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

May 15, 2015 updated by: T. George Hornby

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

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.

Study Overview

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 Type

Interventional

Enrollment (Anticipated)

30

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Illinois
      • Chicago, Illinois, United States, 60611
        • Rehabiliation Institute of Chicago

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: escitalopram oxalate
Exercise testing with escitalopram oxalate dose
10 mg 4.5 hours prior to testing
Other Names:
  • Lexapro
modified bruce protocol for peak oxygen consumption testing
Active Comparator: cyproheptadine
exercise testing with cyproheptadine dose
modified bruce protocol for peak oxygen consumption testing
8mg 4.5 hours prior to testing
Placebo Comparator: placebo
exercise testing with placebo dose
modified bruce protocol for peak oxygen consumption testing
4.5 hour prior to testing

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in blood serum concentration of neuroplastic proteins
Time Frame: 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.
assessed prior to, throughout, and following the duration of a graded exercise test, over an expected average of 2 hours

Secondary Outcome Measures

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Thomas G Hornby, PhD, PT, University of Illinois at Chicago, Rehabiliation Institute of Chicago, Northwestern University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

December 1, 2011

Primary Completion (Actual)

May 1, 2015

Study Completion (Actual)

May 1, 2015

Study Registration Dates

First Submitted

January 24, 2012

First Submitted That Met QC Criteria

February 20, 2012

First Posted (Estimate)

February 24, 2012

Study Record Updates

Last Update Posted (Estimate)

May 19, 2015

Last Update Submitted That Met QC Criteria

May 15, 2015

Last Verified

May 1, 2015

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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