Katelyn Cahill-Rowley

Brain microstructural development at near-term age in very-low-birth-weight preterm infants: an atlas-based diffusion imaging study.

At near-term age the brain undergoes rapid growth and development. Abnormalities identified during this period have been recognized as potential predictors of neurodevelopment in children born preterm. This study used diffusion tensor imaging (DTI) to examine white matter (WM) microstructure in very-low-birth-weight (VLBW) preterm infants to better understand regional WM developmental trajectories at near-term age. DTI scans were analyzed in a cross-sectional sample of 45 VLBW preterm infants (BW≤1500g, GA≤32weeks) within a cohort of 102 neonates admitted to the NICU and recruited to participate prior to standard-of-care MRI, from 2010 to 2011, 66/102 also had DTI. For inclusion in this analysis, 45 infants had DTI, no evidence of brain abnormality on MRI, and were scanned at PMA ≤40weeks (34.7-38.6). White matter microstructure was analyzed in 19 subcortical regions defined by DiffeoMap neonatal brain atlas, using threshold values of trace <0.006mm(2)s(-1) and FA >0.15. Regional fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were calculated and temporal-spatial trajectories of development were examined in relation to PMA and brain region location. Posterior regions within the corona radiata (CR), corpus callosum (CC), and internal capsule (IC) demonstrated significantly higher mean FA values compared to anterior regions. Posterior regions of the CR and IC demonstrated significantly lower RD values compared to anterior regions. Centrally located projection fibers demonstrated higher mean FA and lower RD values than peripheral regions including the posterior limb of the internal capsule (PLIC), cerebral peduncle, retrolenticular part of the IC, posterior thalamic radiation, and sagittal stratum. Centrally located association fibers of the external capsule had higher FA and lower RD than the more peripherally-located superior longitudinal fasciculus (SLF). A significant relationship between PMA-at-scan and FA, MD, and RD was demonstrated by a majority of regions, the strongest correlations were observed in the anterior limb of the internal capsule, a region undergoing early stages of myelination at near-term age, in which FA increased (r=.433, p=.003) and MD (r=-.545, p=.000) and RD (r=-.540, p=.000) decreased with PMA-at-scan. No correlation with PMA-at-scan was observed in the CC or SLF, regions that myelinate later in infancy. Regional patterns of higher FA and lower RD were observed at this near-term age, suggestive of more advanced microstructural development in posterior compared to anterior regions within the CR, CC, and IC and in central compared to peripheral WM structures. Evidence of region-specific rates of microstructural development was observed. Temporal-spatial patterns of WM microstructure development at near-term age have important implications for interpretation of near-term DTI and for identification of aberrations in typical developmental trajectories that may signal future impairment.

Etiology of impaired selective motor control: emerging evidence and its implications for research and treatment in cerebral palsy

Selective motor control (SMC) impairment involves movement patterns dominated by flexor or extensor synergies that interfere with functional movements in children with cerebral palsy (CP). Emerging evidence on neural correlates of impaired SMC has important implications for etiology and for the treatment for children with CP. Early evidence on the microstructure of brain white matter assessed with diffusion tensor imaging in adult patients after stroke suggests that the rubrospinal tract may compensate for injury to the corticospinal tract. Furthermore, the observed changes on diffusion tensor imaging corresponded to the degree of SMC impairment. The rubrospinal tract may provide imperfect compensation in response to corticospinal tract injury, resulting in diminished SMC. Cortical mapping evidence in stroke patients indicates that loss of SMC is also associated with increased overlap of joint representation in the sensorimotor cortices. The severity of SMC impairment can be assessed with the recently developed Selective Control Assessment of the Lower Extremity, a validated observation‐based measure designed for children with spastic CP. Recent advances in neuroimaging and assessment of SMC provide an opportunity to better understand the etiology and impact of impaired SMC, which may ultimately guide strategic treatment for children with CP.

Neonatal physiological correlates of near-term brain development on MRI and DTI in very-low-birth-weight preterm infants

Structural brain abnormalities identified at near-term age have been recognized as potential predictors of neurodevelopment in children born preterm. The aim of this study was to examine the relationship between neonatal physiological risk factors and early brain structure in very-low-birth-weight (VLBW) preterm infants using structural MRI and diffusion tensor imaging (DTI) at near-term age. Structural brain MRI, diffusion-weighted scans, and neonatal physiological risk factors were analyzed in a cross-sectional sample of 102 VLBW preterm infants (BW ≤ 1500 g, gestational age (GA) ≤ 32 weeks), who were admitted to the Lucile Packard Childrens Hospital, Stanford NICU and recruited to participate prior to routine near-term brain MRI conducted at 36.6 ± 1.8 weeks postmenstrual age (PMA) from 2010 to 2011; 66/102 also underwent a diffusion-weighted scan. Brain abnormalities were assessed qualitatively on structural MRI, and white matter (WM) microstructure was analyzed quantitatively on DTI in six subcortical regions defined by DiffeoMap neonatal brain atlas. Specific regions of interest included the genu and splenium of the corpus callosum, anterior and posterior limbs of the internal capsule, the thalamus, and the globus pallidus. Regional fractional anisotropy (FA) and mean diffusivity (MD) were calculated using DTI data and examined in relation to neonatal physiological risk factors including gestational age (GA), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), and sepsis, as well as serum levels of C-reactive protein (CRP), glucose, albumin, and total bilirubin. Brain abnormalities were observed on structural MRI in 38/102 infants including 35% of females and 40% of males. Infants with brain abnormalities observed on MRI had higher incidence of BPD (42% vs. 25%) and sepsis (21% vs. 6%) and higher mean and peak serum CRP levels, respectively, (0.64 vs. 0.34 mg/dL, p = .008; 1.57 vs. 0.67 mg/dL, p= .006) compared to those without. The number of signal abnormalities observed on structural MRI correlated to mean and peak CRP (rho = .316, p = .002; rho = .318, p= .002). The number of signal abnormalities observed on MRI correlated with thalamus MD (left: r= .382, p= .002; right: r= .400, p= .001), controlling for PMA-at-scan. Thalamus WM microstructure demonstrated the strongest associations with neonatal risk factors. Higher thalamus MD on the left and right, respectively, was associated with lower GA (r = −.322, p = .009; r= −.381, p= .002), lower mean albumin (r = −.276, p= .029; r= −.385, p= .002), and lower mean bilirubin (r = −.293, p= .020; r= −.337 p= .007). Results suggest that at near-term age, thalamus WM microstructure may be particularly vulnerable to certain neonatal risk factors. Interactions between albumin, bilirubin, phototherapy, and brain development warrant further investigation. Identification of physiological risk factors associated with selective vulnerability of certain brain regions at near-term age may clarify the etiology of neurodevelopmental impairment and inform neuroprotective treatment for VLBW preterm infants.

Neonatal brain microstructure correlates of neurodevelopment and gait in preterm children 18–22 mo of age: an MRI and DTI study

Background:Near-term brain structure was examined in preterm infants in relation to neurodevelopment. We hypothesized that near-term macrostructural brain abnormalities identified using conventional magnetic resonance imaging (MRI), and white matter (WM) microstructure detected using diffusion tensor imaging (DTI), would correlate with lower cognitive and motor development and slower, less-stable gait at 18–22 mo of age.Methods:One hundred and two very-low-birth-weight preterm infants (≤1,500 g birth weight; ≤32 wk gestational age) were recruited prior to routine near-term brain MRI at 36.6 ± 1.8 wk postmenstrual age. Cerebellar and WM macrostructure was assessed on conventional structural MRI. DTI was obtained in 66 out of 102 and WM microstructure was assessed using fractional anisotropy and mean diffusivity (MD) in six subcortical brain regions defined by DiffeoMap neonatal atlas. Neurodevelopment was assessed with Bayley-Scales-of-Infant-Toddler-Development, 3rd-Edition (BSID-III); gait was assessed using an instrumented mat.Results:Neonates with cerebellar abnormalities identified using MRI demonstrated lower mean BSID-III cognitive composite scores (89.0 ± 10.1 vs. 97.8 ± 12.4; P = 0.002) at 18–22 mo. Neonates with higher DTI-derived left posterior limb of internal capsule (PLIC) MD demonstrated lower cognitive and motor composite scores (r = −0.368; P = 0.004; r = −0.354; P = 0.006) at 18–22 mo; neonates with higher genu MD demonstrated slower gait velocity (r = −0.374; P = 0.007). Multivariate linear regression significantly predicted cognitive (adjusted r2 = 0.247; P = 0.002) and motor score (adjusted r2 = 0.131; P = 0.017).Conclusion:Near-term cerebellar macrostructure and PLIC and genu microstructure were predictive of early neurodevelopment and gait.

Biomechanical and Clinical Correlates of Stance-Phase Knee Flexion in Persons With Spastic Cerebral Palsy

To identify biomechanical and clinical parameters that influence knee flexion (KF) angle at initial contact (IC) and during single limb stance phase of gait in children with spastic cerebral palsy (CP) who walk with flexed‐knee gait.

Neonatal Biomarkers of Inflammation: Correlates of Early Neurodevelopment and Gait in Very-Low-Birth-Weight Preterm Children.

OBJECTIVE Neonatal biomarkers of inflammation were examined in relation to early neurodevelopment and gait in very-low-birth-weight (VLBW) preterm children. We hypothesized that preterm infants exposed to higher levels of neonatal inflammation would demonstrate lower scores on Bayley Scales of Infant Toddler Development, 3rd ed. (BSID-III) and slower gait velocity at 18 to 22 months adjusted age. STUDY DESIGN A total of 102 VLBW preterm infants (birthweight [BW] ≤ 1,500 g, gestational age [GA] ≤ 32 weeks) admitted to neonatal intensive care unit [NICU] were recruited. Neonatal risk factors examined were GA at birth, BW, bronchopulmonary dysplasia, necrotizing enterocolitis, retinopathy of prematurity, sepsis, and serum C-reactive protein (CRP), albumin, and total bilirubin over first 2 postnatal weeks. At 18 to 22 months, neurodevelopment was assessed with BSID-III and gait was assessed with an instrumented mat. RESULTS Children with neonatal CRP ≥ 0.20 mg/dL (n = 52) versus < 0.20 mg/dL (n = 37) had significantly lower BSID-III composite cognitive (92.0 ± 13.1 vs. 100.1 ± 9.6, p = 0.002), language (83.9 ± 16.0 vs. 95.8 ± 14.2, p < 0.001), and motor scores (90.0 ± 13.2 vs. 98.8 ± 10.1, p = 0.002), and slower gait velocity (84.9 ± 19.0 vs. 98.0 ± 22.4 cm/s, p = 0.004). Higher neonatal CRP correlated with lower cognitive (rho =  - 0.327, p = 0.002), language (rho =  - 0.285, p = 0.007), and motor scores (rho =  - 0.257, p = 0.015), and slower gait (rho =  - 0.298, p = 0.008). Multivariate analysis demonstrated neonatal CRP ≥ 0.20 mg/dL significantly predicted BSID-III cognitive (adjusted R(2) = 0.104, p = 0.008), language (adjusted R(2) = 0.124, p = 0.001), and motor scores (adjusted R(2) = 0.122, p = 0.004). CONCLUSIONS Associations between low-level neonatal inflammation and neurodevelopment suggest early biomarkers that may inform neuroprotective treatment for preterm children.

Temporal–spatial reach parameters derived from inertial sensors: Comparison to 3D marker-based motion capture

Reaching is a well-practiced functional task crucial to daily living activities, and temporal-spatial measures of reaching reflect function for both adult and pediatric populations with upper-extremity motor impairments. Inertial sensors offer a mobile and inexpensive tool for clinical assessment of movement. This research outlines a method for measuring temporal-spatial reach parameters using inertial sensors, and validates these measures with traditional marker-based motion capture. 140 reaches from 10 adults, and 30 reaches from nine children aged 18-20 months, were recorded and analyzed using both inertial-sensor and motion-capture methods. Inertial sensors contained three-axis accelerometers, gyroscopes, and magnetometers. Gravitational offset of accelerometer data was measured when the sensor was at rest, and removed using sensor orientation measured at rest and throughout the reach. Velocity was calculated by numeric integration of acceleration, using a null-velocity assumption at reach start. Sensor drift was neglected given the 1-2s required for a reach. Temporal-spatial reach parameters were calculated independently for each data acquisition method. Reach path length and distance, peak velocity magnitude and timing, and acceleration at contact demonstrated consistent agreement between sensor- and motion-capture-based methods, for both adult and toddler reaches, as evaluated by intraclass correlation coefficients from 0.61 to 1.00. Taken together with actual difference between method measures, results indicate that these functional reach parameters may be reliably measured with inertial sensors.

Artificial Walking Technologies to Improve Gait in Cerebral Palsy: Multichannel Neuromuscular Stimulation

Cerebral palsy (CP) is the most common childhood motor disability and often results in debilitating walking abnormalities, such as flexed-knee and stiff-knee gait. Current medical and surgical treatments are only partially effective in improving gait abnormalities and may cause significant muscle weakness. However, emerging artificial walking technologies, such as step-initiated, multichannel neuromuscular electrical stimulation (NMES), can substantially improve gait patterns and promote muscle strength in children with spastic CP. NMES may also be applied to specific lumbar-sacral sensory roots to reduce spasticity. Development of tablet computer-based multichannel NMES can leverage lightweight, wearable wireless stimulators, advanced control design, and surface electrodes to activate lower-limb muscles. Musculoskeletal models have been used to characterize muscle contributions to unimpaired gait and identify high muscle demands, which can help guide multichannel NMES-assisted gait protocols. In addition, patient-specific NMES-assisted gait protocols based on 3D gait analysis can facilitate the appropriate activation of lower-limb muscles to achieve a more functional gait: stance-phase hip and knee extension and swing-phase sequence of hip and knee flexion followed by rapid knee extension. NMES-assisted gait treatment can be conducted as either clinic-based or home-based programs. Rigorous testing of multichannel NMES-assisted gait training protocols will determine optimal treatment dosage for future clinical trials. Evidence-based outcome evaluation using 3D kinematics or temporal-spatial gait parameters will help determine immediate neuroprosthetic effects and longer term neurotherapeutic effects of step-initiated, multichannel NMES-assisted gait in children with spastic CP. Multichannel NMES is a promising assistive technology to help children with spastic CP achieve a more upright, functional gait.

Prediction of cognitive and motor development in preterm children using exhaustive feature selection and cross-validation of near-term white matter microstructure

Background Advanced neuroimaging and computational methods offer opportunities for more accurate prognosis. We hypothesized that near-term regional white matter (WM) microstructure, assessed on diffusion tensor imaging (DTI), using exhaustive feature selection with cross-validation would predict neurodevelopment in preterm children. Methods Near-term MRI and DTI obtained at 36.6 ± 1.8 weeks postmenstrual age in 66 very-low-birth-weight preterm neonates were assessed. 60/66 had follow-up neurodevelopmental evaluation with Bayley Scales of Infant-Toddler Development, 3rd-edition (BSID-III) at 18–22 months. Linear models with exhaustive feature selection and leave-one-out cross-validation computed based on DTI identified sets of three brain regions most predictive of cognitive and motor function; logistic regression models were computed to classify high-risk infants scoring one standard deviation below mean. Results Cognitive impairment was predicted (100% sensitivity, 100% specificity; AUC = 1) by near-term right middle-temporal gyrus MD, right cingulate-cingulum MD, left caudate MD. Motor impairment was predicted (90% sensitivity, 86% specificity; AUC = 0.912) by left precuneus FA, right superior occipital gyrus MD, right hippocampus FA. Cognitive score variance was explained (29.6%, cross-validated Rˆ2 = 0.296) by left posterior-limb-of-internal-capsule MD, Genu RD, right fusiform gyrus AD. Motor score variance was explained (31.7%, cross-validated Rˆ2 = 0.317) by left posterior-limb-of-internal-capsule MD, right parahippocampal gyrus AD, right middle-temporal gyrus AD. Conclusion Search in large DTI feature space more accurately identified neonatal neuroimaging correlates of neurodevelopment.

Toddle temporal-spatial deviation index: Assessment of pediatric gait

This research aims to develop a gait index for use in the pediatric clinic as well as research, that quantifies gait deviation in 18-22 month-old children: the Toddle Temporal-spatial Deviation Index (Toddle TDI). 81 preterm children (≤32 weeks) with very-low-birth-weights (≤1500g) and 42 full-term TD children aged 18-22 months, adjusted for prematurity, walked on a pressure-sensitive mat. Preterm children were administered the Bayley Scales of Infant Development-3rd Edition (BSID-III). Principle component analysis of TD childrens temporal-spatial gait parameters quantified raw gait deviation from typical, normalized to an average(standard deviation) Toddle TDI score of 100(10), and calculated for all participants. The Toddle TDI was significantly lower for preterm versus TD children (86 vs. 100, p=0.003), and lower in preterm children with <85 vs. ≥85 BSID-III motor composite scores (66 vs. 89, p=0.004). The Toddle TDI, which by design plateaus at typical average (BSID-III gross motor 8-12), correlated with BSID-III gross motor (r=0.60, p<0.001) and not fine motor (r=0.08, p=0.65) in preterm children with gross motor scores ≤8, suggesting sensitivity to gross motor development. The Toddle TDI demonstrated sensitivity and specificity to gross motor function in very-low-birth-weight preterm children aged 18-22 months, and has been potential as an easily-administered, revealing clinical gait metric.