November 13, 2018
Written by: Barbara Terzic
Autism spectrum disorder (ASD) is a developmental disease that affects normal communication and behavior, which you’re probably familiar with as an estimated 1 in 100 people are currently diagnosed with some form. It is known as a ‘spectrum’ disorder because there is a wide variation in the type and severity in symptoms people can experience – however, impaired social interactions and repetitive behaviors are two hallmarks. ASD is often diagnosed in early childhood, and many children with ASDs also exhibit unusual sensitivity to sensations such as light, temperature, and touch. These signs of autism typically arise during the first two years of childhood and can negatively impact a person’s ability to function properly in school, work, and other areas of life1; in fact 35% of autistic adults have had no job or received postgraduate education after high-school. However, there are no cures available to treat ASDs, and the range of issues patients face makes it difficult to design one single, effective treatment. Some children take a variety of medications to treat symptoms ranging from irritability, hyperactivity, and attention problems. Clearly there is a pressing need to better understand some of the underlying neurological mechanisms of autism, in order to provide better therapeutics for patients. And surprisingly, it turns out that neuroscientists may find the answer outside of the brain.
Brain and Behavior?
Given its myriad of behavioral issues, ASD is generally thought to be caused by deficits in the brain (particularly during brain development, given the timing of onset). A growing body of scientific evidence, however, suggests that altered sensory processing can also severely impact the behavior and quality of life in patients with autism3. The central nervous system, comprised of the brain and the spinal cord, is predominately implicated in initiating and processing all behaviors (the master regulator, if you will). The peripheral nervous system, on the other-hand, is comprised of the peripheral nerves found throughout the body (including your hands and toes), and its primary role is to communicate sensory information detected from the outside world back to the brain. Could faulty wiring/development of the peripheral nervous system also be contributing to ASD-related deficits? Is there a common insult underlying the touch sensitivity and sociability issues in these patients? Or are these two seemingly unrelated consequences caused by different problems?
The Social Brain
Our sense of touch allows us to navigate not only our physical world, but our social world as well, with specific regions and circuits in the brain dedicated to processing different types of touch. In humans, circuits known to play a role in personality and emotional possessing such as the superior temporal sulcus, medial prefrontal cortex, orbitofrontal cortex, and amygdala have also been shown to activate in response to “social touches” characterized by slow, gentle strokes. These gentle touches consist of stroking speeds that range from 1-10cm/s, and have been reported to evoke “pleasant” feelings in human participants. Although we may still be limited in our understanding of the variety of complex touch humans are capable of processing, these slow gentle touches have been classified as cardinal to social interactions such as those between parent and child or intimate partners4.
Intriguingly, functional imaging studies in ASD patients have reported blunted activation of these brain regions in response to social touch (see here for technical details on functional imaging). These studies also reported a negative correlation between the severity of patients’ autistic symptoms and their response to social touch. In other words, the more severe a patient was on the spectrum, the lower the activation of their “social” circuits in response to normal, social touch. These studies in humans illustrate the important connection between social behavior/touch and social brain function; social interactions are not always distinct from physical interactions.
Troubled Touch
Although the cause of ASD remains uncertain, there have been several gene mutations associated with ASD in humans. Advances in genetic engineering and animal modeling of ASD have made it possible for scientists to directly study how some of these genes are related to ASD. Researchers have been able to artificially generate mutations in genes linked to autism to generate “mouse models” of the disorder, and, interestingly, these animals exhibit similar behavioral deficits as seen in human patients. In addition to impaired sociability and repetitive behaviors, many mouse models of ASD also display tactile deficits and hypersensitivity to touch. Does impaired brain development solely underlie these parallel deficits in mice? Or can dysfunction of other nerves also contribute to these features? With advancing technology, researchers are able to study the role of these genes in ASD by altering them only in certain cell types of nerve cells and studying the effects.
A recent study by neuroscientists at Harvard did just this with a few genes known to be most commonly associated with ASDs – MECP2, GABRB3, FMR1, SHANK3 – and focused on disrupting their function solely in peripheral nerves of the peripheral nervous system. The results showed that mice with mutations in their peripheral nerves were not able to discriminate between different textures when presented with a variety of textured “cubes” or toys in their homes; their tactile perception was impaired. More intriguingly, however, these same mice also exhibited increased anxiety-like behaviors (by avoiding brightly-light areas more often than normal mice) and decreased sociability towards other mice5. This seminal work suggests that developmental dysfunction in peripheral nerves can not only disrupt touch perception, but anxiety-like and social behaviors as well.
The same study also found that mutating a particular ASD-associated gene, MECP2, exclusively in brain cells (while sparing the peripheral nerves) did not result in any autism-related phenotypes such as anxiety, abnormal touch, or social deficits. This striking finding suggests that not only is disruption of this ASD-associated gene in the peripheral nerves sufficient to produce autism-related phenotypes in mice, but that dysfunction of the brain does not underlie the symptoms associated with this specific genetic cause of ASD6.
CNS Calumny
While many individuals with ASD exhibit improper sensitivity to tactile and other sensory stimuli, it is unclear if these responses are reflective of problems with the central nervous system or with the peripheral nervous system. Seminal studies such as the one described above have improved our knowledge of how some of these ASD-associated genes function within different nerve cells of the body and brain. More importantly, however, this work has also altered our understanding of the importance of the peripheral nervous system in affecting complex behaviors such as sociability and anxiety. It is important to note that even if peripheral nerve mis-wiring may underlie many of the behaviors linked to ASD, abnormal feedback to the central nervous system may ultimately lead to secondary issues within the circuits of the brain as well.
Whether the same results as reported for MECP2 will hold for other genes implicated in ASDs remains unknown, but these early findings suggest we may have been focused on a singular culprit, such as the brain, for too long. In general, targeting the peripheral nerves of the body for treatment is more feasible and far-less invasive than manipulations to the brain. If reversing some of the peripheral deficits associated with ASD can improve behaviors such as anxiety and sociability, then scientists may have just unraveled an entirely new avenue of therapeutics for the millions of individuals and families struggling with the burdens of autism.
References
1National Institue of Mental Health (2018). Autism Spectrum Disorder. Retrieved November 11, 2018, from https://www.nimh.nih.gov/health/topics/autism-spectrum-disorders-asd/index.shtml
2Bourgeron T. From the genetic architecture to synaptic plasticity in autism spectrum disorder. Nature Reviews Neuroscience. 2015; 16, 551-563.
3Tuttle AH, Bartsch VB, Zylka MJ. The troubled touch of autism. Cell. 2016; 166(2), 273-274.
4Voos AC, Pelphrey KA, Kaiser MD. Autistic traits are associated with diminished neural response to affective touch. Social Cognitive and Affective Neuroscience. 2012; 8(4), 378-386.
5Orefice LL, Zimmerman AL, Chirila AM, Sleboda SJ, Head JP, Ginty DD. Peripheral mechanosensory neuron dysfunction underlies tactile and behavioral deficits in mouse models of ASDs. Cell. 2016; 166, 299-313
6Yates D. Touching on the issue. Nature Reviews Neuroscience. 2016; 17, 464-465.
Images
Cover Image by Cheryl via Flickr; CC BY-NC-ND 2.0; https://www.flickr.com/photos/93455043@N00/11762339656/in/photolist-iVp4MA-7w2Era-69x7fj-9voe1j-7d4s3t-4WWWNe-c6G18S-F3PV1-H3DLW-512oHE-djxRGA-hgzVUJ-9NV7hp-iUGqmG-6Hadm6-9UKkCV-6GnDNg-a716j3-8ei4b6-w89F2K-bnbZFH-4rqYJN-4HwrJS-JnAKpq-snD14R-fuVWHY-imxgqh-2EzkgN-54uwRi-dZRVQg-dcRj8N-q7VuWQ-6YLWkV-4nSvM5-7sm32s-fgsz3C-6jTQQi-AzvCd-qu8zdB-5TpECo-6qqgAk-aexcwh-mxJK9j-ayKfqM-qwWBU-4tuucv-8UDrph-6HiMCY-5BJEKE-7eorLq
PennNeuroKnow 
Leave a Reply