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

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by Rehabilitation Institute of Chicago
Sponsor:
Collaborators:
University of Medicine and Dentistry of New Jersey
Rehabilitation Institute of Chicago
Information provided by (Responsible Party):
T. George Hornby, Rehabilitation Institute of Chicago
ClinicalTrials.gov Identifier:
NCT01538693
First received: January 24, 2012
Last updated: April 23, 2014
Last verified: April 2014
  Purpose

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 Intervention
Spinal Cord Injury
Drug: escitalopram oxalate
Drug: Cyproheptadine
Drug: sugar pill
Other: Graded intensity exercise

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Basic Science
Official Title: Molecular Markers of Neuroplasticity During High-Intensity Exercise in Subjects With Incomplete Spinal Cord Injury

Resource links provided by NLM:


Further study details as provided by Rehabilitation Institute of Chicago:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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 [ Time Frame: one time, baseline measure ] [ Designated as safety issue: No ]
  • Six Minute Walk Distance [ Time Frame: one time basline measurement ] [ Designated as safety issue: No ]
  • Volitional strength: Lower Extremity Motor Score [ Time Frame: one time baseline measure ] [ Designated as safety issue: No ]
  • Modified Ashworth Scale [ Time Frame: one time baseline measurement ] [ Designated as safety issue: No ]
  • Spinal Cord Assessment tool for Spasticity [ Time Frame: one time baseline measure ] [ Designated as safety issue: No ]
  • Measure of Community mobility [ Time Frame: Step activity monitor worn on lower extremity for 7 days ] [ Designated as safety issue: No ]
  • Sagittal plane kinematics of excursions of hip/knee/ankle [ Time Frame: continuous assessment for an average of ten minutes at each visit ] [ Designated as safety issue: No ]
  • Peak ambulation velocity [ Time Frame: One time measure at the end of each graded intensity treadmilll test ] [ Designated as safety issue: No ]
  • Oxygen consumption [ Time Frame: continuous assessment for an average of ten minutes at each visit ] [ Designated as safety issue: No ]
  • Heart Rate [ Time Frame: continuous assessment for an average of ten minutes at each visit ] [ Designated as safety issue: No ]
  • Rating of Perceived Exertion (Borg Scale) [ Time Frame: continuous assessment for an average of ten minutes at each visit ] [ Designated as safety issue: No ]

Estimated Enrollment: 30
Study Start Date: December 2011
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: escitalopram oxalate
Exercise testing with escitalopram oxalate dose
Drug: escitalopram oxalate
10 mg 4.5 hours prior to testing
Other Name: 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

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.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01538693

Contacts
Contact: Kristan A Leech, PT, BS 312-238-6538 k-leech@northwestern.edu
Contact: Thomas G Hornby, PhD, PT 312-238-1397 g-hornby@northwestern.edu

Locations
United States, Illinois
Rehabiliation Institute of Chicago Recruiting
Chicago, Illinois, United States, 60611
Principal Investigator: Thomas G Hornby, PhD, PT         
Sponsors and Collaborators
T. George Hornby
University of Medicine and Dentistry of New Jersey
Rehabilitation Institute of Chicago
Investigators
Principal Investigator: Thomas G Hornby, PhD, PT University of Illinois at Chicago, Rehabiliation Institute of Chicago, Northwestern University
  More Information

Publications:

Responsible Party: T. George Hornby, Assistant Professor, Rehabilitation Institute of Chicago
ClinicalTrials.gov Identifier: NCT01538693     History of Changes
Other Study ID Numbers: STU00056144
Study First Received: January 24, 2012
Last Updated: April 23, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Rehabilitation Institute of Chicago:
BDNF
serotonin
high-intensity
exercise

Additional relevant MeSH terms:
Spinal Cord Injuries
Central Nervous System Diseases
Nervous System Diseases
Spinal Cord Diseases
Trauma, Nervous System
Wounds and Injuries
Citalopram
Cyproheptadine
Dexetimide
Anti-Allergic Agents
Anti-Dyskinesia Agents
Antidepressive Agents
Antidepressive Agents, Second-Generation
Antiparkinson Agents
Antipruritics
Autonomic Agents
Central Nervous System Agents
Cholinergic Agents
Cholinergic Antagonists
Dermatologic Agents
Gastrointestinal Agents
Histamine Agents
Histamine Antagonists
Histamine H1 Antagonists
Molecular Mechanisms of Pharmacological Action
Muscarinic Antagonists
Neurotransmitter Agents
Neurotransmitter Uptake Inhibitors
Parasympatholytics
Peripheral Nervous System Agents

ClinicalTrials.gov processed this record on October 23, 2014