<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/NCT02196259</url>
  </required_header>
  <id_info>
    <org_study_id>U028860-MICHR-Pilot</org_study_id>
    <nct_id>NCT02196259</nct_id>
  </id_info>
  <brief_title>Anesthesia and Functional Connectivity: An Analysis of fMRI Changes</brief_title>
  <official_title>Anesthesia and Brain Functional Connectivity: An Analysis of fMRI Changes in Chronic Pain and Refractory Depression</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Michigan</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Michigan</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Functional connectivity is defined as a correlation in neural activity between distinct&#xD;
      regions of the brain. Several recent studies have demonstrated areas of low-frequency&#xD;
      functional connectivity inherent to brain tissue at rest. These oscillations can be measured&#xD;
      using functional magnetic resonance imaging (fMRI) and appear to be synchronized between&#xD;
      related areas of the brain.&#xD;
&#xD;
      To date, no investigators have examined the effects of low-dose anesthesia on functional&#xD;
      connectivity. This study will image the human brain under conditions of rest, and low-dose&#xD;
      anesthetic induced sedation. Quality of the acquired signals will be evaluated and functional&#xD;
      networks in the brain will be examined. Of interest is whether administration of a low-dose&#xD;
      anesthetic disrupts functional connectivity in the brain, and whether a disruption of&#xD;
      functional connectivity is responsible for the reported analgesic and antidepressant effects&#xD;
      of a anesthetic.&#xD;
&#xD;
      Participation in the study includes four visits: an in-person interview, an initial fMRI&#xD;
      scan, the anesthesia infusion, and a second fMRI scan. There is an optional follow-up fMRI&#xD;
      scan one week post infusion.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
      A phencyclidine derivative developed by Parke-Davis represented an attempt to mimic&#xD;
      phencyclidine anesthesia without inducing the severe psychomimetic reactions of its parent&#xD;
      compound. Initial reports were promising and received great enthusiasm. At high doses, the&#xD;
      drug was found to provide profound analgesia whilst preserving airway reflexes. It induced&#xD;
      reliable amnesia, yet could be delivered as a simple injection. It was claimed at the time&#xD;
      that this anesthetic heralded a new phase in the history of anesthesia. Today, over 40 years&#xD;
      since the anesthetic was introduced at Michigan, there has been a resurgence of interest in&#xD;
      this old drug. A growing number of investigators are studying the effects of anesthesia on&#xD;
      human subjects. There is currently tremendous interest in anesthesia as an opioid sparing&#xD;
      agent, a model for schizophrenia, an antidepressant, and as an N-Methyl D-Aspartate (NMDA)&#xD;
      antagonist in complex regional pain syndromes.&#xD;
&#xD;
      Functional connectivity is a measure of low-frequency oscillations (&lt;0.08 Hz) that are&#xD;
      inherent to brain tissue at rest. These oscillations are measured on fMRI, and appear to be&#xD;
      synchronized between related areas of the brain. Although research in this area is still in&#xD;
      its infancy, studies of the motor, auditory, visual, and sensorimotor systems, have shown&#xD;
      that functionally related areas of the brain produce correlated low-frequency oscillations.&#xD;
      This fascinating finding raises the possibility of a new approach to studying brain function&#xD;
      as well as a potential tool for the diagnosis of disease. Recent fMRI studies of the&#xD;
      precentral gyrus have demonstrated the ability of functional connectivity studies to&#xD;
      differentiate healthy volunteers from patients with multiple sclerosis. Additional research&#xD;
      is ongoing to determine whether functional connectivity will prove useful in the diagnosis of&#xD;
      early Alzheimer's disease.&#xD;
&#xD;
      Recent research in functional connectivity has identified regions in the brain active at&#xD;
      rest. These regions are often referred to at the &quot;Default-mode network&quot; (DMN). Activity in&#xD;
      the DMN is increased in the brain at rest and decreased when a subject concentrates on a&#xD;
      mental task. The first fMRI study examining functional connectivity in chronic pain patients&#xD;
      was published in a recent issue of the Journal of Neuroscience. In this study abnormal&#xD;
      patterns of functional connectivity were seen in chronic pain patients. Specifically, a&#xD;
      dysfunction in down-regulating the DMN was seen. The chronic pain patients did not deactivate&#xD;
      the medial prefrontal cortex, amygdala, or posterior cingulate cortex to the same degree as&#xD;
      healthy controls.&#xD;
&#xD;
      The only fMRI study examining functional connectivity in major depression was published in&#xD;
      September of 2007. This study also noted a dysfunction in the DMN. Depressed subjects were&#xD;
      found to have increased network functional connectivity in the subgenual cingulate cortex,&#xD;
      thalamus, orbitofrontal cortex, and the precuneus. Notably, the subgenual cingulate cortex is&#xD;
      the location of a recent clinical trial suggesting that deep brain stimulation to this region&#xD;
      may ameliorate symptoms of patients with severe refractory depression.&#xD;
&#xD;
      Interest in anesthesia for the treatment of chronic pain and depression has grown in recent&#xD;
      years. Although there have been no randomized trials of low-dose anesthesia in chronic pain&#xD;
      patients, the evidence currently available indicates it is most effective in the treatment of&#xD;
      allodynia, hyperalgesia, and hyperpathia. For depression, there has been one randomized,&#xD;
      placebo-controlled, double blinded crossover study. In the depression trial, robust and rapid&#xD;
      antidepressant effects were found to result from a single intravenous dose of anesthesia and&#xD;
      last for at least a week.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      To examine functional connectivity in the human brain both at rest and after anesthetic&#xD;
      sedation using functional magnetic resonance imaging (fMRI).&#xD;
&#xD;
      Specific Aims/Hypotheses:&#xD;
&#xD;
        1. Measure the degree of functional connectivity in three study groups (healthy volunteers,&#xD;
           chronic back pain, and refractory depression).&#xD;
&#xD;
        2. Analyze for differences in baseline functional connectivity.&#xD;
&#xD;
        3. Measure changes in functional connectivity after IV low-dose anesthetic sedation.&#xD;
&#xD;
        4. Document study group differences in anesthetic response.&#xD;
&#xD;
        5. Measure for any correlation between fMRI changes and therapeutic effects.&#xD;
&#xD;
      Study Protocol:&#xD;
&#xD;
      Participation in this study includes four main visits and an optional follow-up visit. The&#xD;
      first visit is a baseline interview session to assess participant eligibility using a&#xD;
      structured interview. The second visit is an initial fMRI scan at the fMRI center. The third&#xD;
      visit is the anesthetic infusion at the hospital; management of any adverse events during the&#xD;
      infusion will be monitored by the Post Anesthesia Care Unit ( PACU) personnel. The fourth&#xD;
      visit is a follow-up fMRI scan at the fMRI center. There is an optional one week follow-up&#xD;
      visit at the fMRI center for a final fMRI scan.&#xD;
&#xD;
      fMRI Statistical Analysis: The imaging experiments and analysis of subject-specific data will&#xD;
      lead to maps corresponding to separate measures: resting state functional connectivity maps,&#xD;
      and measures of cerebral blood flow (CBF). Final inferences will be made at the voxel level&#xD;
      and for anatomically specific regions-of-interest (ROIs). The voxel-based analysis will be&#xD;
      performed through the generation of summary images referred to as statistical parametric maps&#xD;
      (SPMs) representing before-infusion vs. after-infusion, and, as data in the two patient&#xD;
      groups become available, two-way ANOVA results of ketamine infusion state and patient&#xD;
      diagnosis (chronic pain or refractory depression). The ROI-based analysis will be driven by&#xD;
      the a priori selected fronto-limbic regions of interest generated in the self-reflection&#xD;
      task, and by the anatomical nodes in the default mode network given in the literature.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Funding cessation.&#xD;
  </why_stopped>
  <start_date>February 2008</start_date>
  <completion_date type="Actual">May 2015</completion_date>
  <primary_completion_date type="Actual">May 2015</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>Single Group Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Functional Connectivity</measure>
    <time_frame>8 minutes scans, acquired between 1 day and 3 days (see above)</time_frame>
    <description>The imaging experiments and analysis of subject-specific data will lead to maps corresponding to separate measures: resting state functional connectivity maps. The outcome of interest is whether ketamine reduces functional connectivity between the anterior (subgenual anterior cingulate corte, sgACC) and posterior regions (posterior cingulate cortex, PCC) of the default mode network. This is the z-score of the functional connectivity correlation.&#xD;
Timepoints for Initial fMRI were: Time 1:Immediately before Infusion, Time 2: After washout (Approx. 40 min after end of infusion).&#xD;
Timepoints for Depression were: Time 1: 1 Day before Infusion, Time 2: 1 Day after Infusion</description>
  </primary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">16</enrollment>
  <condition>Changes in Brain Network Connectivity</condition>
  <arm_group>
    <arm_group_label>Initial MRI</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The subject will receive intravenous ketamine anesthesia at a dose of 0.5mg/kg delivered over 40 minutes in a constant infusion or bolus plus infusion method to maintain steady state (10 minutes initial induction, 30 minutes steady-state, for 40 minutes total)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Initial hospital</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The subject will receive intravenous ketamine anesthesia at a dose of 0.5mg/kg delivered over 40 minutes in a constant infusion or bolus plus infusion method to maintain steady state (10 minutes initial induction, 30 minutes steady-state, for 40 minutes total)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Depression MRI</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The subject will receive intravenous ketamine anesthesia at a dose of 0.5mg/kg delivered over 40 minutes in a constant infusion or bolus plus infusion method to maintain steady state (10 minutes initial induction, 30 minutes steady-state, for 40 minutes total)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Anesthetics, Dissociative</intervention_name>
    <description>The subject will receive intravenous anesthesia at a dose of 0.5mg/kg delivered over 40 minutes in a constant infusion or bolus plus infusion method to maintain steady state (10 minutes initial induction, 30 minutes steady-state, for 40 minutes total)</description>
    <arm_group_label>Depression MRI</arm_group_label>
    <arm_group_label>Initial MRI</arm_group_label>
    <arm_group_label>Initial hospital</arm_group_label>
    <other_name>Ketamine</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Control Group:&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
        (4) Ability to tolerate small, enclosed spaces without anxiety; (6) English fluency.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnant or trying to become pregnant.&#xD;
&#xD;
          -  history of serious head injury;&#xD;
&#xD;
          -  possibility of ferrous metals within the body, e. g. aneurysm clips, retained&#xD;
             particles; or metal that would impair the magnetic resonance (MR) signal, e.g., some&#xD;
             dental hardware;&#xD;
&#xD;
          -  Smoking usage &gt; 10 cigarettes per day&#xD;
&#xD;
          -  Daily intake of caffeine exceeds 2 cups of coffee per day&#xD;
&#xD;
          -  Unstable cardiac problems (e.g. severe or poorly treated hypertension, unstable&#xD;
             arrhythmia, etc.) or concurrent medications for which anesthesia would be&#xD;
             contraindicated&#xD;
&#xD;
          -  Patients with a current general medical illness that is life threatening or&#xD;
             inadequately treated will be excluded: moderate-to-severe chronic pain, evidence of&#xD;
             fracture or malignancy, inflammatory joint disease, severe physical impairment (e.g.,&#xD;
             bilateral amputation, blindness), morbid obesity, autoimmune/inflammatory diseases,&#xD;
             cardiopulmonary disorders (i.e., angina, congestive heart failure, COPD), chronic&#xD;
             renal insufficiency, uncontrolled endocrine or allergic disorders (i.e.,&#xD;
             hyper-/hypothyroidism, diabetes, allergic rhinitis), malignancy.&#xD;
&#xD;
          -  Taking any medication, prescription or non-prescription, with psychotropic effects.&#xD;
&#xD;
          -  History of psychiatric or neurological illness; History of substance abuse or&#xD;
             dependence Positive urine toxicology screen.&#xD;
&#xD;
        Refractory Depression Group:&#xD;
&#xD;
          -  Meets all above control group screening criteria except history of psychiatric illness&#xD;
             and prescription medication usage&#xD;
&#xD;
          -  Included subjects will have a Diagnostic and Statistical Manual of Mental Disorders IV&#xD;
             (DSM-IV) diagnosis of major depressive disorder, recurrent or chronic,&#xD;
             moderate-to-severe, without psychotic features, with medication resistance, accepted&#xD;
             with agreement by two different psychiatrists. For this study, treatment resistance is&#xD;
             defined as ≥2 failed adequate antidepressant trials.&#xD;
&#xD;
          -  Patients with a DSM-IV diagnosis of bipolar disorder, schizophrenia, or&#xD;
             schizoaffective disorder will be excluded. Any history of antidepressant- or&#xD;
             substance- induced hypomania or mania will be excluded.&#xD;
&#xD;
          -  Subjects will be free of comorbid substance abuse or dependence for at least 3 months,&#xD;
             with a negative urine toxicology screen.&#xD;
&#xD;
          -  No current suicide plan or intent.&#xD;
&#xD;
          -  Comorbid Axis I anxiety disorder diagnoses will be permitted if they do not require&#xD;
             current treatment.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Scott Peltier, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Michigan</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Michigan - fMRI Laboratory</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Biswal B, Yetkin FZ, Haughton VM, Hyde JS. Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magn Reson Med. 1995 Oct;34(4):537-41. doi: 10.1002/mrm.1910340409.</citation>
    <PMID>8524021</PMID>
  </reference>
  <reference>
    <citation>Lowe MJ, Mock BJ, Sorenson JA. Functional connectivity in single and multislice echoplanar imaging using resting-state fluctuations. Neuroimage. 1998 Feb;7(2):119-32. doi: 10.1006/nimg.1997.0315.</citation>
    <PMID>9558644</PMID>
  </reference>
  <reference>
    <citation>Cordes D, Haughton VM, Arfanakis K, Wendt GJ, Turski PA, Moritz CH, Quigley MA, Meyerand ME. Mapping functionally related regions of brain with functional connectivity MR imaging. AJNR Am J Neuroradiol. 2000 Oct;21(9):1636-44.</citation>
    <PMID>11039342</PMID>
  </reference>
  <reference>
    <citation>Lowe MJ, Phillips MD, Lurito JT, Mattson D, Dzemidzic M, Mathews VP. Multiple sclerosis: low-frequency temporal blood oxygen level-dependent fluctuations indicate reduced functional connectivity initial results. Radiology. 2002 Jul;224(1):184-92. doi: 10.1148/radiol.2241011005.</citation>
    <PMID>12091681</PMID>
  </reference>
  <reference>
    <citation>Baliki MN, Geha PY, Apkarian AV, Chialvo DR. Beyond feeling: chronic pain hurts the brain, disrupting the default-mode network dynamics. J Neurosci. 2008 Feb 6;28(6):1398-403. doi: 10.1523/JNEUROSCI.4123-07.2008.</citation>
    <PMID>18256259</PMID>
  </reference>
  <reference>
    <citation>Greicius MD, Flores BH, Menon V, Glover GH, Solvason HB, Kenna H, Reiss AL, Schatzberg AF. Resting-state functional connectivity in major depression: abnormally increased contributions from subgenual cingulate cortex and thalamus. Biol Psychiatry. 2007 Sep 1;62(5):429-37. doi: 10.1016/j.biopsych.2006.09.020. Epub 2007 Jan 8.</citation>
    <PMID>17210143</PMID>
  </reference>
  <reference>
    <citation>Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, Schwalb JM, Kennedy SH. Deep brain stimulation for treatment-resistant depression. Neuron. 2005 Mar 3;45(5):651-60. doi: 10.1016/j.neuron.2005.02.014.</citation>
    <PMID>15748841</PMID>
  </reference>
  <reference>
    <citation>Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006 Aug;63(8):856-64. doi: 10.1001/archpsyc.63.8.856.</citation>
    <PMID>16894061</PMID>
  </reference>
  <reference>
    <citation>Woods RP, Grafton ST, Holmes CJ, Cherry SR, Mazziotta JC. Automated image registration: I. General methods and intrasubject, intramodality validation. J Comput Assist Tomogr. 1998 Jan-Feb;22(1):139-52. doi: 10.1097/00004728-199801000-00027.</citation>
    <PMID>9448779</PMID>
  </reference>
  <reference>
    <citation>Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Crivello F, Etard O, Delcroix N, Mazoyer B, Joliot M. Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage. 2002 Jan;15(1):273-89. doi: 10.1006/nimg.2001.0978.</citation>
    <PMID>11771995</PMID>
  </reference>
  <reference>
    <citation>Genovese CR, Lazar NA, Nichols T. Thresholding of statistical maps in functional neuroimaging using the false discovery rate. Neuroimage. 2002 Apr;15(4):870-8. doi: 10.1006/nimg.2001.1037.</citation>
    <PMID>11906227</PMID>
  </reference>
  <reference>
    <citation>Peltier SJ, Kerssens C, Hamann SB, Sebel PS, Byas-Smith M, Hu X. Functional connectivity changes with concentration of sevoflurane anesthesia. Neuroreport. 2005 Feb 28;16(3):285-8. doi: 10.1097/00001756-200502280-00017.</citation>
    <PMID>15706237</PMID>
  </reference>
  <verification_date>March 2017</verification_date>
  <study_first_submitted>July 17, 2014</study_first_submitted>
  <study_first_submitted_qc>July 17, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 22, 2014</study_first_posted>
  <results_first_submitted>May 31, 2016</results_first_submitted>
  <results_first_submitted_qc>March 21, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">May 2, 2017</results_first_posted>
  <last_update_submitted>March 21, 2017</last_update_submitted>
  <last_update_submitted_qc>March 21, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">May 2, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Michigan</investigator_affiliation>
    <investigator_full_name>Scott Peltier</investigator_full_name>
    <investigator_title>Associate Research Scientist, Biomedical Engineering</investigator_title>
  </responsible_party>
  <keyword>Pre-Post</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ketamine</mesh_term>
    <mesh_term>Anesthetics, Dissociative</mesh_term>
    <mesh_term>Anesthetics</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>3 participants were screened out.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Initial MRI</title>
          <description>The subject will receive intravenous anesthesia at a dose of 0.5mg/kg delivered over 40 minutes in a constant infusion or bolus plus infusion method to maintain steady state (10 minutes initial induction, 30 minutes steady-state, for 40 minutes total)&#xD;
Anesthetics, Dissociative: The subject will receive intravenous anesthesia at a dose of 0.5mg/kg delivered over 40 minutes in a constant infusion or bolus plus infusion method to maintain steady state (10 minutes initial induction, 30 minutes steady-state, for 40 minutes total)</description>
        </group>
        <group group_id="P2">
          <title>Hospital</title>
        </group>
        <group group_id="P3">
          <title>Depresssion</title>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="7"/>
                <participants group_id="P3" count="3"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="2"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="3"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Researcher choice</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>
              <title>Partial data analysis</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="3"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Initial MRI</title>
          <description>The subject will receive intravenous anesthesia at a dose of 0.5mg/kg delivered over 40 minutes in a constant infusion or bolus plus infusion method to maintain steady state (10 minutes initial induction, 30 minutes steady-state, for 40 minutes total)&#xD;
Anesthetics, Dissociative: The subject will receive intravenous anesthesia at a dose of 0.5mg/kg delivered over 40 minutes in a constant infusion or bolus plus infusion method to maintain steady state (10 minutes initial induction, 30 minutes steady-state, for 40 minutes total)</description>
        </group>
        <group group_id="B2">
          <title>Initial Hospital</title>
          <description>The subject will receive intravenous anesthesia at a dose of 0.5mg/kg delivered over 40 minutes in a constant infusion or bolus plus infusion method to maintain steady state (10 minutes initial induction, 30 minutes steady-state, for 40 minutes total)</description>
        </group>
        <group group_id="B3">
          <title>Depression</title>
          <description>The subject will receive intravenous anesthesia at a dose of 0.5mg/kg delivered over 40 minutes in a constant infusion or bolus plus infusion method to maintain steady state (10 minutes initial induction, 30 minutes steady-state, for 40 minutes total)</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="3"/>
            <count group_id="B2" value="7"/>
            <count group_id="B3" value="3"/>
            <count group_id="B4" value="13"/>
          </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="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="13"/>
                  </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>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="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="11"/>
                  </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="3"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Functional Connectivity</title>
        <description>The imaging experiments and analysis of subject-specific data will lead to maps corresponding to separate measures: resting state functional connectivity maps. The outcome of interest is whether ketamine reduces functional connectivity between the anterior (subgenual anterior cingulate corte, sgACC) and posterior regions (posterior cingulate cortex, PCC) of the default mode network. This is the z-score of the functional connectivity correlation.&#xD;
Timepoints for Initial fMRI were: Time 1:Immediately before Infusion, Time 2: After washout (Approx. 40 min after end of infusion).&#xD;
Timepoints for Depression were: Time 1: 1 Day before Infusion, Time 2: 1 Day after Infusion</description>
        <time_frame>8 minutes scans, acquired between 1 day and 3 days (see above)</time_frame>
        <population>Primary outcome measure is functional connectivity as measured using the MRI scans, which is only in the Initial MRI and Depression Arms.</population>
        <group_list>
          <group group_id="O1">
            <title>Initial MRI</title>
            <description>The subject will receive intravenous anesthesia at a dose of 0.5mg/kg delivered over 40 minutes in a constant infusion or bolus plus infusion method to maintain steady state (10 minutes initial induction, 30 minutes steady-state, for 40 minutes total)</description>
          </group>
          <group group_id="O2">
            <title>Depression</title>
            <description>The subject will receive intravenous anesthesia at a dose of 0.5mg/kg delivered over 40 minutes in a constant infusion or bolus plus infusion method to maintain steady state (10 minutes initial induction, 30 minutes steady-state, for 40 minutes total)&#xD;
Anesthetics, Dissociative: The subject will receive intravenous anesthesia at a dose of 0.5mg/kg delivered over 40 minutes in a constant infusion or bolus plus infusion method to maintain steady state (10 minutes initial induction, 30 minutes steady-state, for 40 minutes total)</description>
          </group>
        </group_list>
        <measure>
          <title>Functional Connectivity</title>
          <description>The imaging experiments and analysis of subject-specific data will lead to maps corresponding to separate measures: resting state functional connectivity maps. The outcome of interest is whether ketamine reduces functional connectivity between the anterior (subgenual anterior cingulate corte, sgACC) and posterior regions (posterior cingulate cortex, PCC) of the default mode network. This is the z-score of the functional connectivity correlation.&#xD;
Timepoints for Initial fMRI were: Time 1:Immediately before Infusion, Time 2: After washout (Approx. 40 min after end of infusion).&#xD;
Timepoints for Depression were: Time 1: 1 Day before Infusion, Time 2: 1 Day after Infusion</description>
          <population>Primary outcome measure is functional connectivity as measured using the MRI scans, which is only in the Initial MRI and Depression Arms.</population>
          <units>z score</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="2"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Before Infusion sgACC-PCC connectivity</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.3114" spread="0.2199"/>
                    <measurement group_id="O2" value="0.3459" spread="0.018"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>After Infusion sgACC-PCC connectivity</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.4424" spread="0.29"/>
                    <measurement group_id="O2" value="0.3208" spread="0.0465"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Subjects were followed up for possible adverse events up to 4 weeks after the final infusion session.</time_frame>
      <desc>describe monitoring of subjects for adverse symptoms</desc>
      <group_list>
        <group group_id="E1">
          <title>Initial fMRI</title>
          <description>The subject will receive intravenous anesthesia at a dose of 0.5mg/kg delivered over 40 minutes in a constant infusion or bolus plus infusion method to maintain steady state (10 minutes initial induction, 30 minutes steady-state, for 40 minutes total)&#xD;
Anesthetics, Dissociative: The subject will receive intravenous anesthesia at a dose of 0.5mg/kg delivered over 40 minutes in a constant infusion or bolus plus infusion method to maintain steady state (10 minutes initial induction, 30 minutes steady-state, for 40 minutes total)</description>
        </group>
        <group group_id="E2">
          <title>Hospital</title>
          <description>The subject will receive intravenous anesthesia at a dose of 0.5mg/kg delivered over 40 minutes in a constant infusion or bolus plus infusion method to maintain steady state (10 minutes initial induction, 30 minutes steady-state, for 40 minutes total)&#xD;
Anesthetics, Dissociative: The subject will receive intravenous anesthesia at a dose of 0.5mg/kg delivered over 40 minutes in a constant infusion or bolus plus infusion method to maintain steady state (10 minutes initial induction, 30 minutes steady-state, for 40 minutes total)</description>
        </group>
        <group group_id="E3">
          <title>Depression</title>
          <description>The subject will receive intravenous anesthesia at a dose of 0.5mg/kg delivered over 40 minutes in a constant infusion or bolus plus infusion method to maintain steady state (10 minutes initial induction, 30 minutes steady-state, for 40 minutes total)&#xD;
Anesthetics, Dissociative: The subject will receive intravenous anesthesia at a dose of 0.5mg/kg delivered over 40 minutes in a constant infusion or bolus plus infusion method to maintain steady state (10 minutes initial induction, 30 minutes steady-state, for 40 minutes total)</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
              </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="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Discomfort</sub_title>
                <description>One participant reported emotional discomfort with the dissociative effects of the intervention</description>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE 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>These data should be interpreted with caution because of the small sample size due to the nature of this pilot study.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Dr. Scott Peltier</name_or_title>
      <organization>University of Michigan</organization>
      <phone>734-647-8077</phone>
      <email>spelt@umich.edu</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/NCT02196259
org study id: U028860-MICHR-Pilot
nct id: NCT02196259
lead sponsor: 
has dmc: No
Functional connectivity is defined as a correlation in neural activity between distinct
      regions of the brain. Several recent studies have demonstrated areas of low-frequency
      functional connectivity inherent to brain tissue at rest. These oscillations can be measured
      using functional magnetic resonance imaging (fMRI) and appear to be synchronized between
      related areas of the brain.

      To date, no investigators have examined the effects of low-dose anesthesia on functional
      connectivity. This study will image the human brain under conditions of rest, and low-dose
      anesthetic induced sedation. Quality of the acquired signals will be evaluated and functional
      networks in the brain will be examined. Of interest is whether administration of a low-dose
      anesthetic disrupts functional connectivity in the brain, and whether a disruption of
      functional connectivity is responsible for the reported analgesic and antidepressant effects
      of a anesthetic.

      Participation in the study includes four visits: an in-person interview, an initial fMRI
      scan, the anesthesia infusion, and a second fMRI scan. There is an optional follow-up fMRI
      scan one week post infusion.
Background:

      A phencyclidine derivative developed by Parke-Davis represented an attempt to mimic
      phencyclidine anesthesia without inducing the severe psychomimetic reactions of its parent
      compound. Initial reports were promising and received great enthusiasm. At high doses, the
      drug was found to provide profound analgesia whilst preserving airway reflexes. It induced
      reliable amnesia, yet could be delivered as a simple injection. It was claimed at the time
      that this anesthetic heralded a new phase in the history of anesthesia. Today, over 40 years
      since the anesthetic was introduced at Michigan, there has been a resurgence of interest in
      this old drug. A growing number of investigators are studying the effects of anesthesia on
      human subjects. There is currently tremendous interest in anesthesia as an opioid sparing
      agent, a model for schizophrenia, an antidepressant, and as an N-Methyl D-Aspartate (NMDA)
      antagonist in complex regional pain syndromes.

      Functional connectivity is a measure of low-frequency oscillations (<0.08 Hz) that are
      inherent to brain tissue at rest. These oscillations are measured on fMRI, and appear to be
      synchronized between related areas of the brain. Although research in this area is still in
      its infancy, studies of the motor, auditory, visual, and sensorimotor systems, have shown
      that functionally related areas of the brain produce correlated low-frequency oscillations.
      This fascinating finding raises the possibility of a new approach to studying brain function
      as well as a potential tool for the diagnosis of disease. Recent fMRI studies of the
      precentral gyrus have demonstrated the ability of functional connectivity studies to
      differentiate healthy volunteers from patients with multiple sclerosis. Additional research
      is ongoing to determine whether functional connectivity will prove useful in the diagnosis of
      early Alzheimer's disease.

      Recent research in functional connectivity has identified regions in the brain active at
      rest. These regions are often referred to at the "Default-mode network" (DMN). Activity in
      the DMN is increased in the brain at rest and decreased when a subject concentrates on a
      mental task. The first fMRI study examining functional connectivity in chronic pain patients
      was published in a recent issue of the Journal of Neuroscience. In this study abnormal
      patterns of functional connectivity were seen in chronic pain patients. Specifically, a
      dysfunction in down-regulating the DMN was seen. The chronic pain patients did not deactivate
      the medial prefrontal cortex, amygdala, or posterior cingulate cortex to the same degree as
      healthy controls.

      The only fMRI study examining functional connectivity in major depression was published in
      September of 2007. This study also noted a dysfunction in the DMN. Depressed subjects were
      found to have increased network functional connectivity in the subgenual cingulate cortex,
      thalamus, orbitofrontal cortex, and the precuneus. Notably, the subgenual cingulate cortex is
      the location of a recent clinical trial suggesting that deep brain stimulation to this region
      may ameliorate symptoms of patients with severe refractory depression.

      Interest in anesthesia for the treatment of chronic pain and depression has grown in recent
      years. Although there have been no randomized trials of low-dose anesthesia in chronic pain
      patients, the evidence currently available indicates it is most effective in the treatment of
      allodynia, hyperalgesia, and hyperpathia. For depression, there has been one randomized,
      placebo-controlled, double blinded crossover study. In the depression trial, robust and rapid
      antidepressant effects were found to result from a single intravenous dose of anesthesia and
      last for at least a week.

      Objective:

      To examine functional connectivity in the human brain both at rest and after anesthetic
      sedation using functional magnetic resonance imaging (fMRI).

      Specific Aims/Hypotheses:

        1. Measure the degree of functional connectivity in three study groups (healthy volunteers,
           chronic back pain, and refractory depression).

        2. Analyze for differences in baseline functional connectivity.

        3. Measure changes in functional connectivity after IV low-dose anesthetic sedation.

        4. Document study group differences in anesthetic response.

        5. Measure for any correlation between fMRI changes and therapeutic effects.

      Study Protocol:

      Participation in this study includes four main visits and an optional follow-up visit. The
      first visit is a baseline interview session to assess participant eligibility using a
      structured interview. The second visit is an initial fMRI scan at the fMRI center. The third
      visit is the anesthetic infusion at the hospital; management of any adverse events during the
      infusion will be monitored by the Post Anesthesia Care Unit ( PACU) personnel. The fourth
      visit is a follow-up fMRI scan at the fMRI center. There is an optional one week follow-up
      visit at the fMRI center for a final fMRI scan.

      fMRI Statistical Analysis: The imaging experiments and analysis of subject-specific data will
      lead to maps corresponding to separate measures: resting state functional connectivity maps,
      and measures of cerebral blood flow (CBF). Final inferences will be made at the voxel level
      and for anatomically specific regions-of-interest (ROIs). The voxel-based analysis will be
      performed through the generation of summary images referred to as statistical parametric maps
      (SPMs) representing before-infusion vs. after-infusion, and, as data in the two patient
      groups become available, two-way ANOVA results of ketamine infusion state and patient
      diagnosis (chronic pain or refractory depression). The ROI-based analysis will be driven by
      the a priori selected fronto-limbic regions of interest generated in the self-reflection
      task, and by the anatomical nodes in the default mode network given in the literature.
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Functional Connectivity
time frame: 8 minutes scans, acquired between 1 day and 3 days (see above)
description: The imaging experiments and analysis of subject-specific data will lead to maps corresponding to separate measures: resting state functional connectivity maps. The outcome of interest is whether ketamine reduces functional connectivity between the anterior (subgenual anterior cingulate corte, sgACC) and posterior regions (posterior cingulate cortex, PCC) of the default mode network. This is the z-score of the functional connectivity correlation.
Timepoints for Initial fMRI were: Time 1:Immediately before Infusion, Time 2: After washout (Approx. 40 min after end of infusion).
Timepoints for Depression were: Time 1: 1 Day before Infusion, Time 2: 1 Day after Infusion
arm group label: Initial MRI
arm group type: Experimental
description: The subject will receive intravenous ketamine anesthesia at a dose of 0.5mg/kg delivered over 40 minutes in a constant infusion or bolus plus infusion method to maintain steady state (10 minutes initial induction, 30 minutes steady-state, for 40 minutes total)
arm group label: Initial hospital
arm group type: Experimental
description: The subject will receive intravenous ketamine anesthesia at a dose of 0.5mg/kg delivered over 40 minutes in a constant infusion or bolus plus infusion method to maintain steady state (10 minutes initial induction, 30 minutes steady-state, for 40 minutes total)
arm group label: Depression MRI
arm group type: Experimental
description: The subject will receive intravenous ketamine anesthesia at a dose of 0.5mg/kg delivered over 40 minutes in a constant infusion or bolus plus infusion method to maintain steady state (10 minutes initial induction, 30 minutes steady-state, for 40 minutes total)
intervention type: Drug
intervention name: Anesthetics, Dissociative
description: The subject will receive intravenous anesthesia at a dose of 0.5mg/kg delivered over 40 minutes in a constant infusion or bolus plus infusion method to maintain steady state (10 minutes initial induction, 30 minutes steady-state, for 40 minutes total)
arm group label: Depression MRI
arm group label: Initial MRI
arm group label: Initial hospital
other name: Ketamine
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Scott Peltier, PhD
role: Principal Investigator
affiliation: University of Michigan
facility: 
country: United States
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PMID: 8524021
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PMID: 9558644
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PMID: 11039342
citation: Lowe MJ, Phillips MD, Lurito JT, Mattson D, Dzemidzic M, Mathews VP. Multiple sclerosis: low-frequency temporal blood oxygen level-dependent fluctuations indicate reduced functional connectivity initial results. Radiology. 2002 Jul;224(1):184-92. doi: 10.1148/radiol.2241011005.
PMID: 12091681
citation: Baliki MN, Geha PY, Apkarian AV, Chialvo DR. Beyond feeling: chronic pain hurts the brain, disrupting the default-mode network dynamics. J Neurosci. 2008 Feb 6;28(6):1398-403. doi: 10.1523/JNEUROSCI.4123-07.2008.
PMID: 18256259
citation: Greicius MD, Flores BH, Menon V, Glover GH, Solvason HB, Kenna H, Reiss AL, Schatzberg AF. Resting-state functional connectivity in major depression: abnormally increased contributions from subgenual cingulate cortex and thalamus. Biol Psychiatry. 2007 Sep 1;62(5):429-37. doi: 10.1016/j.biopsych.2006.09.020. Epub 2007 Jan 8.
PMID: 17210143
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PMID: 15748841
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PMID: 16894061
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citation: Peltier SJ, Kerssens C, Hamann SB, Sebel PS, Byas-Smith M, Hu X. Functional connectivity changes with concentration of sevoflurane anesthesia. Neuroreport. 2005 Feb 28;16(3):285-8. doi: 10.1097/00001756-200502280-00017.
PMID: 15706237
responsible party type: Principal Investigator
investigator affiliation: University of Michigan
investigator full name: Scott Peltier
investigator title: Associate Research Scientist, Biomedical Engineering
mesh term: Ketamine
mesh term: Anesthetics, Dissociative
mesh term: Anesthetics
sharing ipd: Undecided
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: These data should be interpreted with caution because of the small sample size due to the nature of this pilot study.
point of contact: 