Molecular Markers of Neuroplasticity During Exercise in People With Incomplete Spinal Cord Injury

Sponsor

T. George Hornby (Other)

Overall Status

Completed

CT.gov ID

NCT01538693

Collaborator

University of Medicine and Dentistry of New Jersey (Other), Shirley Ryan AbilityLab (Other)

Enrollment

Location

Arms

Duration (Months)

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether exercising (walking) at different intensities increases levels of factors in the blood and saliva that are known to impact neuroplasticity (how the connections in the spinal cord and brain can change) and if these levels are changed by pairing exercise with a single dose of commonly used prescription drugs or by your mood.

Condition or Disease	Intervention/Treatment	Phase
Spinal Cord Injury	Drug: escitalopram oxalate Drug: Cyproheptadine Drug: sugar pill Other: Graded intensity exercise	N/A

Detailed Description

The protein brain-derived neurotrophic factor (BDNF) is known to promote cell survival, improve synaptic function, and induce neuronal morphological changes. Consequently, BDNF plays a major role in neuroplasticity and the ability of the central nervous system to adapt and recover following injury. Regardless of the molecular mechanisms by which this occurs (which are poorly understood), potentiating the expression of BDNF following spinal cord injury has been shown to improve functional outcomes in animals.(1, 2) It is well documented in both animal and human literature that the production BDNF increases with physical exercise in healthy populations and individuals with chronic disease or disability. (3) The literature suggests that this increase is proportional to the intensity of exercise, though the parameters of exercise to maximize this effect are poorly understood. (2, 4-6) From animal research, it has been postulated that serotonin (5HT) plays a role in the mechanism of increase in BDNF expression, (7-9) with findings that specifically demonstrate potentiation of the exercise-induced expression with antidepressant treatment(10)and a blunted response when monoaminergic signaling is blocked.(11) A specific genetic variation in the BDNF gene, found in approximately 30% of the population has also been noted as an important factor in the proper release of BDNF with associated deficits in motor learning. (12, 13) Initial evidence also suggests that this polymorphism may have an impact of the relationship between exercise and BDNF. (14, 15) The objective of this study is the evaluate the response of serum concentrations of brain-derived neurotrophic factor ([BDNF]s) to an acute bout of exercise in ambulatory people with incomplete spinal cord injury; additionally, to examine the effect of pharmacological agents that alter serotonergic (5HT) transmission on this exercise-induced change in [BDNF]s. To achieve this objective we will investigate [BDNF]s during a treadmill test alone and in combination with two commonly used medications; escitalopram oxalate , a selective-5HT reuptake inhibitor (SSRI) and cyproheptadine (CYPRO), a 5HT antagonist.

Studies have also shown a relationship of BDNF to mood, in particular, depression. A secondary study will be performed in parallel with the primary study with the purpose of examining mood and how it correlates with the molecular markers for neuroplasticity as individuals participate in the repeated exercise and the other stated interventions. As the subjects progress over the course of the study time mood may change and may impact the relationship of the BDNF to the primary interventions.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Basic Science

Official Title:

Molecular Markers of Neuroplasticity During High-Intensity Exercise in Subjects With Incomplete Spinal Cord Injury

Study Start Date :

Dec 1, 2011

Actual Primary Completion Date :

May 1, 2015

Actual Study Completion Date :

May 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: escitalopram oxalate Exercise testing with escitalopram oxalate dose	Drug: escitalopram oxalate 10 mg 4.5 hours prior to testing Other Names: Lexapro Other: Graded intensity exercise modified bruce protocol for peak oxygen consumption testing
Active Comparator: cyproheptadine exercise testing with cyproheptadine dose	Drug: Cyproheptadine 8mg 4.5 hours prior to testing Other: Graded intensity exercise modified bruce protocol for peak oxygen consumption testing
Placebo Comparator: placebo exercise testing with placebo dose	Drug: sugar pill 4.5 hour prior to testing Other: Graded intensity exercise modified bruce protocol for peak oxygen consumption testing

Arm

Intervention/Treatment

Active Comparator: escitalopram oxalate

Exercise testing with escitalopram oxalate dose

Drug: escitalopram oxalate

10 mg 4.5 hours prior to testing

Other Names:

Lexapro

Other: Graded intensity exercise

modified bruce protocol for peak oxygen consumption testing

Active Comparator: cyproheptadine

exercise testing with cyproheptadine dose

Drug: Cyproheptadine

8mg 4.5 hours prior to testing

Other: Graded intensity exercise

modified bruce protocol for peak oxygen consumption testing

Placebo Comparator: placebo

exercise testing with placebo dose

Drug: sugar pill

4.5 hour prior to testing

Other: Graded intensity exercise

modified bruce protocol for peak oxygen consumption testing

Outcome Measures

Primary Outcome Measures

Change in blood serum concentration of neuroplastic proteins [assessed prior to, throughout, and following the duration of a graded exercise test, over an expected average of 2 hours]
During a graded treadmill test, 5mL of blood will be taken at each speed the subject is able to obtain before failure. 5mL of blood will also be taken immediately after completion of the treadmill test and every 10 minutes for up to 30 minutes after completion.

Secondary Outcome Measures

fastest possible walking velocity overground [one time, baseline measure]
Six Minute Walk Distance [one time basline measurement]
Volitional strength: Lower Extremity Motor Score [one time baseline measure]
Modified Ashworth Scale [one time baseline measurement]
Spinal Cord Assessment tool for Spasticity [one time baseline measure]
Measure of Community mobility [Step activity monitor worn on lower extremity for 7 days]
Sagittal plane kinematics of excursions of hip/knee/ankle [continuous assessment for an average of ten minutes at each visit]
Peak ambulation velocity [One time measure at the end of each graded intensity treadmilll test]
Oxygen consumption [continuous assessment for an average of ten minutes at each visit]
Heart Rate [continuous assessment for an average of ten minutes at each visit]
Rating of Perceived Exertion (Borg Scale) [continuous assessment for an average of ten minutes at each visit]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Must be motor incomplete spinal cord injury (ASIA C or D) of 1 year or greater duration, with anatomical lesions between C1-T10
Must be between 18 and 75 years of age
Must be ambulatory with passive range of motion consistent with normal walking, and must include: ankle dorsiflexion ankle to 10° and plantarflexion to 30°, knee flexion from 0 to 90°, hip flexion/extension to 90° to -10°.
Must be medically stable with medical clearance to participate, with absence of concurrent severe medical illness including: unhealed decubiti, existing infection, significant cardiovascular or metabolic disease which limits exercise participation, significant osteoporosis (as indicated by history of fractures following injury), active heterotrophic ossification in the lower extremities, known history of peripheral nerve injury in lower legs, history of known traumatic head injury, mental illness, history of pre-existing QT interval prolongation, congenital long QT syndrome, and history of pulmonary complications, including significant obstructive and/or restrictive lung diseases
May be undergoing concurrent physical therapy
May be of childbearing potential (for women)
Men and women will be recruited for participation in the proposed study at rates consistent with national and local average of gender disparities of SCI (80% male, 20% women)
Individuals of different ethnicities will be recruited at rates similar to the national and local ethnicity rates. Current data since 2005 indicate that of the entire population of SCI, 66.1% are Caucasian, 27.1% are African American, 6.6% are of Hispanic origin, and 2.0% are Asian.

Exclusion Criteria:

Weighing more than 300lbs
Ventilator-dependency
Use of substantial orthopedic bracing to stabilize the cervical or thoracic vertebral column
Inability to tolerate 10 minutes of standing without orthostasis (decrease in blood pressure by 20 mmHg systolic and 10 mmHg diastolic).
Women who are pregnant or who are considering becoming pregnant will be excluded due to the trunk and pelvis restraints required for use during locomotion, and secondary to the unknown effects of the pharmacological agents on the developing fetus
Exhibiting symptoms suggestive of depression according to the Personal health Questionaire (PHQ-9)
Subjects who exhibit hemoglobin levels consistent with anemia (<13g/dL for men and <12g/dL for women) will be excluded from the study.
Currently taking prescribed anti-depressant medications, including specific monoaminergic agents, their precursors or their agonists, antipsychotics, medications known to prolong the QT interval, or other medications with known interactions to the SSRIs. All subjects will be excluded from participation unless both attending physician and patient agree to cease all such medications during the evaluation and training period. A 14-day washout period for SSRIs and a 72 hour washout for Tizanidine will be utilized. Subjects will be financially responsible for the physician visits necessary to wean from medication. Completion of appropriate and safe weaning will be confirmed by the patients' physician.
Currently taking prescribed anti-spastic medications. Specific agents to be excluded include baclofen (Lioresal®) and benzodiazepines (Diazepam®). Selected agents used for pain modulation will be evaluated per subject to ascertain potential interactions with test agent. All subjects will be excluded from participation unless both attending physician and patient agree to cease all such medications during the evaluation and training period. A 72-hour minimum washout period for all such medications will be utilized. Subjects will be financially responsible for the physician visits necessary to wean from medication. Completion of appropriate and safe weaning will be confirmed by the patients' physician.
Clinically diagnosed liver, renal, or other metabolic disease that may interfere with drug action and/or clearance