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
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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
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Charlotte M Pretzsch
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© 2020, Pretzsch and Floris
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Autism: Balancing excitation and inhibition in the autistic brain
eLife 9:e60584.
https://doi.org/10.7554/eLife.60584
Further reading
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Background:
Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is a severe and deadly adverse event following ERCP. The ideal method for predicting PEP risk before ERCP has yet to be identified. We aimed to establish a simple PEP risk score model (SuPER model: Support for PEP Reduction) that can be applied before ERCP.
Methods:
This multicenter study enrolled 2074 patients who underwent ERCP. Among them, 1037 patients each were randomly assigned to the development and validation cohorts. In the development cohort, the risk score model for predicting PEP was established via logistic regression analysis. In the validation cohort, the performance of the model was assessed.
Results:
In the development cohort, five PEP risk factors that could be identified before ERCP were extracted and assigned weights according to their respective regression coefficients: –2 points for pancreatic calcification, 1 point for female sex, and 2 points for intraductal papillary mucinous neoplasm, a native papilla of Vater, or the pancreatic duct procedures (treated as ‘planned pancreatic duct procedures’ for calculating the score before ERCP). The PEP occurrence rate was 0% among low-risk patients (≤0 points), 5.5% among moderate-risk patients (1–3 points), and 20.2% among high-risk patients (4–7 points). In the validation cohort, the C statistic of the risk score model was 0.71 (95% CI 0.64–0.78), which was considered acceptable. The PEP risk classification (low, moderate, and high) was a significant predictive factor for PEP that was independent of intraprocedural PEP risk factors (precut sphincterotomy and inadvertent pancreatic duct cannulation) (OR 4.2, 95% CI 2.8–6.3; p<0.01).
Conclusions:
The PEP risk score allows an estimation of the risk of PEP prior to ERCP, regardless of whether the patient has undergone pancreatic duct procedures. This simple risk model, consisting of only five items, may aid in predicting and explaining the risk of PEP before ERCP and in preventing PEP by allowing selection of the appropriate expert endoscopist and useful PEP prophylaxes.
Funding:
No external funding was received for this work.
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