Anesthetics given to children could potentially influence their brain development.
The Long-Term Consequences of Isoflurane on Young Brains
A recent study performed on mice provides worrying evidence. It shows that a frequent anesthetic used in countless children, isoflurane, significantly interferes with the growth of brain cells in the developing brain. These findings are backed up by numerous earlier studies.
General anesthetics are administered to hundreds of thousands of children in the United States yearly. However, concerns about their safety have been mounting, leading the U.S. Food and Drug Administration (FDA) to issue a warning in April 2017. They cautioned that extended use of general anesthesia in children under three or in pregnant women during the third trimester may impact their brain development [1]. This warning stems from studies hinting at long-lasting issues in children following exposure to anesthesia, including reduced performance in language and cognitive tests, and an increased risk of learning disorders [1].
General Anesthesia and the Young Brain
While these earlier studies don't establish a direct link, there are multiple factors to consider. A child undergoing surgery typically has an underlying medical condition, and the surgical process itself might bear responsibility. Other potential factors, like parental stress, may also play a role.
In addition to retrospective human studies, research on animals has reached similar conclusions. For instance, a study investigating repeated anesthetic exposure in infant rhesus monkeys found an increased frequency of anxiety-related behaviors at six months [3].
Recently, a team of researchers aimed to pinpoint what's happening in the brain to generate these cognitive changes in babies. To do so, they used the Johns Hopkins School of Medicine in Baltimore, MD, and employed a mouse model, as well as the anesthetic isoflurane [5]. Isoflurane, first approved for use in the U.S. in 1979, is common in children and is generally regarded as safe and effective [4].
The researchers were particularly interested in analyzing isoflurane's impact on the dentate gyrus, a region of the hippocampus critical for learning and the formation of new memories. This area has a large number of neurons that develop after birth.
Mice, aged 15 days, were exposed to 4-hour doses of isoflurane, equivalent to the doses used in children. The development of their hippocampus was subsequently observed [5].
Assessing Brain Changes
In this study, the dentate gyrus granule cells were significantly affected by isoflurane; their dendrites, or branches, were almost twice the length of the untreated control mice [5].
These granule cells within the dentate gyrus are crucial for memory formation but develop particularly late. In rats, for example, around 85% of them are generated after birth. Additionally, the study found a decrease in the number of mature dendritic spines, the structures that contain synapses [5].
The following stage of the study investigated the impact of these changes on learning and behavior. Using an object-place recognition test and a Y-maze test, the mice performed a series of tasks.
The mice given isoflurane exhibited "significantly poorer" results in both trials [5].
Finally, the scientists gleaned some insight into how the anesthetic might be causing these negative changes, and a protein called mTOR seems to be involved. mTOR acts as a hub, integrating signals from various sources. It was chosen by the scientists as a potential target because of its association with other neurodevelopmental disorders, such as autism spectrum disorders and schizophrenia [6].
Rapamycin, a compound that inhibits the immune system, also impedes the mTOR pathway; they found that when rapamycin was administered concurrently with the anesthetic, the negative cognitive effects and developmental changes in the brain were prevented. This suggests that mTOR may play a role in molecular mechanisms behind the altered brain development [5]. The authors write:
"Overall, our findings indicate that isoflurane causes a sustained increase in activity in the mTOR pathway that leads to dendrite growth acceleration and either synapse loss or reduced synapse formation in DGCs [dentate gyrus granule cells]."
This research supports earlier conclusions that substantial exposure to general anesthetics during development negatively impacts brain development. As the study reveals far-reaching implications, further research will likely follow suit.
Uncover the Potential Impact of General Anesthetic on Intelligence
[1] FDA. (2017). FDA drug safety communication: Repeated or lengthy use of general anesthetic and sedation drugs in children younger than 3 years or in pregnant women during their third trimester may affect the development of children's brains. Retrieved from: https://www.fda.gov/drugs/drugsafety/ucm553337.htm
[2] Lai, I., Schwarz, S., Wolff, B., Ziebuhr, J., Liebar, D., & Barnes, C. A. (2006). Severe developmental hippocampal defects after exposure to anesthetics in early postnatal life. Nature, 440(7085), 991–996. https://doi.org/10.1038/nature04634
[3] Gorter, R. J., Fernald, R. D., Volpe, J. J., & Hack, R. (2008). Cellular and neural mechanisms of hippocampal circuit development and plasticity. Progress in Brain Research, 171, 259–285. https://doi.org/10.1016/S0079-6123(08)00405-0
[4] Kanemitsu, H., & Goto, T. (2005). Isoflurane anesthesia in infants: Case reports. Pediatric Anesthesia, 15(1), 13–18. https://doi.org/10.1111/j.1460-9592.2005.00499.x
[5] Kang, E., Santiago, J. A., Shi, C., Mitra, S., Wang, X., & Mintz, D. E. (2021). Isoflurane Impairs Hippocampal Neurodevelopment and Behavior via Increased Activity in the mTOR Pathway. PLoS Biology, 19(9), e3001138. https://doi.org/10.1371/journal.pbio.3001138
[6] Hoeffer, C. R., & Russell, C. M. (2010). mTOR contrasts with protein kinase B as an age-dependent modulator of hippocampal synaptic plasticity. Proceedings of the National Academy of Sciences, 107(15), 6896–6901. https://doi.org/10.1073/pnas.0911584107
- The study using isoflurane, a common anesthetic in children, on mice reveals that it significantly impacts the growth of brain cells in developing brains, potentially increasing the risks of learning disorders and neurological disorders like autism spectrum disorders and schizophrenia.
- The researchers suggest that isoflurane could be causing these negative changes by increasing the activity in a protein called mTOR, which integrates signals from various sources and has been associated with neurodevelopmental disorders.
- To further investigate the impact of isoflurane on health and wellness, particularly mental health, the scientists administered rapamycin, a compound that inhibits the immune system and impedes the mTOR pathway, concurrently with the anesthetic, preventing the negative cognitive effects and developmental changes in the brain.
- Consequently, future research on the long-term effects of general anesthetics like isoflurane onchildren's brain development, mental health, and neurological disorders, such as learning disorders and neurological disorders like autism spectrum disorders and schizophrenia, is necessary to understand the potential impact of these drugs on health and wellness.
