RLICC: Effect of Number of Remote Limb Ischemic Conditioning Cycles on Learning Enhancement

• Sponsor: Washington University School of Medicine (Other)
• Overall Status: Completed
• CT.gov ID: NCT03512041
• Collaborator: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)
• Enrollment: 40
• Location: 1
• Arms: 4
• Actual Duration (Months): 14
• Patients Per Site Per Month: 2.9

Study Details

Study Description

Brief Summary

The purpose of this research study is to determine the effect of number of remote limb ischemic conditioning (RLIC) cycles on enhancing learning in neurologically intact young adults.

Condition or Disease	Intervention/Treatment	Phase
Healthy, Young Adults	Behavioral: RLIC - 5 cycles; Behavioral: RLIC - 4 Cycles; Behavioral: RLIC - 3 Cycles; Behavioral: Sham conditioning; Behavioral: Balance training; Behavioral: Arm training; Behavioral: Sequence production training	Phase 1

Detailed Description

It is now understood that the nervous system has remarkable adaptive capacity. Specifically, the central nervous system retains its ability to reorganize in structure and function in response to behavioral experience in neurologically intact people and in individuals with neurological injury. Cognitive and motor learning guide the adaptation of the central nervous system and are essential components of effective training paradigms.

There is a growing body of literature which suggests that inducing a transient state of systemic ischemia has the potential to induce spinal plasticity, strengthen spared pathways to motorneurons, and lead to improved motor recovery following neurological injury.1,2 Specifically, daily systemic ischemic conditioning has been shown to improve both forelimb and respiratory motor function in rodent models of chronic cervical spinal injury.1,3 Moreover, systemic ischemic conditioning resulted in increased ankle strength (single session)2 and augmented walking speed and endurance (5 sessions)4 in humans with motor incomplete spinal cord injuries.

In a related area of research, it has been shown that ischemic conditioning administered peripherally represents a strategy for harnessing the body's endogenous protective capabilities against lethal levels of ischemia. With this technique, applying brief ischemia and reperfusion to a remote organ or tissue results in significantly reduced damage from subsequent exposures to ischemia. For example, applying a tourniquet and creating hypoxia in a rat's hindlimb for 10 minutes reduced the extent of cardiac abnormalities following a sustained ischemic insult.5 This same phenomenon has been shown in humans. Applying an inflated blood pressure cuff to the upper or lower limb has shown efficacy for protection in people undergoing cardiac surgeries,6,7 undergoing elective surgery to repair abdominal aortic aneurysm,8 experiencing MI,9 and with symptomatic intracranial arterial stenosis.7

The mechanisms underlying the neuroplastic and neuroprotective effects of ischemic conditioning are not fully understood. At this time, the literature indicates that there are both humoral and neural mechanisms responsible for the protection and the plasticity. It is clear that ischemic conditioning results in widespread physiological effects and that the observed effects work through multiple mechanistic pathways.

The next translational step is to investigate whether combining ischemic conditioning with behavioral training has the ability to augment motor learning. Specifically, we will employ remote limb ischemic conditioning (via inflation/deflation of a blood pressure cuff) with the objective of activating the endogenous pathways shown to elicit neuroplasticity. If eventually effective, RLIC could have profound effect on the rehabilitation and recovery of motor function in people with stroke. It is important to first start this translational investigation in neurologically intact people in order to determine optimal protocols for people with stroke.

The purpose of this study is to test the effect of number of RLIC cycles on motor learning in neurologically intact adults and if we can find a physiological blood marker related to effective administration of RLIC. We hypothesize that 3 cycles of RLIC will be sufficient to enhance motor leaning compared to sham conditioning, and that there will be a dose-dependent (number of cycles) response in learning, thus making training more efficient, more effective, and longer-lasting. Determining the number of cycles necessary to elicit the benefits of RLIC is important in developing the most effective and least burdensome treatment for future patients with motor deficits.

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Single blinded, randomized controlled trialSingle blinded, randomized controlled trial
• Masking: Single (Participant)
• Masking Description: Participants will be masked to their group assignment (RLIC or Sham conditioning) throughout the study. Participants will intuitively know the dose (number of cycles) of their assignment.
• Primary Purpose: Treatment
• Official Title: Effect of Number of Remote Limb Ischemic Conditioning Cycles on Learning Enhancement in Healthy Young Adults
• Actual Study Start Date: Dec 13, 2016
• Actual Primary Completion Date: Feb 13, 2018
• Actual Study Completion Date: Feb 13, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: RLIC - 5 Cycles Remote Limb Ischemic Conditioning (RLIC) is achieved via blood pressure cuff inflation to 20 mmHg above systolic blood pressure on the non-dominant arm. 5 Cycles of RLIC requires 45 minutes and involves 5 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation. RLIC is performed on visits 1-7.	Behavioral: RLIC - 5 cycles; RLIC is achieved as listed in the arm/group descriptions. RLIC is performed on visits 1-7, which occur on consecutive weekdays.; Other Names: Ischemic conditioning ; Behavioral: Balance training; All participants undergo training on a balance board, learning to hold the board level with equal weight on each leg. Participants perform the balance task for 15, 30-second trials per day at visits 3-7.; Behavioral: Arm training; All participants undergo training on a cup stacking task, learning to assemble and disassemble cup configurations as fast as they can. Participants perform the cup stacking task 5 trials per day at visits 3-7.; Other Names: Cup stacking ; Behavioral: Sequence production training; All participants undergo training on a discrete sequence production task. Participants learn to associate specific color and shape symbols with sequences of key presses on a keyboard. Participants perform the sequence production task for 10-15 minutes per day at visits 3-7.
Experimental: RLIC - 4 Cycles RLIC is achieved via blood pressure cuff inflation to 20 mmHg above systolic blood pressure on the non-dominant arm. 4 Cycles of RLIC requires 35 minutes and involves 4 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation. RLIC is performed on visits 1-7.	Behavioral: RLIC - 4 Cycles; RLIC is achieved as listed in the arm/group descriptions. RLIC is performed on visits 1-7, which occur on consecutive weekdays.; Other Names: Ischemic conditioning ; Behavioral: Balance training; All participants undergo training on a balance board, learning to hold the board level with equal weight on each leg. Participants perform the balance task for 15, 30-second trials per day at visits 3-7.; Behavioral: Arm training; All participants undergo training on a cup stacking task, learning to assemble and disassemble cup configurations as fast as they can. Participants perform the cup stacking task 5 trials per day at visits 3-7.; Other Names: Cup stacking ; Behavioral: Sequence production training; All participants undergo training on a discrete sequence production task. Participants learn to associate specific color and shape symbols with sequences of key presses on a keyboard. Participants perform the sequence production task for 10-15 minutes per day at visits 3-7.
Experimental: RLIC - 3 Cycles RLIC is achieved via blood pressure cuff inflation to 20 mmHg above systolic blood pressure on the non-dominant arm. 3 Cycles of RLIC requires 25 minutes and involves 3 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation. RLIC is performed on visits 1-7.	Behavioral: RLIC - 3 Cycles; RLIC is achieved as listed in the arm/group descriptions. RLIC is performed on visits 1-7, which occur on consecutive weekdays.; Other Names: Ischemic conditioning ; Behavioral: Balance training; All participants undergo training on a balance board, learning to hold the board level with equal weight on each leg. Participants perform the balance task for 15, 30-second trials per day at visits 3-7.; Behavioral: Arm training; All participants undergo training on a cup stacking task, learning to assemble and disassemble cup configurations as fast as they can. Participants perform the cup stacking task 5 trials per day at visits 3-7.; Other Names: Cup stacking ; Behavioral: Sequence production training; All participants undergo training on a discrete sequence production task. Participants learn to associate specific color and shape symbols with sequences of key presses on a keyboard. Participants perform the sequence production task for 10-15 minutes per day at visits 3-7.
Sham Comparator: Sham Conditioning Sham conditioning is achieved via blood pressure cuff inflation to 10 mmHg under diastolic blood pressure on the non-dominant arm. Sham conditioning requires 45 minutes and involves 5 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation. Sham conditioning is performed on visits 1-7.	Behavioral: Sham conditioning; Sham conditioning is achieved as listed in the arm/group descriptions. Sham conditioning is performed on visits 1-7, which occur on consecutive weekdays.; Behavioral: Balance training; All participants undergo training on a balance board, learning to hold the board level with equal weight on each leg. Participants perform the balance task for 15, 30-second trials per day at visits 3-7.; Behavioral: Arm training; All participants undergo training on a cup stacking task, learning to assemble and disassemble cup configurations as fast as they can. Participants perform the cup stacking task 5 trials per day at visits 3-7.; Other Names: Cup stacking ; Behavioral: Sequence production training; All participants undergo training on a discrete sequence production task. Participants learn to associate specific color and shape symbols with sequences of key presses on a keyboard. Participants perform the sequence production task for 10-15 minutes per day at visits 3-7.

Outcome Measures

Primary Outcome Measures

1. Balance Score [Visit 1 and Visit 7, approximately 1 week]

   The change from Visit 1 to Visit 7 in the average amount of time in seconds that a participant maintains the stability platform within ±3° of horizontal position during 5 trials of 30 seconds each. A greater increase in the balance score means more learning has occurred over the course of the study.

2. Cup Stacking Score [Visit 1 and Visit 7, approximately 1 week]

   The change from Visit 1 to Visit 7 in the average amount of time in seconds that a participant takes to stack and unstack pre-determined patterns of cups. A greater decrease in the cup stacking score means more learning has occurred over the course of the study.

3. Discrete Sequence Production Task Score [Visit 1 and Visit 7, approximately 1 week]

   The change from Visit 1 to Visit 7 in the average amount of time in seconds that a participant takes to complete pre-determined patterns of keypresses. A greater decrease in the Discrete Sequence Production Task score means more learning has occurred over the course of the study.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 40 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. Between the age of 18 and 40 years

Exclusion Criteria:

1. History of neurological condition (i.e. stroke, Alzheimer's disease, Parkinson's disease), ADD, ADHD, balance impairment, or vestibular disorder

2. History of sleep apnea

3. History of lower extremity condition, injury, or surgery which could compromise performance on motor training task

4. Any extremity soft tissue, orthopedic, or vascular injury (i.e. peripheral vascular disease) which may contraindicate RLIC

5. Any cognitive, sensory, or communication problem that would prevent completion of the study

6. Current intensive weight lifting or interval training exercise

7. Current substance abuse or dependence

8. Current use of medication with selective serotonin-reuptake inhibitors.

9. Unwillingness to travel for all study visits

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Washington University School of Medicine	Saint Louis	Missouri	United States	63108

Sponsors and Collaborators

• Washington University School of Medicine
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Principal Investigator: Catherine Lang, PT, PhD, Washington University School of Medicine

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 19, 2017

More Information

Publications

None provided.

• Responsible Party: Catherine E. Lang, Professor, Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT03512041
• Other Study ID Numbers: NIHR01HD085930-Aim2; R01HD085930
• First Posted: Apr 30, 2018
• Last Update Posted: Aug 26, 2019
• Last Verified: Aug 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Catherine E. Lang, Professor, Washington University School of Medicine: ischemic conditioning, motor learning
• Additional relevant MeSH terms: Ischemia

Study Results

Participant Flow

Arm/Group Title	RLIC - 5 Cycles	RLIC - 4 Cycles	RLIC - 3 Cycles	Sham Conditioning
Arm/Group Description	Remote Limb Ischemic Conditioning (RLIC) is achieved via blood pressure cuff inflation on the non-dominant arm. 5 Cycles of RLIC requires 45 minutes and involves 5 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation. RLIC is performed on visits 1-7. RLIC - 5 cycles: RLIC is achieved as listed in the arm/group descriptions. RLIC is performed on visits 1-7, which occur on consecutive weekdays. Balance training: All participants undergo training on a balance board, learning to hold the board level with equal weight on each leg. Participants perform the balance task for 15, 30-second trials per day at visits 3-7. Arm training: All participants undergo training on a cup stacking task, learning to assemble and disassemble cup configurations as fast as they can. Participants perform the cup stacking task 5 trials per day at visits 3-7. Sequence production training: All participants underg	RLIC is achieved via blood pressure cuff inflation on the non-dominant arm. 4 Cycles of RLIC requires 35 minutes and involves 4 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation. RLIC is performed on visits 1-7. RLIC - 4 Cycles: RLIC is achieved as listed in the arm/group descriptions. RLIC is performed on visits 1-7, which occur on consecutive weekdays. Balance training: All participants undergo training on a balance board, learning to hold the board level with equal weight on each leg. Participants perform the balance task for 15, 30-second trials per day at visits 3-7. Arm training: All participants undergo training on a cup stacking task, learning to assemble and disassemble cup configurations as fast as they can. Participants perform the cup stacking task 5 trials per day at visits 3-7. Sequence production training: All participants undergo training on a discrete sequence pr	RLIC is achieved via blood pressure cuff inflation on the non-dominant arm. 3 Cycles of RLIC requires 25 minutes and involves 3 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation. RLIC is performed on visits 1-7. RLIC - 3 Cycles: RLIC is achieved as listed in the arm/group descriptions. RLIC is performed on visits 1-7, which occur on consecutive weekdays. Balance training: All participants undergo training on a balance board, learning to hold the board level with equal weight on each leg. Participants perform the balance task for 15, 30-second trials per day at visits 3-7. Arm training: All participants undergo training on a cup stacking task, learning to assemble and disassemble cup configurations as fast as they can. Participants perform the cup stacking task 5 trials per day at visits 3-7. Sequence production training: All participants undergo training on a discrete sequence pr	Sham conditioning is achieved via blood pressure cuff inflation to 10 mmHg under diastolic blood pressure on the non-dominant arm. Sham conditioning requires 45 minutes and involves 5 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation. Sham conditioning is performed on visits 1-7. Sham conditioning: Sham conditioning is achieved as listed in the arm/group descriptions. Sham conditioning is performed on visits 1-7, which occur on consecutive weekdays. Balance training: All participants undergo training on a balance board, learning to hold the board level with equal weight on each leg. Participants perform the balance task for 15, 30-second trials per day at visits 3-7. Arm training: All participants undergo training on a cup stacking task, learning to assemble and disassemble cup configurations as fast as they can. Participants perform the cup stacking task 5 trials per day at visits 3-7. Sequence production training: All
Period Title: Overall Study
STARTED	10	10	11	9
COMPLETED	10	10	11	9
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	RLIC - 5 Cycles	RLIC - 4 Cycles	RLIC - 3 Cycles	Sham Conditioning	Total
Arm/Group Description	Remote Limb Ischemic Conditioning (RLIC) is achieved via blood pressure cuff inflation on the non-dominant arm. 5 Cycles of RLIC requires 45 minutes and involves 5 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation. RLIC is performed on visits 1-7. RLIC - 5 cycles: RLIC is achieved as listed in the arm/group descriptions. RLIC is performed on visits 1-7, which occur on consecutive weekdays. Balance training: All participants undergo training on a balance board, learning to hold the board level with equal weight on each leg. Participants perform the balance task for 15, 30-second trials per day at visits 3-7. Arm training: All participants undergo training on a cup stacking task, learning to assemble and disassemble cup configurations as fast as they can. Participants perform the cup stacking task 5 trials per day at visits 3-7. Sequence production training: All participants underg	RLIC is achieved via blood pressure cuff inflation on the non-dominant arm. 4 Cycles of RLIC requires 35 minutes and involves 4 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation. RLIC is performed on visits 1-7. RLIC - 4 Cycles: RLIC is achieved as listed in the arm/group descriptions. RLIC is performed on visits 1-7, which occur on consecutive weekdays. Balance training: All participants undergo training on a balance board, learning to hold the board level with equal weight on each leg. Participants perform the balance task for 15, 30-second trials per day at visits 3-7. Arm training: All participants undergo training on a cup stacking task, learning to assemble and disassemble cup configurations as fast as they can. Participants perform the cup stacking task 5 trials per day at visits 3-7. Sequence production training: All participants undergo training on a discrete sequence pr	RLIC is achieved via blood pressure cuff inflation on the non-dominant arm. 3 Cycles of RLIC requires 25 minutes and involves 3 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation. RLIC is performed on visits 1-7. RLIC - 3 Cycles: RLIC is achieved as listed in the arm/group descriptions. RLIC is performed on visits 1-7, which occur on consecutive weekdays. Balance training: All participants undergo training on a balance board, learning to hold the board level with equal weight on each leg. Participants perform the balance task for 15, 30-second trials per day at visits 3-7. Arm training: All participants undergo training on a cup stacking task, learning to assemble and disassemble cup configurations as fast as they can. Participants perform the cup stacking task 5 trials per day at visits 3-7. Sequence production training: All participants undergo training on a discrete sequence pr	Sham conditioning is achieved via blood pressure cuff inflation to 10 mmHg under diastolic blood pressure on the non-dominant arm. Sham conditioning requires 45 minutes and involves 5 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation. Sham conditioning is performed on visits 1-7. Sham conditioning: Sham conditioning is achieved as listed in the arm/group descriptions. Sham conditioning is performed on visits 1-7, which occur on consecutive weekdays. Balance training: All participants undergo training on a balance board, learning to hold the board level with equal weight on each leg. Participants perform the balance task for 15, 30-second trials per day at visits 3-7. Arm training: All participants undergo training on a cup stacking task, learning to assemble and disassemble cup configurations as fast as they can. Participants perform the cup stacking task 5 trials per day at visits 3-7. Sequence production training: All	Total of all reporting groups
Overall Participants	10	10	11	9	40
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	25.5 (3.9)	25.9 (2.9)	26.2 (4.6)	26.1 (1.6)	25.9 (3.2)
Sex: Female, Male (Count of Participants)
Female	7 70%	7 70%	6 54.5%	8 88.9%	28 70%
Male	3 30%	3 30%	5 45.5%	1 11.1%	12 30%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	2 20%	1 10%	3 27.3%	3 33.3%	9 22.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	2 20%	2 20%	2 18.2%	1 11.1%	7 17.5%
White	6 60%	7 70%	6 54.5%	5 55.6%	24 60%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	10 100%	10 100%	11 100%	9 100%	40 100%
Body Mass Index (kg/m*m) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m*m]	24.1 (6.6)	23.9 (4.3)	26.7 (5.3)	27.2 (8.1)	25.5 (6.1)
Resting systolic blood pressure (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	113 (14)	116 (14)	117 (11)	116 (12)	116 (13)
Resting diastolic blood pressure (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	73 (10)	74 (10)	75 (8)	74 (8)	74 (9)

Outcome Measures

1. Primary Outcome

Title	Balance Score
Description	The change from Visit 1 to Visit 7 in the average amount of time in seconds that a participant maintains the stability platform within ±3° of horizontal position during 5 trials of 30 seconds each. A greater increase in the balance score means more learning has occurred over the course of the study.
Time Frame	Visit 1 and Visit 7, approximately 1 week

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RLIC - 5 Cycles	RLIC - 4 Cycles	RLIC - 3 Cycles	Sham Conditioning
Arm/Group Description	Remote Limb Ischemic Conditioning (RLIC) is achieved via blood pressure cuff inflation on the non-dominant arm. 5 Cycles of RLIC requires 45 minutes and involves 5 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation. RLIC is performed on visits 1-7. RLIC - 5 cycles: RLIC is achieved as listed in the arm/group descriptions. RLIC is performed on visits 1-7, which occur on consecutive weekdays. Balance training: All participants undergo training on a balance board, learning to hold the board level with equal weight on each leg. Participants perform the balance task for 15, 30-second trials per day at visits 3-7. Arm training: All participants undergo training on a cup stacking task, learning to assemble and disassemble cup configurations as fast as they can. Participants perform the cup stacking task 5 trials per day at visits 3-7. Sequence production training: All participants underg	RLIC is achieved via blood pressure cuff inflation on the non-dominant arm. 4 Cycles of RLIC requires 35 minutes and involves 4 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation. RLIC is performed on visits 1-7. RLIC - 4 Cycles: RLIC is achieved as listed in the arm/group descriptions. RLIC is performed on visits 1-7, which occur on consecutive weekdays. Balance training: All participants undergo training on a balance board, learning to hold the board level with equal weight on each leg. Participants perform the balance task for 15, 30-second trials per day at visits 3-7. Arm training: All participants undergo training on a cup stacking task, learning to assemble and disassemble cup configurations as fast as they can. Participants perform the cup stacking task 5 trials per day at visits 3-7. Sequence production training: All participants undergo training on a discrete sequence pr	RLIC is achieved via blood pressure cuff inflation on the non-dominant arm. 3 Cycles of RLIC requires 25 minutes and involves 3 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation. RLIC is performed on visits 1-7. RLIC - 3 Cycles: RLIC is achieved as listed in the arm/group descriptions. RLIC is performed on visits 1-7, which occur on consecutive weekdays. Balance training: All participants undergo training on a balance board, learning to hold the board level with equal weight on each leg. Participants perform the balance task for 15, 30-second trials per day at visits 3-7. Arm training: All participants undergo training on a cup stacking task, learning to assemble and disassemble cup configurations as fast as they can. Participants perform the cup stacking task 5 trials per day at visits 3-7. Sequence production training: All participants undergo training on a discrete sequence pr	Sham conditioning is achieved via blood pressure cuff inflation to 10 mmHg under diastolic blood pressure on the non-dominant arm. Sham conditioning requires 45 minutes and involves 5 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation. Sham conditioning is performed on visits 1-7. Sham conditioning: Sham conditioning is achieved as listed in the arm/group descriptions. Sham conditioning is performed on visits 1-7, which occur on consecutive weekdays. Balance training: All participants undergo training on a balance board, learning to hold the board level with equal weight on each leg. Participants perform the balance task for 15, 30-second trials per day at visits 3-7. Arm training: All participants undergo training on a cup stacking task, learning to assemble and disassemble cup configurations as fast as they can. Participants perform the cup stacking task 5 trials per day at visits 3-7. Sequence production training: All
Measure Participants	10	10	11	9
Mean (Standard Deviation) [seconds]	9.9 (4.6)	11.5 (5.7)	7.0 (5.1)	11.3 (4.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RLIC - 5 Cycles, RLIC - 4 Cycles, RLIC - 3 Cycles, Sham Conditioning
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.172
	Comments
	Method	ANOVA
	Comments

2. Primary Outcome

Title	Cup Stacking Score
Description	The change from Visit 1 to Visit 7 in the average amount of time in seconds that a participant takes to stack and unstack pre-determined patterns of cups. A greater decrease in the cup stacking score means more learning has occurred over the course of the study.
Time Frame	Visit 1 and Visit 7, approximately 1 week

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RLIC - 5 Cycles	RLIC - 4 Cycles	RLIC - 3 Cycles	Sham Conditioning
Arm/Group Description	Remote Limb Ischemic Conditioning (RLIC) is achieved via blood pressure cuff inflation on the non-dominant arm. 5 Cycles of RLIC requires 45 minutes and involves 5 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation. RLIC is performed on visits 1-7. RLIC - 5 cycles: RLIC is achieved as listed in the arm/group descriptions. RLIC is performed on visits 1-7, which occur on consecutive weekdays. Balance training: All participants undergo training on a balance board, learning to hold the board level with equal weight on each leg. Participants perform the balance task for 15, 30-second trials per day at visits 3-7. Arm training: All participants undergo training on a cup stacking task, learning to assemble and disassemble cup configurations as fast as they can. Participants perform the cup stacking task 5 trials per day at visits 3-7. Sequence production training: All participants underg	RLIC is achieved via blood pressure cuff inflation on the non-dominant arm. 4 Cycles of RLIC requires 35 minutes and involves 4 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation. RLIC is performed on visits 1-7. RLIC - 4 Cycles: RLIC is achieved as listed in the arm/group descriptions. RLIC is performed on visits 1-7, which occur on consecutive weekdays. Balance training: All participants undergo training on a balance board, learning to hold the board level with equal weight on each leg. Participants perform the balance task for 15, 30-second trials per day at visits 3-7. Arm training: All participants undergo training on a cup stacking task, learning to assemble and disassemble cup configurations as fast as they can. Participants perform the cup stacking task 5 trials per day at visits 3-7. Sequence production training: All participants undergo training on a discrete sequence pr	RLIC is achieved via blood pressure cuff inflation on the non-dominant arm. 3 Cycles of RLIC requires 25 minutes and involves 3 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation. RLIC is performed on visits 1-7. RLIC - 3 Cycles: RLIC is achieved as listed in the arm/group descriptions. RLIC is performed on visits 1-7, which occur on consecutive weekdays. Balance training: All participants undergo training on a balance board, learning to hold the board level with equal weight on each leg. Participants perform the balance task for 15, 30-second trials per day at visits 3-7. Arm training: All participants undergo training on a cup stacking task, learning to assemble and disassemble cup configurations as fast as they can. Participants perform the cup stacking task 5 trials per day at visits 3-7. Sequence production training: All participants undergo training on a discrete sequence pr	Sham conditioning is achieved via blood pressure cuff inflation to 10 mmHg under diastolic blood pressure on the non-dominant arm. Sham conditioning requires 45 minutes and involves 5 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation. Sham conditioning is performed on visits 1-7. Sham conditioning: Sham conditioning is achieved as listed in the arm/group descriptions. Sham conditioning is performed on visits 1-7, which occur on consecutive weekdays. Balance training: All participants undergo training on a balance board, learning to hold the board level with equal weight on each leg. Participants perform the balance task for 15, 30-second trials per day at visits 3-7. Arm training: All participants undergo training on a cup stacking task, learning to assemble and disassemble cup configurations as fast as they can. Participants perform the cup stacking task 5 trials per day at visits 3-7. Sequence production training: All
Measure Participants	10	10	11	9
Mean (Standard Deviation) [seconds]	-22.2 (8.8)	-14.9 (3.5)	-11.9 (10.4)	-10.1 (14.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RLIC - 5 Cycles, RLIC - 4 Cycles, RLIC - 3 Cycles, Sham Conditioning
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.169
	Comments
	Method	ANOVA
	Comments

3. Primary Outcome

Title	Discrete Sequence Production Task Score
Description	The change from Visit 1 to Visit 7 in the average amount of time in seconds that a participant takes to complete pre-determined patterns of keypresses. A greater decrease in the Discrete Sequence Production Task score means more learning has occurred over the course of the study.
Time Frame	Visit 1 and Visit 7, approximately 1 week

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RLIC - 5 Cycles	RLIC - 4 Cycles	RLIC - 3 Cycles	Sham Conditioning
Arm/Group Description	Remote Limb Ischemic Conditioning (RLIC) is achieved via blood pressure cuff inflation on the non-dominant arm. 5 Cycles of RLIC requires 45 minutes and involves 5 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation. RLIC is performed on visits 1-7. RLIC - 5 cycles: RLIC is achieved as listed in the arm/group descriptions. RLIC is performed on visits 1-7, which occur on consecutive weekdays. Balance training: All participants undergo training on a balance board, learning to hold the board level with equal weight on each leg. Participants perform the balance task for 15, 30-second trials per day at visits 3-7. Arm training: All participants undergo training on a cup stacking task, learning to assemble and disassemble cup configurations as fast as they can. Participants perform the cup stacking task 5 trials per day at visits 3-7. Sequence production training: All participants underg	RLIC is achieved via blood pressure cuff inflation on the non-dominant arm. 4 Cycles of RLIC requires 35 minutes and involves 4 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation. RLIC is performed on visits 1-7. RLIC - 4 Cycles: RLIC is achieved as listed in the arm/group descriptions. RLIC is performed on visits 1-7, which occur on consecutive weekdays. Balance training: All participants undergo training on a balance board, learning to hold the board level with equal weight on each leg. Participants perform the balance task for 15, 30-second trials per day at visits 3-7. Arm training: All participants undergo training on a cup stacking task, learning to assemble and disassemble cup configurations as fast as they can. Participants perform the cup stacking task 5 trials per day at visits 3-7. Sequence production training: All participants undergo training on a discrete sequence pr	RLIC is achieved via blood pressure cuff inflation on the non-dominant arm. 3 Cycles of RLIC requires 25 minutes and involves 3 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation. RLIC is performed on visits 1-7. RLIC - 3 Cycles: RLIC is achieved as listed in the arm/group descriptions. RLIC is performed on visits 1-7, which occur on consecutive weekdays. Balance training: All participants undergo training on a balance board, learning to hold the board level with equal weight on each leg. Participants perform the balance task for 15, 30-second trials per day at visits 3-7. Arm training: All participants undergo training on a cup stacking task, learning to assemble and disassemble cup configurations as fast as they can. Participants perform the cup stacking task 5 trials per day at visits 3-7. Sequence production training: All participants undergo training on a discrete sequence pr	Sham conditioning is achieved via blood pressure cuff inflation to 10 mmHg under diastolic blood pressure on the non-dominant arm. Sham conditioning requires 45 minutes and involves 5 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation. Sham conditioning is performed on visits 1-7. Sham conditioning: Sham conditioning is achieved as listed in the arm/group descriptions. Sham conditioning is performed on visits 1-7, which occur on consecutive weekdays. Balance training: All participants undergo training on a balance board, learning to hold the board level with equal weight on each leg. Participants perform the balance task for 15, 30-second trials per day at visits 3-7. Arm training: All participants undergo training on a cup stacking task, learning to assemble and disassemble cup configurations as fast as they can. Participants perform the cup stacking task 5 trials per day at visits 3-7. Sequence production training: All
Measure Participants	10	10	11	9
Mean (Standard Deviation) [seconds]	-3.1 (0.7)	-2.9 (0.3)	-2.6 (0.6)	-2.9 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	RLIC - 5 Cycles, RLIC - 4 Cycles, RLIC - 3 Cycles, Sham Conditioning
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.501
	Comments
	Method	ANOVA
	Comments

Adverse Events

Time Frame	1 week
Arm/Group Title	RLIC - 5 Cycles		RLIC - 4 Cycles		RLIC - 3 Cycles		Sham Conditioning
Arm/Group Description	Remote Limb Ischemic Conditioning (RLIC) is achieved via blood pressure cuff inflation on the non-dominant arm. 5 Cycles of RLIC requires 45 minutes and involves 5 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation. RLIC is performed on visits 1-7. RLIC - 5 cycles: RLIC is achieved as listed in the arm/group descriptions. RLIC is performed on visits 1-7, which occur on consecutive weekdays. Balance training: All participants undergo training on a balance board, learning to hold the board level with equal weight on each leg. Participants perform the balance task for 15, 30-second trials per day at visits 3-7. Arm training: All participants undergo training on a cup stacking task, learning to assemble and disassemble cup configurations as fast as they can. Participants perform the cup stacking task 5 trials per day at visits 3-7. Sequence production training: All participants underg		RLIC is achieved via blood pressure cuff inflation on the non-dominant arm. 4 Cycles of RLIC requires 35 minutes and involves 4 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation. RLIC is performed on visits 1-7. RLIC - 4 Cycles: RLIC is achieved as listed in the arm/group descriptions. RLIC is performed on visits 1-7, which occur on consecutive weekdays. Balance training: All participants undergo training on a balance board, learning to hold the board level with equal weight on each leg. Participants perform the balance task for 15, 30-second trials per day at visits 3-7. Arm training: All participants undergo training on a cup stacking task, learning to assemble and disassemble cup configurations as fast as they can. Participants perform the cup stacking task 5 trials per day at visits 3-7. Sequence production training: All participants undergo training on a discrete sequence pr		RLIC is achieved via blood pressure cuff inflation on the non-dominant arm. 3 Cycles of RLIC requires 25 minutes and involves 3 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation. RLIC is performed on visits 1-7. RLIC - 3 Cycles: RLIC is achieved as listed in the arm/group descriptions. RLIC is performed on visits 1-7, which occur on consecutive weekdays. Balance training: All participants undergo training on a balance board, learning to hold the board level with equal weight on each leg. Participants perform the balance task for 15, 30-second trials per day at visits 3-7. Arm training: All participants undergo training on a cup stacking task, learning to assemble and disassemble cup configurations as fast as they can. Participants perform the cup stacking task 5 trials per day at visits 3-7. Sequence production training: All participants undergo training on a discrete sequence pr		Sham conditioning is achieved via blood pressure cuff inflation to 10 mmHg under diastolic blood pressure on the non-dominant arm. Sham conditioning requires 45 minutes and involves 5 cycles of 5 minutes blood pressure cuff inflation followed by alternating 5 minutes of cuff deflation. Sham conditioning is performed on visits 1-7. Sham conditioning: Sham conditioning is achieved as listed in the arm/group descriptions. Sham conditioning is performed on visits 1-7, which occur on consecutive weekdays. Balance training: All participants undergo training on a balance board, learning to hold the board level with equal weight on each leg. Participants perform the balance task for 15, 30-second trials per day at visits 3-7. Arm training: All participants undergo training on a cup stacking task, learning to assemble and disassemble cup configurations as fast as they can. Participants perform the cup stacking task 5 trials per day at visits 3-7. Sequence production training: All
All Cause Mortality
	RLIC - 5 Cycles		RLIC - 4 Cycles		RLIC - 3 Cycles		Sham Conditioning
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		0/11 (0%)		0/9 (0%)
Serious Adverse Events
	RLIC - 5 Cycles		RLIC - 4 Cycles		RLIC - 3 Cycles		Sham Conditioning
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		0/11 (0%)		0/9 (0%)
Other (Not Including Serious) Adverse Events
	RLIC - 5 Cycles		RLIC - 4 Cycles		RLIC - 3 Cycles		Sham Conditioning
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		0/11 (0%)		0/9 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.