Critical Periods: Windows of Opportunity in the Brain
- neuwritephl
- 24 hours ago
- 5 min read
By: Andrea Berghella
April 2025
No matter how determined, dedicated, or Duolingo-obsessed a 30-year-old is, they will never match a toddler when it comes to learning a new language. This is obvious to us based on lived experiences, yet it is a bit counterintuitive when we think about it further: why does the difficulty of the same task change so drastically between these two scenarios?
Interestingly, similar phenomena have been described in the laboratory, with a classic example established by David Hubel and Torsten Wiesel in the 1960s while studying the visual system. In experiments where cats had one eye sutured shut, Hubel and Wiesel found that neurons that originally responded to signals from that eye later became responsive to the unobstructed, open eye, allowing for improved vision. However, this adaptability is only seen in juvenile animals and not in adults (1).
It appears that the brain’s ability to change (known in the neuroscience community as “plasticity”) isn’t constant throughout our lives. To be even more specific, our intrepid 30-year-old aspiring linguist has missed out on what is called a “critical period”: a window of enhanced neural plasticity that allows brain circuits to be more easily adapted based on the surrounding environment. To better understand this concept, imagine the brain was made of cement. When fresh and wet, it is easily moldable to best fit the project at hand, but once it hardens, it takes exponentially more force to change its shape. A critical period is that window of time in which the cement is still new and can be readily influenced by the external situation. While this is most commonly and strikingly seen during development (e.g. language acquisition), limited moments of enhanced plasticity are also seen in adulthood, for example after brain injury; this helps explain why physical therapy is most effective early after suffering a stroke and its benefits dwindle the more time passes (2, 3).
The underlying biology governing critical periods in the brain is complex and still not fully understood, but some key players have been identified. A central factor is the maturation of inhibitory interneurons, cells that can modulate neuronal signaling in neighboring cells through a richly interconnected network (4). Critical periods are also influenced by various extracellular cues, such as secreted proteins from astrocytes (a non-neuronal cell type in the brain) and the establishment of perineuronal nets (structures that enwrap specific subsets of inhibitory interneurons; see Figure 1 (5)). In short, it seems that critical periods of plasticity close based on the maturation of several biological “brakes” in the system.
Figure 1. Perineuronal Nets. An example inhibitory interneuron (green) in the rat brain surrounded by a perineuronal net (red). The merged image is shown on the right. The development of these structures coincides with critical period closure and experimental degradation of perineuronal nets leads to critical period reopening (5). Image from (5). |
But what if we could harness the plasticity of critical periods during disease to drive recovery and enhance clinical outcomes? If we had a key to the system, could we shape critical periods to best serve our needs? It may seem like science fiction, but recent evidence suggests we may already have drugs that can reopen critical periods.
In fact, researchers have been able to regulate critical periods in the laboratory for over two decades. This has been achieved by genetically altering inhibitory interneurons, by administering enzymes that degrade extracellular matrix structures (including perineuronal nets), and even by direct transplantation of interneurons into the brain, to name a few (6, 7, 8). While it is exciting that these manipulations allow us to either close or reopen critical periods, they lack direct clinical potential due to their irreversible nature and invasiveness.
Recent studies have proposed a more clinically favorable “master key” to critical period plasticity: psychedelics. Psychedelic compounds–including psilocybin (the active ingredient in magic mushrooms), LSD, MDMA (ecstasy), and ketamine–generate drastic changes in perception, colloquially known as a “trip”. Astonishingly, research is beginning to show that just a single dose of these substances can induce long-lasting improvements in a host of psychiatric illnesses, including depression, post-traumatic stress disorder (PTSD), and substance use disorders (9). It remains unclear how psychedelics produce these effects, but it has been established that this class of drugs have profound plasticity-promoting properties in the brain. In fact, work published in 2023 from Dr. Gül Dölen’s laboratory at Johns Hopkins University showed that all classes of psychedelics (regardless of their receptor targets in the brain) reopen a critical period of social behavior in mice (10). Further work studying ketamine has found that it can reopen the visual critical period described earlier–adapting neuronal responsiveness when one eye is impaired–in adult mice (11). Even more intriguing, this led to improved eyesight in a mouse model of amblyopia (or “lazy eye”) (11). Some of the pathways we learned about earlier may be driving these effects: ketamine quiets inhibitory interneurons (11) and, with multiple doses, can melt away perineuronal nets via the recruitment of microglia (the resident immune cell in the brain) (12). Importantly, all of these changes are temporary, allowing plasticity to return to normal levels.
Based on the evidence we have so far, psychedelics could be working by opening a window of opportunity in which clinical interventions have an augmented effect. Such a possibility suggests that psychedelics could be helpful not only in reshaping negative thoughts in psychiatric illnesses, but also in other plasticity-limited contexts, such as motor rehabilitation after stroke or even allergy desensitization in adulthood.
As scientific investigation continues to unravel the underlying mechanisms guiding critical period plasticity, there is great hope that these discoveries will inform new clinical therapies that better treat disease and improve patient lives. For now, you can give yourself some grace next time memorizing Spanish conjugations feels like molding cement.
References:
Andrade-Talavera, Y., Pérez-Rodríguez, M., Prius-Mengual, J., & Rodríguez-Moreno, A. (2023). Neuronal and astrocyte determinants of critical periods of plasticity. Trends in neurosciences, 46(7), 566-580.
Dobkin, B. H., & Carmichael, S. T. (2016). The specific requirements of neural repair trials for stroke. Neurorehabilitation and neural repair, 30(5), 470-478.
Hordacre, B., Austin, D., Brown, K. E., Graetz, L., Parees, I., De Trane, S., ... & Rothwell, J. C. (2021). Evidence for a window of enhanced plasticity in the human motor cortex following ischemic stroke. Neurorehabilitation and neural repair, 35(4), 307-320.
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Hensch, T. K., Fagiolini, M., Mataga, N., Stryker, M. P., Baekkeskov, S., & Kash, S. F. (1998). Local GABA circuit control of experience-dependent plasticity in developing visual cortex. Science (New York, N.Y.), 282(5393), 1504–1508.
Pizzorusso, T., Medini, P., Berardi, N., Chierzi, S., Fawcett, J. W., & Maffei, L. (2002). Reactivation of ocular dominance plasticity in the adult visual cortex. Science, 298(5596), 1248-1251.
Southwell, D. G., Froemke, R. C., Alvarez-Buylla, A., Stryker, M. P., & Gandhi, S. P. (2010). Cortical plasticity induced by inhibitory neuron transplantation. Science, 327(5969), 1145-1148.
Nutt, D., & Carhart-Harris, R. (2021). The current status of psychedelics in psychiatry. JAMA psychiatry, 78(2), 121-122.
Nardou, R., Sawyer, E., Song, Y. J., Wilkinson, M., Padovan-Hernandez, Y., De Deus, J. L., ... & Dölen, G. (2023). Psychedelics reopen the social reward learning critical period. Nature, 618(7966), 790-798.
Grieco, S. F., Qiao, X., Zheng, X., Liu, Y., Chen, L., Zhang, H., ... & Xu, X. (2020). Subanesthetic ketamine reactivates adult cortical plasticity to restore vision from amblyopia. Current biology, 30(18), 3591-3603.
Venturino, A., Schulz, R., De Jesús-Cortés, H., Maes, M. E., Nagy, B., Reilly-Andújar, F., ... & Siegert, S. (2021). Microglia enable mature perineuronal nets disassembly upon anesthetic ketamine exposure or 60-Hz light entrainment in the healthy brain. Cell reports, 36(1).
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