research topics on neuroplasticity

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• Review Article
• Published: 04 December 2019

Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model

• Rebecca B. Price 1 &
• Ronald Duman 2  

Molecular Psychiatry volume  25 ,  pages 530–543 ( 2020 ) Cite this article

269 Citations

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• Neuroscience

Chronic stress and depressive-like behaviors in basic neuroscience research have been associated with impairments of neuroplasticity, such as neuronal atrophy and synaptic loss in the medial prefrontal cortex (mPFC) and hippocampus. The current review presents a novel integrative model of neuroplasticity as a multi-domain neurobiological, cognitive, and psychological construct relevant in depression and other related disorders of negative affect (e.g., anxiety). We delineate a working conceptual model in which synaptic plasticity deficits described in animal models are integrated and conceptually linked with human patient findings from cognitive science and clinical psychology. We review relevant reports including neuroimaging findings (e.g., decreased functional connectivity in prefrontal-limbic circuits), cognitive deficits (e.g., executive function and memory impairments), affective information processing patterns (e.g., rigid, negative biases in attention, memory, interpretations, and self-associations), and patient-reported symptoms (perseverative, inflexible thought patterns; inflexible and maladaptive behaviors). Finally, we incorporate discussion of integrative research methods capable of building additional direct empirical support, including using rapid-acting treatments (e.g., ketamine) as a means to test this integrative model by attempting to simultaneously reverse these deficits across levels of analysis.

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This project was supported in part by National Institute of Mental Health grant number R01MH113857 (RBP).

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Price, R.B., Duman, R. Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model. Mol Psychiatry 25 , 530–543 (2020). https://doi.org/10.1038/s41380-019-0615-x

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Harnessing neuroplasticity: modern approaches and clinical future

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• 1 a Division of Applied Biomedical Sciences and Biotechnology, School of Health Sciences , International Medical University , Kuala Lumpur , Malaysia.
• PMID: 29667473
• DOI: 10.1080/00207454.2018.1466781

Background and purpose : Neurological diseases and injuries to the nervous system may cause inadvertent damage to neuronal and synaptic structures. Such phenomenon would lead to the development of neurological and neurodegenerative disorders which might affect memory, cognition and motoric functions. The body has various negative feedback systems which can induce beneficial neuroplastic changes in mediating some neuronal damage; however, such efforts are often not enough to ameliorate the derogatory changes. Materials and methods: Articles discussing studies to induce beneficial neuroplastic changes were retrieved from the databases, National Center for Biotechnology Information (NCBI) and MEDLINE, and reviewed. Results: This review highlights the significance of neuroplasticity in restoring neuronal functions and current advances in research to employ this positive cellular event by inducing synaptogenesis, neurogenesis, clearance of toxic amyloid beta (Aβ) and tau protein aggregates, or by providing neuroprotection. Compounds ranging from natural products (e.g. bilobalides, curcumin) to novel vaccines (e.g. AADvac1, RG7345) have been reported to induce long-lasting neuroplasticity in vitro and in vitro . Activity-dependent neuroplasticity is also inducible by regimens of exercises and therapies with instances in human studies proving major successes. Lastly, mechanical stimulation of brain regions through therapeutic hypothermia or deep brain stimulation has given insight on the larger scale of neuroplasticity within the nervous system. Conclusion: Harnessing neuroplasticity may not only offer an arm in the vast arsenal of approaches being taken to tackle neurological disorders, such as neurodegenerative diseases, but from ample evidence, it also has major implications in neuropsychological disorders.

Keywords: Neuroplasticity; neurogenesis; neurorestoration; physical exercise; synaptogenesis.

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MIT scientists discover fundamental rule of brain plasticity

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Our brains are famously flexible, or “plastic,” because neurons can do new things by forging new or stronger connections with other neurons. But if some connections strengthen, neuroscientists have reasoned, neurons must compensate lest they become overwhelmed with input. In a new study in Science , researchers at the Picower Institute for Learning and Memory at MIT demonstrate for the first time how this balance is struck: when one connection, called a synapse, strengthens, immediately neighboring synapses weaken based on the action of a crucial protein called Arc.

Senior author Mriganka Sur said he was excited but not surprised that his team discovered a simple, fundamental rule at the core of such a complex system as the brain, where 100 billion neurons each have thousands of ever-changing synapses. He likens it to how a massive school of fish can suddenly change direction, en masse, so long as the lead fish turns and every other fish obeys the simple rule of following the fish right in front of it.

“Collective behaviors of complex systems always have simple rules,” says Sur, the Paul E. and Lilah Newton Professor of Neuroscience in the Picower Institute and the Department of Brain and Cognitive Sciences at MIT. “When one synapse goes up, within 50 micrometers there is a decrease in the strength of other synapses using a well-defined molecular mechanism.”

This finding, he said, provides an explanation of how synaptic strengthening and weakening combine in neurons to produce plasticity.

Multiple manipulations

Though the rule they found was simple, the experiments that revealed it were not. As they worked to activate plasticity in the visual cortex of mice and then track how synapses changed to make that happen, lead authors Sami El-Boustani and Jacque Pak Kan Ip, postdocs in Sur’s lab, accomplished several firsts.

In one key experiment, they invoked plasticity by changing a neuron’s “receptive field,” or the patch of the visual field it responds to. Neurons receive input through synapses on little spines of their branch-like dendrites. To change a neuron’s receptive field, the scientists pinpointed the exact spine on the relevant dendrite of the neuron, and then closely monitored changes in its synapses as they showed the mouse a target in a particular place on a screen that differed from the neuron’s original receptive field. Whenever the target was in the new receptive field position they wanted to induce, they reinforced the neuron’s response by flashing a blue light inside the mouse’s visual cortex, instigating extra activity just like another neuron might. The neuron had been genetically engineered to be activated by light flashes, a technique called “optogenetics.”

The researchers did this over and over. Because the light stimulation correlated with each appearance of the target in the new position in the mouse’s vision, this caused the neuron to strengthen a particular synapse on the spine, encoding the new receptive field.

“I think it’s quite amazing that we are able to reprogram single neurons in the intact brain and witness in the living tissue the diversity of molecular mechanisms that allows these cells to integrate new functions through synaptic plasticity,” El-Boustani says.

As the synapse for the new receptive field grew, the researchers could see under the two-photon microscope that nearby synapses also shrank. They did not observe these changes in experimental control neurons that lacked the optogenetic stimulation.

But then they went further to confirm their findings. Because synapses are so tiny, they are near the limit of the resolution of light microscopy. So after the experiments the team dissected the brain tissues containing the dendrites of manipulated and control neurons and shipped them to co-authors at the Ecole Polytechnique Federal de Lausanne in Switzerland. They performed a specialized, higher-resolution, 3-D electron microscope imaging, confirming that the structural differences seen under the two-photon microscope were valid.

“This is the longest length of dendrite ever reconstructed after being imaged in vivo,” said Sur, who also directs the Simons Center for the Social Brain at MIT.

Of course, reprogramming a mouse’s genetically engineered neuron with flashes of light is an unnatural manipulation, so the team did another more classic “monocular deprivation” experiment in which they temporarily closed one eye of a mouse. When that happens synapses in neurons related to the closed eye weaken and synapses related to the still open eye strengthen. Then when they reopened the previously closed eye, the synapses rearrange again. They tracked that action, too, and saw that as synapses strengthen, their immediate neighbors would weaken to compensate.

Solving the mystery of the Arc

Having seen the new rule in effect, the researchers were still eager to understand how neurons obey it. They used a chemical tag to watch how key “AMPA” receptors changed in the synapses and saw that synaptic enlargement and strengthening correlated with more AMPA receptor expression while shrinking and weakening correlated with less AMPA receptor expression.

The protein Arc regulates AMPA receptor expression, so the team realized they had to track Arc to fully understand what was going on. The problem, Sur said, is that no one had ever done that before in the brain of a live, behaving animal. So the team reached out to co-authors at the Kyoto University Graduate School of Medicine and the University of Tokyo, who invented a chemical tag that could do so.

Using the tag, the team could see that the strengthening synapses were surrounded with weakened synapses that had enriched Arc expression. Synapses with reduced amount of Arc were able to express more AMPA receptors whereas increased Arc in neighboring spines caused those synapses to express less AMPA receptors.

“We think Arc maintains a balance of synaptic resources,” Ip says. “If something goes up, something must go down. That’s the major role of Arc.”

Sur says the study therefore solves a mystery of Arc: No one before had understood why Arc seemed to be upregulated in dendrites undergoing synaptic plasticity, even though it acts to weaken synapses, but now the answer was clear. Strengthening synapses increase Arc to weaken their neighbors.

Sur added that the rule helps explain how learning and memory might work at the individual neuron level because it shows how a neuron adjusts to the repeated simulation of another.

Ania Majewska, associate professor of neuroscience in the Center for Visual Science at the University of Rochester, says the study’s advanced methods allowed the team to achieve and important set of new results.

“Because of the difficulty in monitoring and manipulating the tiny and numerous synapses that connect neurons, most studies have been carried out in reduced preparations with artificial stimuli making it unclear how the mechanisms identified are actually implemented in the complicated circuits that function inside a brain reacting to its environment,” Majewska says. “This new study from the Sur lab has great impact because it combines cutting edge imaging and genetic tools to beautifully monitor the function of individual synapses inside a brain that is responding to behaviorally-relevant stimuli that elicit changes in neuronal responses.

“Given the results from this tour de force approach, we can now say that, in the intact brain, synapses that lie in close proximity to one another interact during changes in circuit function through a mechanism that involves a molecular cascade in which arc plays a critical role,” she said. “This information allows us to understand not only how neuronal circuits develop and remodel in a physiological setting, but provides clues that will be important in identifying how these processes go awry in various neurological diseases.”

In addition to Sur, El-Boustani and Ip, the paper’s other authors are Vincent Breton-Provencher, Ghraham Knott, Hiroyuki Okuno and Haruhiko Bito.

Funding for the research came from the Picower Institute Innovation Fund, The Simons Center for the Social Brain, a Marie Curie Postdoctoral Fellowship, a Human Frontier Science Program Long-Term Fellowship, the National Institutes of Health, the National Science Foundation, and KAKENHI.

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Neuroplasticity

Reviewed by Psychology Today Staff

Neuroplasticity is the brain’s capacity to continue growing and evolving in response to life experiences. Plasticity is the capacity to be shaped, molded, or altered; neuroplasticity, then, is the ability for the brain to adapt or change over time, by creating new neurons and building new networks.

Historically, scientists believed that the brain stopped growing after childhood . But current research shows that the brain is able to continue growing and changing throughout the lifespan, refining its architecture or shifting functions to different regions of the brain.

The importance of neuroplasticity can’t be overstated: It means that it is possible to change dysfunctional patterns of thinking and behaving and to develop new mindsets, new memories, new skills, and new abilities.

• The Science of Neuroplasticity
• Neuroplasticity in Everyday Life
• How to Stimulate Neuroplasticity

Neuroplasticity encompasses how nerve cells adapt to circumstances—to respond to stimulation by generating new tendrils of connection to other nerve cells, called synapses, and to respond to deprivation and excess stress by weakening connections.

Neuroplasticity underlies the capacity for learning and memory , and it enables mental and behavioral flexibility. Research has firmly established that the brain is a dynamic organ and can change its design throughout life, responding to experience by reorganizing connections—via so-called “wiring” and “rewiring.” Scientists sometimes refer to the process of neuroplasticity as structural remodeling of the brain.

The brain changes most rapidly in childhood , but it’s now clear that the brain continues to develop throughout life. At any time, day-to-day behaviors can have measurable effects on brain structure and function. For example, a well-known study of British taxi drivers found that memorizing the city streets led to changes in the memory center, the hippocampus, and that those who had driven for longer had more expansion in the hippocampus. These changes in middle age highlight the role of neuroplasticity in learning across the lifespan .

Neurogenesis refers to the creation of new brain cells. Scientists long believed that the brain was not capable of producing new neurons, but modern research has revealed that certain regions of the brain, particularly the hippocampus, are capable of generating new cells throughout adult life.

One of the core concepts of neuroplasticity is known as Hebb’s rule: Neurons that fire together, wire together. In other words, the more that neurons communicate with one another, the stronger their connection will be. Similarly, connections that are not used will be lost.

New research suggests how neurogenesis plays a role in that process. As new cells are created, they build robust connections and have a higher likelihood of “winning out” in the battle to connect than older neurons, demonstrating the interplay between neurogenesis and neuroplasticity .

The ability of the brain to change and grow in response to experience enables people to bounce back from setbacks and adversity—to be resilient. They can bend without breaking.

The disruption of neuroplasticity by severe stress or adversity is characteristic of such conditions as depression and post- traumatic stress disorder. There is quite literally a loss of synapses. In those disorders, people get stuck in neural ruts of negative thinking /feeling/behaving or fear -based memories.

All psychotherapy is intended to foster resilience ; the goal is to help people examine distressing feelings and experience and redirect them into more functional patterns, restoring cognitive and behavioral flexibility.

Aging is thought to decrease resilience through the cumulative detrimental effects of stress on neuroplasticity. The dynamic capacity of the brain to rewire itself in response to experience makes a case for lifelong stimulation as a way to maintain optimal brain health and to decrease the risk of dementia and degenerative disorders like Alzheimer’s disease.

People who have endured traumatic brain injuries have revealed the remarkable capacity for the brain to change and heal. The brain can move critical functions from a damaged area to a healthy one, or recreate connections that were lost.

One powerful example is former U.S. Representative Gabrielle Giffords, who was tragically shot in the head in 2011. She could not speak following the incident, but in the years since, music therapy helped Giffords to recover the ability to express herself.

After a limb is amputated or lost, most people continue to feel sensations in that body part. They often feel pain, but they may also experience sensations such as being touched or wearing clothing. This fascinating phenomenon is due to neurons that continue to transmit sensory information about the body part that they previously controlled.

Due to brain plasticity, the amount of neural "real estate" devoted to a particular body part can increase or decrease. Sometimes this happens quickly; for example, losing a middle finger can lead neighboring fingers to soon take over that territory. Other times this happens slowly or not at all, as in the case of people whose phantom limbs persist for decades.

The existence of neuroplasticity creates the foundation for mental health treatment through rigorous and intensive cognitive training. It means that shifting beliefs and habits through talk therapy can create biological changes that can help overcome conditions such as anxiety and depression. Brain imaging studies have borne this out, demonstrating that therapy can produce lasting changes in brain structure and connectivity.

Humans are creatures of habits, and we often develop routines from which we seldom deviate. But a few practices can help foster cognitive flexibility and overall adaptability: 1. Do something you know how to do, but do it differently. For example, take a different routine home from work, or cook something that you wouldn’t usually make. 2. Pursue new challenges and experiences, such as learning a new language or picking up painting or martial arts. 3. Meet new people, because a diversity of viewpoints can expand your thinking.

It is not only possible but necessary to use your mind and your body to reshape your brain. Enhancing synaptic connectivity through any of a variety of means actively promotes cognitive and mental health and blunts the impact of negative stimuli.

One of the most powerful ways to open up “windows of plasticity” in the brain is physical activity. Aerobic exercise helps the brain as much as the heart. In the brain, it stimulates the release of the substance known as brain-derived neurotropic factor (BDNF), which sets in motion the growth of new synaptic connections and bolsters the strength of signals transmitted from neuron to neuron.

BDNF helps pave networks of neuronal correction, promoting mental and behavioral flexibility. Stress is known to weaken expression of BDNF. Studies show that walking an hour a day, 5 out of 7 days a week, increases brain matter in the hippocampus, the seat of learning and memory.

All drugs known to alleviate depression stimulate the release of BDNF and other biological molecules that promote nerve cell growth and neuroplasticity. Many other nonpharmacologic methods have been shown to directly stimulate and maintain neuroplasticity. They include:

• Engaging in positive social interactions
• Participating in novel activities
• Engaging in play
• Being in enriched and stimulating environments
• Practicing and repeating positive activities—even mentally rehearsing them
• Engaging in mental training strategies such as mindfulness meditation
• Developing a sense of purpose in life.

The proteins responsible for regulating the processes of cell birth and cell death in the brain are known as neurotrophic factors, one of which is BDNF. When a neuron obtains an adequate amount of these proteins during development, it survives, while neurons that do not receive enough die. As these proteins are not abundant, neurons must compete for them during development and even into old age.

Consequently, decreased levels of BDNF have been associated with neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, and Huntington’s disease. Higher levels are associated with improved cognitive functioning, mental health, and memory.

Rigorous exercise can be especially beneficial for neurogenesis and memory. One study found that three weeks of high-intensity cycling and five weeks of aerobic exercise improved cognitive functioning and increased levels of BDNF. Another found that BDNF levels increased with aerobic exercise and that this corresponded with a small increase in hippocampal volume as well.

Sometimes it’s difficult to develop new habits, thought patterns, or social skills—even if we want to. But a few concrete steps can help rewire responses that seem to be entrenched in the brain. First, label the response you want to change. Second, identify the new response that you want to develop. Third, explore what factors might reduce the unwanted response and boost the desired response. Lastly, repeatedly practice the new response so that it becomes ingrained.

Master the art of presence and single-tasking to combat overwhelm, reclaim focus, and rediscover the joy of being fully present in every moment.

In addition to the effects of exercise on adrenal gland functioning, research indicates that exercise has the power to reduce PTSD symptoms by rewiring the brain.

Studies show that experiencing marital conflict as a child makes people more vulnerable to conflict in their adult romantic relationships. Here's how to stop the cycle.

Get out of your comfort zone and learn to rewire your ADHD brain to improve your cognitive skills.

Left-brained? Right-brained? No, just...brained.

How is neuroscientific research affirming that the pleasure of sound and rhythm is linked to the internal rhythms of our heartbeat, our breathing, and our pulse?

It may require very little daily cannabis consumption to produce long-term neuroprotection in the older brain.

Neuropsychopharmacology is another emerging discipline in the "neuro realm," focusing on drug effects and neural constructs on brain and human behavior.

Once viewed only as a general anesthetic or a drug of abuse, ketamine is now being explored as a treatment for a wide range of psychiatric disorders.

Nobel Prize-winning scientists, professional athletes, and tech innovators have utilized psychedelic medicines to enhance their creativity and performance. Read on to learn how.

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The power of neuroplasticity: How your brain adapts and grows as you age

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Over the summer, I spent an evening with my wife’s family, many of whom had recently flown in from France for their annual visit. All crammed on the back patio, we were quite the crowd: my wife and I, her mother, her sister, her nephew, her aunt, and family friends all catching up while sharing drinks. By convenience and habit, the majority of the conversation was in French, which I don’t speak. However, I’d known the visit was coming and had done my best to prepare. I enlisted my wife for tutoring sessions, changed all my favorite shows to French subtitles and dubs, and practiced with a language learning app every day for months.

Of course, aside from courtesies and a few phrases here and there, the conversation was too fast and too complex for me to keep up with. Mostly, I just enjoyed the challenge and quick translations from my mother-in-law.

However, what really struck me was how effortlessly my 4-year-old nephew worked the crowd. As the two most recent additions to the family — through birth in my nephew’s case and marriage in mine — he and I were both still learning the language. Though he was often too shy to speak, it was clear he knew what was going on and was able to adapt to the language much more quickly.

Unlike me, my nephew is not poring over grammar books or language apps — he simply has the advantage of a younger brain with incredible neuroplasticity.

“The ability of the brain to change — to adapt based on the environment, stimuli or experiences — is termed broadly as neuroplasticity,” says Mayo Clinic expert Prashanthi Vemuri, Ph.D., who researches the brain and neurodegenerative disorders.

Though it’s true that people of any age can benefit from the power of neuroplasticity, the brain does change as you get older, meaning it’s important to understand how to care for your cognitive health.

Below, Dr. Vemuri discusses exactly what neuroplasticity is, why it matters and how to optimize your brain’s potential.

Understanding neuroplasticity, even as you age

To understand neuroplasticity, it’s important to get familiar with the basic functioning of the brain. The brain is composed of billions of neurons — nerve cells that collect, process and send information — as well as a complex network of electrical circuits that allow these neurons to “talk” with one another. These connections are crucial, as neurons in the brain also can send messages to other parts of the body through the nervous system. In short, neuroplasticity is the brain’s ability to form and adapt this vast network of neural connections.

When you’re younger, your brain has an abundance of young neurons, which helps your brain take in new information quickly and form new neural connections. And this greater plasticity is exactly why kids have a much easier time learning a new language than adults do, explains Dr. Vemuri.

“Your brain is still developing when you are young — the brain volume is increasing, the brain connectivity is still maturing and the brain development hasn’t yet peaked,” says Dr. Vemuri. “Your brain is still growing and because of that, you can learn new things and the brain adapts much more easily.”

Dr. Vemuri says brain development continues to mature into mid-to-late 20s. From there, the brain slowly shrinks, with the rate of shrinkage increasing after 60 years of age. This change can affect cognitive functions like memory, processing speed, decision-making and learning — all the areas that may leave you feeling a little less sharp as you get older.

However, the brain still has an incredible capacity for change, in large part due to neuroplasticity. Though the number of neurons may decline with age, emerging research has shown that neuroplasticity helps the brain retain its ability to adapt both structurally and functionally throughout life. In short, neuroplasticity means you can retrain your brain, tap into new skills and maybe even learn a new language, no matter your age.

How neuroplasticity can help heal the brain after damage

Interestingly, neuroplasticity can play a key role in helping people bounce back from serious conditions like stroke and even COVID-19.

During a stroke, adequate blood supply doesn’t reach a portion of the brain or bleeding occurs in the brain, typically due to a blocked or burst blood vessel. As a result, brain cells become damaged or die. However, the brain can sometimes recover from this damage, says Dr. Vemuri.

“Let’s say you experience motor or speech symptoms with the stroke — that is, difficulty with mobility or speech. You could, over time with a lot of practice, recover that function because the brain functionally reorganizes itself.”

Additionally, neuroplasticity is helping some people recover from COVID-19. An estimated 20% of those who acquire the illness experience a change in their sense of taste and smell, with another 20% experiencing prolonged changes lasting for weeks to months. But in an estimated 95% of people with these changes, neuroplasticity helps senses improve in less than a year — most effectively through olfactory retraining , which involves smelling scents like clove or lemon to train the nerves to heal and adapt.

How to maintain your neuroplasticity

There are a number of strategies to maintain, and potentially even improve, your brain health.

Dr. Vemuri says sleep is one of the most important — though often overlooked — strategies to maintain your brain health and reduce the risk of Alzheimer’s disease and other types of dementia. Researchers believe that sleep disruption is associated with beta-amyloid, a protein that can harden into plaque — an early sign of the Alzheimer’s cascade.

During sleep, the brain clears itself of toxins like the amyloid protein, Dr. Vemuri explains, potentially lowering the risk of Alzheimer’s. In fact, studies show that people who don’t sleep enough may be twice as likely to develop Alzheimer’s disease, in addition to having an increased risk of dementia.

Other lifestyle factors like regular exercise, managing stress and blood pressure, limiting alcohol consumption, not smoking, and maintaining a strong social network all play a role in maintaining brain health.

And research suggests that the phrase “use it or lose it” applies to your brain and cognitive abilities. To use neuroplasticity to your advantage, especially as you age, Dr. Vemuri recommends regularly stimulating your brain with puzzles and challenges like sudoku, Wordle, or family game night. The more you cultivate this habit, the better. Research suggests that the benefits of these activities accrue over your lifetime.

Likewise, research suggests that you can build up your cognitive reserve — or how your brain copes with certain changes or even cognitive decline — through moderately challenging activities like reading, playing an instrument or learning a new skill. In fact, people who spend more time learning tend to have neural networks better equipped to adapt to the changes brought on by brain disorders.

Retirement is an especially important time to focus on neuroplasticity, says Dr. Vemuri, as many people experience a significant shift in lifestyle at this time.

Often, “cognitive function can decline because you’re doing less complicated tasks and the demands on the brain are lower,” she says. “Retirement therefore presents an opportunity to continue using it to keep it.”

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In the history of neuroscience it had long been a virtually axiomatic belief that the mature mammalian nervous system was hardwired and fixed. This view goes back to the work of Louis Broca in the 1850s and has been perhaps most famously articulated by Ramon y Cajal. The immature nervous system was thought to ...

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• Neural Plast
• v.2019; 2019

Finding the Intersection of Neuroplasticity, Stroke Recovery, and Learning: Scope and Contributions to Stroke Rehabilitation

Leeanne carey.

1 Occupational Therapy, School of Allied Health, Human Sciences and Sport, College of Science, Health and Engineering, La Trobe University, Bundoora, VIC 3086, Australia

2 Neurorehabilitation and Recovery, Stroke Division, Florey Institute of Neuroscience and Mental Health, Heidelberg VIC 3084, Australia

Alistair Walsh

Achini adikari.

3 Research Centre for Data Analytics and Cognition, La Trobe University, Bundoora, VIC 3086, Australia

Peter Goodin

4 Department of Medicine and Neurology, Melbourne Brain Centre, Royal Melbourne Hospital, Parkville, VIC 3050, Australia

Damminda Alahakoon

Daswin de silva, kok-leong ong, michael nilsson.

5 Faculty of Health and Medicine and Centre for Rehab Innovations, The University of Newcastle, Callaghan NSW 2308, Australia

6 LKC School of Medicine, Nanyang Technological University (NTU), 308232, Singapore

7 Djavad Mowafaghian Centre for Brain Health, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada V6T 1Z3

Neural plastic changes are experience and learning dependent, yet exploiting this knowledge to enhance clinical outcomes after stroke is in its infancy. Our aim was to search the available evidence for the core concepts of neuroplasticity, stroke recovery, and learning; identify links between these concepts; and identify and review the themes that best characterise the intersection of these three concepts.

We developed a novel approach to identify the common research topics among the three areas: neuroplasticity, stroke recovery, and learning. A concept map was created a priori , and separate searches were conducted for each concept. The methodology involved three main phases: data collection and filtering, development of a clinical vocabulary, and the development of an automatic clinical text processing engine to aid the process and identify the unique and common topics. The common themes from the intersection of the three concepts were identified. These were then reviewed, with particular reference to the top 30 articles identified as intersecting these concepts.

The search of the three concepts separately yielded 405,636 publications. Publications were filtered to include only human studies, generating 263,751 publications related to the concepts of neuroplasticity ( n = 6,498), stroke recovery ( n = 79,060), and learning ( n = 178,193). A cluster concept map (network graph) was generated from the results; indicating the concept nodes, strength of link between nodes, and the intersection between all three concepts. We identified 23 common themes (topics) and the top 30 articles that best represent the intersecting themes. A time-linked pattern emerged.

Discussion and Conclusions

Our novel approach developed for this review allowed the identification of the common themes/topics that intersect the concepts of neuroplasticity, stroke recovery, and learning. These may be synthesised to advance a neuroscience-informed approach to stroke rehabilitation. We also identified gaps in available literature using this approach. These may help guide future targeted research.

1. Introduction

Neuroplasticity can be defined as the ability of the nervous system to respond to intrinsic or extrinsic stimuli by reorganizing its structure, function, and connections [ 1 ]. Neural plastic changes are associated with development [ 2 ] and learning [ 3 , 4 ]. They occur throughout the lifespan [ 5 ] and may be enhanced following injury [ 6 ]. They are influenced by experience [ 7 ] and the context [ 8 , 9 ] in which that experience occurs. The major drivers of neuroplastic change are meaningful behavior [ 10 ]. Evidence of neural plastic changes can be observed at various levels, e.g., cellular/synaptic changes, changes in the structure and function of brain regions and networks, and changes in behavior such as improved skill and adaptability [ 11 , 12 ]. Strong scientific evidence demonstrates that the brain has remarkable capacity for plasticity and reorganisation, yet exploiting this knowledge to enhance clinical outcomes is in its infancy.

After a brain injury, such as stroke, the person is challenged to sense, move, communicate, and engage in daily activities with the brain and body that are impacted by the stroke. Immediate and long-term effects of stroke include impairment in sensation, movement, cognition, psychological and emotional functions, and reduced independence and quality of life. There may be evidence of improvement and some regaining of lost skill. A trajectory of spontaneous and supported recovery over the days, weeks, and months after stroke has been described [ 13 , 14 ]. Yet rehabilitation outcomes are currently suboptimal and variable [ 15 , 16 ], and evidence supporting novel or more effective treatments is limited.

Neural plastic changes occur following brain injury, such as stroke [ 17 ]. The changes may occur in the days, weeks, months, and years following stroke [ 11 , 13 ]. They may be adaptive or maladaptive [ 18 , 19 ]. For example, a person can learn nonuse of the limb or develop dystonic postures following sensory loss [ 20 ]. However, we have yet to harness this window of opportunity for ongoing recovery both short- and long-term after stroke. The continuum of recovery after stroke presents opportunities for targeted rehabilitation to harness and enhance these mechanisms of neural plasticity for improved outcomes.

Neural plastic changes are experience and learning dependent . Learning is the process of acquiring a relatively lasting change in knowledge and skills [ 21 ]. Learning cannot be measured directly, and assessment may address different criterion indicators of learning [ 21 ]. The potential exists for the phenomenon of neural plasticity to be shaped by the experiences that occur following stroke [ 8 , 9 , 19 ] and to be positively impacted by rehabilitation [ 9 , 19 , 22 ]. The question is how can we build on and shape this experience and drive positive plasticity to achieve better outcomes for stroke survivors?

Neurorehabilitation may be defined as “facilitation of adaptive learning” [ 23 ]. Stroke rehabilitation founded on neuroscience is now recognised for its capacity to achieve more restorative outcomes [ 1 , 19 ]. Experience and learning-dependent plasticity are core to this change [ 12 , 23 ]. There are different conditions under which that plasticity may be enhanced, facilitated, and/or consolidated. These different conditions likely impact the type of neuroplasticity facilitated and behavioral outcomes observed. An advanced understanding of these will help guide the development of neuroscience-based interventions.

The aim of our scoping review was (i) to search the evidence available in relation to the three core concepts of neural plasticity, stroke recovery, and learning; (ii) to identify how these concepts are linked to each other; and (iii) to identify and discuss the themes/topics that best characterise the intersection of these three concepts, in order to better inform the neuroscience basis of stroke rehabilitation and stroke recovery.

In relation to neural plasticity, we were interested in the identification of evidence of neuroplastic changes, e.g., at cellular and neural network levels. This included evidence such as synaptic changes, brain networks, and functional connectivity. We anticipated this literature would be primarily found in neuroscience and neuroimaging type journals. For the concept of stroke recovery, we were interested in outcomes related to impairment, performance, participation, and quality of life, at different times in the recovery trajectory and in relation to rehabilitation. The concept of learning focused on the process of change and included domains such as experience, different types of learning, attention and cognition, adaptation, environment, motivation, and goal. Investigation of the links and intersection between these concepts has the potential to reveal the following: (1) the type of learning experience that can enhance neural plasticity; (2) the evidence that links neural plasticity and improved outcomes for stroke survivors; and (3) how the different learning experiences linked with neural plasticity might influence/contribute to better stroke outcomes.

In achieving our aim, we sought to develop and use a methodology that would enable a broad and comprehensive scoping of the current literature. This included identification of key topics represented in the literature that relate to the three core concepts and an approach that permits searching and identification of related terms that may be used by authors. This was important to maximise the likelihood that a broad range of terms that are likely to have similar or overlapping meaning was able to be searched and accessed.

2. Methodology

A series of steps were conducted to identify the common research interests among the three research areas: neuroplasticity, stroke recovery, and learning. A concept map was first developed to guide the review in relation to our aim. Figure 1 depicts the concept map comprising (a) the three main concepts (neuroplasticity, stroke recovery, and learning); (b) example main keywords related to each of the concepts; (c) arrows depicting the associations among each of the main concepts; and (d) numbers to indicate our key foci/associations of interest. The target population was adult humans with stroke. Health outcomes included improved function, such as skill, performance, and quality of life.

Concept map depicting the three main concepts and the potential associations between them.

Following the initial creation of the concept map, our approach was to scope the literature available in relation to each of the three core concepts separately and then identify the relationship (link) between each other. Given the amount of literature for each of the concepts, we adopted a novel approach to searching and clustering the large number of papers and identifying the links and intersection. In particular, we employed an automatic text processing engine ( Section 2.3 ) to aid the process and identify the unique and common topics among these research concepts. In this way, we were able to map the identified topics to components 1, 2, and 3 in the proposed concept map. A narrative review was then conducted of the common themes and the top articles that were identified as intersecting the three concepts.

Our novel approach consisted of three main phases: data collection and filtering, development of a clinical vocabulary, and the development of an automatic clinical text processing engine. The methodology to build the vocabulary and text processing engine is comprised of three main technical approaches: text mining [ 24 ] — to extract relevant information from the research articles and structure data according to our analysis; natural language processing (NLP) [ 25 ]—to create word embeddings and topic ontology; and text analysis [ 26 ] — to derive insights on how the three concepts are linked together based on the identified topic associations. The details of the techniques are further described in Sections 2.2 and 2.3 .

2.1. Data Collection and Filtering

A comprehensive literature search was conducted using PubMed to assemble research studies addressing neuroplasticity, stroke recovery, and learning. First, we conducted three separate and broad searches. We used the tree of MeSH headings associated with each of these concepts to ensure broad and comprehensive inclusion of data. For example, under the heading of learning [F02.463.425], this included 25 subheadings and further 32 subheadings under these subheadings. As an inclusion criteria for the collected studies, we selected research where experiments were conducted on humans.

The PubMed database was accessed using the Entrez Programming Utilities (E-utilities), a set of eight server side programs that provide a programmatic interface to the National Center for Biotechnology Information (NCBI) database system [ 27 ]. A python helper library, used to interact with the E-utilities and perform other formatting and data managing tasks, is available at https://github.com/alistairwalsh/informatician .

The three separate requests with the query terms “neuroplasticity[MeSH],” “stroke[MeSH],” and “learning[MeSH]” returned associated PubMed ID numbers, which were then used to retrieve all the information available for those articles. The resulting XML documents were then searched for an English abstract along with their article title, abstract, and index terms (i.e., mesh terms and/or keyword lists) to produce a collection of studies that were searched for terms of interest.

Three sources of data were collected and analysed for each article retrieved: title, abstract, and index terms, as identified in the article by the authors. This data was not only selected for its availability but also based on the expectation that key topic words should be captured in these sources. Further, data collected across these data sources should be comparable as the type of information included in abstracts is relatively uniform, with clear expectations, and is usually word limited, thus minimising bias due to variance in article length.

2.2. Development of a Clinical Vocabulary

Following the filtering of the collected documents, text mining tasks were performed to gain insights on the associations between the three concepts. Text mining is the process of extracting useful information from unstructured data and customization according to the requirements. For this purpose, it was necessary to build a vocabulary/initial seed word list, which could be used as the guide for text mining to extract relevant information. Therefore, a clinical vocabulary comprising of prominent topics in all three research areas was required. The following steps were undertaken to develop the vocabulary.

2.2.1. Domain Knowledge from Experts

An initial vocabulary was formed using the domain knowledge from experts. These topic vocabulary terms are listed in Table 1 . This initial vocabulary included keywords as well as key phrases. Three knowledge experts (LC, MN, and LB) contributed to the list.

Domain knowledge from experts used for each of the three concept areas.

2.2.2. Incorporating Index Terms Provided by Authors in Articles Retrieved

Index terms (keywords provided by authors) and MESH terms used by the authors for each article were included to further enrich the vocabulary.

2.2.3. Word Embedding Technique to Expand the Vocabulary

Word embedding is a machine learning technique that intelligently captures the context of a word in a document, i.e., capturing semantic and syntactic similarity as well as identifying the relation with other words. This technique was used to extract synonyms for the original list of terms (i.e., as outlined in Table 1 ). The extracted model was applied to the three sources of data from each article (i.e. title, abstract, and index terms). A word2vec model was trained from the collection of publications that can identify terms that were being used in a similar context. For instance, the word “consolidation” generated a similarly used word list (“formation,” “reconsolidation,” “storage,” and “acquisition”). The generated similar words were manually reviewed for relevance before adding to the vocabulary.

2.3. Development of an Automatic Clinical Text Processing Engine

To analyse the associations between the concepts, we developed an automatic clinical text processing engine, which is capable of automatically extracting key terms from documents and generating a concept link map. A series of natural language processing (NLP) techniques and text analysis were used for this purpose. NLP is known as the application of computational techniques to analyse natural language which is unstructured textual data [ 28 ]. The developed text processing engine is comprised of an array of NLP techniques to extract topics, calculate similarity, and create a concept link map which was used for the analysis of topic associations. The primary tasks of the developed engine are explained below.

2.3.1. Automatic Term Extraction

Intelligent search algorithms [ 29 ] were used to automatically extract relevant terms from the abstracts, titles, and index terms provided by the authors of the publications. The developed vocabulary was used for this purpose. The process generated lists of topics being discussed for each publication.

2.3.2. Term Similarity Identification

Once the terms were extracted, it was essential to identify the common terms between the three groups. We used NLP techniques to automatically group publications that have similar topics and thereby identify unique and common clusters of topics.

2.3.3. Weight Concept Link Map

The results were then used to generate a weighted concept link map illustrating the topics that connect the concepts together. The output concept map represented an overview of the topics that link the three concepts together. Each connection was given a score based on the number of publications, therefore allowing filtering out only the important connections.

The high-level process of the text analysis engine is illustrated in Figure 2 .

The high-level process of the methodology.

2.4. Investigation of Time-Linked Patterns in Keywords Used for Each Concept

We conducted a post hoc analysis to explore if any time-related patterns emerged in relation to the emergence of topics for each of the three concepts over time. First, the three core concepts were analysed with the date of the publication and for each topic; a percentage was calculated for each year indicating the use of that topic in a particular year (i.e., based on sum of times, each keyword was mentioned each year, from 1975 to 2018). We then analysed how the three concepts have been linked together from 1975 to 2018 to explore the emergence of patterns in the linking of concepts over time.

Searching the three core concepts separately yielded 405,636 publications. Publications were filtered to include only studies of humans, generating 263,751 publications from the three groups. This included studies related to the concepts of neuroplasticity ( n = 6,498), stroke recovery ( n = 79,060), and learning ( n = 178,193).

Figure 3 illustrates the topical associations between the three main concepts generated from the automatic text processing engine following the concept map. The three main nodes in the generated concept map represent the focus areas: neuroplasticity, stroke recovery, and learning. Each line connected to the nodes represents topics discussed related to the respective research area. The strength of each line is an indication of the quantity of publications. The encircled components of the generated diagram are based on the proposed concept link map in the methodology. The numbers indicate the links between the concepts as follows:

• Common themes being discussed in neuroplasticity and learning
• Common themes being discussed in neuroplasticity and stroke recovery
• Common themes being discussed in learning and stroke recovery with common themes in neuroplasticity

Generated concept map using the automatic text processing engine—showing 3 main concepts (nodes), strength of link between nodes (number of publications), identification of common themes being discussed based on the proposed concept link map (encircled areas 1, 2, and 3), and topics (words) that help to characterise the concept and/or the links between them.

The common themes identified between the main concepts are listed in Table 2 , together with an indication of the number of publications and normalised score (weights) for each theme.

Common themes identified linking concepts of neuroplasticity, stroke recovery, and learning.

The top 30 articles identified that intersect all three main concepts: neuroplasticity, learning, and stroke recovery, are listed in Table 3 . These articles were selected according to their weighting and are ordered with the most recent at the top. It is noted that 15 articles are reviews and nine are controlled trials. The full text of these articles was downloaded and reviewed for the narrative review.

Top 30 filtered articles that address common themes being discussed in learning and stroke recovery with common themes in neuroplasticity.

3.1. A Time-Based Analysis of the Terminology and the Evolution of Topics over Time

A post hoc analysis of the use of keywords (topics) for each concept and the evolution of how the topics link together over time revealed two outcomes: (1) overall topic distribution over time—this indicated how frequently a given topic was addressed in research studies each year thereby demonstrating the patterns over time; (2) the emergence of topics—this indicated when certain topics first appeared and how they evolved over time. Based on the patterns identified by these outcomes, we further examined the time-based topical associations to observe how the link (intersection) between the three concepts (neuroplasticity, learning, and stroke) had emerged over time. For demonstration purposes, we created three sets of publications based on the patterns detected by the time-based topic distribution. Three time periods emerged: (1) Early era (1975-1990); (2) Emerging era (1997-2003); and (3) Recent era (2012-2018). These time periods emerged primarily from the topic flow graph of neuroplasticity. Using the publications in these three groups, we analysed the evolution of the link between the three concepts. This process was automated by the proposed text mining approach.

Figure 4 highlights the outcomes of this analysis showing the associations of the concepts according to the aforementioned time periods. The Early era (1975-1990) was characterised by only a few topics in neuroplasticity. Prominent topics were “Stimulation,” “Consolidation,” and “Synapses.” The links between neuroplasticity, stroke, and learning are established. This was followed by the Emerging era (1997-2003), a time where many new topics (keywords) first appeared, particularly in relation to neuroplasticity, and more new directions of research were formed. The Recent period (2012-2018) revealed the latest research topics. Many new topics appeared in relation to all three concepts during this period. The link, Neuroplasticity-Stroke, was expanded with “Neurostimulation” and “Cortical activation” other than “Brain”; the link Neuroplasticity-Learning became stronger, with many more research studies; and the link Learning-Stroke emerged, linking all three concepts together.

Generated comparison to demonstrate the evolution of topics over three selected time periods. The weight of the links is a representation of the quantity of publications.

4. Discussion

The aim of this review was to identify the literature that links neuroplasticity, stroke recovery, and learning in order to advance our understanding of and provide direction for a neuroscience-informed approach to stroke rehabilitation. The concept map generated by the text processing engine provides an efficient and rigorous approach to identify associations between different research areas as well as insights on important research themes and topics within a large pool of research publications. Moreover, the weighted link map provided a quantitative measure of the significance of the relationship between the themes; thus, the important topics could be identified. Finally, the intersection between all three concepts was defined and common topics identified. Time-linked patterns emerged from our analysis of the evolution of the link between the three concepts.

4.1. A Novel Methodology to Reveal the Presence and Absence of Topics and How They Are Linked

The methodology used to conduct this review is novel. Commonly, when commencing a literature review, a basic search term of interest will return a very large number of articles. Subsequently, more complex search terms are added until a manageable number of articles are returned. This often means there is little knowledge of the articles being excluded before the human reviewers' start to look at the final articles. The approach detailed here of conducting an extremely broad search of the literature databases and using natural language processing to understand what is present means the choice of articles to include and perhaps more importantly, knowing what is being discarded from review, has the advantage of being controlled and repeatable.

The intent of our approach was to identify key topics related to the core concepts in a systematic and comprehensive manner, thus scoping the currently available literature in the field. To achieve this, our approach employed a broad range of terms that represent the current literature and captured words that might have similar or overlapping meaning between studies and over time. The use of machine learning approaches involving text mining, word embedding, and natural language processing enhanced this feature of our review. However, there are two important considerations when conducting a literature search across different domains and across large spans of time. First, do the different domains use the same term to mean the same concept or are the same terms used to mean different things in their own domain? Second, has the meaning of a term changed over time or were concepts referred to by a different term in the past? Word embedding, which maps words to vectors of real numbers, can help with this, as it understands the context. The meaning of words and word relationships is derived from their use in the text rather than any dictionary definition. In line with this, it can describe what is in the current literature. It does not however attempt to define or evaluate the terminology used.

4.2. Themes and Topics Linking Neuroplasticity, Stroke Recovery, and Learning

The approach used allowed the existing literature to inform the themes and topics that link the three main concepts. In this way, it not only confirmed but also expanded the topics identified by domain experts. The topics identified that linked only two concepts were often quite specialised and limited. In comparison, 23 common themes/topics emerged from the intersection between all three concepts. This is reinforcing and provides direction to inform an integrated neuroscience and learning-based approach to rehabilitation.

Our major focus was on themes, or topics, at the intersection of all three concepts. Cognition was the major theme identified (see Table 3 ), highlighting the importance of this topic. The review of the top 30 articles identified that cognition was discussed both in the context of impairment of cognitive functions post-stroke (e.g., [ 35 ]) and in the context of cognitive and information processing perspectives involved in learning. The evolution of cognitive processing perspectives to a blended approach between neural science and social-cognitive psychological science was highlighted [ 44 ]. In addition, the importance of brain networks and systems that support cognition and its role in recovery and learning-based rehabilitation was evident. For example, a dissociation between disrupted memory modifications in the presence of normal consolidation was reported and may be related to differences in a lesioned brain structure linked with macrostructure network anatomy and microstructural white matter integrity [ 37 ]. Clearly, cognition is important, highlighting the need to recognise and assess cognitive profiles of stroke survivors, even those with reported mild neurological impairment. The issue of cognitive decline [ 60 , 61 ] also needs to be considered.

As expected, Brain was also a topic that was represented in a large number of publications. As well as being a focus in its own right, it was often linked with terms such as brain function, brain damage, brain injury, brain plasticity, brain stimulation, brain imaging, brain activation, and brain networks. Stimulation was primarily referred to in the context of brain stimulation and adjunct therapeutic stimulation techniques, such as functional electrical stimulation (FES) [ 41 ]. This theme highlights the search for and possible role of adjunctive stimulation techniques to enhance neural plastic changes and stroke recovery. It highlights an area of research focus and proof of concept exploration of new therapies to try to manipulate plasticity and recovery.

Different types of learning were identified in the context of neuroplasticity and stroke recovery, representing a clear intersection of all three concepts (Link 3). These included task-based learning and activity-based learning . The common focus on learning in the context of tasks and/or activities ( n = 3,970 publications) was identified using this approach. The topic of task-specific training, a term often used in clinical settings, was also aligned. These learning approaches are seen as potential enhancers of neural plasticity [ 49 ]. Task-based learning and activity-based learning map to concepts of learning-dependent plasticity. The role of learning that is task- and/or activity-based appears to have relevance in the context of stroke recovery and rehabilitation. For example, changes in central nervous system (CNS) structure and function may be modified by “activity,” together with motor learning principles [ 55 ]. In fact, both neuroscience and learning approaches that are integrated into rehabilitation included task-based training as a core element of therapy, consistent with recommendations [ 1 , 9 , 12 , 23 , 57 ].

Aligned with this focus on task- and activity-based learning is skill and skill learning , focusing on the outcomes of learning. Skill learning in the context of stroke recovery and neurorehabilitation links learning-dependent plasticity with restorative therapies. The goal of learning-dependent plasticity is often the learning of a skill, such as juggling and playing a musical instrument. In the context of stroke recovery, it may be learning a sensorimotor skill, such as learning to grasp a cup in a more normal manner following paresis. We have clear evidence from animal studies that training is a critical ingredient to this change [ 10 , 62 ]. In human studies, evidence suggests that skill learning, but not strength training, induces cortical reorganization and cortical changes may only occur with learning of new skills and not just with repetitive use [ 9 , 63 ]. For example, recent evidence highlights that motor skill learning of a repeated sequence altered cortical activation by inducing a more normal, contralateral pattern of brain activation, whereas increasing general arm use did not induce motor learning or alter brain activity [ 63 ].

A relatively large proportion of the publications (20.78%) were focused on motor learning , movement , and motor control . This finding highlights the current focus on movement outcomes, potentially at the expense of other functions or more complex outcomes. A relatively small proportion of articles focused on language and speech (9.2%). In comparison, focus on sensation (vision or touch) appeared to be missing as did more complex outcomes such as daily activities and or transfer to novel and/or complex activities. This likely reflects where the field currently is, i.e., in its infancy, in relation to applying knowledge that integrates neural plasticity with learning and valued stroke recovery outcomes. Nevertheless, the value of learning paradigms, in particular motor learning paradigms, is growing and a push to “infuse” motor learning research into neurorehabilitation practice is argued for in this literature [ 44 ]. An interesting observation was that the capacity for functional restitution after brain damage was different in sensory and motor systems [ 34 ]. The authors identified the role of adaptation and perceptual learning and their linkages with plasticity, as potentially important. Such findings further highlight the importance of systematic investigation across different functions.

Interestingly, experience-dependent learning was identified as a topic linking only neuroplasticity and learning (not the 3-way intersection) in our review (Link 1). Experience-dependent learning is closely aligned with experience-dependent plasticity [ 12 ]. Experience-dependent plasticity refers to the brain's capacity to change in response to environmental stimuli (and learning). It has been a major focus of preclinical studies and has culminated in the evidence of “enriched environments” to enhance recovery. Key features of this type of plasticity include exposure to environments that have multiple sensory attributes, social context etc. [ 12 ]. The potential for enriched environments to impact neural plastic changes and stroke recovery has been identified [ 8 ]; however, it did not emerge from the current review that represents the collective focus of the field. Given the existing link between experience and neural plasticity, the potential to connect this link more strongly with stroke recovery through targeted research is highlighted.

A few topics highlighted outcomes and/or mechanisms of change at a neurobiological level. Those topics that spanned underlying mechanisms or biomarkers included connectivity , neuroimaging , BDNF , functional connectivity , and brain activation . The neurobiological mechanisms underlying recovery in patients with varying severity of impairment and in the longer term, are incompletely understood. New technologies are emerging and have a role in providing new insights [ 64 ] and in helping to predict recovery and ability to benefit from interventions [ 36 , 65 ]. For example, a predictive relationship was elucidated between the type of behavior, e.g., specific visual or distributed memory, and the brain lesion and network disruption [ 38 ]. This was possible using machine learning and multiple measures of the brain and behavior, i.e., resting functional connectivity (FC), lesion topography, and behavior in multiple domains (attention, visual memory, verbal memory, language, motor, and visual). A key role of distributed brain network disruption, beyond focal damage, was highlighted [ 38 ].

The process of and application of learning, including sequence learning to relearning and neurorehabilitation , were also identified as themes. Given the focus on learning and search terms used, it was interesting to note that the current literature often did not include topics that reflect a greater specificity in the nature of the learning, e.g., implicit and explicit learning. An exception was the identification of sequence learning as the approach to motor skill learning by Wadden et al. [ 36 ]. Again, this likely reflects the state of the science in the application these concepts to stroke rehabilitation. The issue of restitution of function, e.g., motor, versus adaptive motor learning strategies to compensate for motor impairments was identified but not resolved [ 39 ]. Nevertheless, we recommend this topic as an important avenue for future research on the basis that the process of learning is dynamic and could be disrupted following brain injury, and specific types of learning might be more beneficial following certain types of brain injury [ 23 ].

Of further interest is the fact that learning terms such as generalization and transfer (included in the MESH term for learning) did not emerge in any of the common themes. This is of potential concern given that outcomes associated with training and therapy need to be able to transfer to novel tasks and complex settings. The issue of sustainable and generalizable gains in motor skills and associated behaviors is highlighted in the rehabilitation literature [ 23 , 57 ]. It is known that transfer to tasks that have not been directly trained in therapy is often very limited [ 57 ]. Transfer of gains in skills to personally-important real-life activities is rarely spontaneous and relatively rarely reported. Improvement in personally important, real-life activities is critical [ 23 ]. However, sensorimotor rehabilitation is historically focused on impairment reduction, with limited focus given to transfer of gains to real-life activities. Greater attention to outcomes that demonstrate different gradients of transfer and generalisation is recommended.

Neuroplasticity, learning, and transfer to novel tasks may be promoted by task complexity [ 12 , 66 , 67 ]. Different neural networks are implicated for learning of sensorimotor skills and transfer [ 68 ] and the value of metacognition strategies suggested [ 69 ]. The need for specific strategies to enhance transfer is supported by evidence from motor learning and neuroscience [ 68 , 69 ]. Activity-dependent plasticity, defined as a form of neuroplasticity that arises from the use of cognitive functions and personal experience [ 67 ], would appear to be particularly relevant in this context. Interestingly, preliminary evidence suggests combined cognitive strategy and task-specific training improve transfer to untrained activities in subacute stroke [ 70 ].

Finally, learning modifiers was also identified as a topic. Factors that modify learning, its effectiveness, and impact at different times in the recovery trajectory are of interest. These factors ranged from factors such as BDNF [ 32 ] to adjunctive therapies, such as transcranial direct current stimulation [ 31 ] and robotics [ 42 , 51 ]. One of the top 30 articles addressed the time course of skill reacquisition after stroke [ 46 ]. Other factors that might be modifiers of learning such as stress, concentration, perception, emotion, mood, and fatigue were not identified as topics despite being included as search terms.

4.3. The Evolution of Themes and Topics over Time

Further analysis was carried out to explore the evolution and associations of topics over time. Our objective was to observe how the topics in neuroplasticity, stroke recovery, and learning had evolved over time (1975-2018) using the collected sample of research studies from 1975 to 2018. Only a few topics were identified in the early time period (1975-1990). The link between neuroplasticity and stroke was established via research focused on “Brain,” while the link between neuroplasticity and learning was established via studies on “Stimulation” and “Consolidation.” In contrast, the Emerging era (1997-2003) showed the appearance of many more topics in neuroplasticity and the links have more weight indicating the availability of more research studies. The analysis of research in the Recent era (2012-2018) disclosed the emergence of many new topics. The link between neuroplasticity and stroke recovery was further expanded by studies on “cortical activation” and “neurostimulation.” It was also observed that the link between stroke recovery and learning was established in this time period, thus linking all three concepts together.

As this analysis was automated by the text mining approach described, further analysis and comparison using different time periods will allow disclosing other interesting patterns and insights regarding the associations among the three concepts. We present this time-based topic analysis as further contribution to the proposed approach as it enables researchers to mine useful time-based patterns from many publications without manual processing.

4.4. Recommendations for Future Research

Some recommendations for future research emerge from our review. The development of computational models of salient neural processes [ 40 ], including plasticity and learning systems of the brain in the context of stroke rehabilitation, is recommended. While focus to date has been primarily on motor function, we should not lose sight of the need to target other functions, such as language and sensation. Further, systematic investigation of outcomes across a profile of outcomes, including impairment and performance, activities, and participation is recommended [ 71 ] to achieve the valued outcomes articulated by people living with stroke [ 72 ]. We should also give greater attention to the processes of learning and how they map to different types of neural plastic changes, i.e. experience-dependent, learning-dependent, and activity-dependent plasticity. This is important as the different types of plasticity are aligned with specific goals, experiences, and learning conditions and may be more able to be enhanced at different times in the recovery trajectory. It is unlikely that one type of learning or principle of training, such as intensity, is likely to meet the skill and activity outcomes valued.

The development of future interventions should match neuroscience and learning principles to specific outcomes. In particular, the need to systematically target the intersect between neural plasticity and learning to achieve better generalisation of training effects and transfer to novel tasks in the context of stroke rehabilitation is critical. With further understanding, the potential to individualise therapy emerges. This may include the recognition of underlying capacities that support a particular type of learning, through genetic variations and strategies that influence modifiers of learning, such as BDNF. Finally, future research should be directed at discovering drivers of the different types of plasticity, as well as when they might best be applied at different times in the recovery trajectory.

5. Conclusions

In summary, the novel approach taken in this review allowed us to identify and characterise not only the topics that are currently being investigated in the literature but also those that are not or are only infrequently mentioned. Identification of the common intersecting themes linked with the core concepts proposed now provides a foundation of literature that may be synthesised to advance a neuroscience-informed approach to stroke rehabilitation. Further, such an approach helps to identify gaps in the field that may be important, as researched and recommended in related fields. For example, the topics of transfer and generalisation have been extensively researched in the field of learning, but did not emerge as an intersection with neural plasticity and stroke recovery. The review of the concepts of neural plasticity, learning, and stroke recovery and the common themes and topics that link them has provided direction for future research, important in the development of new neuroscience and learning-based therapeutic approaches. Finally, the potential also exists to develop theoretical frameworks by which new interventions may be conceptualised, incorporating knowledge of the intersection between contributing fields of research.

Acknowledgments

We acknowledge the support for the analysis, write-up, and researchers from the James S. McDonnell Foundation 21st Century Science Initiative in Cognitive Rehabilitation-Collaborative Award (# 220020413). We also acknowledge the support from the National Health and Medical Research Council of Australia (NHMRC) Project grant (# 1022694), Career Development Award (# 307905), Centre of Research Excellence (# 1077898), and Partnership grant (# 1134495).

Conflicts of Interest

The authors have no conflict of interest to declare.