brain sciences Review Attention-Deficit/Hyperactivity Disorder Predominantly Inattentive Subtype/Presentation: Research Progress and Translational Studies Ike C. de la Peña 1,* , Michael C. Pan 2,3, Chau Giang Thai 1 and Tamara Alisso 1 1 Department of Pharmaceutical and Administrative Sciences, Loma Linda University School of Pharmacy, Loma Linda, CA 92350, USA; [email protected] (C.G.T.); [email protected] (T.A.) 2 Department of Psychology, Korea University, Seoul 02841, Korea; [email protected] 3 Division of Social Sciences, University of the Philippines Visayas Tacloban College, Tacloban 6500, Philippines * Correspondence: [email protected]; Tel.: +1-909-651-5995; Fax: +1-909-558-0446 Received: 23 April 2020; Accepted: 9 May 2020; Published: 14 May 2020 Abstract: Research on the predominantly inattentive attention-deficit/hyperactivity disorder (ADHD-PI) subtype/presentation is important given its high prevalence, but paradoxically it is under-recognized and undertreated. The temporal stability of the inattention symptom could impact the high worldwide prevalence of ADHD-PI. Some evidence suggests differences in the nature of attentional deficit in ADHD-PI vs. that in other subtypes. Impairments in neuropsychological, neurocognitive, and social functioning are also evident in ADHD-PI, which could be specific to the subtype (e.g., processing speed, social perception, and skills), or differ from others in severity. Neuroimaging studies have also revealed ADHD-PI-specific neuropathological abnormalities and those that are shared with other subtypes. ADHD-PI is highly comorbid with learning and internalizing (e.g., anxiety and depression) disorders. There is no solid evidence for ADHD-PI-specific genetic etiologies and differential responses of subtypes to ADHD medications. Translational studies have used the Wistar Kyoto/NCrl substrain which requires further characterizations as an ADHD-PI model. Overall, ADHD-PI research has been conducted in the context of the Diagnostic and Statistical Manual, which arguably does not conform to the widely recognized “dimensional” view of ADHD. The Research Domain Criteria has been proposed to provide a novel framework for understanding the nature of neuropsychiatric illnesses and ultimately improve their diagnosis and treatment. Keywords: ADHD predominantly inattentive; inattention; neuroimaging; comorbidity; genetics; pharmacotherapy; Wistar Kyoto/NCrl; RDoC 1. Introduction Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent, childhood-onset neurodevelopmental disorder which is characterized by developmentally extreme and impairing symptoms that include inattention, motor hyperactivity, and impulsivity, with difficulties that often continuing into adulthood [1,2]. The impairments produced by ADHD cut across multiple domains including educational and vocational problems, familial interaction patterns, and social relationships [3]. As a highly heterogeneous disorder, ADHD manifests differentially across individuals in terms of behaviors, etiology, developmental trajectories, presence of comorbid diagnoses, and response to interventions [3,4]. The heterogeneity in ADHD yields the different subtypes/presentations, namely, predominantly inattentive (ADHD-PI), predominantly hyperactive-impulsive (ADHD-HI), and combined (ADHD-C) presentations (see below). Brain Sci. 2020, 10, 292; doi:10.3390/brainsci10050292 www.mdpi.com/journal/brainsci Brain Sci. 2020, 10, 292 2 of 28 The terminology and diagnostic criteria for ADHD, similar to other neuropsychiatric disorders, have been improved and developed over the past 50 years, in response to the evolving understanding and conceptualization of the core deficits of the disorder [4,5]. The current diagnostic approach of ADHD utilizes the Diagnostic and Statistical Manual of Mental Disorders (DSM) and its counterpart, the International Classification of Diseases (ICD), which conceptualize ADHD as a categorical diagnosis [4]. This approach, however, has some limitations, necessitating the development and determination of alternative diagnostic structures for ADHD [4]. 1.1. A Brief History of the ADHD-PI Since its first appearance in the DSM, there have been controversies surrounding the ADHD-PI subtype of ADHD [5,6]. For instance, the validity of this subtype has been questioned because prior to its representation in the DSM-III in 1980, it was not expected that there would be children who would present significant attention problems without hyperactivity and impulsivity [7]. Since then, a number of studies have examined the validity of this subtype [5–8]. Moreover, works by Lahey et al. [9,10] and Healey et al. [11] were instrumental in the identification of two ADHD symptom clusters, namely, inattention and hyperactivity/impulsivity, which eventually led to the determination of the three ADHD subtypes in the DSM-IV. As noted earlier, these are the ADHD combined (hyperactivity or impulsivity and inattention present to a significant extent), ADHD-HI (hyperactivity or impulsivity with subthreshold inattention), and the ADHD-PI (significant inattention with subthreshold hyperactivity and impulsivity) types. Table1 shows the fifth and the latest DSM criteria for ADHD (DSM-5 criteria for ADHD). The DSM-IV criteria for ADHD have been modified, and other notable updates in the DSM-5 include the addition of two ADHD modifiers, and notably, terminological change from ADHD “subtype” to “presentations.” Table 1. DSM-5 Criteria for Attention-deficit/hyperactivity disorder (ADHD). Criterion Description A persistent pattern of inattention and/or hyperactivity-impulsivity that interferes with functioning or development, as characterized by (1) and/or (2): 1. Inattention: Six (or more) of the following symptoms have persisted for at least 6 months to a degree that is inconsistent with developmental level and that negatively impacts directly on social and academic/occupational activities: Note: The symptoms are not solely a manifestation of oppositional behavior, defiance, hostility, or failure to understand tasks or instructions. For older adolescents and adults (age 17 and older), at least five symptoms are required. Often fails to give close attention to details or makes careless mistakes in schoolwork, • at work, or during other activities (e.g., overlooks or misses details, work is inaccurate). Often has difficulty sustaining attention in tasks or play activities (e.g., has difficulty • remaining focused during lectures, conversations, or lengthy reading). Often does not seem to listen when spoken to directly (e.g., mind seems elsewhere, even • in the absence of any obvious distraction). A Often does not follow through on instructions and fails to finish schoolwork, chores, or • duties in the workplace (e.g., starts tasks but quickly loses focus and is easily sidetracked). Often has difficulty organizing tasks and activities (e.g., difficulty managing sequential • tasks; difficulty keeping materials and belongings in order; messy, disorganized work; has poor time management; fails to meet deadlines). Often avoids, dislikes, or is reluctant to engage in tasks that require sustained mental • effort (e.g., schoolwork or homework; for older adolescents and adults, preparing reports, completing forms, reviewing lengthy papers). Often loses things necessary for tasks or activities (e.g., school materials, pencils, books, • tools, wallets, keys, paperwork, eyeglasses, mobile telephones). Is often easily distracted by extraneous stimuli (for older adolescents and adults, • may include unrelated thoughts). Is often forgetful in daily activities (e.g., doing chores, running errands; for older • adolescents and adults, returning calls, paying bills, keeping appointments). Brain Sci. 2020, 10, 292 3 of 28 Table 1. Cont. Criterion Description 2. Hyperactivity and Impulsivity: Six (or more) of the following symptoms have persisted for at least 6 months to a degree that is inconsistent with developmental level and that negatively impacts directly on social and academic/occupational activities: Note: The symptoms are not solely a manifestation of oppositional behavior, defiance, hostility, or a failure to understand tasks or instructions. For older adolescents and adults (age 17 and older), at least five symptoms are required. Often fidgets with or taps hands or feet or squirms in seat. • Often leaves seat in situations when remaining seated is expected (e.g., leaves his or her • place in the classroom, in the office or other workplace, or in other situations that require remaining in place). Often runs about or climbs in situations where it is inappropriate. (Note: In adolescents • or adults, may be limited to feeling restless.) A Often unable to play or engage in leisure activities quietly. • Is often “on the go,” acting as if “driven by a motor” (e.g., is unable to be or • uncomfortable being still for extended time, as in restaurants, meetings; may be experienced by others as being restless or difficult to keep up with). Often talks excessively. • Often blurts out an answer before a question has been completed (e.g., completes • people’s sentences; cannot wait for turn in conversation). Often has difficulty waiting his or her turn (e.g., while waiting in line). • Often interrupts or intrudes on others (e.g., butts into conversations, games, or activities; • may start using other people’s things without asking or receiving permission; for adolescents and adults, may intrude into or take over what others are doing). B Several inattentive or hyperactive-impulsive symptoms were present prior to age 12