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 Motor recovery refers to achieving the functional goal in the same way it was performed before injury; or using effective and efficient methods but not necessarily the same ways. Levin, Kleim, Wolf, 2008

Therapeutic Strategies Focusing on Recovery locomotor training after spinal cord injury constraint-induced movement therapy after stroke http://www.usc.edu/uscnews/stories/9548.html http://ptjournal.apta.org/content/80/7/688/F1.expansion.html

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 can result from the accumulation of intracellular fluid, or proteins and fluid leaking from damaged blood vessels. One is cytogentic (associated with cells) and the other is vasogenic (associated with blood vessels). Edema causes a compression of axons and blocking of signal transmission.

Edema Edema can result from the accumulation of intracellular fluid, or proteins and fluid leaking from damaged blood vessels. One is cytogentic (associated with cells) and the other is vasogenic (associated with blood vessels). Edema causes a compression of axons and blocking of signal transmission.

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 post- injury), cerebral shock, is a short-term loss of function near and far from lesion site. Full recovery from neural shock is often expected. Diaschisis (at the site remote from the injury site) can be due to a reduction of blood flow and/or metabolism. Drugs such as Amphetamines have shown promising results in promoting the neural recover from diaschisis.

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 Figure 1: The major pathways associated with the progression of secondary injury after a traumatic brain injury. Microcirculatory derangements involve stenosis (1) and loss of microvasculature, and the blood–brain barrier may break down as a result of astrocyte foot processes swelling (2). Proliferation of astrocytes (“astrogliosis”) (3) is a characteristic of injuries to the central nervous system, and their dysfunction results in a reversal of glutamate uptake (4) and neuronal depolarization through excitotoxic mechanisms. In injuries to white and grey matter, calcium influx (5) is a key initiating event in a molecular cascades resulting in delayed cell death or dysfunction as well as delayed axonal disconnection. In neurons, calcium and zinc influx though channels in the AMPA and NMDA receptors results in excitotoxicity (6), generation of free radicals, mitochondrial dysfunction and postsynaptic receptor modifications. These mechanisms are not ubiquitous in the traumatized brain but are dependent on the subcellular routes of calcium influx and the degree of injury. Calcium influx into axons (7) initiates a series of protein degradation cascades that result in axonal disconnection (8). Inflammatory cells also mediate secondary injury, through the release of proinflammatory cytokines (9) that contribute to the activation of cell-death cascades or postsynaptic receptor modifications. Neuronal glutamate that is released into the synaptic space is normally removed from the synaptic space by adjacent glial cells, in which the glutamate is converted to the closely related glutamine, which can then readily diffuse back into the neuron. Glutamine is converted back to glutamate in the neuron. Park E et al. CMAJ 2008;178:1163-1170

ischemia Glutamate release Protein enzyme ↑Ca++ influx ↑Glycolysis ↑Intracellular H2O Oxygen free radicals Lactic acid Metabolic Effect of Brain Injury: Excitotoxicity ↑intracellular Ca++ following brain injury causes 3 pathways leading to cellular death ↑glycolysis  lactic acid  acidosis ↑intracellular water  cell swelling Activate protein enzyme  oxygen free radicals Cell swelling CELL DEATH

Intracellular responses to injury and recovery of function Altering specific synapses Functionally reorganizing Changing neurotransmitter release Re-growth of axons is called sprouting. There are two types of sprouting: Collateral sprouting (reactive synaptogenesis) Regenerative sprouting (regenerative synaptogenesis): This axon regeneration is NOT functional in the CNS 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 http://www.biopsychology.com/6e/step1905.html

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 http://www.nature.com/nature/journal/v403/n6768/abs/403434a0.html

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 http://ptjournal.apta.org/content/90/3/391.full.pdf+html http://ptjournal.apta.org/content/suppl/2010/02/25/90.3.391.DC1/Small_Smile_01.mov Synkinesis is the phenomenon of aberrant regeneration. Some typical abnormal movement patterns (synkinesis) might develop with increasing movement. Electrical stimulation and regimens of facial movement exercises to be performed with maximal effort are common recommendations; however, both approaches are thought by some clinicians to be harmful, perhaps leading to increased synkinesis. Treatment strategies: For example, when participants complained of ocular synkinesis with smiling or puckering their lips for eating, drinking, or talking, smallmovement exercises were taught. They were trained to form a small, symmetric smile while controlling synkinesis of the obicularis oris muscle by widening the orbital region. For midfacial synkinesis, the participants were instructed to gently close their eyes while releasing the synkinesis in the midface. When participants developed synkinesis of the platysma muscle, soft tissue massage of the platysma muscle and active practice in minimizing the synkinesis were used to prevent the overactive depressor function of the platysma muscle from overcoming the effort of the impaired zygomaticus muscle. Meditation with guided visual imagery was focused on relieving the tension in the synkinetic musculature. Verbal cues to help minimize synkinesis included “drain the tension around the eye” (ie, for ocular synkinesis) and “deflate the fully inflated balloon in your cheek” (ie, for midfacial synkinesis felt during closing of the eyes). All participants who developed synkinesis were considered to be eligible to receive chemodenervation for the further management of synkinesis; this technique has been shown to improve the quality of life in subjects with facial paralysis . Botulinum toxin is a potent neurotoxin that causes temporary paralysis of the hyperkinetic musculature .

Woman with a history of Bell palsy 18 years earlier and with synkinesis (A–C) before treatment (D–F) After PT and Chemo-denervation

CNS Recovery: Recovery of Synaptic Effectiveness Recovery from early transient events, such as edema and diaschisis, neural shock Recovery of synaptic effectiveness .

CNS Recovery: Denervation Supersensitivity Occurs when neurons lose input from another brain region, e.g. postsynaptic neurons in the striatum become super- sensitive to dopamine in patient with Parkinson Postsynaptic cells form more receptors to capture more neurotransmitters.

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 post- synaptic 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 Jenkins, et al. 1990

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 Before surgery After surgery After surgery, multiple brain areas, including the ipsilateral side, are activated during the same task of finger and thumb movement. Feinges, et al., 2005

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 10 right-handed (according to the Annett handedness questionnaire10) subjects (8 male; mean SD age of 31.6 9.81 years), who had an injury of the right upper extremity and needed immobilization with a cast or immobilizing sling for at least 14 days. Displayed are FA changes in the corticospinal tract induced by deprivation of motor outputs and sensory inputs. (A) Illustrative construction of the corticospinal tract for time point 1 and time point 2, with the seed and the target regions of interest. (B) Three supplemental representative corticospinal tracts for time point 1 and time point 2 are presented. The colors in A and B indicate the FA values within the corticospinal tract. FA is a measure often used in diffusion MRI imaging where it is thought to reflect fiber density, axonal diameter, and myelination in white matter. 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 http://archneur.ama-assn.org/cgi/content/full/65/12/1571/NNR80008F1

Effect of Training on CNS Non-invasive cortical stimulation http://archneur.ama-assn.org/cgi/content/full/65/12/1571/NNR80008F1 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 TENS to hand muscle increases size of cortical hand map in normal developed subjects

Effect of Training on CNS Somatosensory stimulation http://exceltens.com/images/uploads/TPN300Dig.jpg 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 http://www.ergotherapie-graebner.de/neurologie.php

Principles of Experience-Dependent Plasticity Use it or lose it Use it and improve it Specificity Repetition matters Intensity matters Time matters Salience matters (training experience) Age matters Transference 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 some practice Simple spikes from mossy fibers Complex spikes from climbing fibers Simple spikes from mossy fibers Complex spikes from climbing 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 Glutamate receptors AMPA: ligand gated receptor NMDA: ligand- and voltage-gated receptor Postsynaptic neuron must depolarize when the Glu binds to the NMDA receptor in order to open the gate Prolonged opening of ion channels resulting in long-term potentiation (LTP) cAMP = cyclic adenosine monophosphate CREB = cAMP responsible element-binding protein LTP is the cellular mechanism for forming memory, and recovery following injury. It is similar to sensitization. The weak input is strengthened after LTP. It requires the presynaptic and postsynaptic cells to activate at the same time. It is also responsible for developing chronic pain syndromes. When a stimulus is repeated, there will be synthesis or activation of new proteins. This can either strengthen or inhibit the synaptic connections.

LTP conversion of silent synapses to active synapses Change in pre-synaptic cell to produce new synapse AMPA receptors inserted into membrane p. 73 of Lundy-Ekman (A) The budlike structure is a postsynaptic spine. These are the preferred sites for forming a synapse on the dendrite. The NMDA receptors binds to glutamate and allows Ca++ to flow freely in and out of the cells. This allows positively charged ions, such as Ca++, to move through either direction. Because the AMPA receptors are inside the cell, not in the membrane. This is a silent synapse. (B) LTP is initiated when the NMDA receptors are activated. (C) As a results, there is an increase of Ca++ inflow, into the cell. This causes the AMPA receptors to insert into the cell membrane. (D) With continuous stimulation, the postsynaptic membrane generate a new dedritic spine. (F) Finally a new synapse is form. For LTP to work, 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