Neuroplasticity theory , pathophysiology, practical application neurology

1. NEUROPLAST
ICITY
DR VAROON VADODARIA
DNB NEUROLOGY
KMC MANGALORE
Every man can, if he so desires, become the sculptor of his own brain”
-Santiago Ramon y Cajal

2. NEURO
N

3. TYPES OF NEURONS TYPES OF SYNAPSES

6. Example of a Golgi-Cox
stained pyramidal cell from
layer III of the parietal cortex of
the rat.
A. Higher power magnification
showing spines on an apical
branch.
B. Higher power magnification
showing spines on a basilar
branch.

7. INTRODUCTION
Brain’s ability to change, remodel and reorganize for purpose of
better ability to adapt to new situations
Neural networks are not Fixed, but occurring and disappearing
dynamically throughout our whole life, depending on experiences.
Better ability to perform the practiced task with less waste of energy
‘use it or lose it’ principle.
Neuroplasticity is one fundamental process that describes any
change in final neural activity or behavioral response, or;
Neuroplasticity is an umbrella term for a vast collection of
different brain change and adaptation phenomena.

8. HISTORY
120 years ago, William James : theory of neuroplasticity in his work
Principles of Psychology
Polish neuroscientist Jerzy Konorski : 1st to define ‘neuroplasticity’ in 1948
: theory by which neurons which have been activated by closeness of an
active neural circuit, change and incorporate themselves into that circuit
Donald Hebb, a Canadian psychologist : Hebb’s rule : 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
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
Edward Taub, Michael Merzenich

9. Factors affecting
the synaptic
organization in
normal brain

10. Changes : Beneficial (restoration of function after injury), neutral (no change),
or negative (can have pathological consequences)
An injured brain could compensate for lost tissue: (1) reorganization of existing
neuronal networks; (2) development of novel networks; and (3) regeneration of the
lost tissue
Neuroplasticity is traditionally thought of as occurring in
3 phases, or epochs.
1.First 48 hours: Depending on the mechanism of the injury (such as stroke
or TBI), there is initial damage that cumulates as cell death with the loss of
certain cortical pathways associated with the lost neurons. The brain
attempts to use secondary neuronal networks to maintain function.
2.The following weeks: Recruitment of support cells occurs in this period as
the cortical pathways shift from inhibitory to excitatory. Synaptic plasticity
and new connections are made during this period.
3.Weeks to months afterward: The brain continues to remodel itself via axonal
sprouting and further reorganization around the damage.

11. 2 major mechanisms:
Neuronal regeneration/collateral
sprouting:
Synaptic plasticity and Neurogenesis.
Functional reorganization:
Equipotentiality, vicariation, and diaschisis

12. NEURONAL REGENERATION/COLLATERAL
SPROUTING
Synaptic plasticity: Synaptic plasticity is the ability to make
experience-dependent long-lasting changes in the strength
of neuronal connections
Concept of long-term potentiation

13. The theory of synaptic plasticity has also grown to include more of the
evolving complexity of synaptic communication.
These include:
Spike-timing-dependent plasticity (STDP):
This incorporates the timing of action potentials generated
by presynaptic and postsynaptic neurons to explain how
some synapses are strengthened, and others are weakened.
Metaplasticity:
This broadens the concept to include networks and involves
the activity-dependent changes that occur in synapses and
how they respond.
Homeostatic plasticity:
Mechanisms that maintain homeostasis of the synaptic
network over time.

14. DENDRITIC PLASTICITY
Intracranial self stimulation enhances dendritic
arborization of CA3 pyramidal neurons of the
hippocampus
Prolonged severe immobilization stress causes dendritic
atrophy of CA3 pyramidal neurons of the hippocampus

15. DENDRITIC SPINE PLASTICITY
Dendritic spines are tiny,
specialized postsynaptic receptive
sites that cover the surface of
many neurons and they serve as
major targets for excitatory
synaptic inputs onto principal
neurons in the hippocampus, the
neocortex and other brain regions

16. CYTOSKELETAL PLASTICITY
▸ Neurofilaments are neuron-specific intermediate filament proteins,
which constitute a major component of the neuronal cytoskeleton
and play a critical role in determining shape and volume of neuronal
processes including complex dendritic arborization and axonal
caliber
▸ Under normal conditions the neurofilaments in the neuronal
perikarya and dendrites are non - phosphorylated while in axons
they are phosphorylated

17. NEUROCHEMICAL PLASTICITY
Acetylcholine, noradrenaline, dopamine, gamma-amino butyric acid (GABA),
glutamate, serotonin, somatostatin and neuropeptides
▸ Monoamines and acetylcholine are involved in the formation of specific
dendritic morphology, lamination of cortex or the formation of
topographical afferent and efferent projections
▸ Effect of glutamate on survival, differentiation and metabolic activity of cultured rat
retinal ganglion cells
▸ Dopamine and GABA also modulated retinal ganglion cells (RGCs) survival,
diiferentiation and metabolic activity
▸ Acetylcholine is known to enhance the neuritic outgrowth and in tuning the nerve
growth cones
▸ Stress induced dendritic atrophy is mediated by corticosterone

18. GENES INVOLVED IN NEUROPLASTICITY AND
NEUROTRANSMISSION PATHWAYS
Brain-derived neurotrophic factor (BDNF) is a recognized regulator of synaptic
function, with structural and functional effects. P21- activated kinase (PAK) is
associated with the postsynaptic density
Cell adhesion molecule L1-like (CHL1) product guides migrating cells and
growing neurites during development and learning in adulthood
Sialyltranferase X (ST8SIA2) is involved in the regulation of the adhesive
properties of the neuronal cell adhesion molecule
Among genes related to neurotransmission, Serotonin receptor 2A (HTR2A)
and Catechol-O-methyltransferase (COMT) are known key factors involved in
neurotransmission, psychiatric disorders and the mechanism of action of
several psychotropic drugs
Homer 1 protein (HOMER 1) belongs to a family of scaffolding proteins
interacting with various post-synaptic density (PSD) proteins, where multiple
neurotransmitter converge
Related Orphan Receptor A (RORA) plays a role in several physiological
processes including circadian rhythm, with consistent evidence of involvement
in mood disorders

19. ADULT NEUROGENESIS
Adult neurogenesis is the concept that the brain
continues to make new neurons
Two proposed sites of adult neurogenesis in humans,
one in the olfactory bulb and the other in the
hippocampus.
Specific biomarkers that are associated with
developing neurons have been used to support the
idea of adult neurogenesis in humans

20. MECHANISMS FOR GRAY AND WHITE
MATTER CHANGES
GRAY MATTER
Neurogenesis
Gliogenesis
Synaptogenesis and changes in neuronal morphology
Vascular changes
WHITE MATTER
Myelin
Activity-dependent axonal sprouting, pruning or re-routing

21. Cellular events in gray
matter regions underlying
changes detected by MRI
during learning include
axon sprouting, dendritic
branching and
synaptogenesis,
neurogenesis, changes in
glial number and
morphology, and
angiogenesis.
Underlying cellular and molecular mechanisms

22. Changes in white matter
regions include alterations in
fiber organization, which
could include axon
branching, sprouting,
packing density, axon
diameter, fiber crossing and
the number of axons;
myelination of unmyelinated
axons; changes in myelin
thickness and morphology;
changes in astrocyte
morphology or number; and
angiogenesis
Underlying cellular and molecular mechanisms

23. FUNCTIONAL REORGANIZATION
Equipotentiality :
It is the concept that when one area of the brain is damaged,
the opposing side of the brain would be able to sustain the lost
function.
‘redundancy theory’
If the damage occurred very early, then the brain has the
potential to be able to overtake lost functions
Vicariation :
The brain can reorganize other portions of the brain to overtake
functions that they were not intended to.
 When a part of the brain overtakes a new and unrelated function

24. It is a concept that damage to one part of the brain could
cause a loss of function in another area due to some
connected pathway.
Proposed by Constantin von Monakow in an attempt to
explain why some people lost specific functions (such as
speech) but did not have a lesion in the area of the brain
thought to supply that function.
e.g. hypoperfusion of the ipsilateral thalamus after an acute
middle cerebral artery (MCA) stroke.
Diaschisis ‘at rest’: The classic von Monakow type such as
ipsilateral thalamic hypoperfusion in MCA stroke.
Functional diaschisis: This is when an area of diaschisis is
found when another part of the brain is activated.
E.g. when lesions affected the putamen, when given a
functional task of their ipsilateral hand, causes
hypoactivation of the ipsilateral cerebellums, which had no
signs of hypoactivation at rest.
Diaschisis

25. Connectional diaschisis:
This is when a loss of a part of the brain forces the
rerouting of information. This has been seen in rat models
where subcortical lesions can cause a decrease in
interhemispheric connectivity of the motor strips.
Connectome diaschisis:
As advanced imaging has shown the vast complexity of
connections between neurons, a map can be generated,
called a connectome.
This map shows that there are clusters of high connected
nodes which are then linked by a limited number of nodes
(hubs).
If damage is done to a hub, this can cause much more
severe damage then to a non-hub node.

28. FACTORS AFFECTING
NEUROPLASTICITY
AGE
There are four main types of neuroplasticity observed in children:
Adaptive: changes that occur when children practice a special skill
and allow the brain to adapt to functional or structural changes in the
brain (like injuries);
Impaired: changes occur due to genetic or acquired disorders;
Excessive: the reorganization of new, maladaptive pathways that can
cause disability or disorders;
Plasticity that makes the brain vulnerable to injury: harmful neuronal
pathways are formed that make injury more likely or more impactful
(Mundkur, 2005).
In Adults, It can restore old, lost connections and functions that
have not been used in some time, enhance memory, and even
enhance overall cognitive skills.

29. Early events, including prenatal events, can influence the
brain throughout life.
Area dependent : rats trained on a visuospatial : visual
cortex ; motor tasks : motor cortex
Time-dependent : large increases in spine density and
dendritic length 2weeks after cessation of cocaine
administration, these changes slowly disappear over a 4 m
period
Etiology : equivalent lesions of the sensorimotor cortex but
produced the damage either by arterial occlusion, vascular
stripping, or surgical suction.

30. FORMS OF BRAIN PLASTICITY AND THEIR
MEASUREMENT
At the cellular level
Changes in the number and/or strength of synapses that
can in turn be manifested at a neural network level as
reorganization of representational maps.
At the synaptic level
Increased dendritic spine formation, pruning, and
remodeling
Calcium channel regulation;
Changes in NMDA receptors
Changes in AMPA receptor trafficking.

31. AVAILABLE TECHNIQUES FOR STRUCTURAL
BRAIN IMAGING
Volumetry based on T1-weighted MRI
Voxel-based morphometry (VBM)
Diffusion-weighted MRI
Relaxometry
Magnetization transfer
Deformation-based morphometry
Analysis of sulcal morphology

32. PLASTICITY ACROSS
NEURAL NETWORKS IN
HUMANS CAN BE STUDIED
WITH A NUMBER OF
METHODS
•Transcranial magnetic stimulation (TMS)
•Transcranial direct current stimulation (tDCS).
•These techniques have been used to probe cortical excitability,
short interval cortical inhibition (SICI), intracortical facilitation
(ICF), paired associative stimulation (PAS), representational map
size, and movement directional targets
•Individuals with a greater capacity for synaptic plasticity,
dendritic branching, protein and RNA synthesis, synapse
formation, physiological changes, and map reorganization may
be more likely to experience greater behavioral improvements
following stroke

33. BENEFITS
Recovery from brain events like strokes
Recovery from traumatic brain injuries
Ability to rewire functions in the brain (e.g., if an area that
controls one sense is damaged, other areas may be able to
pick up the slack)
Losing function in one area may enhance functions in
other areas (e.g., if one sense is lost, the others may
become heightened)
Enhanced memory abilities
Wide range of enhanced cognitive abilities
More effective learning
Stroke Recovery ; TBI
Neuroplasticity Help with Depression? Negative + Positive Anxiety, ADHD, OCD,
and Autism ;Treating Chronic Pain

34. NEUROPLASTICITY AND REHABILITATION : 10 KEY PRINCIPLES
Use it or lose it. If you do not drive specific brain functions, functional loss will occur.
Use it and improve it. Therapy that drives cortical function enhances that particular function.
Specificity. The therapy you choose determines the resultant plasticity and function.
Repetition matters. Plasticity that results in functional change requires repetition.
Intensity matters. Induction of plasticity requires the appropriate amount of intensity.
Time matters. Different forms of plasticity take place at different times during therapy.
Salience matters. It has to be important to the individual.
Age matters. Plasticity is easier in a younger brain, but is also possible in an adult brain.
Transference. Neuroplasticity, and the change in function that results from one therapy, can augment the
attainment of similar behaviors.
Interference. Plasticity in response to one experience can interfere with the acquisition of other behaviors.

35. NEUROPLASTICITY INTERVENTIONS
Neuropharmacology
• Can increase neuroplasticity through molecular manipulation of numerous cellular
and synaptic pathways
• Growth promoting factors
• Granulocyte colony-stimulating factor
• Stem cell transplant :
A variety of pluripotent and multipotent stem cells have been harvested from fetal/embryonic
and adult tissue and shown to produce neuronal and glial phenotypes in culture.
▸ These include:
▹ Embryonic stem (ES) cells
▹ Primary cells, acutely isolated from proliferative zones in the developing and mature
CNS. Primary cells can be manipulated genetically or epigenetically
▹ Engineered cells and cell lines (with purposefully introduced genes)

36. PHYSICAL TRAINING AND EXERCISE
Mirror therapy, a technique used in phantom limb pain. In a basic
premise, the patent uses a mirror to cover their amputation and
focuses on watching their intact limb perform activities while imaging
that both limbs are performing the same activity. This has been shown
to have increased activation and functional connectivity in the
frontoparietal network

37. Constraint-induced
movement therapy (CIMT).
Used in patients with a stroke,
the premise is that by
constraining the functional
limb, the affected limb is
engaged in repetitive task
practice and behavioral
shaping.
Using functional magnetic
resonance imaging (fMRI)
technology, patients who
engage in this therapy have
been shown to have increased
activity in their contralateral
premotor and secondary
somatosensory cortex in
association with improved
function.

38. Body weight-supported treadmill training Bilateral arm training

39. Axonal regeneration following brain damage is restricted by myelin-associated
proteins, which signal via the Nogo-66 receptor (NgR), thereby reducing functional
recovery.
Therefore, temporary inactivation of NgR signalling in targeted brain areas could help
to boost plasticity
• Robotic devices
• Behavioural shaping
• Task-orientated physical therapy
• Aerobic exercise
Cognitive training
 An extension of physical therapy to the non-motor aspects of the brain
 Broad potential as part of rehabilitation therapy of patients with stroke

40. Intermittent fasting: increases synaptic adaptation, promotes neuron
growth, improve overall cognitive function, and decreases the risk of
neurodegenerative disease;
Traveling: exposes your brain to novel stimuli and new
environments, opening up new pathways and activity in the brain;
Using mnemonic devices: memory training can enhance connectivity
in the prefrontal parietal network and prevent some age-related
memory loss;
Learning a musical instrument: may increase connectivity between
brain regions and help form new neural networks
Non-dominant hand exercises: can form new neural pathways and
strengthen the connectivity between neurons
Rewiring Brain with Neuroplasticity

41. Reading fiction: increases and enhances connectivity in the brain
Expanding your vocabulary: activates the visual and auditory processes
as well as memory processing
Creating artwork: enhances the connectivity of the brain at rest (the
“default mode network” or DMN), which can boost introspection,
memory, empathy, attention, and focus
Dancing: reduces the risk of Alzheimer’s and increases neural
connectivity
Sleeping: encourages learning retention through the growth of the
dendritic spines that act as connections between neurons and help
transfer information across cells (Nguyen, 2016).

42. Maladaptive plasticity:
Maladaptive plasticity is when a connection that is made
in the brain produces aberrant or negative symptoms.
This can be seen in the examples of use-dependent
dystonia (writer’s cramp) and phantom limb pain.
Both of these examples have shown abnormal primary
sensory cortex changes in association with painful
symptoms

43. NEUROPLASTICITY – CLINICAL TRIALS
Very few large multicentre RCTs in the area of physical rehabilitation following stroke
Extremity Constraint Induced Therapy Evaluation (EXCITE)
 Tested effect of constraint therapy in 224 patients 3-9 months post stroke and with mild-
moderate upper limb impairment
Robot-Assisted Upper-Limb Neurorehabilitation in Stroke Patients
(ULRobot)
 Tested effect of robot-assisted therapy in 127 patients more than 6 months post stroke and
with moderate-severe upper extremity impairment
Locomotor Experience Applied Post-Stroke (LEAPS)
 Tested the effect of locomotor training in 408 patients more than 2 months post stroke and
with moderate-severe walking impairment
Only the EXCITE trial demonstrated a clear superiority of the experimental intervention compared to
the control group, but all interventions were superior to usual care

44. A Randomised Controlled Trial of Efficacy of Cognitive Rehabilitation in
Multiple Sclerosis: A Cognitive, Behavioural, and MRI Study :38 patients with
MS and cognitive impairment on the Brief International Cognitive
Assessment for MS (BICAMS) were enrolled. UK 2016
Effects on Balance and Walking with the CoDuSe Balance Exercise
Program in People with Multiple Sclerosis: A Multicenter Randomized
Controlled Trial. 73 participant. Sweden 2016
Everest Trial :Epidural Electrical Stimulation for Stroke Rehabilitation
Post hoc comparisons indicated treatment effect differences at 24 weeks,
with the control group showing significant decline in the combined primary
outcome measure relative to the investigational group. US 2015
Post-stroke Rehabilitation Training with a Motor-Imagery-Based Brain-
Computer Interface (BCI)-Controlled Hand Exoskeleton: A Randomized
Controlled Multicenter Trial :adding BCI control to exoskeleton-assisted
physical therapy can improve post-stroke rehabilitation outcomes. Russia
2017

45. ENGINEERED NEUROPLASTICITY
The next generation of neural devices operate in a close-loop framework.
These devices sense symptom onset and stimulate only when needed.
Transcutaneous stimulation be tested prior to undergoing surgery to
implant an epidural stimulation electrode.
Epidural stimulators are approved for the treatment of chronic pain
Closed-loop implantable brain stimulators
NeuroPace recently received approval for an implant to treat epilepsy
Medtronic is testing several low channel-count devices for treatment of
essential tremor and Parkinson disease.
Both startup (e.g., Neuralync, Kernel) and established companies (e.g.,
Galvani/GSK/Google) are ramping up to produce more complex closed-loop
devices, which are expected to emerge in the next 5–10 years to enable
specific and targeted engineered neuroplasticity.

46. Combinatorial Therapies to Enhance Plasticity and CNS Recovery
Neural stem cell grafts hold great promise for restoring function to
degenerating or damaged neural tissue. Approaches involve neuron cell
replacement, remyelination, and environment modulation.
Engineered devices in combination with stem-cell therapies offer the
potential to create appropriate and targeted neural activity, thereby
synchronizing the host and graft to promote the formation of functional
connections.
Pharmacological interventions may generally enhance neuroplasticity, while
engineered devices can collaborate to shape this plasticity into specific and
functional circuits
E.G bacterial enzyme chondroitinase ABC (ChABC), known to dissolve
perineuronal nets, thereby enhancing plasticity.
Combination of ChABC and an anti-body treatment to restrict the Nogo
signals in myelin resulted in even greater recovery

47. THANK YOU