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Human Networks for Behaviors Related to the Expectation of Pain.

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ClinicalTrials.gov Identifier: NCT03739645
Recruitment Status : Not yet recruiting
First Posted : November 14, 2018
Last Update Posted : April 6, 2020
Sponsor:
Collaborators:
Ohio State University
University of Maryland, College Park
University of North Carolina
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
Johns Hopkins University

Brief Summary:
The conditioned expectation of pain is an important aspect of pain-related disability produced by environments and stimuli associated with a painful injury on the job, although the neuroscience of this expectation is unclear. The mechanisms of expectation of pain will be studied by recording electrical signals through electrodes implanted at sites in the brain during the surgical treatment of epilepsy. These sites will be identified by electrical activity novel connectivity based Diffusion Tensor Imaging (DTI) MRI techniques. The results of this study may lead to testable hypotheses regarding the neural basis of the fear of pain and its treatment by anatomically based surgical or stimulation therapies.

Condition or disease Intervention/treatment Phase
Fear Pain Behavioral: conditioned fear Not Applicable

Detailed Description:

The conditioned expectation or fear of pain often results in disability produced by stimuli related to a painful injury on the job, although the neuroscience of this expectation is unclear. Conditioned expectation in humans can be produced by a protocol that consists of a train of two visual conditioning stimuli, one of which is paired (CS+) with a painful laser pulse unconditioned stimulus (US), while the other is not. This protocol will be used to study the expectation of pain in this study. The results of this study may lead to testable hypotheses regarding the neural basis of the fear of pain and its treatment by anatomically based surgical or stimulation therapies.

The long-term research goal of this study is to determine the networks related to the Expectation of pain. A neural network consists of neural elements, their connections, and connectional weights which are often equated with components in the brain, axons, and synapses, respectively. Functional connectivity within such a network can be conceived of as the network properties that enable its components jointly to process inputs or outputs, or both.

The expectation of pain will be studied by recording local field potentials (LFP) directly from parts of the brain involved in that expectation. These recordings are carried out by exploiting the opportunity afforded by implantation of electrodes in and on the brain for the treatment of epilepsy, a platform with unrivaled clarity and resolution. Parts of the brain related to the expectation of pain will be characterized by activation and interactions. Activations are measured by the proportion of electrodes in a part of the brain with a significant ratio of electrical power following an event over baseline (event related spectral perturbation, ERSP).

Interactions will be measured by causal interactions following an event over baseline. The approach of this protocol is that causal interactions are based upon causal influences by an approach based upon the concept of linear predictability. Briefly, a signal Y is said to exert grc upon signal X when the predication error of the X is reduced by adding the past information of Y (causal interaction). The signals from any two components will be analyzed by ERC for causal interactions to determine the magnitude and direction of causal interactions between the two to determine pain related directed interactions related to aversive conditioning. The ERC (event related causality) is the ratio of interactions following event over interactions in a baseline period.

Investigators' Preliminary Data shows LFP activations in model networks for the expectation of pain are consistent with the evidence of studies of anatomic projections and Functional MRI (fMRI) signals. These models include nuclei of the Amygdala, Anterior and Mid-Cingulate, as well as the Hippocampal formation, Insula, and Lateral Prefrontal Cortex. The premise of this study is that components in models for expectation will be involved in both pain and conditioning processes, and show the activations and interactions of parts of the brain that define distributed networks for the expectation of pain.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: A similar analysis will be carried out for experience to identify components with greater proportions for conditioned vs nociceptive stages. Correlation of those proportions with CS+ SCR, pain ratings and pain sensitivity will be taken as confirmatory evidence for components involved in the experience Network. Power analysis for a two-way ANOVA was conducted to determine a sufficient sample size using an alpha of 0.05, power 0.80, a high effect size (pilot data indicate η2 values for main effects > 0.5). Based on these assumptions, we conservatively use a sample size of 40.
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Human Networks for Behaviors Related to the Expectation of Pain.
Estimated Study Start Date : February 1, 2021
Estimated Primary Completion Date : June 2028
Estimated Study Completion Date : June 2029

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Epilepsy

Arm Intervention/treatment
Experimental: 1 group. patients with intracranial electrodes for epilepsy.
Exploratory study with 1 intervention.which is painful (laser) stimulation conditioned fear with patient as his/her own control. EEG activity will be recorded from the brain during this behavioral state, an opportunity afforded by implantation of electrodes in the brain for treatment of epilepsy. Electrical activation of parts of the brain will be measured by event related spectral perturbations (ERSP).
Behavioral: conditioned fear
Subjects will be involved in a protocol producing fear conditioning protocol with colored lights as conditioned stimuli and laser pulses (duration 1`ms visual analog scale of pain 5/10) as the US and rating scales and questionnaires are administered. Networks will be defined parts of the brain which are activated (ERSP) and interact with each other as measured by event related causality (ERC).




Primary Outcome Measures :
  1. Electrical brain activation related to pain. [ Time Frame: The whole duration of the study up to 5 years. ]
    The basic metric is electrical signals (in volts) in the brain which are analyzed in the spectral power domain to demonstrate activation in response to the painful laser. This measure of activation is the proportion of electrodes in a part of the brain that show activation based upon the ratio of spectral power following an the laser versus that for a baseline interval. This variable is measured in decibels, and is known as the event related spectral perturbation (ERSP). We will test statistically whether the proportion of electrodes in parts of the brain with significant ERSP is more than expected at random.

  2. Brain activation related to the cue. [ Time Frame: The whole duration of the study up to 5 years. ]
    This outcome is measured by the number of electrodes in parts of the brain with significant ERSP related to increases both in the autonomic activity of the skin (skin conductance response (SCR)) and in the subject's ratings of the likelihood that that the cue predicts the laser during the conditioning protocol. The presence of a relationship between ERSP and both SCR plus the laser cue association will lead to the conclusion that these parts of the brain are involved in the expectation of pain.

  3. Brain networks defined by interactions of parts of the brain [ Time Frame: The whole duration of the study up to 5 years. ]
    The metric from which outcome 3 is calculated is the interaction of the electrical signal for electrodes in one part of the brain upon the the signal for electrodes in another part of the brain. Specifically, this effect is measured by the ratio of the causal interactions following the event over the interactions for a baseline interval (event related causality (ERC, unitless)). The final measure for outcome 3 is the proportion of electrodes in a part of the brain with signals that have significant causal influences (ERC) upon the signals for other parts of the brain.

  4. Electrical brain activation related to conditioning. [ Time Frame: The whole duration of the study up to 5 years. ]
    The basic outcome metric is electrical signals (in volts) in the brain which are analyzed in the spectral power domain to demonstrate activation in response to the cue stimulus which is associated with the painful laser stimulus. After presentation of these two stimuli together the cue evokes responses like those produced by the laser i.e. the cue becomes conditioned. The final output measure of activation is the proportion of electrodes in a part of the brain that show activation based upon the ratio of power following an event versus that for a baseline interval. This variable is measured in decibels, and is known as event related spectral perturbation (ERSP). We will test statistically whether the proportion of electrodes in parts of the brain with significant ERSP is more than expected at random.


Secondary Outcome Measures :
  1. Parts of the brain outside the predicted models. [ Time Frame: The whole duration of the study up to 5 years ]
    This outcome will be identified by the proportion of electrodes in parts of the brain outside the predicted models with both activation (ERSP) and interactions with other parts of the brain (ERC). If there is significance for both these measures in a part of the brain then it may be added to the network for expectation of pain.



Information from the National Library of Medicine

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Ages Eligible for Study:   16 Years to 88 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Man or woman between 18 and 80 years of age.
  • Fluent speaker of English.
  • Undergoing seizure monitoring at Hopkins Hospital through intracranial electrodes.
  • Possess ability to understand study procedures and comply with them for the entire length of the study;
  • Women of childbearing age must use pharmacological contraception (oral or patch) for the duration of the study follow-up.

Exclusion Criteria:

  • Inability or unwillingness of individual to give written informed consent. Presence of any neurological disease other than epilepsy which is unstable or is not optimally treated.
  • Presence of a significant abnormality on routine neuropsychological testing.
  • Presence of any medical or psychiatric disease which is unstable or is not optimally treated.

Presence of an abnormal MRI scan except for Normal variants or Medial Temporal Sclerosis (altered pathology and MRI signal in temporal lobe).

  • Women who are pregnant or women of childbearing capacity who may become pregnant (i.e. not using contraception).
  • Presence of generalized seizures, or reflex seizures i.e. triggered by a sensory stimulus.
  • Presence of a language or hearing impairment.
  • Non-English speakers.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03739645


Contacts
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Contact: Fred A Lenz, MD PhD 4109606817 flenz1@jhmi.edu
Contact: Nathan E Crone, MD 410 955 6772 ncrone@jhmi.edu

Locations
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United States, Maryland
Hopkins Epilepsy Monitoring Unit, Zayhed 12.
Baltimore, Maryland, United States, 21287-7713
Sponsors and Collaborators
Johns Hopkins University
Ohio State University
University of Maryland, College Park
University of North Carolina
National Institute of Neurological Disorders and Stroke (NINDS)
Investigators
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Principal Investigator: Fred A Lenz, MD PhD Dept of Neurosurgery, Hopkins University.
Publications of Results:
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Responsible Party: Johns Hopkins University
ClinicalTrials.gov Identifier: NCT03739645    
Other Study ID Numbers: NA_00084856
2R56NS038493-16A1 ( U.S. NIH Grant/Contract )
First Posted: November 14, 2018    Key Record Dates
Last Update Posted: April 6, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: The PI and Co-PIs are working with the Johns Hopkins Pain Research Institute to set up a website for the Institute to include the labs carrying out pain research in the Department of neurosurgery. As a part of this effort we will include the Functional Neurosurgery Lab to share the following information in the public domain: 1. Our research focus. 2. Biosketches of the investigators 3. All publications as final manuscripts at the time of acceptance for publication, 4. Funded grant applications 5. Collaborators 6. Contact information.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: The website will be complete in 3 years.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Johns Hopkins University:
fear
pain
conditioning
skin conductance response
Ratings of Pain and Conditioning
Intracranial Electrophysiology