Roadmap: neuroplasticity and motor learning

Transcription

1 Advanced rehabilitation strategies to optimize neurological recovery after SCI Edelle C. Field-Fote, PhD, PT, FAPTA Professor, Physical Therapy & Neurological Surgery Principal Investigator, The Miami Project to Cure Paralysis Roadmap: neuroplasticity and motor learning 1. What neural mechanisms underlie neuroplasticity? 2. How does training influence neuroplasticity? 3. What is important about the type and amount of training? 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 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 1

2 Possible Mechanisms Underlying Neuroplasticity Altered Synaptic Efficacy Increased/decreased excitability Unmasking of Latent Connections New Connections sprouting synaptogenesis Neurogenesis Rapid Mechanisms of Plasticity Altered synaptic efficacy Changing the balance of excitatory and inhibitory connections Rapid Mechanisms of Plasticity Unmasking of latent connections (silent synapses) Telephone operators circa

3 Roadmap: neuroplasticity and motor learning Changes in synaptic efficacy underlie changes in neural excitability and responsiveness 1. What neural mechanisms underlie neuroplasticity? 2. How does training influence neuroplasticity? 3. What is important about the type and amount of training? Kandel, Schwartz & Jessell, Principles of Neural Science, 2000 Changes in synaptic efficacy underlie ability to retain effects of activation Slow Mechanisms of Plasticity Sprouting and synaptogenisis Sprouting of new dendrites Increased number of synapses Kandel, Schwartz & Jessell, Principles of Neural Science,

4 Neurogenesis in Humans Neurogenesis postnatally in: Hippocampus Subventricular Zone Olfactory Bulb Running / exercise increase hippocampal neurogenesis in adult mice After 12 days After 4 weeks van Praag, Kempermann G, and Gage. Nat Neurosci Walking associated with hippocampal neurogenesis in older adults Stimulation Speaks the Language of the Nervous System Erickson et al. PNAS Field-Fote. Exerc Sport Sci Rev,

5 Roadmap: neuroplasticity and motor learning 1. What neural mechanisms underlie neuroplasticity? 2. How does training influence neuroplasticity? 3. What is important about the type and amount of training? Operational premise: The goal of therapy is to: engage specific neural circuits in order to enhance the activity of those circuits in order to facilitate the related motor function Requirements for Proficient Motor Performance Relevant movement experience Repetition Neuroplasticity 5

6 Chondroitinase + specific training improves reaching Reaching task performance García-Alías et al. Nat Neurosci. 2009;12: García-Alías et al. Nat Neurosci. 2009;12: Ladder walking task impairs reaching skill acquisition BUT improves ladder walking Dose Literature: animal models of practice dose 100 s 1,000 s of reps/session over weeks to months Pellet retrieval Ladder missteps García-Alías et al. Nat Neurosci. 2009;12: Chen XY Wolpaw JR, et al. Neurosci Lett. 302: 85 88, Remple MS and Kleim JA, et al. Behav Brain Res 123: , Nudo & Milliken. J Neurophysiol. 1996;75: Chau C, Barbeau H, Rossignol S. J Neurophysiol 1998;79: de Leon RD, Hodgson JA, Roy RR, Edgerton VR. J Neurophysiol 1998;79:

7 Dose Literature: rehab studies of practice dose UE studies: 100+ reps/session LE studies: steps/session (many studies acknowledge importance of high repetitions but do not report the actual numbers) Carey JR, Kimberley TJ, et al. Brain. 2002;125: Boyd L, Winstein C. J Neurol Phys Ther. 2006;30: Fine MS, Thoroughman KA. J Neurophysiol. 2006;96: Dose Literature: studies of real-world practice dose Upper Extremity (reps) 1 Lang CE et al. J Neurol Phys Ther. 2007;31: Kimberley TJ et al J Rehabil Res Dev. 2010;47: Lower extremity (steps) Mean reps 95%CI Mean steps 95%CI Stroke Stroke TBI Understanding therapy dose Sleep consolidation Important for identifying Dose-response relationships Minimum dose needed for detectable change Dose associated with optimal change Walker et al Leaning and Memory,

8 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? Unfavorable Neuroplasticity Occurs after CNS Injury Maladaptive plasticity of the motor cortex after stroke What is the source motor impairment after SCI? Damage to descending tracts Detrimental spinal reorganization Damage to ascending tracts Detrimental cortical reorganization Nudo et al. J Neurosci,

9 Cortical plasticity in individuals with SCI The cortex reorganizes after SCI does this contribute to functional deficits? Curt et al. J Neurotrauma, 2002 Green et al. Neurology, 1998 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? Nudo RJ. Mol Psychiatry,

10 Cortical activity associated with loss and recovery of hand funcion after csci resembles that after stroke Mental practice improves function and promotes cortical plasticity Subject with csci activation of M1 and activation of associated sensorimotor areas 1 mo 3 mo Non-disabled subject 6 mo 12 mo (Jurkiewicks et al., 2007) Pascual-Leone et al J Neurophysiol. 1995; 74: Protocol: Mental Practice Pre Test Performance & cortical excitability Correlation between increases in cortical excitability and motor performance 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 (Kim et al,

11 Sensory input influences the motor cortex Cortical excitability is increased with sensory stimulation Pre MEP Post MEP Asanuma & Mackel Jpn J Physiol, Ridding et al, Exp Brain Res, 2000 Somatosensory stimulation enlarges cortical areas activated by movement Sensory stimulation increases pinch strength post stroke Wu et al. Neuroimage, 2005 Conforto et al. Ann Neurol

12 Effects of sensory stimulation + training on function post stroke Sensory stim + training improves function in individuals with stroke (single session) Median nerve stim (supra thrshld) Control stim (sub thrshld) (single session) Conforto et al. J Neurol, Conforto et al. J Neurol, Cortical Plasticity Occurs with LE Stimulation FES for footdrop modifies MEP of TA TENS to hand muscle increases size of cortical hand map in ND subjects TENS to APB 100 Hz 250 µs pulse width 21 days 1hr/day N = 24, 12/group Thompson &Stein. Exp Brain Res, 2004 Meesen et al. Human Brain Mapping,

13 TENS improves hand sensory function in individuals with MS (but not ND individuals) Protocol: Massed Practice + Somatosensory Stimulation Pre Test Performance, strength, cortical excitability 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 Cuyers et al. Neurorehabil Neural Repair, 2010 Beekhuizen & Field-Fote. Arch Phys Med Rehabil, 89: , 2008 Roadmap: functional recovery in the upper extremity Hand function is highest priority among those with tetraplegia 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? Anderson K. J Neurotrauma,

14 Massed practice for task-specific training effects Massed practice categories and sample tasks Pinch Grip Gross UE Movement Pinch with rotation Grip with rotation Beekhuizen & Field-Fote. Arch Phys Med Rehabil, 89: , 2008 Beekhuizen & Field-Fote. Arch Phys Med Rehabil, 89: , 2008 Task Modification for Success / Challenge 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) 14

15 Protocol: Massed Practice + Somatosensory Stimulation Pre Test Performance, strength, cortical excitability Functional hand use Jebsen -Taylor Hand Function test 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 Strength Sensory Function Beekhuizen &Field-Fote. Arch Phys Med Rehabil, 2008 Beekhuizen &Field-Fote. Arch Phys Med Rehabil,

16 Pre training Functional Test Post training Functional Test Unimanual Training Bimanual Training Bimanual activity engages more cortical areas than unimanual activity Bi Asym Bimanual Training Bi Sym Uni (Left) Hoffman & Field-Fote. J Neurol Phys Ther, 34: , 2010 De Weerd et al.,

17 EXCITATION INHIBITION Rationale: unilateral arm use is associated with inhibition of the inactive cortex but EXCITATION EXCITATION bilateral arm use is associated with bihemispheric excitation BASELINE BILATERAL ACTIVE CORTEX (UNI) INACTIVE CORTEX (UNI) BASELINE BILATERAL ACTIVE CORTEX (UNI) INACTIVE CORTEX (UNI) (Mc Combe & Waller, 2008) (Mc Combe & Waller, 2008) Unimanual hand function outcomes bimanual hand function outcomes Hoffman & Field-Fote. J Neurol Phys Ther, 34: , 2010 Hoffman & Field-Fote. J Neurol Phys Ther, 34: ,

18 V V 1 8 V V TMS cortical mapping to assess cortical plasticity Cortically Evoked Potentials after SCI ADC ADC ADC ADC Keyboard s MEP at 60%MSO in ND individual MEP at 90% MSO in individual incomplete cervical SCI wit Sample Thenar MEP at 88% MSO Pre-training The cortex reorganizes after SCI does this contribute to functional deficits? Post-training Green et al. Neurology,

19 Plasticity of the Motor Map Accompanying Recovery of Function Following SCI Subject with incomplete C5 injury Cortical Mapping Green JB et al. Neurology,1999. Hoffman & Field-Fote. Phys Ther, 2007 Biophysics of TMS Cortical stimulation as an intervention 19

20 rtms in SCI and ND High frequency (excitatory) rtms Direct cortical activation Elicits motor response Results: functional outcomes (Pascual-Leone, 1994; Beradelli et al, 1998; Butefish et al, 2004; Kim et al, 2006; Tallelli & Rothwell, 2006) Dashed line indicates threshold for moderate effect size 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 Transcranial direct current stimulation (tdcs) Polarizing currents applied to cortex modulate neuronal excitability Anodal = lowers threshold Cathodal = raises threshold Appears effective for hemiparesis Increase excitability of lesioned ctx Decrease excitability of non-lesioned ctx ANODAL Lesioned hemisphere CATHODAL Non-Lesioned hemisphere (Fregni & Pascual-Leone, 2007) 20

21 Uni-hemispheric tdcs in stroke Bi-hemispheric (anodal/cathodal) more effective than uni-hemispheric (ND subjects) Boggio et al. Rest Neurol Neurosci, 2007 Vines et al. BMC Neurosci, 2008 Protocol: Transcranial Direct Current Stimulation tdcs 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) Cervical Spinal Cord Injury - Bilateral upper extremity impairment - What about bilateral excitatory stimulation? Post Test Functional hand performance Boggio et al. Rest Neurol Neurosci,

22 Experimental Setup Bilateral anodal corticomotor tdcs (1 ma, 20 min) or sham Outcome Measures: BT and STM tasks Bimanual finger-sequencing scores * Rios-Gomes & Field-Fote. In review, 2013 Evidence suggests that stimulation can potentiate effects of motor practice Is there an advantage in choosing one modality over another? Methods/Research Design OR OR VERSUS VERSUS tdcs Vibration TENS T E S T I N G MOTOR TRAINING T E S T I N G SESSION 30 MIN BREAK T E S T I N G ONE SESSION PER WEEK 3 SESSIONS TOTAL OUTCOME MEASURES Active MEP Threshold Pinch Grip Strength Visuomotor Tracking Task 9-hole peg test 22

23 Hand function in persons with tetraplegia - effects of direct vs indirect cortical activation 2.5 Conclusions Even in chronic CNS injury there is potential for improvement of hand function HPT (pegs) Pinch force (kg) tdcs TENS VIB Both stimulation & training affect neural structures that underlie movement effects may be additive. There are changes in cortical neurophysiologic measures associated with functional change. Clinically available devices can be employed to increase cortical excitability 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? The smart spinal cord The spinal cord functions as part of the brain and not its servant -- Reggie Edgerton 23

24 Stretch Reflex H-reflex: the electrical analogue of the stretch reflex Spinal circuits generate innate rhythmic behaviors Spinal Cord Performs Sensory Motor Transformation 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: ,

25 The spinal cord controls limb coordination of innate, rhythmic behaviors Scratching in the spinal turtle Field &Stein. J Neurophys, 1997 Intra- and interlimb coordination following complete spinal cord transection Spinal stepping response in human infant 25

26 Involuntary stepping after SCI as evidence of human locomotor CPG Principles of motor control generalize across species Similar case in: Calancie et al. Brain, 1994 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 26

27 Modulation of spinal circuitry is essential for normal movement Excitability in response to stretch can be quantified The Pendulum Test High spasticity Low spasticity Lundbye-Jensen & Nielsen. J Physiol, Disrupted reflex modulation is associated with disordered motor output Motor Disorder Probable Origin Immobilization of ND subjects induces reflex changes similar to CNS injury Spasticity Increased responsiveness to stretch, ETC. Clonus Loss/reduction of post-activation depression Co-contraction Loss/reduction of reciprocal inhibition Flexor spasms Increased responsiveness to FRA input Spastic gait pattern Decreased phase-dependent modulation Lundbye-Jensen & Nielsen, J Physiol

28 Foot contact Toe off Spasticity during walking is correlated with severity of SCI non-disabled mildly impaired moderately impaired severely impaired 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 Spinal reflexes respond to training Stimulation improves reciprocal inhibition in those with spasticity ND subjects (n =74) o subjects with spasticity (n=39) subjects with spasticity who used CPN stim (n=4) Wolpaw et al, Brain Res, 1983 Crone et al. Brain,

29 CPN stimulation improves phase-dependent 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, 1994 Should we train to reflexes or to voluntary control? Sample SOL Outcome N =12 3 baseline sessions 12 training sessions (3/wk x 4 wks) Manella, Roach, Field-Fote. J Neurophys. In press, 2013 Manella, Roach, Field-Fote. J Neurophys. In press,

30 Outcomes EMG, clinical, walking, reflexes 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 Approaches to locomotor training in individuals with chronic CNS injury Treadmill-based training with BWS manual assisted FES assisted robotic assisted Overground training Treadmill vs skilled overground training in chronic SCI 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 N = 4 (8 per group) Musselman et al. Phys Ther,

31 Locomotor training improves walking in those with chronic incomplete SCI. But what is the best approach to improving walking function? Protocol: Locomotor Training Pre Test Walking speed & distance, reflexes, balance, etc 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,

32 Changes in Walking Speed by Intervention Group Proportion of subjects who increased walking speed by more than.05 m/sec Speed (m/s) 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, 2011 Changes in Walking Distance by Intervention Group Proportion of subjects who increased walk distance by more than 2 meters Speed (m/s) Field-Fote & Roach. Phys Ther, 91:48-60, 2011 Field-Fote & Roach. Phys Ther, 91:48-60,

33 Proportion of subjects who improved in distance and/or speed What is the influence of training speed? Proportion Mean Speed (m/s) Training Speed TM TS OG LR Groups Pre Test Post Test Field-Fote & Lindley J Neurol Phys Ther, 2005 Pre-Intervention 2-Minute Walk Test Post-Intervention 2-Minute Walk Test 33

34 Pendulum Test Percentage Change Degrees of Motion Pendulum Test Change in ROM * TM TS OG LR Groups Knee Angle at First Contraction TM TS OG LR PRE POST * sig increase in ROM p =.044 How might we use what we know about effects of sensory input to improve locomotor function? Groups How might vibration influence the locomotor CPG? 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: ,

35 Vibration elicits involuntary stepping in individuals with SCI ND Individual: Involuntary Stepping with Muscle Vibration Vibration: 60 Hz, ~1 mm displacement Field-Fote et al, Neurorehabil Neural Repair Motor-incomplete SCI: Involuntary Stepping with Muscle Vibration Motor-complete SCI: Involuntary Stepping with Muscle Vibration Field-Fote et al, Neurorehabil Neural Repair Field-Fote et al, Neurorehabil Neural Repair

36 Whole-body Vibration (WBV) Literature supports: decreased spasticity in individuals with CP (Ahlborg 06) Increased walking speed in elders and individuals with PD (Kawanabe 07, Ebersbach 08) Improved balance in individuals with stroke (van Nes, 04 & 06) WBV is associated with decreased quadriceps spasticity FSE (degrees) Ness & Field-Fote. Restor Neurol Neurosci, WBV influences on spasticity cumulative multi-session effects early within-session effects late within-session effects WBV is associated with improved gait speed and quality FSE (degrees) Intervention week Ness & Field-Fote. Restor Neurol Neurosci, 2009 Ness & Field-Fote. Gait & Posture,

37 Improved walking following 12-session course of WBV 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) Journey s End 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 Activating the nervous system can make a difference today 37

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