Roadmap Neuroplasticity

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1 REACTIVATE, REWIRE, RESTORE: challenging the nervous system to optimize function after SCI Edelle [Edee] Field-Fote, PT, PhD, FAPTA Director of Spinal Cord Injury Research Shepherd Center Crawford Research Institute Contemporary Concepts in Neuroplasticity Old Views: You are born with all the neurons you will ever have The nervous system is a hardwired New Views: New neurons are generated even in adults There are new connections made between neurons The new connections rely on training and practice Roadmap Neuroplasticity The capacity of the CNS to undergo changes in function and structure in response to use and motor learning May be favorable or unfavorable Roadmap: neuroplasticity and motor learning 1. What neural mechanisms underlie neuroplasticity? 2. What is known to be important about the structure of training? 3. What are the corollaries between motor learning and neuroplasticity? Possible Mechanisms Underlying Neuroplasticity Altered Synaptic Efficacy Increased/decreased excitability Unmasking of Latent Connections New Connections sprouting synaptogenesis Neurogenesis 1

2 Rapid Mechanisms of Plasticity Altered synaptic efficacy Changing the balance of excitatory and inhibitory connections + Practice puts brains in your muscles Sam Snead Rapid Mechanisms of Plasticity Unmasking of latent connections (silent synapses) Slow Mechanisms of Plasticity Sprouting and synaptogenisis Sprouting of new dendrites Increased number of synapses Neurogenesis in Humans Neurogenesis postnatally in: Hippocampus Subventricular Zone Olfactory Bulb Telephone operators circa

3 Running / exercise increase hippocampal neurogenesis in adult mice Activation-dependent Plasticity in Upper Extremity Function After 12 days After 4 weeks van Praag, Kempermann G, and Gage. Nat Neurosci Walking associated with hippocampal neurogenesis in older adults Is (direct) cortical stimulation more beneficial than (indirect) somatosensory stimulation? Erickson et al. PNAS Stimulation Speaks the Language of the Nervous System Roadmap: functional recovery in the upper extremity 1. What neuroplastic changes occur in the brain after CNS injury. 2. What is the evidence that training and stimulation can promote adaptive neuroplasticity? 3. What functional changes are observed with combined training and stimulation? Field-Fote. Exerc Sport Sci Rev,

4 Unfavorable Neuroplasticity Occurs after CNS Injury What is the source motor impairment after SCI? Damage to descending tracts Detrimental spinal reorganization Damage to ascending tracts Detrimental cortical reorganization Maladaptive plasticity of the motor cortex after stroke Cortical plasticity in individuals with SCI Nudo et al. J Neurosci, 1996 Curt et al. J Neurotrauma, 2002 Motor Cortical Reorganization after Stroke with Left Hemiparesis The cortex reorganizes after SCI does this contribute to functional deficits? Feydy et al. Stroke, 2002 Green et al. Neurology,

5 Roadmap: functional recovery in the upper extremity In subjects with stroke functional changes with massed practice are associated with neuroplasticity 1. What neuroplastic changes occur in the brain after CNS injury. 2. What is the evidence that training and stimulation can promote adaptive neuroplasticity? 3. What functional changes are observed with combined training and stimulation? Pre Post Pt 1 Pt 3 Pt 4 Note: Pt 4 had no functional or fmri change Szaflarski et al. Arch Phys Med Rehabil. 2006;87: Cortical activity associated with loss and recovery of hand funcion after csci resembles that after stroke Subject with csci activation of M1 and activation of associated sensorimotor areas 1 mo 3 mo Non-disabled subject 6 mo 12 mo Nudo RJ. Mol Psychiatry, 1997 (Jurkiewicks et al., 2007) Cortical plasticity in rats occurs in response to skill training. NonReachCond=No training ControlReachCond=Skill training PowerReachCond = Power training Strength increases from the motor program Imagery group Contraction group = pretraining = posttraining Green = distal Control group Blue = proximal limb representat ions Remple et al, Behav Brain Res, 2001 Yue G, Cole KJ. J Neurophysiol

6 Mental practice improves function and promotes cortical plasticity Projections from sensory to motor cortex by neurons activated from group I muscle afferents Pascual-Leone et al J Neurophysiol. 1995; 74: Zarzecki, Shinoda& Asanuma. Exp Brain Res, Protocol: Mental Practice Pre Test Performance & cortical excitability S1 contributions to M1 are critical for motor learning Mental Practice 2 hrs 5x/week Sit in front of piano Visualize finger sequence Imagine sound Post Test Performance & cortical excitability Pascual-Leone et al J Neurophysiol. 74: , 1995 but once task is learned S1 lesion does not affect performance of learned task Pavlides, Miyashita & Asanuma. J Neurophys, Why be Interested in Sensory Cortex? It contributes to corticospinal tract Somatosensory stimulation With longer pulse durations, lower stim intensities are needed to activate sensory fibers Dum & Strick. Physiol Behav, 2002 Panizza et al, Electroencephalogr Clin Neurophysiol

7 How long must a session be to change cortical excitability? Median nerve stim (supra thrshld) Effects of sensory stimulation + training on function post stroke (single session) Control stim (sub thrshld) (single session) McKay et al, Neuroreport Conforto et al. J Neurol, Somatosensory stimulation enlarges cortical areas activated by movement Sensory stim + training improves function in individuals with stroke Wu et al. Neuroimage, 2005 Conforto et al. J Neurol, Sensory stimulation increases pinch strength post stroke Cortical Plasticity Occurs with LE Stimulation FES for footdrop modifies MEP of TA Conforto et al. Ann Neurol Thompson &Stein. Exp Brain Res,

8 TENS to hand muscle increases size of cortical hand map in ND subjects Protocol: Massed Practice + Somatosensory Stimulation Pre Test Performance, strength, cortical excitability TENS to APB 100 Hz 250 µs pulse width 21 days 1hr/day N = 24, 12/group Meesen et al. Human Brain Mapping, 2010 Massed Practice + Stim 2 hrs 5x/week for 3 weeks 5 categories of tasks (everyday activities) ~ concurrent with ~ SS to median nerve, 500ms trains, 10Hz Post Test Performance, strength, cortical excitability Beekhuizen & Field-Fote. Arch Phys Med Rehabil, 89: , 2008 e2 TENS: what frequency is best? Roadmap: functional recovery in the upper extremity Both low-rate (4Hz)/ high-width TENS and high-rate (100Hz), lowwidth TENS activated the large sensory fibers 1. What neuroplastic changes occur in the brain after CNS injury. 2. What is the evidence that training and stimulation can promote adaptive neuroplasticity? 3. What functional changes are observed with combined training and stimulation? Radhakrishnan R, Sluka KA. J Pain, 2005 TENS improves hand sensory function in individuals with MS (but not ND individuals) Hand function is highest priority among those with tetraplegia Cuyers et al. Neurorehabil Neural Repair, 2010 Anderson K. J Neurotrauma,

9 Slide 44 e2 spell abbreviation out the first time efield, 01/04/2011

10 Low motor unit firing rates mean low force production after SCI Massed practice categories and sample tasks MVC firing frequency = 0.8 Hz Involuntary spasm firing frequency = 2.2 Hz Zijdewind & Thomas. J Neurophysiol, 2003 Beekhuizen & Field-Fote. Arch Phys Med Rehabil, 89: , 2008 Small increases in firing rate (via stimulation) result in large increases in force even in paralyzed muscle Motor learning principles: modify tasks for success / challenge Hager-Ross, Klein & Thomas J Neurophysiol, 2006 Pinch Pinch with rotation Massed practice for task-specific training effects Gross UE Movement Grip Grip with rotation Beekhuizen & Field-Fote. Arch Phys Med Rehabil, 89: , 2008 Somatosensory Stimulation Parameters 2 hrs/day median nerve stimulation (at wrist) Either: in conjunction with MP training (MP +SS) or alone (SS) Parameters: trains of stimulation 10 Hz (500ms on / 500 ms off) 1 msec pulse duration Submotor threshold intensity (no visible thumb contraction) Goal: Preferentially activate large proprioceptive and cutaneous sensory fibers stimulating electrode placement over the median nerve recording electrodes over thenar eminence Ridding et al. Exp Brain Res, 2000 (ND) Conforto et al. Ann Neurol, 2002 (Stroke) 9

11 Protocol: Massed Practice + Somatosensory Stimulation Sensory Function Pre Test Performance, strength, cortical excitability Massed Practice + Stim 2 hrs 5x/week for 3 weeks 5 categories of tasks (everyday activities) SS to median nerve 500ms trains, 10Hz Post Test Performance, strength, cortical excitability Beekhuizen & Field-Fote. Arch Phys Med Rehabil, 89: , 2008 Beekhuizen &Field-Fote. Arch Phys Med Rehabil, 2008 Functional hand use Jebsen -Taylor Hand Function test Hypothesized mechanism Beekhuizen &Field-Fote. Arch Phys Med Rehabil, 2008 Strength Bimanual activity engages more cortical areas than unimanual activity Bi Asym Bi Sym Uni (Left) Beekhuizen &Field-Fote. Arch Phys Med Rehabil, 2008 De Weerd et al.,

12 EXCITATION INHIBITION Unilateral movement: excitation in the active cortex inhibition in the inactive cortex INTRACORTICAL FACILITATION Unimanual hand function outcomes MEPs (mv) BASELINE BILATERAL ACTIVE CTX (UNI) INACTIVE CTX (UNI) (Mc CombeWaller et al, 2008) Hoffman & Field-Fote. J Neurol Phys Ther, 34: , 2010 Unilateral movement: excitation in the active cortex inhibition in the inactive cortex INTRACORTICAL FACILITATION bimanual hand function outcomes MEPs (mv) BASELINE BILATERAL ACTIVE CTX (UNI) INACTIVE CTX (UNI) (Mc CombeWaller et al, 2008 Hoffman & Field-Fote. J Neurol Phys Ther, 34: , 2010 Pilot Study: Bimanual Training Unimanual Training Even those with greatest deficits benefit from training Bimanual Training Hoffman & Field-Fote. J Neurol Phys Ther, 34: ,

13 Cortically Evoked Potentials after SCI MEP at 60%MSO in ND individual MEP at 90% MSO in individual incomplete cervical SCI wit Biophysics of TMS Outcome measures by group Transcranial Magnetic Stimulation (TMS) (Magnetically) Induced electrical stimulation Activation of structures oriented horizontal to coil Pyramidal cells through interneuron activation Motor evoked potential Change in hand function is associated with change in cortical excitability Sample thenar MEPs at 80% MSO (avg of 5 traces) (Merabet, Pascual-Leone, 2009; Davey et al, 1999) Beekhuizen &Field-Fote. Arch Phys Med Rehabil,

14 The cortex reorganizes after SCI does this contribute to functional deficits? Reorganization of cortical map Green et al. Neurology, 1998 Hoffman & Field-Fote. Phys Ther, 2007 Plasticity of the Motor Map Accompanying Recovery of Function Following SCI Somatosensory stimulation as an accessible approach to augmenting hand practice Subject with incomplete C5 injury Green JB et al. Neurology,1999. Can sensory stimulation augment motor training? Approaches for direct cortical stimulation Repetitive transcranial magnetic stimulation Activates neurons Studies in persons with stroke High frequency Transcranial direct current stimulation (tdcs) Modulates neuronal excitability Studies in persons with stroke anodal vscathodal Beekhuizen &Field-Fote. Arch Phys Med Rehabil,

15 rtms in SCI and ND High frequency rtms 10Hz [excitatory]) 80% biceps RMT (Pascual-Leone, 1994; Beradelli et al, 1998; Butefish et al, 2004; Kim et al, 2006; Tallelli & Rothwell, 2006) EVEREST Study Overview Phase III, RCT of patients with chronic hemiparesis Targeted cortical stimulation during intensive rehab Randomize 151 subjects (100 implanted, 51 control) 21 sites Primary OMs: Composite endpoint at 4 weeks post Upper extremity Fugl-Meyer (UEFM) Arm Motor Ability Test (AMAT) Secondary outcome at 24 weeks Targeted primary efficacy endpoint: 20% difference between groups rtms is associated with improved functional scores in persons with SCI Dashed line indicates threshold for moderate effect size Gomes-Osman & Field-Fote. Clin Rehabil, 2014 Outcomes Safety confirmed no adverse effects At 4 weeks (primary end point) clinically meaningful improvements did not meet criteria of 20% difference: 30.8% of patients receiving stim + MP 29.1% of patients MP only At 25 weeks, significantly greater AMAT improvement in stim + MP group Questions raised about dosing levels (EVEREST investigator, Robert Levy) tdcs represents a clinically accessible approach to direct cortical stimulation Anodal= EXCITATION Cathodal= INHIBITION ANODE CATHODE Is direct cortical activation more beneficial than indirect (somatosensory) activation? Transcranial direct current stimulation (tdcs) Electrodes applied to the scalp Simple unidirectional direct current 1 ma current Session time: 20 min Mild adverse effects (itching), non-invasive, painless (Fregni & Pascual-Leone, 2007) 14

16 Uni-hemispheric tdcs in stroke tdcs Cervical Spinal Cord Injury - Bilateral upper extremity impairment - What about bilateral excitatory stimulation? Boggio et al. Rest Neurol Neurosci, 2007 Bi-hemispheric (anodal/cathodal) more effective than uni-hemispheric (ND subjects) Is direct cortical activation more effective than indirect (somatosensory) activation? Assessment of clinically available approaches tdcs TENS Vibration Vines et al. BMC Neurosci, 2008 Protocol: Transcranial Direct Current Stimulation tdcs is associated with most effect TENS also influenced function Pre Test Functional hand performance * tdcs Electrodes applied to the scalp M1 & contra forehead (anodal ~OR~ cathodal) ~OR~ M1 & ipsi forehead (anodal + cathodal) 1 ma current 20 min session duration Mild adverse effects (itching) * * * Post Test Functional hand performance Boggio et al. Rest Neurol Neurosci, 2007 Dashed line= moderate effect size Gomes-Osman & Field-Fote. J Neurol Phys Ther,

17 Conclusions Even in chronic CNS injury there is potential for improvement of hand function. Locomotor practice modulates reflex excitability FRR R1 Both stimulation & training affect neural structures that underlie movement effects may be additive. There are changes in cortical neurophysiologic measures associated with functional change. H/M LFD Clinically available devices can be employed Neuroplasticity Alterations in the nervous system in response to experience Repeated experience practice May be adaptive or maladaptive Requirements Sufficient intensity Sufficient time } DOSE Vibration elicits involuntary steplike movement in ND individuals Vibration elicits locomotor-like movements Single muscle or contralateral leg Cyclic behavior suggesting CPG origin Gurfinkel et al. Eur J Neurosci, 10: ,

18 Motor-complete SCI: Involuntary Stepping with Muscle Vibration Vibration elicits involuntary stepping in individuals with SCI ND Individual: Involuntary Stepping with Muscle Vibration Activation-dependent Plasticity in Lower Extremity Function Motor-incomplete SCI: Involuntary Stepping with Muscle Vibration Whole-body Vibration (WBV) improves walking and decreases spasticity in SCI Subjects: 17 individuals with chronic SCI 50 Hz, low amplitude (2-4 mm) 3 days/week x 4 wks Outcomes: increased walking speed decreased quad spasticity Walking function: Ness & Field-Fote. Gait & Posture, 2009 Spasticity: Ness & Field-Fote. Restor Neurol Neurosci,

19 Improved walking following 12-session course of WBV WBV influences on spasticity cumulative multi-session effects early within-session effects late within-session effects FSE (degrees) Intervention week Ness & Field-Fote. Restor Neurol Neurosci, 2009 WBV is associated with improved gait speed and quality Speed, CAD, SSL, WSL When spinal reflexes are problematic is it more effective to focus on decreasing involuntary activity ~or~ increasing voluntary activity? Initial Final Test session Ness & Field-Fote. Gait & Posture, 2009 Pendulum Test High spasticity Low spasticity Biomechanical quantification of stretch reflex excitability but if we really want to improve walking, then we should probably practice walking 18

20 Is there a best approach to locomotor practice? Ia Reciprocal Inhibition (3ms ISI) Treadmill training with manual assistance (TM) Treadmill training with CPN stimulation assist (TS) PRE Overground training with CPN stimulation assist (Walkaide II stimulator; OG) TM TS CONTROL H-Reflex CONDITIONED H-Reflex Treadmill training with robotic assistance (Lokomat robotic orthosis; LR) POST N = 74 enrolled, 64 completed (across 4 groups) OG LR Field-Fote & Roach. Phys Ther, 91:48-60, 2011 Groupwise changes in Walking Speed & Distance EMG Timing and Amplitude Pre Training Post Training Field-Fote & Roach. Phys Ther, 91:48-60, 2011 Locomotor practice modulates reflex excitability Limb Coordination is the Hallmark of Motor Control FRR R1 19

21 Intralimb Coordination Subject with SCI - pre & post training Stages of Motor Learning Cognitive Stage: Establishment of reference of correctness Requires total attention to task Performance is inconsistent Associative Stage: Experimentation and refinement Able to recognize errors Still requires conscious attention to rules Autonomous: Able to perform automatically and autonomously Able to adapt pattern as needed Able to dual-task and deal with distractions The Caudal End Stimulation (electric & vibration) activates much the same circuitry as training In people with SCI, training promotes adaptive neuroplasticity of cortical and spinal circuits Clinically accessible stimulation can be a valuable adjuvant to training Continued training at a sufficient dose is necessary to maintain gains Retention and Specificity of Learning Acquisition: performance during practice Retention: performance after period of no practice (may be short- or long-term) Transfer: performance of task in different environment Generalizability: use of skills gained in practice in performance of a different task Roadmap: neuroplasticity and motor learning Roadmap: neuroplasticity and motor learning 1. What neural mechanisms underlie neuroplasticity? 2. What is known to be important about the structure of training? 3. What are the corollaries between motor learning and neuroplasticity? 1. What neural mechanisms underlie neuroplasticity? 2. What is known to be important about the structure of training? 3. What are the corollaries between motor learning and neuroplasticity? 20

22 Roadmap: functional recovery in the lower extremity 1. What are the innate capabilities of the spinal cord? 2. How do spinal reflex circuits change after CNS injury? 3. Can we influence spinal circuits do we want to? 4. How can stimulation augment training for improved walking? H-reflex: the electrical analogue of the stretch reflex The smart spinal cord H-Reflex Test The spinal cord functions as part of the brain and not its servant -- Reggie Edgerton Stretch Reflex (Kandel & Schwartz) high intensity low intensity 21

23 The true picture is somewhat more complicated Spinal Cord Performs Sensory Motor Transformation reciprocal Ia inhibition Ib inhibition presynaptic inhibition recurrent inhibition Ia excitation Hultborn. J Rehabil Med, The Wiping Reflex of the Spinal Frog: Target-Specific Movement Trajectory. From Fukson OI, Berkinblit MB, Feldman AG. The spinal frog takes into account the scheme of its body during the wiping reflex. Science 209: , 1980 Spinal mechanisms contribute to muscle forces generated by ES The spinal cord controls limb coordination of innate, rhythmic behaviors Collins. Exerc Sport Sci Rev, 2007 Field &Stein. J Neurophys, 1997 Spinal circuits generate innate rhythmic behaviors Stepping responses in pre-ambulatory infants follow the rules of other vertebrate models Hultborn. J Rehabil Med, Pang & Yang. J Physiol,

24 Involuntary stepping after SCI as evidence of human locomotor CPG Disrupted reflex modulation Similar case in: Calancie et al. Brain, 1994 Principles of motor control generalize across species Modulation of spinal circuitry is essential for normal movement Lundbye-Jensen & Nielsen. J Physiol, Roadmap: functional recovery in the lower extremity 1. What are the innate capabilities of the spinal cord? 2. How do spinal reflex circuits change after CNS injury? 3. Can we influence spinal circuits do we want to? 4. How can stimulation augment training for improved walking? Disrupted reflex modulation is associated with disordered motor output Motor Disorder Spasticity Clonus Co-contraction Flexor spasms Spastic gait pattern Probable Origin Increased responsiveness to stretch, ETC. Loss/reduction of post-activation depression Loss/reduction of reciprocal inhibition Increased responsiveness to FRA input Decreased phase-dependent modulation 23

25 Immobility contributes to spasticity Agonist-antagonist reciprocal inhibition is impaired in those with spasticity Lundbye-Jensen & Nielsen, J Physiol 2008 Adapted: Morita H et al, Brain, 2001 Excitability in response to stretch can be quantified Reciprocal facilitation post CVA and SCI The Pendulum Test High spasticity Low spasticity Crone et al, Brain, 2003 Clonus Phase-dependent H-reflex modulation is deficient after SCI Able bodied SCI Subject 1 Subject 2 Edamura et al Yang et al,

26 CPG output responds to stimuli in a phase-dependent manner Immobilization of ND subjects induces reflex changes similar to CNS injury Non stimulated swing (A.1) and stance (B.1) Stim applied at s during swing (A.2) and stance (B.2) Forssberg H, Grillner S, Rossignol S. Phasic gain control of reflexes from the dorsum of the paw during spinal locomotion. Brain Res, 132:121-39, 1977 Lundbye-Jensen & Nielsen. J Physiol, Foot contact Toe off Impairment of modulation is correlated with severity of SCI non-disabled mildly impaired moderately impaired severely impaired Note difference in late stance reflex amplitude between ND subjects and those with SCI Roadmap: functional recovery in the lower extremity 1. What are the innate capabilities of the spinal cord? 2. How do spinal reflex circuits change after CNS injury? 3. Can we influence spinal circuits do we want to? 4. How can stimulation augment training for improved walking? Fung & Barbeau J Neurophysiol, 1994 Position-dependent reflex modulation is impaired in SCI reciprocal inhibition SCI post-activation depression Spinal reflexes respond to training ND = sitting = standing Perez & Field-Fote, Neurosci Lett, 2003 Field-Fote et al. Neurosci Lett, 2006 Wolpaw et al, Brain Res,

27 Stimulation improves reciprocal inhibition in those with spasticity Effect of Stimulation on Plasticity of Reciprocal Ia Inhibition in AB Subjects ND subjects (n =74) o subjects with spasticity (n=39) Effect of Stim Protocol Pre Post Timecourse of Effects subjects with spasticity who used CPN stim (n=4) Crone et al. Brain, 1994 Stimulation to peroneal nerve, measure effect on soleus H-reflex Stimulation forms: A ()= patterned stim -- train of 10 pulses (at 100Hz) every 1500ms B ()= combined -- patterned stim with TMS every 8 sec C ()= uniform stimulation (1 pulse every 150 ms) Perez, Field-Fote & Floeter. J Neurosci, 2003 Passive cycling promotes more typical reflex modulation in individual with SCI Effect of Vibration versus Stimulation on Plasticity of RI in Subjects with SCI Timecourse of Effects Effect of Vibration Stimulation to peroneal nerve, measure effect on soleus H-reflex Stimulation forms: = patterned stim -- train of 10 pulses (at 100Hz) every 1500ms = vibration at 60 Hz Kiser et al J Spinal Cord Med, 2005 Perez, Floeter & Field-Fote. J Neurol Phys Ther, 2004 CPN stimulation improves phasedependent reflex modulation static walking Central pattern generators respond to training CPG plasticity Fung & Barbeau. J Neurophysiol,1994; 72: Hodgson et al Med Sci Sports Exerc,

28 Should we train to reflexes or to voluntary control? N =12 3 baseline sessions 12 training sessions (3/wk x 4 wks) Roadmap: functional recovery in the lower extremity 1. What are the innate capabilities of the spinal cord? 2. How do spinal reflex circuits change after CNS injury? 3. Can we influence spinal circuits do we want to? 4. How can stimulation augment training for improved walking? Manella, Roach, Field-Fote. J Neurophys. In press, 2013 Sample SOL Outcome Who wants to walk? Walking is a high priority for recovery among consumers with spinal cord injury irrespective of severity of injury, time of injury and age at time of injury. Manella, Roach, Field-Fote. J Neurophys. In press, 2013 Ditunno et al. Spinal Cord, 2008 Outcomes EMG, clinical, walking, reflexes Approaches to locomotor training in individuals with chronic CNS injury Treadmill-based training with BWS manual assisted FES assisted robotic assisted Overground training Manella, Roach, Field-Fote. J Neurophys. In press,

29 Locomotor training improves walking in those with chronic incomplete SCI Robot vs manual assisted TT in chronic stroke Field-Fote et al. J Neurol Phys Ther, groups: TT with robotic vs manual assistance 12 sessions Conclusion: Manual assist resulted in greater improvements in speed, symmetry, and measures of activity and participation N = 48 (24 per group) Hornby et al. Stroke, 2008 Fast and slow treadmill training and OG training in ambulatory individuals with subacute stroke Treadmill vs skilled overground training in chronic SCI 3 groups: Fast TT, Moderate TT, OG training 12 training sessions Conclusion: Fast TT group improved most in speed, cadence and stride length N = 60 (20 per group) Crossover design case series: BWSTT followed by OG or BWSTT 2 3x/week for 12 weeks Conclusion: speed gains with skill-based OG training were greater than with BWSTT Pohl et al. Stoke, 2002 N = 4 (8 per group) Musselman et al. Phys Ther, 2009 Lokomat vs manual-assisted and fast vs slow training in chronic stroke Locomotor training improves walking in those with chronic incomplete SCI. But what is the best approach to improving walking function? 2 groups (lokomat vs manual) stratefied by speed (fast vs slow) 3x/wk for 4 weeks Conclusion: no between-groups differences in primary outcome measures (self-selected OG speed & step length ratio). However, withingroup improvements were greater in the Lokomat group. No differences in fast vs slow training speeds. N = 16 (8 per group) 28

30 Systematic review Mehrholz et al. Cochrane Database Systematic Review, 2008 OBJECTIVES: To assess the effects of locomotor training on improvement in walking for people with traumatic SCI. SEARCH STRATEGY: Searched multiple databases: Cochrane Central Registery, MEDLINE, EMBASE, CINAHL, AMED, PEDro, COMPENDEX INSPEC, and other databases. Also handsearched relevant conference proceedings. SELECTION CRITERIA: We included randomised controlled trials (RCT) that compared locomotor training to any other exercise provided with the goal of improving walking function after SCI or to a no-treatment control group. DATA COLLECTION AND ANALYSIS: The primary outcomes were the speed of walking and walking capacity at follow up. MAIN RESULTS: Four RCTs involving 222 patients were included in this review. Overall, the results were inconclusive. AUTHORS' CONCLUSIONS: There is insufficient evidence from RCTs to conclude that any one locomotor training strategy improves walking function more than another for people with SCI. Research in the form of large RCTs is needed to address specific questions about the type of locomotor training which might be most effective in improving walking function of people with SCI Subjects AIS C or D Chronic SCI N = 74 enrolled N = 64 Outcome Measures Speed (10m Walk) Distance (2-Min Walk) Kinematics ASIA (motor/sensory) Balance (Berg, MFR) Reflexes Metabolic efficiency Pulmonary capacity Quality of life Protocol: Locomotor Training Pre Test Walking speed & distance, reflexes, balance, etc CONSORT Diagram Randomization to 1 of 4 groups 1 hr/day 5 days/wk 12 week training Post Test Walking speed & distance, reflexes, balance, etc Field-Fote & Roach. Phys Ther, 91:48-60, 2011 Locomotor training improves walking in SCI is there a best approach? Treadmill training with manual assistance (TM) Lokomat using passive mechanical guidance only Treadmill training with CPN stimulation assist (TS) Overground training with CPN stimulation assist (Walkaide II stimulator; OG) TM TS Treadmill training with robotic assistance (Lokomat robotic orthosis; LR) N = 74 enrolled, 64 completed (across 4 groups) OG LR Field-Fote & Roach. Phys Ther, 91:48-60,

31 Changes in Walking Distance by Intervention Group Changes in Walking Speed by Intervention Group Speed (m/s) Speed (m/s) Field-Fote & Roach. Phys Ther, 91:48-60, 2011 Proportion of subjects who increased walk distance by more than 2 meters Walking speed in ND individuals is 1.2 m/s (2.7mph) Field-Fote & Roach. Phys Ther, 91:48-60, 2011 Field-Fote & Roach. Phys Ther, 91:48-60, 2011 Proportion of subjects who increased walking speed by more than.05 m/sec Proportion of subjects who improved in distance and/or speed Proportion Field-Fote & Roach. Phys Ther,

32 Proportion of weak subjects who improved in distance and/or speed Retention at followup Speed (m/s) = 2 = 2 = 4 = m/s +0.08m/s N = 10 Field-Fote & Roach. Phys Ther, 91:48-60, 2011 Proportion of strong subjects who improved in distance and/or speed Treadmill KINEMATIC DATA Week 0 Week 6 Week 12 What is the influence of training speed? Intralimb Coordination ND Subject Field-Fote & Lindley J Neurol Phys Ther,

33 Intralimb Coordination Subject with SCI - pre & post training Changes in R-LEMS by intervention group EMG Timing and Amplitude Pre Training Post Training Subjects in the OG group exhibit a median change of 6 pts*. Other groups: TM=3, TS=2, LR=3 *a 6 pt change is considered clinically significant in elderly (Shumway-Cook, 1997). Changes in L-LEMS by Intervention Group Pendulum Test 32

34 Flexor Reflex Response Reciprocal Inhibition Reflex in response to noxious stimuli Activation of sensory neuron causes activation or motor neuron and muscle contraction Persons with spasticity have an increased response to noxious stimuli Improvement = a decrease in response to stimulus after treatment ms % of test initial % test final * Ability to inhibit antagonist muscle in response to agonist muscle stimulation In people with spasticity, dysregulation of this reflex causes cocontraction of agonist and antagonist muscles Improvement = a decrease in response of antagonist muscle to stimulation 0.0 OG TS TM LR Flexor Reflex Response H reflex * FRR_50mA_i FRR_50mA_f Reflex in response to noxious stimuli Activation of sensory neuron causes activation or motor neuron and muscle contraction Persons with spasticity have an increased response to noxious stimuli Improvement = a decrease in response to stimulus after treatment Electrically induced stretch reflex Use electrical stimulation instead of muscle stretch Measure of synaptic transmission from sensory neurons to motor neurons H-reflex = Measure of muscle response to sensory nerve stimulation (twitch response) Normalized to maximum motor response Improvement = decrease in response to stimulation 0 OG TS TM LR Reciprocal Inhibition H reflex Ability to inhibit antagonist muscle in response to agonist muscle stimulation In people with spasticity, dysregulation of this reflex causes cocontraction of agonist and antagonist muscles Improvement = a decrease in response of antagonist muscle to stimulation Hmratio i Hmratio f H/M Ratio Electrically induced stretch reflex Use electrical stimulation instead of muscle stretch Measure of synaptic transmission from sensory neurons to motor neurons H-reflex = Measure of muscle response to sensory nerve stimulation (twitch response) Normalized to maximum motor response Improvement = decrease in response to stimulation 0.0 OG TS TM LR 33

35 Low Frequency Depression % Change * LFD I LFD F OG TS TM LR Depression of a neural pathway is induced by low frequency stimulation In subjects with spasticity, this adaptation is not present to the same degree An improvement in this measure = a decrease in response to low frequency stimulation How might we use what we know about effects of sensory input to improve locomotor function and reduce spasticity? Relationships among outcomes The vibration paradox responses of soleus H-reflex to soleus vibration in 2 ND subjects Change in H/M Ratio (%) r = Change in Pendulum Angle Change in H/M Ratio r = Change in Intralimb Coordination Van Boxtel. J Neurophysiol, Restoration of walking function improves quality of life often in unexpected ways Protocol: Whole Body Vibration Pre Test Quad spasticity, walking speed (10m) WBV: Static squat 50 Hz low amplitude 4x45sec 1min rest 3 days/week x 4 wks Post Test Quad spasticity, walking speed (10m) Ness & Field-Fote. Gait & Posture, 2009 (Walking function) Ness & Field-Fote. Restor Neurol Neurosci, 2009 (Spasticity) 34

36 Whole-body vibration decreases spasticity and improves walking in persons with SCI WBV influences on spasticity cumulative multi-session effects early within-session effects late within-session effects WBV protocol details Training Sequence Testing Sequence Ness & Field-Fote. Gait & Posture, 2009 (Walking function) Ness & Field-Fote. Restor Neurol Neurosci, 2009 (Spasticity) WBV is associated with decreased quadriceps spasticity FSE (degrees) FSE (degrees) Intervention week Ness & Field-Fote. Restor Neurol Neurosci, 2009 WBV is associated with increased walking speed Ness & Field-Fote. Gait & Posture, 2009 WBV is associated with improved gait speed and quality Ness & Field-Fote. Restor Neurol Neurosci, Ness & Field-Fote. Gait & Posture,

37 Improved walking following 12-session course of WBV Vibration elicits involuntary stepping in individuals with SCI Vibration: 60 Hz, ~1 mm displacement How might vibration influence the locomotor CPG? ND Individual: Involuntary Stepping with Muscle Vibration Field-Fote et al, Neurorehabil Neural Repair Vibration elicits involuntary steplike movement in ND individuals Motor-incomplete SCI: Involuntary Stepping with Muscle Vibration Vibration elicits locomotor-like movements Single muscle or contralateral leg Cyclic behavior suggesting CPG origin Gurfinkel et al. Eur J Neurosci, 10: , 1998 Field-Fote et al, Neurorehabil Neural Repair

38 Motor-complete SCI: Involuntary Stepping with Muscle Vibration Targets for Intervention (1) reduction of edema and free-radical production, (2) rescue of neural tissue at risk of dying in secondary processes, (3) control of inflammation, (4) rescue of neuronal/glial populations at risk of apoptosis, (5) repair of demyelination and conduction deficits, (6) promote neurite growth via improved extracellular environment, (7) cell replacement therapies, (8) efforts to bridge the gap with transplantation approaches, (9) efforts to retrain and relearn motor tasks, (10) restoration of lost function by electrical stimulation, (11) relief of chronic pain syndromes. Field-Fote et al, Neurorehabil Neural Repair Hulsebosch CE. Adv Physiol Educ. 2002; 26: Roadmap: 1. Neural mechanisms underlying neuroplasticity rely on changes excitability 2. Excitability is influenced by practice and by stimulation 3. Neuroplastic cortical changes appear to reflect changes in function 4. Spinal reflex and pattern-generating circuits respond training in the same way as cortical circuits 5. Combining training and stimulation may represent an optimal approach to promoting adaptive neuroplasticity Journey s End There are maladaptive changes in cortex and spinal cord after CNS injury Maladaptive plasticity contributes to motor dysfunction Stimulation and training promote adaptive neuroplasticity of both cortical and spinal circuits that are supportive of improved function Stimulation (electric & vibration) activates much the same circuitry as training The BAD News: To date no intervention has been shown to be more effective than rehabilitation at improving function The GOOD News: To date no intervention has been shown to be more effective than prevention & rehabilitation at improving function 37

39 Activating the nervous system can make a difference today 38