xml: <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/NCT05967598</url>
    </required_header>
    <id_info>
      <org_study_id>012052/2020-2</org_study_id>
      <nct_id>NCT05967598</nct_id>
    </id_info>
    <brief_title>Effect of taVNS of Brainstem Activation in Early and Late Parkinson's Disease Patients - an fMRI Study</brief_title>
    <official_title>Effect of Transcutaneous Auricular Vagl Nerve Electrostimulation of Brainstem Structures in Early and Late Parkinson's Disease Patients - an fMRI Study</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>University of Ljubljana</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>University Medical Centre Ljubljana</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>University of Ljubljana</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 is a randomised, within-subject, double-blinded, placebo-controlled study to assess the&#xD;
        fMRI correlates of central nervous system (CNS) response to taVNS in early vs late-stage&#xD;
        Parkinsons disease (PD), at two different frequencies. Forty PD patients will be included:&#xD;
        twenty patients with early-stage (Hoehn and Yahr stage (HY) 1-2) and twenty patients with&#xD;
        late-stage (HY 3-4) PD. Each patient will undergo one stimulation session, where they will&#xD;
        receive active taVNS at 100 Hz (taVNS100), taVNS at 25Hz (taVNS25) or will have positioned&#xD;
        electrodes without stimulation (xVNS). The order of taVNS100, taVNS25 and xVNS will be&#xD;
        randomized between subjects. The session will include (1) xVNS and taVNS; (2) MRI and fMRI&#xD;
        and (3) heart rate and breathing rate monitoring. Clinical assessment with the Movement&#xD;
        Disorder Society-Unified Parkinson's Disease Rating Scale will be done before the session.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Each participant will complete 1 visit, where the investigators will first assess the&#xD;
        MDS-UPDRS score, afther that the sesnsitivity threasholds for taVNS at 25Hz and taVNS at&#xD;
        100Hz will be assessed. The Nemos® electrode for taVNS will be positioned in the left cymba&#xD;
        conchae with the following parameters: square-shaped pseudobiphasic pulse, interpulse&#xD;
        duration 80μs, pulse width 300μs. taVNS25 will be applied at 25Hz and taVNS100 will be&#xD;
        applied at 100Hz. The sensory threshold will be assessed for each frequency and in the MRI&#xD;
        scanner a pulse intensity of 0,1mA above the perceptual threshold will be applied.&#xD;
  &#xD;
        After that the participant will be escorted to the MRI scanner where the MRI-safe electrode&#xD;
        will be positioned in the left cymba conchae. The participant will be instructed to hold&#xD;
        their head still during the complete experiment and that they will receive 3 different&#xD;
        electrical stimulation types during 3 separate sessions. They will be further instructed that&#xD;
        a black dot that will appear on the screen before each stimulation session and that they&#xD;
        should fix their gaze on the dot. The instructions will be repeated before each BOLD MRI&#xD;
        session.&#xD;
  &#xD;
        MRI will be performed at the Center for Clinical physiology at the Medical faculty in&#xD;
        Ljubljana (Center za klinično fiziologijo; CKF), using a 3T Philips Achieva 3TX dStream&#xD;
        (Best, The Netherlands).&#xD;
  &#xD;
        The investigators will acquire high-resolution T1-weighted and T2-weighted (0.7 x 0.7 x 0.7&#xD;
        mm^3) volumes of the brain. The area of brainstem and cerebellum will be scanned using a&#xD;
        T1-weighted spectral pre-saturation with inversion recovery (SPIR) sequence to enhance the&#xD;
        contrast of neuromelanin structures (and better delineate LC). The three structural scans&#xD;
        will be interspaced with 3 time slots, containing three 8 minutes long block design blood&#xD;
        oxygen level-dependent (BOLD MRI; fMRI) sessions (~1.75mm^3 isometric voxel). During each&#xD;
        fMRI slot participants will receive a different type of stimulation (taVNS,25, taVNS100 and&#xD;
        xVNS). While the participant will receive electrical stimulation during taVNS25 and taVNS100,&#xD;
        there will be no current applied during xVNS. To reduce any carryover effect the&#xD;
        investigators will randomise the order of the 3 fMRI sessions. The order of stimulation will&#xD;
        not be revealed until the automated data and statistical analysis.&#xD;
  &#xD;
        The timeline of the complete imaging session would be as follows: Survey scan - Slot 1 - T1 -&#xD;
        Slot 2 - T2 - Slot 3 - neuromelanin sequence. The session should last up to 60 min. During&#xD;
        this time the investigators will monitor heart rate and breathing rate remotely.&#xD;
  &#xD;
        For the analysis T1-weighted images will be first segmented into grey, white and&#xD;
        cerebrospinal fluid (CSF) tissue compartments using DARTEL, implemented in SPM12. This also&#xD;
        provides spatial normalization and co-registration to the standard MNI space. Images from&#xD;
        other modalities will first be co-registered to T1-weighted structural scans and next to the&#xD;
        MNI template as secondary images using the identical transform algorithm. From the fMRI data&#xD;
        the investigators will analyse (i) brainstem activation patterns (ROI analysis); and (ii)&#xD;
        block design connectivity between nucleus tractus solitarii and central nervous system (CNS)&#xD;
        structures and locus coeruleus and CNS stuctures. fMRI analyses will be done with Analysis of&#xD;
        Functional NeuroImages (AFNI) tools.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Actual">February 15, 2023</start_date>
    <completion_date type="Anticipated">December 2023</completion_date>
    <primary_completion_date type="Anticipated">October 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>Factorial Assignment</intervention_model>
      <intervention_model_description>40 participants with the diagnosis of PD patients aged &gt; 45 years will be included. Patients will be recruited from the outpatient and inpatient clinics. PD will be diagnosed according to the UK PD Society Brain Bank criteria: the investigators aim to include 20 patients with early-stage and 20 patients with late-stage PD. Each participant will complete 1 visit at the MRI scanning facility, during which they will complete 3 blocks of 8min block design fMRI. During each block they will receive a different kind of stimulation (taVNS25, taVNS100, xVNS; see detailed description).&#xD;
  The effect will be compared within each group (early and advanced patients) and between groups (early vs advanced PD patients).</intervention_model_description>
      <primary_purpose>Basic Science</primary_purpose>
      <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
      <masking_description>Before the experiment the stimulation threshold (i.e. current) for each stimulation (taVNS25 and taVNS100) will be assessed by a third person.&#xD;
  The participant will be told, that the investigators are comparing the effect of 3 different stimulation types and that each will be delivered at a different intensity.&#xD;
  The order of stimulation will be randomised across the 3 fMRI slots by a third person and the stimulation type will be noted in a separate log file.&#xD;
  The outcomes assessor will be blinded to the stimulation type until the end of the analysis process.</masking_description>
    </study_design_info>
    <primary_outcome>
      <measure>Comparison of Brainstem activation pattern on fMRI (ROI analysis) during taVNS compared to xVNS</measure>
      <time_frame>Only the online/acute effect measured during stimulation (time frame duration of 8 minutes per stimulation type) will be analysed.</time_frame>
      <description>Block-design fMRI analysis will be performed on brainstem ROIs to assess activation in neuromodulatory brainstem nuclei during taVNS compared with xVNS using the tools of the AFNI program. Final analysis will be performed on group level.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Comparison of Functional connectivity pattern on fMRI (block design) of nucleus tractus solitarii and the rest of the nervous system during taVNS compared to xVNS</measure>
      <time_frame>Only the online/acute effect measured during stimulation (time frame duration of 8 minutes per stimulation type) will be analysed.</time_frame>
      <description>Functional connectivity (fMRI, block design) between the nucleus tractus solitarii (NTS) and the rest of the central nervous system will be analysed with AFNI Context-Dependent Correlation Analysis to determine whether taVNS produces a different pattern of connectivity compared with xVNS.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Comparison of Functional connectivity pattern on fMRI (block design) of locus coeruleus (LC) and the rest of the nervous system during taVNS compared to xVNS</measure>
      <time_frame>Only the online/acute effect measured during stimulation (time frame duration of 8 minutes per stimulation type) will be analysed.</time_frame>
      <description>Functional connectivity pattern (fMRI, block design) between the nucleus locus coeruleus (LC) and the rest of the central nervous system will be analysed with AFNI Context-Dependent Correlation Analysis to determine whether taVNS produces a different pattern of connectivity compared with xVNS.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Comparison of Brainstem activation pattern on fMRI (ROI analysis) during taVNS25 compared to taVNS100</measure>
      <time_frame>Only the online/acute effect measured during stimulation (time frame duration of 8 minutes per stimulation type) will be analysed.</time_frame>
      <description>Block-design fMRI analysis will be performed on brainstem ROIs to assess activation in neuromodulatory brainstem nuclei during taVNS100 compared with taVNS25 using the tools of the AFNI program. Final analysis will be performed on group level.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Comparison of Functional connectivity pattern on fMRI (block design) of nucleus tractus solitarii and the rest of the nervous system during taVNS25 compared to taVNS100</measure>
      <time_frame>Only the online/acute effect measured during stimulation (time frame duration of 8 minutes per stimulation type) will be analysed.</time_frame>
      <description>Functional connectivity (fMRI, block design) between the nucleus tractus solitarii (NTS) and the rest of the central nervous system will be analysed with AFNI Context-Dependent Correlation Analysis to determine whether taVNS produces a different pattern of connectivity compared with xVNS.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Comparison of Functional connectivity pattern on fMRI (block design) of locus coeruleus (LC) and the rest of the nervous system during taVNS100 compared to taVNS25</measure>
      <time_frame>Only the online/acute effect measured during stimulation (time frame duration of 8 minutes per stimulation type) will be analysed.</time_frame>
      <description>Functional connectivity pattern (fMRI, block design) between the nucleus locus coeruleus (LC) and the rest of the central nervous system will be analysed with AFNI Context-Dependent Correlation Analysis to determine whether taVNS100 produces a different pattern of connectivity compared with taVNS25.</description>
    </secondary_outcome>
    <number_of_arms>6</number_of_arms>
    <enrollment type="Anticipated">40</enrollment>
    <condition>Parkinson Disease</condition>
    <condition>Neurologic Disorder</condition>
    <arm_group>
      <arm_group_label>taVNS100 in advanced PD patients</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>Noninvasive electrostimulation will be applied to the left cyma conchae through the Nemos® electrode at 100Hz to advanced PD patients. Participants will complete an 8 minute block design fMRI block.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>taVNS25 in advanced PD patients</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>Noninvasive electrostimulation will be applied to the left cyma conchae through the Nemos® electrode at 25Hz to advanced PD patients. Participants will complete an 8 minute block design fMRI block.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>xVNS in advanced PD patients</arm_group_label>
      <arm_group_type>Placebo Comparator</arm_group_type>
      <description>The electrode will be placed in the left cyma conchae however no electrical current will be applied to advanced PD patients. Participants will complete an 8 minute block design fMRI block.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>taVNS100 in early PD patients</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>Noninvasive electrostimulation will be applied to the left cyma conchae through the Nemos® electrode at 100Hz to early PD patients. Participants will complete an 8 minute block design fMRI block.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>taVNS25 in early PD patients</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>Noninvasive electrostimulation will be applied to the left cyma conchae through the Nemos® electrode at 25Hz to early PD patients. Participants will complete an 8 minute block design fMRI block.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>xVNS in early PD patients</arm_group_label>
      <arm_group_type>Placebo Comparator</arm_group_type>
      <description>The electrode will be placed in the left cyma conchae however no electrical current will be applied to early PD patients. Participants will complete an 8 minute block design fMRI block.</description>
    </arm_group>
    <intervention>
      <intervention_type>Device</intervention_type>
      <intervention_name>Noninvasive transcutaneous auricular vagus nerve stimulation at 100Hz</intervention_name>
      <description>Noninvasive electrostimulation will be applied to the left cyma conchae through the Nemos® electrode with the following parameters: square-shaped pseudobiphasic pulse, interpulse duration 80μs, pulse width 300μs, pulse intensity 0,1mA above the perceptual threshold at 100Hz. The intensity for each separate stimulation will be adjusted for each participant at the beginning of the experiment</description>
      <arm_group_label>taVNS100 in advanced PD patients</arm_group_label>
      <arm_group_label>taVNS100 in early PD patients</arm_group_label>
      <other_name>taVNS100</other_name>
    </intervention>
    <intervention>
      <intervention_type>Device</intervention_type>
      <intervention_name>Noninvasive transcutaneous auricular vagus nerve stimulation at 25Hz</intervention_name>
      <description>Noninvasive electrostimulation will be applied to the left cyma conchae through the Nemos® electrode with the following parameters: square-shaped pseudobiphasic pulse, interpulse duration 80μs, pulse width 300μs, pulse intensity 0,1mA above the perceptual threshold at 25Hz. The intensity for each separate stimulation will be adjusted for each participant at the beginning of the experiment.</description>
      <arm_group_label>taVNS25 in advanced PD patients</arm_group_label>
      <arm_group_label>taVNS25 in early PD patients</arm_group_label>
      <other_name>taVNS25</other_name>
    </intervention>
    <intervention>
      <intervention_type>Device</intervention_type>
      <intervention_name>Sham cyma conchae stimulation</intervention_name>
      <description>The electrode will be placed at the cymba conchae location, however no electrical current will be applied. All other experimental conditions will be the same as for the active taVNS stimulation.</description>
      <arm_group_label>xVNS in advanced PD patients</arm_group_label>
      <arm_group_label>xVNS in early PD patients</arm_group_label>
      <other_name>xVNS</other_name>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  diagnosis of Parkinson's disease according to the UK PD Society Brain Bank criteria&#xD;
  &#xD;
            -  ability to walk independently for at least 2 minutes&#xD;
  &#xD;
            -  cognitive impairment that might prevent cooperation during tests&#xD;
  &#xD;
            -  stable antiparkinsonian medications during the previous 1 month&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  medication resistant rest tremor or dyskinesias&#xD;
  &#xD;
            -  history of seizures&#xD;
  &#xD;
            -  implanted medical devices or metal implants&#xD;
  &#xD;
            -  pregnancy&#xD;
  &#xD;
            -  claustrophobia&#xD;
  &#xD;
            -  fixed or severe kyphosis&#xD;
  &#xD;
            -  any conditions that would prevent our patients from lying still for 1 hour in a supine&#xD;
               position (i.e. muscle pain, degenerative joint diseases…).&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>45 Years</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Andrej Vovk, PhD</last_name>
      <role>Principal Investigator</role>
      <affiliation>Medical Faculty, University of Ljubljana</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Vesna M van Midden, MD</last_name>
      <phone>+38615223200</phone>
      <email>vesna.vanmidden@kclj.si</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Andrej Vovk, PhD</last_name>
      <email>andrej.vovk@mf.uni-lj.si</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Neurology Department, UMC Ljubljana</name>
        <address>
          <city>Ljubljana</city>
          <zip>1000</zip>
          <country>Slovenia</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Nina Vovk</last_name>
        <email>nina.vovk@kclj.si</email>
      </contact>
      <contact_backup>
        <last_name>Maja Bartolo</last_name>
        <email>maja.bartolo@kclj.si</email>
      </contact_backup>
    </location>
    <location_countries>
      <country>Slovenia</country>
    </location_countries>
    <verification_date>July 2023</verification_date>
    <study_first_submitted>April 5, 2023</study_first_submitted>
    <study_first_submitted_qc>July 20, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 1, 2023</study_first_posted>
    <last_update_submitted>July 31, 2023</last_update_submitted>
    <last_update_submitted_qc>July 31, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 2, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>University of Ljubljana</investigator_affiliation>
      <investigator_full_name>Andrej Vovk</investigator_full_name>
      <investigator_title>Principal investigator</investigator_title>
    </responsible_party>
    <keyword>Parkinson disease</keyword>
    <keyword>taVNS</keyword>
    <keyword>transcutaneous auricular vagal nerve stimulation</keyword>
    <keyword>fMRI</keyword>
    <keyword>brainstem ROI analysis</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Parkinson Disease</mesh_term>
      <mesh_term>Nervous System Diseases</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>Yes</sharing_ipd>
      <ipd_description>The investigators plan to share the anonymised data with researchers upon request.</ipd_description>
      <ipd_info_type>Study Protocol</ipd_info_type>
      <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
      <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
      <ipd_info_type>Analytic Code</ipd_info_type>
      <ipd_time_frame>Upon request after study publication</ipd_time_frame>
      <ipd_access_criteria>Data will be shared with researchers upon reasonable request</ipd_access_criteria>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT05967598
  org study id: 012052/2020-2
  nct id: NCT05967598
  lead sponsor: 
  collaborator: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  This is a randomised, within-subject, double-blinded, placebo-controlled study to assess the
        fMRI correlates of central nervous system (CNS) response to taVNS in early vs late-stage
        Parkinsons disease (PD), at two different frequencies. Forty PD patients will be included:
        twenty patients with early-stage (Hoehn and Yahr stage (HY) 1-2) and twenty patients with
        late-stage (HY 3-4) PD. Each patient will undergo one stimulation session, where they will
        receive active taVNS at 100 Hz (taVNS100), taVNS at 25Hz (taVNS25) or will have positioned
        electrodes without stimulation (xVNS). The order of taVNS100, taVNS25 and xVNS will be
        randomized between subjects. The session will include (1) xVNS and taVNS; (2) MRI and fMRI
        and (3) heart rate and breathing rate monitoring. Clinical assessment with the Movement
        Disorder Society-Unified Parkinson's Disease Rating Scale will be done before the session.
  Each participant will complete 1 visit, where the investigators will first assess the
        MDS-UPDRS score, afther that the sesnsitivity threasholds for taVNS at 25Hz and taVNS at
        100Hz will be assessed. The Nemos® electrode for taVNS will be positioned in the left cymba
        conchae with the following parameters: square-shaped pseudobiphasic pulse, interpulse
        duration 80μs, pulse width 300μs. taVNS25 will be applied at 25Hz and taVNS100 will be
        applied at 100Hz. The sensory threshold will be assessed for each frequency and in the MRI
        scanner a pulse intensity of 0,1mA above the perceptual threshold will be applied.
  
        After that the participant will be escorted to the MRI scanner where the MRI-safe electrode
        will be positioned in the left cymba conchae. The participant will be instructed to hold
        their head still during the complete experiment and that they will receive 3 different
        electrical stimulation types during 3 separate sessions. They will be further instructed that
        a black dot that will appear on the screen before each stimulation session and that they
        should fix their gaze on the dot. The instructions will be repeated before each BOLD MRI
        session.
  
        MRI will be performed at the Center for Clinical physiology at the Medical faculty in
        Ljubljana (Center za klinično fiziologijo; CKF), using a 3T Philips Achieva 3TX dStream
        (Best, The Netherlands).
  
        The investigators will acquire high-resolution T1-weighted and T2-weighted (0.7 x 0.7 x 0.7
        mm^3) volumes of the brain. The area of brainstem and cerebellum will be scanned using a
        T1-weighted spectral pre-saturation with inversion recovery (SPIR) sequence to enhance the
        contrast of neuromelanin structures (and better delineate LC). The three structural scans
        will be interspaced with 3 time slots, containing three 8 minutes long block design blood
        oxygen level-dependent (BOLD MRI; fMRI) sessions (~1.75mm^3 isometric voxel). During each
        fMRI slot participants will receive a different type of stimulation (taVNS,25, taVNS100 and
        xVNS). While the participant will receive electrical stimulation during taVNS25 and taVNS100,
        there will be no current applied during xVNS. To reduce any carryover effect the
        investigators will randomise the order of the 3 fMRI sessions. The order of stimulation will
        not be revealed until the automated data and statistical analysis.
  
        The timeline of the complete imaging session would be as follows: Survey scan - Slot 1 - T1 -
        Slot 2 - T2 - Slot 3 - neuromelanin sequence. The session should last up to 60 min. During
        this time the investigators will monitor heart rate and breathing rate remotely.
  
        For the analysis T1-weighted images will be first segmented into grey, white and
        cerebrospinal fluid (CSF) tissue compartments using DARTEL, implemented in SPM12. This also
        provides spatial normalization and co-registration to the standard MNI space. Images from
        other modalities will first be co-registered to T1-weighted structural scans and next to the
        MNI template as secondary images using the identical transform algorithm. From the fMRI data
        the investigators will analyse (i) brainstem activation patterns (ROI analysis); and (ii)
        block design connectivity between nucleus tractus solitarii and central nervous system (CNS)
        structures and locus coeruleus and CNS stuctures. fMRI analyses will be done with Analysis of
        Functional NeuroImages (AFNI) tools.
  allocation: Randomized
  intervention model: Factorial Assignment
  intervention model description: 40 participants with the diagnosis of PD patients aged > 45 years will be included. Patients will be recruited from the outpatient and inpatient clinics. PD will be diagnosed according to the UK PD Society Brain Bank criteria: the investigators aim to include 20 patients with early-stage and 20 patients with late-stage PD. Each participant will complete 1 visit at the MRI scanning facility, during which they will complete 3 blocks of 8min block design fMRI. During each block they will receive a different kind of stimulation (taVNS25, taVNS100, xVNS; see detailed description).
  The effect will be compared within each group (early and advanced patients) and between groups (early vs advanced PD patients).
  primary purpose: Basic Science
  masking: Triple (Participant, Investigator, Outcomes Assessor)
  masking description: Before the experiment the stimulation threshold (i.e. current) for each stimulation (taVNS25 and taVNS100) will be assessed by a third person.
  The participant will be told, that the investigators are comparing the effect of 3 different stimulation types and that each will be delivered at a different intensity.
  The order of stimulation will be randomised across the 3 fMRI slots by a third person and the stimulation type will be noted in a separate log file.
  The outcomes assessor will be blinded to the stimulation type until the end of the analysis process.
  measure: Comparison of Brainstem activation pattern on fMRI (ROI analysis) during taVNS compared to xVNS
  time frame: Only the online/acute effect measured during stimulation (time frame duration of 8 minutes per stimulation type) will be analysed.
  description: Block-design fMRI analysis will be performed on brainstem ROIs to assess activation in neuromodulatory brainstem nuclei during taVNS compared with xVNS using the tools of the AFNI program. Final analysis will be performed on group level.
  measure: Comparison of Functional connectivity pattern on fMRI (block design) of nucleus tractus solitarii and the rest of the nervous system during taVNS compared to xVNS
  time frame: Only the online/acute effect measured during stimulation (time frame duration of 8 minutes per stimulation type) will be analysed.
  description: Functional connectivity (fMRI, block design) between the nucleus tractus solitarii (NTS) and the rest of the central nervous system will be analysed with AFNI Context-Dependent Correlation Analysis to determine whether taVNS produces a different pattern of connectivity compared with xVNS.
  measure: Comparison of Functional connectivity pattern on fMRI (block design) of locus coeruleus (LC) and the rest of the nervous system during taVNS compared to xVNS
  time frame: Only the online/acute effect measured during stimulation (time frame duration of 8 minutes per stimulation type) will be analysed.
  description: Functional connectivity pattern (fMRI, block design) between the nucleus locus coeruleus (LC) and the rest of the central nervous system will be analysed with AFNI Context-Dependent Correlation Analysis to determine whether taVNS produces a different pattern of connectivity compared with xVNS.
  measure: Comparison of Brainstem activation pattern on fMRI (ROI analysis) during taVNS25 compared to taVNS100
  time frame: Only the online/acute effect measured during stimulation (time frame duration of 8 minutes per stimulation type) will be analysed.
  description: Block-design fMRI analysis will be performed on brainstem ROIs to assess activation in neuromodulatory brainstem nuclei during taVNS100 compared with taVNS25 using the tools of the AFNI program. Final analysis will be performed on group level.
  measure: Comparison of Functional connectivity pattern on fMRI (block design) of nucleus tractus solitarii and the rest of the nervous system during taVNS25 compared to taVNS100
  time frame: Only the online/acute effect measured during stimulation (time frame duration of 8 minutes per stimulation type) will be analysed.
  description: Functional connectivity (fMRI, block design) between the nucleus tractus solitarii (NTS) and the rest of the central nervous system will be analysed with AFNI Context-Dependent Correlation Analysis to determine whether taVNS produces a different pattern of connectivity compared with xVNS.
  measure: Comparison of Functional connectivity pattern on fMRI (block design) of locus coeruleus (LC) and the rest of the nervous system during taVNS100 compared to taVNS25
  time frame: Only the online/acute effect measured during stimulation (time frame duration of 8 minutes per stimulation type) will be analysed.
  description: Functional connectivity pattern (fMRI, block design) between the nucleus locus coeruleus (LC) and the rest of the central nervous system will be analysed with AFNI Context-Dependent Correlation Analysis to determine whether taVNS100 produces a different pattern of connectivity compared with taVNS25.
  arm group label: taVNS100 in advanced PD patients
  arm group type: Active Comparator
  description: Noninvasive electrostimulation will be applied to the left cyma conchae through the Nemos® electrode at 100Hz to advanced PD patients. Participants will complete an 8 minute block design fMRI block.
  arm group label: taVNS25 in advanced PD patients
  arm group type: Active Comparator
  description: Noninvasive electrostimulation will be applied to the left cyma conchae through the Nemos® electrode at 25Hz to advanced PD patients. Participants will complete an 8 minute block design fMRI block.
  arm group label: xVNS in advanced PD patients
  arm group type: Placebo Comparator
  description: The electrode will be placed in the left cyma conchae however no electrical current will be applied to advanced PD patients. Participants will complete an 8 minute block design fMRI block.
  arm group label: taVNS100 in early PD patients
  arm group type: Active Comparator
  description: Noninvasive electrostimulation will be applied to the left cyma conchae through the Nemos® electrode at 100Hz to early PD patients. Participants will complete an 8 minute block design fMRI block.
  arm group label: taVNS25 in early PD patients
  arm group type: Active Comparator
  description: Noninvasive electrostimulation will be applied to the left cyma conchae through the Nemos® electrode at 25Hz to early PD patients. Participants will complete an 8 minute block design fMRI block.
  arm group label: xVNS in early PD patients
  arm group type: Placebo Comparator
  description: The electrode will be placed in the left cyma conchae however no electrical current will be applied to early PD patients. Participants will complete an 8 minute block design fMRI block.
  intervention type: Device
  intervention name: Noninvasive transcutaneous auricular vagus nerve stimulation at 100Hz
  description: Noninvasive electrostimulation will be applied to the left cyma conchae through the Nemos® electrode with the following parameters: square-shaped pseudobiphasic pulse, interpulse duration 80μs, pulse width 300μs, pulse intensity 0,1mA above the perceptual threshold at 100Hz. The intensity for each separate stimulation will be adjusted for each participant at the beginning of the experiment
  arm group label: taVNS100 in advanced PD patients
  arm group label: taVNS100 in early PD patients
  other name: taVNS100
  intervention type: Device
  intervention name: Noninvasive transcutaneous auricular vagus nerve stimulation at 25Hz
  description: Noninvasive electrostimulation will be applied to the left cyma conchae through the Nemos® electrode with the following parameters: square-shaped pseudobiphasic pulse, interpulse duration 80μs, pulse width 300μs, pulse intensity 0,1mA above the perceptual threshold at 25Hz. The intensity for each separate stimulation will be adjusted for each participant at the beginning of the experiment.
  arm group label: taVNS25 in advanced PD patients
  arm group label: taVNS25 in early PD patients
  other name: taVNS25
  intervention type: Device
  intervention name: Sham cyma conchae stimulation
  description: The electrode will be placed at the cymba conchae location, however no electrical current will be applied. All other experimental conditions will be the same as for the active taVNS stimulation.
  arm group label: xVNS in advanced PD patients
  arm group label: xVNS in early PD patients
  other name: xVNS
  criteria: 
  gender: All
  minimum age: 45 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Andrej Vovk, PhD
  role: Principal Investigator
  affiliation: Medical Faculty, University of Ljubljana
  last name: Vesna M van Midden, MD
  phone: +38615223200
  email: vesna.vanmidden@kclj.si
  last name: Andrej Vovk, PhD
  email: andrej.vovk@mf.uni-lj.si
  facility: 
  status: Recruiting
  contact: 
  contact backup: 
  country: Slovenia
  responsible party type: Principal Investigator
  investigator affiliation: University of Ljubljana
  investigator full name: Andrej Vovk
  investigator title: Principal investigator
  mesh term: Parkinson Disease
  mesh term: Nervous System Diseases
  sharing ipd: Yes
  ipd description: The investigators plan to share the anonymised data with researchers upon request.
  ipd info type: Study Protocol
  ipd info type: Statistical Analysis Plan (SAP)
  ipd info type: Informed Consent Form (ICF)
  ipd info type: Analytic Code
  ipd time frame: Upon request after study publication
  ipd access criteria: Data will be shared with researchers upon reasonable request