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

Abstract

Approximately one quarter of individuals with an autism spectrum disorder (ASD) display self-injurious behavior (SIB) ranging from head banging to self-directed biting and punching. Sometimes, these behaviors are extreme and unresponsive to pharmacological and behavioral therapies. We have found electroconvulsive therapy (ECT) can produce life-changing results, with more than 90% suppression of SIB frequency. However, these patients typically require frequent maintenance ECT (mECT), as often as every 5 days, to sustain the improvement gained during the acute course. Long-term consequences of such frequent mECT started as early as childhood in some cases are unknown. Accordingly, there is a need for alternative forms of chronic stimulation for these patients. To explore the feasibility of deep brain stimulation (DBS) for intractable SIB seen in some patients with an ASD, we utilized two genetically distinct mouse models demonstrating excessive self-grooming, namely the Viaat-Mecp2 − /y and Shank3B −/− lines, and administered high-frequency stimulation (HFS) via implanted electrodes at the subthalamic nucleus (STN-HFS). We found that STN-HFS significantly suppressed excessive selfgrooming in both genetic lines. Suppression occurs both acutely when stimulation is switched on, and persists for several days after HFS is stopped. This effect was not explained by a change in locomotor activity, which was unaffected by STN-HFS. Likewise, social interaction deficits were not corrected by STN-HFS. Our data show STN-HFS suppresses excessive self-grooming in two autism-like mouse models, raising the possibility DBS might be used to treat intractable SIB associated with ASDs. Further studies are required to explore the circuitry engaged by STN-HFS, as well as other potential stimulation sites. Such studies might also yield clues about pathways, which could be modulated by non-invasive stimulatory techniques.

Subthalamic nucleus pathology contributes to repetitive behavior expression and is reversed by environmental enrichment

“…In rats, bilateral high frequency stimulation of STN as well as pharmacological inactivation of STN reduced quinpirole‐induced compulsive checking . High frequency stimulation of STN also reduced excessive self‐grooming in 2 mouse models relevant to ASD . This works also follows from the rich literature on the role of the STN in behavioral inhibition.…”

“…[65][66][67] High frequency stimulation of STN also reduced excessive self-grooming in 2 mouse models relevant to ASD. 68 This works also follows from the rich literature on the role of the STN in behavioral inhibition. Normal function of the STN is thought to be important for inhibiting behaviors that are inconsistent with goal-directed behavior 69,70 and increasing STN firing rate with optogenetic stimulation can inhibit even goal-directed behaviors.…”

Tourette syndrome research highlights from 2016

“…DBS in a mouse model suggests that self-injurious behaviors, probably over-represented in TS patients referred for surgery, may be amenable to DBS of the subthalamic nucleus 82 .…”

Functional Analysis of Distinct Populations of Subthalamic Nucleus Neurons on Parkinson’s Disease and OCD-like Behaviors in Mice

“…Similarly, pharmacologic hyperactivation of the STN in monkeys can induce an array of behaviors, including compulsive, stereotyped behaviors characteristic of OCD such as repetitive grooming, smacking, and licking (20). In rodents, high-frequency stimulation of the STN can suppress excessive self-grooming in autism-like mouse models (21) and reduce compulsive lever pressing in rats (22), while STN lesions impair impulse control (23,24). The STN has also been involved in the reward circuit, both in evaluating the valence of stimuli (reward/aversion) (25,26) and of action outcome (27).…”