Ignite Creation Date:
2024-05-06 @ 8:28 PM
Last Modification Date:
2024-10-26 @ 3:28 PM
Study NCT ID:
NCT06396520
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-05-03
First Post:
2024-04-29
Brief Title:
Neuroimaging of Babies During Natural Sleep to Assess Typical Development and Cerebral Palsy
Sponsor:
Danish Research Centre for Magnetic Resonance
Organization:
Danish Research Centre for Magnetic Resonance
Study Overview
Official Title:
Neuroimaging of Babies During Natural Sleep to Assess Typical Development and Cerebral Palsy
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
NIBS-CP
Brief Summary:
Background Early diagnosis of cerebral palsy CP is crucial enabling intervention when neuroplasticity is at its highest Magnetic resonance imaging MRI plays a vital role in CP diagnosis Currently diagnostic MRI of newborns and infants with suspected brain damage relies heavily on structural MR images The current study aims to i establish procedures for clinical infant and toddler MRI during natural sleep ii use advanced MRI sequences such as advanced diffusion-weighted imaging DWI that may be more sensitive in detecting early brain damage and iii map relationships between early brain development and motor function and development
Methods The NIBS-CP study will enroll approximately 200 infants either at risk for CP or typically developing Infants will be followed longitudinally for three waves between 3 months and 2 years of age with cerebral MRI at 3 Tesla and comprehensive assessments of motor and cognitive functioning The MRI protocol includes advanced diffusion-weighted imaging high-resolution structural MRI and MR spectroscopy The motor and cognitive assessments include Hand Assessment in Infants Alberta Infant Motor Scales Hammersmith Infant Neurological Examination Peabody Developmental Motor Scales Bayley Scales of Infant Development and Ages and Stages Questionnaires NIBS-CP aims to establish normative material on early brain development of Danish children and conduct normative modeling of typical and atypical development to identify deviations in brain development at the level of the single child
Discussion Identifying predictive brain structural features of motor function and motor development is key to the future use of early MRI in the clinical work-up as this promotes early diagnosis and clinical intervention strategies tailored to the individual child
Methods The NIBS-CP study will enroll approximately 200 infants either at risk for CP or typically developing Infants will be followed longitudinally for three waves between 3 months and 2 years of age with cerebral MRI at 3 Tesla and comprehensive assessments of motor and cognitive functioning The MRI protocol includes advanced diffusion-weighted imaging high-resolution structural MRI and MR spectroscopy The motor and cognitive assessments include Hand Assessment in Infants Alberta Infant Motor Scales Hammersmith Infant Neurological Examination Peabody Developmental Motor Scales Bayley Scales of Infant Development and Ages and Stages Questionnaires NIBS-CP aims to establish normative material on early brain development of Danish children and conduct normative modeling of typical and atypical development to identify deviations in brain development at the level of the single child
Discussion Identifying predictive brain structural features of motor function and motor development is key to the future use of early MRI in the clinical work-up as this promotes early diagnosis and clinical intervention strategies tailored to the individual child
Detailed Description:
Diagnostic magnetic resonance imaging MRI of newborns and infants with suspected brain damage is today based on conventional structural MR images with the focus on identifying major structural brain pathology However advanced MRI sequences such as advanced diffusion-weighted imaging may be more sensitive to detecting brain damage The NeuroImaging of Babies during natural Sleep to assess typical development and CP NIBS-CP study is a longitudinal cohort study of infants and toddlers aged 3-24 months aimed at studying early brain development in infants at risk of cerebral palsy CP and typically developing infants using advanced MRI sequences The NIBS-CP cohort consists of
1 Infants at risk for CP recruited from the Cerebral Palsy Early Diagnosis and Intervention Trial CP-EDIT
The ongoing Danish CP-EDIT by principal investigator Professor Christina Høi-Hansen is registered with ClinicalTrialsgov ID NCT05835674 CP-EDIT will enroll 160 infants aged 3-11 months with CP or high risk of CP Infants will be followed longitudinally with a large battery of motor neurological and cognitive assessments during the first two years of life In addition CP-EDIT contains information from patient journals on diagnostic MRI but CP-EDIT does not include the collection of MRI scans as part of the study For infants enrolled in CP-EDIT participation in NIBS-CP only includes advanced MRI scans and parent-reported questionnaires All neurological motor and cognitive assessments will be undertaken in CP-EDIT
2 Typically developing infants recruited specifically for NIBS-CP For these infants participation in NIBS-CP includes advanced MRI scans neurological motor and cognitive assessments similar to the ones included in CP-EDIT and parent-reported questionnaires NIBS-CP provides a control cohort of typically developing infants that will give rise to a normative Danish sample of early brain development to the infants at high risk of CP as CP-EDIT does not include a control cohort of typically developing infants
AIMS
The NIBS-CP project aims to
1 Establish procedures for infant and toddler MRI during natural sleep without the use of sedation or GA at Hvidovre Hospital
2 Employ advanced MRI sequences for scanning infants and toddlers eg advanced diffusion-weighted imaging high-resolution structural MRI and MR spectroscopy which are likely to be more sensitive in detecting brain injury and damage than conventional diagnostic MRI
3 Initiate a cohort of typically developing infants and toddlers and perform longitudinal advanced MRI of infants at high risk for CP The NIBS-CP cohort will be used to
Establish a dataset of normative material of early brain development of Danish children
Conduct normative modeling of typical and atypical early brain development ie analogous to growth charts to inform about differences in brain development at the level of a single child
Map relationships between early brain development and motor function and development Identifying predictive features of brain structure with MRI is key to the future use of early MRI in the clinical work-up as these features may enable a better prediction of the prospects of motor function and motor development of the child
HYPOTHESES
The primary hypotheses are that
Infants with CP will show reduced hand functioning which relates to decreased myelination and microstructural integrity primarily in the corticospinal tract
Infants with unilateral brain injuries will display asymmetrical hand functioning which will be linked to asymmetrical corticospinal tract microstructure and myelination
The secondary hypotheses are that
Reduced hand functioning and hand functioning asymmetry will also be related to
decreased myelination and microstructural integrity in other key motor regions such as the basal ganglia motor cortex cerebellum and white matter tracts
the metabolic profile of the basal gangliainternal capsule
Infants with CP will show reduced gross motor functioning which relates to decreased myelination and microstructural integrity in key motor regions such as the basal ganglia motor cortex cerebellum and white matter tracts eg the corticospinal tract
Furthermore the normative modeling framework similar to pediatric growth curves will be used to elucidate how individual infants with high risk for CP deviate from the norm on different brain outcome measures The relationships between developing motor functioning and brain structural outcome measures will also be mapped as little is known about how individual differences in hand and motor functions of the clinically used assessments with the brain outcome measures Elucidating brain outcome measures that relate to developing motor functions is crucial for using early MRI scans in medical evaluations Such patterns could help predict a childs motor skills and how these might develop which could be important for directing future interventions
METHODS
The following methods will be used for the NIBS-CP study
Magnetic Resonance Imaging MRI The MRI protocol consists of several different structural MRI sequences diffusion-weighted imaging and MR-spectroscopy Children will be scanned using a 3 Tesla MR scanner The MRI protocol takes approximately 45 minutes If the infanttoddler moves during a specific sequence the specific sequence will be redone if possible In such cases the protocol may take up to 1 hour Earplugs as well as headphones will help minimize the scanner-related noise experienced by the infanttoddler
Structural magnetic resonance imaging sMRI gives high-resolution images of the brain anatomy with different contrasts eg T1-weighted and T2-weighted images This kind of scanning allows for the quantification of different brain measures such as volumes of specific brain regions and cortical thickness estimates Moreover sMRI provides the images that the neuroradiologist will read and use diagnostically
Diffusion-weighted imaging DWI provides information about the microstructure of both gray and white matter tissue as well as structural connectivity
Proton MR spectroscopy MRS will yield a metabolic profile of the basal gangliainternal capsule region including markers of neuronal integrity eg N-acetyl-aspartate and glutamate and glial markers eg myoinositol Voxels will include the left or right basal ganglia and internal capsule to capture the metabolic profile in this region
Sequences will be ordered so that the most important sequences sMRI DWI MRS will be acquired first to optimize the chances of getting the sequences needed for diagnostic purposes for the infants at high risk of CP needing a diagnostic scan
Neurological assessments Hammersmith Infant Neurological Examination HINE will be conducted by a pediatrician at Hvidovre Hospital for the typically developing infants and within the CP-EDIT study for the infants at risk for CP
Motor and cognitive assessments
Motor and cognitive assessments of the typically developing infants will be conducted by physio- and occupational therapists at Hvidovre Hospital Infants at risk for CP will undergo the same tests within the CP-EDIT protocol The following motor and cognitive tests are included
Alberta Infant Motor Scale AIMS
Hand Assessments for Infants HAI
Bayley Scales of Infant and Toddler Development 4th Edition BSID-4
Peabody Developmental Motor Scales 2nd Edition PDMS-2
Questionnaires
Neuropsychological data will be collected using the following parent-reported questionnaires for all participants typically developing and at-risk for CP
Ages Stages ASQ There are two questionnaires one assessing motor and cognitive development and one assessing socio-emotional development
Demographics Background
STUDY OUTLINE
Study outline for the typically developing infants in NIBS-CP
The NIBS-CP study consists of three assessment rounds
Round 1 inclusion at age 3-6 months infants may range from age 2 months or to 11 months including MRI HINE AIMS HAI and Demographics Background
Round 2 at age 12 months including MRI AIMS HAI ASQ and Demographics Background
Round 3 at age 24 months including MRI PDMS-2 ASQ BSID-4 and Demographics Background
Study outline for CP-EDIT participants in NIBS-CP
Families enrolled in CP-EDIT will be asked to participate in three MRI scans at age 2-11 months Round 1 inclusion age 12 months Round 2 first follow-up and age 24 months Round 3 second follow-up in parallel to CP-EDIT Participation in NIBS-CP only includes MRI scans and parent-reported questionnaires ASQ and Demographics Background
STATISTICAL CONSIDARATIONS Longitudinal data will be collected from 200 infants Infant cohorts are typically smaller than adult cohorts because of the challenges of MR-scanning this age group Korom et al 2022 The success rate of the scans is expected to be around 75 for sMRI 60 for DWI and 50 for MRS The decline in success rate is due to the order of the sequences given the higher risk of infants waking up the longer the scan time
Statistical analyses will be conducted in statistical software tools such as R and SPSS and in image analysis specific tools such as FreeSurfer and FSL We will use eg analysis of covariance ANCOVA and multiple linear regression for cross-sectional data and eg linear mixed models generalized additive mixed models GAMM and repeated measurements analysis of variance ANOVA for longitudinal data
CP patient cohorts are biologically and clinically heterogeneous Thus in addition to examining differences in group averages the normative modeling framework will be used Rutherford et al 2023 2022 to quantify heterogeneity in structural brain measures by mapping structural brain changes at the level of the individual Normative modeling is a leading tool in precision medicine as it allows for elucidating differences at the individual level mapped in relation to a reference model of normative data similar to height growth charting in pediatric medicine Here normative modeling involves charting percentiles of variation across a population in terms of mappings of brain measures or eg between brain measures and motor functioning Publicly available datasets such as the Healthy Brain and Child Development HBCD study will be used to enhance our training dataset In all models with MRI age sex and variables estimating subject motion during MRI will be utilized as covariates
1 Infants at risk for CP recruited from the Cerebral Palsy Early Diagnosis and Intervention Trial CP-EDIT
The ongoing Danish CP-EDIT by principal investigator Professor Christina Høi-Hansen is registered with ClinicalTrialsgov ID NCT05835674 CP-EDIT will enroll 160 infants aged 3-11 months with CP or high risk of CP Infants will be followed longitudinally with a large battery of motor neurological and cognitive assessments during the first two years of life In addition CP-EDIT contains information from patient journals on diagnostic MRI but CP-EDIT does not include the collection of MRI scans as part of the study For infants enrolled in CP-EDIT participation in NIBS-CP only includes advanced MRI scans and parent-reported questionnaires All neurological motor and cognitive assessments will be undertaken in CP-EDIT
2 Typically developing infants recruited specifically for NIBS-CP For these infants participation in NIBS-CP includes advanced MRI scans neurological motor and cognitive assessments similar to the ones included in CP-EDIT and parent-reported questionnaires NIBS-CP provides a control cohort of typically developing infants that will give rise to a normative Danish sample of early brain development to the infants at high risk of CP as CP-EDIT does not include a control cohort of typically developing infants
AIMS
The NIBS-CP project aims to
1 Establish procedures for infant and toddler MRI during natural sleep without the use of sedation or GA at Hvidovre Hospital
2 Employ advanced MRI sequences for scanning infants and toddlers eg advanced diffusion-weighted imaging high-resolution structural MRI and MR spectroscopy which are likely to be more sensitive in detecting brain injury and damage than conventional diagnostic MRI
3 Initiate a cohort of typically developing infants and toddlers and perform longitudinal advanced MRI of infants at high risk for CP The NIBS-CP cohort will be used to
Establish a dataset of normative material of early brain development of Danish children
Conduct normative modeling of typical and atypical early brain development ie analogous to growth charts to inform about differences in brain development at the level of a single child
Map relationships between early brain development and motor function and development Identifying predictive features of brain structure with MRI is key to the future use of early MRI in the clinical work-up as these features may enable a better prediction of the prospects of motor function and motor development of the child
HYPOTHESES
The primary hypotheses are that
Infants with CP will show reduced hand functioning which relates to decreased myelination and microstructural integrity primarily in the corticospinal tract
Infants with unilateral brain injuries will display asymmetrical hand functioning which will be linked to asymmetrical corticospinal tract microstructure and myelination
The secondary hypotheses are that
Reduced hand functioning and hand functioning asymmetry will also be related to
decreased myelination and microstructural integrity in other key motor regions such as the basal ganglia motor cortex cerebellum and white matter tracts
the metabolic profile of the basal gangliainternal capsule
Infants with CP will show reduced gross motor functioning which relates to decreased myelination and microstructural integrity in key motor regions such as the basal ganglia motor cortex cerebellum and white matter tracts eg the corticospinal tract
Furthermore the normative modeling framework similar to pediatric growth curves will be used to elucidate how individual infants with high risk for CP deviate from the norm on different brain outcome measures The relationships between developing motor functioning and brain structural outcome measures will also be mapped as little is known about how individual differences in hand and motor functions of the clinically used assessments with the brain outcome measures Elucidating brain outcome measures that relate to developing motor functions is crucial for using early MRI scans in medical evaluations Such patterns could help predict a childs motor skills and how these might develop which could be important for directing future interventions
METHODS
The following methods will be used for the NIBS-CP study
Magnetic Resonance Imaging MRI The MRI protocol consists of several different structural MRI sequences diffusion-weighted imaging and MR-spectroscopy Children will be scanned using a 3 Tesla MR scanner The MRI protocol takes approximately 45 minutes If the infanttoddler moves during a specific sequence the specific sequence will be redone if possible In such cases the protocol may take up to 1 hour Earplugs as well as headphones will help minimize the scanner-related noise experienced by the infanttoddler
Structural magnetic resonance imaging sMRI gives high-resolution images of the brain anatomy with different contrasts eg T1-weighted and T2-weighted images This kind of scanning allows for the quantification of different brain measures such as volumes of specific brain regions and cortical thickness estimates Moreover sMRI provides the images that the neuroradiologist will read and use diagnostically
Diffusion-weighted imaging DWI provides information about the microstructure of both gray and white matter tissue as well as structural connectivity
Proton MR spectroscopy MRS will yield a metabolic profile of the basal gangliainternal capsule region including markers of neuronal integrity eg N-acetyl-aspartate and glutamate and glial markers eg myoinositol Voxels will include the left or right basal ganglia and internal capsule to capture the metabolic profile in this region
Sequences will be ordered so that the most important sequences sMRI DWI MRS will be acquired first to optimize the chances of getting the sequences needed for diagnostic purposes for the infants at high risk of CP needing a diagnostic scan
Neurological assessments Hammersmith Infant Neurological Examination HINE will be conducted by a pediatrician at Hvidovre Hospital for the typically developing infants and within the CP-EDIT study for the infants at risk for CP
Motor and cognitive assessments
Motor and cognitive assessments of the typically developing infants will be conducted by physio- and occupational therapists at Hvidovre Hospital Infants at risk for CP will undergo the same tests within the CP-EDIT protocol The following motor and cognitive tests are included
Alberta Infant Motor Scale AIMS
Hand Assessments for Infants HAI
Bayley Scales of Infant and Toddler Development 4th Edition BSID-4
Peabody Developmental Motor Scales 2nd Edition PDMS-2
Questionnaires
Neuropsychological data will be collected using the following parent-reported questionnaires for all participants typically developing and at-risk for CP
Ages Stages ASQ There are two questionnaires one assessing motor and cognitive development and one assessing socio-emotional development
Demographics Background
STUDY OUTLINE
Study outline for the typically developing infants in NIBS-CP
The NIBS-CP study consists of three assessment rounds
Round 1 inclusion at age 3-6 months infants may range from age 2 months or to 11 months including MRI HINE AIMS HAI and Demographics Background
Round 2 at age 12 months including MRI AIMS HAI ASQ and Demographics Background
Round 3 at age 24 months including MRI PDMS-2 ASQ BSID-4 and Demographics Background
Study outline for CP-EDIT participants in NIBS-CP
Families enrolled in CP-EDIT will be asked to participate in three MRI scans at age 2-11 months Round 1 inclusion age 12 months Round 2 first follow-up and age 24 months Round 3 second follow-up in parallel to CP-EDIT Participation in NIBS-CP only includes MRI scans and parent-reported questionnaires ASQ and Demographics Background
STATISTICAL CONSIDARATIONS Longitudinal data will be collected from 200 infants Infant cohorts are typically smaller than adult cohorts because of the challenges of MR-scanning this age group Korom et al 2022 The success rate of the scans is expected to be around 75 for sMRI 60 for DWI and 50 for MRS The decline in success rate is due to the order of the sequences given the higher risk of infants waking up the longer the scan time
Statistical analyses will be conducted in statistical software tools such as R and SPSS and in image analysis specific tools such as FreeSurfer and FSL We will use eg analysis of covariance ANCOVA and multiple linear regression for cross-sectional data and eg linear mixed models generalized additive mixed models GAMM and repeated measurements analysis of variance ANOVA for longitudinal data
CP patient cohorts are biologically and clinically heterogeneous Thus in addition to examining differences in group averages the normative modeling framework will be used Rutherford et al 2023 2022 to quantify heterogeneity in structural brain measures by mapping structural brain changes at the level of the individual Normative modeling is a leading tool in precision medicine as it allows for elucidating differences at the individual level mapped in relation to a reference model of normative data similar to height growth charting in pediatric medicine Here normative modeling involves charting percentiles of variation across a population in terms of mappings of brain measures or eg between brain measures and motor functioning Publicly available datasets such as the Healthy Brain and Child Development HBCD study will be used to enhance our training dataset In all models with MRI age sex and variables estimating subject motion during MRI will be utilized as covariates
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None