<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03806023</url>
  </required_header>
  <id_info>
    <org_study_id>Wu-17-18</org_study_id>
    <nct_id>NCT03806023</nct_id>
  </id_info>
  <brief_title>EMG Triggered Closed-Loop Stimulation for Spinal Cord Injury Individuals</brief_title>
  <official_title>EMG Triggered Closed-Loop Stimulation for Spinal Cord Injury Individuals</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Bronx VA Medical Center</agency>
      <agency_class>U.S. Fed</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Bronx VA Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Most individuals with spinal cord injury (SCI) have residual nerve circuits. The&#xD;
      investigators aim to strengthen those circuits to improve motor recovery after injury. To do&#xD;
      this, the investigators are attempting to pair electrical and magnetic stimulation with&#xD;
      physical training targeted toward the connections between nerve circuits. Past studies by&#xD;
      other groups have shown that synapse strength can be improved temporarily after a short&#xD;
      period of paired stimulation between the brain (motor cortex) and the peripheral nerves&#xD;
      serving target muscles - in other words, &quot;Fire Together, Wire Together&quot;.&#xD;
&#xD;
      The brain's intention to move a muscle can be read by recording surface electrical activity&#xD;
      over target muscles (electromyography or EMG). In animal models of SCI, scientists have&#xD;
      successfully used target muscle EMG to trigger spinal cord electrical stimulation pulses&#xD;
      while the animals perform physical exercises. Using the body's own signals to trigger nerve&#xD;
      stimulation is called &quot;closed-loop stimulation&quot;. This might be an optimal method to&#xD;
      coordinate brain and nerve activity, especially with the clinical advantage of being possible&#xD;
      to combine with physical exercise training. However, whether EMG-triggered closed loop&#xD;
      stimulation has the same amount of effect when applied non-invasively in humans is still&#xD;
      unknown.&#xD;
&#xD;
      This proposed study is a proof-of-principle to demonstrate the potential of non-invasive&#xD;
      closed-loop stimulation in humans with incomplete cervical SCI. We will test different&#xD;
      combinations of triggered and non-triggered electrical and magnetic stimulation, and record&#xD;
      the short-term effects on nerve transmission and skilled function of hand muscles. This pilot&#xD;
      study will be a foundation for future studies combining EMG-triggered stimulation with&#xD;
      long-term physical exercise training.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In both animal models and humans with spinal cord injury (SCI), synaptic efficacy between&#xD;
      corticospinal axons and spinal motor neurons has improved temporarily after a short period of&#xD;
      paired stimulation between motor cortex and spinal or peripheral sites. In a demonstration of&#xD;
      closed-loop stimulation in SCI rats, target muscle electromyography (EMG) signals were used&#xD;
      to trigger spinal cord electrical stimulation while performing physical retraining. Results&#xD;
      showed that EMG-triggered stimulation plus physical retraining led to greater motor recovery&#xD;
      than non-triggered stimulation or physical training alone. However, these studies used&#xD;
      invasive direct spinal cord stimulation in rodent models. Whether this approach can work&#xD;
      non-invasively in humans remains unknown.&#xD;
&#xD;
      Twenty participants (10 able bodied and 10 SCI subjects) will be recruited. Each subject will&#xD;
      undergo five different 20-minute interventions. Stimulation will be delivered at the motor&#xD;
      cortex via transcranial magnetic stimulation (TMS), the median nerve, or both. Stimulation&#xD;
      will occur either while the subject is passively at rest or triggered by reaching endogenous&#xD;
      EMG threshold during a pinch task. Outcomes will be measured at baseline and every 20 minutes&#xD;
      for one hour after the intervention.&#xD;
&#xD;
      The investigators hypothesize that for at least 20 minutes after stimulation, one session of&#xD;
      EMG-triggered stimulation will significantly improve motor evoked potential amplitude,&#xD;
      increase cortical silent period duration, and decrease time required to complete a pegboard&#xD;
      task compared with one session of passively delivered stimulation. The investigators further&#xD;
      hypothesize that EMG triggered median nerve stimulation alone will provide equal or greater&#xD;
      benefits as EMG triggered TMS or EMG-triggered paired stimulation.&#xD;
&#xD;
      Hypothesis 1: One session of EMG-triggered stimulation will significantly improve motor&#xD;
      evoked potential (MEP) amplitude, increase cortical silent period duration of APB, and&#xD;
      decrease time required to complete a manual pegboard task compared with one session of&#xD;
      passively delivered stimulation or one session of voluntary contraction alone for at least 20&#xD;
      minutes post-stimulation.&#xD;
&#xD;
      Hypothesis 2: EMG-triggered PNS alone will result in equal or greater effects than EMG&#xD;
      triggered TMS or TMS+PNS paired stimulation. This would indicate that EMG triggered PNS might&#xD;
      be used as a potential intervention to add during physical training, a setting in which TMS&#xD;
      is difficult to apply.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Funding expired due to grant for new project (NCT03851302)&#xD;
  </why_stopped>
  <start_date type="Actual">February 1, 2018</start_date>
  <completion_date type="Actual">February 28, 2020</completion_date>
  <primary_completion_date type="Actual">February 28, 2020</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in motor evoked potential (MEP) amplitude of the abductor pollicis brevis (APB) muscle response to single pulses of TMS</measure>
    <time_frame>Assessed pre, then 0, 20, 40, and 60 minutes post-intervention.</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Hand dexterity</measure>
    <time_frame>Assessed pre, then 0, 20, 40, and 60 minutes post-intervention.</time_frame>
    <description>Timed performance on a grooved pegboard task.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Grip strength</measure>
    <time_frame>Assessed pre, then 0, 20, 40, and 60 minutes post-intervention.</time_frame>
    <description>Strength will be quantified using hand-held wireless dynamometry.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in the duration of the 'cortical silent period' after TMS stimulation during APB contraction</measure>
    <time_frame>Assessed pre, then 0, 20, 40, and 60 minutes post-intervention.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>F-wave responses of the APB muscle</measure>
    <time_frame>Assessed pre, then 0, 20, 40, and 60 minutes post-intervention.</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">8</enrollment>
  <condition>Spinal Cord Injuries</condition>
  <arm_group>
    <arm_group_label>All subjects</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>All subjects undergo same full protocol, including PNS and TMS at rest and active hand movements (signals from thumb muscle) triggered PNS and TMS.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>hand movements (signals from thumb muscle) triggered PNS and TMS</intervention_name>
    <description>PNS, TMS or PNS+TMS will be delivered while the participant performs specific finger tasks at different degrees of effort.&#xD;
This is an experiment designed to detect momentary changes in muscle function.</description>
    <arm_group_label>All subjects</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age between 18 and 75 years;&#xD;
&#xD;
          -  Chronic (more than 12 months since injury) motor-incomplete SCI between neurological&#xD;
             levels C2-C8&#xD;
&#xD;
          -  Score of 3 or more (out of 5) on manual muscle testing of finger extension, finger&#xD;
             flexion, or finger abduction in left or right hand;&#xD;
&#xD;
          -  Detectable F-wave responses of the left or right abductor pollicis brevis (APB) to&#xD;
             median nerve stimulation;&#xD;
&#xD;
          -  Detectable motor evoked potentials in left or right APB;&#xD;
&#xD;
          -  Able to perform thumb-middle finger opposition pinch task with detectable APB EMG&#xD;
             muscle activity.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Multiple spinal cord lesions;&#xD;
&#xD;
          -  History of seizures;&#xD;
&#xD;
          -  Ventilator dependence or patent tracheostomy site;&#xD;
&#xD;
          -  Use of medications that significantly lower seizure threshold, such as tricyclic&#xD;
             antidepressants, amphetamines, neuroleptics, dalfampridine, and bupropion;&#xD;
&#xD;
          -  History of stroke, brain tumor, brain abscess, or multiple sclerosis;&#xD;
&#xD;
          -  History of moderate or severe head trauma (loss of consciousness for greater than one&#xD;
             hour or evidence of brain contusion or hemorrhage or depressed skull fracture on prior&#xD;
             imaging);&#xD;
&#xD;
          -  History of implanted brain/spine/nerve stimulators, aneurysm clips, ferromagnetic&#xD;
             metallic implants, or cardiac pacemaker/defibrillator;&#xD;
&#xD;
          -  Significant coronary artery or cardiac conduction disease;&#xD;
&#xD;
          -  Recent history (within past 6 months) of recurrent autonomic dysreflexia, defined as a&#xD;
             syndrome of sudden rise in systolic pressure greater than 20 mm Hg or diastolic&#xD;
             pressure greater than 10 mm Hg, without rise in heart rate, accompanied by symptoms&#xD;
             such as headache, facial flushing, sweating, nasal congestion, and blurry vision (this&#xD;
             will be closely monitored during all screening and testing procedures);&#xD;
&#xD;
          -  History of bipolar disorder;&#xD;
&#xD;
          -  History of suicide attempt;&#xD;
&#xD;
          -  Active psychosis;&#xD;
&#xD;
          -  Heavy alcohol consumption (greater than equivalent of 5 oz of liquor) within previous&#xD;
             48 hours;&#xD;
&#xD;
          -  Open skin lesions over the face, neck, shoulders, or arms;&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Unsuitable for study participation as determined by study physician.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Noam Y Harel, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>James J. Peters VA Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>James J. Peters VA Medical Center</name>
      <address>
        <city>Bronx</city>
        <state>New York</state>
        <zip>10468</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2020</verification_date>
  <study_first_submitted>January 14, 2019</study_first_submitted>
  <study_first_submitted_qc>January 14, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 16, 2019</study_first_posted>
  <last_update_submitted>October 1, 2020</last_update_submitted>
  <last_update_submitted_qc>October 1, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">October 5, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Bronx VA Medical Center</investigator_affiliation>
    <investigator_full_name>Noam Y. Harel</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>transcutaneous electric nerve stimulation</keyword>
  <keyword>transcranial magnetic stimulation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Spinal Cord Injuries</mesh_term>
    <mesh_term>Wounds and Injuries</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>A Limited Dataset (LDS) will be shared in electronic format pursuant to a VA-approved Data Use Agreement. Individually Identifiable Data will be shared pursuant to valid HIPAA Authorization, Informed Consent, and an appropriate written agreement limiting use of the data to the conditions as described in the authorization and consent, and a written assurance from the recipient that the information will be maintained in accordance with the security requirements of 38 CFR Part 1.466.</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03806023
org study id: Wu-17-18
nct id: NCT03806023
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: Yes
Most individuals with spinal cord injury (SCI) have residual nerve circuits. The
      investigators aim to strengthen those circuits to improve motor recovery after injury. To do
      this, the investigators are attempting to pair electrical and magnetic stimulation with
      physical training targeted toward the connections between nerve circuits. Past studies by
      other groups have shown that synapse strength can be improved temporarily after a short
      period of paired stimulation between the brain (motor cortex) and the peripheral nerves
      serving target muscles - in other words, "Fire Together, Wire Together".

      The brain's intention to move a muscle can be read by recording surface electrical activity
      over target muscles (electromyography or EMG). In animal models of SCI, scientists have
      successfully used target muscle EMG to trigger spinal cord electrical stimulation pulses
      while the animals perform physical exercises. Using the body's own signals to trigger nerve
      stimulation is called "closed-loop stimulation". This might be an optimal method to
      coordinate brain and nerve activity, especially with the clinical advantage of being possible
      to combine with physical exercise training. However, whether EMG-triggered closed loop
      stimulation has the same amount of effect when applied non-invasively in humans is still
      unknown.

      This proposed study is a proof-of-principle to demonstrate the potential of non-invasive
      closed-loop stimulation in humans with incomplete cervical SCI. We will test different
      combinations of triggered and non-triggered electrical and magnetic stimulation, and record
      the short-term effects on nerve transmission and skilled function of hand muscles. This pilot
      study will be a foundation for future studies combining EMG-triggered stimulation with
      long-term physical exercise training.
In both animal models and humans with spinal cord injury (SCI), synaptic efficacy between
      corticospinal axons and spinal motor neurons has improved temporarily after a short period of
      paired stimulation between motor cortex and spinal or peripheral sites. In a demonstration of
      closed-loop stimulation in SCI rats, target muscle electromyography (EMG) signals were used
      to trigger spinal cord electrical stimulation while performing physical retraining. Results
      showed that EMG-triggered stimulation plus physical retraining led to greater motor recovery
      than non-triggered stimulation or physical training alone. However, these studies used
      invasive direct spinal cord stimulation in rodent models. Whether this approach can work
      non-invasively in humans remains unknown.

      Twenty participants (10 able bodied and 10 SCI subjects) will be recruited. Each subject will
      undergo five different 20-minute interventions. Stimulation will be delivered at the motor
      cortex via transcranial magnetic stimulation (TMS), the median nerve, or both. Stimulation
      will occur either while the subject is passively at rest or triggered by reaching endogenous
      EMG threshold during a pinch task. Outcomes will be measured at baseline and every 20 minutes
      for one hour after the intervention.

      The investigators hypothesize that for at least 20 minutes after stimulation, one session of
      EMG-triggered stimulation will significantly improve motor evoked potential amplitude,
      increase cortical silent period duration, and decrease time required to complete a pegboard
      task compared with one session of passively delivered stimulation. The investigators further
      hypothesize that EMG triggered median nerve stimulation alone will provide equal or greater
      benefits as EMG triggered TMS or EMG-triggered paired stimulation.

      Hypothesis 1: One session of EMG-triggered stimulation will significantly improve motor
      evoked potential (MEP) amplitude, increase cortical silent period duration of APB, and
      decrease time required to complete a manual pegboard task compared with one session of
      passively delivered stimulation or one session of voluntary contraction alone for at least 20
      minutes post-stimulation.

      Hypothesis 2: EMG-triggered PNS alone will result in equal or greater effects than EMG
      triggered TMS or TMS+PNS paired stimulation. This would indicate that EMG triggered PNS might
      be used as a potential intervention to add during physical training, a setting in which TMS
      is difficult to apply.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Change in motor evoked potential (MEP) amplitude of the abductor pollicis brevis (APB) muscle response to single pulses of TMS
time frame: Assessed pre, then 0, 20, 40, and 60 minutes post-intervention.
measure: Hand dexterity
time frame: Assessed pre, then 0, 20, 40, and 60 minutes post-intervention.
description: Timed performance on a grooved pegboard task.
measure: Grip strength
time frame: Assessed pre, then 0, 20, 40, and 60 minutes post-intervention.
description: Strength will be quantified using hand-held wireless dynamometry.
measure: Change in the duration of the 'cortical silent period' after TMS stimulation during APB contraction
time frame: Assessed pre, then 0, 20, 40, and 60 minutes post-intervention.
measure: F-wave responses of the APB muscle
time frame: Assessed pre, then 0, 20, 40, and 60 minutes post-intervention.
arm group label: All subjects
arm group type: Experimental
description: All subjects undergo same full protocol, including PNS and TMS at rest and active hand movements (signals from thumb muscle) triggered PNS and TMS.
intervention type: Device
intervention name: hand movements (signals from thumb muscle) triggered PNS and TMS
description: PNS, TMS or PNS+TMS will be delivered while the participant performs specific finger tasks at different degrees of effort.
This is an experiment designed to detect momentary changes in muscle function.
arm group label: All subjects
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Noam Y Harel, MD, PhD
role: Principal Investigator
affiliation: James J. Peters VA Medical Center
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Bronx VA Medical Center
investigator full name: Noam Y. Harel
investigator title: Principal Investigator
mesh term: Spinal Cord Injuries
mesh term: Wounds and Injuries
sharing ipd: Yes
ipd description: A Limited Dataset (LDS) will be shared in electronic format pursuant to a VA-approved Data Use Agreement. Individually Identifiable Data will be shared pursuant to valid HIPAA Authorization, Informed Consent, and an appropriate written agreement limiting use of the data to the conditions as described in the authorization and consent, and a written assurance from the recipient that the information will be maintained in accordance with the security requirements of 38 CFR Part 1.466.