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/NCT06013956</url>
    </required_header>
    <id_info>
      <org_study_id>23-358</org_study_id>
      <nct_id>NCT06013956</nct_id>
    </id_info>
    <brief_title>Personalized Real-Time DBS and PD Mechanisms</brief_title>
    <official_title>Identifying Circuit Dynamics Underlying Motor Dysfunction in Parkinson's Disease Using Real-Time Neural Control</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>David Escobar</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>The Cleveland Clinic</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>The Cleveland Clinic</source>
    <oversight_info>
      <has_dmc>No</has_dmc>
      <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
      <is_fda_regulated_device>Yes</is_fda_regulated_device>
      <is_unapproved_device>Yes</is_unapproved_device>
      <is_us_export>No</is_us_export>
    </oversight_info>
    <brief_summary>
      <textblock>
        A prospective cohort of patients scheduled to undergo deep brain stimulation (DBS)&#xD;
        implantation surgery for the treatment of Parkinson's disease as per standard of care will be&#xD;
        invited to participate in this study. This mechanistic study is aimed at better understanding&#xD;
        the role of basal ganglia beta band (11-35 Hz) oscillations and resonance in the&#xD;
        manifestation of Parkinson's disease (PD) motor signs using closed-loop electrical&#xD;
        neurostimulation, levodopa medication, and computational modeling. The ultimate goal of this&#xD;
        study is to inform the development of closed-loop neuromodulation technology that can be&#xD;
        programmed and adjusted in real time based on patient-specific neural activity.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        While much research has been dedicated to understanding the pathophysiology of Parkinson's&#xD;
        disease (PD), the neural dynamics underlying the manifestation of motor signs remain unclear.&#xD;
        Studies over the past two decades have shown a correlation of the amplitude and incidence of&#xD;
        beta band oscillations in the subthalamic nucleus (STN) and internal segment of the globus&#xD;
        pallidus (GPi) with changes in bradykinesia and rigidity mediated by levodopa or deep brain&#xD;
        stimulation (DBS) therapies. Yet, no study has conclusively or deductively demonstrated a&#xD;
        causal link. A limitation to establishing causality is the lack of available neuromodulation&#xD;
        tools capable of predictably and precisely controlling neural oscillatory activity in the&#xD;
        human brain in real time without introducing confounding factors. Establishing these tools&#xD;
        and clarifying whether the relationship of beta band oscillations with PD motor signs is&#xD;
        causal or epiphenomenon are critical steps to better understand PD pathophysiology and&#xD;
        advance personalized DBS technology in PD and other brain conditions. This study aims to&#xD;
        address these technology and knowledge gaps by leveraging feedback control engineering and&#xD;
        patient-specific computational modeling tools.&#xD;
  &#xD;
        In this study, the investigators will employ a neural control approach, referred to as evoked&#xD;
        interference closed-loop DBS (eiDBS), to characterize the degree by which controlled&#xD;
        suppression or amplification of beta oscillations in the STN and GPi influences bradykinesia&#xD;
        and rigidity in PD (Specific Aim 1, SA1). The investigators will test the hypothesis that&#xD;
        stimulation-induced suppression or amplification of beta oscillations in the STN or GPi will&#xD;
        result in changes in bradykinesia and rigidity measures. In SA2, the investigators will&#xD;
        employ levodopa medication to characterize how changes in bradykinesia and rigidity relate to&#xD;
        variations in the amplitude of neural oscillations in the STN, GPi, and primary motor cortex&#xD;
        (MC) evoked by STN and GPi stimulation. The investigators will test the hypothesis that&#xD;
        levodopa administration will result in a decrease in the amplitude of stimulation-evoked beta&#xD;
        oscillations that will correlate with changes in bradykinesia and rigidity. The results from&#xD;
        SA2 will help to gain a greater understanding of intrinsic circuit dynamics associated with&#xD;
        PD and identify strategies to optimize closed-loop DBS algorithms (e.g., eiDBS) in the face&#xD;
        of concurrent levodopa therapy, a step to bring this technology to future clinical trials.&#xD;
        Combining electrophysiological data with high-resolution (7T) magnetic resonance (MR) imaging&#xD;
        and computational modeling, the investigators will examine which specific neuronal pathways&#xD;
        connected with the STN and GPi need to be activated to evoke frequency-specific neural&#xD;
        responses in the STN, GPi, and MC (SA3). The data from SA3 will shed light on which&#xD;
        sub-circuits are involved in the generation of stimulation-evoked and spontaneous beta&#xD;
        oscillations in PD, and inform how to use directional DBS leads to shape electric fields in&#xD;
        the STN and GPi to selectively modulate the STN or GPi via eiDBS or other neurostimulation&#xD;
        techniques. The investigators will address the three aims of this study with the&#xD;
        participation of PD patients implanted with DBS leads in the STN or GPi, whose DBS lead&#xD;
        extensions will be externalized and connected to our recording and closed-loop stimulation&#xD;
        infrastructure.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Anticipated">September 15, 2023</start_date>
    <completion_date type="Anticipated">June 30, 2028</completion_date>
    <primary_completion_date type="Anticipated">June 30, 2028</primary_completion_date>
    <phase>Phase 4</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>Each participant is assigned to four different conditions. Kinematic, behavioral, and neurophysiological variables are compared across the conditions.</intervention_model_description>
      <primary_purpose>Basic Science</primary_purpose>
      <masking>Triple (Participant, Care Provider, Outcomes Assessor)</masking>
      <masking_description>The sequence order for the conditions will be randomized for each study participant.</masking_description>
    </study_design_info>
    <primary_outcome>
      <measure>Effect of eiDBS suppression vs. off-stimulation on finger tapping speed</measure>
      <time_frame>Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.</time_frame>
      <description>The finger tapping speed will be measured with an inertial measuring unit. The relationship (slope/effect) between this kinematic variable (response variable) and the mean amplitude of beta (11-35 Hz) oscillations (predictor physiological variable) will be estimated via linear mixed-effects (LME) models. The LME models will include the stimulation conditions in this study (e.g., eiDBS-suppression) as fixed effects with the off-stimulation condition as a reference/control group, and random intercepts as random effects that account for the heterogeneity between subjects.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Effect of eiDBS amplification vs. off-stimulation on finger tapping speed</measure>
      <time_frame>Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.</time_frame>
      <description>The relationship (slope/effect) between the kinematic variable (response variable) and the mean amplitude of beta (11-35 Hz) oscillations (predictor physiological variable) will be estimated via linear mixed-effects (LME) models.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Effect of eiDBS suppression vs. off-stimulation on forearm speed</measure>
      <time_frame>Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.</time_frame>
      <description>The forearm speed will be measured with an inertial measuring unit. The relationship (slope/effect) between this kinematic variable (response variable) and the mean amplitude of beta (11-35 Hz) oscillations (predictor physiological variable) will be estimated via linear mixed-effects (LME) models.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Effect of eiDBS amplification vs. off-stimulation on forearm speed</measure>
      <time_frame>Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.</time_frame>
      <description>The relationship (slope/effect) between the kinematic variable (response variable) and the mean amplitude of beta (11-35 Hz) oscillations (predictor physiological variable) will be estimated via linear mixed-effects (LME) models.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Effect of eiDBS suppression vs. off-stimulation on UPDRS-III rigidity subscore</measure>
      <time_frame>Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.</time_frame>
      <description>The relationship (slope/effect) between this UPDRS-III rigidity subscore (response variable) and the mean amplitude of beta (11-35 Hz) oscillations (predictor physiological variable) will be estimated via linear mixed-effects (LME) models.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Effect of eiDBS amplification vs. off-stimulation on UPDRS-III rigidity subscore</measure>
      <time_frame>Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.</time_frame>
      <description>The relationship (slope/effect) between this UPDRS-III rigidity subscore (response variable) and the mean amplitude of beta (11-35 Hz) oscillations (predictor physiological variable) will be estimated via linear mixed-effects (LME) models.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Correlation between levodopa-related changes in finger tapping speed and the amplitude of stimulation-evoked beta oscillations</measure>
      <time_frame>Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.</time_frame>
      <description>The amplitude of beta oscillations evoked by stimulation will be characterized using the wavelet transform. The relationship (slope) between the kinematic measurements (response variable) and the beta oscillations amplitude (predictor variable) will be estimated via the linear mixed-effects models.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Correlation between levodopa-related changes in forearm speed and the amplitude of stimulation-evoked beta oscillations</measure>
      <time_frame>Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.</time_frame>
      <description>The relationship (slope) between the kinematic measurements (response variable) and the beta oscillations amplitude (predictor variable) will be estimated via the linear mixed-effects models.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Correlation between levodopa-related changes in UPDRS-III rigidity subscore and the amplitude of stimulation-evoked beta oscillations.</measure>
      <time_frame>Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.</time_frame>
      <description>The relationship (slope) between the UPDRS-III subscores (response variable) and the beta oscillations amplitude (predictor variable) will be estimated via the linear mixed-effects models.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Effect of eiDBS suppression vs. off-stimulation on finger tapping displacement</measure>
      <time_frame>Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.</time_frame>
      <description>The finger tapping displacement will be derived based on data from an inertial measuring unit via a Kalman filter. The relationship (slope/effect) between this kinematic variable (response variable) and the mean amplitude of beta (11-35 Hz) oscillations (predictor physiological variable) will be estimated via linear mixed-effects (LME) models.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Effect of eiDBS amplification vs. off-stimulation on finger tapping displacement</measure>
      <time_frame>Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.</time_frame>
      <description>The relationship (slope/effect) between the kinematic variable (response variable) and the mean amplitude of beta (11-35 Hz) oscillations (predictor physiological variable) will be estimated via linear mixed-effects (LME) models.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Effect of eiDBS suppression vs. off-stimulation on forearm displacement</measure>
      <time_frame>Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.</time_frame>
      <description>The relationship (slope/effect) between the kinematic variable (response variable) and the mean amplitude of beta (11-35 Hz) oscillations (predictor physiological variable) will be estimated via linear mixed-effects (LME) models.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Effect of eiDBS amplification vs. off-stimulation on forearm displacement</measure>
      <time_frame>Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.</time_frame>
      <description>The relationship (slope/effect) between the kinematic variable (response variable) and the mean amplitude of beta (11-35 Hz) oscillations (predictor physiological variable) will be estimated via linear mixed-effects (LME) models.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Effect of eiDBS suppression vs. off-stimulation on UPDRS-III bradykinesia subscore</measure>
      <time_frame>Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.</time_frame>
      <description>The relationship (slope/effect) between this UPDRS-III subscore (response variable) and the mean amplitude of beta (11-35 Hz) oscillations (predictor physiological variable) will be estimated via linear mixed-effects (LME) models.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Effect of eiDBS amplification vs. off-stimulation on UPDRS-III bradykinesia subscore</measure>
      <time_frame>Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.</time_frame>
      <description>The relationship (slope/effect) between this UPDRS-III subscore (response variable) and the mean amplitude of beta (11-35 Hz) oscillations (predictor physiological variable) will be estimated via linear mixed-effects (LME) models.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Correlation between levodopa-related changes in finger tapping displacement and the amplitude of stimulation-evoked beta oscillations</measure>
      <time_frame>Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.</time_frame>
      <description>The relationship (slope) between the kinematic measurements (response variable) and the beta oscillations amplitude (predictor variable) will be estimated via the linear mixed-effects models.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Correlation between levodopa-related changes in forearm displacement and the amplitude of stimulation-evoked beta oscillations</measure>
      <time_frame>Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.</time_frame>
      <description>The relationship (slope) between the kinematic measurements (response variable) and the beta oscillations amplitude (predictor variable) will be estimated via the linear mixed-effects models.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Correlation between levodopa-related changes in UPDRS-III bradykinesia subscore and the amplitude of stimulation-evoked beta oscillations</measure>
      <time_frame>Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.</time_frame>
      <description>The relationship (slope) between the UPDRS-III subscores (response variable) and the beta oscillations amplitude (predictor variable) will be estimated via the linear mixed-effects models.</description>
    </secondary_outcome>
    <number_of_arms>4</number_of_arms>
    <enrollment type="Anticipated">30</enrollment>
    <condition>Parkinson Disease</condition>
    <arm_group>
      <arm_group_label>eiDBS suppression</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Closed-loop evoked interference DBS that suppresses beta oscillations.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Off DBS</arm_group_label>
      <arm_group_type>No Intervention</arm_group_type>
      <description>Off-stimulation and off-medication</description>
    </arm_group>
    <arm_group>
      <arm_group_label>eiDBS amplification</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Closed-loop evoked interference DBS that amplifies beta oscillations.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Levodopa medication</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>On-medication, off-stimulation</description>
    </arm_group>
    <intervention>
      <intervention_type>Device</intervention_type>
      <intervention_name>Neurostimulation</intervention_name>
      <description>Electrical stimulation delivered via deep brain stimulation electrodes based on measurements of brain activity.</description>
      <arm_group_label>eiDBS amplification</arm_group_label>
      <arm_group_label>eiDBS suppression</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Carbidopa 25/Levodopa 100Mg Tab</intervention_name>
      <description>Anti-parkinsonian medication.</description>
      <arm_group_label>Levodopa medication</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Key Inclusion Criteria:&#xD;
  &#xD;
            -  Ability to provide informed consent.&#xD;
  &#xD;
            -  Clinical diagnosis of idiopathic Parkinson's disease.&#xD;
  &#xD;
            -  Determined, as per standard of care, to be a candidate for deep brain stimulation&#xD;
               (DBS) surgery targeting either the subthalamic nucleus or the internal segment of the&#xD;
               globus pallidus.&#xD;
  &#xD;
            -  Ability to tolerate delays in taking daily standard Parkinson's disease medications.&#xD;
  &#xD;
          Key Exclusion Criteria:&#xD;
  &#xD;
          - Secondary Parkinsonism, stroke, or progressive central nervous system disease other than&#xD;
          Parkinson's disease.&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>40 Years</minimum_age>
      <maximum_age>80 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_contact>
      <last_name>David Escobar, PhD</last_name>
      <phone>216-390-1907</phone>
      <email>escobad2@ccf.org</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Jeffrey Negrey, MA</last_name>
      <phone>216-316-6896</phone>
      <email>negreyj2@ccf.org</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Cleveland Clinic</name>
        <address>
          <city>Cleveland</city>
          <state>Ohio</state>
          <zip>44195</zip>
          <country>United States</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>David Escobar, PhD</last_name>
        <phone>216-390-1907</phone>
        <email>escobad2@ccf.org</email>
      </contact>
      <contact_backup>
        <last_name>Jeffrey Negrey, MA</last_name>
        <phone>216-316-6896</phone>
        <email>negreyj2@ccf.org</email>
      </contact_backup>
    </location>
    <location_countries>
      <country>United States</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>August 22, 2023</study_first_submitted>
    <study_first_submitted_qc>August 25, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 28, 2023</study_first_posted>
    <last_update_submitted>August 25, 2023</last_update_submitted>
    <last_update_submitted_qc>August 25, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 28, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor-Investigator</responsible_party_type>
      <investigator_affiliation>The Cleveland Clinic</investigator_affiliation>
      <investigator_full_name>David Escobar</investigator_full_name>
      <investigator_title>Assistant Staff</investigator_title>
    </responsible_party>
    <keyword>Deep Brain Stimulation</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Parkinson Disease</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Levodopa</mesh_term>
      <mesh_term>Carbidopa</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>Yes</sharing_ipd>
      <ipd_description>Individual participant data that underlie the results reported in the published articles (text, tables, figures, and appendices), after deidentification, will be shared.</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>Data will be shared immediately following publication. There is no end date for this data sharing.</ipd_time_frame>
      <ipd_access_criteria>Data sharing requests should be directed to escobad2@ccf.org. To gain access, data requestors may need to sign a data access agreement.</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/NCT06013956
  org study id: 23-358
  nct id: NCT06013956
  lead sponsor: 
  collaborator: 
  has dmc: No
  is fda regulated drug: Yes
  is fda regulated device: Yes
  is unapproved device: Yes
  is us export: No
  A prospective cohort of patients scheduled to undergo deep brain stimulation (DBS)
        implantation surgery for the treatment of Parkinson's disease as per standard of care will be
        invited to participate in this study. This mechanistic study is aimed at better understanding
        the role of basal ganglia beta band (11-35 Hz) oscillations and resonance in the
        manifestation of Parkinson's disease (PD) motor signs using closed-loop electrical
        neurostimulation, levodopa medication, and computational modeling. The ultimate goal of this
        study is to inform the development of closed-loop neuromodulation technology that can be
        programmed and adjusted in real time based on patient-specific neural activity.
  While much research has been dedicated to understanding the pathophysiology of Parkinson's
        disease (PD), the neural dynamics underlying the manifestation of motor signs remain unclear.
        Studies over the past two decades have shown a correlation of the amplitude and incidence of
        beta band oscillations in the subthalamic nucleus (STN) and internal segment of the globus
        pallidus (GPi) with changes in bradykinesia and rigidity mediated by levodopa or deep brain
        stimulation (DBS) therapies. Yet, no study has conclusively or deductively demonstrated a
        causal link. A limitation to establishing causality is the lack of available neuromodulation
        tools capable of predictably and precisely controlling neural oscillatory activity in the
        human brain in real time without introducing confounding factors. Establishing these tools
        and clarifying whether the relationship of beta band oscillations with PD motor signs is
        causal or epiphenomenon are critical steps to better understand PD pathophysiology and
        advance personalized DBS technology in PD and other brain conditions. This study aims to
        address these technology and knowledge gaps by leveraging feedback control engineering and
        patient-specific computational modeling tools.
  
        In this study, the investigators will employ a neural control approach, referred to as evoked
        interference closed-loop DBS (eiDBS), to characterize the degree by which controlled
        suppression or amplification of beta oscillations in the STN and GPi influences bradykinesia
        and rigidity in PD (Specific Aim 1, SA1). The investigators will test the hypothesis that
        stimulation-induced suppression or amplification of beta oscillations in the STN or GPi will
        result in changes in bradykinesia and rigidity measures. In SA2, the investigators will
        employ levodopa medication to characterize how changes in bradykinesia and rigidity relate to
        variations in the amplitude of neural oscillations in the STN, GPi, and primary motor cortex
        (MC) evoked by STN and GPi stimulation. The investigators will test the hypothesis that
        levodopa administration will result in a decrease in the amplitude of stimulation-evoked beta
        oscillations that will correlate with changes in bradykinesia and rigidity. The results from
        SA2 will help to gain a greater understanding of intrinsic circuit dynamics associated with
        PD and identify strategies to optimize closed-loop DBS algorithms (e.g., eiDBS) in the face
        of concurrent levodopa therapy, a step to bring this technology to future clinical trials.
        Combining electrophysiological data with high-resolution (7T) magnetic resonance (MR) imaging
        and computational modeling, the investigators will examine which specific neuronal pathways
        connected with the STN and GPi need to be activated to evoke frequency-specific neural
        responses in the STN, GPi, and MC (SA3). The data from SA3 will shed light on which
        sub-circuits are involved in the generation of stimulation-evoked and spontaneous beta
        oscillations in PD, and inform how to use directional DBS leads to shape electric fields in
        the STN and GPi to selectively modulate the STN or GPi via eiDBS or other neurostimulation
        techniques. The investigators will address the three aims of this study with the
        participation of PD patients implanted with DBS leads in the STN or GPi, whose DBS lead
        extensions will be externalized and connected to our recording and closed-loop stimulation
        infrastructure.
  allocation: Randomized
  intervention model: Crossover Assignment
  intervention model description: Each participant is assigned to four different conditions. Kinematic, behavioral, and neurophysiological variables are compared across the conditions.
  primary purpose: Basic Science
  masking: Triple (Participant, Care Provider, Outcomes Assessor)
  masking description: The sequence order for the conditions will be randomized for each study participant.
  measure: Effect of eiDBS suppression vs. off-stimulation on finger tapping speed
  time frame: Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.
  description: The finger tapping speed will be measured with an inertial measuring unit. The relationship (slope/effect) between this kinematic variable (response variable) and the mean amplitude of beta (11-35 Hz) oscillations (predictor physiological variable) will be estimated via linear mixed-effects (LME) models. The LME models will include the stimulation conditions in this study (e.g., eiDBS-suppression) as fixed effects with the off-stimulation condition as a reference/control group, and random intercepts as random effects that account for the heterogeneity between subjects.
  measure: Effect of eiDBS amplification vs. off-stimulation on finger tapping speed
  time frame: Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.
  description: The relationship (slope/effect) between the kinematic variable (response variable) and the mean amplitude of beta (11-35 Hz) oscillations (predictor physiological variable) will be estimated via linear mixed-effects (LME) models.
  measure: Effect of eiDBS suppression vs. off-stimulation on forearm speed
  time frame: Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.
  description: The forearm speed will be measured with an inertial measuring unit. The relationship (slope/effect) between this kinematic variable (response variable) and the mean amplitude of beta (11-35 Hz) oscillations (predictor physiological variable) will be estimated via linear mixed-effects (LME) models.
  measure: Effect of eiDBS amplification vs. off-stimulation on forearm speed
  time frame: Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.
  description: The relationship (slope/effect) between the kinematic variable (response variable) and the mean amplitude of beta (11-35 Hz) oscillations (predictor physiological variable) will be estimated via linear mixed-effects (LME) models.
  measure: Effect of eiDBS suppression vs. off-stimulation on UPDRS-III rigidity subscore
  time frame: Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.
  description: The relationship (slope/effect) between this UPDRS-III rigidity subscore (response variable) and the mean amplitude of beta (11-35 Hz) oscillations (predictor physiological variable) will be estimated via linear mixed-effects (LME) models.
  measure: Effect of eiDBS amplification vs. off-stimulation on UPDRS-III rigidity subscore
  time frame: Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.
  description: The relationship (slope/effect) between this UPDRS-III rigidity subscore (response variable) and the mean amplitude of beta (11-35 Hz) oscillations (predictor physiological variable) will be estimated via linear mixed-effects (LME) models.
  measure: Correlation between levodopa-related changes in finger tapping speed and the amplitude of stimulation-evoked beta oscillations
  time frame: Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.
  description: The amplitude of beta oscillations evoked by stimulation will be characterized using the wavelet transform. The relationship (slope) between the kinematic measurements (response variable) and the beta oscillations amplitude (predictor variable) will be estimated via the linear mixed-effects models.
  measure: Correlation between levodopa-related changes in forearm speed and the amplitude of stimulation-evoked beta oscillations
  time frame: Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.
  description: The relationship (slope) between the kinematic measurements (response variable) and the beta oscillations amplitude (predictor variable) will be estimated via the linear mixed-effects models.
  measure: Correlation between levodopa-related changes in UPDRS-III rigidity subscore and the amplitude of stimulation-evoked beta oscillations.
  time frame: Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.
  description: The relationship (slope) between the UPDRS-III subscores (response variable) and the beta oscillations amplitude (predictor variable) will be estimated via the linear mixed-effects models.
  measure: Effect of eiDBS suppression vs. off-stimulation on finger tapping displacement
  time frame: Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.
  description: The finger tapping displacement will be derived based on data from an inertial measuring unit via a Kalman filter. The relationship (slope/effect) between this kinematic variable (response variable) and the mean amplitude of beta (11-35 Hz) oscillations (predictor physiological variable) will be estimated via linear mixed-effects (LME) models.
  measure: Effect of eiDBS amplification vs. off-stimulation on finger tapping displacement
  time frame: Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.
  description: The relationship (slope/effect) between the kinematic variable (response variable) and the mean amplitude of beta (11-35 Hz) oscillations (predictor physiological variable) will be estimated via linear mixed-effects (LME) models.
  measure: Effect of eiDBS suppression vs. off-stimulation on forearm displacement
  time frame: Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.
  description: The relationship (slope/effect) between the kinematic variable (response variable) and the mean amplitude of beta (11-35 Hz) oscillations (predictor physiological variable) will be estimated via linear mixed-effects (LME) models.
  measure: Effect of eiDBS amplification vs. off-stimulation on forearm displacement
  time frame: Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.
  description: The relationship (slope/effect) between the kinematic variable (response variable) and the mean amplitude of beta (11-35 Hz) oscillations (predictor physiological variable) will be estimated via linear mixed-effects (LME) models.
  measure: Effect of eiDBS suppression vs. off-stimulation on UPDRS-III bradykinesia subscore
  time frame: Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.
  description: The relationship (slope/effect) between this UPDRS-III subscore (response variable) and the mean amplitude of beta (11-35 Hz) oscillations (predictor physiological variable) will be estimated via linear mixed-effects (LME) models.
  measure: Effect of eiDBS amplification vs. off-stimulation on UPDRS-III bradykinesia subscore
  time frame: Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.
  description: The relationship (slope/effect) between this UPDRS-III subscore (response variable) and the mean amplitude of beta (11-35 Hz) oscillations (predictor physiological variable) will be estimated via linear mixed-effects (LME) models.
  measure: Correlation between levodopa-related changes in finger tapping displacement and the amplitude of stimulation-evoked beta oscillations
  time frame: Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.
  description: The relationship (slope) between the kinematic measurements (response variable) and the beta oscillations amplitude (predictor variable) will be estimated via the linear mixed-effects models.
  measure: Correlation between levodopa-related changes in forearm displacement and the amplitude of stimulation-evoked beta oscillations
  time frame: Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.
  description: The relationship (slope) between the kinematic measurements (response variable) and the beta oscillations amplitude (predictor variable) will be estimated via the linear mixed-effects models.
  measure: Correlation between levodopa-related changes in UPDRS-III bradykinesia subscore and the amplitude of stimulation-evoked beta oscillations
  time frame: Data will be collected in assessment blocks multiple times throughout enrollment. Assessments will be performed for up to nine days, starting the day after the DBS surgery. Assessments may also be performed in one visit 3-12 months after DBS surgery.
  description: The relationship (slope) between the UPDRS-III subscores (response variable) and the beta oscillations amplitude (predictor variable) will be estimated via the linear mixed-effects models.
  arm group label: eiDBS suppression
  arm group type: Experimental
  description: Closed-loop evoked interference DBS that suppresses beta oscillations.
  arm group label: Off DBS
  arm group type: No Intervention
  description: Off-stimulation and off-medication
  arm group label: eiDBS amplification
  arm group type: Experimental
  description: Closed-loop evoked interference DBS that amplifies beta oscillations.
  arm group label: Levodopa medication
  arm group type: Experimental
  description: On-medication, off-stimulation
  intervention type: Device
  intervention name: Neurostimulation
  description: Electrical stimulation delivered via deep brain stimulation electrodes based on measurements of brain activity.
  arm group label: eiDBS amplification
  arm group label: eiDBS suppression
  intervention type: Drug
  intervention name: Carbidopa 25/Levodopa 100Mg Tab
  description: Anti-parkinsonian medication.
  arm group label: Levodopa medication
  criteria: 
  gender: All
  minimum age: 40 Years
  maximum age: 80 Years
  healthy volunteers: No
  last name: David Escobar, PhD
  phone: 216-390-1907
  email: escobad2@ccf.org
  last name: Jeffrey Negrey, MA
  phone: 216-316-6896
  email: negreyj2@ccf.org
  facility: 
  status: Recruiting
  contact: 
  contact backup: 
  country: United States
  responsible party type: Sponsor-Investigator
  investigator affiliation: The Cleveland Clinic
  investigator full name: David Escobar
  investigator title: Assistant Staff
  mesh term: Parkinson Disease
  mesh term: Levodopa
  mesh term: Carbidopa
  sharing ipd: Yes
  ipd description: Individual participant data that underlie the results reported in the published articles (text, tables, figures, and appendices), after deidentification, will be shared.
  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: Data will be shared immediately following publication. There is no end date for this data sharing.
  ipd access criteria: Data sharing requests should be directed to escobad2@ccf.org. To gain access, data requestors may need to sign a data access agreement.