The neural circuitry of restricted repetitive behavior: Magnetic resonance imaging in neurodevelopmental disorders and animal models

Highlights

• Mapping the neural circuitry of RRB is in its early stages.

• MRI provides needed translational studies of the network connectivity mediating RRB.

• MRI findings implicate cortico-basal ganglia and cerebellar circuits in RRB.

• MRI studies of animal models of RRB are lacking and sorely needed.

• Advanced MRI with in vitro neuroscience methods are needed to confirm RRB circuitry.

Abstract

Restricted, repetitive behaviors (RRBs) are patterns of behavior that exhibit little variation in form and have no obvious function. RRBs although transdiagonstic are a particularly prominent feature of certain neurodevelopmental disorders, yet relatively little is known about the neural circuitry of RRBs. Past work in this area has focused on isolated brain regions and neurotransmitter systems, but implementing a neural circuit approach has the potential to greatly improve understanding of RRBs. Magnetic resonance imaging (MRI) is well-suited to studying the structural and functional connectivity of the nervous system, and is a highly translational research tool. In this review, we synthesize MRI research from both neurodevelopmental disorders and relevant animal models that informs the neural circuitry of RRB. Together, these studies implicate distributed neural circuits between the cortex, basal ganglia, and cerebellum. Despite progress in neuroimaging of RRB, there are many opportunities for conceptual and methodological improvement. We conclude by suggesting future directions for MRI research in RRB, and how such studies can benefit from complementary approaches in neuroscience.

Introduction

Restricted, repetitive behaviors (RRBs) are seemingly purposeless patterns of behavior that exhibit little variation in form, interfere with appropriate behavior, and in some cases may even cause direct harm (e.g., self-injury). RRBs encompass a broad variety of behaviors, including motor stereotypies (e.g., hand-flapping or body-rocking), compulsions, rituals, and circumscribed interests (e.g., fixation on trains or electronic devices). RRBs are often categorized as either “lower-order” repetitive motor behaviors, or “higher-order” repetitive behaviors that are associated with insistence on sameness or resistance to change (Turner, 1999). RRBs are present in a number of human conditions and disorders but the broad range of these behaviors are diagnostic for Autism Spectrum Disorder (ASD) and highly prevalent in syndromic and non-syndromic intellectual and developmental disability (IDD; Flores et al., 2011; Mount et al., 2002; Oakes et al., 2016). It is these disorders of development that will be the focus of this review. As the prevalence of neurodevelopmental disorders, particularly ASD, has dramatically increased over the past two decades (Boyle et al., 2011), RRBs impact a larger portion of clinical populations than ever before. For example, diagnoses of ASD have grown from one in 150 children in the year 2000 to one in 68 children as of 2012 (Christensen et al., 2016). Although behavioral interventions have some degree of success in treating RRB (Boyd et al., 2012; Rapp and Vollmer, 2004a,b), pharmacological interventions are currently aimed at treating associated problems (e.g., aggressive behavior) and have no demonstrated efficacy for RRB in ASD and IDD (Carrasco et al., 2012; King et al., 2013). This shortcoming is largely due to an incomplete understanding of the neural circuitry mediating RRB.

A great deal of previous research directed toward understanding the etiology and pathophysiology of neurodevelopmental disorders has focused on alterations in specific brain regions, targeted neurotransmitter systems, and/or select genes. Although these efforts have made important contributions toward the current state of the science, much is yet to be learned about mechanisms that mediate RRB in neurodevelopmental disorders. As highlighted by Gunaydin and Kreitzer (2016), recent advances in neuroscience have fostered a shift in thinking as to how various clinical disorders and behaviors are mediated, with evidence pointing to subtle alterations across multiple brain regions, neurotransmitter systems, and synaptic processes that converge as neural circuits. ASD, for example, has been conceptualized by some as a brain network connectivity disorder (Just et al., 2004) where the integrated activity of large-scale neuronal networks are impaired. Adopting a neural circuit approach has resulted in great progress in other research areas such as drug-addiction, where convergent circuitry is affected by drugs acting through multiple molecular mechanisms (Kalivas et al., 2006). Similarly, a circuit-oriented approach is likely to provide great utility towards understanding the complex and heterogeneous phenomena of RRB appearing in ASD and related neurodevelopmental disorders. Although little is currently known about how RRB is mediated at the level of neural circuits, previous research in neurodevelopmental disorders (Langen et al., 2011b; Leekam et al., 2011; Lewis and Kim, 2009) and animal models of RRB (Ahmari, 2016; Bechard and Lewis, 2012; Langen et al., 2011a), suggests a critical role for networks involving the basal ganglia. Previous efforts dedicated to understanding the pathophysiology of RRB in animal models through investigating components of basal ganglia circuitry (e.g., Bechard et al., 2016; Presti and Lewis, 2005; Tanimura et al., 2008, 2010, 2011), have added much to our understanding of this phenomenon, but little work has been done to place these findings in the broader context of large-scale brain networks. The basal ganglia are a point of convergence for multiple large-scale brain networks, but there are also opportunities for basal ganglia and cerebellar networks to interact at the level of cortex, thalamus, and pontine nuclei (see Fig. 1). The complexity of such networks are further evidenced by the existence of multiple functionally distinct cortico-basal ganglia macro-circuits (see Fig. 2).

Magnetic resonance imaging (MRI) provides the best method for non-invasive evaluation of the structure and function of neural circuits in clinical disorders, and has enabled great progress in many areas of clinical research. Moreover, neuroimaging is being increasingly applied to the study of animal models of psychiatric conditions and neurodevelopmental disorders (Lythgoe et al., 2003; Oguz et al., 2012). Prior neuroimaging reviews have described brain alterations in ASD, but did not focus on how these alterations map onto specific behavioral domains such as RRB (e.g., Dichter, 2012; Ecker et al., 2015; Mahajan and Mostofsky, 2015; Müller et al., 2011; Rane et al., 2015). Similarly, although neuroimaging findings from animal models relevant to ASD and IDD have been described (Ellegood et al., 2015; Ellegood and Crawley, 2015), there has been almost no exploration of how these findings pertain to RRB, or other abnormal behaviors, in such models.

Although a small body of neuroimaging findings related to RRB in ASD has been previously reviewed (Traynor and Hall, 2015), there has been no attempt to synthesize these findings with what is presently known in the literature about the neural circuitry of RRB from other clinical disorders and from relevant animal models. Thus, there is a pressing need for synthesis of findings from multiple neurodevelopmental disorders and corresponding animal models in order to move the field forward. In this review we aim to (1) critically review and synthesize neuroimaging findings from RRB in ASD and IDD and corresponding relevant animal models, (2) determine what these findings, taken together, inform us about the specific neural circuitry of RRB, and (3) suggest future directions for neuroimaging investigations of RRB that have been effectively employed in other areas within neuroscience. Although RRBs are observed in clinical populations other than ASD and IDD (e.g., Tourette syndrome [TS], obsessive compulsive disorder [OCD], drug addiction, frontotemporal dementia), it is beyond the scope of this review to evaluate neuroimaging findings pertinent to RRB in such disorders.