Autism Therapy: Social Behavior Restored via Brain Stimulation
It may be feasible to effectively treat behavioral symptoms associated with autism spectrum disorder (ASD) using neuromodulation, new research suggests.
Researchers believe the new findings are the first evidence that the right crus I (RCrusI) plays a strong role in ASD behaviors. The RCrusl is an area of the cerebellum that has long been thought to have a role only in coordinating movement.
Using neuroimaging and neuromodulation in humans and animal models, the investigators found that RCrusl dysfunction plays a pivotal role and that stimulation of this area may alleviate social impairments, a hallmark symptom of the disorder.
Dr Peter Tsai
"This is potentially quite a powerful finding," principal investigator Peter T. Tsai, MD, PhD, a child neurologist and assistant professor of neurology and neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, said in a statement.
"From a therapeutic standpoint, this part of the cerebellum is an enticing target. And although neuromodulation would not cure the underlying genetic cause of a person's autism, improving social deficits in children with autism could make a huge impact on their quality of life," Dr Tsai added.
The study was published in Nature Neuroscience.
Great Support
ASD affects about 1 in 68 children in the United States. The condition is characterized by challenges in social interaction and communication and by repetitive patterns of behavior, sometimes referred to as perseveration.
Previous studies, including some by Dr Tsai's team in mice, suggest that cerebellar dysfunction contributes to autism.
"We showed that cerebellar dysfunction was sufficient, just by itself, to generate these abnormal autistic behaviors," he said.
The RCrusI, located near the brain stem, has long been thought to only play a role in coordinating movement. But previous work in patients with ASD found that gray matter volume in the RCrusI correlates with some core ASD symptoms.
Here, the researchers carried out a number of experiments and tests on humans and mice.
The study involved 35 healthy, neurotypical adult volunteers (mean age, 24 years) who had no history of neurologic conditions, head trauma, or psychiatric or developmental disorders. The researchers showed that RCrusI is functionally connected to multiple whole-brain networks.
They randomly assigned the participants to receive transcranial direct current stimulation (tDCS) or sham stimulation. The stimulation decreased the connectivity between the RCrusI and the left inferior parietal lobe (IPL).
The researchers also carried out imaging studies on 81 children aged 8 to 13 years (mean age, about 10 years) who had ASD and 81 typically developing children of about the same age. They showed that functional connectivity in these circuits is atypical in the children with ASD.
"There is a parallel disruption in the connectivity in kids with autism compared to typically developing children," said Dr Tsai. This provides "great support" for the idea that this area is an important target, he added.
Most Implicated Region
The researchers also conducted experiments on mice bred to develop ASD behaviors.
In this model, the investigators demonstrated RCrusI-cerebral functional connectivity that mirrored the RCrusI-IPL circuit identified in the human cohort.
Again, there was a parallel between the processes in humans and in the mouse model, said Dr Tsai.
"We already knew from a number of autism studies that this area was implicated, but this had never been demonstrated before. What made this so appealing was that this was probably the most implicated region in the cerebellum in terms of autism studies," he said.
In humans, modulation of the RCrusI altered functional connectivity with the IPL, and in mice, the modulation altered functional connectivity with a corresponding region.
The IPL is another region that has been implicated in autism. The left IPL is believed to integrate visuospatial, motor, and cognitive information and to be critical for imitating and interpreting the gestures of others.
"These functions are consistent with evidence that children with ASD struggle to efficiently integrate visual information to guide skilled behaviors, which is necessary for both imitation and normal social interaction and may be critical to the development of core ASD symptoms," the authors write.
The researchers then studied control mice, which acted normally. In these mice, they inhibited the RCrusI, which led to social impairments and repetitive and inflexible behaviors.
"That says that just inhibiting this area in and of itself is sufficient to generate these abnormal behaviors," said Dr Tsai.
The researchers carried out "all manner of tests looking at behavior in multiple paradigms" in the mice to confirm that the social impairments and increased repetitive behaviors produced by RCrusI inhibition were not due to motor coordination deficits. This was important, inasmuch as the cerebellum plays a role in motor control.
Stimulation of this same region restored normal social behaviors in the animals.
"These findings point to a role for cerebellar RCrusI in the regulation of these behaviors in mice," the authors note.
No Impact on Repetitive, Inflexible Behaviors
Dr Tsai noted that stimulating the RCrusI improved only social impairments and did not affect the repetitive or inflexible behaviors.
There could be a number of explanations for this, he said. First, it could have something to do with timing. All the animal experiments were conducted in adults, and there could be a "critical period" past which the stimulation only improves social impairment.
Another possibility is that the RCrusI is more important for social behaviors and that another region of the cerebellum is more crucial for repetitive behaviors, said Dr Tsai.
In the mice, there were no detrimental effects in terms of anxiety or locomotor function following the stimulation. The effects lasted for the few hours that the mice were observed.
The investigators did not assess whether cerebellar neuromodulation would improve ASD behaviors in patients with ASD, but the results suggest that this strategy might be worth pursuing.
"If modulation can rescue a mouse, and you have all these parallels between the mouse model and humans, it kind of begs the question, Would modulation in kids with autism actually provide therapeutic benefit?" said Dr Tsai.
He is cautiously optimistic that this approach would be successful in such children.
"One is always guarded ― a mouse is a mouse and a human is a human. But I think the fact that we see these parallels between the mouse and the human lends a little bit more optimism that this potentially might provide a benefit," he said.
The authors note that cerebellar neuromodulation has shown promise in the treatment of other neuropsychiatric disorders, including epilepsy and schizophrenia.
"Striking, Convincing" Parallels
Commenting on the findings for Medscape Medical News, Alik Widge, MD, PhD, director, Translational NeuroEngineering Laboratory, Division of Neurotherapeutics, Massachusetts General Hospital, assistant professor of psychiatry, Harvard Medical School, and clinical fellow, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Boston, said the research was "very technically impressive."
"It connects animal to human research in a way that one rarely sees. The parallels are striking and convincing, with good controls," he said.
Dr Widge added that the new research "definitely makes me interested in seeing what happens if their cerebellar tDCS approach was applied in humans with ASDs."
He said that although the researchers "clearly showed" that increasing right-crus activity improved social function, increasing this activity did not affect repetitive behaviors or perseveration.
"So this may have value as an autism therapy, but likely would affect only some of the symptoms," said Dr Widge.
Dr Tsai and Dr Widge have disclosed no relevant financial relationships.
Nat Neurosci. 2017;20:1744-1751. Abstract
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This article written by Pauline Anderson
December 18, 2017