Anatomical and Functional Imaging Correlates of Chronic Pain in Cerebral Palsy

• ClinicalTrials.gov Identifier: NCT05197946
• Recruitment Status: Recruiting
• First Posted: January 20, 2022
• Last Update Posted: August 17, 2022
• Sponsor: Hugo W. Moser Research Institute at Kennedy Krieger, Inc.
• Collaborators: Johns Hopkins University; Mount Washington Pediatric Hospital; Neurosurgery Pain Research Institute; Cerebral Palsy Alliance
• Information provided by (Responsible Party): Hugo W. Moser Research Institute at Kennedy Krieger, Inc.

Study Description

Brief Summary:

The investigators hope to use MRI biomarkers to identify and characterize sensorimotor network disruption patterns associated with chronic pain and sensory deficits in CP. Investigators will use existing information in the medical record as well as subjective reports from interview, physical exam data, and anatomical and functional MRI data to non-invasively identify brain and spine injury correlates of pain and sensory deficits.

Condition or disease	Intervention/treatment
Cerebral Palsy; Chronic Pain	Diagnostic Test: MRI

Detailed Description:

Chronic pain is reported in 2/3 of adults with cerebral palsy (CP) 1. Physicians have historically attributed pain to orthopedic complications, tone abnormalities, and systemic complications 2, which would be expected to be nociceptive. However, over 40% of hemiplegic CP respondents with pain report neuropathic pain characteristics 3. Alterations in brain somatosensory pathways have been found both structurally and functionally. Sensory thalamocortical white matter tracts appear to be affected in children with CP born preterm 4. Cortical somatosensory representation also appears to be altered 5. Decreased mechanical pain sensitivity 6 and higher-level cortical sensory deficits 7 have been described in CP. Contributions of sensory deficits and alterations in cortical processing to chronic pain symptoms frequently reported in CP are not well-understood. The investigators hypothesize that neuropathic pain amplification in CP as well as motor and other sensory deficits are symptoms of the same widespread sensorimotor network disruption extending beyond periventricular white matter. This hypothesis predicts that individuals with more severe motor deficits have more features of neuropathic pain as well as more abnormal anatomic connectivity in somatosensory networks. The investigators anticipate data that will increase understanding of chronic pain in CP by identifying presence of a component of neuropathic pain. Better understanding could affect management of pain in patients with CP.

Objectives:

Primary: Identify and characterize sensorimotor network disruption patterns associated with chronic pain and motor deficits in CP

Secondary:

• Improve understanding of anatomical brain network changes in CP associated with sensory deficits and pain
• Identify non-invasive imaging-based neurobiomarkers applicable to sensory loss and pain in CP

Paper documents indicating consent will be kept in a locked compartment in a locked room, and only investigators will have access. Following consent, subjects will be assigned a pseudorandom numeric identifier (see separate identifier number table); the table of research identifier/personally-identifying subject correspondences will be kept in a single file on the secure KKI server system.

Review of medical records: Following consent, medical records will be reviewed and extracted by provider-level research associates (for subjects with CP only). Data extracted from the medical record, the structured interview, and the structured physical exam will be entered by provider-level research associates into a database indexed by the research identifier number via a secure data entry system (REDCap, Nashville, TN) recording data directly into secure JH servers. Extant brain and spine imaging will be stored as de-identified DICOM files on secure KKI servers. Items for the REDCap form (see separate sample data sheet for information extracted from the medical record, from the structured interview, and from the structured physical examination) are primarily based on the CP Research Network (CPRN) database entries but are expanded using validated instruments to NIH-NINDS recommended common data elements (CDE) for CP. Instruments include quality of life scales (AQoL-8D) and the NIH-developed PROMIS pain scales. The collected information is designed to be cross-compliant with both NIH and CPRN standards while adequately addressing the question at hand and minimizing burden to subjects.

Structured Interview and Physical Examination (discontinued post-COVID restrictions): Information not attainable from the medical record (e.g. subjective measures regarding pain, quality of life, and sociopsychological functioning) will be obtained via a structured interview between a provider-level research associate and the subject +/- caretaker. The subject +/- caretaker will communicate responses, which will be recorded into RedCAP in real-time by the research associate. The degree of reliance on individual interview responses vs. pre-filled questionnaire will be determined by degree of communicative ability (example breakdown in table below). A non-invasive physical examination will then document and quantify motor abnormalities (e.g. grading of spasticity and dystonia) as well as other contributing abnormalities (e.g. balance abnormalities or orthopedic deformities), which will similarly be recorded into REDCap in real-time by the research associate. In the process of optimizing the structured interview, investigators may reformat items and add or remove interview instruments but will maintain overall interview/exam length less than 2 hours. If a subject desires, the study visit can be halted at any time and either continued at a later date or not.

Analysis of existing neuroimaging: Previously-acquired traditional MRI obtained for clinical purposes will be requested and reviewed to detect correlation between routine neuroimaging markers of perinatal brain injury and CP and pain. If of suitable quality, quantitative analysis methods (e.g. analysis of brain lobe and ventricular volumes for volumetric anatomical sequences, analysis of white matter volumes from DTI sequences) may be applied to prior images.

MR Scanning Methods: Research unsedated MRI scans (outside of usual care) will be performed using a 3T Philips scanner at the F.M. Kirby Research Center. An MRI scanning protocol will be at the F.M. Kirby Research Center; the protocol will not last more than 1.5 hours. Acquisitions will include a triplanar survey, functional and anatomical multi-slice imaging of the brain as well as MRI of selected spinal levels. Protocols will be used that do not involve use of contrast agents and limit power/tissue absorption as well as otherwise remain within FDA and Kirby Center safety regulations. When possible, MRI will be performed within 3 months of initial survey/interview administration. If MRI is scheduled >3 months after initial survey/interview administration, a brief survey will be re-administered to screen for changes in pain/clinical status.

The imaging protocol will require no more than 1.5 hours of scan time per participant; participants will be selected who can complete scanning in one session. A control group of typical subjects without CP with groupwise similar ages and genders will be included to demonstrate typical norms.

An ANOVA will be used to compare MRI-based parameters (e.g. volumes and diffusion MRI scalars) between the three groups. Tracts of interest and specific diffusion MRI scalars will be selected a priori to minimize multiple comparisons confounds. Based on effect size seen in the PLIC tract in a prior study using DTI including 24 subjects with CP16, a power analysis suggests that a sample size of 7 per group allows a power of 0.8 while maintaining α of 0.05. As higher-order diffusion sequences gather strictly more information than DTI techniques, the investigators expect them to be even more sensitive.

The proposed research presents no more than minimal physical, psychological, legal, or financial risk to participants. Magnetic resonance imaging is a minimal risk procedure when able to be done without sedation, as planned based on the age range for this study. Subjects that are susceptible to injury from high-power magnetic fields (e.g. presence of metallic objects (such as pacemakers) implanted in body) will be identified using the Johns Hopkins Radiographic Sciences Department screening form prior to imaging. Study team members who will be in the control room or scanning room of the MRI suite are required to undergo MRI safety training provided by the Radiographic Sciences Department. Risks during the scan may include anxiety from loud noises or the enclosed space of the scanner. Breach of confidentiality and incidental findings on MRI is also a potential risk. The investigators do not anticipate any risks to study personnel, as only subjects who are trained in MRI safety will be allowed access to the MRI scanner.

The magnet in the scanner can cause electronic devices like pacemakers, beepers, and watches to malfunction, and some metal objects can be pulled into the magnet. If a subject has an electronic device (like a pacemaker) implanted in body there is a risk that the metal may move or be dislodged. To minimize this risk, the investigators will ask subjects/parents a series of questions before the scan to make sure the subject does not have any metal on or in the participant's body and will ask the participant to take off any metal objects the participant may be wearing (such as a watch or jewelry). No sedation is used. Scanning sessions will be terminated immediately upon the request of the participant, or if the participant becomes upset by the noise, claustrophobia, anxiety or poor performance during testing. Participants with implanted electrical devices or ferromagnetic foreign bodies in critical soft tissues will be excluded from this study.

Also, the investigators may discover an abnormality on the MR exam that investigators are not expecting. Some findings may require additional tests to find out what they are. Any unexpected results will be shared with the participant. The participant will also be told any new facts that could affect whether the participant wants to stay in the study. All assessment information will be considered confidential. No participant will be identified by name in any presentation of the results. Identification numbers will code data entered for computer analysis, and the data coordinator will keep all names and code numbers. Findings will be made available to legitimate agents of the participants (physicians) only with the express, written consent of the subject. Unanticipated problems or study deviations will be reported to the Johns Hopkins IRB within 48 hours of occurrence. Strict maintenance of confidentiality of subject data and identifying information will be utilized to minimize legal risks. Any physical data will be kept in a locked office in a locked cabinet to which only key study members have the key. Electronic data will be kept on a secure, password-protected server with access limited to key research team members; image processing will occur on a dedicated, password-protected computer in a locked office with access limited to key research team members. Study documents and files outside of the linking document will be deidentified and marked with a study identifier only.

Study Design

• Study Type: Observational
• Estimated Enrollment: 300 participants
• Observational Model: Case-Control
• Time Perspective: Prospective
• Official Title: Anatomical and Functional Imaging Correlates of Chronic Pain in Cerebral Palsy
• Actual Study Start Date: December 4, 2018
• Estimated Primary Completion Date: June 2023
• Estimated Study Completion Date: September 5, 2023

Groups and Cohorts

Group/Cohort	Intervention/treatment
Subjects with CP survey; Subjects in this group are age 8 and older with a diagnosis of cerebral palsy. Participants are either able to affirmatively consent or assent with LAR consent. This sample will have a CFCS score ranging between 1 and 3 and should be able to unambiguously respond to a 65 item multiple choice survey.
Control Subjects survey; Subjects in this group are age 8 and older with no clinically significant neurologic or developmental diagnosis. Participants are either able to affirmatively consent or assent with LAR consent.
Subjects with CP MRI; Subjects are 8 years or older with a diagnosis of cerebral palsy and clinical imaging demonstrating isolated periventricular white matter injury. Clinical assessment states that neurologic symptoms are attributed to this isolated injury. Subjects in this group must be able to lie still in a scanner for 1.5 hours in at most 2 sessions and be able to have an MRI. Participants must be able to affirmatively consent or assent with LAR consent.	Diagnostic Test: MRI; Research unsedated MRI scans (outside of usual care) will be performed using a 3T Philips scanner at the F.M. Kirby Research Center. An MRI scanning protocol will be at the F.M. Kirby Research Center; the protocol will not last more than 1.5 hours. Acquisitions will include a triplanar survey, functional and anatomical multi-slice imaging of the brain as well as MRI of selected spinal levels. Protocols will be used that do not involve use of contrast agents and limit power/tissue absorption as well as otherwise remain within FDA and Kirby Center safety regulations. When possible, MRI will be performed within 3 months of initial survey/interview administration. If MRI is scheduled >3 months after initial survey/interview administration, a brief survey will be re-administered to screen for changes in pain/clinical status.
Control Subjects MRI; Subjects in this group are age 8 and older with no clinically significant neurologic or developmental diagnosis. Participants are able to affirmatively consent and are able to have an MRI. Subjects also should be able to lie still in a scanner for 1.5 hours.	Diagnostic Test: MRI; Research unsedated MRI scans (outside of usual care) will be performed using a 3T Philips scanner at the F.M. Kirby Research Center. An MRI scanning protocol will be at the F.M. Kirby Research Center; the protocol will not last more than 1.5 hours. Acquisitions will include a triplanar survey, functional and anatomical multi-slice imaging of the brain as well as MRI of selected spinal levels. Protocols will be used that do not involve use of contrast agents and limit power/tissue absorption as well as otherwise remain within FDA and Kirby Center safety regulations. When possible, MRI will be performed within 3 months of initial survey/interview administration. If MRI is scheduled >3 months after initial survey/interview administration, a brief survey will be re-administered to screen for changes in pain/clinical status.

Outcome Measures

Primary Outcome Measures :

1. Brain volume [ Time Frame: <3 months ]
   Brain volume will be measured using MR processing software (likely unit used will be milliliters).
2. Spine volume [ Time Frame: <3 months ]
   Spine volume will be measured using MR processing software (likely unit used will be milliliters).
3. Diffusion scalars [ Time Frame: <3 months ]
   Diffusion scalars for tracts of interest including the posterior thalamic radiations as well as somatosensory association fibers and the spinal spinothalamic tract will be captured.

Eligibility Criteria

• Ages Eligible for Study: 8 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes
• Sampling Method: Non-Probability Sample

Study Population

Children and adults with cerebral palsy and typically-developing adults and children

Criteria

Subjects with CP (Caregiver questionnaire only):

Inclusion Criteria:

• Individual 8+ years of age
• Diagnosis of cerebral palsy

Exclusion Criteria:

-None

Subjects with CP: Core Study (Survey):

Inclusion Criteria:

• Individual 8+ years of age
• Adult subject able to indicate understanding and affirmative consent OR Adult/child subject unable to indicate understanding and affirmative consent AND subject assents AND LAR consents
• Diagnosis of cerebral palsy
• CFCS I-III and able to respond unambiguously to at least 65 multiple-choice items

Exclusion Criteria:

-None

Control subjects: Core Study (Survey):

Inclusion Criteria:

• Individual 8+ years of age
• Adult subject able to indicate understanding and affirmative consent OR Adult/child subject unable to indicate understanding and affirmative consent AND subject assents AND LAR consents

Exclusion Criteria:

-Clinically-significant neurologic or developmental diagnosis

Subjects with CP undergoing MRI:

Inclusion Criteria:

• Individual 8+ years of age
• Adult subject able to indicate understanding and affirmative consent OR Adult subject unable to indicate understanding and affirmative consent AND subject assents AND LAR consents
• Diagnosis of cerebral palsy
• Clinical imaging demonstrating isolated periventricular white matter injury
• Clinical judgment that all neurologic symptoms are attributable to non-progressive periventricular white matter injury
• Able to lie still in scanner for 1.5 hours in at most 2 sessions and be able to have MRI

Exclusion Criteria:

-None

Control subjects undergoing MRI:

Inclusion Criteria:

• Individual 8+ years of age
• Adult subject able to indicate understanding and affirmative consent
• Able to lie still in scanner for 1.5 hours and be able to have MRI

Exclusion Criteria:

-Clinically-significant neurologic or developmental diagnosis

Contacts and Locations

Contacts

Contact: Colleen Lenz, MS; (443) 923-2706; CPpainStudy@kennedykrieger.org

Contact: Nicole Gorny, MS; (443) 923-9272; CPpainStudy@kennedykrieger.org

Locations

United States, Maryland

Mt. Washington Pediatric Hospital; Recruiting

Baltimore, Maryland, United States, 21209

Contact: Stephen Nichols, MD 410-578-8600 snichols@mwph.org

F.M. Kirby Center; Recruiting

Baltimore, Maryland, United States, 21287

Contact: Alexander Hoon, MD, MPH 443-923-9147 hoon@kennedykrieger.org

Johns Hopkins Hospital; Recruiting

Baltimore, Maryland, United States, 21287

Contact: Shenandoah Robinson, MD 667-208-9378 srobin81@jhmi.edu

Kennedy Krieger Institute; Recruiting

Baltimore, Maryland, United States, 21287

Contact: Alexander Hoon, MD, MPH 443-923-9147 hoon@kennedykrieger.org

Sponsors and Collaborators

Hugo W. Moser Research Institute at Kennedy Krieger, Inc.

Johns Hopkins University

Mount Washington Pediatric Hospital

Neurosurgery Pain Research Institute

Cerebral Palsy Alliance

Investigators

• Principal Investigator: Eric Chin, MD; Hugo W. Moser Research Institute at Kennedy Krieger, Inc.

  Study Documents (Full-Text)

Documents provided by Hugo W. Moser Research Institute at Kennedy Krieger, Inc.:

Study Protocol and Statistical Analysis Plan  [PDF] August 23, 2021

Informed Consent Form  [PDF] August 30, 2021

More Information

• Responsible Party: Hugo W. Moser Research Institute at Kennedy Krieger, Inc.
• ClinicalTrials.gov Identifier: NCT05197946
• Other Study ID Numbers: IRB00181801
• First Posted: January 20, 2022
• Last Update Posted: August 17, 2022
• Last Verified: August 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Cerebral Palsy; Chronic Pain; Pain; Neurologic Manifestations; Nervous System Diseases; Brain Damage, Chronic; Brain Diseases; Central Nervous System Diseases