Neural Balance in the Brain is Connected to Brain Maturity and Cognitive Ability

Issue 52
Nov 2024

SCIENCE OF LIFE

In a world where external and internal stimuli can throw our entire body system off balance, how does our brain prevent itself from becoming overly stimulated?

The answer lies in our brain’s ability to maintain the balance of neural excitation (E) and inhibition (I), known as the E/I ratio. By regulating the E/I ratio, the brain prevents over- and under-stimulation.

The E/I ratio of children decreases with healthy development. Children with a lower E/I ratio were observed to have better performance than their peers in cognitive tests such as memory and intelligence, according to studies by researchers from the Centre for Sleep and Cognition at the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine).

The study analysed MRI scans of
885
youths from the US and
154
children from Singapore

With the aim of drawing meaningful connections between E/I ratio and brain maturation, the study team, led by fourth-year PhD student Zhang Shaoshi, Associate Professor Thomas Yeo from the Centre for Sleep and Cognition at NUS Medicine, Assistant Professor Bart Larsen from the University of Minnesota and Associate Professor Theodore Satterthwaite from the University of Pennsylvania, looked at how E/I ratio changes in youths, by studying the Magnetic Resonance Imaging (MRI) brain scans of 885 children, adolescents and young adults from the US and 154 children from Singapore. The E/I ratio is an aspect that is continually changing and developing throughout childhood and adolescence. The Singaporean data cohort was obtained from GUSTO, Singapore’s largest and most comprehensive birth cohort study that seeks to help the next generation become healthier.

Importance of the right balance

Described as the Yin and Yang of the brain, researchers have found that too much excitation or excessive inhibition can be harmful, leading to a higher risk of developing brain disorders, such as autism, Alzheimer’s disease and schizophrenia.

In less severe situations, someone with too much excitation might overthink in social situations, resulting in anxiety. In more severe scenarios, over-excitation can cause an epileptic seizure. On the opposite end of the spectrum, too much inhibition indicates an absence of brain activity, effectively putting the person in a vegetative state. Therefore, inhibition is needed to balance excitation. Overall, a balanced E/I ratio is important for a well-functioning brain.

Measuring the E/I ratio markers

Despite E/I’s importance for brain health, it is hard to measure its ratio in the human brain without using invasive techniques. Therefore, the team developed a technique, combining artificial intelligence and biophysical modeling to infer E/I ratios from non-invasive, non-radioactive MRI scans. The team demonstrated the validity of their estimated E/I ratios through an experiment. During which, participants ingested Xanax—a common drug for reducing anxiety symptoms which increases neural inhibition and reduces neural excitation—or a placebo.

The team’s hypothesis is that once Xanax was ingested, inhibition will increase, so the overall E/I ratio decreases. To test this hypothesis, the research team scanned healthy individuals on 2 separate occasions. A participant is given Xanax before 1 MRI session and placebo in another MRI session. For some participants, Xanax might be administered in the first session, while for others Xanax might be administered in the second session. All parties involved in this experiment were not privy to whether an MRI session involved the placebo or the anti-anxiety drug. The team found that the estimated E/I ratio markers were indeed lower after participants had ingested Xanax compared to the placebo, thus validating their technique.

Computer images of MRI brain scans. Left: North American Youth brain. Right: Singapore Children.

The study team discovered that E/I ratios decrease with healthy development. The team also found that high performing groups have lower E/I ratios than their peers of the same age, suggesting that cognitive abilities improve as the E/I ratio matures during development.

Correlation between E/I ratio and brain development

The study team then proceeded to use MRI brain scans to study brain development in a sample of more than 1,000 children, adolescents and young adults from Singapore and the US. They discover that E/I ratios decrease with healthy development. Next, to establish the link between E/I ratios and cognitive function, the team divided participants, ranging aged 7 to 23, into high- and low-performance groups based on their scores on certain cognitive tests. They found that the high performing groups had lower E/I ratios than their peers of the same age, suggesting that cognitive abilities improve as the E/I ratio matures during development.

Beyond their study on neurodevelopment, the team is keen on applying their approach to gain mechanistic insights into various brain disorders, by studying how the E/I ratio differs between healthy participants and patients battling mental disorders. The team also aims to study how the E/I ratio changes as people age, to gain insights into neurodegenerative disorders, such as Alzheimer’s Disease.

A/Prof Thomas Yeo, who is also from the NUS College of Design and Engineering and Principal Investigator of this study, added, “Our findings enhance our understanding of brain development and highlight potential avenues for understanding the emergence of psychopathology in youth. Hopefully, these findings will lead us to figure out which brain circuits get over-excited or over-inhibited easily, or pinpoint certain abnormal brain regions specific to an individual patient. This could shed more light on how medication or brain stimulation can be customised according to individuals, that would shape the course of treatment of brain disorders in the long run.”

This study is published in Proceedings of the National Academy of Sciences of the United States of America, titled “In vivo whole-cortex marker of excitation-inhibition ratio indexes cortical maturation and cognitive ability in youth”.

Click here to read the full paper.