Neuroplasticity

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Brain: Important Facts

• CNS begins from 2 • Uses 20% of the body weeks gestation energy • At birth, human brain • Consume 20 % of the weighs 350 g, at 1 year body oxygen 1000 g • All parts of brain are ISTE 2012 • 10% of the cells are involved in learning, neurons (100 billion) some more than other • Each neuron makes 1,000 to 20,000 connections

Tractography of Whole Brain Brain Growth

• The number of neurons that a child is born with is largely fixed around four months before birth. • The most important mechanisms involved in the massive brain spurt that occurs in the early years of life are: – Myelination – Production of glial cells – Synaptogenesis: Formation of new synapses Copyright@ Pradip Ghosh 2019 3 Copyright@ Pradip Ghosh 2019 4

Neuroplasticity Developmental Plasticity vs Adaptive Plasticity Developmental Plasticity Adaptive Plasticity • It can be described as brain’s ability to reorganize Definition Changes in neural connections as a The brain’s ability to compensate result of interactions with the for lost functionality due to brain itself by forming new neural connections throughout environment (our experiences during damage as well as in response to the life. childhood) as a consequence of interaction with the environment developmental processes. by reorganizing its structure • Neuronal connections are continuously being created e.g. Development of visual cortex and broken and all modeled by our experiences, and Occurs in It is predetermined and occurs in Compensation for brain injury our states of health or diseases. response to response to the initial processing of and in adjustment to new sensory information by the immature experiences. • Neuroplasticity allows neurons in the brain: brain

– To adjust neural activities in response to new situations or Neuronal Synaptogenesis, synaptic pruning, Sprouting to changes in their environment (developmental plasticity) changes neural migration, myelination Rerouting – To compensate the loss from injury and neural diseases When it occurs Over the lifespan, but diminishes with Over the lifespan, but is more (adaptive plasticity) age efficient and effective during infancy/early childhood

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Neuroplasticity Neuroplasticity in Normal Brain

• It involves forming neuronal connections (synapses • It is now clear that mammalian brain is and pathways) in response to information derived capable of change throughout the life time in from experiences in the environment, sensory stimulation, and normal development. response to the environment and subsequent sensory experience. • Plasticity occurs on a variety of levels: – Cellular changes involved in learning – Large-scale changes involved in cortical remapping in • Numerous research studies examined the response to injury effects of sensory and social stimulation • Widely recognized forms of plasticity are learning, memory, and recovery from brain damage through enrichment of environment on the

rodent brain.

Neuroplasticity in Normal Brain Neuroplasticity in Normal Brain: Environment and Neuroplasticity Synaptogenesis

• Environmental stimulation and exercise has • Black et al in 1990 examined the cerebellar neurons of rats after placing them in 4 housing conditions. significant influence in neuroplastic changes – Obstacle course (AC) in the brain. – Forced treadmill exercise (FX) • – Voluntary running wheel (VX) Van Praag and his group have shown – In a cage (IC) increased number of neurons in the • Observations: hippocampus when mice were housed in – increased capillary density in the cerebellum of rats from FX and VX. enriched environment with free access to the – increased synapses per neuron of the Purkinje cells of cerebellum of rats from AC running wheel. • Van Praag H, Kemperman G, Gage FH. Nature Neurosci 1999; 2: 266-270 Black JE, Isaacs KR, Anderson BJ, Alcantara AA, Greenough WI. Proc Natl Acad Sci 1990; 87: 5568-72

Neuroplasticity in Normal Brain Neuroplasticity in Normal Brain Synaptic Configuration Enriched Environment

• Plastic changes in the brain are associated with changes in synaptic configurations.

• Comery et al conducted studies by housing one group of rats in a toy- and object-filled environment and by keeping the other group in the standard cages for 30 days.

• They observed an increased number of bifurcating and multi- headed spines in neurons of the caudate nucleus of rats housed in enriched environments.

Comery TA, Stadmondia CX, Irwin SA, Greenough WT. Neurobiol Learn Mem. 1996; 66: 93-96 Copyright@ Pradip Ghosh 2019 11 Copyright@ Pradip Ghosh 2019 12

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Neuroplasticity in Normal Brain Neuronal changes in the Brain Changes in the strength of Synaptic Connections

Role of BDNF on Reaching Functions after Role of BDNF on Reaching Functions after Focal Focal Ischemia Ischemia

• It is also known that exercise can increase brain Infused antisense BDNF to lateral Rehabilitation derived neurotrophic factor (BDNF) in the brain ventricle after inducing ischemia in (Running, (Neeper et. al, 1995) one group of rats while no infusion Skilled to the 2nd group (control) reaching)

• Ploughman et al tested the hypothesis by evaluating the contribution of BDNF to motor skill relearning after endothelin-1–induced middle Found reaching skills Rats ran for 10 min in cerebral artery occlusion in rats. diminished in antisense BDNF motorized running infused rats while reaching wheel followed by Neeper SA, Gomez-Pinilla F, Choi J, Cotman C. Nature. 1995; 373: 109 improved in non infused rats reach training Ploughman M, Windle V, MacLellan CL, White N, Doré JJ, Corbett D. Stroke. 2009;40:1490-1495

Plastic Changes in Human Brain Influence of Repetitive Movements • Motor tasks are accomplished by using repetitive sensory feedback to learn and refine the skill. • Pascual-Leone et al trained adult human volunteers on finger/thumb repetitive movements. • Observations: – Training groups had progressively larger cortical output to the involved muscles along with improved performance.

– They also observed an increase in cortical map size followed by a subsequent decrease to baseline after the motor sequence was learned indicating possible contribution of other brain structures rather than primary motor cortex.

• Pascual-Leone A, Grafman J, Hallerr M. Science 1994; 263: 1287-89 Copyright@ Pradip Ghosh 2019 17 Copyright@ Pradip Ghosh 2019 18

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Plastic Changes in the Human Brain Plastic Changes in the Human Brain Deafferentiation Influence of Immobilization • Brasil-Neto and associates examined the speed and topography of cortical plasticity during short term • Liepert et al examined individuals with ankle deafferentiation using blood pressure cuff on the arm and immobilization following ankle injury with no peripheral leg of human subjects. nerve damage. • They have shown a decreased cortical map representation • They found an increased motor evoked potential (MEP) from for the tibialis anterior muscle. the proximal muscles to the tourniquet within minutes. • So, cortical maps change on a daily and even minute-to minute basis depending on increase or decrease in sensory • They also observed an enlarged cortical representation area input and motor activity. for those proximal muscles. • Therefore movement along with sensation from periphery is essential for maintaining cortical map. Brasil-Neto JP, Cohen LG, Pascual-Leone A, Jabir FK, Wall RT, Hallett M. Neurol 1992; 42: 1302-06 Liepert J, Tegentoff M, Malin JP. Electroencephal Clin Neurophysiol 1995; 97: 382-86

Plastic Changes in Grey Matter Thickness Plastic Changes in Grey Matter Thickness

3 months of intensive juggling training is performed in a  Licensed London taxi drivers with extensive navigation group of 12 individuals whereas 12 controls are experience were analyzed and compared with those of control subjects who did not drive taxis provided as “non-jugglers” (experiment: 3-ball cascade juggling)  Voxel-based morphometry was employed to reveal fine changes of grey matter volume on anatomical MR images Voxel-based morphometry was employed to reveal fine changes of grey matter volume on anatomical MR  Key findings were: images  The posterior hippocampi of taxi drivers were significantly larger  Hippocampal volume correlated with the amount of time Transient changes take place in grey matter in specific spent as a taxi driver (positively in the posterior and motion-selective areas. negatively in the anterior hippocampus)

Draganski B, Gaser C, Busch V, Schuierer G, Bogdahn U, May A . Nature 2004; 427: 311-312 Maguire EA, Gadian DG, Johnsrude IS, Good CD, Ashburner J, Frackowiak RSJ, Frith CD Proc Natl A Sci 2000; 97: 4398-4403.

Two current concepts Types of Neuroplasticity Type Mechanism Duration Enhancement of existing Formation of new connections connections 1. Enhancement of existing connections A. Synapse development Physiological ms-1 to hours B. Synapse strengthening Biochemical hours to days

2. Formation of new connections A veryVery active researchresearch area; area; concepts concepts are are continually continually being being updated updated A. Unmasking Physiological minutes to days B. Sprouting Structural days to months

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Enhancement of existing connections

• Increased use of a synapse in existing pathways e.g. learning a new task . – The more we do something (ex: practice for Increased afferent input skilled activity), the more synapses will be used + and more synapses can be developed + New synapses evolve leading to • + Alternative pathways following damage increased – If one pathway gets damaged, the alternative excitation pathways will be activated and used to compensate.

Synapse strengthening

Effectiveness of a synapse can be increased due to change in the structure to enhance transmission 1. Seconds and minutes (short-term memory) 2. Hours and days (intermediate-term memory) 3. Months and years (long-term memory)

Such changes can take place at three cellular locations:

Ragert et al., 2004 1. Presynaptic terminal 2. Postsynaptic membrane A study looked at cortical plasticity in piano players and found that the fingers and 3. Postsynaptic nucleus 28 hand were over representedCopyright@ in the sensorimotor Pradip Ghosh cortex . 27 Copyright@ Pradip Ghosh 2019 2019 Kidd et al., 1992

Formation of new connections

Two point discrimination threshold in pianists index finger Unmasking of pre-existing pathways

Sprouting of new pathways

Ragert et al., 2004

R L

Comparison of musicians to non-musicians Findings were long-lasting piano practising resulted in lower spatial discrimination thresholds in the index finger of piano players in comparison to non-musicians. This decrease in threshold was related to the number of hours practiced per day (>3 hours), not to the numberCopyright@ of years Pradip they Ghosh had been 29playing 2019

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Possible reasons for some silent synapses Parallel pathway; neurons with a comparable role

Inhibited by dominant pathways Too little transmitter Dominant pathway Subservient pathway + Too few receptors on post- + synaptic membrane Don’t fire with other inputs

Cell body Sprouting occurs following damage or Lesion to Subservient pathway is dominant denervation to the unmasked pathway Axon nervous system and

+ is the growth of new + axons from from adjacent neurons Activity is forming new continued pathways despite lesion

INJURY INJURY The release of Following nerve growth Neurite induced denervation, factors to sprout by NGF neurotrophic factors stimulates lesion lesion or nerve growth neurites or new factors are released, axons to sprout Nerve they are polypeptides NGF Growth and look for capable of promoting Factor the source of neuronal survival. (NGF) the NGF

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Changes in the Brain

Injury results in cell death • Structural change • Synaptic plasticity • Synaptogenesis • Neuronal migration • Neurogenesis Cell is re-innervated from alternative • Biochemical change stimulus • Nucleic acid synthesis Sprouting may be a means of recovery; it may also produce • Protein synthesis unwanted effects For example spinal cord injury patients may

experience strange sensations. Copyright@ Pradip Ghosh 2019 38

Neuronal Migration Neuronal Migration

• In the adult brain, neuroblasts (immature neurons) are continuously generated in the ventricular-subventricular zone (V-SVZ).

• These neuroblasts migrate rapidly to the olfactory bulb, where they mature and are integrated into the neuronal circuitry.

• After a brain injury, neuroblasts migrate to the injury site and differentiate into functional neurons (Yamashita et al. 2006).

Yamashita, T., Ninomiya, M., Hernandez Acosta, P. et al. J. Neurosci. 2006: 26: 6627– 6636. Copyright@ Pradip Ghosh 2019 39 Copyright@ Pradip Ghosh 2019 40

Neurogenesis Neurogenesis • Under normal condition, neural progenitor • It is the process by which neurons are cells (NPC) in the brain is less active and their generated from neural stem cells. numbers are less. • Recent studies show that neurogenesis continues to occur in the adult mammalian • NPC activity needs to be up in order to brain and can persist well into old age. produce new neurons. – This appears to occur in the hippocampus, olfactory bulb, and cerebellum. – In the rest of the brain, neurons can die, but • Different stimuli including sensory, chemical cannot be formed. play a role in neurogenesis.

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Neuroplasticity: Balancing Inhibition Animation of Plastic Brain and Excitation

• In the cortex GABA is inhibitory, glutamate is excitatory • Reduced activity at GABAergic interneurons allows plasticity in adults • Enhanced glutamatergic signaling leads to LTP • So, altering the balance of inhibition/excitation is important in reopening new periods of plasticity in adult cortex

Reorganization of Brain Reorganization of Brain

• Brain activity associated with a given • Brain remodeling: Brain remodel is based on function can move to a different location. – Repetitions • This concept allows for the treatment of – Functional Movement acquired brain injury. – Environment • The adult brain is not hard-wired with fixed • Synaptogenesis and synaptic pruning: neuronal circuits. • New connections are formed based on • Cortical and subcortical rewiring of neuronal repetitions of tasks. If neuronal circuits happens in response to training and connections and pathways are not used, in response to injury. they will be lost.

The Role of Movement Therapy How? • Provide positive sensory input. 1. Strengthen and develop – Appropriate handling normal synapses – Sensation through purposeful movement • Facilitate “functional” movement. Therapists need to 2. Guide axonal sprouting – Promote repetition of functional and goal directed movement. – 3. Facilitate unmasking of Challenge individual based on tolerance. – alternative or previously Promote active participation subservient pathways • Provide treatment at “optimum” time • Education

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How Does Rehabilitation Help in Cortical Reorganization Regaining Functions? • Dendritic arbors increased in the unaffected brain and increases the number of • Sensory stimulation through movement that synapses (top picture) uses proprioception, kinesthetic sensation, • Researchers found that tactile sensation. dendritic arbor retracts • Supports new connections in the brain when injured brain stops receiving afferent signals especially in the hippocampus (memory) (bottom picture) causing • Prevents secondary cascade in the brain maladaptive response following injury after injury

Exercise and Activities: Role in Vascular Injury: Stroke Neuro-rehabilitation • Exercise or functional activities 1. Reduces the rate of cognitive decline. 2. Keeps the brain cells more active 3. Increases the formation of BDNF in the brain (acts as brain fertilizer) 4. Reduces the risk of neurodegeneration 5. Reduces the risk of dementia 6. Improves stress tolerance

Brain Excitability after Stroke Brain Excitability after Stroke

Uptake of GABA is Periinfarct cortex Increased level of Increased Periinfarct cortex reduced by Increased extracellular Stimulation reactive neuronal Hypo-excitability GABA (edogenous or BNDF signaling astrocytes exogenous) excitability

Decreased Diminished Tonic neuronal Increased inhibition Synaptogenesis recovery excitability Recovery

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Brain Excitability after Stroke: Yin and Yang Stroke Progression Consequences in the Brain Following Stroke Arch Neurol. 2012; 69(2): 161-167

• It is an established fact that “adverse Impaired blood flow, Primary Insult Secondary Insult metabolic imbalances, influences” such as stress, depression, and (Pathophysiological Tissue damages, (Primary damage) Processes) Membrane chronic GC treatments may cause shrinkage of permeability the hippocampal formation [23].

• This may be due to the changes in the tissue Inflammation, such as reductions in neuronal dendrites. Axon terminal Cell depolarization, release of excitatory Death neurotransmitters, Intracellular breakdown

Spontaneous Recovery Vs Function after Stroke Training Induced Recovery

Time I Copyright@ Pradip Ghosh 2019 57 Copyright@ Pradip Ghosh 2019 58

Neuroplasticity After Stroke Neuroplasticity and Rehabilitation Changes in residual functional architecture Following Stroke

affected • Stroke is a leading cause of chronic disability through A side the world. • Impairments and movement limitations in upper extremity are more prevalent in post stroke 10 days 17 days 24 days 31 days 3 months infarct post stroke post stroke post stroke post stroke post stroke disabilities. B affected side • Compensatory reliance on the nonparetic hand exacerbates impairments in the paretic side by encouraging its disuse and for further inhibition on the affected brain through interhemispheric mechanisms.

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Neuroplasticity and Rehabilitation Neuroplasticity and Rehabilitation Following Stroke Following Stroke • Movement therapy approaches are the main tools • There are windows of opportunity to drive during rehabilitation after stroke and brain injury. functional reorganization of brain through • The efficacy of rehabilitation following stroke functional based movement training. depends on multiple factors (age, intensity, • frequency, early vs late etc). As well as there are windows of vulnerability for keeping the brain less functionally active. • Ischemic injury triggers prolonged periods of both structural and functional reorganization. • So questions are • Early after stroke, changes in the brain are more – When is the “early”? dynamic and promoting functional reorganization is – When is it safe? crucial.

Plastic Changes Following Stroke Neuroplasticity and Rehabilitation Following Stroke New axonal growth surrounding • Considerable variability in neural remodeling ischemic area time courses can be expected between individuals and across brain regions (Riley et al)

Post stroke hyper • It is important to note that earlier is not better excitability Reduced GABA always for everything. STROKE mediated surrounding inhibition lesion area • Peri-infarct tissue is vulnerable to use-dependent excitotoxicity in very early periods after stroke (Humm et al, 1998)

Unmasking of • Riley JD, Le V, Der-Yeghiaian L, See J, Newton JM, Ward NS et al. Stroke 2011; 42: 421-426 ipsilateral pathways • Humm JL, Kozlowski DA, James DC, Gotts JE, and Schallert T. Brain Res. 1998; 783: 286-292

Skill Learning Neural Remodeling

• Manual skill learning depends on practice dependent • Neuronal loss in the core of ischemic injury structural and functional reorganization of motor leaves connected region partially cortex (Dayan and Cohen, 2011) denervated. • The developing brain depends on external stimuli to shape neural circuitry patterns via mechanisms of • Synapse densities around infract also synaptic competition. decline and then recover over time to • Here most effectively activated neural connections varying degrees depending on proximity to are selectively maintained and matured and those the infarct core (Sigler and Murphy, 2010). less well activated are eliminated • Sigler A, and Murphy TH. Stroke 2010; 41: 117-123 • Dayan E, and Cohen LG. Neuron 2011; 72: 443-454

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Neural Remodeling Glial Remodeling

• Post ischemic reactions of neurons and astrocytes • Goal directed ovement therapy (MT) can induce are tightly coordinated. growth permissive environment that promotes • axonal sprouting and synaptogenesis from Astrocytes are intricately involved in synaptic plasticity (Eroglu and Barres, 2010). remaining projections leading to re-innervation. • Astrocytes release thrombospondins to promote • Rehabilitation through MT and other treatments synaptogenesis (Eroglu et al, 2009), release may also cause persistent alterations in excitatory cholesterol to promote synapse maturation (Goritz and inhibitory activity patterns (Zeiler et al, et al, 2005). 2013). Eroglu C, and Barres BA. Nature 2010; 468: 223-231 Zeiler SR, Gibson EM, Hoesch RE. Li MY, Worley PF, O’Brien RJ et al. Stroke 2013; 44: 483-489 Eroglu C, Allen NJ, Susman MW, O’Rourke NA, Park CY, Ozkan E et al Cell 2009; 139: 380-392 Goritz C, Mauch DH, and Pfrieger FW. Mol Cell Neurosci 2005; 29: 190-201

Glial Remodeling Vascular Remodeling

• Ischemic stroke results in areas of reduced cerebral blood • Astrocytic behavior is neural activity and flow (CBF) and capillary density. experience dependent (Theodosis et al, 2008). • With time, proangiogenic factors elevated to promote • Astrocytic reactions to denervation in motor angiogenic micro envirenment for making neuronal cortex are elevated by forced forelimb use in connections. rats (Bury et al, 2000) • Sufficient blood flow is essential for activity dependent neural remodeling. • Whitaker et al have shown that sensory stimulation • Theodosis DT, Poulain DA, and Oliet SH. Physiol Rev. 2008; 88: 983-1008 • Bury SD, Eichhorn AC, Kotzer CM, and Jones TA. Neuropharmacol 2000; 39: 745-755 starting after 3 days of cortical ischemia in mice can promote angiogenesis and CBF recovery.

• Whitaker VR, Cui L, Miller S, Yu SP, and Wei L. J Cereb Blood Flow Metab 2007; 27: 57-68

Neuro-regeneration Time Earlier Intervention is Better • Time courses and magnitudes of astrocytic and • Several studies support the fact that motor vascular reactions to injury are altered with age rehabilitation training (MRT) is more effective if initiated earlier after stroke. (Popa-Wagner et al 2011), injury severity (Kim and Jones, 2010). • Nudo and his group have reported that MRT beginning within 1 week of motor cortical infarct in • Aging involves brain changes including reductions monkeys spares the paretic hand representation of in synaptic density, demyelination and increased motor cortex compared with controls. vulnerability in synaptic connectivity (Hof and • This effect gets lost if training is delayed until 30 days Morrison, 2004) post-infarct (Barbay et al 2006) • Popa-Wagner A, Buga AM, and Kokaia Z. Ageing Res Rev. 2011; 10: 71-79 • • Kim SY and Jones TA. Synapse 2010; 64: 659-671 Nudo RJ, Wise BM, SiFuentes F, and Milliken GW. Science 1996; 272: 1791-1794 • • Hof PR, Morrison JH. Trends Neurosci. 2004;27:607–613. Barbay S, Plautz EJ, Friel KM, Frost SB, Dancause N, etal Exp Brain Res. 2006; 169: 106-116

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Earlier Intervention is Better Early in not Better for Everything • Researchers support the fact that highly intense physical • In humans, initiation of interventions within 4 days of activity very early after injury onset can be risky. stroke are associated with reduced disability at the time of hospital discharge compared with later interventions • Schallert and colleagues discovered that forced use of a (Matsui et al, 2010). paretic limb via constraint of the nonparetic limb can be detrimental if done too early (Schallert et al 2003). • Lang and her group have shown that initiation of CIMT within 3-9 months post stroke enhaces performance in • In humans, initiation of high intensity CIMT after 10 days of several fine motor tasks compared to delayed (>9 stroke can decrease the functional improvement compared months) initiation of CIMT. with the lower intensity treatment (Dromerick et al, 2009).

• Matsui H, Hashimoto H, Horiguchi H et al. BMC Health Serv Res. 2010; 10: 213 • Schallert T, Fleming SM, and Woodlee MT. Med Rehabil Clin N Am. 2003; 14: 27-46 • Lang KC, Thompson PA, and Wolf SL. Neurorehabil Neural Repair 2013; 27: 654-663 • Dromerick AW, Lang CE, Birkenmeier RL, Wagner JM et al. Neurology 2009; 73: 195-201

Functional Movement and Neuroplasticity Neuroplasticity and Motor Learning • Researchers support the fact that functional movement • Movement therapies which induce cortical based therapy can promote both structural and reorganization are based on the principles of motor functional organization of brain following stroke. learning.

• Richards and colleagues have reported that functional • Sprouting of dendrites, formation of new synapse, movement based therapy induces neural changes in the alterations of existing synapse take place during sensorimotor cortex of the lesioned hemisphere (fMRI, motor learning. PET and TMS) and changes accompany the gains of motor functions in the paretic upper extremity (Richards et al, 2008) • If practice is meaningful, repetitive and intensive in

Richards LG, Stewart KC, Woodbury ML, Senesac C, Cauraugh JH Neuropsychologia 2008; 46: 3-11 nature, changes will be greater and retention will be long lasting.

True Motor Recovery vs Compensatory Neuroplasticity and Motor Learning Motor Recovery • If we ask our clients following stroke to reach for a • True motor recovery occurs when undamaged or glass filled with water in order to attempt to drink alternative pathways send command to the involved (meaningful) 30 times (repetitive) and 3 times daily muscles following stroke or brain injury. (intensive), individual will gain more permanent elbow extension that can be used for other • This may be due to the redundancy of motor cortical functional tasks. areas with unmasking of pre-existing cortico-cortical connections (Teasell et al, 2005). • Therefore, stroke rehabilitation methods should consist of intensive and repetitive practice of • Compensation is the use of alternative muscles to meaningful tasks. accomplish the task goal

• Teasell R, Bayona NA, Bitensky J. Top Stroke Rehabil 2005; 12: 11-26 Copyright@ Pradip Ghosh 2019 77 Copyright@ Pradip Ghosh 2019 78

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Task Specific Training and Task Specific Training and Neuroplasticity Neuroplasticity • Task specific training (TST) emphasizes the practice and • It has been observed that functional recovery is associated repetition of skilled motor performance to improve with the changes in cortical activation pattern. functional abilities. • Researchers recorded brain activities using fMRI after TST • TST may restore functions by using spare parts of the and showed decreased activation in the unaffected brain brain which are generally adjacent to the lesion or by and increase activity in the affected primary sensorimotor cortex (Jang et al 2003). recruiting supplementary part of the brain (Nudo et al, 2000). • Another group of researchers observed increased activation in the contralesional cerebrum and ipsilesional cerebellum in • TST induces long lasting motor learning through cortical response to repetitive bilateral arm training (Luft et al, reorganization (Harvey, 2009). 2004).

• Nudo RJ, Friel KM, Delia SW. Neuropharmcol 2000; 39: 733-742 • Harvey RL. Curr.Treat. Options Cardiovasc Med. 2009; 11: 251-259 • Jang SH, Kim YH, Cho SH, Lee JH, Park JW, Kwon YH. Neuroreport 2003; 14: 137-141

Task Specific Training and TST and Environment Neuroplasticity • Environment for the training is also important in motor • Langhammer and Stanghelle compared the effects learning and cortical reorganization. of motor relearning program between task oriented strategies and Bobath techniques using • Training with enriched environment improves the facilitation/inhibition strategies. performance as it provides individual with clear understanding of what is being expected of them during task specific training (Davis 2006) • They found patients showed better results on motor functions with task oriented strategies when • For example, an individual would stand for a longer period of compared to Bobath techniques (Langhammer and time if he/she brushes his/her teeth in front of the Stanghelle, 2000). washbasin compared to someone who stands without doing nothing. • Langhammer B, Stanghelle JK. Clin Rehabil 2000; 14: 361-369 • Davis JZ. Top Stroke Rehabil. 2006; 13: 1-11

Gait Training with Gait Training Sling TST with FES and Repitition

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Repitition of Functional Movement TST, Repetition, Enriched Environment using Saeboflex • Therefore, rehabilitation program for patients with stroke should include repetitive task-specific movement training in an enriched environment in order to promote cortical reorganization, motor and functional recovery.

Mental Practice and Cortical PET/MR Scan: Physical Movement Vs Reorganization Imagined Movement

• Mental practice or motor imagery is an act of • This image illustrates that a similar network of cerebral producing an internal representation of a movement structures (e.g., premotor without generating any motor output. cortex) is activated when normal control subjects • It is the imagination of movements of body parts execute physically or imagine a sequence of up-down foot when individual cannot move due to hemiparesis. movements. • Brain mapping techniques have shown the activation • This suggests that mental practice with motor imagery of the motor cortex and other associated areas can be used as a therapeutic approach to keep active the during imagery as well as during execution of neural circuits involved during movement (de Vries and Mulder, 2007). practice and hence facilitating the rehabilitation of patients • De Vries S, Mulder T. J Rehabil Med. 2007; 39: 5-13 who sustained damage to the brain. Copyright@ Pradip Ghosh 2019 87 Copyright@ Pradip Ghosh 2019 88

Watching the Brain In Action: Functional Neuroimaging Mental Practice and Cortical Reorganization • Studies have shown that mental practice (30 min therapy sessions + 30 min mental

Generating practice) can lead to activation of premotor Verbs area and primary motor cortex ipsilateral and contralateral of the affected hand as well as

Speaking superior parietal cortex ipsilateral to the words affected hand following stroke (Page et al, Hearing words 2009) Seeing words Page SJ, Szaflarski JP, Eliassen JC, Pan H, Cramer SC. Neurorehabil Neural Repair 2009; 23: 382-388

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Mental Practice and Cortical Motor Imagery Using Mirror Box Reorganization • It is well known that mental practice alone is not enough to induce recovery after stroke. • It should be used as a complement or adjunct to another evidence based motor rehabilitation approaches such as repetitive task practices or CIMT (Zimmermann-Schlatter et al, 2008; Page et al, 2009).

Zimmermann-Schlatter A, Schuster C, Puhan MA, Siekierka E, Steurer J. J Neuroeng Rehabil. 2008; 14: 8 Page SJ, Szaflarski JP, Eliassen JC, Pan H, Cramer SC. Neurorehabil Neural Repair 2009; 23: 382-388

Body Weight Supported Treadmill Training and Body Weight Supported Treadmill Training and Cortical Reorganization Cortical Reorganization

• BWST can reduce load on the paretic leg which can • BWSTT can lead to bilateral cortical activation in results in more straight trunk and thereby reduces the individual with chronic stroke. deviation during walking. • A group of researchers have shown increased brain activity in the bilateral primary sensory cortices, • In addition, due to the movement of treadmill, there cingulate motor areas and caudate nuclei (Enzinger et will be a decrease in double limb support time and al 2009). increase in single limb support time (swing phase). • This might be due to the requirement of motor control in response to environmental demand, position sense • This can provide an environment for specific and and balance during walking on treadmill.

repetitive training for walking. • Enzinger C, Dawes H, Johansen-Berg H et al. Stroke 2009; 40: 2460-2467

Constraint-Induced Movement Constraint-induced Movement Therapy (CIMT): Cortical Reorganization Therapy • CIMT was developed originally to reduce the • Training typically involves restraining the unaffcted phenomenon “learned non-use” in which individuals limb and using the affected limb for 90% of waking hours. with stroke form the habit of not using their paretic

upper extremity. • Receiving CIMT early (3-9 months post-stroke) results • In CIMT training, individual with stroke will be forced to in greater functional gains than receiving delayed use the affected extremity by constraining the less treatment (15-21 months post-stroke). affected UE with mitt during waking hours. • This therapy improves upper extremity or lower • Factors for success of CIMT extremity function in individual with stroke and or – Repetitive functional practice using affected limb. brain injury. – The unaffected limb must be constrained 90% of the waking time

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Constraint-Induced Movement Constraint-Induced Movement Therapy (CIMT): Cortical Reorganization Therapy (CIMT): Cortical Reorganization • CIMT approach has evidence for the • Another group of researchers have shown profuse increase physiological and structural brain changes as in the gray matter in the sensory and motor cortical areas in both contralateral and ipsilateral brain following CIMT well as improvement in the affected upper limb (Gauthier et al 2008). function in patients with stroke. • A group of researchers have shown that CIMT • They have also shown the changes are accompanied by can cause changes in cortical excitability, improvements in spontaneous arm functions. metabolic rate and cortical blood flow in individual with stroke (Schaechter et al, 2002). • Therefore, CIMT may be considered as one of the important movement therapies for individual with chronic stroke • Schaechter JD, Kraft E, Hilliard TS et al. Neurorehabil Neural Repair 2002; 16: 326-338 • Gauthier LV, Taub E, Perkins C, Ortmann M, Mark VW, Uswatte G. Stroke 2008; 39: 1520-1525

CIMT vs Control after Stroke Virtual Training and Cortical Activity measured by TMS Reorganization • Virtual training (VT) technique is an interactive intervention approach which involves real-time simulation of an environment and activities that allow user interaction. • With VR, practice intensity and sensory feedback (visual, auditory) can be systematically manipulated to provide the most appropriate, individualized real- life motor training. • Various types of VR devices are available to facilitate movement even for walking.

Virtual Training and Cortical Action Observation Reorganization • VR has been found to induce cortical reorganization with improved associated motor functions in individual with chronic stroke (Adamovich et al, 2009; Kim et al, 2009) • Another group of researchers have shown fMRI changes in the sensorimotor cortex of patients with chronic stroke after locomotor VR training (You et al, 2005) • Adamovich SV, Fluet GG, Tunic E, Merians AS. Neuro Rehabil. 2009; 25: 29-44 • Kim JH, Jang SH, Kim CS, Jung JH, You JH. Am J Phys Med Rehabil 2009; 88: 693-701 • You SH, Jang SH, Kim YH et al. Stroke 2005; 36: 1166-1171

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Bilateral Training Virtual Training using Wii Game Right Left Both Relative Intensity CS 1.00

9 days 0.75

post-stroke 0.50

0.25

0.05 28 days post-stroke

3 months post-stroke R L Z: + 54 mm

Unmasking Ipsilateral Pathways Transcranial Magnetic Stimulation

Is Neuron Repair in the Brain Possible? THANK YOU

Dr. Pradip Ghosh, PT, PhD, DMS, MS Professor