The neurotoxic effects of anesthesia on developing brains are well established in today’s scientific world. Anesthetic agents acting as NMDA antagonists, such as nitrous oxide and ketamine, as well as GABA agonists, such as propofol, barbiturates, and volatile anesthetics, are known to induce neuro-apoptotic effects. Research done on animal models has suggested the most vulnerable period is synaptogenesis, where new brain connections are created, since damage to new neurons and synapses can induce long-term changes in learning, memory, social activity, and attention.^1,2 These concerns have led to significant research on the effect of anesthesia in childhood on cognitive abilities.

The Western Australian Pregnancy Cohort (Raine) Study is the oldest pre-birth longitudinal study in the world, collecting demographic and medical data from 2686 children at various time points, including prenatally, at birth, and at ages 1, 2, 3, 5, 8, 10, 13, and 16.³ A later retrospective study was conducted using data from the Raine study to determine the association between exposure to anesthesia in childhood before the age of three and outcomes in language, motor skills, cognitive ability, and behavior at age 10. On average, exposed children scored lower on the Cognitive Progressive Matrices (CPM) and the Clinical Evaluation of Language Fundamentals (CELF), neuropsychological assessments meant to gauge cognitive function and language proficiency, respectively.⁴ Exposed children were also found at follow-up to have a significantly increased rate of clinical disability in language and abstract reasoning. Further statistical testing revealed higher risk ratios for multiple exposures, suggesting that although all participants exposed to anesthesia during childhood before age three were more likely to develop disability in the long-term, the cognitive risk increases as the number of exposures increases. 

Long-term potentiation (LTP) is the long-lasting increase in synaptic efficacy; the most highly studied pathway of LTP is the CA1 synapse in the hippocampus, a neural region critical to learning and memory. Since the functionality of this pathway hinges on NMDA and AMPA receptors, blockade of these receptors impairs learning in rodents.⁵ Although at varying degrees, these important receptors are also depressed by volatile, intravenous, and gaseous anesthetics. However, simply increasing the activity of these receptors may easily lead to excitotoxicity, where the destabilization of intracellular calcium produces cell death and, downstream, can cause cognitive dysfunction.⁵In a murine in vivo study, researchers tested the effect of isoflurane on suppression of fear conditioning to tone as well as suppression of fear conditioning to context; the former process is thought to involve the amygdala but not the hippocampus, and the latter is thought to involve both neural regions. Their results demonstrated it required a much lower isoflurane concentration to suppress fear learning to context, suggesting again that isoflurane impairs synapses and cognitive function through damage to the hippocampus.⁶ Memory processes and LTP can also be compromised by an enhancement of GABAergic mechanisms, such as the increase in GABA_A receptor activity. A rodent study on CA1 hippocampal slices revealed isoflurane inhibits LTP, but blocking the GABA_A receptors prevented this effect.⁷

The results of these animal studies suggest the impairment of LTP and similar cognitive processes may be responsible for the transient loss of recall and cognitive impairment after anesthesia in juvenile and adult brains.⁷ However, the clinical data on this topic point to a more pertinent problem; these cognitive deficits may be long-lasting if exposure to anesthesia is early enough in the neurodevelopmental period. This suggests that earlier childhood exposure to anesthesia may have a higher risk of later cognitive dysfunction. However, it is difficult to account for all confounding variables in correlation studies, as experimental studies in humans are not ethically permissible. What a safe threshold may be is also important to study.  Collectively, both animal and human studies allude to the importance of more research on this topic, to improve anesthesia distribution and clinical outcomes worldwide.

References 

1. Jevtovic-Todorovic, Vesna, et al. “Early Exposure to Common Anesthetic Agents Causes Widespread Neurodegeneration in the Developing Rat Brain and Persistent Learning Deficits.” Journal of Neuroscience, vol. 23, no. 3, Feb. 2003, pp. 876–82. www.jneurosci.org, https://doi.org/10.1523/JNEUROSCI.23-03-00876.2003 
2. Satomoto, Maiko, et al. “Neonatal Exposure to Sevoflurane Induces Abnormal Social Behaviors and Deficits in Fear Conditioning in Mice.” Anesthesiology, vol. 110, no. 3, Mar. 2009, pp. 628–37. DOI.org (Crossref), https://doi.org/10.1097/ALN.0b013e3181974fa2 
3. The Raine Study, https://rainestudy.org.au/. Accessed 9 Oct. 2023.
4. Ing, Caleb, et al. “Long-Term Differences in Language and Cognitive Function After Childhood Exposure to Anesthesia.” Pediatrics, vol. 130, no. 3, Sept. 2012, pp. e476–85. DOI.org (Crossref), https://doi.org/10.1542/peds.2011-3822 
5. Jungwirth, Bettina, et al. “Anesthesia and Postoperative Cognitive Dysfunction (POCD).” Mini Reviews in Medicinal Chemistry, vol. 9, no. 14, Dec. 2009, pp. 1568–79. IngentaConnect, https://doi.org/10.2174/138955709791012229 
6. Dutton, Robert C., et al. “The Concentration of Isoflurane Required to Suppress Learning Depends on the Type of Learning.” Anesthesiology, vol. 94, no. 3, Mar. 2001, pp. 514–19. DOI.org (Crossref), https://doi.org/10.1097/00000542-200103000-00024 
7. Simon, Wanda, et al. “Isoflurane Blocks Synaptic Plasticity in the Mouse Hippocampus.” Anesthesiology, vol. 94, no. 6, June 2001, pp. 1058–65. DOI.org (Crossref), https://doi.org/10.1097/00000542-200106000-00021