Development and Psychopathology 28 (2016), 1177–1208 # Cambridge University Press 2016 doi:10.1017/S0954579416000754 Neural substrates of trait impulsivity, anhedonia, and irritability: Mechanisms of heterotypic comorbidity between externalizing disorders and unipolar depression AIMEE ZISNER AND THEODORE P. BEAUCHAINE The Ohio State University Abstract Trait impulsivity, which is often defined as a strong preference for immediate over delayed rewards and results in behaviors that are socially inappropriate, maladaptive, and short-sighted, is a predisposing vulnerability to all externalizing spectrum disorders. In contrast, anhedonia is characterized by chronically low motivation and reduced capacity to experience pleasure, and is common to depressive disorders. Although externalizing and depressive disorders have virtually nonoverlapping diagnostic criteria in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders, heterotypic comorbidity between them is common. Here, we review common neural substrates of trait impulsivity, anhedonia, and irritability, which include both low tonic mesolimbic dopamine activity and low phasic mesolimbic dopamine responding to incentives during reward anticipation and associative learning. We also consider how other neural networks, including bottom-up emotion generation systems and top-down emotion regulation systems, interact with mesolimbic dysfunction to result in alternative manifestations of psychiatric illness. Finally, we present a model that emphasizes a translational, transdiagnostic approach to understanding externalizing/depression comorbidity. This model should refine ways in which internalizing and externalizing disorders are studied, classified, and treated. In child and adolescent psychopathology research, most psy- Population-level covariation among syndromes within the chiatric disorders are classified as either internalizing syn- internalizing and externalizing spectra suggests that comor- dromes, including depressive and anxiety disorders, or exter- bidity of disorders at the individual level should be common nalizing syndromes, including attention-deficit/hyperactivity (see, e.g., Angold, Costello, & Erkanli, 1999; Beauchaine, disorder (ADHD), disruptive behavior disorders, and sub- Hinshaw & Pang, 2010; Beauchaine & McNulty, 2013; Klein stance use disorders (SUDs). The internalizing/externalizing & Riso, 1993). Homotypic comorbidity refers to cases in distinction follows from a long tradition of empirically based which an individual experiences two or more internalizing taxonomy in developmental psychopathology (see Beau- disorders, or two or more externalizing disorders. Given re- chaine & Klein, in press). In such research, factor analysis sults from factor analyses, and given substantial overlap in consistently parses behavioral symptoms of psychopathology criterion sets, homotypic comorbidity has proved to be the into broadband internalizing and externalizing dimensions rule rather than the exception in child, adolescent, and adult (e.g., Achenbach, 2011; Achenbach, & Edelbrock, 1983). psychopathology research, both in the United States and More recent structural analyses of symptoms expressed abroad (see, e.g., Angold et al., 1999; Ferdinand, Dieleman, among both twin samples and population-based samples of Ormel, & Verhulst, 2007; Gau et al., 2010; Kessler, Chiu, adults confirm the internalizing/externalizing distinction. Demler, & Walters, 2005; Kessler et al., 1994; Maughan, These analyses invariably yield a hierarchical latent structure Rowe, Messer, Goodman, & Meltzer, 2004). of psychopathology in which (a) higher order internalizing In contrast to homotypic comorbidity, heterotypic comor- and externalizing factors account for much of the covariation bidity refers to cases in which an individual experiences at among specific lower order syndromes (i.e., disorders), and least one internalizing disorder and at least one externalizing (b) higher order internalizing and externalizing factors are disorder (Angold et al., 1999). Even though internalizing and themselves correlated (e.g., Kendler et al., 2011; Krueger, externalizing disorders comprise largely nonoverlapping cri- 1999; Krueger et al., 2002; Lahey, Van Hulle, Singh, Wald- terion sets, heterotypic comorbidity is exceedingly common man, & Rahouz, 2011; Tuvblad, Zheng, Raine, & Baker, (e.g., Costello, Mustillo, Erkanli, Keeler, & Angold, 2003;Gil- 2009; Wright et al., 2013). This pattern emerges regardless liom & Shaw, 2004; Keiley, Bates, Dodge, & Pettit, 2000; of the age of participants. Marmorstein & Iacono, 2003). For example, up to half of pre- school and school-age children with ADHD experience a co- Address correspondence and reprint requests to: Theodore P. Beauchaine, De- morbid mood disorder (Wilens et al., 2002), and externalizing partment of Psychology, The Ohio State University, 225 Psychology Building, disorders in childhood predict depression in adulthood (Loth, 1835 Neil Avenue, Columbus, OH 43210; E-mail: [email protected]. Drabick, Leibenluft, & Hulvershorn, 2014). Furthermore, wor- 1177 Downloaded from http:/www.cambridge.org/core. Children's Hospital of Columbus, on 24 Oct 2016 at 14:21:58, subject to the Cambridge Core terms of use, available at http:/www.cambridge.org/core/terms. http://dx.doi.org/10.1017/S0954579416000754 1178 A. Zisner and T. P. Beauchaine sening externalizing problems across time predict worsening order (CD), SUDs, and antisocial personality disorder internalizing problems, particularly among children with high (ASPD; see Beauchaine & McNulty, 2013; Neuhaus, & baseline levels of psychopathology (Gilliom & Shaw, 2004; Beauchaine, in press). Trait impulsivity is therefore a primary Keiley et al., 2000). However, heterotypic comorbidity is vulnerability to homotypic comorbidity among externalizing not a transient phenomenon of childhood, and is also ob- disorders (Beauchaine, Zisner, & Sauder, in press). served in adolescent, young adult, and adult samples (see Bie- derman et al., 2008; Chan, Dennis, & Funk, 2008; Kessler Objectives et al., 2005; Krueger, McGue, & Iacono, 2001). Other behavioral traits are transdiagnostic vulnerabilities to both internalizing and externalizing syndromes (see Beau- Artifactual, Spurious, and True Comorbidity chaine, 2015b; Beauchaine & Thayer, 2015). For example, From a validity standpoint, sources of comorbidity can be di- emotion dysregulation, often defined as the inability to modu- vided into three overarching categories (see, e.g., Angold late affective states in the service of adaptive behavior, is ob- et al., 1999; First, 2005; Klein & Riso, 1993; Lilienfeld, served across a wide range of psychiatric disorders, including 2003). These include artifactual comorbidity, which occurs major depressive disorder (MDD; e.g., Ehring, Tuschen- when one disease entity is mistakenly split into multiple diag- Caffier, Schnu¨lle, Fischer, & Gross, 2010), externalizing spec- noses; spurious comorbidity, which occurs when distinct dis- trum disorders (e.g., Beauchaine, Gatzke-Kopp, & Mead, ease entities are assigned shared diagnostic criteria; and true 2007), and anxiety disorders (e.g., Mennin, Heimberg, Turk, comorbidity, which occurs when an individual suffers from &Fresco,2005), to name but a few. We and others have sum- separate disease entities. To date, most research on comorbid- marized the role of emotion dysregulation in conferring ity has focused either on tabulating symptoms to determine transdiagnostic vulnerability to psychopathology in recent whether rates of diagnostic co-occurrence exceed chance reviews (Beauchaine, 2001, 2015a; Beauchaine & Thayer, levels (see Angold et al., 1999; Kessler et al., 1994, 2005), 2015). The purpose of this paper is to describe how mesolimbic or on evaluating patterns of symptoms among large popula- dopamine (DA) dysfunction confers transdiagnostic vulner- tion-based and twin samples using advanced statistical mod- ability to both externalizing spectrum disorders and unipolar eling (e.g., Krueger & Markon, 2006; Tackett, Waldman, Van depression.1 We synthesize accumulating research on common Hulle, & Lahey, 2011). neural substrates of trait impulsivity, anhedonia, and irritability, Although these approaches yield important descriptive in- and present several interpretations of relations among these ten- formation about diagnostic co-occurrence and about herit- dencies. As we demonstrate in sections to follow, considerable abilities of comorbidity, they provide no information about evidence now supports the following set of conjectures: neurobiological mechanisms. This is a significant limitation because etiology-based diagnosis is often a precondition for 1. Trait impulsivity, anhedonia, and irritability (hallmarks of determining whether apparent comorbidity is artifactual, externalizing spectrum disorders and depression) derive spurious, or true (see Beauchaine & Marsh, 2006; First, from chronically low tonic mesolimbic DA activity and 2005; Jensen, 2003; Preskorn & Baker, 2002). Lacking spec- blunted phasic DA responding during anticipation of in- ification of etiology, we must infer psychopathology solely centives. from symptoms, which are often nonspecific, insensitive 2. A primary route to heterotypic comorbidity is through this markers of disease state (see Beauchaine, Lenzenweger, & transdiagnostic neural vulnerability in incentive process- Waller, 2008; Meehl, 1995). ing. Advances in behavioral genetics, molecular genetics, and 3. Hypofunctioning of the mesolimbic