The pathophysiology of restricted repetitive behavior

Abstract

Restricted, repetitive behaviors (RRBs) are heterogeneous ranging from stereotypic body movements to rituals to restricted interests. RRBs are most strongly associated with autism but occur in a number of other clinical disorders as well as in typical development. There does not seem to be a category of RRB that is unique or specific to autism and RRB does not seem to be robustly correlated with specific cognitive, sensory or motor abnormalities in autism. Despite its clinical significance, little is known about the pathophysiology of RRB. Both clinical and animal models studies link repetitive behaviors to genetic mutations and a number of specific genetic syndromes have RRBs as part of the clinical phenotype. Genetic risk factors may interact with experiential factors resulting in the extremes in repetitive behavior phenotypic expression that characterize autism. Few studies of individuals with autism have correlated MRI findings and RRBs and no attempt has been made to associate RRB and post-mortem tissue findings. Available clinical and animal models data indicate functional and structural alterations in cortical-basal ganglia circuitry in the expression of RRB, however. Our own studies point to reduced activity of the indirect basal ganglia pathway being associated with high levels of repetitive behavior in an animal model. These findings, if generalizable, suggest specific therapeutic targets. These, and perhaps other, perturbations to cortical basal ganglia circuitry are mediated by specific molecular mechanisms (e.g., altered gene expression) that result in long-term, experience-dependent neuroadaptations that initiate and maintain repetitive behavior. A great deal more research is needed to uncover such mechanisms. Work in areas such as substance abuse, OCD, Tourette syndrome, Parkinson’s disease, and dementias promise to provide findings critical for identifying neurobiological mechanisms relevant to RRB in autism. Moreover, basic research in areas such as birdsong, habit formation, and procedural learning may provide additional, much needed clues. Understanding the pathophysioloy of repetitive behavior will be critical to identifying novel therapeutic targets and strategies for individuals with autism.

Striatopallidal dysfunction underlies repetitive behavior in Shank3-deficient model of autism

“…To the best of our knowledge, this is the first study to provide direct evidence that a primary dysfunction in the striatal indirect pathway could give rise to repetitive behavior in a mouse model of autism. Previous studies have suggested that an imbalance of the direct and indirect pathways of the basal ganglia may underlie repetitive behavior (78,79,84). Recently, it was shown in neuroligin-1 and neuroligin-3 mutant mice that abnormality of D1 MSNs can lead to autistic-like behaviors, including repetitive behavior (85,86).…”

“…One prominent hypothesis posits that repetitive behavior is a consequence of relative hyperactivity along cortico-basal ganglia-cortical feedback circuits, implicating an imbalanced activity between the 2 striatal pathways in the basal ganglia, which eventually facilitate the release of compulsive motor programs (84,95,96). Our findings, in particular the correction of repetitive grooming by enhancing D2 MSN activity with the DREADD system in an attempt to regain balanced activity between the 2 striatal pathways in Shank3B-KO mice, largely support such an activity-imbalance theory.…”

High-Frequency Stimulation at the Subthalamic Nucleus Suppresses Excessive Self-Grooming in Autism-Like Mouse Models

“…For example, injections into SNr of muscimol, a GABA receptor agonist, trigger dose-dependent increases in selfbiting behavior (Baumeister and Frye, 1984), and diminished GPi volume has been shown to correlate with the frequency of RRSBs in ASD (Estes et al, 2011). Therefore, one possibility based on expression studies of GABA in rodents after ECS (Ferraro et al, 1990) is that ECT enhances the inhibitory tone of the SNr and GPi, which may mute abnormal motor thalamic spike patterns associated with stereotypy (Lewis and Kim, 2009). Consistent with this hypothesis, Viaat-Mecp2 À /y mice have reduced GABA in the striatum (Chao et al, 2010) which could contribute to their stereotypies and which might be restored by ECS.…”

A Dopamine Hypothesis of Autism Spectrum Disorder

“…Next, the stereotyped behaviors observed in autistic patients could arise from a dysfunction of the NS pathway, which has been shown to be involved in mediating stereotypies [16] . Considering its central role in controlling goal-directed motor behavior [9] , an NS pathway dysfunction could lead to autistic-like behavior by entrapment into loops of purposeless, stereotyped patterns of behavior.…”