Paradigm Shift in Neuroscience 9/7/2016. Fashion or Need?

Transcription

1 Hermano Igo Krebs IEEE Fellow Disclosure: Dr. H. I. Krebs is co inventor in the MIT held patents for the robotic devices used to treat patients in this work. He holds equity positions in Bionik Laboratories, Watertown, MA a company that manufacturers this type of technology under license to MIT. Massachusetts Institute of Technology Fashion or Need? Stroke In the US 795, strokes every year economic burden of $73.7 billion for 21 7% of the survivors need therapy total of 6 Million stroke survivors In Europe 9, strokes every year In Japan 21, strokes every year In Brazil Number #1 cause of death Introduction AHA Guidelines UE Robotics LE Robotics State of the Art in UE Paradigm Shift in Neuroscience Myth and Legend: Traditional care assumes that brain is hardwired and cannot recover once sensorimotor areas are destroyed Reality: New understanding: after stroke and other neurological injuries plasticity occurs and might accounts for remapping of new pathways 1

2 Hardwired Since the 1928 work of Santiago Ramón y Cajal, famed neuroscientist, the prevailing assumption has been that the central nervous system is hardwired, non malleable, and incapable of repairing itself. Clinicians have selected compensation as a rehabilitation strategy for non remediable deficits of strength, voluntary motor control, sensation, and balance. Rationale for Restorative Efforts and Training in Stroke Recovery: Animal Models for Activity Dependent Plasticity Nudo et al., Science; 1996 Paradigm Shift in Neuroscience Myth and Legend: Traditional care assumes that brain is hardwired and cannot recover once sensorimotor areas are destroyed Reality: New understanding: after stroke and other neurological injuries plasticity occurs and might accounts for remapping of new pathways 2

3 Assistive, Prosthesis, Robotics Paradigm shift :Rehabilitation robots market at $43.3 million* 22:Rehabilitation robots market expected to grow to $1.8 billion Wintergreen Research; Number of Publications rehab robotics service robotics arm prosthesis Toyota Honda Yaskawa Teijin Hyundai LG Parker Hannifin year Lockheed Martin 3

4 21 Guidelines Introduction AHA Guidelines UE Robotics LE Robotics State of the Art in UE Outpatient & Chronic Inpatient 21 Guidelines 4

5 216 Guidelines 216 AHA Is this true? 5

6 216 AHA CSP558 Veteran Affairs Randomized Clinical Trial CSP558: Robotic Assisted Upper-Limb Neurorehabilitation in Stroke Patients Introduction AHA Guidelines UE Robotics LE Robotics State of the Art in UE Study Randomization Groups Robot assisted Therapy (RT) proximal or distal upper extremity segment movements and integrated whole arm movements Usual Care (UC) Customary VA chronic post stroke care includes in average 3 therapy sessions per week of upper extremity training Matching time in therapy Intensive Comparison Therapy (ICT) a structured rehabilitative protocol that employs conventional techniques to match robot assisted therapy in number of sessions, type, intensity, and quantity of movements ( Charlie Chaplin Modern Times therapy Volpe et al, Neurorehab & Neural Repair, 22:3:35 31; 28) Matching time and intensity Active treatment: 36 therapy sessions over 12 weeks. Evaluations at 6, 12, 24 and 36 weeks RT better than UC by 5 points (MCID) RT better than ICT by 3 points (MCID patients retain gains) 6

7 Study Population 18 years Moderate to severe upper extremity impairment Fugl Meyer score: 7 to 38 Stroke occurring at least 6 months prior No upper limit on time since stroke Single Stroke Volunteers with multiple strokes were not excluded Robots Consisted of 4 modules: Shoulder elbow Antigravity Wrist Grasp hand Intensive Comparison Therapy 7

8 Baseline Entry Characteristics Age = 64.6 (±11.3) years 96% male 78% were white; 19% were black Ischemic stroke = 85% Time since index stroke = 4.7 years (.5 to 23.6) Multiple strokes identified by imaging = 33% Fugl Meyer Assessment = 18.9 (±9.5) Wolf Test times = 71.1 seconds (±33.2) Stroke Impact Scale = 49.4 (±14.7) Timeline Chart: Ideal UC Patient s choice retention placebo Usual care random 24 months Intensive Matched Robot Group Timeline Chart: Adaptive Algorithm 15 months UC Patient s choice retention placebo cost reduction Usual care random Intensive Matched Robot Group 24 months 8

9 Primary Outcome Fugl Meyer Change at 12 weeks Comparison at 15 months when UC was dropped months trial MCID 5 points Alternate MCID 3points N RT =25 N UC =27 N RT =47 N ICT =46-3 Robot UC -3 Robot Overall Mean Difference over 12 weeks Overall Mean Difference -2 ICT over 12 weeks Fugl Meyer Robot vs. UC = 2.17, p=. 8 Wolf Robot vs. UC = 4.41sec, p=.22 SIS Robot vs. UC = 7.64, p =.9 Robot vs. ICT=.14, p=. 92 Wolf Robot vs. ICT =.93sec, p=.82 SIS Robot vs. UC=.54, p=.81 Evaluations at week 12 1 random 15 months Their choice 24 months Usual care Intensive Matched Robot Group Change Fugl Meyer 1st half 2nd half Timeline and Evaluation 15 months Their choice Evaluations at 6, 12, 24,36 weeks 6 months No therapy Usual care random Intensive Matched Robot Group 24 months 9

10 Fugl-Meyer Change:12 Weeks Intervention, Follow-Up at 36 Weeks Comparison at 15 months when UC was dropped 24 months trial 2 pts MCID 5 points Alternate MCID 3points N RT =25 N UC =27 N RT =47 N ICT =46 Overall Mean Difference over 36 weeks Fugl Meyer Robot vs. UC = 2.88, p=.16 Wolf Robot vs. UC = 8.1sec, p=.5 SIS Robot vs. UC = 5.95, p=.4 Overall Mean Difference over 36 weeks Robot vs. ICT =.58, p=.63 Wolf Robot vs. ICT = 2.13sec, p=.55 SIS Robot vs. UC = 1.19, p=.55 Cost for the VA Healthcare System Cost of 4 modules: Shoulder elbow Antigravity Wrist Hand module USD 23,75 1

11 Cost for the VA Healthcare System Average per patient additional cost of therapy Robot Therapy U$5,152 p<.1 ICT U$7,382 Usual Care U$ Average total cost over 36 weeks (therapy + all other healthcare utilization) Robot U$17,831 (other healthcare $12,679) ICT U$19,746 (other healthcare $12,364) Usual Care U$19,98(other healthcare $19,98) Cost for the VA Healthcare System total health care cost U$19,746 U$19,98 U$17,831 U$12,679 U$12,364 Is that placebo? U$14,513 p=.4 U$7,777 U$25,68 U$34, weeks End FY29 9/3/29 Generalizability of CSP 558 Outcome Assessments, mean (SD) 2 individuals screened,127 enrolled (64%) Time since index stroke = 4.7 years Multiple strokes identified by imaging = 33% Fugl Meyer Assessment = 18.9 (±9.5) Wolf Test times = 71.1 seconds (±33.2) Stroke Impact Scale = 49.4 (±14.7) Constraint Induced Movement Therapy 3,626 individuals screened, 222 enrolled (6%) Fugl Meyer 42.5 (11.7) 11

12 Sub Acute (Inpatient) 1 st study 2 inpatients (1 exp, 1 control) Experimental: at least 25 hours of interactive sensorimotor training Control: 5 hours of sensory training Aisen, M.L.; Krebs, H.I.; McDowell, F.; Hogan, N.; Volpe, B.T.; The Effect of Robot Assisted Therapy & Rehabilitative Training on Motor Recovery Following a Stroke ; Archives of Neurology; 54: , April nd Study (3 exp, 26 controls) Volpe, B.T., Krebs, H.I., Hogan, N., Edelstein, L., Diels, C.M., Aisen, M.; A Novel Approach to Stroke Rehabilitation: Robot Aided Sensorimotor Stimulation, Neurology, 54: , inpatients (55 exp, 41 control) Volpe, B.T., Krebs, H.I., Hogan, N.; "Is robot aided sensorimotor training in stroke rehabilitation a realistic option?", Current Opinion in Neurology, Lippincott Williams & Wilkins, 14: , 21. Inpatients: Clinical Results Between Group Comparisons: Final Evaluation Minus Initial Evaluation Robot Trained (N = 55) Control (N = 41) P- Value Impairment Measures (± sem) Fugl Meyer shoulder/elbow(fm-se) 6.7 ± ±.7 NS Motor Power (MP) 4.1 ±.4 2.2±.3 <.1 Motor Status shoulder/elbow (MS-se) 8.6 ±.8 3.8±.5 <.1 Motor Status Wrist / Hand (MS/wh) 4.1 ± ±.8 NS Disability Evaluation Functional Independence Measure (FIM) 32. ± ± 6.5 NS Inpatients:Long Term Benefits Is robot aided sensorimotor training in stroke rehabilitation a realistic option? ; Volpe, Krebs, Hogan; Current Opinion in Neurology 21, vol.14 12

13 Therapeutic Robotic Training: Inpatients Mass repetition: 2,48 point-topoint movements (4 week program) Impact of our Movement Therapy: experimental group improved 2 x control group (absolute scale: 1%) Recovery might continue far beyond 11 weeks post-stroke. The improved outcome was sustained after 3 years Meta Analysis of Robot Therapy Trials on Motor Recovery G Kwakkel; B J Kollen; H I Krebs, Effects of Robot assisted therapy on upper limb recovery after stroke: A Systematic Review, Neurorehabilitation and Neural Repair (in press) 248 Stroke Patients 13

14 RATULS: Robot Assisted Training for the Upper Limb after Stroke NHS: National Health Service UK NICE: National Institute for Health and Clinical Excellence 4 hubs: Addenbrookes (Cambridge), Queens Hospital Romford (London), Western Infirmary (Glasgow) and North Tyneside Hospital North Shields (Newcastle) 16 hospitals 72 stroke patients Completion 218 VA Multi Site Trial 14

15 Structure Practice Session Multitude of variables that may influence outcome, but little is known of the independence or interaction among these variables, nor their actual impact on outcomes. Drive Neural Plasticity Apply Motor Learning Principles Principle Description 1. Use it or Lose it Failure to drive specific brain functions can lead to functional degradation. 2. Use It and Improve it Training that drives a specific brain function can lead to an enhancement of that function. 3. Specificity The nature of the training experience dictates the nature of the plasticity. 4. Repetition Matters Induction of plasticity requires sufficient repetition. 5. Intensity Matters Induction of plasticity requires sufficient training intensity. 6. Time Matters Different forms of plasticity occur at different times during training. 7. Salience Matters The training experience must be sufficiently salient to induce plasticity. 8. Age Matters Training induced plasticity occurs more readily in younger brains. 9. Transference Plasticity in response to one training experience can enhance the acquisition of similar behaviors. 1. Interference Plasticity in response to one experience can interfere with the acquisition of other behaviors. 4. Repetition Matters Induction of plasticity requires sufficient repetition. Shoulder 6, Orthologic, Tempe, AZ backdriveability 15

16 Continuous Passive Motion Machine (sub acute patients) Group Pat # Score, adjusted mean ± SEM Time MP MSS/S,E F-M/S,E Joint stability CPM N=17 Adm 3.71± ± ± ±.45 Disch 9.7 ± ± ± ±.4 Contr N=15 Adm 1.33± ± ± ±1.94 Disch 7. ± ± ± ±.4 Lynch, D, Ferraro, M, Krol, J, Trudell, C.M. Christos, P, Volpe, BT. Continuous Passive Motion Improves Shoulder Joint Integrity Following Stroke. Clinical Rehabilitation 24. Drive Neural Plasticity Apply Motor Learning Principles Principle Description 1. Use it or Lose it Failure to drive specific brain functions can lead to functional degradation. 2. Use It and Improve it Training that drives a specific brain function can lead to an enhancement of that function. 3. Specificity The nature of the training experience dictates the nature of the plasticity. 4. Repetition Matters Induction of plasticity requires sufficient repetition. 5. Intensity Matters Induction of plasticity requires sufficient training intensity. 6. Time Matters Different forms of plasticity occur at different times during training. 7. Salience Matters The training experience must be sufficiently salient to induce plasticity. 8. Age Matters Training induced plasticity occurs more readily in younger brains. 9. Transference Plasticity in response to one training experience can enhance the acquisition of similar behaviors. 1. Interference Plasticity in response to one experience can interfere with the acquisition of other behaviors. Passive vs Intention Driven Training Amount of Guidance in Unimpaired 16

17 Passive vs Intention Driven Training in Motor Habilitation Earth mean radius = 6,371km Earth perimeter = 4,3km 2 miles per day = 3.22 km 1 year = 1,175 km 66 years = 77,55km Korea June 216 CP Passive vs Intention Driven % change Fugl-Meyer, SHUEE, Modified Ashworth Spasticity Scale & Muscle strength/grip 3% Fugl-Meyer SHUEE Ashworth Muscle strength/grip 2% 1% % wrist, hand total strength grip -1% shoulder, elbow, forearm coordinat/speed grasp/release dynam positional spontan functional -2% -3% Korea June 216 Proximal Limb Segment Korea June

18 Y Y Y Y Hand Displacement X Hand Displacement X Hand Displacement X Hand Displacement X Y Y Y Y Hand Displacement X Hand Displacement X Hand Displacement X Hand Displacement X Distal Limb Segment Learning, Not Adaptation, Characterizes CP Motor Habilitation: Evidence from Kinematic Changes Induced by Robot Assisted Therapy in Trained and Untrained Task in the Same Workspace. Krebs HI, Fasoli SE, Dipietro L, Fragala Pinkham M, Hughes R, Stein J, Hogan N, Motor Learning Characterizes Habilitation of Children with Hemiplegic Cerebral Palsy, Neurorehabilitation and Neural Repair (212). Admission Discharge Pii2 Pii3 Pii4 Pii5 (displacement in meters) 18

19 Aim Metric Base Mid Disch F/U Mean Speed Metric Base Mid Disch F/U Smoothness Metric Base Mid Disch F/U Ellipse Ratio Metric Base Mid Disch F/U Deviation Metric Base Mid Disch F/U Peak Speed Metric Base Mid Disch F/U Movement Duration Base Mid Disch F/U * P <.5 * P <.5 NS NS Ratio Minor/Major Axes Speed (m/s) Peak Speed (m/s) Smoothness (non-dimensional) Duration(s) Aim (Rad) Deviation (m) NS NS NS NS * P <.5 NS * P <.5 NS * P <.5 NS Training with Gravity Compensation vs. without Gravity Compensation Spatial Training: Myth or Reality S. S. Conroy, J. Whitall, L. Dipietro, L. M. Jones Lush, M. Zhan, M. A. Finley, G. F. Wittenberg, H. I. Krebs, C. T. Bever. Effect of Gravity on Robot Assisted Motor Training After Chronic Stroke: A Randomized Trial, Arch of Phys Med Rehab, 92:11: , November,

20 Drive Neural Plasticity Apply Motor Learning Principles Principle Description 1. Use it or Lose it Failure to drive specific brain functions can lead to functional degradation. 2. Use It and Improve it Training that drives a specific brain function can lead to an enhancement of that function. 3. Specificity The nature of the training experience dictates the nature of the plasticity. 4. Repetition Matters Induction of plasticity requires sufficient repetition. 5. Intensity Matters Induction of plasticity requires sufficient training intensity. 6. Time Matters Different forms of plasticity occur at different times during training. 7. Salience Matters The training experience must be sufficiently salient to induce plasticity. 8. Age Matters Training induced plasticity occurs more readily in younger brains. 9. Transference Plasticity in response to one training experience can enhance the acquisition of similar behaviors. 1. Interference Plasticity in response to one experience can interfere with the acquisition of other behaviors. Training Proximal vs. Distal Limb Segments Training Proximal vs. Distal Limb Segments 12 weeks 1 week 1 session 19 outpatients (target 16 outpatients) at Burke at NY Presbyterian robotic wrist therapy robotic shoulder/elbow therapy at Unicampus Group A: 6 weeks wrist + Does 6 weeks shoulder/elbow sequence matter? Group B: 6 weeks shoulder/elbow + Does robotic General 6 weeks wrist wrist therapy across improve Group C: 12 weeks alternating days joints? motor shoulder/elbow and wrist performance Interference? across joints? Group D: 12 weeks same day shoulder/elbow and wrist 2

21 Changes per Site Tableau ANOVA pour FM Disch-Adm ddl Somme des carrés Carré moyen Valeur de F Valeur de p Lambda Puissance Site Résidu Tableau de moyennes pour FM Disch-Adm Effet : Site Nombre Moyenne Dév. Std. Err. Std. Burke Campus Biomedico NY Presbytherian Graphique des interactions pour FM Disch-Adm Effet : Site Moy. cell Burke Campus Biomedico NY Presbytherian Cell Test PLSD de Fisher pour FM Disch-Adm Effet : Site Niveau de significativité : 5 % Diff. moy. Diff. crit. Valeur p Burke, Campus Biomedico Burke, NY Presbytherian Campus Biomedico, NY Presbytherian Training Proximal vs. Distal Limb Segments Graphique des interactions pour FM Disch-Adm Effet : group Graphique des interactions pour FM Followup-Admission Effet : group alternate planar-wrist within wrist-planar Cell alternate planar-wrist within wrist-planar Cell Test PLSD de Fisher pour FM Followup-Admission Effet : group Niveau de significativité : 5 % Diff. moy. Diff. crit. Valeur p alternate, planar-wrist alternate, within alternate, wrist-planar planar-wrist, within planar-wrist, wrist-planar within, wrist-planar S Drive Neural Plasticity Apply Motor Learning Principles Principle Description 1. Use it or Lose it Failure to drive specific brain functions can lead to functional degradation. 2. Use It and Improve it Training that drives a specific brain function can lead to an enhancement of that function. 3. Specificity The nature of the training experience dictates the nature of the plasticity. 4. Repetition Matters Induction of plasticity requires sufficient repetition. 5. Intensity Matters Induction of plasticity requires sufficient training intensity. 6. Time Matters Different forms of plasticity occur at different times during training. 7. Salience Matters The training experience must be sufficiently salient to induce plasticity. 8. Age Matters Training induced plasticity occurs more readily in younger brains. 9. Transference Plasticity in response to one training experience can enhance the acquisition of similar behaviors. 1. Interference Plasticity in response to one experience can interfere with the acquisition of other behaviors. 21

22 Functionally Based Rehabilitation: Benefit or Buzzword? Breakfast with Tiffany s Functionally Based Rehabilitation: Benefit or Buzzword? Protocol combined robot assist for transport with graded distal tasks involving actual objects. Hypothesis: Specific, task oriented training that combines robot assist with object grasp or manipulation would produce greater gains than standard robot training. 22

23 Functionally Based Rehabilitation: Benefit or Buzzword? Functionally Based Rehabilitation: Benefit or Buzzword? (MEAN STD) Group A Transport of Arm (N=32) Group B Transport of Arm and Actual Grasp (N=1) Group C Transport of Arm and Virtual Grasp (N=5) ANOVA p-value Between Groups FMA PRE- CHANGE FMA TREATMENT (/66) (/66) CHANGE FMA S/E (/42) CHANGE FMA W/H (/24) 25. ± ± NS NS A vs B: p=.2 A vs C: p=.3 NS Krebs, Mernoff, Fasoli, Hughes, Stein, Hogan. A Comparison of Functional and Impairment Based Robotic Training in Severe to Moderate Chronic Stroke: A Pilot Study. NeuroRehabilitation 23:1:81 87 (28) Transition to Task Impairment based (A) vs. functionally based (B) Which is best intervention for whom? Motor Thresholds may indicate whether Rx A or B is most appropriate. Continuum of intervention methods functional impairment functional time 23

24 Transition to Task Transition to Task FM: Wrist Hand Section Mean FM W H Change Score Robot 4 week 8 week 12 week 24 week Evaluation Week Functionally Based Rehabilitation: Benefit or Buzzword? D. Reinkensmeyer 24

25 Functionally Based Rehabilitation: Benefit or Buzzword? 25

26 Transition to Task Impairment based (A) vs. functionally based (B) Which is best intervention for whom? Motor Thresholds may indicate whether Rx A or B is most appropriate. Continuum of intervention methods functional impairment functional time 26

27 UE Robotic Therapy: Efficiency? Assessing a rehabilitation technique: whether gains are as good or better than other modalities whether gains persist for a significant period after training whether gains generalize to untrained tasks Whether cost/benefit are as good or better than other modalities total health care cost U$19,746 U$19,98 U$17,831 U$12,679 U$12,364 Is that placebo? U$14,513 p=.4 U$7,777 U$25,68 U$34, weeks End FY29 9/3/29 Thank you hikrebs@mit.edu Massachusetts Institute of Technology 27