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

Effect of Number of Remote Limb Ischemic Conditioning Cycles on Learning Enhancement in Healthy Young Adults

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.

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.

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.

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.

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.

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.

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.

RLIC is achieved as listed in the arm/group descriptions. RLIC is performed on visits 1-7, which occur on consecutive weekdays.

RLIC is achieved as listed in the arm/group descriptions. RLIC is performed on visits 1-7, which occur on consecutive weekdays.

RLIC is achieved as listed in the arm/group descriptions. RLIC is performed on visits 1-7, which occur on consecutive weekdays.

Sham conditioning is achieved as listed in the arm/group descriptions. Sham conditioning is performed on visits 1-7, which occur on consecutive weekdays.

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.

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.

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.

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.

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.

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.

Inclusion Criteria: 1. Between the age of 18 and 40 years Exclusion Criteria: History of neurological condition (i.e. stroke, Alzheimer's disease, Parkinson's disease), ADD, ADHD, balance impairment, or vestibular disorder History of sleep apnea History of lower extremity condition, injury, or surgery which could compromise performance on motor training task Any extremity soft tissue, orthopedic, or vascular injury (i.e. peripheral vascular disease) which may contraindicate RLIC Any cognitive, sensory, or communication problem that would prevent completion of the study Current intensive weight lifting or interval training exercise Current substance abuse or dependence Current use of medication with selective serotonin-reuptake inhibitors. Unwillingness to travel for all study visits

After completion of the study, all of the individual participant data after de-identification will be submitted to Washington University data repository.

Data will be available to anyone who wishes to access it through Washington University data repository.