle, WA 98195, USA; [email protected] (A.B.A.); [email protected] (M.A.S.) * Correspondence: [email protected] † Both authors contributed equally to the manuscript. Abstract: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that has become increasingly prevalent worldwide. Its core symptoms, including difficulties regulating attention, activity level, and impulses, appear in early childhood and can persist throughout the lifespan. Current pharmacological options targeting catecholamine neurotransmissions have effec- tively alleviated symptoms in some, but not all affected individuals, leaving clinicians to implement trial-and-error approach to treatment. In this review, we discuss recent experimental evidence from both preclinical and human studies that suggest imbalance of excitation/inhibition (E/I) in the fronto- striatal circuitry during early development may lead to enduring neuroanatomical abnormality of the circuitry, causing persistence of ADHD symptoms in adulthood. We propose a model of precision medicine care that includes E/I balance as a candidate biomarker for ADHD, development of GABA- modulating medications, and use of magnetic resonance spectroscopy and scalp electrophysiology methods to monitor the effects of treatments on shifting E/I balance throughout the lifespan. Keywords: amphetamine; inhibitory control; methylphenidate; executive function; dopamine; nore- pinephrine Citation: Mamiya, P.C.; Arnett, A.B.; Stein, M.A. Precision Medicine Care in ADHD: The Case for Neural 1. Introduction: Need for Precision Medicine Care in ADHD Excitation and Inhibition. Brain Sci. Attention-deficit/hyperactivity disorder (ADHD) is a common, impairing neurodevel- 2021, 11, 91. https://doi.org/ 10.3390/brainsci11010091 opmental disorder affecting more than six million children in the United States (https://www.cdc.gov/ncbddd/adhd/data.html), many of whom will continue to ex- Received: 21 November 2020 perience symptoms and associated dysfunction well into adolescence and adulthood [1]. Accepted: 11 January 2021 In addition to core symptoms of ADHD, individuals are at increased risk of psychiatric Published: 13 January 2021 comorbidity, including substance use, and impaired academic, occupational, and health maintenance [2,3]. Moreover, societal costs in the United States of the disorder are estimated Publisher’s Note: MDPI stays neu- to exceed 124 billion dollars [4]. tral with regard to jurisdictional clai- Patients with ADHD and their clinical providers are challenged with the considerable ms in published maps and institutio- heterogeneity in clinical presentation, symptom trajectory, and treatment response [5]. nal affiliations. Currently, there are multiple pharmacological treatment options, including derivatives of methylphenidate and amphetamine stimulant classes, which target dopamine transporters, as well as several non-stimulants, which act as receptor agonists for norepinephrine and epinephrine systems [6]. However, critical limitations to ADHD treatment remain: approxi- Copyright: © 2021 by the authors. Li- mately 25% of children with ADHD are stimulant “non-responders” and many individuals censee MDPI, Basel, Switzerland. experience intolerable side effects of these medications and discontinue treatment despite This article is an open access article distributed under the terms and con- persistent symptoms [7,8]. Clinical subtypes of ADHD (e.g., predominantly inattentive, ditions of the Creative Commons At- versus predominantly hyperactive/impulsive, versus combined presentations) are not tribution (CC BY) license (https:// predictive of treatment response [9,10], likely due to poor test–retest reliability of these creativecommons.org/licenses/by/ categorizations [11]. Known etiological subtypes of ADHD, such as prenatal exposure 4.0/). to alcohol, may be associated with differential response to stimulant classes, but there Brain Sci. 2021, 11, 91. https://doi.org/10.3390/brainsci11010091 https://www.mdpi.com/journal/brainsci Brain Sci. 2021, 11, x FOR PEER REVIEW 2 of 12 Brain Sci. 2021, 11, 91 2 of 12 these categorizations [11]. Known etiological subtypes of ADHD, such as prenatal expo- sure to alcohol, may be associated with differential response to stimulant classes, but there nonetheless remains substantial heterogeneity in treatment response within these pop- nonetheless remains substantial heterogeneity in treatment response within these popu- ulations [12]. Clinicians are thus left to employ a trial-and-error approach to treatment lations [12]. Clinicians are thus left to employ a trial-and-error approach to treatment plan- planning, which can lead patients to experience medication trial fatigue before identifying ning, which can lead patients to experience medication trial fatigue before identifying their most effective agent and dose. Alternatively, a precision medicine care could be their most effective agent and dose. Alternatively, a precision medicine care could be de- developed and evaluated where biomarkers and clinical features could guide treatment veloped and evaluated where biomarkers and clinical features could guide treatment planning at the individual level. planning at the individual level. There is a vast collection of extant literature on neurobiological correlates of ADHD There is a vast collection of extant literature on neurobiological correlates of ADHD that could ultimately inform a precision medicine approach [13,14]. In this review, we focus that could ultimately inform a precision medicine approach [13,14]. In this review, we on deficient fronto-striatal connectivity driven by atypical balance of neural excitation andfocus inhibition on deficient (E/I). fronto-striatal We propose connectivity that E/I imbalance driven by impacts atypical the balance development of neural of neuralexcita- circuitrytion and andinhibition organization (E/I). We of synapticpropose connectionsthat E/I imbalance in developing impacts brains. the development Over the course of neu- of development,ral circuitry and these organization effects could of lead synaptic to atypical connections brain structural in developing and functional brains. measuresOver the incourse adolescents of development, and adults these with effects ADHD. could We review lead to literature atypical thatbrain strongly structural implicates and functional GABA andmeasures glutamate in adolescents as contributing and adults to E/I with imbalance ADHD among. We review individuals literature with that ADHD. strongly Finally, im- weplicates consider GABA methods and glutamate for precise as measurement contributing of to E/I E/I balance imbalance in the among prefrontal individuals cortex (PFC) with andADHD. striatum, Finally, as we a biomarker consider methods that could for inform precise precision measurement medicine of E/I care. balance Altogether, in the pre- we aimfrontal to review cortex evidence(PFC) and that striatum, E/I imbalance as a biomarker contributes that to could atypical inform neurodevelopment, precision medicine and wecare. consider Altogether, support we foraim this to pathogenesisreview evidence as a potentialthat E/I imbalance treatment targetcontributes for children to atypical and adolescentsneurodevelopment, with ADHD and (Figurewe consider1). support for this pathogenesis as a potential treat- ment target for children and adolescents with ADHD (Figure 1). Figure 1. Precision medicine care for attention-deficit/hyperactivity disorder (ADHD). Red line representsFigure 1. Precision atypical brain medicine development care for attention-deficit/hyperactivit and the blue line represents healthyy disorder brain (ADHD). growth. Red The dashedline linerepresents represents atypical projected brain healthydevelopment brain growthand the achievedblue line repres by precisionents healthy medicine brain care growth. through The early medicaldashed line interventions represents guided projected by the healthy measurements brain growth of excitation achieved and by inhibitionprecision medicine (E/I) balance care and 1/f through early medical interventions guided by the measurements of excitation and inhibition (E/I) ratio using MR spectroscopy (MRS) and electroencephalogram (EEG) methods. balance and 1/f ratio using MR spectroscopy (MRS) and electroencephalogram (EEG) methods. 2. Imbalance of E/I in ADHD 2. Imbalance of E/I in ADHD Neurotransmitter Systems: Decades of literature point to catecholamine (i.e., dopamine and norepinephrine)Neurotransmitter deficiency Systems: amongDecades individuals of literature with point ADHD to catecholamine [15–17]. ADHD (i.e., symp-dopa- tomsmine areand associated norepinephrine) with response deficiency to dopamine among individuals agonists, intracellular with ADHD dopamine [15–17]. receptor ADHD availability,symptoms are and associated dopamine with transporter response genotypes to dopamine [18 –agonists,20]. Moreover, intracellular dopamine dopamine levels re- in theceptor PFC-striatal availability, circuitry and havedopamine been linkedtransporter to behaviors genotypes that are[18–20]. not core Moreover, clinical symptomsdopamine of ADHD, but are nonetheless associated with the disorder, such as risk-taking
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