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Healing secrets of the body guide a revolution in regeneration and rehabilitation

Plasticity: The capability to be molded, receive shape, or be made to assume a desired form.
Plasticity (physics): The tendency of a material to undergo permanent deformation under load.
Plasticity (biology): The ability of an organism to change in response to changes in the environment.
Plasticity (brain): The capacity for continuous alterations of the neural pathways and synapses of the living brain and nervous system in response to experience or injury, also known as neuroplasticity.

For many years, scientists knew that the cells that line the intestine are replaced every two weeks. The dead cells on the surface of our skin slough off, and new cells move up to take their place every few months. The liver is capable of natural regeneration of lost tissue; as little as 25% of a liver can regenerate into a whole liver. Conversely, as recently as 15 years ago, scientists believed that people were born with all of the brain cells they would ever have.

The belief was that, unlike the intestine, skin and liver, the brain and nerves could not regenerate to take the place of damaged cells. Observations of stroke patients and individuals with brain trauma and disease suggested that brain damage from accidents or disease was permanent. Nerves and areas of the brain that controlled the movement of specific limbs were not expected to regain function following injury or disease. If improvements were seen in individuals that had experienced trauma, the assumption was that the injury was "incomplete" and that recovery was due to nerves and tissues that had escaped severe injury.

The combined beliefs that brain and nerve cells could not regenerate and that damaged areas of the brain did not seem capable of recovering or relearning lost functions perpetuated the notion that the brain and nervous system lacked plasticity.

One line of investigation that began to suggest the existence of plasticity in the brain and nervous system was in the area of brain cell regeneration. The first evidence that brain cells could divide to form "newly born" brain cells in an adult animal came nearly 50 years ago.

In experiments in rats, researchers found a region of the rat brain where new nerve cells were generated. These new cells were found in the hippocampus, which is the part of the brain where memories of new places and things are formed. The researchers found two hollow cavities in the hippocampus (known as ventricles) where the new cells were born. Known as stem cells because they can change into different types of brain cells as needed, the newly formed cells migrated to different parts of the brain and assumed the functions of that area of the brain.

One of the first observations was the migration of stem cells to the olfactory bulb, where they became the type of brain cell that mediates the sense of smell. In 1998, NIH-supported researchers teamed up with Swedish scientists to demonstrate that new neurons were produced in the hippocampus of humans.

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Observations in Patients

In parallel, over approximately the same period, neurologists, anatomists and physical therapists were working with patients with brain injuries and performing experiments in animal models to determine whether the brain could be re-trained following injury. These researchers were instrumental in "mapping" which part of the brain controlled specific functions.

Over the years, neurologists determined what part of the brain controlled the movement of various body parts such as toes, legs, fingers, and arms, and even different parts of the face, such as the eyelids, cheeks, jaws, and lips. An important part of this work was observing the types of physical therapies and retraining regimens that were most effective in helping patients that had suffered brain trauma to recover some of the functions that were lost because of the injury.


Finding Plasticity in the Nervous System

A key early observation by the scientists looking for brain stem cells in animals was that new brain cells appeared to regenerate more rapidly in response to changes experienced by the animal, such as training―e.g. physical exertion of a specific limb―injury, or infection.

A similar observation was made by neurologists in experiments in animals where physical therapy appeared to cause the brain to "remap." That is, their experiments showed that the brain appeared to have "adaptive plasticity," meaning that it could be trained to use a different brain region to "take over" control of a specific limb or function in place of a damaged brain region that previously controlled the function.

Based on experiments in animals and humans over the past 20 years, researchers established that the cortex, which is the dominant feature of the human brain, has significant plasticity―the ability to reconfigure its functional organization as the result of experience, such as training.

This is supported in animal experiments where a number of physiological changes are observed in response to behavioral training. These include changes in the size and shape of brain regions, speeding up and/or slowing down of neuron signaling, increases in the molecules that help transmit signals through the brain, and the growth of new neurons.


Studying, Harnessing & Enhancing Healing

With the discovery of the body's plastic regenerative responses to injury, researchers and therapists are using this information to optimize therapies that induce plasticity and repair for a number of diseases, disorders, and injuries.

Different types of interventions are used and include specific types of training activities, pharmacological interventions, and cognitive therapies, among others. The following are examples of approaches. They include those that are currently in practice and those being tested in animal models, as well as potential future therapies based on the increasing understanding of the cellular and molecular pathways that induce plasticity.

In spinal cord injury, plasticity resulting in improved function can be induced by interventions such as intense repetitive training, which involves various types of exercise that provide certain benefits depending on the specifics of the rehabilitative training regimen. For example, NICHD-funded researchers determined that passive exercise can be used to maintain or improve neuromuscular function and involves, for example, cycling on a motorized device that does not require effort by the patient. Active exercise requires subjects to perform assisted or unassisted movements that require effort by the patient and provides the benefits of passive exercise but also promotes the additional benefit of functional activation of muscles. In each case, the movement training induces plasticity, i.e. physiological and functional changes in nerve, muscle, and the connections between them.

Traumatic brain injury (TBI) affects nearly 2 million Americans annually, and 100,000 of those injuries result in long-term behavioral disturbances that adversely affect quality of life. NICHD-funded researchers have found that, following injury, the brain is receptive to neuroplasticity, repair, and recovery, and the success of these processes can be enhanced by specific rehabilitation strategies.

One successful rehabilitation strategy is known as environmental enrichment. Environmental enrichment consists of an enhanced living environment with increased social interaction and novel stimuli that together promote physical and cognitive stimulation. Remarkably, the enhanced environment results in numerous neuroplastic changes in the brain, such as increased neuron size, increased density and branching of neurons, and increased size of the brain cortex (measured in animal experiments). While environmental enrichment is being used to improve function in TBI patients, researchers in the laboratory are working to understand the physiological, cellular, and molecular mechanisms that mediate these effects in an effort to continue to improve rehabilitation strategies.

One notable discovery is the identification of brain-derived growth factor (BDNF) as a possible key player in the neuroplastic response to an enhanced environment. Experiments show that exposure to complex environments in normal animals can increase levels of BDNF in multiple brain regions. Early studies in animals with experimental TBI show increased levels of BDNF in response to an enriched environment. Similarly, changes in levels of neurotransmitters (molecules involved in neuron signals) in response to TBI are under study with the goal of using the understanding of the molecular pathways involved in the neuroplastic process to design more successful rehabilitation regimens.

Imaging techniques such as magnetic resonance imaging (MRI) can also detect neuroplastic events. Used to study stroke patients, MRI revealed a cellular and molecular reorganization around the stroke site. In work performed by NIH researchers, including those funded by the NICHD, two major regenerative events were observed: Neurons sprout new connections that extend into the area surrounding the site, and newly born neurons appear and migrate into the area of the stroke. Also, to accelerate the healing process, molecules that normally inhibit the growth of new neurons are turned off.

Researchers are working to determine the molecules that cause these healing changes so they might eventually be used in conjunction with physical therapies to develop improved interventions following a stroke that enhance the naturally occurring healing processes that promote neuronal regeneration and remodeling.


From Research to Rehabilitation

To harness the plasticity demonstrated experimentally and attempt to apply it clinically, the National Center for Medical Rehabilitation and Research within the NICHD supports major clinical trials in rehabilitation, often funded in collaboration with other institutes at NIH.

The EXCITE trial (EXtremity Constraint Induced Extremity Evaluation) built on early experimental approaches in stroke patients and in animal models of stroke that involved repetitive training of a paralyzed upper extremity on task-oriented activities. The study tested a training technique known as constraint induced movement therapy (CIMT), where the functional limbs are constrained to force use of the injured limb. Participants were assigned to receive either CIMT (wearing a restraining mitt on the less-affected hand while engaging in repetitive task practice and behavioral shaping with the paralyzed hand) or usual and customary care.

The results of this randomized controlled trial indicated that among patients that had a stroke within the previous 3 to 9 months, CIMT produced significant and clinically relevant improvements in arm motor function that persisted for at least one year. A subsequent trial demonstrated that individuals that received the identical intervention 15 to 21 months after stroke achieved approximately the same benefit as the 3 to 9 month group and that the improvement remained at 24 months post-treatment for both groups.

In addition to renewing its connections in the brain, forcing use of the affected hand is thought to help overcome "learned nonuse," a maladaptive plastic response where the brain remaps to shut down connections with the nonfunctioning limb. Studying such maladaptive plasticity is also extremely important as researchers seek to identify the molecules and pathways responsible for this phenomenon, with the ultimate goal of blocking maladaptive responses as part of enhanced treatment.


A Path to Independence

Brain-computer interfaces (BCIs) are artificial systems that control external devices or body muscles with signals generated by neural activity, and are one of the most dramatic examples of the current and future potential for a revolution in rehabilitation based on neuroplasticity.

The device consists of a grid of electric leads that are worn like a swim cap on the head or are sometimes implanted under the skull. The electrodes pick up brain impulses and send them to a computer, which translates the impulses into actions, such as the movement of a computer cursor to a desired location.

When a BCI is in use, research shows that the brain changes its own functions and structures as it learns to operate external devices more efficiently. Therefore, the process of a paralyzed individual working, for example, to move a cursor on a computer screen just by thinking about moving it is dependent on neuroplastic changes as the brain learns to cooperate with the user and essentially rewire and reroute signals to achieve what the user is working to accomplish.

Importantly, experiments in animals demonstrate specific plastic changes in firing frequency and synchronization of neurons during the period that animals are learning to operate devices through the BCI. Amazingly, as the brain learns what it is being asked to do, it reorganizes to find the most efficient neural route to perform the task.

The development of BCIs was supported by NIH and a number of other government agencies, as well as private companies. Recently, NICHD and other NIH-supported scientists used BCI technology to develop an assistive device to allow persons with severe paralysis to be able to reach and grasp objects using their own brain signals. Two people with long-standing tetraplegia (total loss of use of all their limbs and torso) used BCI control of a robotic arm and hand to perform three-dimensional reach and grasp movements. One of the participants was able to drink from a bottle using the robotic arm, which responded to her thoughts of moving the arm via the brain computer interface. Read the NICHD news release about this finding.


The Future

The examples on the preceding pages give a glimpse of what can be accomplished when advanced knowledge of the body's innate plastic and adaptive healing mechanisms guide new rehabilitation approaches.

Stem cells

The discovery of stem cells, which offer the promise to create and replace damaged cells to cure degenerative disease and injuries, is clearly an area of intense research. For example, diabetes is a disease long thought to be amenable to stem cell therapy because the disease is caused by the loss of the single type of cell that produces insulin and, therefore, might be cured by providing insulin-producing cells made in the laboratory.

NICHD-supported researchers took advantage of the fact that the uterus contains numerous stem cells needed to make the new cells that replenish the uterine lining every month. Researchers took this rich source of stem cells and added various nutrients and growth factors that caused the cells to "differentiate" into insulin-producing cells. These cells were injected into a diabetic mouse model, where they secreted insulin and stabilized blood glucose levels. This impressive example of stem cell-based therapy suggests that women could successfully be treated for diabetes or other disorders using cells from the lining of the uterus. Such research is an excellent example of the potential of stem cell therapy to effectively address major, chronic disorders.

Mechanisms of plasticity

Regarding rehabilitation following traumatic injury and assistive technologies for those with disabilities that limit function, scientists are now working to expand their understanding of plasticity in its broadest sense, including the mechanisms that underlie adaptive as well as maladaptive change at the molecular, cellular, organ, and system levels.

Fully understanding the natural mechanisms that promote plasticity and regeneration, combined with understanding how individuals adapt to disabilities, holds the promise for ever-improving therapies to enable individuals that have suffered injuries to recover as much function as possible and offers severely impaired individuals opportunities for an unprecedented level of independence for leading active, productive lives.

For example, while the use of brain-computer interfaces to operate prosthetics is an amazing feat, restoring movements of the patient's own limbs is a preferred approach and an active area of research. Future BCI systems may help to achieve this if they can be coupled to functional electrical stimulation of muscles or the spinal cord instead of a robotic device. Another example of a futuristic yet active area of research is the development of brain-computer interfaces that allow tetraplegics to operate their wheelchairs simply by thinking about the route they wish to take.

Plasticity and adaptation

Based on years of research and observations, we now know that the basic processes that allow us to recover from illness and injury are plasticity and adaptation. Plasticity is the change in the body's structure and physiology in reaction to injury and it occurs in virtually all tissues of the body, from the central nervous system to bone. Adaptation refers to the changes in strategies that individuals use to accomplish tasks in new ways to overcome their disabilities.

Learning how to enhance and improve the body's natural mechanisms of plasticity is central to developing more effective regeneration and rehabilitation interventions. With the remarkable progress that has already been made, it may not be such a leap to envision a time when one might see a tetraplegic individual parallel parking their solar-powered car, given they have the essentials: their driver's license, their car keys, and their thoughts.


Last Reviewed: 12/03/2012
Vision National Institutes of Health Home BOND National Institues of Health Home Home Storz Lab: Section on Environmental Gene Regulation Home Machner Lab: Unit on Microbial Pathogenesis Home Division of Intramural Population Health Research Home Bonifacino Lab: Section on Intracellular Protein Trafficking Home Lilly Lab: Section on Gamete Development Home Lippincott-Schwartz Lab: Section on Organelle Biology