<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/NCT03810079</url>
  </required_header>
  <id_info>
    <org_study_id>2015/251</org_study_id>
    <nct_id>NCT03810079</nct_id>
  </id_info>
  <brief_title>Closed-loop tDCS in Patients in Minimally Conscious State</brief_title>
  <official_title>Closed-loop Application of tDCS to Promote Responsiveness of Patients in MCS</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Liege</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Liege</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This research will test a closed-loop system using EEG-arousal measures (spectral entropy) to&#xD;
      define the best moment of the day for application of transcranial direct current stimulation&#xD;
      (tDCS) in patients in MCS&#xD;
&#xD;
      This study aims at answering the following questions:&#xD;
&#xD;
        1. Is tDCS applied during high vigilance states more effective in increasing the level of&#xD;
           conscious awareness than low vigilance states in patients in minimally conscious state&#xD;
           (MCS)?&#xD;
&#xD;
        2. Is the EEG pattern (connectivity, complexity) different after application of active or&#xD;
           sham tDCS at high vigilance or low vigilance states?&#xD;
&#xD;
        3. Is there a difference in the profile of tDCS-responders as compared to non-responders&#xD;
           with regards to etiology, clinical diagnosis (MCS+/MCS-), age, gender, time post-injury,&#xD;
           functional outcome, structural and functional neuroimaging findings and EEG markers?&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      During the last 20 years, with the rediscovering and development of noninvasive brain&#xD;
      stimulation (NIBS); techniques such as transcranial direct current stimulation (tDCS) and&#xD;
      transcranial magnetic stimulation (TMS) have flourished thanks to the advancements in&#xD;
      functional imaging, elegant neurophysiological assessments, computer generated modeling, and&#xD;
      most importantly, the groundwork of well-designed research methodology.&#xD;
&#xD;
      TDCS represents a safe, inexpensive and straightforward technique that could be easily&#xD;
      integrated in rehabilitation programs. In a first sham-controlled double-blind randomized&#xD;
      crossover study, the effect of a single prefrontal tDCS was evaluated in a heterogeneous&#xD;
      population of patients with disorders of consciousness (DOC), vegetative state (VS) and&#xD;
      minimally conscious state (MCS), acute-subacute (&lt; 3months) and chronic, with traumatic or&#xD;
      non-traumatic etiologies. At the individual level, tDCS responders were defined as patients&#xD;
      who presented a new sign of consciousness (e.g., command following; visual pursuit;&#xD;
      recognition, manipulation or localization of objects); after the active tDCS session, that&#xD;
      was not present before nor during the sham tDCS session. 13/30 patients in MCS showed a&#xD;
      tDCS-related improvement. 2 acute (&lt;3 months) patients in VS out of 25 showed a tDCS response&#xD;
      (i.e. showed command following and visual pursuit present after the anodal stimulation not&#xD;
      present at baseline or pre- or post- sham-tDCS). At group level, a treatment effect, as&#xD;
      measured by the Coma Recovery Scale-Revised (CRS-R) was observed in the MCS but not in the VS&#xD;
      patients' group. In addition, no tDCS related side effects were observed. In another&#xD;
      sham-controlled study tDCS was applied for five days either over the primary motor cortex or&#xD;
      over the left prefrontal cortex in 10 chronic patients with DOC. In this trial, the effect of&#xD;
      tDCS have been assessed up to 12 months post stimulation. This study highlighted that even&#xD;
      chronic patients in DOC could improve and the effect could last up to 12 months post tDCS.&#xD;
&#xD;
      Several tDCS studies have been performed by the Coma Science Group (Dr Thibaut) and other&#xD;
      groups. So far, a total of 221 patients with DOC have been included in eight studies without&#xD;
      any serious adverse event. In addition, three other trials performed by Naro et al including&#xD;
      a total of 59, did not report any adverse event either. Therefore, tDCS appears as a safe&#xD;
      technique, especially when applied by experts and highly trained investigators with a strong&#xD;
      background in both non-invasive brain stimulation and patients with disorders of&#xD;
      consciousness.&#xD;
&#xD;
      From a neurophysiological point of view, tDCS increases the neuronal excitability by&#xD;
      facilitating the action potential release and modification of the excitability of NMDA&#xD;
      receptors. Moreover, tDCS may strengthen task-related dynamical synaptic connections. The&#xD;
      effect of a single tDCS session last about 60 to 90 min. While, when the stimulation is&#xD;
      repeated for 10 to 20 sessions, the effects have been found to last up to 3 months after the&#xD;
      end of the stimulation sessions.&#xD;
&#xD;
      A major challenge in the application of tDCS to patients with DOC is the variability in the&#xD;
      individual behavioral response. Indeed, in previous studies conducted by the Coma Science&#xD;
      Group and other groups, the rate of responders was inconsistent across studies. As stated&#xD;
      above, a responder is a patient who showed a new sign of consciousness following the&#xD;
      application of active tDCS that was never observed beforehand nor before or after sham&#xD;
      stimulation. However, given the specificity of crossover designs used in these studies, this&#xD;
      definition was recently updated as a patient who showed a new sign of consciousness for the&#xD;
      first time after the application of active tDCS.&#xD;
&#xD;
      The next steps to optimize the applications of tDCS include a better identification of tDCS&#xD;
      responders beforehand. To that end, Thibaut and colleagues conducted a retrospective study&#xD;
      comparing the structural and metabolic neuroimagery profiles of patients who responded to&#xD;
      tDCS (n=8) and patients who did not (n=13), by the means of structural MRI T1 data and&#xD;
      18-fluorodeoxyglucose position emission tomography. The results showed a greater atrophy in&#xD;
      non-responders in regions including the left DLPFC, the medial-prefrontal cortex and the left&#xD;
      thalamus as compared to responders. The same areas as well as the thalamus were hypometabolic&#xD;
      in non-responders as compared to responders. This suggest that response to tDCS requires at&#xD;
      least partial structural and metabolic preservation of the stimulated area, as well as in&#xD;
      subcortical brains areas involved in attention and working memory. Later, the authors used&#xD;
      the same sample and retrospectively analyzed resting state EEG brain connectivity. The&#xD;
      results showed higher theta centrality in responders (as compared to non-responders) meaning&#xD;
      this new biomarker can be used to predict tDCS response in patients with DOC (Thibaut et al.&#xD;
      2018). Another key component to responsiveness is the timing of the stimulations. Indeed,&#xD;
      patients with DOC typically present fluctuations in vigilance impacting their responsiveness&#xD;
      to any kind of external stimuli. Patients in MCS even show a periodicity of 70 minutes in&#xD;
      these fluctuations (range 57-80), comparable to the fluctuations in attention observed in&#xD;
      healthy controls, while patient in VS do not present this type of periodicity. Piarulli and&#xD;
      colleagues used the spectral entropy measured with resting EEG to highlight the periodicity&#xD;
      in its fluctuations and suggested that the EEG spectral entropy variability in MCS could&#xD;
      mirror the fluctuation of awareness previously described in this population. Administering&#xD;
      tDCS during specific time windows (i.e., periods of low or high arousal) could therefore&#xD;
      influence its clinical efficacy in patients in MCS since it is known that the positive&#xD;
      effects of tDCS are dependent on the brain neural state. To this end, recent advances in&#xD;
      information technology enable the implementation of a closed-loop set-up by complex&#xD;
      computations being performed in real-time. Using this technology to target specific levels of&#xD;
      vigilance with tDCS in patient in MCS could provide insight in understanding the patterns of&#xD;
      responding to that treatment and optimize future applications.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">August 1, 2019</start_date>
  <completion_date type="Anticipated">December 2023</completion_date>
  <primary_completion_date type="Anticipated">December 2023</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <intervention_model_description>Randomized double-blind sham-controlled crossover</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in EEG</measure>
    <time_frame>It will be measured throughout the 6 hour session and reported over the course of about 3 weeks</time_frame>
    <description>20 channels EEG will be continuously recorded to identify potential cortical changes induced by the stimulation.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in the CRS-R total score</measure>
    <time_frame>It will be measured at the beginning of the 6 hour session for 30 minutes, at the end of the 6 hour session for 30 minutes and reported over the course of about 3 days</time_frame>
    <description>Coma Recovery Scale-Revised (CRS-R- will be performed before and after tDCS (anodal and sham).</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">16</enrollment>
  <condition>Minimally Conscious State</condition>
  <arm_group>
    <arm_group_label>Anodal tDCS High Vigilance</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients will undergo continuous 20 channels EEG and receive anodal tDCS (bilateral prefrontal stimulation) at a pre-determined high level of EEG-derived spectral entropy during 20 minutes followed by a clinical assessment (Coma Recovery Scale-Revised)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Anodal tDCS Low Vigilance</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients will undergo continuous 20 channels EEG and receive anodal tDCS (bilateral prefrontal stimulation) at a pre-determined low level of EEG-derived spectral entropy during 20 minutes followed by a clinical assessment (Coma Recovery Scale-Revised)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Anodal tDCS Random Vigilance</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>Patients will undergo continuous 20 channels EEG and receive tDCS (bilateral prefrontal stimulation) at a random level of EEG-derived spectral entropy during 20 minutes followed by a clinical assessment (Coma Recovery Scale-Revised)</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Anodal transcranial direct current stimulation</intervention_name>
    <description>Neuromodulation of bilateral prefrontal areas using 2 mA tDCS delivered during 20 minutes via sponge electrodes on the scalp</description>
    <arm_group_label>Anodal tDCS High Vigilance</arm_group_label>
    <arm_group_label>Anodal tDCS Low Vigilance</arm_group_label>
    <arm_group_label>Anodal tDCS Random Vigilance</arm_group_label>
    <other_name>Anodal tDCS</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  CNS medication stable for at least a week,&#xD;
&#xD;
          -  Stable diagnosis of MCS (no diagnosis change based on 2 CRS-R performed within 1&#xD;
             week).&#xD;
&#xD;
          -  Adult (16 years old - 65 years old)&#xD;
&#xD;
          -  &gt; 28 days post injury&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  open craniotomies,&#xD;
&#xD;
          -  VPS under the stimulated area (prefrontal cortex),&#xD;
&#xD;
          -  pacemaker,&#xD;
&#xD;
          -  metallic cerebral implant, according to safety criteria for transcranial electric&#xD;
             stimulation,&#xD;
&#xD;
          -  severe medical conditions that might influence clinical diagnosis and EEG activity&#xD;
             (e.g., severe hepatic insufficiency or renal failure, or sub-continuous or abundant&#xD;
             epileptiform discharges on standard EEG recordings).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>16 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>University Hospital of Liege</name>
      <address>
        <city>Liege</city>
        <zip>4000</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Aurore Thibaut, PhD</last_name>
      <phone>003243668069</phone>
      <email>athibaut@ulg.ac.be</email>
    </contact>
    <contact_backup>
      <last_name>Alice Barra, MSc</last_name>
      <phone>003243668069</phone>
      <email>abarra@uliege.be</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Belgium</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>January 11, 2019</study_first_submitted>
  <study_first_submitted_qc>January 17, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 18, 2019</study_first_posted>
  <last_update_submitted>May 9, 2023</last_update_submitted>
  <last_update_submitted_qc>May 9, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 10, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Liege</investigator_affiliation>
    <investigator_full_name>Aurore Thibaut</investigator_full_name>
    <investigator_title>PhD</investigator_title>
  </responsible_party>
  <keyword>transcranial direct current stimulation</keyword>
  <keyword>minimally conscious state</keyword>
  <keyword>disorders of consciousness</keyword>
  <keyword>non invasive brain stimulation</keyword>
  <keyword>neuromodulation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Persistent Vegetative State</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/NCT03810079
org study id: 2015/251
nct id: NCT03810079
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This research will test a closed-loop system using EEG-arousal measures (spectral entropy) to
      define the best moment of the day for application of transcranial direct current stimulation
      (tDCS) in patients in MCS

      This study aims at answering the following questions:

        1. Is tDCS applied during high vigilance states more effective in increasing the level of
           conscious awareness than low vigilance states in patients in minimally conscious state
           (MCS)?

        2. Is the EEG pattern (connectivity, complexity) different after application of active or
           sham tDCS at high vigilance or low vigilance states?

        3. Is there a difference in the profile of tDCS-responders as compared to non-responders
           with regards to etiology, clinical diagnosis (MCS+/MCS-), age, gender, time post-injury,
           functional outcome, structural and functional neuroimaging findings and EEG markers?
During the last 20 years, with the rediscovering and development of noninvasive brain
      stimulation (NIBS); techniques such as transcranial direct current stimulation (tDCS) and
      transcranial magnetic stimulation (TMS) have flourished thanks to the advancements in
      functional imaging, elegant neurophysiological assessments, computer generated modeling, and
      most importantly, the groundwork of well-designed research methodology.

      TDCS represents a safe, inexpensive and straightforward technique that could be easily
      integrated in rehabilitation programs. In a first sham-controlled double-blind randomized
      crossover study, the effect of a single prefrontal tDCS was evaluated in a heterogeneous
      population of patients with disorders of consciousness (DOC), vegetative state (VS) and
      minimally conscious state (MCS), acute-subacute (< 3months) and chronic, with traumatic or
      non-traumatic etiologies. At the individual level, tDCS responders were defined as patients
      who presented a new sign of consciousness (e.g., command following; visual pursuit;
      recognition, manipulation or localization of objects); after the active tDCS session, that
      was not present before nor during the sham tDCS session. 13/30 patients in MCS showed a
      tDCS-related improvement. 2 acute (<3 months) patients in VS out of 25 showed a tDCS response
      (i.e. showed command following and visual pursuit present after the anodal stimulation not
      present at baseline or pre- or post- sham-tDCS). At group level, a treatment effect, as
      measured by the Coma Recovery Scale-Revised (CRS-R) was observed in the MCS but not in the VS
      patients' group. In addition, no tDCS related side effects were observed. In another
      sham-controlled study tDCS was applied for five days either over the primary motor cortex or
      over the left prefrontal cortex in 10 chronic patients with DOC. In this trial, the effect of
      tDCS have been assessed up to 12 months post stimulation. This study highlighted that even
      chronic patients in DOC could improve and the effect could last up to 12 months post tDCS.

      Several tDCS studies have been performed by the Coma Science Group (Dr Thibaut) and other
      groups. So far, a total of 221 patients with DOC have been included in eight studies without
      any serious adverse event. In addition, three other trials performed by Naro et al including
      a total of 59, did not report any adverse event either. Therefore, tDCS appears as a safe
      technique, especially when applied by experts and highly trained investigators with a strong
      background in both non-invasive brain stimulation and patients with disorders of
      consciousness.

      From a neurophysiological point of view, tDCS increases the neuronal excitability by
      facilitating the action potential release and modification of the excitability of NMDA
      receptors. Moreover, tDCS may strengthen task-related dynamical synaptic connections. The
      effect of a single tDCS session last about 60 to 90 min. While, when the stimulation is
      repeated for 10 to 20 sessions, the effects have been found to last up to 3 months after the
      end of the stimulation sessions.

      A major challenge in the application of tDCS to patients with DOC is the variability in the
      individual behavioral response. Indeed, in previous studies conducted by the Coma Science
      Group and other groups, the rate of responders was inconsistent across studies. As stated
      above, a responder is a patient who showed a new sign of consciousness following the
      application of active tDCS that was never observed beforehand nor before or after sham
      stimulation. However, given the specificity of crossover designs used in these studies, this
      definition was recently updated as a patient who showed a new sign of consciousness for the
      first time after the application of active tDCS.

      The next steps to optimize the applications of tDCS include a better identification of tDCS
      responders beforehand. To that end, Thibaut and colleagues conducted a retrospective study
      comparing the structural and metabolic neuroimagery profiles of patients who responded to
      tDCS (n=8) and patients who did not (n=13), by the means of structural MRI T1 data and
      18-fluorodeoxyglucose position emission tomography. The results showed a greater atrophy in
      non-responders in regions including the left DLPFC, the medial-prefrontal cortex and the left
      thalamus as compared to responders. The same areas as well as the thalamus were hypometabolic
      in non-responders as compared to responders. This suggest that response to tDCS requires at
      least partial structural and metabolic preservation of the stimulated area, as well as in
      subcortical brains areas involved in attention and working memory. Later, the authors used
      the same sample and retrospectively analyzed resting state EEG brain connectivity. The
      results showed higher theta centrality in responders (as compared to non-responders) meaning
      this new biomarker can be used to predict tDCS response in patients with DOC (Thibaut et al.
      2018). Another key component to responsiveness is the timing of the stimulations. Indeed,
      patients with DOC typically present fluctuations in vigilance impacting their responsiveness
      to any kind of external stimuli. Patients in MCS even show a periodicity of 70 minutes in
      these fluctuations (range 57-80), comparable to the fluctuations in attention observed in
      healthy controls, while patient in VS do not present this type of periodicity. Piarulli and
      colleagues used the spectral entropy measured with resting EEG to highlight the periodicity
      in its fluctuations and suggested that the EEG spectral entropy variability in MCS could
      mirror the fluctuation of awareness previously described in this population. Administering
      tDCS during specific time windows (i.e., periods of low or high arousal) could therefore
      influence its clinical efficacy in patients in MCS since it is known that the positive
      effects of tDCS are dependent on the brain neural state. To this end, recent advances in
      information technology enable the implementation of a closed-loop set-up by complex
      computations being performed in real-time. Using this technology to target specific levels of
      vigilance with tDCS in patient in MCS could provide insight in understanding the patterns of
      responding to that treatment and optimize future applications.
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: Randomized double-blind sham-controlled crossover
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Change in EEG
time frame: It will be measured throughout the 6 hour session and reported over the course of about 3 weeks
description: 20 channels EEG will be continuously recorded to identify potential cortical changes induced by the stimulation.
measure: Change in the CRS-R total score
time frame: It will be measured at the beginning of the 6 hour session for 30 minutes, at the end of the 6 hour session for 30 minutes and reported over the course of about 3 days
description: Coma Recovery Scale-Revised (CRS-R- will be performed before and after tDCS (anodal and sham).
arm group label: Anodal tDCS High Vigilance
arm group type: Active Comparator
description: Patients will undergo continuous 20 channels EEG and receive anodal tDCS (bilateral prefrontal stimulation) at a pre-determined high level of EEG-derived spectral entropy during 20 minutes followed by a clinical assessment (Coma Recovery Scale-Revised)
arm group label: Anodal tDCS Low Vigilance
arm group type: Active Comparator
description: Patients will undergo continuous 20 channels EEG and receive anodal tDCS (bilateral prefrontal stimulation) at a pre-determined low level of EEG-derived spectral entropy during 20 minutes followed by a clinical assessment (Coma Recovery Scale-Revised)
arm group label: Anodal tDCS Random Vigilance
arm group type: Sham Comparator
description: Patients will undergo continuous 20 channels EEG and receive tDCS (bilateral prefrontal stimulation) at a random level of EEG-derived spectral entropy during 20 minutes followed by a clinical assessment (Coma Recovery Scale-Revised)
intervention type: Device
intervention name: Anodal transcranial direct current stimulation
description: Neuromodulation of bilateral prefrontal areas using 2 mA tDCS delivered during 20 minutes via sponge electrodes on the scalp
arm group label: Anodal tDCS High Vigilance
arm group label: Anodal tDCS Low Vigilance
arm group label: Anodal tDCS Random Vigilance
other name: Anodal tDCS
criteria: 
gender: All
minimum age: 16 Years
maximum age: 75 Years
healthy volunteers: No
facility: 
status: Recruiting
contact: 
contact backup: 
country: Belgium
responsible party type: Principal Investigator
investigator affiliation: University of Liege
investigator full name: Aurore Thibaut
investigator title: PhD
mesh term: Persistent Vegetative State
sharing ipd: No