<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/NCT02253758</url>
  </required_header>
  <id_info>
    <org_study_id>TASMC-14-IM-0383-CTIL</org_study_id>
    <nct_id>NCT02253758</nct_id>
  </id_info>
  <brief_title>Arousal Pathways and Emergence From Sedation</brief_title>
  <official_title>Arousal Pathways and Emergence From Sedation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Tel-Aviv Sourasky Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Tel-Aviv Sourasky Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Emergence from sedation involves an increase in both the level of consciousness and arousal.&#xD;
      Some insight to the neural core of consciousness was gained in the recent past. Our research&#xD;
      objective is to characterize for the first time the spatiotemporal mobilization of the&#xD;
      ascending reticular activating system during emergence from sedation; stated otherwise - to&#xD;
      capture the neural core of arousal.&#xD;
&#xD;
      To achieve this objective we plan to utilize the advanced imaging modality of EEG-fMRI. In&#xD;
      short, volunteers will be placed in the MRI. Following baseline recordings they will be&#xD;
      sedated with a continuous drip of propofol, titrated to deep sedation. Once in that sedation&#xD;
      level, propofol administration will cease until emerging to an awake-calm/light sedation.&#xD;
&#xD;
      Continuous EEG recordings and fMRI scans will be taken, both task specific (auditory oddball)&#xD;
      and resting-fMRI. Analyses will focus (but will not be restricted to) on constituents of the&#xD;
      ascending reticular activating system.&#xD;
&#xD;
      The expected advances of this proposal are:&#xD;
&#xD;
        1. Emergence from sedation (and anesthesia) is one of the critical stages and least&#xD;
           elucidated area in the practice of anesthesia. Delayed awakening of varying degree is&#xD;
           not uncommon after anesthesia and may have a number of different causes, individual or&#xD;
           combined, which may be both drug or non-drug related, thus causing a diagnostic dilemma.&#xD;
           Eventually - better insight into this subject will lead to better clinical practice and&#xD;
           better understanding why patients emerge in such a diverse and sometimes unexpected&#xD;
           manner.&#xD;
&#xD;
        2. Knowledge of the internal structure underlying arousal from anesthesia will help develop&#xD;
           / upgrade brain monitors that could tell the anesthesiologist the patient's level of&#xD;
           consciousness and prediction of arousal.&#xD;
&#xD;
        3. A detailed reproducible mapping of the arousal process may serve as the core of a drug&#xD;
           screening platform for drugs that may expedite patient arousal.&#xD;
&#xD;
        4. Elucidation of the arousal paradigm from sedation will enhance our knowledge of&#xD;
           physiological sleep.&#xD;
&#xD;
      Research hypothesis&#xD;
&#xD;
      Return of consciousness is a complex phenomenon comprising of interplay between the cortex&#xD;
      and deeper brain structures. We hypothesize that the activation signature is conserved and&#xD;
      similar between subjects. Furthermore, we hypothesize that inter-subject variability will&#xD;
      arise mainly in the time domain, as evident from the clinical observation of variable time to&#xD;
      emergence in different patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Sedation and general anesthesia are at the hub of modern medicine. The practice of the&#xD;
      administration of anesthesia and sedation has evolved considerably and is now considered safe&#xD;
      and reproducible. Still, one of the critical parts of anesthesia practice is the emergence:&#xD;
      with the phenomenological variability of the clinical presentations of emergence, and its&#xD;
      increased inherent risks of airway patency, insufficient respiratory mechanics, hyperreflexia&#xD;
      and altered mental state.&#xD;
&#xD;
      Our understanding of the underlying mechanisms of sedation and anesthesia is still somewhat&#xD;
      lacking: The body of evidence concerning induction and maintenance is more evolved[1-4],&#xD;
      whereas the most profound gaps of knowledge concern emergence.&#xD;
&#xD;
      While anesthetic agent exert a global effect on the brain, it is clear that some foci are&#xD;
      more sensitive[5] and more relevant to the achievement of the anesthetic goals of hypnosis,&#xD;
      amnesia, and reduced responsiveness.&#xD;
&#xD;
      Mechanisms of unconsciousness induced by general anesthesia[1] can be broadly dissected to&#xD;
      two elements: consciousness and arousal: Current consciousness theories[6,7] ascribe to&#xD;
      consciousness the ability to experience. To achieve that goal, information complexity and&#xD;
      information integration are paramount. These faculties reside mainly in the neocortex.&#xD;
      Arousal on the other hand, resides mainly in the thalamus, hypothalamus, midbrain and pons&#xD;
      with the neural machinery of physiological sleep[8,9]. We tend to associate consciousness&#xD;
      with arousability. Dreaming however - is a straightforward example of consciousness without&#xD;
      arousal.&#xD;
&#xD;
      A given level of arousal is the output of the balance of the mutual inhibition between the&#xD;
      sleep promoting locus - the ventrolateral preoptic nucleus - and the multiple arousal loci,&#xD;
      commonly known as the ARAS (Ascending Reticular Activating System)[10,11]. Shortly, this&#xD;
      dispersed system is comprised of multiple nuclei with different neurotransmitters. Some of&#xD;
      the nuclei have thalamic projections and some are extra-thalamic with direct and diverse&#xD;
      cortical projections. The transition between sleep and wakefulness is further enhanced by the&#xD;
      Orexigenic neurons in the hypothalamus[12,13], which serve as a flip flop mechanism.&#xD;
&#xD;
      The research into consciousness has made some progress[14] using anesthetic approaches and&#xD;
      most specifically, emergence from sedation and anesthesia, to describe the neural core of&#xD;
      consciousness. Recently, publications by Purdon et al.[15,16] identified an EEG signature of&#xD;
      consciousness transition state.&#xD;
&#xD;
      The body of evidence concerning arousal pathways is less formidable, possibly due to the&#xD;
      dispersed array of nuclei, and their &quot;deep&quot; subcortical locations, complicating their&#xD;
      evaluation in less invasive methods (such as scalp EEG). The classic research tool of this&#xD;
      field is lesions studies (both in animal models and unfortunate patients)[17,18] in discrete&#xD;
      loci with an observed change in sleep-wake physiology. Recently, pioneering ex vivo (rat pups&#xD;
      midbrain slices) research by Garcia-rill and Charlesworth[19], using intracellular recordings&#xD;
      provided compelling data supporting electrical coupling and coherence of neurons within&#xD;
      nuclei of the ARAS. However, to the best of our knowledge to this date there has been no&#xD;
      explicit trial to capture or characterize the dynamic changes in the ARAS of human subjects&#xD;
      emerging from sedation.&#xD;
&#xD;
      Research objectives&#xD;
&#xD;
        1. To characterize the spatiotemporal signature sequence of the arousing brain, focusing&#xD;
           (but not restricted to) on deep brain structures. Arousal signature may include the&#xD;
           following:&#xD;
&#xD;
             -  A conserved sequence of brain structures mobilization.&#xD;
&#xD;
             -  Summation of foci activations (without an explicit order).&#xD;
&#xD;
             -  Hierarchy between different loci (cholinergic vs. monoaminic components of the&#xD;
                ARAS).&#xD;
&#xD;
        2. To identify a reproducible signal heralding imminent return of consciousness.&#xD;
&#xD;
      Methods:&#xD;
&#xD;
      The proposed study has been submitted to the Institutional Review Board committee for&#xD;
      approval.&#xD;
&#xD;
      Experiment summary:&#xD;
&#xD;
      The proposed study is an interventional, single center study, conducted on 20 volunteers. A&#xD;
      sample size of 20 was chosen in light of the relatively low signal to noise ratio inherent to&#xD;
      fMRI imaging. subjects will be healthy males age 20-40, who are not taking chronic&#xD;
      medications or using illicit drugs. All subjects, after signing the informed consent form,&#xD;
      will fill a standard MRI questionnaire for the detection of metallic implants and will&#xD;
      undergo medical evaluation and examination by the anesthesiologist. During the study period&#xD;
      volunteers will be monitored by non invasive standard patient ASA monitoring: ECG, blood&#xD;
      pressure, pulse oximetry, and exhaled CO2 levels. Each subject will be connected to an EEG&#xD;
      recording cap, and will be placed in the magnet. Baseline recordings of EEG, MRI and fMRI&#xD;
      will be taken. Then sedation will be induced with continuous IV propofol infusion with a&#xD;
      Target Controlled Infusion pump - TCI, using the Marsh model[14,20,21]. Depth of sedation&#xD;
      will be titrated to deep sedation (Ramsay scale 5)[22]. Subsequently, propofol administration&#xD;
      will be discontinued, and continuous EEG and fMRI recordings will be taken until emerging&#xD;
      from sedation to an awake calm/light sedation (Ramsay 2-3), as verified by a response to the&#xD;
      subject's given name. At this point EEG monitoring and fMRI scans will cease. The subject&#xD;
      will be helped out of the magnet and transferred to a post anesthesia care unit (PACU).&#xD;
&#xD;
      All subjects will be monitored until reaching discharge criteria ascertained by an&#xD;
      examination performed by an anesthesiologist.&#xD;
&#xD;
      Brain monitoring&#xD;
&#xD;
        1. Functional Magnetic Resonance (fMRI): brain BOLD fMRI - blood oxygen level dependent&#xD;
           fMRI - harnessing the magnetic properties of the ferric ion of hemoglobin to image&#xD;
           changes in blood flow to metabolically active brain loci. The underlying assumption of&#xD;
           the imaging modality (similar to Positron Emission Tomography) is the metabolic coupling&#xD;
           of cellular activity and blood flow. Analyses will focus but will not be restricted to&#xD;
           subthalamic structures involved in the RAS.&#xD;
&#xD;
        2. EEG (electroencephalogram), while in the MRI - EEG-fMRI. Combining the superior temporal&#xD;
           resolution of the EEG with the localizing resolution of the MRI. The EEG will serve as&#xD;
           an adjunct to the level of sedation and as source for data concerning thalamocortical&#xD;
           pathways or arousal.&#xD;
&#xD;
      Expected results:&#xD;
&#xD;
      The results from this research project may help improve patient safety through the prediction&#xD;
      of his/her arousal status. Anesthesia/Arousal level monitors have yet to prove their&#xD;
      contribution to patient safety. Integration of deep brain structures data may prove to be the&#xD;
      missing link to improving monitors' performance. Additionally, a thorough understanding of&#xD;
      the arousal process can potentially help develop agents to hasten arousal, as it may serve as&#xD;
      a screening paradigm for known pharmaceuticals (expanding their clinical indications) as well&#xD;
      as new chemical entities (NCEs).&#xD;
&#xD;
      Feasibility and perceived strengths:&#xD;
&#xD;
      The feasibility of the proposed research project is very high. The project will be performed&#xD;
      in Tel Aviv Medical Center in the Wohl Center for Advanced Imaging. The Wohl Center involves&#xD;
      a prominent neuroscience research group with a significant number of publications related to&#xD;
      emotional and cognitive processing in health and disease. Some of these studies include&#xD;
      volunteers[23,24] and the use of fMRI and EEG to follow propofol induced sedation[25,26]. The&#xD;
      proposed project will enjoy a full collaboration with the research center. In this light, the&#xD;
      completion of the proposed imaging sessions and their subsequent analyses is realistic.&#xD;
&#xD;
      A thorough characterization of the emergence process warrants careful, dedicated attention to&#xD;
      deep brain structures while designing the experiment throughout its execution and during&#xD;
      analyses. As stand-alone scalp EEG recordings have fallen short of finding the &quot;emergence&#xD;
      fingerprint&quot; (as EEG signal represent mostly cortical activity) we contest that a combined&#xD;
      EEG-fMRI carries more hopes for the characterization of emergence from sedation.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date>October 2014</start_date>
  <completion_date type="Anticipated">December 2016</completion_date>
  <primary_completion_date type="Anticipated">December 2015</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Characterization of brain network connectivity underlying arousal from anesthesia.</measure>
    <time_frame>Data collection time frame will not exceed one hour post propofol infusion cessation.</time_frame>
    <description>Network connectivity of brain loci involved in arousal pathways will be evaluated for each patient at these time points: baseline, deep sedation and return to conscious state. The identification of these time points will be decided according to the Ramsay clinical scale for sedation depth. A score of 2 for baseline, 5 for deep sedation, and 2-3 for regaining consciousness. An external validation for these time points will derive from the oddball auditory test, in which the brain reaction to a sound in a different pitch is recorded. In the sedated state this reaction is perturbed.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Characterization of the internal structure and temporal hierarchy underlying arousal from anesthesia.</measure>
    <time_frame>Data collection time frame will not exceed one hour post propofol infusion cessation.</time_frame>
    <description>At the group level an attempt will be made to discern temporal hierarchy (which of the aforementioned nuclei is the first to regain activity within the network) between the different ROIs (in voxels and normalized to a standarized brain) involved in the arousal pathways. The basal forebrain, laterodorsal tegmental nuclei, pedunculupontine nuclei, the ventral hypothalamus and the thalamus will all be included in the putative connectivity map.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">20</enrollment>
  <condition>Anesthesia</condition>
  <arm_group>
    <arm_group_label>Sedation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Volunteers will be sedated to Ramsay score 4-5 with propofol, and data will be recorded during arousal</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Propofol</intervention_name>
    <description>Propofol will be injected as a continuous infusion by TCI intravenously</description>
    <arm_group_label>Sedation</arm_group_label>
    <other_name>Propofol Liporum 1%</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Healthy males (ASA scale 1-2), volunteers only&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Use of chronic medications or illicit drugs&#xD;
&#xD;
          -  Metallic implants&#xD;
&#xD;
          -  Previous brain injury&#xD;
&#xD;
          -  General anaesthesia up to a week earlier to research examination&#xD;
&#xD;
          -  Known drug sensitivity to Propofol, soybean oil or peanuts&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>40 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Idit Matot, Prof. M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Tel-Aviv Sourasky Medical Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Idit Matot, Prof. M.D.</last_name>
    <phone>97236974758</phone>
    <email>iditm@tlvmc.gov.il</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Miri Davidovich</last_name>
    <phone>97236974758</phone>
    <email>mirid@tlvmc.gov.il</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Whol Institute for Advanced Imaging, Tel Aviv Sourasky Medical Center</name>
      <address>
        <city>Tel Aviv</city>
        <country>Israel</country>
      </address>
    </facility>
    <contact>
      <last_name>Talma Hendler, M.D. PhD</last_name>
      <phone>97236973094</phone>
      <email>hendlert@gmail.com</email>
    </contact>
    <investigator>
      <last_name>Talma Hendler, M.D. PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Division of Anesthesia, Pain and Critical Care, Tel-Aviv Sourasky Medical Center</name>
      <address>
        <city>Tel-Aviv</city>
        <country>Israel</country>
      </address>
    </facility>
    <contact>
      <last_name>Idit Matot, Prof. M.D.</last_name>
      <phone>97236974758</phone>
      <email>iditm@tlvmc.gov.il</email>
    </contact>
    <contact_backup>
      <last_name>Miri Davidovich</last_name>
      <phone>97236974758</phone>
      <email>mirid@tlvmc.gov.il</email>
    </contact_backup>
    <investigator>
      <last_name>Idit Matot, Prof. M.D.</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Tomer Nir, Resident</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Israel</country>
  </location_countries>
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    <citation>Ben Bashat D, Kronfeld-Duenias V, Zachor DA, Ekstein PM, Hendler T, Tarrasch R, Even A, Levy Y, Ben Sira L. Accelerated maturation of white matter in young children with autism: a high b value DWI study. Neuroimage. 2007 Aug 1;37(1):40-7. doi: 10.1016/j.neuroimage.2007.04.060. Epub 2007 May 18.</citation>
    <PMID>17566764</PMID>
  </reference>
  <verification_date>September 2014</verification_date>
  <study_first_submitted>August 10, 2014</study_first_submitted>
  <study_first_submitted_qc>September 28, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 1, 2014</study_first_posted>
  <last_update_submitted>September 28, 2014</last_update_submitted>
  <last_update_submitted_qc>September 28, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">October 1, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Tel-Aviv Sourasky Medical Center</investigator_affiliation>
    <investigator_full_name>michal roll</investigator_full_name>
    <investigator_title>Dr. Michal Roll</investigator_title>
  </responsible_party>
  <keyword>Magnetic Resonance Imaging</keyword>
  <keyword>Electroencephalography</keyword>
  <keyword>Conscious Sedation</keyword>
  <keyword>Deep Sedation</keyword>
  <keyword>Arousal</keyword>
  <keyword>Consciousness</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Propofol</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02253758
org study id: TASMC-14-IM-0383-CTIL
nct id: NCT02253758
lead sponsor: 
has dmc: No
Emergence from sedation involves an increase in both the level of consciousness and arousal.
      Some insight to the neural core of consciousness was gained in the recent past. Our research
      objective is to characterize for the first time the spatiotemporal mobilization of the
      ascending reticular activating system during emergence from sedation; stated otherwise - to
      capture the neural core of arousal.

      To achieve this objective we plan to utilize the advanced imaging modality of EEG-fMRI. In
      short, volunteers will be placed in the MRI. Following baseline recordings they will be
      sedated with a continuous drip of propofol, titrated to deep sedation. Once in that sedation
      level, propofol administration will cease until emerging to an awake-calm/light sedation.

      Continuous EEG recordings and fMRI scans will be taken, both task specific (auditory oddball)
      and resting-fMRI. Analyses will focus (but will not be restricted to) on constituents of the
      ascending reticular activating system.

      The expected advances of this proposal are:

        1. Emergence from sedation (and anesthesia) is one of the critical stages and least
           elucidated area in the practice of anesthesia. Delayed awakening of varying degree is
           not uncommon after anesthesia and may have a number of different causes, individual or
           combined, which may be both drug or non-drug related, thus causing a diagnostic dilemma.
           Eventually - better insight into this subject will lead to better clinical practice and
           better understanding why patients emerge in such a diverse and sometimes unexpected
           manner.

        2. Knowledge of the internal structure underlying arousal from anesthesia will help develop
           / upgrade brain monitors that could tell the anesthesiologist the patient's level of
           consciousness and prediction of arousal.

        3. A detailed reproducible mapping of the arousal process may serve as the core of a drug
           screening platform for drugs that may expedite patient arousal.

        4. Elucidation of the arousal paradigm from sedation will enhance our knowledge of
           physiological sleep.

      Research hypothesis

      Return of consciousness is a complex phenomenon comprising of interplay between the cortex
      and deeper brain structures. We hypothesize that the activation signature is conserved and
      similar between subjects. Furthermore, we hypothesize that inter-subject variability will
      arise mainly in the time domain, as evident from the clinical observation of variable time to
      emergence in different patients.
Sedation and general anesthesia are at the hub of modern medicine. The practice of the
      administration of anesthesia and sedation has evolved considerably and is now considered safe
      and reproducible. Still, one of the critical parts of anesthesia practice is the emergence:
      with the phenomenological variability of the clinical presentations of emergence, and its
      increased inherent risks of airway patency, insufficient respiratory mechanics, hyperreflexia
      and altered mental state.

      Our understanding of the underlying mechanisms of sedation and anesthesia is still somewhat
      lacking: The body of evidence concerning induction and maintenance is more evolved[1-4],
      whereas the most profound gaps of knowledge concern emergence.

      While anesthetic agent exert a global effect on the brain, it is clear that some foci are
      more sensitive[5] and more relevant to the achievement of the anesthetic goals of hypnosis,
      amnesia, and reduced responsiveness.

      Mechanisms of unconsciousness induced by general anesthesia[1] can be broadly dissected to
      two elements: consciousness and arousal: Current consciousness theories[6,7] ascribe to
      consciousness the ability to experience. To achieve that goal, information complexity and
      information integration are paramount. These faculties reside mainly in the neocortex.
      Arousal on the other hand, resides mainly in the thalamus, hypothalamus, midbrain and pons
      with the neural machinery of physiological sleep[8,9]. We tend to associate consciousness
      with arousability. Dreaming however - is a straightforward example of consciousness without
      arousal.

      A given level of arousal is the output of the balance of the mutual inhibition between the
      sleep promoting locus - the ventrolateral preoptic nucleus - and the multiple arousal loci,
      commonly known as the ARAS (Ascending Reticular Activating System)[10,11]. Shortly, this
      dispersed system is comprised of multiple nuclei with different neurotransmitters. Some of
      the nuclei have thalamic projections and some are extra-thalamic with direct and diverse
      cortical projections. The transition between sleep and wakefulness is further enhanced by the
      Orexigenic neurons in the hypothalamus[12,13], which serve as a flip flop mechanism.

      The research into consciousness has made some progress[14] using anesthetic approaches and
      most specifically, emergence from sedation and anesthesia, to describe the neural core of
      consciousness. Recently, publications by Purdon et al.[15,16] identified an EEG signature of
      consciousness transition state.

      The body of evidence concerning arousal pathways is less formidable, possibly due to the
      dispersed array of nuclei, and their "deep" subcortical locations, complicating their
      evaluation in less invasive methods (such as scalp EEG). The classic research tool of this
      field is lesions studies (both in animal models and unfortunate patients)[17,18] in discrete
      loci with an observed change in sleep-wake physiology. Recently, pioneering ex vivo (rat pups
      midbrain slices) research by Garcia-rill and Charlesworth[19], using intracellular recordings
      provided compelling data supporting electrical coupling and coherence of neurons within
      nuclei of the ARAS. However, to the best of our knowledge to this date there has been no
      explicit trial to capture or characterize the dynamic changes in the ARAS of human subjects
      emerging from sedation.

      Research objectives

        1. To characterize the spatiotemporal signature sequence of the arousing brain, focusing
           (but not restricted to) on deep brain structures. Arousal signature may include the
           following:

             -  A conserved sequence of brain structures mobilization.

             -  Summation of foci activations (without an explicit order).

             -  Hierarchy between different loci (cholinergic vs. monoaminic components of the
                ARAS).

        2. To identify a reproducible signal heralding imminent return of consciousness.

      Methods:

      The proposed study has been submitted to the Institutional Review Board committee for
      approval.

      Experiment summary:

      The proposed study is an interventional, single center study, conducted on 20 volunteers. A
      sample size of 20 was chosen in light of the relatively low signal to noise ratio inherent to
      fMRI imaging. subjects will be healthy males age 20-40, who are not taking chronic
      medications or using illicit drugs. All subjects, after signing the informed consent form,
      will fill a standard MRI questionnaire for the detection of metallic implants and will
      undergo medical evaluation and examination by the anesthesiologist. During the study period
      volunteers will be monitored by non invasive standard patient ASA monitoring: ECG, blood
      pressure, pulse oximetry, and exhaled CO2 levels. Each subject will be connected to an EEG
      recording cap, and will be placed in the magnet. Baseline recordings of EEG, MRI and fMRI
      will be taken. Then sedation will be induced with continuous IV propofol infusion with a
      Target Controlled Infusion pump - TCI, using the Marsh model[14,20,21]. Depth of sedation
      will be titrated to deep sedation (Ramsay scale 5)[22]. Subsequently, propofol administration
      will be discontinued, and continuous EEG and fMRI recordings will be taken until emerging
      from sedation to an awake calm/light sedation (Ramsay 2-3), as verified by a response to the
      subject's given name. At this point EEG monitoring and fMRI scans will cease. The subject
      will be helped out of the magnet and transferred to a post anesthesia care unit (PACU).

      All subjects will be monitored until reaching discharge criteria ascertained by an
      examination performed by an anesthesiologist.

      Brain monitoring

        1. Functional Magnetic Resonance (fMRI): brain BOLD fMRI - blood oxygen level dependent
           fMRI - harnessing the magnetic properties of the ferric ion of hemoglobin to image
           changes in blood flow to metabolically active brain loci. The underlying assumption of
           the imaging modality (similar to Positron Emission Tomography) is the metabolic coupling
           of cellular activity and blood flow. Analyses will focus but will not be restricted to
           subthalamic structures involved in the RAS.

        2. EEG (electroencephalogram), while in the MRI - EEG-fMRI. Combining the superior temporal
           resolution of the EEG with the localizing resolution of the MRI. The EEG will serve as
           an adjunct to the level of sedation and as source for data concerning thalamocortical
           pathways or arousal.

      Expected results:

      The results from this research project may help improve patient safety through the prediction
      of his/her arousal status. Anesthesia/Arousal level monitors have yet to prove their
      contribution to patient safety. Integration of deep brain structures data may prove to be the
      missing link to improving monitors' performance. Additionally, a thorough understanding of
      the arousal process can potentially help develop agents to hasten arousal, as it may serve as
      a screening paradigm for known pharmaceuticals (expanding their clinical indications) as well
      as new chemical entities (NCEs).

      Feasibility and perceived strengths:

      The feasibility of the proposed research project is very high. The project will be performed
      in Tel Aviv Medical Center in the Wohl Center for Advanced Imaging. The Wohl Center involves
      a prominent neuroscience research group with a significant number of publications related to
      emotional and cognitive processing in health and disease. Some of these studies include
      volunteers[23,24] and the use of fMRI and EEG to follow propofol induced sedation[25,26]. The
      proposed project will enjoy a full collaboration with the research center. In this light, the
      completion of the proposed imaging sessions and their subsequent analyses is realistic.

      A thorough characterization of the emergence process warrants careful, dedicated attention to
      deep brain structures while designing the experiment throughout its execution and during
      analyses. As stand-alone scalp EEG recordings have fallen short of finding the "emergence
      fingerprint" (as EEG signal represent mostly cortical activity) we contest that a combined
      EEG-fMRI carries more hopes for the characterization of emergence from sedation.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Characterization of brain network connectivity underlying arousal from anesthesia.
time frame: Data collection time frame will not exceed one hour post propofol infusion cessation.
description: Network connectivity of brain loci involved in arousal pathways will be evaluated for each patient at these time points: baseline, deep sedation and return to conscious state. The identification of these time points will be decided according to the Ramsay clinical scale for sedation depth. A score of 2 for baseline, 5 for deep sedation, and 2-3 for regaining consciousness. An external validation for these time points will derive from the oddball auditory test, in which the brain reaction to a sound in a different pitch is recorded. In the sedated state this reaction is perturbed.
measure: Characterization of the internal structure and temporal hierarchy underlying arousal from anesthesia.
time frame: Data collection time frame will not exceed one hour post propofol infusion cessation.
description: At the group level an attempt will be made to discern temporal hierarchy (which of the aforementioned nuclei is the first to regain activity within the network) between the different ROIs (in voxels and normalized to a standarized brain) involved in the arousal pathways. The basal forebrain, laterodorsal tegmental nuclei, pedunculupontine nuclei, the ventral hypothalamus and the thalamus will all be included in the putative connectivity map.
arm group label: Sedation
arm group type: Experimental
description: Volunteers will be sedated to Ramsay score 4-5 with propofol, and data will be recorded during arousal
intervention type: Drug
intervention name: Propofol
description: Propofol will be injected as a continuous infusion by TCI intravenously
arm group label: Sedation
other name: Propofol Liporum 1%
criteria: 
gender: Male
minimum age: 20 Years
maximum age: 40 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Idit Matot, Prof. M.D.
role: Principal Investigator
affiliation: Tel-Aviv Sourasky Medical Center
last name: Idit Matot, Prof. M.D.
phone: 97236974758
email: iditm@tlvmc.gov.il
last name: Miri Davidovich
phone: 97236974758
email: mirid@tlvmc.gov.il
facility: 
contact: 
investigator: 
facility: 
contact: 
contact backup: 
investigator: 
investigator: 
country: Israel
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PMID: 17566764
responsible party type: Principal Investigator
investigator affiliation: Tel-Aviv Sourasky Medical Center
investigator full name: michal roll
investigator title: Dr. Michal Roll
mesh term: Propofol