High Intensity Aerobic Exercise to Enhance Plasticity Post-Stroke Susan Linder, PT, DPT, NCS Cleveland Clinic [email protected]

Anson Rosenfeldt, PT, DPT, MBA Cleveland Clinic [email protected]

February 7, 2015 APTA Combined Sections Meeting

Jay L. Alberts, Ph.D. Cleveland Clinic [email protected]

Disclosure • JLA has authored intellectual property related to the forced exercise control algorithm.

Course Objectives At the end of the presentation, the participants will be able to: • Describe the potential role of BDNF in neuroplasticity after stroke. • Describe an evidence based approach to implementing aerobic exercise in individuals after stroke.

• Discuss the impact of a FE paradigm on the future of stroke rehabilitation.

Course Outline I. Rationale for our research II. Cellular response to forced exercise III. Forced exercise and Parkinson’s disease IV. Methodology for implementing forced exercise paradigm in individuals with stroke

V. Motor and non-motor results VI. Clinical translation and future directions

Effects of aerobic exercise on brain health • Enhances acquisition and retention of information • Improves memory and executive function

• May protect against age related brain atrophy • Evidence of increased brain volume in older adults (white and gray matter)

• Treatment for depression

Neurotrophic Factors • Neurotrophins signal neurons to survive, differentiate, and grow

• Brain derived neurotrophic factor (BDNF)

– Of particular interest in rehabilitation

Upregulation of BDNF via Aerobic Exercise Training • Dependent on – Exercise Type – Exercise Intensity – Exercise Duration – Genetics

• Increased levels tend to be transient

What can animal models tell us about exercise and neuroplasticity?

Forced-exercise and neuroprotection in rodent models of PD

Effects of Forced Exercise (FE) in Animal Models of PD • Increased release of dopamine

• Decreased synaptic clearance of dopamine • Increase in dopamine D2 receptor • Increase in neurotrophic factors (BDNF, GDNF, IGF-1) – Greater intensity (forced-exercise) results in higher levels of neurotrophic factors and more extensive the anatomical regions involved

From the Cornfields to a Clinical Trial to Community Outreach 2003

2007

Present

Closing the gap between animal and human studies

What is FE in a patient population? • Voluntary efforts of the patient are augmented – Exercise rate increased by approximately 30-35% – Consistent pedaling rate at high RPMs – Consistent pedaling pattern

• Aerobic – 60-80% target HR zone

• FE is not passive

Forced-Exercise Mechanisms(?) of Action

Design of bike

Forced vs. Voluntary Exercise Intervention: • Randomly assigned to forced- or voluntary exercise groups • Three 1 hr. sessions/wk for 8 weeks • 10 min. warm up, 40 min. main set, 10 min cool down • 60-80% ACSM target HR • Forced-exercise group pedaled 30% faster and produced 42% less work compared to the voluntary exercise group.

Forced-exercise

Voluntary exercise

Ridgel et al., 2010

Aerobic exercise improves fitness, only FE improves clinical ratings

** 80

UPDRS Motor III Score

Estimated V02 (ml/kg/min) max

40

Forced Voluntary

35 30 25 20 15 10

70 60 50

**

40

**

30 20 10

5

0

0

Baseline

Baseline

EOT

Mid

EOT

-35%

EOT+2

-28%

EOT+4

-5%

1996

Study enrollment

1999 EOT 2003 Post EOT 2006

Forced-exercise Improves UE Motor Function

Reduced Anosmia with Increased Cadence Change in UPSIT Score from Baseline to EOT+4 weeks 95

Average RPM during trial

93 91 89 87 85 83 81

Assisted Voluntary

79 77 75 73 71 -12

-9

-6

-3

0

3

Change in UPSIT Score

6

9

12

Exercise Induced Changes Measured with fMRI

Aerobic Exercise improves Cardiovascular fitness in Patients with Stroke • At 1 month s/p stroke, peak VO2 limited

• In subacute (as early as 15 days) and chronic stroke, a CV exercise program has been shown to be feasible

• Stoller (2012) systematic review: favorable results with improving peak VO2 and 6MWT, but not gait speed

• CV training is a safe intervention for well-screened patients

Challenges in using aerobic exercise to drive motor recovery • Varied exercise interventions – Dose – Intensity – Timing in disease process – Duration – Reliance on clinical assessments

• Small sample sizes • Mixed patient characteristics

• Physical limitations in a diseased population

How can aerobic exercise promote neuroplasticity? • Upregulation of brain-derived neurotrophic factor (BDNF) – Enhance long term potentiation – Promote neurogenesis – Promote angiogenesis

– Suppress oxidative stress • Increase insulin-like growth factor

• Increase neurotransmitters

Mang, 2013

What can animal models in stroke tell us about exercise and neuroplasticity? • Mixed Results • Intensive FE (aerobic and forced use) applied immediately post-lesioning may result in increased lesion size & worse behavioral outcomes

• An enriched environment is beneficial to long-term behavioral recovery

• FE improves motor outcomes, but optimal dose and timing are unknown

Timing of Exercise and RTP Intervention impact Outcomes • Aerobic exercise – As early as 11-15 days, but lower intensity (≤60% of HHR) – Majority of research done in subacute to chronic stroke

• RTP – EXCITE trial  3-9 months post stroke – VECTORS trial  10 days post stroke 1) Traditional therapy 2) Standard CIMT: 2 hrs of shaping/day, constraint mitten x 6hrs 3) High Intensity CIMT: 3hrs of shaping/day, constraint mitten x 90% of waking hours

What is Forced Exercise In Stroke Rehabilitation? • Animal models – forced motor practice • Animal models – forced aerobic exercise • Human models – forced motor practice • Human models – forced aerobic exercise

Can FE be used to enhance Recovery of Function after Stroke?

Motor and Sensory Representation

Functional Outcomes for Stroke Patients • 35% do not regain full function of the leg • 65% cannot use their affected upper extremity for daily tasks

• 18% experience residual aphasia • ~30% live with severe, permanent disability

Barriers to Optimizing Functional Recovery

Difficult to Rehabilitate the Damaged Brain

Time-Consuming & Expensive

Cuts in Reimbursement & Caps on Therapy Visits

Current Approaches to Stroke Rehabilitation • Exercises/Activities to Increase Active Movement

• Teach compensatory strategies

• Retrain Functional Tasks Using Motor Learning Approach

The Challenge in Applying Aerobic Exercise to Individuals with Stroke to Facilitate Neuroplasticity • Hemiplegia / Hemiparesis – Decreased motor output

• Changes in skeletal muscle physiology

• Sensory loss • Spasticity • Severe deconditioning

Call for Novel Approaches to Stroke Rehabilitation: Our Solution

Prime the CNS via AE

Intensive Motor Practice

Study Aims • To determine the differential effects of forced and voluntary exercise on motor function, non-motor function, and cardiovascular fitness in individuals with chronic stroke

Hypothesis: Aerobic exercise will influence motor recovery and nonmotor function in individuals with stroke Anticipated Outcome: Those in the FE intervention group will have a greater recovery of motor and non-motor function than RTP alone

Proposed Mechanism of FE after Stroke

Study Overview

Screening & Consent

Baseline Biking Stress Test

Baseline Testing 3x/wk for 8 wks

FE + RTP

VE + RTP

End of Treatment (EOT) Testing EOT Biking Stress Test

EOT + 4 weeks

RTP Only

Inclusion/Exclusion Criteria Inclusion • 18-85 years old • 6-12 months post ischemic stroke • Approval from physician to participate in stress test • 19-55 on Fugl-Meyer upper extremity motor assessment • Ability to follow 1-2 step commands

Exclusion • Hospitalization for MI, CHF, heart •

• • • •

•

surgery within the past 3 months Serious cardiac or pulmonary contraindication to exercise (cardiomyopathy, PE, afib, etc.) Other musculoskeletal contraindications to exercise Major psychiatric disorder Anti-spasticity injections (botox) within the past 3 months Resting SBP>200mmHg or DBP> 110mmHg Fall in SBP>20mmHg with exercise

Time-Matched Interventions Group 1 (FE)

Group 2 (VE)

Group 3 (RTP)

Forced Exercise (45 min)

Voluntary Exercise (45 min)

RTP (45 min)

+

+

+

RTP (45 min)

RTP (45 min)

RTP (45 min)

Outcome measures • Motor outcomes

• Non motor outcomes

– Fugl-Meyer Assessment

– Center for Epidemiologic

(FMA) – Wolf Motor Function Test (WMFT)

Studies Depression Scale (CES-D) – Stroke Impact Scale (SIS)

• Cardiovascular – Peak VO2 – 6 Minute Walk Test (6MWT)

• Intervention-Related outcomes – Cycling: HR, cadence, power – RTP: # of reps, HR

Screening for Safety • Review of Medical History • Cardiopulmonary Exercise Stress Test – Physiologic response to intensive exercise – Baseline data –Heart rate (resting, maximal) –Blood pressure –Oxygen uptake –Cadence –Pedaling symmetry

Cardiopulmonary Stress Test (CPX) • Continuous, incremental

• •

•

metabolic stress test employed on a stationary bike Beginning with a workload of 20W and increasing by 20W every two minutes A 12-lead EKG and gas analysis to determine peak VO2 were continuously monitored RPE every 2 min

Cardiovascular Targets and Monitoring • Karvonen Formula: THR: (HRmax-HRrest) * 60-80% + HRrest

• Beta Blockers • Use of RPE

Applying 2 modes of Aerobic Exercise training to individuals with stroke Forced Exercise

•Patient’s voluntary efforts are augmented •Rate (cadence) is increased & constant •Exercise at 60-80% of HR reserve Voluntary Exercise

•Efforts toward exercise are not augmented •Rate is self-selected •Exercise at 60-80% of HR reserve

Repetitive Task Practice (RTP) • Focus on maximizing reps – Typically between 75-100+ reps of 1 task

• Type of practice – Blocked, whole part – Patient goal setting with reps or time

• Standing vs. Sitting • Minimize rest time • Incorporate ROM into •

functional activity Grading of activities

Screened (n=147)

Randomization (n=20)

BASELINE

FE + RTP (n=6)

N=1 Recurrent Stroke N=1 Dropout

EOT

FE + RTP (n=6)

RTP (n=6)

VE + RTP (n=8)

N=1 Dropout

VE + RTP (n=6)

RTP (n=5)

VE + RTP (n=6)

RTP (n=5)

N=1 Received Botox

EOT + 4

FE + RTP (n=5)

Top Reasons for Exclusion • Too low/high functioning UE

• Cardiac co-morbidities • Lack of Transportation

Study compliance and outcomes • Transportation • Attendance • Dropouts (N = 3) 1) Disappointed about randomization

2) Non-compliant with attendance 3) Medical complication unrelated to intervention

• Unusable data (N = 1) 1) Botox before EOT+4

Study Demographics RTP

VE

FE

N

5

6

6

Age (years)

61.6

60.7

44.8

Males

5/5

5/6

5/6

Race

4 white 5 white 1 African-American 1 African-American

3 white 2 African-American 1 Asian

Avg Time Since CVA

9.1 months

9.9 months

8.7 months

Avg Baseline FM Score (out of 66)

25.4

30.5

36.1

Safe Delivery of AE and Improvements in Function

Results of CPX for screening • 41 uneventful stress tests • 2 abnormal stress tests at baseline 1) ST segment depression - Pharmacological stress test with nuclear imaging  no ischemia and he was cleared to exercise

2) ST segment depression - Decided not to obtain follow up care - Did not continue with study

Patients with Stroke are Deconditioned Subject

Peak VO2 (mL/kg/min)

Percent of predicted peak VO2

Subject

Peak VO2 (mL/kg/min)

Percent of predicted peak VO2

H-01

20.3

66%

H-11

17.2

70%

H-02

17.3

52%

H-13

13.7

33%

H-03

33.0

78%

H-14

16.1

55%

H-04

17.1

54%

H-16

12.6

35%

H-05

28.9

69%

H-17

22.4

53%

H-06

14.1

79%

H-18

20.5

56%

H-07

11.9

44%

H-21

16.0

45%

H-08

19.1

54%

H-22

16.0

45%

H-09

12.8

35%

Representative Day of HR Data

AE Groups Received Half the Dosage of RTP Number of Repetitions

500

50

400

40

300

30

200

20

100

10

0

0

Reps/Session

Min/Session

Minutes Engaged in RTP

RTP VE FE

Participants were able to exercise at recommended aerobic levels HRR Percentage (%)

80

VE FE

60

40

20

0 1

2

3

4

5

6

7

Subject

8

9 10 11 12

Cardiovascular Outcomes

24

Aerobic exercise improves cardiovascular function

Peak VO2 (mL/kg/min)

23 22 RTP VE FE

21 20 19 18 17 16 15 Baseline

EOT

Time

Motor Outcomes

FE produces greater change in 55

Fugl-Meyer Scores

FMA Score (points)

50 RTP VE FE

45 40 35 30 25 Baseline

EOT

Time

EOT+4

Greater Improvements in Motor Recovery with Fewer Repetitions of UE Task Practice

Higher Cadence May Improve Motor Outcomes

Relationship Between Baseline FMA and Motor Recovery

Age did not correlate with motor recovery

All groups improve number of task completed on the WMFT

Group

Baseline

EOT

EOT + 4 weeks

Avg. Time in Seconds (# of items unable to complete) FE

1.148 (0)

1.884 (0)

2.173 (0)

FE

6.831 (0)

3.701 (0)

3.738 (0)

FE

9.192 (2)

14.732 (0)

NA - Botox

FE

1.836 (0)

1.693 (0)

1.547 (0)

FE

2.311 (0)

2.191 (0)

1.614 (0)

FE

2.093 (0)

1.922 (0)

1.717 (0)

VE

1.865 (0)

1.726 (0)

1.979 (0)

VE

3.712 (0)

4.419 (0)

3.912 (0)

VE

9.543 (11)

16.735 (11)

43.301 (8)

VE

6.993 (0)

6.028 (0)

6.150 (0)

VE

35.977 (5)

30.346 (4)

33.495 (3)

VE

23.647 (7)

23.070 (5)

20.679 (5)

RTP

19.984 (0)

13.619 (0)

9.274 (0)

RTP

12.848 (9)

23.810 (7)

10.258 (9)

RTP

8.458 (0)

10.205 (0)

7.521 (0)

RTP

3.109 (0)

2.360 (0)

2.254 (0)

RTP

28.939 (8)

35.673 (7)

34.151 (7)

Non-Motor Outcomes

FE group with significant improvements in depression scale Score on CES-D (points)

22 RTP VE FE

20 18 16 14 12 10 8 Baseline

EOT Time

EOT+4

All groups improve on motor domains of Stroke Impact Scale (SIS) QOL Measure SIS - Strength Domain RTP VE FE

70

60

50

Normalized SIS Score

Normalized SIS Score

SIS - ADL Domain

90

80

80

70

60 RTP VE FE

50

40

40

30 Baseline

EOT

Baseline

EOT+4

EOT+4

SIS - Percent Recovery

SIS - Hand Function Domain

RTP VE FE

60 50 40

Normalized SIS Score

80

70

Normalized SIS Score

EOT

Time

Time

70

60

50 RTP VE FE

40

30

30

20 Baseline

EOT

Time

EOT+4

Baseline

EOT

Time

EOT+4

Clinical Implications: Barriers and Possibilities

AHA/ASA Guidelines Aerobic Exercise Recommendations for Stroke Survivors Mode Large-muscle activities (i.e. walking, stationary cycle, combined armleg ergometry, seated stepper)

Intensity - 40-70% peak O2 uptake - 40-70% HRR - 50-80% max HR - RPE 11-14 (6-20 scale) or 1.5-3 (010 scale)

Frequency

Duration

3-7 days/wk

- 20-60 min/ session - multiple 10 min sessions

Time in Target HR Range (Percent)

Subjects’ HR Responses to RTP 100

Time Spent >40% of Target HR Range during RTP 87%

80

70%

60

40 27%

20

31%

27%

12%

11%

0 1

2

3

4

Subject

5

6

7

Mixed Results regarding Aerobic Response during PT/OT Observational studies during PT/OT sessions MacKay-Lyons, 2002 • ≥ 40% of HR reserve (HRR)

– PT: 5% of the session (2.8 ± 0.9 minutes) – OT: 2% (0.7 ± 0.2 minutes)

Kuys, 2006 • Average HR intensity during PT session was 24.2% of HHR

Koopman, 2013 • ~ 2hrs of a patient’s day in a was spent >40% HRR • Attributed standing time in PT/OT to eliciting this strain

Understanding what is done in research setting to guide clinical utilization • Constraint Induced Movement Therapy (CIMT)  6hrs/day

• Modified CIMT  3 hrs/day • What can be done in 45-60 min? Birkenmeier et al., 2010 - >300 reps in 1 hour OP setting

Waddell et al., 2014 - >280 reps in 1 hour IP rehabilitation session

What is occurring in the clinic How many reps are patients actually performing?

• Lang, et al. (2009) Activity

Mean Number of Reps

UE passive exercise

33

UE active exercise

54

UE functional task

32

LE active exercise

75

Gait

357

Transfers

11

Implementing RTP with Patients of various levels of UE function Impairment/Functional Limitation

Task

Grading of Task

Lower functioning UE Using gross motor Decreased shoulder AROM shoulder flex/abd to and strength making knock down dominos donning a coat difficult dispersed on tray table

Move domino location on table

Higher functioning UE Impaired intrinsic hand coordination limiting writing legibility

Writing practice on a lined white board

Changing the size of the lines to vary letter size requirements

Decreased shoulder ER resulting in difficulty washing hair

Overhead throwing to target with emphasis on external rotation during ‘wind-up’

Varying the distance of the target

Number of reps does not impact HR Range Number of Repetitions

400

350

300

250

Pearson's r

10

20

30

40

50

60

70

80

90

Percentage (%) of Time > 40% of HRR During 45 minute RTP Session

0.03683

Number of Reps in 45 Min. Session

Number of reps show weak correlation with baseline level of UE function 400 350 300 250 200 Pearson's r

0.32446

150

20

25

30

35

40

45

Baseline FMA Score

50

55

Do all patients need a formal stress test? • AHA/ASA recommend that individuals with stroke

•

•

undergo a graded exercise test with EKG. “If the physician overseeing the patient’s care determines an exercise test is not indicated or such an assessment in a given facility is not possible, the initiation of an exercise training program, individually tailored to a patient’s physical capabilities, should not be delayed.” “In lieu of graded maximal exercise tests, submaximal tests may be considered for stroke survivors.”

– 6MWT Billinger, et al., Physical Activity and Exercise Recommendations for Stroke Survivors: A Statement for Healthcare Professionals From the AHA/ASA. Stroke. 2014.

Eliminating barriers to cycling intervention • Keeping feet on pedals – Hypertonic, hypontonic, altered sensation and proprioception – Clip in biking shoe – Theraband for pedals, hip abduction – Warm up time

• Baseline deconditioning – 10 min increments with seated rest breaks if needed

Clinical Translation

Summary of Motor, Non-motor, & CV Results • Motor – All 3 groups improved overall in motor function – VE and FE groups improved ≥ RTP group despite receiving only ~half the RTP reps

• Non motor – Significant improvement in depression for FE group – Global improvements in QOL for all 3 groups

• Cardiovascular – VE and FE groups displayed improved cardiovascular fitness as measured by peak VO2

Conclusions • With proper screening, aerobic exercise training (forced & voluntary) is a safe and feasible intervention for individuals with chronic stroke.

• Aerobic exercise (forced & voluntary) when paired with half of an RTP dosage is efficacious in improving:

– Motor function – Mood and Quality of Life – Cardiovascular fitness

• FE appears to be superior to VE & time-matched RTP in improving motor impairment

Future Directions • Larger clinical trial – Stratified randomization

• Refining motor outcomes – Arm Motor Ability Test – Biomechanical Assessment of Bimanual Dexterity

• Further investigate HR response to RTP

• Facilitate the cost-effective implementation of this approach into clinical practice

• Investigate potential mechanism for neuroplasticity

Is Exercise Medicine? Yes

No

Acknowledgements

• Tanujit Day, PhD

• Cindy Clark, OTR/L • Mandy Penko, MS • Rami Rizk, MS • Liz Jansen, BS • Matthew Rasanow, BS • Andrew Bazyk

• This study was supported by NIH R03HD073566 from the from the National Institute of Neurological Disorders And Stroke

• The Research Electronic Data Capture (REDCap©) Database was used to record and store data for this study.

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• • • • • •

• • • • • •

statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke; a journal of cerebral circulation. Aug 2014;45(8):2532-2553. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics--2014 update: a report from the american heart association. Circulation. Jan 21 2014;129(3):e28-e292. Knaepen K, Goekint M, Heyman EM, Meeusen R. Neuroplasticity - exercise-induced response of peripheral brainderived neurotrophic factor. Sports Med. 2010;40:765-801 Ploughman M, McCarthy J, Bosse M, Sullivan HJ, Corbett D. Does treadmill exercise improve performance of cognitive or upper-extremity tasks in people with chronic stroke? A randomized cross-over trial. Arch Phys Med Rehabil. 2008;89:2041-2047 Seifert T, Brassard P, Wissenberg M, Rasmussen P, Nordby P, Stallknecht B, et al. Endurance training enhances bdnf release from the human brain. Am J Physiol Regul Integr Comp Physiol. 2010;298:R372-377 MacKay-Lyons M. Cardiovascular stress during a contemporary stroke rehabilitation program: Is the intensity adequate to induce a training effect? Arch Phys Med Rehabil. 2002;83:1378-1383 Pang MY, Eng JJ, Dawson AS, Gylfadottir S. The use of aerobic exercise training in improving aerobic capacity in individuals with stroke: A meta-analysis. Clinical Rehabilitation. 2006;20:97-111 Stinear CM, Barber PA, Coxon JP, Fleming MK, Byblow WD. Priming the motor system enhances the effects of upper limb therapy in chronic stroke. Brain. 2008;131:1381-1390 Ivey FM, Hafer-Macko CE, Macko RF. Exercise training for cardiometabolic adaptation after stroke. J Cardiopulm Rehabil Prev. 2008;28:2-11 Alberts JL, Linder S, Penko AL, Lowe MJ, Phillips M. It is not about the bike, it is about the pedaling: Forced exercise and parkinon's disease. Exercise Sports Science Reviews. 2011;37:177-186 Beall EB, Lowe MJ, Alberts JL, Frankemolle AM, Thota AK, Shah C, et al. The effect of forced-exercise therapy for parkinson's disease on motor cortex functional connectivity. Brain connectivity. 2013;3:190-198 Yates JS, Studenski S, Gollub S, Whitman R, Perera S, Lai SM, Duncan PW. Bicycle ergometry in subacute stroke survivors: Feasibility, safety and exercise performance. J Aging and Physical Activity. 2004;11:64-74 Luft A, Macko R, Forrester L, Goldberg A, Hanley DF. Post-stroke exercise rehabilitation: What we know about retraining the motor system and how it may apply to retraining the heart. Cleveland Clinic Journal of Medicine. 2008;75:S83-S86

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•

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