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PTP 512 Neuroscience in Physical Therapy Neuroplasticity Reading Assignments Lundy-Ekman: 72-74, 78-80 Shumway-Cook: 39-43, 83-89, 91-103 Min H. Huang, PT, PhD, NCS RECOVERY OF FUNCTION Recovery • Restoration of damaged structures; reactivation in brain areas surrounding lesion • Clinical improvement in the ability to perform a movement or task in the same way as premorbid, and regardless of the mechanisms underlying changes • e.g. constrain-induced movement therapy to enhance motor recovery after stroke Levin, Kleim, Wolf, 2008 Therapeutic Strategies Focusing on Recovery constraint-induced movement therapy after stroke locomotor training after spinal cord injury Compensation • Compensation refers to behavioral substitution; activation in alternate brain areas; appearance of new motor patterns due to adaptation of remaining motor patterns of substitution • Performing an old movement in a new way • e.g. use of adaptive device, equipment, functional electrical stimulation, external visual cues Levin, Kleim, Wolf, 2008 Compensation adaptive device for gait Factors Affecting Recovery of Function • Biological factors (endogenous) – Age, gender, weight, genetic factors, weight, premorbid condition – Lesion size and progression speed – Neurotrophic factors, e.g. brain-derived neurotrophic factor (BDNF) • Environmental factors (exogenous) – Preinjury factors, e.g. dietary restriction, exercise, environmental enrichment – Postinjury factors, e.g. pharmacologic Rx EARLY RESPONSES TO INJURY AND RECOVERY OF FUNCTION Mechanisms Underlying Recovery of Function • Direct mechanisms: resolution of temporary changes and recovery of injured neural tissue • Indirect mechanisms: recovery completely different neural circuits enable the recover of lost or impaired function Early Transient Events that Depress Brain Function: Edema • Common response following brain injury • Edema can be local or remote from the site of injury • Edema may compress neuron’s cell body or axon, causing focal ischemia, which disrupts neural function, including synthesis and transportation of neurotransmitter. Eventually the synapse become inactive and silent. Edema Early Transient Events that Depress Brain Function: Diaschisis • Loss of function in a structurally intact brain area due to loss of input from an anatomically connected area that is injured • Neural shock due to diaschisis, such as spinal cord shock (lasting 4-6 weeks postinjury), cerebral shock, is a short-term loss of function near and far from lesion site. Full recovery from neural shock is often expected. Metabolic Effect of Brain Injury: Excitotoxicity • After brain injury, neurons deprived of oxygen die. These neurons also release excessive glutamate from their axon terminals, which causes surrounding neurons to overexcite and triggers a cascade of cell death, i.e. excitotoxicity. • Damage after brain injury is not only limited to direct neuronal death, but also the indirect death from excitotoxicity. Secondary injury after traumatic brain injury Park E et al. CMAJ 2008;178:1163-1170 ischemia Glutamate release ↑Glycolysis ↑Ca++ influx Protein enzyme Lactic acid ↑Intracellular H2 O Oxygen free radicals Cell swelling CELL DEATH INTRACELLULAR RESPONSES TO INJURY AND RECOVERY OF FUNCTION PNS and CNS Recovery: Collateral Sprouting • Axon of remaining neuron forms a collateral sprout to reinnervate denervated target With injury, younger rats develop more collateral sprouts than older rats Collateral sprouting PNS and CNS Recovery: Neural Regeneration • Presynaptic axon and its target cell (postsynpatic ) are damaged • Injured axon sprouts to new targets • Regenerate the axon at 1mm/month Regenerative sprouting in CNS is not functional and does not occur • Neural regeneration occurs most frequently in PNS because Schwann cells produce nerve growth factor, which help recovery. • Astrocytes and microglia form glial scars, which physically block axonal regeneration • Oligodendrocytes produce Nogo (neurite outgrowth inhibitor), which inhibits axonal regeneration • Axons don’t naturally regenerate very large distances Synkinesis: aberrant regenerative sprouting in PNS • Axon sprouting can cause problems when an inappropriate targets is innervated. • After injury, motor axons innervate different muscle than they previously did, causing unwanted abnormal movements when the neurons fire. – e.g. Bell’s Palsy (CN VII): patients wink when they intend to purse lips. • Typically lasts no more than a few months Woman with a history of Bell palsy 18 years earlier and with synkinesis (A–C) before treatment (D–F) After PT and Chemodenervation CNS Recovery: Recovery of Synaptic Effectiveness • Recovery from early transient events, such as edema and diaschisis, neural shock CNS Recovery: Denervation Supersensitivity • Occurs when neurons lose input from another brain region, e.g. postsynaptic neurons in the striatum become supersensitive to dopamine in patient with Parkinson CNS Recovery: Synaptic Hypereffectiveness • Occurs when only some branches of presynaptic axons are damaged • Remaining axons receive all neurotransmitters that would normally be distributed among all branches • Larger amount of neurotransmitters released to postsynaptic receptors CNS Recovery: Unmasking of Silent Synapses • In normal CNS, many neurons are not used due to competition of neural pathways • Unused neurons become active Functional Reorganization (remapping) of Cerebral Cortex Training can expand cortical representation areas (i.e. cortical map) A1 = pre-training A2 = post-training Cortical area 3b In adult monkey, sensory training for 3 months on task requiring repeated use of tips of distal phalanges of digits 2, 3, and sometimes 4 Functional Reorganization (remapping) of Cerebral Cortex • Only patients with phantom limb pain (PLP) showed an expansion of areas representing lip into areas previously representing the hand on fMRI Lotze, et al., 2001 Functional Reorganization (remapping) of Cerebral Cortex • fMRI shows significant brain reorganization in patients who develop hand paresis after removal of brain tumor After surgery, multiple brain areas, including the ipsilateral side, are activated during the same task of finger and thumb movement. Before surgery After surgery Structural Changes in Gray Matter and White Matter after Reduced Sensory and Motor Input • Limb immobilization caused reduced nerve fiber density and cortical thickness in the brain 48 hours later 16 days later Langer, 2012 STRATEGIES AND PRINCIPLES TO ENHANCE NEURAL PLASTICITY Effect of Training on CNS • Type of training – Skill learning associated with cortical reorganization – Strength training is not associated with cortical reorganization • Early Intensive Training – Early, high-dose, constrain-induced movement therapy (CIMT) results in the worse outcome compared to moderate intensity CIMT or conventional therapy Effect of Training on CNS • Non-invasive cortical stimulation – Stimulation applied during or shortly before skill training enhances motor learning. In contrast, stimulation after skill training interferes with the skill acquisition – e.g. transcranial direct current stimulation (ionto- phoresor), rTMS Effect of Training on CNS • Non-invasive cortical stimulation Transcranial direct current stimulation (iontophoresor) Transcranial magnetic stimulation (TMS) Effect of Training on CNS • Somatosensory stimulation – Using sensory-level electrical stimulation combined with training – e.g. TENS to hand muscles increase the size of cortical hand map – e.g. Cortical plasticity also occurs with functional electrical stimulation applied to lower extremities: ↑descending input from corticospinal tract to activate TA Effect of Training on CNS • Somatosensory stimulation Transcutaneous electrical nerve stimulation (TENS) Functional electrical stimulation (FES) Effect of Training on CNS • Constraint-Induced Movement Therapy (CIMT) – Restrain unaffected limb and work other limb intensely (e.g. put intact arm in a sling and use the affected arm) – Affected limb must actively engages in exercise, functional activities to benefit from CIMT Principles of ExperienceDependent Plasticity 1. Use it or lose it 2. Use it and improve it 3. Specificity 4. Repetition matters 5. Intensity matters 6. Time matters 7. Salience matters (training experience) 8. Age matters 9. Transference 10.Interference: PLASTICITY AND LEARNING Shift from short term to long term learning is reflected in a move along the continuum of neural modifiability. Neurophysiologic Concepts of Motor Learning • Short-term learning occurs by altering existing synapses – ↑or ↓release of neurotransmitter affecting the excitatory postsynaptic potential (EPSP) Neurophysiologic Concepts of Motor Learning • Long-term learning occurs by the reduction or formation of new synapses or structural changes on neurons, e.g. – Habituation: decrease in synapses (C) – Sensitization: increase in synapses (D) Procedural Learning: Role of Cerebellum • Purkinje cells are output cells • Climbing fibers signal error, critical for correcting ongoing movements • Mossy fibers bring sensory feedback about ongoing movements, critical for controls movements • When climbing fiber increases its activity, mossy fiber signals to Purkinje cells is reduced, which change the synaptic strength for the circuit Procedural Learning: Role of Cerebellum Monkeys move arm (1) Against an expected load (already learned) (2) Against an unexpectedly increased load (3) Against same load as in (2) after Simple spikes from mossy fibers Complex spikes from climbing some practice fibers Declarative Forms of Learning: Long-Term Potentiation • LTP requires simultaneous firing of both presynaptic and postsynaptic cells • Postsynaptic neuron must depolarize when the Glutamate binds to the NMDA receptor in order to open the ion channel LTP conversion of silent synapses to active synapses Change in presynaptic cell to produce new synapse AMPA receptors inserted into membrane New dendritic spines formed Lundy-Ekman Fig. 4-1 Complex Form of Motor Learning • Sensory cortex of cats is absolutely necessary to learn a new skill, how to supinate the forearm to retrieve food. • Once learned, ablation of the sensory cortex will not affect the movement Acquisition of Skills: Shift to Automaticity • Automaticity during skill acquisition is associated with a reduction of brain activation in several regions • Older adults or individuals with neurological diseases may activate more brain areas or increase the activity levels in order to perform the skills at the same level as health individuals