Dopamine, Neurobehavioral Manifestations, Perinatal Hypoxia
Conditions
Keywords
Hypoxia, Brain, Neural networks, Magnetic Resonance Imaging
Brief summary
This observational study will investigate whether differences in birth events and oxygen levels during the newborn period affects the brain activity of children during the middle childhood years.
Detailed description
The investigators will conduct an observational study comparing two groups of children to determine whether differences in birth events and oxygen levels during the newborn period lead to structural and functional impairment within the brain's dopaminergic pathways and the cortical regions innervated by those pathways. The dopaminergic system is involved in modulating motor control and cognitive function. Using magnetic resonance diffusion tensor imaging, structural integrity of dopaminergic circuits will be quantified and compared in post-hypoxic former preterm children versus healthy control children born at term closely matched by age/sex/race. Functional activity during executive function tasks will be quantified and compared in post-hypoxic former preterm children versus healthy control children born at term using functional magnetic resonance imaging-blood oxygen level dependent (fMRI-BOLD). Assessment of motor function (grooved pegboard task) will also be performed.
Interventions
OTHERMagnetic Resonance Imaging
MRI uses a strong magnetic field and radio waves to create detailed images of the brain while the person's head is positioned inside a round tunnel.
OTHERCognitive Performance Testing
For the Grooved Pegboard task: After the MRI scan, children will be timed as they place pegs into holes with randomly positioned slots.
Sponsors
Case Western Reserve University
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
8 Years to 15 Years
Healthy volunteers
Yes
Inclusion criteria
1. For Study Group Children: Birth gestational age between 23-28 weeks and birth weight appropriate for gestational age (AGA) with available oxygen saturation level data recorded continuously from the first day of life to 8 weeks postnatal age (n=11) 2. For Healthy Control Children: Birth gestational age ≥ 38 weeks gestation and birth weight appropriate for term gestation (n=10) matched by age/sex/race to participating cohort children. 3. Born in years 2005-2009 (age range will be 8-15 years during the funding period) 4. Ability of the child to provide assent, with the parent/legal guardian able to provide written informed consent for study procedures. 5. Sensory and motor capability to complete study tasks (i.e. Grooved Pegboard test). Mental Development index must be \> 80 at 2-year-old follow-up for preterm cohort.
Exclusion criteria
1. Past history of concussion requiring medical treatment to avoid confounding of MRI data 2. Current diagnosis of autism. 3. Child who suffers from claustrophobia (per parent report). 4. Unable to participate in neuroimaging due to claustrophobia, or medical contraindication to MRI including any implanted medical device, dental braces, surgical clips for aneurysms in the head, heart valve prostheses, electrodes or other metallic objects, pregnancy. 5. Healthy control children who were treated in the Neonatal ICU in the newborn period for breathing difficulties. 6. Healthy control children who were hospitalized for breathing problems in the first 3 months of infancy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Structural Integrity of Dopaminergic Circuits | 30 minutes | Assessment of dopaminergic circuits originating in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA). Includes right and left nucleus accumbens, right and left mamillary body, right and left hippocampus. Measured using Magnetic Resonance T1-weighted magnetization prepared rapid gradient echo (MPRAGE) scans with three-dimensional volumetrics analysis |
| Functional Activity During Executive Function Tasks | 30 minutes | Subjects in each group were evaluated for changes in functional connectivity between the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA), as evaluated by functional magnetic resonance imaging blood oxygen level dependent (fMRI-BOLD), using whole brain analysis. The measurement is increase/decrease of MRI signal intensity in a given region, thresholded at p \<0.05, summarized into a value representing 'size of region of increase' or 'size of region of decrease' after subjects' scans were combined/mapped onto a standard MNI brain. Only clusters of over 50 voxels were included, and the size of the region is reported in voxel size. The averaged brains for prematurely born fMRI was subtracted from the full term treatment for each group, and then these averaged differences were subtracted from each other. While other areas of the brain met threshold criteria in the analysis, only brain regions innervated by primary or collateral dopaminergic pathways are reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cognitive Performance-Fine Motor Function | 20 minutes | Measured using the grooved pegboard task (number of seconds required to place 25 pegs using the dominant hand) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Post-hypoxic Former Preterm Born in the years 2005-2009 with birth gestational age between 23-28 weeks and birth weight appropriate for gestational age (AGA). Part of a research cohort with available oxygen saturation level data recorded continuously from the first day of life to 8 weeks postnatal age (n=11).Children will undergo Magnetic Resonance Imaging, Electroencephalography, and Cognitive Performance Testing.
Magnetic Resonance Imaging: MRI uses a strong magnetic field and radio waves to create detailed images of the brain while the person's head is positioned inside a round tunnel.
Electroencephalography: EEG tracks and records brain wave patterns. A head cap with small discs and thin wires (electrodes) is placed on the scalp, and then send signals to a computer.
Cognitive Performance Testing: For the Verbal n-back: During the fMRI scan, children will respond to a letter displayed on a small screen and indicate (by pushing a button) whether the letter shown is the same as a previously displayed letter. Children will repeat this test during the EEG.
For the Grooved Pegboard task: After the MRI scan, children will be timed as they place pegs into holes with randomly positioned slots. | 9 |
| Healthy Term-born Children Born in the years 2005-2009 with birth gestational age ≥ 38 weeks gestation and birth weight appropriate for term gestation (n=10) matched by age/sex/race to participating cohort children with no history of respiratory difficulty suggesting hypoxic exposure. Children will undergo Magnetic Resonance Imaging, Electroencephalography, and Cognitive Performance Testing.
Magnetic Resonance Imaging: MRI uses a strong magnetic field and radio waves to create detailed images of the brain while the person's head is positioned inside a round tunnel.
Electroencephalography: EEG tracks and records brain wave patterns. A head cap with small discs and thin wires (electrodes) is placed on the scalp, and then send signals to a computer.
Cognitive Performance Testing: For the Verbal n-back: During the fMRI scan, children will respond to a letter displayed on a small screen and indicate (by pushing a button) whether the letter shown is the same as a previously displayed letter. Children will repeat this test during the EEG.
For the Grooved Pegboard task: After the MRI scan, children will be timed as they place pegs into holes with randomly positioned slots. | 7 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Unable to schedule | 0 | 3 |
Baseline characteristics
| Characteristic | Post-hypoxic Former Preterm | Healthy Term-born Children | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 9 Participants | 7 Participants | 16 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 11.15 years STANDARD_DEVIATION 0.93 | 12.13 years STANDARD_DEVIATION 2.06 | 11.58 years STANDARD_DEVIATION 1.55 |
| Birth gestation | 26.11 weeks STANDARD_DEVIATION 1.9 | 39.00 weeks STANDARD_DEVIATION 1 | 31.75 weeks STANDARD_DEVIATION 6.78 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 7 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 3 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 4 Participants | 5 Participants |
| Region of Enrollment United States | 9 participants | 7 participants | 16 participants |
| Sex: Female, Male Female | 6 Participants | 3 Participants | 9 Participants |
| Sex: Female, Male Male | 3 Participants | 4 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 7 |
| other Total, other adverse events | 0 / 9 | 0 / 7 |
| serious Total, serious adverse events | 0 / 9 | 0 / 7 |
Outcome results
Primary
Functional Activity During Executive Function Tasks
Subjects in each group were evaluated for changes in functional connectivity between the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA), as evaluated by functional magnetic resonance imaging blood oxygen level dependent (fMRI-BOLD), using whole brain analysis. The measurement is increase/decrease of MRI signal intensity in a given region, thresholded at p \<0.05, summarized into a value representing 'size of region of increase' or 'size of region of decrease' after subjects' scans were combined/mapped onto a standard MNI brain. Only clusters of over 50 voxels were included, and the size of the region is reported in voxel size. The averaged brains for prematurely born fMRI was subtracted from the full term treatment for each group, and then these averaged differences were subtracted from each other. While other areas of the brain met threshold criteria in the analysis, only brain regions innervated by primary or collateral dopaminergic pathways are reported.
Time frame: 30 minutes
Population: All participants who met criteria for a technically acceptable functional magnetic resonance imaging scan (less than 3mm movement artifact) were included in these analyses. FSL (FMRIB Software Library)-defined cluster sizes greater than 50 voxels, with p\<0.05, within cognitive areas of interest are included in the outcome table. That table provides the number of voxels in clusters that showed increased or decreased connectivity.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Post-hypoxic Former Preterm | Functional Activity During Executive Function Tasks | Left thalamus | 310 Cluster size (voxels) |
| Post-hypoxic Former Preterm | Functional Activity During Executive Function Tasks | Left middle temporal gyrus | 95 Cluster size (voxels) |
| Healthy Term-born Children | Functional Activity During Executive Function Tasks | Left thalamus | 358 Cluster size (voxels) |
| Healthy Term-born Children | Functional Activity During Executive Function Tasks | Left middle temporal gyrus | 75 Cluster size (voxels) |
p-value: <0.05t-test, 2 sided
Primary
Structural Integrity of Dopaminergic Circuits
Assessment of dopaminergic circuits originating in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA). Includes right and left nucleus accumbens, right and left mamillary body, right and left hippocampus. Measured using Magnetic Resonance T1-weighted magnetization prepared rapid gradient echo (MPRAGE) scans with three-dimensional volumetrics analysis
Time frame: 30 minutes
Population: All participants who had a usable structural magnetic resonance imaging (MRI) scan
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Post-hypoxic Former Preterm | Structural Integrity of Dopaminergic Circuits | left nucleus accumbens | 148.90 mm^3 | Standard Deviation 50.12 |
| Post-hypoxic Former Preterm | Structural Integrity of Dopaminergic Circuits | right nucleus accumbens | 177.25 mm^3 | Standard Deviation 31.46 |
| Post-hypoxic Former Preterm | Structural Integrity of Dopaminergic Circuits | left mamillary body | 89.34 mm^3 | Standard Deviation 18.18 |
| Post-hypoxic Former Preterm | Structural Integrity of Dopaminergic Circuits | right mamillary body | 67.78 mm^3 | Standard Deviation 17.34 |
| Post-hypoxic Former Preterm | Structural Integrity of Dopaminergic Circuits | left hippocampus | 2741.09 mm^3 | Standard Deviation 511.83 |
| Post-hypoxic Former Preterm | Structural Integrity of Dopaminergic Circuits | right hippocampus | 3329.34 mm^3 | Standard Deviation 682.48 |
| Healthy Term-born Children | Structural Integrity of Dopaminergic Circuits | left hippocampus | 3419.48 mm^3 | Standard Deviation 619 |
| Healthy Term-born Children | Structural Integrity of Dopaminergic Circuits | left nucleus accumbens | 175.93 mm^3 | Standard Deviation 25.41 |
| Healthy Term-born Children | Structural Integrity of Dopaminergic Circuits | right mamillary body | 44.70 mm^3 | Standard Deviation 15.03 |
| Healthy Term-born Children | Structural Integrity of Dopaminergic Circuits | right nucleus accumbens | 192.78 mm^3 | Standard Deviation 16.48 |
| Healthy Term-born Children | Structural Integrity of Dopaminergic Circuits | right hippocampus | 4241.03 mm^3 | Standard Deviation 659.36 |
| Healthy Term-born Children | Structural Integrity of Dopaminergic Circuits | left mamillary body | 54.78 mm^3 | Standard Deviation 18.02 |
Secondary
Cognitive Performance-Fine Motor Function
Measured using the grooved pegboard task (number of seconds required to place 25 pegs using the dominant hand)
Time frame: 20 minutes
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Post-hypoxic Former Preterm | Cognitive Performance-Fine Motor Function | 102.11 seconds | Standard Deviation 42.77 |
| Healthy Term-born Children | Cognitive Performance-Fine Motor Function | 82.71 seconds | Standard Deviation 15.59 |