Critical Periods: Envisioning New Treatments for Lazy Eye

By: Audrey Effenberger

“How many circles do you see?”

“Two red.”

“Two red,” the physician echoes.

“I really thought that there was nothing that could be done for my condition beyond childhood,” says adult patient Zach Fuchs in a recent TIME interview (1). He has amblyopia, or lazy eye, a developmental disorder that occurs when neural connections don’t properly form between the brain and one eye, causing the brain to favor the other. Zach’s sentiment is a prevailing one; in neuroscience, brain and central nervous system (CNS) development has long been regarded as a mystery untouchable by current medical methods.

There remains a wealth of open questions regarding neuron development, maturation, activity, and function. Why do spinal cord injuries often fail to heal? How does learning occur? What happens to memory in old age? Currently, diseases and injuries that affect cognitive function leave patients with limited medical recourse beyond therapy and adaptation to newfound limitations. However, new techniques and understanding of critical periods may lead researchers to newfound solutions for patients like Zach.

Critical periods are well studied in behavioral psychology and linguistics. For example, ducklings infer that the first adult birds they see are their parents, a phenomenon known as imprinting. In humans, it’s thought that infants must experience language at a young age in order to develop the ability to decode and produce words themselves (2). These important times between an organism’s birth and the “closing” of such cognitive windows are dubbed critical periods. Scientists are now discovering critical periods from the systemic level to the cellular. One day, the molecular bases of such critical periods may be used to manipulate the nervous system for medical good.

Cellular Networking

How do neurons encode information during critical periods? More broadly, how do neurons encode information at all? The answer lies in how they are connected. One of the most important features of a neuron is the axon, a long and thin projection from the neuron’s cell body that conducts electrical signals from the cell body to the axon terminal. The neuron transforms a stimulus or signal into an electric current. Once the current reaches the axon terminal, neurotransmitter molecules are released; they diffuse across the gap, or synapse, between the first neuron and the next. The neurotransmitters enter the postsynaptic cell and cause a specific reaction, such as triggering that cell to fire a subsequent signal. By transferring the signal between presynaptic neurons and postsynaptic neurons, the nervous system propagates signals throughout the body like batons in a relay race.

So what do these basic phenomena have to do with higher-level functions? We can think of neurons like components in an electrical circuit, and their functions as a result of the circuit’s properties. Just as a circuit made of metal and plastic can be carefully arranged to turn a light bulb on, a neural circuit can grow and connect to carry out all kinds of activities. This intricate and carefully weighted network of axons and synapses can be tuned to encode different information. For example, some neurons excite those downstream, while others inhibit neural activity, and the precise balance of these effects can be used to store memories (3). Creating new synapses, changing the proportions of excitatory to inhibitory neurotransmitters, and modulating the responses of postsynaptic cells can all affect the overall function of a neural network (4).

For this reason, the retina and visual cortex—the main processing center in the CNS for vision—must develop many connections very quickly in early development in order for a newborn brain to make sense of the world. Faulty connections or improper weighting, albeit rare, result in disorders like amblyopia. And until recently, it was believed that patients with lazy eye who were past the critical period of visual development, ending around age 8 or 9, could not be treated (5).

Old Dogs…

There’s some truth to the phrase that “old dogs can’t learn new tricks.” Old brains react to new information very differently from young ones, because most neurons naturally become less flexible or capable of forming new connections with age. The property they lose is plasticity, the ability of the nervous system to reorganize itself. While the brain is never completely static at any time, it does become less receptive to change, and plasticity has important implications for the neurons’ ability to grow and react to stimuli (6).

Why don’t brains stay plastic forever? While it would allow them to heal, rewire, and increase their storage capacity, a perpetually plastic brain might be more vulnerable to detrimental environmental stimuli like emotional trauma or drugs, which could contribute to higher rates of mental illness or degenerative diseases (7). Furthermore, by reducing plasticity, brains can become more computationally efficient; they require fewer total neurons and less time to carry out useful functions (7). The trade-off between plasticity and stability, dictated by evolution, has resulted in the unique capabilities of the modern Homo sapiens brain.

Brains lose their plasticity in a controlled and timed way—by having critical periods. One way of timing critical periods relates back to the balance of excitatory and inhibitory circuits. Once certain neuronal networks attain a certain state, they become mature and lose most of their plasticity. Another important mechanism of closing the critical period is active suppression of neuronal growth and regeneration after a certain age (6, 8). While new information is always entering the nervous system, the brain reduces its plasticity by producing molecular “brakes” that dampen the effect of neurotransmitters that correspond to new stimuli. Through experimental verification, we see that plasticity is never fully lost, merely suppressed (7).

For patients with lazy eye or amblyopia, the brain’s ruthless optimization and closing of the developmental critical period ultimately facilitate the progression of the condition. By taking the most immediately efficient route of sensory integration and favoring the “good” eye, overall visual acuity—clarity, sharpness, and depth perception—suffers (9).

However, with the advancement of new molecular techniques, biologists have begun to bend the rules of critical periods. By carefully manipulating molecular factors in model organisms, biologists have created organisms of identical chronological age that are in vastly different locations on the timeline of critical periods (7). This has already shown great potential in addressing developmental disorders or loss of sensory function.

Recoding the Critical Periods

Promising research has already demonstrated the potential of various treatments to lift the “brakes” on neuronal plasticity. Surveys of existing research in model organisms, such as cats, mice, and rats, have demonstrated the remarkable effects of tiny manipulations in cell chemistry (8). By infusing growth factors, transplanting cells that modulate learning and memory, and genetically removing suspected inhibitory factors, plasticity can be restored. Noninvasive medications and drugs have also been demonstrated to disrupt behaviors and induce plasticity (8).

Medical applications of these newfound tools can be extended to amblyopia. In amblyopia, one eye lacks proper connections to the brain, and vision is gradually lost as the brain favors one over the other. When the critical period is still open, young patients have great success with training games or virtual reality simulations that encourage “rewiring” of the visual cortex. The potential to chemically open critical periods for older patients would give physicians more freedom to correct amblyopia and could revolutionize the prognosis of this disorder.

In 2010, the protein Lynx1 was identified as inhibiting plasticity in the adult visual cortex.10 By disabling this protein, signaling increases in the visual cortex and is correlated with heightened sensitivity to environmental fluctuations. When wild-type (normal) mice and mutant (lacking Lynx1) mice were subjected to temporary blinding in one eye, the mutant mice were much more likely to develop amblyopia because their brains adapted much more quickly to the lack of visual input by ignoring the eye entirely (10).

The most intriguing result of this experiment points to potential treatment for lazy eye. Once allowed to use both of their eyes, mutant mice were much more likely to recover from amblyopia, because their brains remained much more responsive to their environment (10). Though the technology does not yet exist for safe treatment of human patients, the concept of briefly sensitizing the brain to redefine itself is powerful, exciting, and the subject of more cutting-edge research today.

The Outlook for the Lazy Eye

“Without depth perception, walking in a forest is more like walking through a hallway than it is walking through this big open place… People who have vision impairment are always wondering what it is they’re missing” (1).

Though the path from basic biological research to medical treatments is a long one, the potential of molecular intervention to extend and reopen critical periods is immense. Amblyopic patients may soon be able to undergo treatment that, over the course of several days or weeks, resensitizes their brains to visual input from their “lazy” eyes, ultimately regaining visual acuity. By combining training games with direct critical period mediation, amblyopia could become a condition of the past. One day, people like Zach won’t have to miss anything.

Audrey Effenberger ‘19 is a freshman in Greenough Hall.


[1] Tsai, D. This Virtual Reality Game Could Help Treat Lazy Eye. TIME, Jan. 5, 2016. (accessed Feb. 29, 2016).

[2] Neuroscience, 2; Purves, D. et al., Eds.; Sinauer Associates: Sunderland, MA, 2001; Ch. 24.

[3] Chklovskii, D. B. et al. Nat. 2004, 431(7010), 782-788.

[4] Brunel, N. J. Comp. Neurosci. 2001, 8(3), 183-208.

[5] Park, K. H. et al. Eye. 2004, 18, 571-574.

[6] Rakic, P. Nat. Rev. Sci. 2002, 3, 65-71.

[7] Takesian A. E.; Hensch, T. K. Prog. Brain Res. 2013, 207, 3-34.

[8] Bavelier, D. et al. J. Neurosci. 2010, 30(45), 14964-14971.

[9] National Eye Institute. (accessed Mar. 23, 2016).

[10] Morishita, H. et al. Sci. 2010, 330(6008), 1238-1240.

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