Neuroplasticity refers to the brain's ability to change and reorganize itself in response to experience. The brain forms new connections and pathways when we learn new skills or have new experiences. Neuroplasticity allows the brain to compensate for injury and disease and is responsible for development throughout childhood. Promising therapies that may enhance neuroplasticity include brain stimulation, cognitive training, and certain drugs. Assessing neuroplasticity in humans through biomarkers can help predict treatment response and monitor recovery. Harnessing neuroplasticity is key for rehabilitation from brain injuries and disorders.

1. NEUROPLASTICITY
-DR. RAVIKIRAN H M
Introduction:
Every man can, if he so desires, become the sculptor of his own brain.
Neural networks are not fixed, but occurring and disappearing dynamically throughout our whole
life, depending on experiences.
While we repeatedly practice one activity such as a sequence of movements or a mathematical
problem, neuronal circuits are being formed, leading to better ability to perform the practiced
task with less waste of energy.
Once we stop practicing a certain activity, the brain will redirect these neuronal circuits by a
much known ‘use it or lose it’ principle.
Neuroplasticity leads to many different occurrences, such as habituation, sensitization to a
certain position, medication tolerance, even recovery following brain injury.
Definition:
Defined as brain’s ability to change, remodel & reorganize for purpose of better ability to adapt
to new situations.
History:
About 120 years ago, William James was the first to suggest the theory of neuroplasticity in his
work Principles of Psychology.
Donald Hebb, a Canadian psychologist established a Hebb’s rule, defined also as pre-post
coincidence, implying that changes of biochemical processes in one neuron can stimulate
neighboring simultaneously activated synapses, this being the basic principle of synaptic
plasticity.

2. Paul Bach-y-Rita is the pioneer in demonstrating neuroplasticity on actual cases, claiming that
healthy regions of the brain can take over the functions of injured parts of the brain. This was the
basis of his treatment for people who suffered vestibular damage.
Types:
1. Adaptive: when associated with a gain in function. It should be distinguished from
compensatory behaviors, which are behaviors that arise from mechanisms different from
those operative in the distributed neural networks that typically support behavior prior to
disease onset
2. Maladaptive: when associated with negative consequences such as loss of function or
increased injury.
Also classified as:
1. Structural
2. Functional
Structural neuroplasticity:
Refers to changes in the strength between neurons (synapses), chemical or electric
meeting points between brain cells.
Synaptic plasticity is a general term, and the name itself has no meaning other that
something changed within the synapse, but can include many specific processes such as
long-term changes in the number of receptors for certain neurotransmitters, or changes
where some proteins are being synthetized more within the cell.
Synaptogenesis refers to formation and fitting of synapse or group of synapses into a
neural circuit.
Structural plasticity is a normal marking of fetal neurons during brain development and is
called developmental plasticity, including neurogenesis and neuronal migration.
Neuronal migration is a process in which neurons travel from their ‘place of birth’ in
fetal ventricular or subventricular zone, towards their final position in the cortex.

3. During development, brain areas become specialized for certain tasks such as processing
signals form the surrounding areas through sensory receptors. For example, in occipital
brain area, the fourth layer of cortex hypertrophies in order to receive signals from the
visual pathway.
Neurogenesis is formation of new neurons. It is a process which mainly takes place
during brain development, even though in the last decade neurogenesis was found in
adult brain as well. On the other hand, neuronal death occurs throughout life, due to brain
damage or programmed cell death.
Other forms of structural neuroplasticity include changes in white or gray matter
density which can be visualized by magnetic resonance.
Functional neuroplasticity
Depends upon two basic processes, learning and memory.
They also represent a special type of neural and synaptic plasticity, based on certain types
of synaptic plasticity causing permanent changes in synaptic effectiveness.
During learning and memory permanent changes occur in synaptic relationships between
neurons due to structural adjustments or intracellular biochemical processes.
Neurobiological basis of neuroplasticity
When looking at neuroplasticity on molecular level, all types of synaptic plasticity share
neurotransmitter exocytosis modulation, on the level of one single synapse or among a
larger neuronal network.
Synaptic plasticity mainly depends on receptors binding neurotransmitters.
Mental events activate a large neural molecular cascade, including regulatory factors
referring to DNA and RNA.
↓
Within the cortex, glutamate receptors play the key role, as glutamate is the most
important excitatory neurotransmitter.
↓

4. If several impulses, from neighboring neurons, in a very short time, activation of
metabotropic glutamate receptors (NMDA) occurs.
↓
This enables calcium influx which participates in protein synthesis, and permanently
changes postsynaptic neuron.

5. Figure 1: summary of neuroplasticity.

6. HARNESSING NEUROPLASTICITY FOR CLINICAL APPLICATIONS
Central nervous system injury/stroke, mental/addictive disorders, paediatric/developmental
disorders and neurodegeneration/ ageing identified cardinal examples of neuroplasticity.
Promising therapies that may enhance training-induced cognitive and motor learning, such as
brain stimulation and neuropharmacological interventions, were identified, along with questions
of how best to use this body of information to reduce human disability
Improved means of assessing neuroplasticity in humans, including biomarkers for predicting and
monitoring treatment response, are needed.
Neuroplasticity occurs with many variations, in many forms, and in many contexts. However,
common themes in plasticity that emerge across diverse central nervous system conditions
include experience dependence, time sensitivity and the importance of motivation and attention.
Figure 2: Conceptual overview of the relationship between clinical phenotypes, neuroplasticity,
therapeutic interventions and assessment of function.

7. Remodeling of neuronal circuits following brain damage:
 After establishing the fact that brain has a possibility of remodeling its own neural
maps, the main question for neurorehabilation medicine is how to direct this
neuroplasticity to regain lost functions caused by a neurologic deficit.
 This emphasizes the need to neuroanatomically define every neurologic lesion.
 When we know which neural pathway is damaged, we can start looking for bypasses.
Movement rehabilitation
 When we learn complex movements, the brain firstly recognizes basic motoric
movements, and divides them and stores them into a given model which is then
remembered.
 The same network of neurons will activate every time we observe, think, or make
a certain movement, or hear sounds which remind us of that movement.
 If we focus on repetitive movements, it is important to understand the purpose of
the movement.
 For example, for a patient practicing hand pronation, the movement itself is not
the purpose; the purpose is for him to be able to open the door again.
 Plasticity after injury is often experience dependent.
 For example, recovery of language in a patient with post-stroke aphasia is
influenced by optimal language therapy
 This way we can stimulate other neuronal circuits which can lead to execution of
this final goal.
 Neurological rehabilitation must focus on expediency of the movement.
 This makes familiarizing with patient’s habits before stroke very important.
 Most complex movements that we perform, we were first observing during
childhood.
 It is helpful to repeat these movements during rehabilitation process.
 Ventral premotor cortex and base of parietal lobe are cortical areas belonging to
mirror neuron system. These areas have shown to be great neuroanatomical target
areas for rehabilitation exercises.

8.  The goal is to reach their activation through any connected healthy part of the
cortical network.
 The mirror neuron system will activate differently in every person, depending on
individual’s level of practice of specific movement.
 For example, if a patient played a guitar and danced tango prior to stroke, the
observation of these activities itself will strongly activate his mirror neurons,
which leads to stimulation of larger network area and reconnection of large
number of synapses.
Neuronal processing of different signals
 In 1821, a French soldier named Charles Barbier, visited a Royal institution
„night writing”, in Paris, presenting his invention, a code of 12 dots which offer
possibilities to soldiers to communicate and share information on the battle field,
without the need for speech. Usage of the code showed to be too difficult for
soldiers, but not for a blind boy from that institution, Louis Braille.
 Braille lowered the number of dots from 12 to 6, and published the first Braille
book in 1829. In 1839 he added mathematical and music symbols.
 How can a blind person process and translate position of the dots so fast?
 If the experience is changing dramatically or parts of the brain are damaged,
parts of the brain can change their function without structural changes.
 From this example, visual cortex in a blind person, if it’s not receiving
information from the visual pathway, it can process the sense of touch.
 Spontaneous intra-hemispheric changes, such as in representational maps, e.g. the
hand area can shift dorsally to invade the shoulder region
 Inter-hemispheric balance can shift such that the uninjured hemisphere has
supranormal activity in relation to movement
 Another principle is that not all plasticity has a positive impact on clinical
status—in some cases, plasticity might have negative consequences.
 For example, new onset epilepsy is a common complication of cerebral trauma,
often arising months to years after the insult. This delayed onset suggests that
progressive changes in the brain, such as axonal sprouting and the formation of

9. new connections, produce alterations in neuronal signalling and disinhibition that
result in the induction of seizures
 Other examples suggestive of maladaptive plasticity include chronic pain and
allodynia following injury to a limb (such as amputation) or to CNS (dorsal spinal
cord or thalamus), dystonia after various CNS injuries and autonomic dysreflexia
after spinal cord injury.
Neuropsychiatric disorders
 Similar to CNS injury with some differences.
 Mental and addictive disorders do not result from specific localizable lesions in the
nervous system, in contrast to the relatively well-defined lesions that occur in stroke and
trauma. Instead, these disorders are characterized by abnormalities in the distributed
limbic, prefrontal and frontostriatal neural circuits that underlie motivation, perception,
cognition, behaviour, social interactions and regulation of emotion.
 Also in contrast to stroke and trauma, the onset of mental and addictive disorders is
usually insidious; the course of illness tends to be chronic or recurring/episodic; recovery
in most of these disorders is slow when present; and relapse rates are high, with each
episode of illness increasing the likelihood of future episodes
 Mental and addictive disorders are known to have a strong neurodevelopmental
component and are associated with polygenic risk factors. However, their clinical
trajectories are also experience dependent, and so heavily influenced by environmental
and experiential phenomena such as stress, exposure to substance use, psychological
trauma, social attachments, internal representations of self and other sociocultural
influences such as the degree of early stress and of nurturing.
 Prefrontal cortical association areas are particularly noteworthy in relation to clinical
expression of neuropsychiatric disorders.
 Heightened neural sensitivity to specific triggers reflects plasticity in N-methyl-D-
aspartate receptor functioning in addiction
 Plasticity in neuropsychiatric disease can also arise as a consequence of therapy, as in the
maladaptive plasticity occurring in the form of tardive dyskinesia, associated with many
antipsychotic medications, particularly first-generation drugs.

10.  Maladaptive plasticity in subcortical reward circuitry, one that is highly resistant to
reversal, making it difficult to establish new behaviours compete with drug seeking
 Deep brain stimulation that disrupts focal pathological activity in limbic-cortical circuits
can reverse symptoms of treatment-resistant depression, and these antidepressant effects
are associated with plasticity in downstream limbic and cortical sites.
 At the cellular level, increased hippocampal neurogenesis, potentially reflective of
reparative events and thus plasticity, has been demonstrated in animal models with
antidepressant medications, electroconvulsive therapy and stress reduction techniques
such as environmental enrichment and exercises.
Paediatric congenital and acquired disorders:
 This superimposes injury on a developing nervous system that has a unique capacity for
certain forms of plasticity.
 Injury to the developing brain can modify synaptic mechanisms, change neuronal
activity, interfere with normal development and plasticity, or alter the range of activities
and experiences to which a child is exposed during development
 Many forms of neuroplasticity are at their maximum during early developmental stages
that are exclusive to the developing brain. For example, cross-modal plasticity, defined as
the ability of sensory maps to reorganize across afferent modalities when normal input is
deprived, has been described in humans who have sustained an early neural insult
 Too early the brain injury can impair subsequent plasticity
 Interaction of development with neuroplasticity occur.
 Developmental events, such as maturation of inhibition, extracellular matrix and
myelination, might also account for the closure of developmental critical periods with
their unique forms of plasticity
 Plasticity during development can also be adaptive or maladaptive.
 Adaption: Two cardinal examples of adaptive plasticity in relation to development are the
age-dependent recovery of language and motor functions following hemispherectomy for
intractable epilepsy And the ability to benefit from a cochlear implant in early childhood.
Congenitally deaf children appear to benefit most from cochlear implants within the first

11. 3.5 years of life, time during which the central auditory pathways show maximal
plasticity.
 Maladaption: lack of typical experience imposed by deafness results in a failure of proper
development of projections from secondary back to primary auditory areas, which
weakens important feedback loops
 Early-onset diseases of the nervous system often affect specific cell types or
neurotransmitter systems, which are reiterated across multiple brain regions and
functional domains, and which are important modulators of neuroplasticity. For example,
Down syndrome is associated with a general deficit of cholinergic function, several
motor disorders involve alterations of dopaminergic circuitry, and epilepsy may involve
deficits in GABAergic function. Likewise, hormonal (e.g. thyroid disease) and metabolic
(e.g. phenylketonuria) disorders can have diffuse effects on the developing brain.
Fortunately, some of these effects can be prevented with early detection and treatment.
 One of the most surprising findings of recent years comes from animal studies that
suggest that many genetic developmental defects, including those that affect neural
plasticity, can largely or completely be reversed in adult life by reversing the biochemical
defect
Neuroplastic changes in neurodegeneration and ageing:
 May represent pathogenic or compensatory responses, and are likely of functional
consequences, at least in their earlier stages
 Increased association cortex responsiveness in the early stages of Alzheimer’s disease
might reflect dynamic compensation for the impaired transmission of signals from
primary cortex processing centres. However, over time, such compensatory activity
might have detrimental consequences, possibly mediated by excitotoxic mechanisms.
Similar ideas have been advanced in other neurodegenerative conditions; for example, in
Huntington’s disease, the high frequency of synaptic activation required to maintain
medium-sized spiny neurons in an excitable state might render these cells more
susceptible to cellular stress
 Declines and reduced plasticity associated with normal ageing.

12.  Such age-related changes include reductions in processing speed, working memory and
peripheral nervous system functions, which may be associated with changes in brain
volume, white matter integrity, regional brain activation patterns and cellular function
NEUROPLASTICITY-BASED INTERVENTIONS
1. Non-invasive brain stimulation
o Two methods:
 Transcranial magnetic stimulation
 Transcranial direct current stimulation
o used for Stroke, hallucination
2. Deep brain stimulation:
 MOA: functional lesion via inhibition within the stimulated region and,
alternatively, that deep brain stimulation activates the neuronal network connected
to the stimulated region, leading to modulation of pathological network activity.
 Used for Parkinson’s disease, OCD, Tourette’s syndrome
3. Pharmacotherapies can increase neuroplasticity
 Through molecular manipulation of numerous cellular and synaptic pathways, such as
HDAC inhibitors, mTOR inhibitors and trkB agonists.
 D-cycloserine to significantly augment the effects of exposure/extinction therapy for
anxiety disorders by facilitating the activation of N-methyl-Daspartate glutamate
receptors.
 Behavioural gains induced by plasticity-promoting pharmacological interventions can
be lost, for example, with N-methyl-D-aspartate blockade or increased GABAergic
tone. Indeed, many classes of drugs can retard neuroplasticity
4. Physical training and exercise
 for brain & spinal cord injury
5. Cognitive training

13.  Can be thought of as a direct extension of physical therapy to the non-motor
aspects of the human brain and so has been examined across a number of disease
conditions.
 Used for depression, anxiety disorders, schizophrenia, ADHD
6. Feedback using real-time functional magnetic resonance imaging:
 Subjects can indeed learn volitional control over a specific brain region.
 For example, healthy subjects can be taught to control brain activity within the
anterior insula
7. Others:
 Appreciation of learning theory, Hebbian principles, task-specific training, social
influences, mechanisms of verbal encoding and the interplay across brain
modalities (such as influence of deafferentation on motor function).
Assessing neuroplastic capacity and monitoring circuit reorganization:
 Used both as Prognostic and Surrogate marker
 Example: fMRI, PET
ANESTHESIA & NEUROPLASTICITY
Chronic pain
MOA: by central sensitization and/or reorganisation. Via NMDA.
Rx: Ketamine, N2O, behavioral therapy
Prevention: periop adequate pain management
Example:
1. Phantom limb pain
2. Complex regional pain syndrome
3. Migraine
4. Tension headache
5. Fibromylagia

14. Role of preemptive analgesia
Anesthesia induced neuroplasticity & neurotoxicity in developing brain and aging brain
Sleep deprivation / alteration effect neuroplasticity
Scorpion sting and resistance to local anesthesia: receptor mutation
References:
1. Vida Demarin et al. Neuroplasticity. Period biol, Vol 116, No 2, 2014.
2. S. C. Cramer et al. Harnessing neuroplasticity for clinical applications. Brain 2011: 134;
1591–1609
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4. BJA