RDoC-based categorization of amygdala functions and its implications in autism
Introduction
The principal focus of the field of social neuroscience in recent decades has been the elucidation of social brain networks capable of detecting cues, empathizing, interacting with others, and responding adaptively in ambiguous contexts (Dunbar, 2009; Frith, 2007; Stanley and Adolphs, 2013). An imperative of this work has been uncovering how psychiatric diseases impact these networks, particularly in autism spectrum disorder (ASD). One region consistently highlighted by this research as important in social functioning is the amygdala (Bickart et al., 2014).
The amygdala is a prime example of how neuroscience has shifted from a phrenological perspective mapping one function—fear—to one brain region and towards a network paradigm where actions arise from a dynamic affiliation of neural assemblages communicating with one another (Pessoa, 2014; Weiskrantz, 1956). The amygdala is now seen as a hub in several other, distinct networks: establishing valence or salience, cognition, reward, and social learning (Rutishauser et al., 2015). Despite its small size, the amygdala’s anatomy and functioning is complex, including disparate nuclei with dense connectivity to cortical and subcortical brain regions.
Increasing knowledge of the amygdala is paralleled by new investigations of the social brain and autism. Since the original descriptions of Kanner (1943) and Asperger (1944), substantial research has been done to expand the understanding of autism leading, along with better awareness, to greatly increased rates of diagnosis (Fombonne, 2009; U.S. Department of Health and Human Services, 2014; Volkmar and Pauls, 2003; Wing, 2005, 1993, 1981; Wing and Potter, 2002). ASD’s etiology remains obscure and has been posited to arise from the breakdown of particular genes, networks, or brain regions (Anney et al., 2012; Baron-Cohen et al., 2000; Markram et al., 2007; Poelmans et al., 2013; Voineagu et al., 2011). Presently, it is thought to be the product of altered expression in hundreds of genes, highly heritable, influenced by epigenetic factors, and deficits in connectivity between many different brain regions, including the amygdala (Eapen et al., 2013; Hallmayer et al., 2011; Kosmicki et al., 2017; Mintz, 2017).
Based on the 5th revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5, American Psychiatric Association, 2013), ASD is characterized by: “a) persistent deficits in social interaction and communication as well as b) restricted, repetitive patterns of behaviors, interests, or activities with an early onset of deficits.” The detection of ASD is predicated on clinical measures that rely on parental reports, and on observations of the child’s social aptitude during interactive tasks. These measures are crucial for diagnosing autism and categorizing the severity of symptoms. However, the DSM does not account for the vast heterogeneity of ASD and consequently it may not be the best predictor for treatment outcomes; it is thought that only 50% of individuals with ASD who receive treatment achieve significant gains as a result (Stahmer et al., 2010). In addition to improved clinical diagnosis, we need objective tools that acknowledge biological markers to demarcate variation in ASD. Towards this end the NIMH is adopting a new methodology, Research Domain Criteria (RDoC), to better characterize variation from typical behavior and enable precision medicine to improve psychiatric outcomes as it has in oncology and cardiology (Insel et al., 2010; Insel and Cuthbert, 2009). RDoC looks at psychological constructs dimensionally: from healthy to abnormal, examining the underlying genetics, neuropeptides, circuits, and physiology that ultimately gives rise to behavior (Cuthbert and Insel, 2013).
Along with renewed interest in nosology, there are questions regarding the amygdala and its contribution to neuropsychiatric disorders, including autism. Here we propose that by using RDoC to classify amygdala functions into constructs and dimensions, we can better characterize its role in normal functioning and explicate how it is altered in autism. Of the five currently defined RDoC domains—Negative Valence Systems, Positive Valence Systems, Cognitive Systems, Social Processes, and Arousal and Regulatory Systems—the amygdala is represented in each, within one or more constructs. The amygdala is not a unitary structure and we will decorticate its role in these domains and constructs by drawing on studies of lesions, animal behavior, in vivo and ex vivo electrophysiology, genetics, functional imaging, and optogenetics.
In this review, we will highlight: how conceptualizations of the amygdala’s anatomy, development, and function within the social brain have changed over time; amygdala functions in RDoC; dysfunction of the amygdala in autism throughout development; linkages to comorbid psychiatric disorders; amygdala alterations seen in the valproic acid (VPA) model of autism; and the effects of oxytocin (OT) on the amygdala and behavior. By understanding the diversity of amygdala functions, and the myriad ways it can be altered in autism, the route to improved therapies and outcomes for people with autism can be illuminated.
Section snippets
Anatomy
The human amygdala (Fig. 1) comprises 13 nuclei, distinguished by cytoarchitectonics, histochemistry, and connectivity with other brain regions. To greatly simplify the anatomical layout of the amygdala (see Duvarci & Pare, 2014; or Sah et al., 2003 for review), there are two main divisions 1) the basolateral complex (BLA) encompassing the lateral (LA), basal (BA) and accessory basal (AB) nuclei with extensive connections to sensory and cortical brain regions and 2) the central amygdala (CeA)
Amygdala functions and RDoC
Using RDoC, we have here classified amygdala functions in the domains of negative valence, positive valence, cognition, social functions, and arousal. We are interested in both the behaviors and neural circuitry of these different constructs and the relative importance of the amygdala within them.
Amygdala dysfunction in autism
The separation of a heterogeneous clinical population by biomarkers holds great promise in the treatment of many complex psychiatric disorders but particularly in autism (Clementz et al., 2016; Loth et al., 2016). Using biomarkers, such as characteristics of the amygdala, to parcellate ASD allows the development of targeted therapies and facilitates overall understanding of autism.
Conclusion: synthesis of RDoC, the amygdala, and autism
While we have described each of the domains and constructs of RDoC, and their associated neural networks, as independent systems, they exist in dynamic equilibrium. Evaluating competing needs: fear of punishment vs. possibility of reward, or interest in complex systems vs. in conspecifics, is one of the essential tasks of the brain across all species and all levels of development. Disruption of this mechanism, manifested in one construct or many is, in a sense, the definition of mental illness;
Funding
T. H. is supported by NIH grant 5P50MH100023-05
E.A. is supported by NIH grants 1P50MH100023 and P51OD11132 to YNPRC.
D. R. is supported by NIH grants 5P50MH100023-05, 5R01MH072908-12 and 5R01MH069852-12
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