Neuroplasticity

by Moheb Costandi

In today’s era of instant information gratification, we have ready access to opinions, rationalizations, and superficial descriptions. Much harder to come by is the foundational knowledge that informs a principled understanding of the world.

not only capable of changing, but it does so continuously throughout life, in response to everything we do and every experience

Malacarne then did so, using pairs of dogs from the same litter and pairs of birds from the same clutch of eggs. He trained one animal from each pair extensively for several years then examined their brains, and claimed that the cerebellum was significantly larger in the trained animals than in the untrained ones.

William James.

“If habits are due to the plasticity of materials to outward agents, we can immediately see to what outward influences, if to any, the brain-matter is plastic... and it is to the infinitely attenuated currents that pour in through [the sensory nerve-roots] that the hemispherical cortex shows itself to be so peculiarly susceptible. The currents, once in, must find a way out. In getting out they leave their traces in the paths which they take. The only thing they can do, in short, is to deepen old paths or to make new ones.”

syn, meaning “together,” and haptein, meaning “to clasp,” and stated that synapses are probably the sites at which learning takes place. He referred explicitly to synaptic strengthening: “Shut off from all opportunities of reproducing itself, the nerve cell directs its pent-up energy towards amplifying its connections with its fellows, in response to the events which stir it up.”

long-term potentiation (LTP), a physiological mechanism by which synapses could be strengthened for prolonged periods of time. This was another seminal discovery. Today, synaptic modification is widely regarded as the cellular basis of learning and memory, and as such, LTP is by far the most intensively studied and best understood mode of neuroplasticity.

In 1861, a French physician named Pierre Paul Broca described a handful of stroke patients who had been admitted to the hospital where he worked, all of whom had lost the ability to speak. Upon their death, Broca examined their brains, and noted that all of them were damaged in the same region of the left frontal lobe. Ten years later, the German pathologist Karl Wernicke described another group of stroke patients, who had lost the ability to understand spoken language due to damage affecting a region of the left temporal lobe.

Canadian neurosurgeon Wilder Penfield

The brain is an extremely complex organ, and neurosurgery always runs the risk of causing collateral damage to areas involved in important functions such as language and movement. To avoid such damage, Penfield deliberately kept his patients conscious while he electrically stimulated the cortex, so that they could report their experiences back to him. When he stimulated the postcentral gyrus, for example, patients described feeling a touch sensation on some part of their body; stimulation of the precentral gyrus caused muscles in the corresponding part of the body to twitch; and stimulation of parts of the left frontal lobe interfered with the ability to speak. In this way he could delineate the boundaries of the abnormal tissue and remove it without inflicting damage on the surrounding tissue.

The McGurk effect is a powerful illusion that arises when there is a discrepancy between what we see and what we hear: the best example is a film clip of someone saying the letter g, dubbed with a voice saying the letter b, which is perceived as d.

Some researchers now argue that sensory substitution shares characteristics of, and is an artificial form of, a neurological condition called synesthesia, in which sensory information of one type gives rise to percepts in another sensory modality.9 For example, the physicist Richard Feynman was a grapheme-color synesthete, for whom each letter of the alphabet elicited the sensation of a specific color, so that he saw colored letters when he looked at equations. The artist Wassily Kandinsky had another form of synesthesia. He experienced sound sensations in response to colors, and once said that he tried to create the visual equivalent of a Beethoven symphony in his paintings.

According to the neurotrophic hypothesis, nerve cells are initially overproduced but then compete for a limited supply of target-derived NGF; those that receive the signal survive and undergo maturation, whereas those that do not wither and die.

Cell death is under genetic control, and requires “executioner” genes that encode enzymes called caspases. During development, the absence of neurotrophic signaling eventually switches these cell death genes on. Once the cellular suicide program has been activated, the caspase proteins begin to break the cell down from within: the cell’s DNA and scaffold proteins are cut into fragments, causing chromosome condensation, cell shrinkage, and membrane blebbing, all of which give the dying cell a characteristic appearance. Finally, immune cells called macrophages engulf and clear away the cellular debris.

Immature neurons in the developing brain are highly promiscuous, forming many more synaptic connections than they need, before trimming back the exuberant, mismatched, and redundant ones.

“Since the full grown forest turns out to be impenetrable and indefinable,” he wrote in his autobiography, Recollections of My Life, “why not revert to the study of the young wood, in the nursery stage, as we might say?”

The end of the developing nerve fiber takes the form of a growth cone—a dynamic structure covered with finger-like projections called filopodia—which detects chemical cues in the local environment to guide the growing tip of the nerve fiber to its proper destination, laying down new material as it proceeds.

Innervation of the muscle by the nerve increases the conductance of the receptors already present in the muscle, and also elicits the synthesis of new receptor molecules, which are inserted into the muscle membrane. Consequently, the muscle mass eventually splits into individual muscle fibers, each with a specialized receptor zone called an endplate. When the process is complete, there will be approximately 20,000 acetylcholine receptors per square micrometer of endplate, several thousand times the density of other regions of the muscle membrane.

Thus, while the human brain reaches its full size by about 16 years of age, the prefrontal cortex does not reach full maturity until this pruning is complete, and these gradual brain changes are associated with changes in behavior. The frontal cortex is associated with complex functions such as decision-making and evaluation of rewards and, because it takes so long to reach full maturity, adolescents tend to place great emphasis on gaining approval from their peers, and often engage in risky behavior to do so.

The brain contains various types of interneurons, but many of these have not yet been properly characterized, and we probably still do not fully appreciate their diverse forms and functions. But one type in particular—the large basket cells—are evidently responsible for plasticity in the developing visual system. Large basket cells are present in the primary visual cortex, but they mature slowly. When newborn mice first open their eyes, a protein called Otx2 is transported along the optic nerve from the retina to the visual cortex, where it accumulates inside the large basket cells. At this stage, the large basket cells are still immature, forming numerous weak inhibitory connections with their neighboring neurons. When the concentration of Otx2 reaches a certain level, the molecules enter the nucleus, where they activate a genetic program that promotes maturation of the large basket cells.15 As this program unfolds, the large basket cells begin to refine their connections. Certain synapses are stabilized and strengthened while others are eliminated by pruning. Meanwhile, the maturing network of large basket cells is gradually ensheathed by a net of extracellular matrix proteins, which strengthens the new synaptic connections further. Thus, sensory experience refines the microscopic structure of the visual cortex by driving maturation of the large basket cells, which puts the brakes on plasticity by consolidating the emerging circuitry at a time when its representation of ...

an infusion of brain-derived neurotrophic factor (BDNF), a growth factor needed for the survival and maturation of large basket cells, accelerates closure of the critical period.

Conversely, when an enzyme that breaks down the extracellular net is injected into the mouse brain, it reopens the critical period; and the transplantation of immature interneurons into the brains of newborn mice induces a second period of plasticity corresponding with maturation of the transplanted cells.17

Nerve terminals are often referred to as synaptic boutons, and the postsynaptic elements of excitatory synapses are arranged within tiny protuberances called dendritic spines, whereas those of inhibitory synapses are located in specialized areas of the postsynaptic membrane, found either on the dendrite shaft itself or around the cell body.

Of all the known forms of neuroplasticity, one form of synaptic plasticity, called long-term potentiation (LTP), is the most intensively studied and, therefore, the best understood. LTP is a process that increases the efficiency of synaptic transmission, which is now widely believed to be the neural basis of most, if not all, forms of learning and memory. Modification of synapses also plays an important role in addiction, a maladaptive form of neuroplasticity that involves aberrant learning (see chapter 8).

In their correspondences during the 1780s, the Swiss naturalist Charles Bonnet and the Italian anatomist Michele Vincenzo Malacarne discussed the idea that mental exercise can induce brain growth. Malacarne agreed to test the idea by taking pairs of dogs and birds and training one from each pair. A few years later, he dissected the animals’ brains, and found that the trained animals had more folds in their cerebella than the untrained ones.

In the 1940s, the Canadian psychologist Donald Hebb noticed that the lab rats he took home as pets for his children outperformed others on problem-solving tasks when returned to the lab several weeks later. This seemed to show that early experience can have dramatic and permanent effects on brain development and function. Hebb reported these findings in his influential 1949 book, The Organization of Behavior, concluding that “the richer experience of the pet group... made them better able to profit by new experience at maturity—one of characteristics of the ‘intelligent’ human being.”

the Canadian psychologist Donald Hebb noticed that the lab rats he took home as pets for his children outperformed others on problem-solving tasks when returned to the lab several weeks later. This seemed to show that early experience can have dramatic and permanent effects on brain development and function. Hebb reported these findings in his influential 1949 book, The Organization of Behavior, concluding that “the richer experience of the pet group... made them better able to profit by new experience at maturity—one of characteristics of the ‘intelligent’ human being.”

“Let us assume that the persistence or repetition of a reverberatory activity (or ‘trace’) tends to induce lasting cellular changes that add to its stability,” he wrote. “When an axon of cell A is near enough to excite a cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A’s efficiency, as one of the cells firing B, is increased.” In other words, neurons that fire together, wire together.

The induction of LTP is dependent upon binding of the excitatory neurotransmitter glutamate to N-methyl-D-aspartate (NMDA) receptors. The NMDA receptor is an ion channel that is permeable to sodium, potassium, and calcium, but the central pore that allows these ionic currents to pass is blocked by a magnesium ion. Under normal circumstances, this magnesium block remains, and the glutamate released from a nerve terminal works through two other receptor types, the AMPA and kainate receptors. High-frequency stimulation of the kind that induces LTP increases the amount of glutamate released by the nerve terminal and removes the magnesium block, allowing currents to flow through the NMDA receptors. The influx of calcium is particularly important, as it triggers various enzymes needed for the cellular processes underlying LTP.

methods, researchers have shown that neurons have mobile and immobile pools of glutamate and GABA receptors on their surface, and that receptor molecules can move rapidly around inside neurons.

sensory experience can produce structural changes to dendritic spine morphology, and that LTP can induce rapid changes in the size, shape, and number of synapses. Following induction of LTP, new spines form on the dendrite, sometimes forming connections with the same synaptic bouton that triggered their formation. The heads of existing spines grow larger, while their necks become shorter and wider. Spine head volume can increase threefold within one minute of repeated electrical stimulation. All of these changes facilitate the trafficking of receptors into the spine heads, making them more sensitive to glutamate.

There is even some evidence suggesting that merely handling brain tissue in preparation for experiments can alter the density of spines within it.

and its thought

Synaptic modification takes place continuously throughout the brain, and it is likely that millions of synapses are modified in the human brain every second in one way or another.

Traditionally, synapses were thought to consist of just two elements, the presynaptic bouton and postsynaptic membrane. In the early 1990s, however, evidence began to emerge that they are in fact tripartite structures, and that glial cells called astrocytes regulate the chemical signals that are transmitted between neurons. Astrocytes are star-shaped cells that were initially thought to fill the extracellular spaces in brain tissue. But it is now clear that they not only respond to neuronal activity but can also produce their own electrical signals, and they synthesize and release a whole host of neurochemical transmitters, including glutamate and GABA.

Astrocytes are by far the most numerous cell type in the brain. Each one has many fine branches that come into contact with hundreds of dendrites and up to 150,000 individual synapses. These processes are highly motile, and rapidly extend toward and envelop active synapses. Electron microscopic examination of brain tissue reveals that their fibers interact with large dendritic spines in response to neuronal activity, and that these fibers are less motile than those associated with small spines. Large spines tend to be more persistent than smaller ones, and so it seems that astrocytes help to stabilize those spines with active synapses. There is also some evidence that astrocytes can modulate synaptic signaling by clasping synapses to restrict the diffusion of neurotransmitters, or loosening their grip to allow them to flow more freely.

It turns out that the developing brain treats unwanted synaptic connections in exactly the same way. Unwanted connections are “tagged” for destruction with immune system molecules called complement proteins. Microglia recognize this as a signal saying “eat me,” and engulf all the tagged synapses they come across. It’s now thought that microglia are responsible for synaptic pruning throughout the developing brain, as well as for the extensive pruning that occurs in adolescence

During early development, the nervous system consists of a hollow tube running along the back of the embryo, and the inner lining of this neural tube is packed with stem cells, which divide to produce immature neurons that migrate through the thickness of the tube. At the front end of the tube, successive waves of migrating cells jostle past each other to form the layers of the cerebral cortex, one after the other, from the inside out. Further back, smaller numbers of cells migrate outward to form the spinal cord.

In adults, neural stem cells are restricted to two discrete niches within the walls of the lateral ventricles: the subventricular zone, which creates cells that migrate through the rostral migratory stream to the tip of the olfactory bulb, and the dentate gyrus of the hippocampus, whose new cells stay near their birthplace and differentiate into granule neurons.10

the addition of new neurons to the olfactory bulb is essential for the formation of new smell memories, while those added to the hippocampus contribute to spatial memory, object recognition, and pattern separation, the process by which the brain distinguishes between similar patterns of neural activity.

Certain environmental factors can regulate the process to dramatically affect the rate at which new neurons are produced. For example, physical activity, environmental enrichment, and learning tasks enhance the proliferation of neural stem cells and, in some cases, promote the survival of newborn neurons, whereas stress, certain types of inflammation, and sensory deprivation have the opposite effect.

a 2013 study by researchers in Sweden shows that the human hippocampus produces about 700 cells per day—which corresponds to an annual turnover of about 1.75% of the total number of cells in that part of the brain—and that the rate decreases only slightly with age.17 More recently, the same group published evidence of adult neurogenesis in the human striatum, a subcortical structure involved in motor control, reward, and motivation. These cells apparently originate in the subventricular zone and go on to form interneurons, whose fibers are restricted to the immediate area and whose inhibitory signals are vital for circuit function.18

bilingualism is associated with increased gray matter density in the left inferior parietal lobule, a region of the brain that has been implicated in a number of important language-related functions, such as phonological working memory (or memory for language sounds), lexical learning, and the integration of information from diverse sources, and so the volume increase may reflect acquisition of second-language vocabulary.

Even short-term language training alters brain structure: various studies show that college students and military interpreters who enrolled in intensive three-month language courses exhibited brain differences compared to controls who had not.

The anatomical changes associated with language learning appear to be reversible, though. One brain scanning study found that adult Japanese speakers who took a six-week English-language course had increased gray matter density, compared to controls, in certain language regions of the brain. Follow-up scans performed a year later revealed even bigger increases in those who had kept up their language practice. In those who had stopped, however, gray matter density in the affected brain regions had returned to pre-training levels.

Unlike commercially available brain training products, language learning does appear to have transfer effects, and evidence that lifelong bilingualism confers certain advantages is beginning to emerge. Bilingualism requires switching between languages and selecting the correct vocabulary, among other tasks that exercise so-called executive functions such as reasoning, task switching, and problem solving. Furthermore, learning a second language apparently has neuroprotective effects; thus it may reduce the risk of Alzheimer’s disease and other neurodegenerative conditions, even when it takes place in later life, by increasing “cognitive reserve”—

Thus, classical musicians who started training before the age of 7 have a larger corpus callosum than those who started their training later and nonmusical controls.

training optimizes the brain areas and neural pathways involved in performing a given task; as a result, the individual’s performance on that task improves, and the task eventually becomes automatized and effortless.

The available data suggest that gaining expertise in any domain requires at least four hours of training per day for approximately 10 years. Remarkably, there is also compelling evidence that motor imagery—that is, visualizing certain movements in the mind’s eye—can also enhance the learning and execution of certain skills. Thus, imagined movements appear to be equivalent to those that are actually performed, and merely “going through the motions” in one’s mind can lead to the same kind of plastic changes in the brain.

The animal studies suggest that axons and dendrites can grow for distances of up to 3 millimeters during reorganization of the somatosensory cortex, while the boundaries of representations in the motor cortex can shift rapidly by up to 2 millimeters.