Could general anesthetics alter brain development in infants?
General anesthetics are used on hundreds of thousands of children each year in the United States. But over recent years, some concerns have been raised regarding this. So much so that in April 2017, the U.S. Food and Drug Administration (FDA) warned of potential risks to developing brains.
They write that "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."
The warning comes following studies that have hinted at long-term cognitive deficits in children following anesthesia. For instance, retrospective studies found that children who underwent surgery performed worse in language and cognitive tests, and saw an increase in Medicaid billing codes relevant to learning disorders.
General anesthesia and the developing brain
In itself, the earlier studies do not prove a direct link. When a child undergoes surgery, there must be an underlying medical condition, and, of course, the surgical procedure itself could be to blame. There are other factors that might also play a role, such as parental stress.
Beyond the retrospective human studies, there is a growing body of animal research that has come to similar conclusions. For instance, a study published in 2015 investigating repeated anesthetic exposure to infant rhesus monkeys found an increased frequency of anxiety-related behaviors at the age of 6 months.
Recently, a team of researchers set out to understand what might be going on in the brain to produce these cognitive changes in infants. To this end, they used a mouse model and the general anesthetic isoflurane.
The group was led by Eunchai Kang and Dr. David Mintz, both of the Johns Hopkins School of Medicine in Baltimore, MD, and their findings are published this week in PLOS Biology.
Isoflurane was first approved for use in the U.S. in 1979. It is regularly used in children and is generally considered safe and effective.
The researchers were specifically interested in charting its impact on the dentate gyrus, a part of the hippocampus. This region of the brain is vital for learning and the formation of new memories. The hippocampus houses a large population of neurons that develop in the period shortly after birth.
Fifteen-day-old mice were exposed to 4-hour doses of isoflurane, equivalent to the doses used in children. The development of their hippocampus was subsequently recorded.
Charting brain changes
In particular, the dentate gyrus granule cells were significantly affected by the anesthetic; their dendrites, or branches, were almost twice the length of those in the untreated control mice.
The granule cells in the dentate gyrus are known to be important in memory formation but develop particularly late. In rats, for instance, approximately 85 percent of them are generated after birth.
The team also saw a reduction in the number of mature dendritic spines, the structures that house synapses.
In the next phase of the study, the researchers investigated the effect of these changes on learning and behavior. Using an object-place recognition test and a Y-maze test, the mice were put through their paces.
The mice given isoflurane performed "significantly worse" in both trials.
In the final arm of the study, the researchers gleaned some insight into how the anesthetic might be producing these negative changes, and a protein known as mTOR appears to be involved.
mTOR acts as a hub, collating signals from a number of sources. It was chosen by the scientists as a potential target in this study because it has been linked with other neurodevelopmental disorders, such as autism spectrum disorders and schizophrenia.
Rapamycin, a compound that suppresses the immune system, also inhibits the mTOR pathway; they found that when rapamycin was given alongside the anesthetic, the negative cognitive effects and developmental changes in the brain were prevented. This infers that mTOR may be involved in the molecular mechanisms behind the altered brain development. The authors write:
"Taken together, 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]."
The study firms up earlier conclusions that significant exposure to general anesthetics during development negatively impacts the growing brain. Because of the wide-ranging implications of the study, more research will no doubt follow hot on its heels.