<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/NCT04500119</url>
  </required_header>
  <id_info>
    <org_study_id>STUDY00000572</org_study_id>
    <secondary_id>5U01NS117839-03</secondary_id>
    <nct_id>NCT04500119</nct_id>
  </id_info>
  <brief_title>Neuronal Mechanisms of Human Episodic Memory</brief_title>
  <official_title>Neuronal Mechanisms of Human Episodic Memory</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Cedars-Sinai Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Johns Hopkins University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Colorado, Denver</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University Health Network, Toronto</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Boston Children's Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of California, Santa Barbara</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Institute of Neurological Disorders and Stroke (NINDS)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>California Institute of Technology</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Cedars-Sinai Medical Center</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose the research is to better understand how the human brain accomplishes the basic&#xD;
      cognitive tasks of learning new information, recalling stored information, and making&#xD;
      decisions or choices about presented information. These investigations are critical to better&#xD;
      understand human cognition and to design treatments for disorders of learning and memory.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The rapid formation of new memories and the recall of old memories to inform decisions is&#xD;
      essential for human cognition, but the underlying neural mechanisms remain poorly understood.&#xD;
      The long-term goal of this research is a circuit-level understanding of human memory to&#xD;
      enable the development of new treatments for the devastating effects of memory disorders. The&#xD;
      study experiments utilize the rare opportunity to record in-vivo from human single neurons&#xD;
      simultaneously in multiple brain areas in patients undergoing treatment for drug resistant&#xD;
      epilepsy. The overall objective is to continue and expand a multi-institutional (Cedars&#xD;
      Sinai/Caltech, Johns Hopkins, U Toronto, Children's/Harvard, UC Denver, UCSB), integrated,&#xD;
      and multi-disciplinary team. Jointly, the investigators have the expertise and patient volume&#xD;
      to test key predictions on the neural substrate of human memory. The study will utilize a&#xD;
      combination of (i) in-vivo recordings in awake behaving humans assessing memory strength&#xD;
      through confidence ratings, (ii) focal electrical stimulation to test causality, and (iii)&#xD;
      computational analysis and modeling.&#xD;
&#xD;
      These techniques will be applied to investigate three overarching hypotheses on the&#xD;
      mechanisms of episodic memory. First, to determine the role of persistent neuronal activity&#xD;
      in translating working memories into longterm declarative memories (Aim 1). Second, to&#xD;
      determine how declarative memories are translated into decisions (Aim 2). Third, to&#xD;
      investigate how event segmentation, temporal binding and reinstatement during temporally&#xD;
      extended experience facilitate episodic memory.&#xD;
&#xD;
      The expected outcomes of this work are an unprecedented characterization of how episodic&#xD;
      memories are formed, retrieved and used for decisions, and how temporally extended&#xD;
      experiences are segmented to form distinct but linked episodes. This work is significant&#xD;
      because it moves beyond a &quot;parts list&quot; of neurons and brain areas by testing circuit-based&#xD;
      hypotheses by simultaneously recording single-neurons from multiple frontal cortical and&#xD;
      subcortical temporal lobe areas in humans who are forming, declaring and describing their&#xD;
      memories. The proposed work is unusually innovative because it combines single-neuron&#xD;
      recordings in multiple areas in behaving humans, develops new methods for non-invasive&#xD;
      localization of implanted electrodes and electrical stimulation and directly test&#xD;
      long-standing theoretical predictions on the role of evidence accumulation in memory&#xD;
      retrieval.&#xD;
&#xD;
      A second significant innovation is the study team, which combines the patient volume and&#xD;
      expertise of several major centers to maximally utilize the rare neurosurgical opportunities&#xD;
      available to directly study the human nervous system. This innovative approach permits&#xD;
      investigation of circuit-level mechanisms of human memory that cannot be studied&#xD;
      non-invasively in humans nor in animal models. This integrated multi-disciplinary combination&#xD;
      of human in-vivo single-neuron physiology, behavior, and modeling will contribute&#xD;
      significantly to the understanding of the circuits and patterns of neural activity that give&#xD;
      rise to human memory, which is a central goal of human neuroscience in general and the BRAIN&#xD;
      initiative in particular.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Enrolling by invitation</overall_status>
  <start_date type="Actual">August 12, 2020</start_date>
  <completion_date type="Anticipated">August 2025</completion_date>
  <primary_completion_date type="Anticipated">August 2025</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>Persistent Neuronal Activity (Firing Rates)</measure>
    <time_frame>3 years</time_frame>
    <description>Neuronal firing rates (measured in spike rates per second) of cells in the frontal and temporal lobes during working memory.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Persistent Neuronal Activity (Power)</measure>
    <time_frame>3 years</time_frame>
    <description>Power of local field potential bandwidths (measured in amplitude across frequency of the bandwidths) in the frontal and temporal lobes during working memory.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Decision Making (Firing Rates)</measure>
    <time_frame>5 years</time_frame>
    <description>Neuronal firing rates of cells (measured in spike rates per second) in the frontal and temporal lobes during a decision-making process.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Decision Making (Power)</measure>
    <time_frame>5 years</time_frame>
    <description>Power of local field potential bandwidths (measured in amplitude across frequency of the bandwidths) in the frontal and temporal lobes during a decision-making process.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Decision Making (Timing)</measure>
    <time_frame>5 years</time_frame>
    <description>Timing of neuronal discharges (measured in spike rates per second) across the frontal and temporal lobes during a decision-making process.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Disruption of learning and memory via electrical stimulation (firing rates)</measure>
    <time_frame>5 years</time_frame>
    <description>Measure the change in firing rates of neurons (measured in amplitude across frequency of the bandwidths) after applying small pulse of electrical activity during a learning task.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Disruption of learning and memory via electrical stimulation (memory)</measure>
    <time_frame>5 years</time_frame>
    <description>Measure the change in memory (measured in spike rates per second) observed after applying small pulse of electrical activity during a learning task.</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">200</enrollment>
  <condition>Epilepsy Intractable</condition>
  <arm_group>
    <arm_group_label>Behavioral Testing</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Behavioral and Neuronal Recordings</description>
  </arm_group>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Cedrus RB-844 response pad; Adtech Behnke-Fried micro-electrodes; Neurolynx electrophysiology system; Blackrock Cerestim stimulator</intervention_name>
    <description>Devices listed are components of a single intervention that includes: Record patient responses (Cedrus RB-844), record neuronal activity (Neurolynx) from electrodes (Adtech Behnke-Fried), apply intermittent electrical stimulation (Blackrock Cerestim)</description>
    <arm_group_label>Behavioral Testing</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Intractable epilepsy, undergoing invasive monitoring&#xD;
&#xD;
          -  Age ≥13&#xD;
&#xD;
          -  Full Scale Intelligence Quotient &gt; 70&#xD;
&#xD;
          -  Ability to comprehend and perform simple behavioral tasks by pressing buttons on&#xD;
             laptop computer in response to questions.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Determination by clinicians and investigators that a patient is unable to complete the&#xD;
             behavioral tasks required for the protocol due to either cognitive limits,&#xD;
             psychological limits, or pain.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>13 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ueli Rutishauser, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Cedars-Sinai Medical Center</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Adam Mamelak, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Cedars-Sinai Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Cedars-Sinai Medical Center</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90048</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>July 29, 2020</study_first_submitted>
  <study_first_submitted_qc>August 3, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 5, 2020</study_first_posted>
  <last_update_submitted>August 17, 2023</last_update_submitted>
  <last_update_submitted_qc>August 17, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 21, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Cedars-Sinai Medical Center</investigator_affiliation>
    <investigator_full_name>Adam Mamelak, MD</investigator_full_name>
    <investigator_title>Professor of Neurosurgery</investigator_title>
  </responsible_party>
  <keyword>Epilepsy</keyword>
  <keyword>Decision-making</keyword>
  <keyword>Memory</keyword>
  <keyword>Depth Electrode</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Epilepsy</mesh_term>
    <mesh_term>Drug Resistant Epilepsy</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04500119
org study id: STUDY00000572
secondary id: 5U01NS117839-03
nct id: NCT04500119
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
is fda regulated drug: No
is fda regulated device: No
The purpose the research is to better understand how the human brain accomplishes the basic
      cognitive tasks of learning new information, recalling stored information, and making
      decisions or choices about presented information. These investigations are critical to better
      understand human cognition and to design treatments for disorders of learning and memory.
The rapid formation of new memories and the recall of old memories to inform decisions is
      essential for human cognition, but the underlying neural mechanisms remain poorly understood.
      The long-term goal of this research is a circuit-level understanding of human memory to
      enable the development of new treatments for the devastating effects of memory disorders. The
      study experiments utilize the rare opportunity to record in-vivo from human single neurons
      simultaneously in multiple brain areas in patients undergoing treatment for drug resistant
      epilepsy. The overall objective is to continue and expand a multi-institutional (Cedars
      Sinai/Caltech, Johns Hopkins, U Toronto, Children's/Harvard, UC Denver, UCSB), integrated,
      and multi-disciplinary team. Jointly, the investigators have the expertise and patient volume
      to test key predictions on the neural substrate of human memory. The study will utilize a
      combination of (i) in-vivo recordings in awake behaving humans assessing memory strength
      through confidence ratings, (ii) focal electrical stimulation to test causality, and (iii)
      computational analysis and modeling.

      These techniques will be applied to investigate three overarching hypotheses on the
      mechanisms of episodic memory. First, to determine the role of persistent neuronal activity
      in translating working memories into longterm declarative memories (Aim 1). Second, to
      determine how declarative memories are translated into decisions (Aim 2). Third, to
      investigate how event segmentation, temporal binding and reinstatement during temporally
      extended experience facilitate episodic memory.

      The expected outcomes of this work are an unprecedented characterization of how episodic
      memories are formed, retrieved and used for decisions, and how temporally extended
      experiences are segmented to form distinct but linked episodes. This work is significant
      because it moves beyond a "parts list" of neurons and brain areas by testing circuit-based
      hypotheses by simultaneously recording single-neurons from multiple frontal cortical and
      subcortical temporal lobe areas in humans who are forming, declaring and describing their
      memories. The proposed work is unusually innovative because it combines single-neuron
      recordings in multiple areas in behaving humans, develops new methods for non-invasive
      localization of implanted electrodes and electrical stimulation and directly test
      long-standing theoretical predictions on the role of evidence accumulation in memory
      retrieval.

      A second significant innovation is the study team, which combines the patient volume and
      expertise of several major centers to maximally utilize the rare neurosurgical opportunities
      available to directly study the human nervous system. This innovative approach permits
      investigation of circuit-level mechanisms of human memory that cannot be studied
      non-invasively in humans nor in animal models. This integrated multi-disciplinary combination
      of human in-vivo single-neuron physiology, behavior, and modeling will contribute
      significantly to the understanding of the circuits and patterns of neural activity that give
      rise to human memory, which is a central goal of human neuroscience in general and the BRAIN
      initiative in particular.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Persistent Neuronal Activity (Firing Rates)
time frame: 3 years
description: Neuronal firing rates (measured in spike rates per second) of cells in the frontal and temporal lobes during working memory.
measure: Persistent Neuronal Activity (Power)
time frame: 3 years
description: Power of local field potential bandwidths (measured in amplitude across frequency of the bandwidths) in the frontal and temporal lobes during working memory.
measure: Decision Making (Firing Rates)
time frame: 5 years
description: Neuronal firing rates of cells (measured in spike rates per second) in the frontal and temporal lobes during a decision-making process.
measure: Decision Making (Power)
time frame: 5 years
description: Power of local field potential bandwidths (measured in amplitude across frequency of the bandwidths) in the frontal and temporal lobes during a decision-making process.
measure: Decision Making (Timing)
time frame: 5 years
description: Timing of neuronal discharges (measured in spike rates per second) across the frontal and temporal lobes during a decision-making process.
measure: Disruption of learning and memory via electrical stimulation (firing rates)
time frame: 5 years
description: Measure the change in firing rates of neurons (measured in amplitude across frequency of the bandwidths) after applying small pulse of electrical activity during a learning task.
measure: Disruption of learning and memory via electrical stimulation (memory)
time frame: 5 years
description: Measure the change in memory (measured in spike rates per second) observed after applying small pulse of electrical activity during a learning task.
arm group label: Behavioral Testing
arm group type: Experimental
description: Behavioral and Neuronal Recordings
intervention type: Behavioral
intervention name: Cedrus RB-844 response pad; Adtech Behnke-Fried micro-electrodes; Neurolynx electrophysiology system; Blackrock Cerestim stimulator
description: Devices listed are components of a single intervention that includes: Record patient responses (Cedrus RB-844), record neuronal activity (Neurolynx) from electrodes (Adtech Behnke-Fried), apply intermittent electrical stimulation (Blackrock Cerestim)
arm group label: Behavioral Testing
criteria: 
gender: All
minimum age: 13 Years
maximum age: N/A
healthy volunteers: No
last name: Ueli Rutishauser, PhD
role: Principal Investigator
affiliation: Cedars-Sinai Medical Center
last name: Adam Mamelak, MD
role: Principal Investigator
affiliation: Cedars-Sinai Medical Center
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Cedars-Sinai Medical Center
investigator full name: Adam Mamelak, MD
investigator title: Professor of Neurosurgery
mesh term: Epilepsy
mesh term: Drug Resistant Epilepsy
sharing ipd: No