<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/NCT02231892</url>
  </required_header>
  <id_info>
    <org_study_id>999914186</org_study_id>
    <secondary_id>14-DA-N186</secondary_id>
    <nct_id>NCT02231892</nct_id>
  </id_info>
  <brief_title>Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study</brief_title>
  <official_title>Repetitive Transcranial Magnetic Stimulation Equipment Testing and Pilot Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Institute on Drug Abuse (NIDA)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Institutes of Health Clinical Center (CC)</source>
  <oversight_info>
    <has_dmc>Yes</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>
      Background:&#xD;
&#xD;
      - Brain stimulation called repetitive transcranial magnetic stimulation (rTMS) may help&#xD;
      people quit drugs. Researchers want to study how it works in healthy people first.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      - To learn how to use rTMS to stimulate a brain area and to see how it affects brain function&#xD;
      and thinking.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      - Healthy, right-handed adults ages 18-55.&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  Participants will be screened under another protocol.&#xD;
&#xD;
        -  They will have 4-11 study visits.&#xD;
&#xD;
        -  To start each visit, participants will have:&#xD;
&#xD;
        -  Physical exam.&#xD;
&#xD;
        -  Urine sample.&#xD;
&#xD;
        -  Breath tests for alcohol and cigarette smoke.&#xD;
&#xD;
        -  Questions about drug use and medications.&#xD;
&#xD;
        -  Visit 1: participants will have:&#xD;
&#xD;
        -  Single TMS pulses on the head to determine the right strength. They will wear earplugs&#xD;
           and a cap. A wire coil will be placed on the head and an electrical current will go&#xD;
           through it. Participants may perform simple muscle movements. They will repeat the&#xD;
           procedures wearing another coil, in a helmet.&#xD;
&#xD;
        -  A few TMS pulses to show how rTMS feels.&#xD;
&#xD;
        -  A practice thinking task, maybe in a scanner that looks and sounds like a magnetic&#xD;
           resonance imaging (MRI) scanner but does not take pictures. The MRI scanner is a metal&#xD;
           cylinder surrounded by a strong magnetic field. The participant will lie on a table that&#xD;
           slides in and out of the cylinder.&#xD;
&#xD;
        -  They may have a real MRI scan.&#xD;
&#xD;
        -  Visits 2-11, participants will:&#xD;
&#xD;
        -  Complete two questionnaires.&#xD;
&#xD;
        -  Get varied rTMS stimulation. Their heart rate and blood pressure may be monitored.&#xD;
&#xD;
        -  Have their vital signs checked.&#xD;
&#xD;
        -  They may perform thinking tasks at a computer, in a mock scanner, or in an MRI scanner.&#xD;
           They may just lie still in the MRI scanner.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Objective: To establish an effective repetitive transcranial magnetic stimulation (rTMS)&#xD;
      protocol for stimulating circuits relevant for addiction. Specifically, we will develop&#xD;
      stimulation parameters and outcome measures for rTMS of the anterior cingulate cortex (ACC)&#xD;
      with a specialized TMS coil: the HAC coil (Brainsway Ltd.). Various parameters of rTMS&#xD;
      stimulation (frequency and intensity) will be varied, and the sensitivity of behavioral tasks&#xD;
      and MRI measures to this stimulation will be determined. The objective of this protocol is&#xD;
      therefore to allow for the development, assessment and refinement of rTMS parameters for&#xD;
      stimulating ACC targets. In addition, outcome measures will be developed to capture the&#xD;
      effects of this stimulation. Results from this development protocol will be applied to&#xD;
      subsequent cognitive imaging protocols.&#xD;
&#xD;
      Study population: Up to 50 healthy, non-smoking adults will be tested in several conditions&#xD;
      over up to two weeks. Subjects must fit exclusion/inclusion criteria for TMS and MRI. We&#xD;
      expect 140 subjects to be enrolled to arrive at a number of 50 who complete the protocol.&#xD;
&#xD;
      Design: Within-subject design with each subject completing up to 10 rTMS sessions.&#xD;
&#xD;
      Outcome measures: In a first phase, the outcome measure will be the behavioral response on a&#xD;
      task that relies on the ACC. In a second phase, outcome measures will be the effects on MR&#xD;
      measures. These will include task-related blood oxygen level-dependent (BOLD) responses, as&#xD;
      well as resting state BOLD functional magnetic resonance imaging (fMRI). Other MR measures,&#xD;
      such as magnetic resonance spectroscopy (MRS) and arterial spin labeling (ASL), will also be&#xD;
      explored as potential biomarkers.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>September 3, 2014</start_date>
  <completion_date type="Actual">September 18, 2019</completion_date>
  <primary_completion_date type="Actual">January 3, 2019</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <intervention_model_description>Within-subject design with each subject completing up to 10 rTMS sessions.</intervention_model_description>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Behavioral Outcome Measure</measure>
    <time_frame>3x per session in Behavioral phase (before TMS, immediately after TMS, and 1 hour after TMS), and 2x per session in MRI Phase (before TMS and immediately after TMS).</time_frame>
    <description>Behavioral effects of INTENSITY (Sham/100%MT/110%MT) and demand for cognitive control, DEMAND (High/Medium/Low), were planned to be quantified via correct response time (RT) and trial accuracy using R Project for Statistical Computing (package afex, function mixed (Singmannet al, 2015)). RT data were planned to be submitted to a linear mixed model with a random intercept per subject and fixed effects of INTENSITY and DEMAND. Accuracy data were planned to be submitted to a generalized linear mixed model with a binomial distribution and logit link function with a random intercept per subject and fixed effects of INTENSITY and DEMAND.&#xD;
During the Behavioral phase of the study, this data was collected before TMS, immediately after TMS, and 1 hour after TMS. During the MRI phase of the study, this data was only collected before TMS and immediately after TMS.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Imaging Outcome Measures</measure>
    <time_frame>Twice per session in MRI Phase (pre-TMS and immediately post-TMS)</time_frame>
    <description>These measures include resting state (seed-based functional connectivity), Arterial Spin labeling (ASL), and MRI Spectroscopy (MRS).&#xD;
Seed based - correlation coefficient changes&#xD;
ASL - % change&#xD;
MRS - % change</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">104</enrollment>
  <condition>Healthy Volunteer</condition>
  <arm_group>
    <arm_group_label>Real TMS</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>rTMS (frequency and intensity)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sham TMS</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>Sham setting on coil</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>TMS</intervention_name>
    <description>HAC coil (real rTMS or sham rTMS)</description>
    <arm_group_label>Real TMS</arm_group_label>
    <arm_group_label>Sham TMS</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
        Subjects must:&#xD;
&#xD;
          1. Be able to give valid informed consent&#xD;
&#xD;
          2. Be 18 55 years of age.&#xD;
&#xD;
               1. Justification: Many neural processes change with age, and these changes could&#xD;
                  introduce unwanted variability in both behavioral and MRI signals. In addition,&#xD;
                  the risk of difficult-to-detect medical abnormalities such as silent cerebral&#xD;
                  infarcts increases with age.&#xD;
&#xD;
               2. Screening tool: History. Government-issued forms of identification (e.g. driver s&#xD;
                  license, birth certificate) will be required when participant appears to be out&#xD;
                  of age range.&#xD;
&#xD;
          3. Be in good health.&#xD;
&#xD;
               1. Justification: Many illnesses may alter neural functioning as well as fMRI&#xD;
                  signals.&#xD;
&#xD;
               2. Screening tools: Medical Assessment, Medical History and Physical Examination.&#xD;
                  Medical assessments include: Vital Signs, EKG, oral HIV test, height/weight&#xD;
                  measurements, urinalysis and blood sample. Tests on the blood sample include&#xD;
                  complete blood count (CBC), complete metabolic profile, thyroid-stimulating&#xD;
                  hormone (TSH), erythrocyte sedimentation rate (ESR), Serologic Test For Syphilis&#xD;
                  (STS) and HIV (if needed to confirm a positive salivary test for HIV). The&#xD;
                  following individual laboratory results will independently disqualify&#xD;
                  individuals: Cholesterol &gt;250 mg/dl, Hemoglobin &lt; 10.5 g/dl, white blood cell&#xD;
                  count (WBC) &lt; 2400/microl, liver function tests (LFTs) &gt; 3x normal, Human&#xD;
                  chorionic gonadotropin (HCG) positive, Casual serum glucose &gt; 200 mg/dl, Urine&#xD;
                  protein &gt; 1+. The medically accountable investigator (MAI) will retain discretion&#xD;
                  to exclude at less extreme values, depending on the clinical presentation. (Serum&#xD;
                  glucose over 140 mg/dl will be followed up with a fasting serum glucose&#xD;
                  assessment. Those with fasting glucose below 100 mg/dl may be considered for the&#xD;
                  protocol. Others will be rejected and referred for work-up.) MAI will make the&#xD;
                  final judgment on any questionable lab results.&#xD;
&#xD;
          4. Right-handed.&#xD;
&#xD;
               1. Justification: Using right-handed individuals will reduce variability in BOLD MRI&#xD;
                  data.&#xD;
&#xD;
               2. Screening tool: Edinburgh Handedness Inventory.&#xD;
&#xD;
          5. Estimated intelligence quotient (IQ) greater than or equal to 85&#xD;
&#xD;
               1. Justification: Subjects must be able to perform a cognitively challenging task to&#xD;
                  a high standard.&#xD;
&#xD;
               2. Screening tool: Wechsler Abbreviated Scale of Intelligence.&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          1. Personal history of stroke, brain lesions, previous neurosurgery, any personal history&#xD;
             of seizure or fainting episode of unknown cause, or head trauma resulting in loss of&#xD;
             consciousness, lasting over 30 minutes or with sequela lasting longer than two days.&#xD;
&#xD;
             Justification: Stroke or head trauma can lower the seizure threshold, and are&#xD;
             therefore contra-indications for TMS. Fainting episodes or syncope of unknown cause&#xD;
             could indicate an undiagnosed condition associated with seizures.&#xD;
&#xD;
             Screening tool: TMS adult safety questionnaire, Medical History.&#xD;
&#xD;
          2. First-degree family history of any neurological disorder with a potentially hereditary&#xD;
             basis, including migraines, epilepsy, or multiple sclerosis.&#xD;
&#xD;
               1. Justification: Neurological disorders can lower the seizure threshold, and are&#xD;
                  therefore contra-indications for TMS. First-degree family history of certain&#xD;
                  neurological disorders with a hereditary component increases the risk of the&#xD;
                  subject having an undiagnosed condition that is associated with lowered seizure&#xD;
                  threshold.&#xD;
&#xD;
               2. Screening tool: TMS adult safety screening, Medical History.&#xD;
&#xD;
          3. Cardiac pacemakers, neural stimulators, implantable defibrillator, implanted&#xD;
             medication pumps, intracardiac lines, or acute, unstable cardiac disease, with&#xD;
             intracranial implants (e.g. aneurysm clips, shunts, stimulators, cochlear implants, or&#xD;
             electrodes) or any other metal object within or near the head that precludes MRI&#xD;
             scanning.&#xD;
&#xD;
               1. Justification: Any metal around the head is a contraindication for both MRI and&#xD;
                  TMS, as both methods involve exposure to a relatively strong magnetic field.&#xD;
&#xD;
               2. Screening tool: TMS adult safety screening, MRI safety screening, Medical&#xD;
                  History.&#xD;
&#xD;
          4. Noise-induced hearing loss or tinnitus.&#xD;
&#xD;
               1. Justification: individuals with noise-induced hearing problems may be&#xD;
                  particularly vulnerable to the acoustic noise generated by TMS and MRI equipment.&#xD;
&#xD;
               2. Screening tools: TMS adult safety screening.&#xD;
&#xD;
          5. Current use (any use in the past 4 weeks, chronic use within 6 past six months) of any&#xD;
             investigational drug or of any medications with psychotropic, anti or pro-convulsive&#xD;
             action.&#xD;
&#xD;
               1. Justification: The use of certain medications or drugs can lower seizure&#xD;
                  threshold and is therefore contra-indicated for TMS.&#xD;
&#xD;
               2. Screening tools: MRI safety screening questionnaire, Medical history, Medical&#xD;
                  Assessments: Urine toxicology analyzes for presence of a broad range of&#xD;
                  prescription and nonprescription drugs.&#xD;
&#xD;
          6. Lifetime history of major depressive disorder, schizophrenia, bipolar disorder, mania,&#xD;
             or hypomania.&#xD;
&#xD;
               1. Justification: The population of interest here is a healthy control population&#xD;
                  with no psychiatric disorders. In subjects with depression, bipolar disorder,&#xD;
                  mania or hypomania, there is a small chance that TMS can trigger (hypo)manic&#xD;
                  symptoms.&#xD;
&#xD;
               2. Screening tools: Structured Clinical Interview for the Diagnostic and Statistical&#xD;
                  Manual for Mental Disorders (SCID) Screen Patient Questionnaire. Potential&#xD;
                  diagnoses will be further evaluated by a counsellor.&#xD;
&#xD;
          7. Meet current Diagnostic and Statistical Manual (DSM) V criteria for moderate to severe&#xD;
             substance use disorder (excluding nicotine), smoke daily, or urine toxicology positive&#xD;
             for any illicit substance inconsistent with history given.&#xD;
&#xD;
               1. Justification: The population of interest here is a healthy control population&#xD;
                  with no substance use disorder. Current use of illicit substances could impact on&#xD;
                  seizure threshold and is therefore contra-indicated for TMS.&#xD;
&#xD;
               2. Screening tools: SCID Screen Patient Questionnaire. Potential diagnoses will be&#xD;
                  further evaluated by a counsellor, Drug Use Survey (DUS), Substance Use Disorder&#xD;
                  Evaluation, Medical Assessments: urine qualitative drug screen is performed for&#xD;
                  methadone, benzodiazepines, cocaine, amphetamine/methamphetamine, opiates,&#xD;
                  barbiturates, and tetrahydrocannabinol.&#xD;
&#xD;
          8. Have met DSM V criteria for moderate to severe substance use disorder (excluding&#xD;
             nicotine, alcohol and cannabis) in the past, or have met DSM V criteria for moderate&#xD;
             to severe substance use disorder for cannabis or alcohol in the past 5 years.&#xD;
&#xD;
               1. Justification: the population of interest here is a healthy control population&#xD;
                  with no present or past substance use disorder.&#xD;
&#xD;
               2. Screening tools: SCID Screen Patient Questionnaire. Potential diagnoses will be&#xD;
                  further evaluated by a counselor. Drug Use Survey (DUS), Substance Use Disorder&#xD;
                  Evaluation.&#xD;
&#xD;
          9. History of myocardial infarction, angina, congestive heart failure, cardiomyopathy,&#xD;
             stroke or transient ischemic attack, or any heart condition currently under medical&#xD;
             care.&#xD;
&#xD;
               1. Justifications: the risk of TMS for individuals with a heart condition is&#xD;
                  unknown.&#xD;
&#xD;
               2. Screening tool: physical assessment (EKG), medical history.&#xD;
&#xD;
         10. Pregnant women or women with reproductive potential who are sexually active and not&#xD;
             using an acceptable form of contraception.&#xD;
&#xD;
               1. Justification: it is unknown whether TMS poses a risk to fetuses.&#xD;
&#xD;
               2. Screening tool: Medical assessments (urine pregnancy test) at the beginning of&#xD;
                  each visit that involves TMS or MRI.&#xD;
&#xD;
         11. History of learning disability or current attention deficit hyperactivity disorder&#xD;
             (ADHD)&#xD;
&#xD;
               1. Justification: Subjects should be able to perform cognitive tasks to a high&#xD;
                  degree of accuracy, both in the MRI scanner and outside the scanner. Subjects&#xD;
                  with ADHD/LD may engage different neural circuitry even if they can perform the&#xD;
                  tasks.&#xD;
&#xD;
               2. Screening tool: Wechsler Abbreviated Scale of Intelligence, Medical history,&#xD;
                  Adult ADHD Self-Report Scale.&#xD;
&#xD;
         12. Participation in an rTMS session less than two weeks ago.&#xD;
&#xD;
               1. Justification: in order to limit exposure to TMS, we will not enroll subjects who&#xD;
                  have received TMS less than two weeks ago.&#xD;
&#xD;
               2. Screening tool: TMS safety screening questionnaire.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Elliot Stein, Ph.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Institute on Drug Abuse (NIDA)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>National Institute on Drug Abuse</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21224</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>September 18, 2019</verification_date>
  <study_first_submitted>September 3, 2014</study_first_submitted>
  <study_first_submitted_qc>September 3, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 4, 2014</study_first_posted>
  <results_first_submitted>December 16, 2019</results_first_submitted>
  <results_first_submitted_qc>February 20, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">February 24, 2020</results_first_posted>
  <last_update_submitted>February 20, 2020</last_update_submitted>
  <last_update_submitted_qc>February 20, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">February 24, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Repetitive TMS (rTMS)</keyword>
  <keyword>Parameter Development</keyword>
  <keyword>Cognitive Tasks</keyword>
  <keyword>MRI (Magnetic Resonance Imaging)</keyword>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>November 30, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/92/NCT02231892/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>Orientation occurred prior to starting repetitive transcranial magnetic stimulation (rTMS) days. Orientation consisted of single-pulse TMS (allowed participant to experience TMS and researcher to find motor hotspot) and habituation (allowed participant to habituate to varied TMS intensities). Many ppts withdrew or were excluded during orientation.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Low Frequency rTMS - Behavioral Phase</title>
          <description>Participants in this arm received sham or active 1 hertz (Hz) rTMS at 100% and 110% of motor threshold during the behavioral phase.</description>
        </group>
        <group group_id="P2">
          <title>High Frequency rTMS - Behavioral Phase</title>
          <description>Participants in this arm received sham or active 10 hertz (Hz) rTMS at 100% and 110% of motor threshold during the behavioral phase</description>
        </group>
        <group group_id="P3">
          <title>High Frequency rTMS - MRI Phase</title>
          <description>Participants in this arm received sham or active 10 hertz (Hz) rTMS at 100% and 110% of motor threshold during the MRI phase of the study.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="17"/>
                <participants group_id="P2" count="17"/>
                <participants group_id="P3" count="70"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Sham</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="5"/>
                <participants group_id="P3" count="26"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>100% MT</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="6"/>
                <participants group_id="P3" count="25"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>110% MT</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
                <participants group_id="P2" count="5"/>
                <participants group_id="P3" count="27"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="5">3 participants completed this phase and Hi Frequency MRI phase, but are only counted in Hi Freq MRI.</participants>
                <participants group_id="P3" count="25">3 participants completed this phase and Hi Frequency Beh phase, but are only counted in Hi Freq MRI.</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="11"/>
                <participants group_id="P2" count="12"/>
                <participants group_id="P3" count="45"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="3"/>
                <participants group_id="P3" count="15"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="4"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Motor activity when stimulating ante ACC</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="7"/>
                <participants group_id="P3" count="12"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Participant motor threshold was &gt;83%</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="9"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Could not find motor threshold</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Could not find reliable motor hotspot</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Low Frequency rTMS - Behavioral Phase</title>
          <description>Participants in this arm received sham or active 1Hz rTMS at 100% and 110% of motor threshold during the behavioral phase</description>
        </group>
        <group group_id="B2">
          <title>High Frequency rTMS - Behavioral Phase</title>
          <description>Participants in this arm received sham or active 10Hz rTMS at 100% and 110% of motor threshold during the behavioral phase</description>
        </group>
        <group group_id="B3">
          <title>High Frequency rTMS - MRI Phase</title>
          <description>Participants in this arm received sham or active 10Hz rTMS at 100% and 110% of motor threshold during the MRI phase of the study.</description>
        </group>
        <group group_id="B4">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="17"/>
            <count group_id="B2" value="17"/>
            <count group_id="B3" value="70"/>
            <count group_id="B4" value="104"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                    <measurement group_id="B2" value="17"/>
                    <measurement group_id="B3" value="68"/>
                    <measurement group_id="B4" value="102"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="30.12" lower_limit="21" upper_limit="48"/>
                    <measurement group_id="B2" value="28.55" lower_limit="19" upper_limit="55"/>
                    <measurement group_id="B3" value="32.39" lower_limit="18" upper_limit="55"/>
                    <measurement group_id="B4" value="31.27" lower_limit="18" upper_limit="55"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="39"/>
                    <measurement group_id="B4" value="56"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="31"/>
                    <measurement group_id="B4" value="48"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="6"/>
                    <measurement group_id="B4" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                    <measurement group_id="B2" value="15"/>
                    <measurement group_id="B3" value="64"/>
                    <measurement group_id="B4" value="94"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="8"/>
                    <measurement group_id="B4" value="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="36"/>
                    <measurement group_id="B4" value="62"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="25"/>
                    <measurement group_id="B4" value="30"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                    <measurement group_id="B2" value="17"/>
                    <measurement group_id="B3" value="70"/>
                    <measurement group_id="B4" value="104"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Behavioral Outcome Measure</title>
        <description>Behavioral effects of INTENSITY (Sham/100%MT/110%MT) and demand for cognitive control, DEMAND (High/Medium/Low), were planned to be quantified via correct response time (RT) and trial accuracy using R Project for Statistical Computing (package afex, function mixed (Singmannet al, 2015)). RT data were planned to be submitted to a linear mixed model with a random intercept per subject and fixed effects of INTENSITY and DEMAND. Accuracy data were planned to be submitted to a generalized linear mixed model with a binomial distribution and logit link function with a random intercept per subject and fixed effects of INTENSITY and DEMAND.&#xD;
During the Behavioral phase of the study, this data was collected before TMS, immediately after TMS, and 1 hour after TMS. During the MRI phase of the study, this data was only collected before TMS and immediately after TMS.</description>
        <time_frame>3x per session in Behavioral phase (before TMS, immediately after TMS, and 1 hour after TMS), and 2x per session in MRI Phase (before TMS and immediately after TMS).</time_frame>
        <population>Data have not yet been analyzed due to personnel turnover. There are currently no resources to complete data analysis at this time. We have transferred data to a repository protocol for future analysis when resources for data analysis are available.</population>
        <group_list>
          <group group_id="O1">
            <title>Low Frequency rTMS - Behavioral Phase</title>
            <description>Participants in this arm received sham or active 1Hz rTMS at 100% and 110% of motor threshold during the behavioral phase</description>
          </group>
          <group group_id="O2">
            <title>High Frequency rTMS - Behavioral Phase</title>
            <description>Participants in this arm received sham or active 10Hz rTMS at 100% and 110% of motor threshold during the behavioral phase</description>
          </group>
          <group group_id="O3">
            <title>High Frequency rTMS - MRI Phase</title>
            <description>Participants in this arm received sham or active 10Hz rTMS at 100% and 110% of motor threshold during the MRI phase of the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Behavioral Outcome Measure</title>
          <description>Behavioral effects of INTENSITY (Sham/100%MT/110%MT) and demand for cognitive control, DEMAND (High/Medium/Low), were planned to be quantified via correct response time (RT) and trial accuracy using R Project for Statistical Computing (package afex, function mixed (Singmannet al, 2015)). RT data were planned to be submitted to a linear mixed model with a random intercept per subject and fixed effects of INTENSITY and DEMAND. Accuracy data were planned to be submitted to a generalized linear mixed model with a binomial distribution and logit link function with a random intercept per subject and fixed effects of INTENSITY and DEMAND.&#xD;
During the Behavioral phase of the study, this data was collected before TMS, immediately after TMS, and 1 hour after TMS. During the MRI phase of the study, this data was only collected before TMS and immediately after TMS.</description>
          <population>Data have not yet been analyzed due to personnel turnover. There are currently no resources to complete data analysis at this time. We have transferred data to a repository protocol for future analysis when resources for data analysis are available.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Imaging Outcome Measures</title>
        <description>These measures include resting state (seed-based functional connectivity), Arterial Spin labeling (ASL), and MRI Spectroscopy (MRS).&#xD;
Seed based - correlation coefficient changes&#xD;
ASL - % change&#xD;
MRS - % change</description>
        <time_frame>Twice per session in MRI Phase (pre-TMS and immediately post-TMS)</time_frame>
        <population>Data have not yet been analyzed due to personnel turnover. There are currently no resources to complete data analysis at this time. We have transferred data to a repository protocol for future analysis when resources for data analysis are available.</population>
        <group_list>
          <group group_id="O1">
            <title>Low Frequency rTMS - Behavioral Phase</title>
            <description>Participants in this arm received sham or active 1Hz rTMS at 100% and 110% of motor threshold during the behavioral phase</description>
          </group>
          <group group_id="O2">
            <title>High Frequency rTMS - Behavioral Phase</title>
            <description>Participants in this arm received sham or active 10Hz rTMS at 100% and 110% of motor threshold during the behavioral phase</description>
          </group>
          <group group_id="O3">
            <title>High Frequency rTMS - MRI Phase</title>
            <description>Participants in this arm received sham or active 10Hz rTMS at 100% and 110% of motor threshold during the MRI phase of the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Imaging Outcome Measures</title>
          <description>These measures include resting state (seed-based functional connectivity), Arterial Spin labeling (ASL), and MRI Spectroscopy (MRS).&#xD;
Seed based - correlation coefficient changes&#xD;
ASL - % change&#xD;
MRS - % change</description>
          <population>Data have not yet been analyzed due to personnel turnover. There are currently no resources to complete data analysis at this time. We have transferred data to a repository protocol for future analysis when resources for data analysis are available.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse event (AE) monitoring took place from participant consent to 3 weeks after final TMS session. The actual timeframe varied based on participant schedules and availability. Participants completed a TMS monitoring questionnaire before and after each TMS session, as well as 3 weeks after their final TMS session. Participants also completed a nursing assessment the morning of TMS appointments and had vitals taken at the end of each TMS appointment.</time_frame>
      <desc>AE collection was broken down by phase of the study (Behavioral vs. MRI), TMS Frequency (1Hz vs 10Hz), and Percentage of Motor Threshold (100%, 110%, Sham). Percentage of Motor Threshold (MT) corresponds with the milestones listed in the participant flow section.</desc>
      <group_list>
        <group group_id="E1">
          <title>Low Frequency rTMS - 100% MT - Behavioral Phase</title>
          <description>Active 1Hz rTMS at 100% of motor threshold during the behavioral phase</description>
        </group>
        <group group_id="E2">
          <title>Low Frequency rTMS - 110% MT - Behavioral Phase</title>
          <description>Active 1Hz rTMS at 110% of motor threshold during the behavioral phase</description>
        </group>
        <group group_id="E3">
          <title>Low Frequency rTMS - Sham - Behavioral Phase</title>
          <description>Low Frequency rTMS, sham, during behavioral phase.</description>
        </group>
        <group group_id="E4">
          <title>High Frequency rTMS - 100% MT - Behavioral Phase</title>
          <description>Active 10Hz rTMS at 100% of motor threshold during the behavioral phase</description>
        </group>
        <group group_id="E5">
          <title>High Frequency rTMS - 110% MT - Behavioral Phase</title>
          <description>Active 10Hz rTMS at 110% of motor threshold during the behavioral phase</description>
        </group>
        <group group_id="E6">
          <title>High Frequency rTMS - Sham - Behavioral Phase</title>
          <description>High Frequency rTMS, sham, during behavioral phase.</description>
        </group>
        <group group_id="E7">
          <title>High Frequency rTMS - 100% MT - MRI Phase</title>
          <description>Active 10Hz rTMS at 100% of motor threshold during the MRI phase of the study.</description>
        </group>
        <group group_id="E8">
          <title>High Frequency rTMS - 110% MT - MRI Phase</title>
          <description>Active 10Hz rTMS at 110% of motor threshold during the MRI phase of the study.</description>
        </group>
        <group group_id="E9">
          <title>High Frequency rTMS - Sham - MRI Phase</title>
          <description>High Frequency rTMS, sham, during MRI phase.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E7" subjects_affected="0" subjects_at_risk="25"/>
                <counts group_id="E8" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E9" subjects_affected="0" subjects_at_risk="26"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E7" subjects_affected="0" subjects_at_risk="25"/>
                <counts group_id="E8" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E9" subjects_affected="0" subjects_at_risk="26"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="7"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E7" subjects_affected="3" subjects_at_risk="25"/>
                <counts group_id="E8" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E9" subjects_affected="0" subjects_at_risk="26"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <description>Participants developed a headache during the rTMS session - stimulation was stopped upon request of participant. Expected, non-serious, related adverse event.</description>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="7"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E7" events="0" subjects_affected="0" subjects_at_risk="25"/>
                <counts group_id="E8" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E9" events="0" subjects_affected="0" subjects_at_risk="26"/>
              </event>
              <event>
                <sub_title>Headache and Dizziness</sub_title>
                <description>Participant reported headache and dizziness. Expected, non-serious, related adverse event.</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E7" events="1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E8" events="2" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E9" events="0" subjects_affected="0" subjects_at_risk="26"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Involuntary Movement After TMS</sub_title>
                <assessment>Systematic Assessment</assessment>
                <description>Participants showed involuntary motor activity (twitch in foot) after stimulation for motor threshold determination. Participants were withdrawn from the study and offered follow-up neurological assessment. Expected, non-serious, related AE.</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E7" events="1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E8" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E9" events="0" subjects_affected="0" subjects_at_risk="26"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Hypomanic Episode</sub_title>
                <description>Participant reported on 4/3/2017 that after orientation session on 3/13/17, she felt elevated mood and restlessness that lasted until the next day. Expected, non-serious, possibly related adverse event.</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E7" events="1" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E8" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E9" events="0" subjects_affected="0" subjects_at_risk="26"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>Data collection closed 9/17/2019. Data have not yet been analyzed due to personnel turnover. There are currently no resources to complete data analysis. Data were transferred to a repository protocol for future analysis when resources are available.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Dr. Elliott Stein</name_or_title>
      <organization>National Institute on Drug Abuse</organization>
      <phone>443-740-2650</phone>
      <email>estein@mail.nih.gov</email>
    </point_of_contact>
  </clinical_results>
</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/NCT02231892
org study id: 999914186
secondary id: 14-DA-N186
nct id: NCT02231892
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: Yes
Background:

      - Brain stimulation called repetitive transcranial magnetic stimulation (rTMS) may help
      people quit drugs. Researchers want to study how it works in healthy people first.

      Objective:

      - To learn how to use rTMS to stimulate a brain area and to see how it affects brain function
      and thinking.

      Eligibility:

      - Healthy, right-handed adults ages 18-55.

      Design:

        -  Participants will be screened under another protocol.

        -  They will have 4-11 study visits.

        -  To start each visit, participants will have:

        -  Physical exam.

        -  Urine sample.

        -  Breath tests for alcohol and cigarette smoke.

        -  Questions about drug use and medications.

        -  Visit 1: participants will have:

        -  Single TMS pulses on the head to determine the right strength. They will wear earplugs
           and a cap. A wire coil will be placed on the head and an electrical current will go
           through it. Participants may perform simple muscle movements. They will repeat the
           procedures wearing another coil, in a helmet.

        -  A few TMS pulses to show how rTMS feels.

        -  A practice thinking task, maybe in a scanner that looks and sounds like a magnetic
           resonance imaging (MRI) scanner but does not take pictures. The MRI scanner is a metal
           cylinder surrounded by a strong magnetic field. The participant will lie on a table that
           slides in and out of the cylinder.

        -  They may have a real MRI scan.

        -  Visits 2-11, participants will:

        -  Complete two questionnaires.

        -  Get varied rTMS stimulation. Their heart rate and blood pressure may be monitored.

        -  Have their vital signs checked.

        -  They may perform thinking tasks at a computer, in a mock scanner, or in an MRI scanner.
           They may just lie still in the MRI scanner.
Objective: To establish an effective repetitive transcranial magnetic stimulation (rTMS)
      protocol for stimulating circuits relevant for addiction. Specifically, we will develop
      stimulation parameters and outcome measures for rTMS of the anterior cingulate cortex (ACC)
      with a specialized TMS coil: the HAC coil (Brainsway Ltd.). Various parameters of rTMS
      stimulation (frequency and intensity) will be varied, and the sensitivity of behavioral tasks
      and MRI measures to this stimulation will be determined. The objective of this protocol is
      therefore to allow for the development, assessment and refinement of rTMS parameters for
      stimulating ACC targets. In addition, outcome measures will be developed to capture the
      effects of this stimulation. Results from this development protocol will be applied to
      subsequent cognitive imaging protocols.

      Study population: Up to 50 healthy, non-smoking adults will be tested in several conditions
      over up to two weeks. Subjects must fit exclusion/inclusion criteria for TMS and MRI. We
      expect 140 subjects to be enrolled to arrive at a number of 50 who complete the protocol.

      Design: Within-subject design with each subject completing up to 10 rTMS sessions.

      Outcome measures: In a first phase, the outcome measure will be the behavioral response on a
      task that relies on the ACC. In a second phase, outcome measures will be the effects on MR
      measures. These will include task-related blood oxygen level-dependent (BOLD) responses, as
      well as resting state BOLD functional magnetic resonance imaging (fMRI). Other MR measures,
      such as magnetic resonance spectroscopy (MRS) and arterial spin labeling (ASL), will also be
      explored as potential biomarkers.
allocation: Non-Randomized
intervention model: Crossover Assignment
intervention model description: Within-subject design with each subject completing up to 10 rTMS sessions.
primary purpose: Basic Science
masking: Double (Participant, Investigator)
measure: Behavioral Outcome Measure
time frame: 3x per session in Behavioral phase (before TMS, immediately after TMS, and 1 hour after TMS), and 2x per session in MRI Phase (before TMS and immediately after TMS).
description: Behavioral effects of INTENSITY (Sham/100%MT/110%MT) and demand for cognitive control, DEMAND (High/Medium/Low), were planned to be quantified via correct response time (RT) and trial accuracy using R Project for Statistical Computing (package afex, function mixed (Singmannet al, 2015)). RT data were planned to be submitted to a linear mixed model with a random intercept per subject and fixed effects of INTENSITY and DEMAND. Accuracy data were planned to be submitted to a generalized linear mixed model with a binomial distribution and logit link function with a random intercept per subject and fixed effects of INTENSITY and DEMAND.
During the Behavioral phase of the study, this data was collected before TMS, immediately after TMS, and 1 hour after TMS. During the MRI phase of the study, this data was only collected before TMS and immediately after TMS.
measure: Imaging Outcome Measures
time frame: Twice per session in MRI Phase (pre-TMS and immediately post-TMS)
description: These measures include resting state (seed-based functional connectivity), Arterial Spin labeling (ASL), and MRI Spectroscopy (MRS).
Seed based - correlation coefficient changes
ASL - % change
MRS - % change
arm group label: Real TMS
arm group type: Experimental
description: rTMS (frequency and intensity)
arm group label: Sham TMS
arm group type: Sham Comparator
description: Sham setting on coil
intervention type: Device
intervention name: TMS
description: HAC coil (real rTMS or sham rTMS)
arm group label: Real TMS
arm group label: Sham TMS
criteria: 
gender: All
minimum age: 18 Years
maximum age: 55 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Elliot Stein, Ph.D.
role: Principal Investigator
affiliation: National Institute on Drug Abuse (NIDA)
facility: 
country: United States
responsible party type: Sponsor
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Data collection closed 9/17/2019. Data have not yet been analyzed due to personnel turnover. There are currently no resources to complete data analysis. Data were transferred to a repository protocol for future analysis when resources are available.
point of contact: 