Two Cerebellum-Related Tests Could Improve Autism Treatments

Two tests may help to advance the precision of individualized autism treatments.

Posted Jun 08, 2018

Wikipedia/Public Domain
Anonymous researcher checking fMRI images provided by NIMH - US Department of Health and Human Services: National Institute of Mental Health. (Public Domain)
Source: Wikipedia/Public Domain

For the first time, new research from the University of Missouri provides evidence that there may be a correlation between cerebro-cerebellar functional connectivity and the balance of excitation-to-inhibition neurotransmitters in the cerebellum of individuals with autism spectrum disorder (ASD). The MU researchers speculate that clinical implementation of two tests used for this study — resting state functional magnetic resonance imaging (fMRI) and proton magnetic resonance spectroscopy (1 H-MRS) — could eventually lead to more precise and individualized medical treatments for patients with ASD.

This study, "Cerebro-Cerebellar Functional Connectivity is Associated with Cerebellar Excitation-Inhibition Balance in Autism Spectrum Disorder," was conducted by researchers from the University of Missouri School of Medicine and MU Thompson Center for Autism & Neurodevelopmental Disorders and published online May 23 in the Journal of Autism and Developmental Disorders.

Yesterday, I spoke with David Beversdorf, who was the senior author of this paper and is a professor of psychological sciences, neurology, and the William and Nancy Thompson Endowed Chair in Radiology at the MU School of Medicine. Beversdorf directs the Cognitive Neuroscience Laboratory and is also the President and Chair of the Executive Committee at The Society for the Neuroscience of Creativity (SFNC).

During our conversation, Beversdorf emphasized that this potentially groundbreaking research on ASD was the brainchild of first author John Hegarty, who conceived of the study, participated in its design, coordinated the investigation, and drafted the manuscript as a graduate student in the interdisciplinary neuroscience program at MU. Hegarty is currently a postdoctoral research fellow in child psychiatry at the Stanford Autism Center at Packard Children’s Hospital in the School of Medicine at Stanford University

Hegarty et al. describe the premise and design of this study: “Atypical functional connectivity (FC) and an imbalance of excitation-to-inhibition (E/I) have been previously reported in cerebro-cerebellar circuits in autism spectrum disorder. The current investigation used resting state fMRI and proton magnetic resonance spectroscopy (1 H-MRS) to examine the relationships between E/I (glutamate+glutamine/GABA) and FC of the dorsolateral prefrontal cortex and posterolateral cerebellar hemisphere from 14 adolescents/adults with ASD and 12 age/sex/IQ-matched controls.”

More specifically, the primary regions of interest for the researchers were the right posterolateral cerebellar hemisphere (R Cereb Hemi) and the left dorsolateral prefrontal cortex (L DLPFC). The interplay between these contralateral brain regions is believed to play a central role in social communication and language processing. Notably, study participants with low functional connectivity between these brain regions also displayed a lower ability to infer meaning from verbal information.

Wikipedia/Public Domain
Early 20th-century anatomical illustration of the human brain (from below) showing the left and right hemispheres of both the cerebellum and cerebrum. "Cerebro-Cerebellar" generally refers to the functional connectivity and interplay between regions of the cerebrum and regions of the cerebellum. 
Source: Wikipedia/Public Domain

In this small sample of study participants, cerebro-cerebellar FC was positively associated with cerebellar E/I and listening comprehension abilities in individuals with ASD but not controls. Additionally, Hegarty and colleagues found that a subgroup of individuals with ASD and low functional connectivity exhibited reduced E/I and impaired listening comprehension. Based on these preliminary findings, the researchers speculate that altered functional coherence of cerebro-cerebellar circuits in ASD may be related to cerebellar excitation-to-inhibition imbalance.

Before diving into more specifics about the findings of this study, it's important to note that during our phone conversation, Beversdorf reiterated that one limitation of this research is the small sample size. Therefore, he advises that any findings should be interpreted with caution until they can be demonstrated in larger samples. As the authors write, "Future studies with larger more representative samples, including younger individuals with higher variability of disorder severity, will need to be conducted to determine the prevalence of functional abnormalities in cerebro-cerebellar circuits in ASD.”

That being said, this research is significant because it is the first time neuroscientists have identified a possible link between cerebro-cerebellar functional connectivity, neurotransmitter imbalance in the cerebellum, and the potential use of fMRI and 1 H-MRS tests to identify specific biomarkers for ASD.

As the authors explain, "Our findings indicate that excitatory and inhibitory signaling within the cerebellum and dorsolateral prefrontal cortex, as well as functional coordination between these regions, may be interrelated with some aspects of the autism phenotype. Thus, we advocate that fMRI and 1 H-MRS can provide complementary probes of brain tissue that, when used together, improve our understanding of the neural substrates associated with ASD. The application of such complementary multi-modal approaches could assist in subgrouping individuals with ASD based on specific neurobiological abnormalities, which may be of particular importance for addressing the neurobiological heterogeneity of ASD and advancing the development of precision medicine.”   

In a statement, Beversdorf expanded on this part of the discussion. He said, "One of the issues with approaching treatment of autism is there are many subtypes and many different genes and potentially other factors that contribute to the disorder. If you have a treatment that works in one subpopulation, it might not work in another. However, if we can determine why that is, we can pursue individualized approaches and make a lot more progress in developing new treatments." Beversdorf added, "This finding begins to suggest how biomarkers relate with each other in autism. There may be whole other sets of biomarkers that may be inter-related and may be telling us something. It may serve as a biomarker to predict who will respond to what drug."

Lastly, the researchers hypothesize that “Although speculative, excitation/inhibition in the cerebellar hemispheres may reflect the ability of glutamatergic interneurons to provide excitatory input to cerebellar Purkinje cells, which could alter modulatory signals from the deep cerebellar nuclei to the contralateral cerebral hemispheres.” Hegarty et al. also conclude, "Thus, it appears that reduced E/I in the cerebellum, potentially increased E/I in the prefrontal cortex, and altered coordinated activation between these regions and may be associated with some aspects of the clinical presentation of ASD, which warrants further investigation.”

In addition to David Beversdorf and John Hegarty, the co-authors of this study included Dylan Weber of the University of Missouri-Kansas City School of Dentistry and Carmen Cirstea, Assistant Research Professor of Physical Medicine and Rehabilitation at the MU School of Medicine.

References

John P. Hegarty II, Dylan J. Weber, Carmen M. Cirstea, David Q. Beversdorf. "Cerebro-Cerebellar Functional Connectivity is Associated with Cerebellar Excitation–Inhibition Balance in Autism Spectrum Disorder." Journal of Autism and Developmental Disorders (First Online: May 23, 2018) DOI: 10.1007/s10803-018-3613-y

Anila D’Mello and Catherine J. Stoodley. "Cerebro-Cerebellar Circuits in Autism Spectrum Disorder." Frontiers in Neuroscience (2015) DOI: 10.3389/fnins.2015.00408

Catherine J. Stoodley and Jeremy D. Schmahmann. "Evidence for Topographic Organization in the Cerebellum of Motor Control Versus Cognitive and Affective Processing." Cortex (2010) DOI: 10.1016/j.cortex.2009.11.008

Jeremy D. Schmahmann and Deepak N. Pandya. "The Cerebrocerebellar System" International Review of Neurobiology (1997) DOI: 10.1016/S0074-7742(08)60346-3