Autism: Balancing excitation and inhibition in the autistic brain
A metric called the Hurst exponent could be a useful biomarker for studies exploring brain differences between men and women with autism spectrum disorder.
- Department of Forensic and Neurodevelopmental Sciences, Kings' College London, United Kingdom
- Donders Centre for Cognitive Neuroimaging, Netherlands
Balance and stability are important for the human body. This is clearly true for some physical tasks, such as walking or running without falling over, but it is also true inside the brain. Neurons receive both excitatory and inhibitory inputs, and maintaining a balance between the two – that is, maintaining what is known as the excitation-inhibition or E:I balance – is crucial for the brain to work properly (Yizhar et al., 2011).
Disruptions to the E:I balance, such as increased levels of excitatory inputs, have been linked to autism and a number of other neurological conditions, and can affect brain function and social behavior (Rubenstein and Merzenich, 2003). It has also been shown that the E:I balance can depend on sex, especially in regions of the brain that support social behavior, such as the ventromedial prefrontal cortex (Lai et al., 2019). However, research into the relationships between autism, sex and social behavior have been hampered by a lack of non-invasive tools. Now, in eLife, Michael Lombardo (Istituto Italiano di Tecnologia and University of Cambridge) and colleagues – including Stavros Trakoshis and Pablo Martínez-Cañada as joint first authors – report how it may be possible to measure the E:I balance without causing damage to the brain (Trakoshis et al., 2020).
The researchers – who are based in Italy, Cyprus, South Korea, the United Kingdom, Switzerland, and Canada – first created a computational model of the brain and used data from this model to calculate a metric called the Hurst exponent. This metric is a measure of the long-term memory of a time series of data. The model was then tweaked to simulate the effect of a ligand called CNO (which is short for clozapine-N-oxide) on two receptors hM3Dq and hM4Di, which are synthetic proteins designed to bind synthetic drugs. When CNO binds to hM3Dq it increases excitation, and when it binds to hM4Di it reduces both excitation and inhibition. Trakoshis et al. found that the change in the E:I balance caused by CNO also changed the Hurst exponent: specifically, an increase in excitation decreased the Hurst exponent (Figure 1).
Figure 1
Maintaining a balance of excitatory and inhibitory input in neurons.
An imbalance between excitatory and inhibitory inputs to neurons in certain regions of the brain has been linked to neuropsychiatric conditions such as autism spectrum disorder (ASD). However, it is not possible to measure such imbalances directly, so it would be useful to have a proxy marker. Based on computer simulations and experiments on genetically manipulated mice (top), Trakoshis et al. found that a metric called the Hurst exponent, which can be determined using non-invasive electrical and magnetic measurements, can provide information on imbalances between excitatory and inhibitory input. In particular, an increase in excitation (E) led to a decrease in the Hurst exponent (H). Experiments on autistic and typically developing (TD) men and women show that: i) the value of H for men with autism is much lower than the value for TD men; ii) the value of H for women with autism is higher than the value for TD women; iii) in women with autism, the value of H further correlated with social behavior.
Second, the researchers tested if they could replicate these computational results in mice that had undergone chemogenetic manipulation to express hM3Dq and hM4Di. This involved measuring electrical activity in the prefrontal cortex of the mice before, during and after the administration of CNO, and then computing the Hurst exponent. They found that the in vivo results in mice confirmed the predictions of their computational model. Specifically, a drug-induced increase in excitation led to a decrease in the Hurst exponent.
Third, Trakoshis et al. wanted to find out why E:I processes may differ between males and females. They found that genes associated with autism that also affect the E:I balance (especially excitation) overlapped with genes that are sensitive to male-specific hormones. A comparison of these results with a gene expression map called the Allan Human Brain Atlas (Hawrylycz et al., 2012) further revealed that these genes are expressed in many regions of the brain, including the ventromedial prefrontal cortex.
To investigate how the E:I balance may differ between autistic men and women, and how those differences may relate to social behavior, Trakoshis et al. collected neural time series data and computed the Hurst exponent in individuals with and without autism (who were similar in age and IQ). In the ventromedial prefrontal cortex, the Hurst exponent of individuals with autism was lower than that of typically developing individuals, with the difference between the two being larger in males than in females. Moreover, in women with autism, the Hurst exponent was linked with social behavior: a higher (i.e., more typical) value was accompanied by a better ability to 'socially camouflage' – that is, the ability to compensate for social-communicative difficulties.
Taken together, these results suggest that the Hurst exponent may be a useful biomarker to examine the E:I balance and its relationship with sex and social behavior across the autism spectrum. More research is needed to investigate if shifting the E:I balance in the ventromedial prefrontal cortex could alter social behavior in people with autism. In the future, this approach could be extended into other conditions linked to E:I balance and sex-differences, such as attention deficit hyperactivity disorder.
References
-
Model of autism: increased ratio of excitation/inhibition in key neural systemsGenes, Brain and Behavior 2:255–267.https://doi.org/10.1034/j.1601-183X.2003.00037.x
Article and author information
Author details
Charlotte M Pretzsch
Publication history
Copyright
© 2020, Pretzsch and Floris
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 3,364
- views
-
- 286
- downloads
-
- 7
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Autism: Balancing excitation and inhibition in the autistic brain
eLife 9:e60584.
https://doi.org/10.7554/eLife.60584
Further reading
-
- Medicine
- Neuroscience
Background:
Subarachnoid hemorrhage (SAH) is characterized by intense central inflammation, leading to substantial post-hemorrhagic complications such as vasospasm and delayed cerebral ischemia. Given the anti-inflammatory effect of transcutaneous auricular vagus nerve stimulation (taVNS) and its ability to promote brain plasticity, taVNS has emerged as a promising therapeutic option for SAH patients. However, the effects of taVNS on cardiovascular dynamics in critically ill patients, like those with SAH, have not yet been investigated. Given the association between cardiac complications and elevated risk of poor clinical outcomes after SAH, it is essential to characterize the cardiovascular effects of taVNS to ensure this approach is safe in this fragile population. Therefore, this study assessed the impact of both acute and repetitive taVNS on cardiovascular function.
Methods:
In this randomized clinical trial, 24 SAH patients were assigned to either a taVNS treatment or a sham treatment group. During their stay in the intensive care unit, we monitored patient electrocardiogram readings and vital signs. We compared long-term changes in heart rate, heart rate variability (HRV), QT interval, and blood pressure between the two groups. Additionally, we assessed the effects of acute taVNS by comparing cardiovascular metrics before, during, and after the intervention. We also explored acute cardiovascular biomarkers in patients exhibiting clinical improvement.
Results:
We found that repetitive taVNS did not significantly alter heart rate, QT interval, blood pressure, or intracranial pressure (ICP). However, repetitive taVNS increased overall HRV and parasympathetic activity compared to the sham treatment. The increase in parasympathetic activity was most pronounced from 2 to 4 days after initial treatment (Cohen’s d = 0.50). Acutely, taVNS increased heart rate, blood pressure, and peripheral perfusion index without affecting the corrected QT interval, ICP, or HRV. The acute post-treatment elevation in heart rate was more pronounced in patients who experienced a decrease of more than one point in their modified Rankin Score at the time of discharge.
Conclusions:
Our study found that taVNS treatment did not induce adverse cardiovascular effects, such as bradycardia or QT prolongation, supporting its development as a safe immunomodulatory treatment approach for SAH patients. The observed acute increase in heart rate after taVNS treatment may serve as a biomarker for SAH patients who could derive greater benefit from this treatment.
Funding:
The American Association of Neurological Surgeons (ALH), The Aneurysm and AVM Foundation (ALH), The National Institutes of Health R01-EB026439, P41-EB018783, U24-NS109103, R21-NS128307 (ECL, PB), McDonnell Center for Systems Neuroscience (ECL, PB), and Fondazione Neurone (PB).
Clinical trial number:
-
- Immunology and Inflammation
- Medicine
Together with obesity and type 2 diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global epidemic. Activation of the complement system and infiltration of macrophages has been linked to progression of metabolic liver disease. The role of complement receptors in macrophage activation and recruitment in MASLD remains poorly understood. In human and mouse, C3AR1 in the liver is expressed primarily in Kupffer cells, but is downregulated in humans with MASLD compared to obese controls. To test the role of complement 3a receptor (C3aR1) on macrophages and liver resident macrophages in MASLD, we generated mice deficient in C3aR1 on all macrophages (C3aR1-MφKO) or specifically in liver Kupffer cells (C3aR1-KpKO) and subjected them to a model of metabolic steatotic liver disease. We show that macrophages account for the vast majority of C3ar1 expression in the liver. Overall, C3aR1-MφKO and C3aR1-KpKO mice have similar body weight gain without significant alterations in glucose homeostasis, hepatic steatosis and fibrosis, compared to controls on a MASLD-inducing diet. This study demonstrates that C3aR1 deletion in macrophages or Kupffer cells, the predominant liver cell type expressing C3ar1, has no significant effect on liver steatosis, inflammation or fibrosis in a dietary MASLD model.
