Abstract
Objective:
Evaluate longitudinal changes in brain microstructure and volumes in very preterm during the first year of life with and without intervention.
Design:
Descriptive pilot study
Methods:
Five preterm infants in a three-arm clinical trial, one SPEEDI Early, two SPEEDI Late, and two usual care. Brain structural and diffusion MRI’s were acquired within 72 hours after neonatal intensive care unit discharge (n=5), three months post-baseline (n=5), and six months post-baseline (n=3). Fractional anisotropy (FA), Mean diffusivity (MD), and volume metrics were computed for five brain regions.
Results:
More than 60% of eligible participants completed 100% of the scheduled MRIs. FA and volume increased from baseline to six months across all brain regions. Rate of white matter volume change from baseline to six months was highest in SPEEDI Early.
Conclusions:
Non-sedated longitudinal MRI is feasible in very preterm infants and appears to demonstrate longitudinal changes in brain structure and connectivity.
Keywords: DTI, corticospinal tract, preterm infants, intervention
Introduction
Preterm birth is a significant public health challenge, and accounts for almost 12% of the total deliveries in the United States. While technological advances have led to an increase in survival rates, long-term neurodevelopmental outcomes remain a major concern.1 Specifically, 10-15% of very preterm infants are reported to develop cerebral palsy, 40% develop some type of motor deficits, and 30-60% experience cognitive delays.2
Preterm infants are at a risk for periventricular leukomalacia (PVL) and intraventricular hemorrhage (IVH).3 Multiple risk factors such as arrested growth during critical times frames of intrauterine brain development, higher ex utero vulnerability due to physiological immaturity, prolonged neonatal ventilatory support, or risk of infection all increase the likelihood of brain injury and risk of neurodevelopmental delays.4,5 Hence, early and accurate diagnosis of a brain insult is an important prerequisite before targeted interventions can be designed and implemented during period of maximum brain plasticity.
The emergence of new technology has allowed for advances in evaluation and diagnosis of brain injury. Structural MRI is a sensitive tool to identify subtle structural lesions and to provide further information regarding the volume and cortical morphology as compared to cranial ultrasound (cUS).1 Diffusion-weighted MRI (DWI) can evaluate the microstructural organization of the brain white matter, based on mapping of water diffusion in biologic tissues.6 When combined with DWI analysis methods including Diffusion Tensor Imaging (DTI), parameters such as Fractional Anisotropy (FA), Mean Diffusivity (MD) and white matter volume can be extracted. These parameters provide an overall quantification of the underlying brain white matter structure, such as the axonal density and myelination.7 In addition, the availability of non-sedated MRI protocols has increased the safety of doing MRI in infants.
Elucidating the brain white matter microstructure is critically important as it has an enduring impact on multiple developmental domains. Infants with a lower FA and decreased fiber lengths of posterior limb of internal capsule (PLIC) at term equivalent age are at a risk for psychomotor delays and more often diagnosed with cerebral palsy at two years of age.8 FA values of corona radiata (CR) and corticospinal tracts (CST) at term equivalent age in preterm infants are also positively associated with motor and cognitive outcomes at 18 months of age.9 Preterm infants in general also have lower brain volumes as compared to term born peers. Reduced white matter volume is reported to be associated with intellectual delay and impaired executive functioning.10
The majority of MRI studies conducted in preterm infants are completed cross-sectionally at term-equivalent age.11 The lack of longitudinal data limits our understanding about the relationship between brain injury, activity, and efficacy of intervention to induce plasticity and spontaneous recovery. Thus, there is a need to quantify changes in brain white matter microstructure longitudinally during the first year of life.
Quantifying changes in the CNS in response to intervention would aid in the development and subsequent efficacy assessment of evidence-based interventions for infants at high-risk of motor impairments. At present, only a handful of studies have evaluated changes in the CNS in response to intervention in children. For instance, DTI done on children receiving constraint induced movement therapy12 and Hand and Arm Bimanual Intensive Therapy Including Lower Extremities13 reported corticospinal tract reorganization post-intervention. However, this work was completed in older children with longstanding brain injuries and a diagnosis of unilateral spastic cerebral palsy. While this evidence indicates the neuroplastic benefits of rehabilitation interventions, additional research looking at intra and inter subject variability, and changes in neural connectivity over time in response to rehabilitation, are required to evaluate the associations, understand the mechanisms, and identify the causal pathways.
The primary purpose of this study was to evaluate the feasibility of performing longitudinal non-sedated MRI at NICU discharge (baseline/visit 1), three months post-baseline (visit 2), and six months post-baseline (visit 3). The second aim was to determine the feasibility of measuring structural and connectivity changes in white matter regions that play an important role in motor output and motor learning and to begin to estimate the effect of age on white matter microstructure. The third and an exploratory aim of this study was to explore the feasibility of assessing neuroplastic changes in response to a rehabilitation intervention in very preterm infants.
Methods:
Participants
Ten very preterm infants i.e. <29 weeks Gestational Age (GA), from the initial sub-set of the Does Timing Matter? Supporting Play, Exploration, and Early Development Intervention trial (SPEEDI2 - ClinincalTrials.gov Identifier: NCT03518736) were approached for possible enrollment in this pilot study. Very preterm infants cared for in one of the two participating neonatal intensive care units (NICU), medically stable and off ventilator support by 42 weeks of gestation, residing within 100 miles of the participating hospitals were included in this study. Participants were excluded if they were diagnosed with any genetic abnormalities at the time of enrollment and were from non-English speaking families. Details on participant selection, allocation concealment and group randomization are available in the intervention trial’s protocol paper.14
Intervention description
The SPEEDI2 intervention trial comprises of three groups: SPEEDI Early, SPEEDI Late, and usual care. Both the early and late SPEEDI intervention groups receive the same intervention key components, the only difference being the timing of when the intervention is initiated. The SPEEDI Early group receives intervention starting in the NICU and continuing for 15 weeks. While the SPEEDI Late intervention begins at 16 weeks post-baseline and is continued for 15 weeks. In addition, both the intervention groups along with the usual care group receive standard care in the NICU and community. The primary goal of the SPEEDI2 intervention is to provide increased learning opportunities for an infant born very preterm by engaging the parents to provide an enriched environment. Daily parent provided play-based activities strive to enhance cognitive and motor development through play. Details of the key elements of intervention, strategies to implement, dosage, and fidelity assessment are available in the protocol paper.14
MRI imaging acquisition procedure
Non-sedated MRI scans were performed using a 3T Siemens Skyra scanner dedicated for pediatric use in the outpatient department of the Children’s Hospital of Richmond (CHOR). The same scanner was used for all the participants to maintain uniform comparison of images over time. The MRI scans were completed at three longitudinal time points: i) within 72 hours after NICU discharge (baseline/visit 1) as close to baseline as possible, but on an outpatient basis, ii) three months post baseline (visit 2), and iii) six months post baseline (visit 3). The time points of the scans were chosen based on the start and completion of intervention for each group. An infant-parent friendly protocol consisting of two crucial parameters was employed for non-sedated scanning data acquisition. The first parameter was the “timing” of scanning. The MRI scans were completed in the evening, usually coinciding with the infant’s developmental assessments. This ensured that the infant was tired and ready for a natural sleep progression during the scanning procedure. The second parameter was “infant comfort”. The infants were provided with earmuffs, fed, and rocked to sleep before the scans. They were then swaddled in a papoose, which provided containment and deep pressure, additional earmuffs and foam blocks were used to maintain the infant’s head in midline when placed in the 20-channel coil. Parents were allowed in the MRI suite to be readily available to help calm the baby if needed during the scans, after completion of an MRI safety questionnaire. Given the ethical implications of medically unnecessary sedation, these additional steps were taken to ensure increased likelihood of natural sleep during the MRI.15 This study was approved by the Human Subjects Board at Virginia Commonwealth University and a parent signed permission for their own and their child’s participation as well as access to their child’s medical records throughout the study period.
Imaging Protocol
Three main sequences were used to capture T1-weighted and T2-weighted images for detection of structural abnormalities, along with DWI to quantify white matter fiber structure. Magnetization Prepared Rapid Gradient Echo, 3-D SPACE (Sampling Perfection with Application optimized Contrasts using different flip angle Evolution), and diffusion-weighted Echo-Planar Images (20 directions at b=1000 s/mm2, plus 1 b=0 s/mm2 image) were acquired as outlined in Table 1. Susceptibility weighted images (SWI) were also acquired but were not analyzed in the current study. Total scan time varied between 18-30 minutes depending on motion artifact as the technician re-ran segments to minimize artifacts whenever possible.
Table 1.
MRI imaging sequence and image parameters.
| Sequence | Field of view (FOV) | Echo Time (TE) | Repetition Time (TR) | Voxel resolution |
|---|---|---|---|---|
| Magnetization Prepared Rapid Gradient Echo (MPRAGE) | 256 mm | 2.26 ms | 1410 ms | 1mm x 1mm x 1mm |
| T2w 3-D SPC | 200 mm | 408 ms | 2000 ms | 0.9 mm x 0.4 mm x 0.4 mm |
| Diffusion Echo-Planar Imaging | 200 mm | 112 ms | 3400 ms | 0.7 mm x 0.7 mm x 3 mm |
| Axial Susceptibility-weighted imaging (SWI) | 200 mm | 18 ms | 24 ms | 0.8 mm x 0.8 mm x 1.5 mm |
mm; millimeters, ms; milliseconds.
Image preprocessing
Diffusion-weighted images were preprocessed using Functional MRI of the Brain Software Library (FSL version 6. 0. 3).16 Images were motion corrected (including outlier detection and replacement, slice-to-volume motion correction, and b-vector rotation),17–19 resampled to 1.5mm isotropic voxels, and brain extracted, and the diffusion tensor model was fitted.20 The b=0s/mm2 image for each participant was registered linearly (using the FSL linear registration tool)21 and non-linearly (using Advanced Normalization Tools)22 to the Melbourne Children’s Regional Infant Brain (M-CRIB) T2-weighted template, and the inverse transform was applied to the M-CRIB white matter (M-CRIB-WM) atlas to parcellate each participant’s scan into white matter regions.23
Outcome measures
The outcome measures for this study comprised of feasibility parameters, and DTI and white matter volume metrics. The feasibility parameters consisted of enrollment rate, retention rate, and scan success rate and were operationally defined as follows: enrollment rate was the percentage of participants who gave consent to participate in the study and retention rate was the percentage of participants who completed all the scheduled scans. We considered anything higher than 50 percent as “good” or else it was considered “poor”. Lastly, scan success rate was defined as quantifiable image on each MRI. While the target was to retrieve 100 percent of quantifiable MR images, we estimated 75 percent of those consented would represent feasibility.24
DTI metrics (FA and MD) and volume were calculated for five white matter regions of interest (ROIs): i) corticospinal tract (CST), ii) posterior limb of internal capsule (PLIC), iii) corona radiata (CR), iv) cerebral peduncles (CP), and v) cerebellar peduncles (CBP). In case of cerebellar peduncle we averaged superior, middle, and inferior cerebellar peduncle together to obtain one single value each for FA and MD. However, volume was derived by adding the values of all three regions together into one. The CST was chosen to be the primary region of interest based on its importance in the output of voluntary movement, as well as the extensive literature on CST dysfunction in preterm infants.25 Likewise, the PLIC is commonly used to predict the development of cerebral palsy based on the amount of myelination.26 Lastly, the corona radiata, cerebral peduncles, and cerebellar peduncles (superior, middle, and inferior) were included based on their role in motor learning and motor processing.27,28
Data Analysis:
Descriptive statistics were used to describe the demographic details of the participants. Due to the feasibility nature of this work and a small sample size, a complete statistical analysis could not be performed. A summary measure of percentage was used to determine the enrollment, retention, and scan success rate. Longitudinal changes for FA, MD, and volume values for both the right and left hemisphere at baseline, three months post baseline, and six months post baseline were reported. To explore the role of intervention on neuroplastic changes, the DTI metrics and white matter volume from all five ROIs for one infant from each group (SPEEDI Early, SPEEDI Late, and usual care), who had completed all three scans, were visually represented using line graphs. The left and right hemisphere DTI metrics and volume values were averaged together, and overall change was calculated by subtracting the baseline value from the six-month value.
Results:
A total of 10 infants were planned for enrollment, however only eight were approached prior to a research shutdown during the COVID-19 Pandemic. During the enrollment period, more than 60% (5/8) of the participants approached were eligible and consented for participation. Two infants were excluded for MRI safety reasons and one declined to participate. Before the COVID-19 closure, 100% of the scheduled visits were successfully completed. Two infants’ six-month visits were missed, one due to COVID-19 and the other infant was unable to continue due to social issues. High-quality images were obtained from 100% of the scheduled visits, allowing all metrics to be calculated. There was minimal motion artifact in the final images since the technician repeated any section in which artifact was noted. None of the five participants had previously received an MRI while being treated in the NICU but all participants had at least one cUS completed. The demographic characteristics of infants included in the study are provided in Table 2.
Table 2.
Demographic characteristics of infants
| ID | GA | BW | Race | Sex | Ethnicity | Ventilation | Oxygen | Age at scan 1 | Scan 1 Findings | Scan 2 Findings | Scan 3 Findings | # MRI |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 * | 23 | 580g | AA | M | Not H/L | 29+ days | Yes | 42 | Possible collection of blood in the left caudothalamic groove | Possible collection of blood in the left caudothalamic groove | Possible collection of blood in the left caudothalamic groove | 3 |
| 2 | 28 | 870g | AA | F | NR | 3-14 days | Yes | 38 | No abnormal findings | No abnormal findings | 2 | |
| 3 * | 27 | 840g | W | F | Not H/L | 29+ days | Yes | 42 | Proteinaceous subdural collection for possible hematoma | Possible thinning of the CC; blood collection resolved | Possible thinning of the CC; no other abnormal findings | 3 |
| 4 * | 27 | 1030g | W | M | Not H/L | 29+ days | Yes | 40 | No abnormal findings | Possible collection of blood in right frontal falx | Blood collection resolved; no other abnormal findings | 3 |
| 5 | 27 | 970g | AA | F | Not H/L | 3-14 days | Yes | 36 | Small arachnoid cysts in cerebellomedullary angle | Small arachnoid cysts in cerebellomedullary angle | 2 |
ID; identification number,
indicates participants used in exploratory aims of group differences
GA; Gestational age, BW; Birth weight, W; White, AA; African American, F; Female, M; Male, H/L; Hispanic/Latino, NR; not reported, Not H/L; Not Hispanic or Latino, days on ventilation, oxygen use, adjusted age in weeks at the time of scan 1 (visit 1; baseline), findings at scan 1(visit 1; baseline), findings at scan 2 (visit 2; 3 months post baseline), findings at scan 3 (visit 3; 6 months post baseline), and #number of scans completed.
Longitudinal DTI metrics:
FA, MD, and white matter volume values were reported for the right and left hemisphere at baseline, 3 months, and 6 months post baseline respectively for each of the five motor ROIs in Table 3 & Table 4. The overall trend was an increase in FA and white matter volume values and a decrease in MD values from baseline to six months post baseline in all the participants.
Table 3.
Fractional anisotropy (FA) and mean diffusivity (MD) for each participant from baseline to six months post baseline.
| ROIs | ID | FA Values | MD (x10−3 mm2/sec) Values | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Left | Right | Left | Right | ||||||||||
| Visit 1 | Visit 2 | Visit 3 | Visit 1 | Visit 2 | Visit 3 | Visit 1 | Visit 2 | Visit 3 | Visit 1 | Visit 2 | Visit 3 | ||
| CST | 1 | 0.169 | 0.219 | 0.286 | 0.183 | 0.239 | 0.292 | 1.141 | 1.07 | 0.945 | 1.135 | 1.03 | 0.945 |
| 2 | 0.184 | 0.235 | 0.165 | 0.235 | 1.129 | 0.941 | 1.126 | 0.924 | |||||
| 3 | 0.195 | 0.236 | 0.264 | 0.226 | 0.261 | 0.284 | 1.115 | 1.056 | 0.968 | 1.083 | 1.026 | 1.01 | |
| 4 | 0.194 | 0.225 | 0.257 | 0.194 | 0.24 | 0.246 | 1.193 | 1.093 | 1.103 | 1.132 | 1.13 | 1.132 | |
| 5 | 0.171 | 0.223 | 0.153 | 0.225 | 1.234 | 1.029 | 1.195 | 1.035 | |||||
| PLIC | 1 | 0.311 | 0.42 | 0.456 | 0.394 | 0.441 | 0.522 | 1.093 | 0.913 | 0.849 | 1.058 | 0.894 | 0.855 |
| 2 | 0.319 | 0.453 | 0.308 | 0.402 | 1.125 | 0.927 | 1.107 | 0.931 | |||||
| 3 | 0.3 | 0.36 | 0.469 | 0.254 | 0.431 | 0.398 | 1.096 | 0.938 | 0.874 | 1.079 | 0.952 | 0.85 | |
| 4 | 0.403 | 0.455 | 0.446 | 0.255 | 0.4 | 0.423 | 1.056 | 0.919 | 0.87 | 1.045 | 0.897 | 0.846 | |
| 5 | 0.185 | 0.356 | 0.248 | 0.298 | 1.213 | 0.968 | 1.194 | 0.978 | |||||
| CR | 1 | 0.148 | 0.234 | 0.23 | 0.148 | 0.243 | 0.245 | 1.668 | 1.315 | 1.288 | 1.632 | 1.224 | 1.219 |
| 2 | 0.156 | 0.247 | 0.138 | 0.232 | 1.624 | 1.16 | 1.673 | 1.166 | |||||
| 3 | 0.159 | 0.256 | 0.262 | 0.167 | 0.246 | 0.266 | 1.492 | 1.186 | 1.125 | 1.509 | 1.166 | 1.101 | |
| 4 | 0.167 | 0.255 | 0.259 | 0.165 | 0.278 | 0.294 | 1.652 | 1.132 | 1.063 | 1.645 | 1.133 | 1.064 | |
| 5 | 0.123 | 0.201 | 0.126 | 0.217 | 1.595 | 1.206 | 1.613 | 1.186 | |||||
| CP | 1 | 0.295 | 0.405 | 0.447 | 0.327 | 0.418 | 0.475 | 1.064 | 1.039 | 0.97 | 1.041 | 0.97 | 0.935 |
| 2 | 0.287 | 0.362 | 0.28 | 0.404 | 1.121 | 1.018 | 1.047 | 0.946 | |||||
| 3 | 0.3 | 0.383 | 0.422 | 0.32 | 0.419 | 0.447 | 1.073 | 0.982 | 0.948 | 1.038 | 1.006 | 0.927 | |
| 4 | 0.321 | 0.407 | 0.411 | 0.294 | 0.42 | 0.423 | 1.144 | 1.044 | 1.055 | 1.06 | 0.979 | 1.026 | |
| 5 | 0.222 | 0.339 | 0.255 | 0.294 | 1.069 | 1.036 | 1.05 | 1.004 | |||||
| CBP | 1 | 0.282 | 0.359 | 0.429 | 0.230 | 0.332 | 0.396 | 1.003 | 0.889 | 0.855 | 1.228 | 0.883 | 0.852 |
| 2 | 0.219 | 0.239 | 0.209 | 0.230 | 1.170 | 1.371 | 1.164 | 1.254 | |||||
| 3 | 0.259 | 0.368 | 0.381 | 0.255 | 0.342 | 0.392 | 1.068 | 0.954 | 0.937 | 1.034 | 0.973 | 0.889 | |
| 4 | 0.246 | 0.363 | 0.414 | 0.240 | 0.353 | 0.435 | 1.044 | 0.984 | 0.917 | 1.207 | 0.950 | 0.896 | |
| 5 | 0.194 | 0.316 | 0.180 | 0.289 | 1.067 | 0.922 | 1.171 | 0.910 | |||||
ROI; region of interest, ID; identification number, CST; Corticospinal tract, PLIC; posterior limb of internal capsule, CR; corona radiata, CP; cerebral peduncle, and CBP; cerebellar peduncle, visit 1; baseline, visit 2; 3 months post baseline, visit 3; 6 months post baseline.
Table 4.
White matter volumes for each participant from baseline to six months.
| ROI | ID | Volume (mm3) | |||||
|---|---|---|---|---|---|---|---|
| Left | Right | ||||||
| Visit 1 | Visit 2 | Visit 3 | Visit 1 | Visit 2 | Visit 3 | ||
| CST | 1 | 246 | 381 | 408 | 250 | 324 | 412 |
| 2 | 162 | 240 | 179 | 273 | |||
| 3 | 240 | 452 | 537 | 233 | 419 | 533 | |
| 4 | 226 | 395 | 479 | 273 | 388 | 493 | |
| 5 | 257 | 250 | 253 | 297 | |||
| PLIC | 1 | 439 | 594 | 702 | 408 | 550 | 628 |
| 2 | 392 | 554 | 368 | 466 | |||
| 3 | 483 | 756 | 894 | 496 | 719 | 857 | |
| 4 | 520 | 736 | 844 | 442 | 594 | 773 | |
| 5 | 368 | 574 | 358 | 486 | |||
| CR | 1 | 3750 | 5201 | 5822 | 3736 | 5360 | 5950 |
| 2 | 2852 | 3689 | 3267 | 4350 | |||
| 3 | 4300 | 5896 | 7850 | 4097 | 6740 | 7756 | |
| 4 | 3699 | 5859 | 7553 | 4020 | 6335 | 6973 | |
| 5 | 2666 | 4570 | 2808 | 4874 | |||
| CP | 1 | 206 | 300 | 354 | 216 | 280 | 365 |
| 2 | 196 | 240 | 206 | 223 | |||
| 3 | 233 | 361 | 442 | 246 | 375 | 503 | |
| 4 | 203 | 324 | 375 | 206 | 354 | 392 | |
| 5 | 189 | 260 | 155 | 287 | |||
| CBP | 1 | 483 | 608 | 780 | 608 | 770 | 881 |
| 2 | 385 | 530 | 486 | 624 | |||
| 3 | 500 | 837 | 1026 | 635 | 1043 | 1283 | |
| 4 | 486 | 753 | 948 | 597 | 915 | 1002 | |
| 5 | 405 | 597 | 469 | 705 | |||
ROI; region of interest, ID; identification number, CST; Corticospinal tract, PLIC; posterior limb of internal capsule, CR; corona radiata, CP; cerebral peduncle, and CBP; cerebellar peduncle, visit 1; baseline, visit 2; 3 months post baseline, visit 3; 6 months post baseline.
Exploratory Analysis of Group Differences in response to intervention:
Data from three infants were analyzed to determine the change in DTI metrics and volume with intervention i.e. one each from SPEEDI Early, SPEEDI Late, and usual care (Figure 1 (A–J)). The overall change in FA from baseline to 6 months in three groups differed by ROIs. We observed that SPEEDI Early had a higher change in FA in the PLIC; SPEEDI Late had a greater overall change in FA in the CST and CP; and usual care infant had a greater overall change in the CR and CBP (Table 5). The SPEEDI Early infant demonstrated a greater overall change in volume for all five ROIs when compared to SPEEDI Late and usual care. However, SPEEDI Late infant reported consistently lower volumes in all five regions as compared to the usual care infant (Table 5).
Figure 1.
FA and volume (mm3) change over time in SPEEDI Early, SPEEDI Late and usual care group
CST; Corticospinal tract, PLIC; posterior limb of internal capsule, CR; corona radiata, CP; cerebral peduncle, and CBP; cerebellar peduncle, visit 1; baseline, visit 2; 3 months post baseline, visit 3; 6 months post baseline.
Table 5.
Rate of change in FA and volume in SPEEDI Early, SPEEDI Late and usual care group
| ROI | Group | FA Values | Volume (mm3) | ||||
|---|---|---|---|---|---|---|---|
| Change V1-V2 | Change V2-V3 | Overall change V3-V1 | Change V1-V2 | Change V2-V3 | Overall change V3-V1 | ||
| CST | Early | 0.038 | 0.025 | 0.063 | 199 | 100 | 299 |
| Late | 0.053 | 0.06 | 0.113 | 105 | 57 | 162 | |
| Usual care | 0.038 | 0.019 | 0.057 | 142 | 95 | 236 | |
| PLIC | Early | 0.118 | 0.038 | 0.156 | 248 | 138 | 386 |
| Late | 0.078 | 0.059 | 0.137 | 149 | 93 | 241 | |
| Usual care | 0.098 | 0.007 | 0.105 | 184 | 143 | 327 | |
| CR | Early | 0.088 | 0.013 | 0.101 | 2120 | 1485 | 3605 |
| Late | 0.090 | −0.001 | 0.089 | 1537 | 606 | 2143 | |
| Usual care | 0.100 | 0.010 | 0.111 | 2238 | 1166 | 3404 | |
| CP | Early | 0.091 | 0.034 | 0.124 | 128 | 105 | 233 |
| Late | 0.101 | 0.050 | 0.150 | 79 | 69 | 149 | |
| Usual care | 0.106 | 0.004 | 0.109 | 135 | 44 | 179 | |
| CBP | Early | 0.098 | 0.032 | 0.130 | 373 | 214 | 587 |
| Late | 0.089 | 0.067 | 0.156 | 143 | 142 | 285 | |
| Usual care | 0.115 | 0.066 | 0.181 | 292 | 142 | 434 | |
ROI; region of interest, V1; visit 1, V2; visit 2, V3; visit 3, FA; fractional anisotropy, CST; corticospinal tract PLIC; posterior limb of internal capsule, CR corona radiata, CP; cerebral peduncle, and CBP; cerebellar peduncle.
Discussion:
The results of this study support the feasibility of 1) performing non-sedated longitudinal MRI in very preterm infants, 2) quantifying longitudinal changes in white matter structures, and 3) utilizing change in white matter microstructure as an outcome measure to quantify changes in response to intervention in the first 6 months of life.
There is a dearth of research evaluating the feasibility of performing and quantifying longitudinal structural or connectivity changes in very preterm infants especially during the first six months of life. Our enrollment rate was 60%, which is excellent given the decline in enrollment during the 2020 COVID-19 pandemic. The proportion of families who consented to participate was higher than anticipated and is consistent with a previous neuroimaging study conducted in preterm infants.29
We also had a high retention rate, which can be attributed to the parent and infant friendly nature of the imaging protocol. Retention of participants is one of the most challenging aspects in follow up studies with the dropouts reported to be as high as 70%.30 There is evidence that parents experience higher stress due to hospital visits.31 While designing our study, we focused on the existing successful retention strategies for at-risk infants and incorporated them.32–34 For instance, mutual trust, regular family contact by a research coordinator, flexible appointment schedules (a two-week flexibility window), assistance in transport (reimbursement), granting parents the permission to accompany their infant in the actual MRI unit while image acquisition, and allowing siblings to attend the visits were some of the crucial strategies employed during this study.
Presence of a highly practiced research team and advancement in simultaneous multi-slice acquisition (SMS) for the 3T pediatric scanner, significantly reduced the time of image acquisition.35 A previous study with a 3T scanner has also reported that 3T scanner decreases the image acquisition time by a factor of 4.36 Faster and efficient scanning techniques may have contributed to the increased scan success rates with minimal motion artifacts. The success rate observed in this study regarding image acquisition and image quality is consistent with Mathur et al., who reported a success rate of 93% with image acquisition and 97% with image quality.37 To summarize, good enrollment rate, high retention rate, and increased scan success rates support the feasibility of doing non-sedated longitudinal MRI in preterm infants.
A longitudinal trend for imaging parameters was observed with an overall increase in FA values and decrease in MD in the CST, PLIC, CR, CP and CBP from baseline to six months post baseline in all five infants. This is consistent with the findings of a systematic review which reported that FA increases and MD decreases with increasing postmenstrual age in both term and preterm infants. This trend represents the ongoing organization, (pre) myelination, and decreasing water content in the brain white matter.38
Similar trends were also observed in white matter volume trajectories across all five ROIs in the five infants. The postnatal period is marked by an exponential growth in brain volume and the white matter volume increases by 11% in the first year in preterm infants.39 An increase in the white matter volume denotes multiple processes occurring successively or concomitantly such as neuronal migration, glial cell proliferation, axonal generation, oligodendrocyte proliferation, and axonal myelination.40
In the present study, we wanted to explore the potential of non-sedated MRI parameters to detect neuroplastic changes in response to intervention in very preterm infants. Our results show that FA values in the selected five ROIs showed an inconsistent longitudinal trend with regard to group allocation i.e. intervention vs no intervention. However, volume values showed a trend with the infant in the SPEEDI Early group displaying a greater increase in volume as compared to the SPEEDI Late and the usual care infant. Although no conclusions regarding the intervention effectiveness or timing can be made from this very small sample of infants, we can cautiously infer that the volume parameter could be a sensitive measure that could be used to quantify change in response to intervention. A larger sample size is needed to quantify change in FA values in response to intervention.
An interesting finding was observed in the volume values of SPEEDI Late infant. This infant scored lower than both SPEEDI Early and usual care group. The potential interpretation of these consistently lower volumes observed in the SPEEDI late infant may be related to increased biological risk as this infant was born at 23 weeks of gestation as compared to the other two infants who were born at 27 weeks of gestation. Gestational age at birth is reported to be associated with lower volumes in extremely preterm infants at term equivalent age.41 However, due to our small sample size, caution is warranted in interpreting these findings.
This pilot study has some limitations. Although our results support the feasibility of performing non-sedated MRI in very preterm infants, pertinent conclusions about the longitudinal changes observed in DTI parameters cannot be drawn from such a small sample size. The marked increase in volume over first 6 months in the one SPEEDI Early infant could be by chance and cannot be used to draw any conclusion regarding the effect of intervention. The present study did not use any standard measure to evaluate the brain injury, it was based on the clinical assessment of the pediatric neuroradiologist. However, the DTI metrics and volume interpretations were based on standardized techniques and well-developed protocol. There was also an unequal distribution of infants in the intervention and usual care group. The aim was to enroll 2 infants per group, but due to the COVID-19 pandemic we were unable to enroll the last infant and capture all the images.
Future studies should consider expanding the time points to capture the long-term longitudinal trajectory of brain development in preterm and term infants using a larger sample size. Methodologically rigorous randomized controlled designs are needed to understand and interpret the neuroplastic changes in response to intervention. Tracking the impact of intervention over time would be a determining factor about which aspects of intervention are most meaningful and support development. This will entail and empower early interventionists to provide intervention in a targeted and individualized manner.
Clinical Implications:
Despite having a small sample, we do believe these results have clinical implications beginning in the NICU. Longitudinal DTI in preterm infants should be considered to determine the exact location and extent of injury. Understanding the injury can facilitate the provision of targeted interventions during crucial window of neuroplasticity in high risk infants.
Acknowledgement:
We would like to thank children and parents who participated in this study. This work was supported under Grant #NIH NICHD 1R01HD093624 and ULTR002649 for the CTSA funding for the imaging. CEK and DKT acknowledge the support of the Royal Children’s Hospital Foundation, Murdoch Children’s Research Institute, The University of Melbourne Department of Paediatrics, and the Victorian Government’s Operational Infrastructure Support Program.
Footnotes
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
Contributor Information
Sonia Khurana, Motor Development Lab, Virginia Commonwealth University, Richmond, Virginia.
Megan E Evans, Motor Development Lab, Virginia Commonwealth University, Richmond, Virginia.
Claire E Kelly, Victorian Infant Brain Studies (VIBeS) and Developmental Imaging, Murdoch Children’s Research Institute, Parkville, Victoria, Australia..
Deanne K Thompson, Victorian Infant Brain Studies (VIBeS) and Developmental Imaging, Murdoch Children’s Research Institute, Parkville, Victoria, Australia; Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia.
Jennifer Burnsed, Division of Neonatology, University of Virginia, Charlottesville, Virginia.
Amy Harper, Department of Neurology, Virginia Commonwealth University, Richmond, Virginia.
Karen Hendricks-Munoz, Department of Pediatrics, Virginia Commonwealth University School of Medicine, Children’s Hospital of Richmond at VCU Richmond, Virginia.
Mary S Shall, Department of Physical Therapy, Virginia Commonwealth University, Richmond, Virginia.
Richard D Stevenson, Division of Neurodevelopmental and Behavioral Pediatrics, Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, Virginia.
Ketaki Inamdar, Rehabilitation and Movement Sciences, Motor Development Lab, Virginia Commonwealth University, Richmond, Virginia.
Greg Vorona, Department of Radiology, Virginia Commonwealth University, Richmond, Virginia.
Stacey C Dusing, Motor Development Lab, Department of Biokinesiology and Physical Therapy, University of Southern California.
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