Neuroplasticity, also known as brain plasticity, is a general term that encompasses both synaptic plasticity and non-synaptic plasticity—it refers to changes in neural pathways and synapses due to changes in behavior, environment, neural processes, thinking, emotions, as well as changes resulting from bodily injury. Neuroplasticity has replaced the formerly-held position that the brain is a physiologically static organ, and explores how – and in which ways – the brain changes throughout life.
Neuroplasticity occurs on a variety of levels, ranging from cellular changes due to learning, to large-scale changes involved in cortical remapping in response to injury. The role of neuroplasticity is widely recognized in healthy development, learning, memory, and recovery from brain damage. During most of the 20th century, the consensus among neuroscientists was that brain structure is relatively immutable after a critical period during early childhood. This belief has been challenged by findings revealing that many aspects of the brain remain plastic even into adulthood.
Hubel and Wiesel had demonstrated that ocular dominance columns in the lowest neocortical visual area, V1, were largely immutable after the critical period in development. Critical periods also were studied with respect to language; the resulting data suggested that sensory pathways were fixed after the critical period. However, studies determined that environmental changes could alter behavior and cognition by modifying connections between existing neurons and via neurogenesis in the hippocampus and other parts of the brain, including the cerebellum.
Decades of research have now shown that substantial changes occur in the lowest neocortical processing areas, and that these changes can profoundly alter the pattern of neuronal activation in response to experience. Neuroscientific research indicates that experience can actually change both the brain’s physical structure (anatomy) and functional organization (physiology). Neuroscientists are currently engaged in a reconciliation of critical period studies demonstrating the immutability of the brain after development with the more recent research showing how the brain can, and does, change in response to hitherto unsuspected stimuli.
Biology of Neuroplasticity
One of the fundamental principles of how neuroplasticity functions is linked to the concept of synaptic pruning, the idea that individual connections within the brain are constantly being removed or recreated, largely dependent upon how they are used. This concept is captured in the aphorism, “neurons that fire together, wire together”/”neurons that fire apart, wire apart,” summarizing Hebbian theory. If there are two nearby neurons that often produce an impulse simultaneously, their cortical maps may become one. This idea also works in the opposite way, i.e. that neurons which do not regularly produce simultaneous impulses will form different maps.
Cortical organization, especially for the sensory systems, is often described in terms of maps. For example, sensory information from the foot projects to one cortical site and the projections from the hand target in another site. As the result of this somatotopic organization of sensory inputs to the cortex, cortical representation of the body resembles a map (or homunculus).
In the late 1970s and early 1980s, several groups began exploring the impacts of removing portions of the sensory inputs. Michael Merzenich, Jon Kaas and Doug Rasmusson used the cortical map as their dependent variable. They found—and this has been since corroborated by a wide range of labs—that if the cortical map is deprived of its input it will become activated at a later time in response to other, usually adjacent inputs.
Merzenich’s 1984 study involved the mapping of owl monkey hands before and after amputation of the third digit. Before amputation, there were five distinct areas, one corresponding to each digit of the experimental hand. Sixty-two days following amputation of the third digit, the area in the cortical map formerly occupied by that digit had been invaded by the previously adjacent second and fourth digit zones. The areas representing digit one and five are not located directly beside the area representing digit three, so these regions remained, for the most part, unchanged following amputation.
This study demonstrates that only those regions bordering a certain area will invade it to alter the cortical map. In the somatic sensory system, in which this phenomenon has been most thoroughly investigated, JT Wall and J Xu have traced the mechanisms underlying this plasticity. Re-organization is not cortically emergent, but occurs at every level in the processing hierarchy; this produces the map changes observed in the cerebral cortex.
Merzenich and William Jenkins (1990) initiated studies relating sensory experience, without pathological perturbation, to cortically observed plasticity in the primate somatosensory system, with the finding that sensory sites activated in an attended operant behavior increase in their cortical representation. Shortly thereafter, Ford Ebner and colleagues (1994) made similar efforts in the rodent whisker barrel cortex (also somatic sensory system).
These two groups largely diverged over the years. The rodent whisker barrel efforts became a focus for Ebner, Matthew Diamond, Michael Armstrong-James, Robert Sachdev, and Kevin Fox. Great inroads were made in identifying the locus of change as being at cortical synapses expressing NMDA receptors, and in implicating cholinergic inputs as necessary for normal expression. However, the rodent studies were poorly focused on the behavioral end, and Ron Frostig and Daniel Polley (1999, 2004) identified behavioral manipulations as causing a substantial impact on the cortical plasticity in that system.
Merzenich and DT Blake (2002, 2005, 2006) went on to use cortical implants to study the evolution of plasticity in both the somatosensory and auditory systems. Both systems show similar changes with respect to behavior. When a stimulus is cognitively associated with reinforcement, its cortical representation is strengthened and enlarged.
In some cases, cortical representations can increase two to threefold in 1–2 days at the time at which a new sensory motor behavior is first acquired, and changes are largely finished within at most a few weeks. Control studies show that these changes are not caused by sensory experience alone: they require learning about the sensory experience, and are strongest for the stimuli that are associated with reward, and occur with equal ease in operant and classical conditioning behaviors.
An interesting phenomenon involving cortical maps is the incidence of phantom limbs. Phantom limbs are experienced by people who have undergone amputations in hands, arms, and legs, but it is not limited to extremities. Although the neurological basis of phantom limbs is still not entirely understood it is believed that cortical reorganization plays an important role.
Norman Doidge, following the lead of Michael Merzenich, separates manifestations of neuroplasticity into adaptations that have positive or negative behavioral consequences. For example, if an organism can recover after a stroke to normal levels of performance, that adaptiveness could be considered an example of “positive plasticity“.
Changes such as an excessive level of neuronal growth leading to spasticity or tonic paralysis, or an excessive release of neurotransmitters in response to injury which could kill nerve cells, would have to be considered “negative” plasticity. In addition, drug addiction and obsessive-compulsive disorder are deemed examples of “negative plasticity” by Dr. Doidge, as the synaptic rewiring resulting in these behaviors is also highly maladaptive.
A 2005 study found that the effects of neuroplasticity occur even more rapidly than previously expected. Medical students’ brains were imaged during the period when they were studying for their exams. In a matter of months, the students’ gray matter increased significantly in the posterior and lateral parietal cortex.
Applications of Neuroplasticity
Treatment of Brain Damage
A surprising consequence of neuroplasticity is that the brain activity associated with a given function can move to a different location; this can result from normal experience and also occurs in the process of recovery from brain injury. Neuroplasticity is the fundamental issue that supports the scientific basis for treatment of acquired brain injury with goal-directed experiential therapeutic programs in the context of rehabilitation approaches to the functional consequences of the injury.
The adult brain is not entirely “hard-wired” with fixed neuronal circuits. There are many instances of cortical and subcortical rewiring of neuronal circuits in response to training as well as in response to injury. There is solid evidence that neurogenesis (birth of brain cells) occurs in the adult, mammalian brain—and such changes can persist well into old age. The evidence for neurogenesis is mainly restricted to the hippocampus and olfactory bulb, but current research has revealed that other parts of the brain, including the cerebellum, may be involved as well.
In the rest of the brain, neurons can die, but they cannot be created. However, there is now ample evidence for the active, experience-dependent re-organization of the synaptic networks of the brain involving multiple inter-related structures including the cerebral cortex. The specific details of how this process occurs at the molecular and ultrastructural levels are topics of active neuroscience research.
The manner in which experience can influence the synaptic organization of the brain is also the basis for a number of theories of brain function including the general theory of mind and epistemology referred to as Neural Darwinism and developed by immunologist Nobel laureate Gerald Edelman.
The concept of neuroplasticity is also central to theories of memory and learning that are associated with experience-driven alteration of synaptic structure and function in studies of classical conditioning in invertebrate animal models such as Aplysia. This latter program of neuroscience research has emanated from the ground-breaking work of another Nobel laureate, Eric Kandel, and his colleagues at Columbia University College of Physicians and Surgeons.
Paul Bach-y-Rita, deceased in 2006, was the “father of sensory substitution and brain plasticity.” In working with a patient whose vestibular system had been damaged he developed BrainPort, a machine that “replaces her vestibular apparatus and [will] send balance signals to her brain from her tongue.” After she had used this machine for some time it was no longer necessary, as she regained the ability to function normally. Her balancing-act days were over.
Plasticity is the major explanation for the phenomenon. Because her vestibular system was “disorganized” and sending random rather than coherent signals, the apparatus found new pathways around the damaged or blocked neural pathways, helping to reinforce the signals that were sent by remaining healthy tissues. Bach-y-Rita explained plasticity by saying,
“If you are driving from here to Milwaukee and the main bridge goes out, first you are paralyzed. Then you take old secondary roads through the farmland. Then you use these roads more; you find shorter paths to use to get where you want to go, and you start to get there faster. These “secondary” neural pathways are “unmasked” or exposed and strengthened as they are used. The “unmasking” process is generally thought to be one of the principal ways in which the plastic brain reorganizes itself.”
Randy Nudo’s group found that if a small stroke (an infarction) is induced by obstruction of blood flow to a portion of a monkey’s motor cortex, the part of the body that responds by movement will move when areas adjacent to the damaged brain area are stimulated. In one study, intracortical microstimulation (ICMS) mapping techniques were used in nine normal monkeys. Some underwent ischemic-infarction procedures and the others, ICMS procedures.
The monkeys with ischemic infarctions retained more finger flexion during food retrieval and after several months this deficit returned to preoperative levels. With respect to the distal forelimb representation, “postinfarction mapping procedures revealed that movement representations underwent reorganization throughout the adjacent, undamaged cortex.”
Understanding of interaction between the damaged and undamaged areas provides a basis for better treatment plans in stroke patients. Current research includes the tracking of changes that occur in the motor areas of the cerebral cortex as a result of a stroke. Thus, events that occur in the reorganization process of the brain can be ascertained. Nudo is also involved in studying the treatment plans that may enhance recovery from strokes, such as physiotherapy, pharmacotherapy, and electrical-stimulation therapy.
Neuroplasticity is gaining popularity as a theory that, at least in part, explains improvements in functional outcomes with physical therapy post stroke. Rehabilitation techniques that have evidence to suggest cortical reorganization as the mechanism of change include Constraint-induced movement therapy, functional electrical stimulation, treadmill training with body-weight support, and virtual reality therapy. Robot assisted therapy is an emerging technique, which is also hypothesized to work by way of neuroplasticity, though there is currently insufficient evidence to determine the exact mechanisms of change when using this method.
Jon Kaas, a professor at Vanderbilt University, has been able to show “how somatosensory area 3b and ventroposterior (VP) nucleus of the thalamus are affected by longstanding unilateral dorsal-column lesions at cervical levels in macaque monkeys.”
Adult brains have the ability to change as a result of injury but the extent of the reorganization depends on the extent of the injury. His recent research focuses on the somatosensory system, which involves a sense of the body and its movements using many senses. Usually when people damage the somatosensory cortex, impairment of the body perceptions are experienced. He is trying to see how these systems (somatosensory, cognitive, motor systems) are plastic as a result of injury.
One of the most recent applications of neuroplasticity involves work done by a team of doctors and researchers at Emory University, specifically Dr. Donald Stein (who has been in the field for over three decades) and Dr. David Wright. This is the first treatment in 40 years that has significant results in treating traumatic brain injuries while also incurring no known side effects and being cheap to administer.
Dr. Stein noticed that female mice seemed to recover from brain injuries better than male mice. Also in females, he noticed that at certain points in the estrus cycle females recovered even more. After lots of research, they attributed this difference due to the levels of progesterone. The highest level of progesterone present led to the fastest recovery of brain injury in these mice.
They developed a treatment that includes increased levels of progesterone injections to give to brain-injured patients. “Administration of progesterone after traumatic brain injury (TBI) and stroke reduces edema, inflammation, and neuronal cell death, and enhance spatial reference memory and sensory motor recovery.”
In their clinical trials, they had a group of severely injured patients that after the three days of progesterone injections had a 60% reduction in mortality. Sam was in a horrific car accident that left him with marginal brain activity; according to the doctors, he was one point away from being brain dead. His parents decided to have him participate in Dr. Stein’s clinical trial and he was given the three-day progesterone treatment. Three years after the accident, he had achieved an inspiring recovery with no brain complications and the ability to live a healthy, normal life.
Stein has done some studies in which beneficial effects have been seen to be similar in aged rats to those seen in youthful rats. As there are physiological differences in the two age groups, the model was tweaked for the elderly animals by reducing their stress levels with increased physical contact. During surgery, anesthesia was kept at a higher oxygen level with lower overall isoflurane percentage and “the aged animals were given subcutaneous lactated ringers solution post-surgery to replace fluids lost through increased bleeding.”
The promising results of progesterone treatments “could have a significant impact on the clinical management of TBI.” These treatments have been shown to work on human patients who receive treatment soon after the TBI. However, Dr. Stein now focuses his research on those persons who have longstanding traumatic brain injury in order to determine if progesterone treatments will assist them in the recovery of lost functions as well.
A study published in the New England Journal of Medicine in 2014 detailing the results of a multi-center NIH-funded phase III clinical trial of 882 patients found that treatment of acute traumatic brain injury with the hormone progesterone provides no significant benefit to patients when compared with placebo.
Brain-machine interface (BMI) is a rapidly developing field of neuroscience. According to the results obtained by Mikhail Lebedev, Miguel Nicolelis and their colleagues, operation of BMIs results in incorporation of artificial actuators into brain representations. The scientists showed that modifications in neuronal representation of the monkey’s hand and the actuator that was controlled by the monkey brain occurred in multiple cortical areas while the monkey operated a BMI. In these single day experiments, monkeys initially moved the actuator by pushing a joystick.
After mapping out the motor neuron ensembles, control of the actuator was switched to the model of the ensembles so that the brain activity, and not the hand, directly controlled the actuator. The activity of individual neurons and neuronal populations became less representative of the animal’s hand movements while representing the movements of the actuator. Presumably as a result of this adaptation, the animals could eventually stop moving their hands yet continue to operate the actuator. Thus, during BMI control, cortical ensembles plastically adapt, within tens of minutes, to represent behaviorally significant motor parameters, even if these are not associated with movements of the animal’s own limb.
Active laboratory groups include those of John Donoghue at Brown, Richard Andersen at Caltech, Krishna Shenoy at Stanford, Nicholas Hatsopoulos of University of Chicago, Andy Schwartz at University of Pittsburgh, Sandro Mussa-Ivaldi at Northwestern and Miguel Nicolelis at Duke. Donoghue and Nicolelis’ groups have independently shown that animals can control external interfaces in tasks requiring feedback, with models based on activity of cortical neurons, and that animals can adaptively change their minds to make the models work better. Donoghue’s group took the implants from Richard Normann’s lab at Utah (the “Utah” array), and improved it by changing the insulation from polyimide to parylene-c, and commercialized it through the company Cyberkinetics. These efforts are the leading candidate for the first human trials on a broad scale for motor cortical implants to help quadriplegic or locked-in patients communicate with the outside world.
The experience of Phantom limbs is a phenomenon in which a person continues to feel pain or sensation within a part of their body which has been amputated. This is strangely common, occurring in 60-80% of amputees. An explanation for this refers to the concept of neuroplasticity, as the cortical maps of the removed limbs are believed to have become engaged with the area around them in the postcentral gyrus. This results in activity within the surrounding area of the cortex being misinterpreted by the area of the cortex formerly responsible for the amputated limb.
The relationship between phantom limbs and neuroplasticity is a complex one. In the early 1990s V.S. Ramachandran theorized that phantom limbs were the result of cortical remapping. However, in 1995 Herta Flor and her colleagues demonstrated that cortical remapping occurs only in patients who have phantom pain. Her research showed that phantom limb pain (rather than referred sensations) was the perceptual correlate of cortical reorganization. This phenomenon is sometimes referred to as maladaptive plasticity.
In 2009 Lorimer Moseley and Peter Brugger carried out a remarkable experiment in which they encouraged arm amputee subjects to use visual imagery to contort their phantom limbs into impossible configurations. Four of the seven subjects succeeded in performing impossible movements of the phantom limb. This experiment suggests that the subjects had modified the neural representation of their phantom limbs and generated the motor commands needed to execute impossible movements in the absence of feedback from the body. The authors stated:
“In fact, this finding extends our understanding of the brain’s plasticity because it is evidence that profound changes in the mental representation of the body can be induced purely by internal brain mechanisms–the brain truly does change itself.”
Individuals who suffer from chronic pain experience prolonged pain at sites that may have been previously injured, yet are otherwise currently healthy. This phenomenon is related to neuroplasticity due to a maladaptive reorganization of the nervous system, both peripherally and centrally. During the period of tissue damage, noxious stimuli and inflammation cause an elevation of nociceptive input from the periphery to the central nervous system.
Prolonged nociception from periphery will then elicit a neuroplastic response at the cortical level to change its somatotopic organization for the painful site, inducing central sensitization. For instance, individuals experiencing complex regional pain syndrome demonstrate a diminished cortical somatotopic representation of the hand contralaterally as well as a decreased spacing between the hand and the mouth.
Additionally, chronic pain has been reported to significantly reduce the volume of grey matter in the brain globally, and more specifically at the prefrontal cortex and right thalamus. However, following treatment, these abnormalities in cortical reorganization and grey matter volume are resolved, as well as their symptoms. Similar results have been reported for phantom limb pain, chronic low back pain and carpal tunnel syndrome.