The human brain is an incredible learning machine. It helps us transform ourselves from helpless wiggling neonates at birth to the most dominant living organism in the known universe. Its rich imagination helped mankind to develop technologies that cleverly manipulate the environment and turn it in our favour. It helps us to, consciously perceive the world, make complex decisions, and execute movement commands all at the same time. Human beings were, are and will always be intrigued by this 1 ½ kg semisolid cauliflower shaped structure, the mysteries of which both perplex and exhilarate at the same time.

The journey from the immutable to the plastic brain:  Our modern understanding of the brain has developed after the invention of microscope and staining procedure in the late 19^th century. Camillo Golgi and Santiago Ramόn y Cajal (pronounced as Ramon e’ Cahol) were the first to use these techniques to make extensive observations and descriptions about neurons and its synaptic connections at various regions of the central nervous system (CNS). They both shared the Nobel Prize in Physiology and Medicine in 1906 for their significant contributions to the field of neuroscience. Ramon y Cajal’s believed that adult CNS was hard wired and once damaged it becomes irreparable. His statement was, “the adult CNS is fixed and immutable; everything may die, and nothing may regenerate”. This had a significant influence in the way the CNS was perceived for decades and patients with neurological problems were treated. Medical and health care professions in general took this gospel so seriously that they never parted from this axiom for nearly a century. As a result, rehabilitation had compensation as a primary premise to treat individuals who had difficulty in walking or using their hands, due to CNS insult. Therefore, they were either taught the use of body parts that are unaffected or were told to use external aids to regain function. Another significant observation was made by Nobel laureate Charles Sherrington, a British neurophysiologist, in the early 20^th century. Based on his experiments with cats he envisioned a CNS that was analogous to a giant corporate organization with a very strict hierarchical order of control where the spinal cord was considered the office clerk, taking in information and carrying out final orders from the boss, the cortex. Everything in between these parts in the nervous system was thought to works as intermediates with very limited autonomy. He believed that just as cells are the smallest independent unit in tissues & organs, reflexes were the smallest units of movement. Complex movement behaviours emerged by chaining of these simple reflexes. This model of the nervous system was known as reflex hierarchical model of the CNS where the reflexes were considered to arise from lower centers, and modulated by higher centres in the hierarchy. This theory is still heralded as the physiology counterpart of Newton’s Principals in Physics.English neurologist, Hughling Jackson confirmed these findings in humans by observations he made in patients with neurological lesion. He reported that these patients had the signs of re-emergence of reflexive movements seen only in early human infants, thus reversing the “order of evolution” of the brain hierarchical organization​

An American neurosurgeon, Wilder Penfield, opened the back box of brain and used electrodes to map out the specific regions on it that receive sensory input (sensory homunculus) and generate movement output (motor homunculus) for the first time in history. He found that each brain area had a specific role in controlling body function, and a loss of specific region of the brain cortex due to stroke or other neurological problem resulted in corresponding loss of function in the body with no potential for recovery of function. This led him to conclude that the brain cortex is arranged in a modular fashion with clearly demarcated function.This observation further supported the hard-wired CNS theory of Ramόn y Cajal. Up until the 1970’s, Cajal’s theory of a hard-wired adult nervous system was so strong that any contradictory research finding was quickly brushed aside as anomaly or pure experimental error. The early evidence exposing the cracks in Cajal’s theory was discovered by the Canadian psychologist Donald Hebb,and American Psychologist Mark Rosenzweig. They reported that rats kept in cages with enriched environments learnt better problem solving ability than those kept in normal cages. This learning was associated with actual cellular changes in their brain neuronal network. The rats with the opportunity to play had a greater amount of neuronal dendritic branching and synaptic connections along with larger brain cortices than rats kept in sensory impoverished cage environments!  This was in direct contradiction to the Cajal’s idea of the CNS in which no change n the neural circuitry was possible in an adult mammalian brain. Taking inspiration from these observations in rats and other smaller animals, Eleanor Maguire, professor of cognitive neuroscience, at the University college of London decided to test this phenomenon in humans. Of course, she could not cage humans as in the animal model work, so she chose to study the brain of a group which was the closest human model to “rats in a maze”: the taxi drivers, who navigate through the highly complex driving routes of the city of London. The results were identical to the one seen with rats as drivers structural MRI showed that they had a larger hippocampus (a region in the brain were memory is formed)  as compared to non taxi drivers. This made it clear that the adult brain indeed responds to environmental influences and can be modified with appropriate training. The word neuro-plasticity was finally getting acceptance from the scientific community. According to the Society of neuroscience, it is defined as the “changes in structure, connections or function in response to experimental manipulations or injury”.

Theory of Traditional Neurorehabilitation: During the last century, physiotherapy evolved as a profession to help individuals restore movement function after neurologic and musculoskeletal injury. Initially, physiotherapists (PT) worked with wounded soldiers of the 1^st and 2^nd world war who suffered brain and spinal cord injury, and children with post polio palsy. Over the years, the emphasis got expanded to stroke and other significant health problems that cause physical impairments. Spinal cord injury (SCI) rehabilitation was primarily based on Cajal’s theory of a hardwired CNS with the goal of therapy being to compensate for the loss of movement function. This was achieved by strengthening muscles and teaching movement substitution of non-affected limbs or instruction in using assistive devices. In the case of stroke, and other brain injury or disease rehabilitation, most of the pioneering therapists were heavily influenced by the Sherrington’s reflex hierarchical model of the CNS, where sensory input was seen as a window to influence the nervous system in order to generate movements reflexively.  As a result of this, the American Occupational therapist Margaret Roods thought of providing sensory input to the nervous system by brushing and stroking the patients’ skin. She called her approach the “Sensory re-education therapy”. An American neurophysiologist Herman Kabat and his assistant Margeret Knoll thought more critically, they reasoned that stimulating or facilitating the movement receptors (muscle spindles, Golgi organs, load receptors in the joints) might be the right way to approach so they developed a technique known as Proprioceptive Neuromuscular facilitation(PNF). In England, physiologist Karel Bobath and physiotherapist Berta  Bobath  developed an approach that they believed retraced the evolution of the nervous system from early infancy. They trained their patients through the various developmental sequences in the same order as an infant learns to move (eg: rolling, lying to sit, sit to stand and then walking). They called this therapy the Neuro developmental Therapy (NDT). A Swedish physical therapist Signe Brunnstrom was more inclined towards Cajal’s idea that the damage to the nervous system is permanent, so she decided that encouraging the patient to use whatever abilities were spared to compensate for the loss of function was appropriate as long as that made the person functionally independent.During the 1970’s and 1980’s, the emergence of movement science as a discipline gave impetus to therapies for stroke rehabilitation that were based on correcting the abnormal movement pattern in individuals with neurological injury. This shifted the emphasis from impairments in the nervous system to assessing the quality of movement biomechanically and correcting them behaviorally. The goal now was to restore functional tasks, which were affected by practicing the missing components. Clinically, the results were good for stroke and other brain injury populations, although it was unclear to what extend this was due to the training and to what part it was due to spontaneous recovery during the acute phase i.e. within 6-8months after onset of injury. On the other hand, the focus in spinal cord rehabilitation remained on functional compensation with no treatment aimed at recovering function below the level of lesion. However, many clinical therapists observed that their patient who received therapy continued to show signs of improvement long after the period of spontaneous recovery in the case of stroke and below the level of lesion in the case of spinal cord injury, when compared to others who didn’t. If this was true, the question that arose was where is this new site of re-learning in the nervous system located? Is there a cellular or molecular basis for this learning? What are its rules and how can we tap into this property of the nervous system more effectively to regain function in the affected regions of the body? However, since at that point of time, PTs worked in their own professional world without much interaction with any other scientific community, they were less aware of the developments taking place outside their discipline. These questions therefore were difficult to tackle.

The Age of Inter-disciplinary Translational Research: Matter started to change dramatically when curious and concerned therapists including PTs and various other disciplines of rehabilitation such as speech therapists, occupational therapists and psychologists got involved in research in order to seek answers to the questions that the nervous system and its plastic behavior posed to their respective practice. Since the problems in rehabilitation are multifaceted an interdisciplinary approach and team work are necessary to reach optimal answers. This led the clinical researchers to either collaborate with basic scientists who did experiments on animals or they themselves started to pursue animal research work. As a result of this collaboration, a new field called translational neuroscience in rehabilitation evolved. Translational research aims to improve human health, scientific discoveries must be translated into practical applications. Such discoveries typically begin at “the bench” with basic research in which scientists study disease at a molecular or cellular level in animals and then progress to the clinical level, or the patient's “bedside.” Since then, the quest to understand the cellular level mechanics of movement control and learning took center stage and clinical therapy based on scientific evidence took roots. Translational research in the field of neuro-rehabilitation has started to bear its fruits. Today, we have some ideas about how neuroplasticity works, but we are no where near understanding the complete mechanics of it. It is now accepted that the brain is constantly changing in response to learning, disease and exercise. The neuroplastic changes in the nervous system can happen anywhere in the brain upto the motor neurons of the spinal cord and even in the peripheral neuromuscular system. These changes can include the strength and number of synaptic connections,  uncovering of latent or existing connections,  activation of existing but silent synapses,  formation of new dendrites, and even formation of new neurons within the nervous system. The mechanisms with which these changes can happen are as follows. These mechanisms are linked and  interdependent, therefore, they should not be seen as independent phenomena.

1) Neurons that fire together wire together (Hebbian mechanism): This is one of the central tenants of neuroplasiticity which means that if certain groups of neurons rapidly fire at quick successions then they become 'associated', so that activity in one facilitates activity in the other. When one cells  repeatedly assists in firing another, the axon of the first cell develops synaptic knobs (or enlarges them if they already exist) in contact with the soma of the second cell. Now let’s consider this with an example of chronic non specific back pain. The initial trigger for the pain might be an inflammation due to weakness, injury or micro trauma which leads to muscle guarding and spasm.  If this protective mechanism lasts for a longer period of time due to personal or environmental factors, the brain may start to perceive pain and movement sensation as an independent input and it responds by  lowering the pain threshold. This lead to early conscious perception of pain in the absence of any inflammation or pathology in the actual tissue when the person starts to move the latter (try to recall Pavlov’s classical conditioning experiment in which after conditioning the dog salivates to the sound of the bell in the absence of food). This phenomenon of heightened pain perception in the nervous system is now known as ‘central sensitization’ mechanism. Here, one of the treatment options might be to “unlearn” the pain and movement association by using the same Hebbian mechanism. However, this time in a positive manner by encouraging the patient to move in the pain free direction and later progressing it through the pain barrier. This movement will act as a reward with a positive experience (no pain) and therefore, the pain with movement will be disassociated. Similarly, for many other neurological problems, the Hebbian mechanism can be used to modify the synaptic circuitry in the nervous system. However, other forms of learning such as anti-hebbian mechanism and non Hebbian mechanism of learning have also been reported in the nervous system.

2) Long term potentiation (LTP) and long term depression (LTD): Learning is associated with actual changes in the neuronal synaptic junction. When increased demand is imposed on the nervous system repeatedly, there is an increase in the  activity of existing receptors and the number of receptors on the post synaptic cell surface which is known as LTP.²¹ The opposite happens when there is reduced activity in a neural circuit, known as LTD. This change is relatively permanent and is very specific to the brain region that is used during the process. This means that in order to target a particular region in the CNS, only an activity that targets that specific region will be effective. For example, the cerebellum is known to process error signals during skilled movement and it is also one of the sites where motor learning of skilled task takes place. Therefore, if you intent to teach a new movement pattern to your client, allowing them  to do the movement with minimal corrective feedback will increase learning speed due to proper repeated activation of the cerebellar circuitry. This might be one of the reasons why variability in training and not the practice of the same movement is important during therapy for effective motor learning. A similar effect of variability of practice has been reported in the spinal cord, which indicates that movement correction and long term learning by LTP take place even in spinal cord circuitries.

3) The brain is modular yet plastic: As Penfield and Broadmann reported more than  60 years ago, the brain is still considered modular. However, recent brain imaging in human and lesion studies in monkeys have shown that it is far more plastic in its control of function than previously thought. Classic studies on monkeys by American neuroscientist Michael M. Merzenich and Edward Taub have shown that the real estate space in the cerebral cortex is distributed and redistributed based on the amount of activity in a the body part controlled by it. They reported that if a brain area is silent due to injury or non-use, then its cortical map representation shrinks and is redistributed to the parts of the body used more often. This redistribution of the cortical real estate is normally seen in healthy populations but it becomes a problem in individuals with stroke, who develop “learned non-use” of the affected limb over a period of time. In the experiments involving training the brain of lesioned monkeys to forcefully engage the affected limb (by constraining the unaffected side), the cortical organization of the brain was restored back to pre injury level long after the period of spontaneous recovery (i.e 6-8 months from the time of insult to the brain. Today, these findings in monkeys are successfully translated into clinical practice, known as “constraint induced movement therapy” (CIMT), which has become a part of accepted clinical practice all across the globe. The good news is that individuals with stroke continue to recover years after their initial attack if intensive CIMT training is provided to them!

4) Activity dependent plasticity: The plasticity in the nervous system is dependent upon the type of sensory-motor experience to which the nervous system is exposed. This was tested extensively in the last 30 years in spinalized animals by the American exercise physiologist Reggie Edgerton and colleagues. They found that a spinal cord injured cat trained to step on a treadmill with partial body weight support and minimal assistance learns to step. When the same cat is trained to stand, it learns how to stand, but not to step. Edgerton reported that in the cat, the spinal local circuitries have a certain degree of automaticity. With intense training using appropriate sensory input or with a certain amount of fine tuning (or neuromodulation) from higher centres, the spinal cord can itself produce reciprocal muscular contractions consistent with stepping movements.Based on these findings in animals, the training in humans is formulated to focus on optimizing recovery by training walking with appropriate limb biomechanics, maximal limb loading, and by providing correct sensory cues by the therapist. The emphasis in this approach is placed on recovery of normal stepping movements and prevention of the use of compensatory movements during treadmill and overground training.This type of ambulatory training is named “body weight supported locomotor training” (LT).  This therapy is been successfully translated into humans with incomplete spinal cord injury in Germany, Sweden and Switzerland with significant amount of success and is been currently tested for clinical efficacy in USA, and Canada. The remarkable ability of the spinal cord to learn from activity dependent training shows that spinal cord is much more than an office clerk as stated by Charles Sherrington. In fact it is smart enough to learn movement control if the right amount of sensory experience is provided to it. This has raised hope for individuals with spinal cord and with brain injuries and diseases to walk again. Based on the present understanding of the nervous system, the following principles of experience dependent neuroplasticity have been laid out by the American Neuroscientist Jeffery Kleim, 2008. They are:

​Exercise as the best medicine: PTs have always known that exercise is a very good medicine. Now we can state that more emphatically since even scientific evidence supports our claim. Intense endurance exercise is known to release certain chemicals and neurotransmitters in the brain and spinal cord (Brain derived neurotrophic factor, Seratonin, Neurotrophic factor) that favour neuroplasticity by synaptogenesis, and strengthen learning.  Exercise also acts as anti-spastic agent by acting as an antagonist to Glutamate and Glycine which are neurotransmitters known to cause spasticity after spinal cord after injury. It is also known to increase cerebral blood flow by favouring the formation of new blood vessels in the brain. 

“What can do good, can do harm”:  Neuroplasticity is not always good. It can cause maladaptive changes due to wrong wiring of the neural network, which may in turn lead to abnormal movement behavior or sensory experience. “Learned nonuse” in Stroke and chronic nonspecific pain, as discussed earlier, are examples of such changes. Based on the current evidences, physical activity based therapy will always be required in order to make positive neuroplasticity directed at recovery of lost function, irrespective of the emergence of other novel therapies.

The future of neuro-rehabilitation: Neuro-rehabilitation has come a long way from Ramόn y Cajal’s theory of a hard-wired CNS to the age of  Taub’s and Edgerton’s evidence supporting the idea of a plastic nervous system, but the journey is far from being over. We have barely scratched the surface of the science of neuroplasticity, along with its positive therapeutic and negative disruptive effects. There is a lot of research being conducted all around the world to explore the cellular and gene level mechanisms of neuroplastic changes.  Many adjunct therapies such as intermittent hypoxia, stem cell implantation, epidural stimulation, electromagnetic stimulation, repetitive trans-cranial magnetic stimulation, gene therapy by transfection with viruses, and pharmacological interventions are been intensely investigated to supplement the exercise or activity dependent neuro-plasticity. Efforts are also in place to develop outcome measures that are sensitive to measure recovery and differentiate it from compensatory movements. But all efforts at generating meaningful neuroplastic changes will not be successful unless an adequate and appropriate type and amount of activity based therapy is provided to the patient. In the near future, as the boundaries between disciplines blur and technology continues to expand, therapists will be expected to work in collaboration with other professionals and handle hi-tech devices as a part of routine clinical practice. Therefore, it becomes imperative that physiotherapist must take up the responsibility of constantly updating their knowledge, be ready to collaborate with other professionals such as scientists and engineers; and equip themselves with the necessary skills to stay competent in this dynamic world of neuro-rehabilitation.  More importantly in order to strengthen the collaboration between PT and basic sciences in rehabilitation, physiotherapy education needs to be updated to include the influence of mechanical forces due to exercises on the cellular and molecular levels along with its effects on the whole body and tissue