Neonatal Brain Microstructure and Machine-Learning-Based Prediction of Early Language Development in Children Born Very Preterm.

BACKGROUND: Very-low-birth-weight preterm infants have a higher rate of language impairments compared with children born full term. Early identification of preterm infants at risk for language delay is essential to guide early intervention at the time of optimal neuroplasticity. This study examined near-term structural brain magnetic resonance imaging (MRI) and white matter microstructure assessed on diffusion tensor imaging (DTI) in relation to early language development in children born very preterm. METHODS: A total of 102 very-low-birth-weight neonates (birthweight≤1500g, gestational age ≤32-weeks) were recruited to participate from 2010 to 2011. Near-term structural MRI was evaluated for white matter and cerebellar abnormalities. DTI fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity were assessed. Language development was assessed with Bayley Scales of Infant-Toddler Development-III at 18 to 22 months adjusted age. Multivariate models with leave-one-out cross-validation and exhaustive feature selection identified three brain regions most predictive of language function. Distinct logistic regression models predicted high-risk infants, defined by language scores >1 S.D. below average. RESULTS: Of 102 children, 92 returned for neurodevelopmental testing. Composite language score mean ± S.D. was 89.0 ± 16.0; 31 of 92 children scored <85, including 15 of 92 scoring <70, suggesting moderate-to-severe delay. Children with cerebellar asymmetry had lower receptive language subscores (P = 0.016). Infants at high risk for language impairments were predicted based on regional white matter microstructure on DTI with high accuracy (sensitivity, specificity) for composite (89%, 86%), expressive (100%, 90%), and receptive language (100%, 90%). CONCLUSIONS: Multivariate models of near-term structural MRI and white matter microstructure on DTI may assist in identification of preterm infants at risk for language impairment, guiding early intervention.

Prediction of Gait Impairment in Toddlers Born Preterm From Near-Term Brain Microstructure Assessed With DTI, Using Exhaustive Feature Selection and Cross-Validation.

AIM: To predict gait impairment in toddlers born preterm with very-low-birth-weight (VLBW), from near-term white-matter microstructure assessed with diffusion tensor imaging (DTI), using exhaustive feature selection, and cross-validation. METHODS: Near-term MRI and DTI of 48 bilateral and corpus callosum regions were assessed in 66 VLBW preterm infants; at 18-22 months adjusted-age, 52/66 participants completed follow-up gait assessment of velocity, step length, step width, single-limb support and the Toddle Temporal-spatial Deviation Index (TDI). Multiple linear models with exhaustive feature selection and leave-one-out cross-validation were employed in this prospective cohort study: linear and logistic regression identified three brain regions most correlated with gait outcome. RESULTS: Logistic regression of near-term DTI correctly classified infants high-risk for impaired gait velocity (93% sensitivity, 79% specificity), right and left step length (91% and 93% sensitivity, 85% and 76% specificity), single-limb support (100% and 100% sensitivity, 100% and 100% specificity), step width (85% sensitivity, 80% specificity), and Toddle TDI (85% sensitivity, 75% specificity). Linear regression of near-term brain DTI and toddler gait explained 32%-49% variance in gait temporal-spatial parameters. Traditional MRI methods did not predict gait in toddlers. INTERPRETATION: Near-term brain microstructure assessed with DTI and statistical learning methods predicted gait impairment, explaining substantial variance in toddler gait. Results indicate that at near term age, analysis of a set of brain regions using statistical learning methods may offer more accurate prediction of outcome at toddler age. Infants high risk for single-limb support impairment were most accurately predicted. As a fundamental element of biped gait, single-limb support may be a sensitive marker of gait impairment, influenced by early neural correlates that are evolutionarily and developmentally conserved. For infants born preterm, early prediction of gait impairment can help guide early, more effective intervention to improve quality of life. WHAT THIS PAPER ADDS: • Accurate prediction of toddler gait from near-term brain microstructure on DTI.• Use of machine learning analysis of neonatal neuroimaging to predict gait.• Early prediction of gait impairment to guide early treatment for children born preterm.

The Pediatric Temporal-spatial Deviation Index: quantifying gait impairment for children with cerebral palsy.

AIM: To develop an easily-administered metric to quantify gait impairment in children and to assess its use in children with cerebral palsy (CP). METHOD: The Pediatric Temporal-spatial Deviation Index (TDI) was developed from gait data collected from 75 typically developing children (37 males, 38 females; mean age 9y 4mo; interquartile range [IQR] 8-10y) and 17 children diagnosed with spastic CP (nine males, eight females; mean age 9y 9mo; IQR 9-11y), in Gross Motor Function Classification System (GMFCS) levels I to III, aged 7 to 11 years. Children walked on a pressure-sensitive mat. Children with CP also completed 3D gait analysis. The Kaiser-Meyer-Olkin test of sampling adequacy was used for temporal-spatial feature selection. Principal components obtained from temporal-spatial gait parameters quantified deviation from typically developing gait. Deviation was normalized to a Pediatric TDI score mean (standard deviation [SD]) of 100 (10). The Pediatric TDI for children with CP was compared to 3D motion capture-based Gait Deviation Index (GDI). RESULTS: The Pediatric TDI was significantly lower for children with CP compared to typically developing children (p<0.001), correlated with average GDI (r=0.610, p=0.009), and demonstrated sensitivity (0.78) and specificity (0.88) to gait function, assessed with GDI. INTERPRETATION: The Pediatric TDI is an easily administered, revealing gait metric that can be used in children with CP in pediatric clinics and for research. Detection of gait abnormalities in the clinic can expedite diagnosis and treatment. What this paper adds The Pediatric Temporal-spatial Deviation Index (TDI) is a single-score index of gait deviation, based on nine parameters. The Pediatric TDI was more revealing than single temporal-spatial gait parameters. The Pediatric TDI is quick and simple to administer in the clinic.

Temporal-spatial reach parameters derived from inertial sensors correlate to neurodevelopment in toddlers born preterm.

Temporal-spatial reach parameters are revealing of upper-limb function in children with motor impairments, but have not been quantified in a toddler population. This work quantitatively characterizes temporal-spatial reach in typically-developing (TD) and very-low-birth-weight (VLBW) preterm toddlers, who are at increased risk of motor impairment. 47 children born VLBW (<1500 g birth-weight; ≤32 weeks gestation) and 22 TD children completed a reaching assessment at 18-22 months of age, adjusted for prematurity. Inertial sensors containing accelerometers, gyroscopes and magnetometers were fixed to toddlers' wrists while they reached for a cube. Reach time, path length, velocity at contact, peak velocity magnitude and timing, acceleration at contact, and peak acceleration were derived from inertial-sensor and high-speed video data. Preterm children also received the Bayley Scales of Infant Development-3rd Edition (BSID-III). Compared to TD toddlers, preterm toddlers had significantly different reach path length, velocity at contact, peak velocity magnitude and timing, acceleration at contact, and peak acceleration. Among preterm toddlers, decreased reach time (rho = -.346, p = .018), decreased time to peak velocity (r = -.390, p = .007), and increased peak acceleration (r = .298, p = .044) correlated to higher BSID-III fine motor scores. Toddlers with below-average fine motor scores had significantly higher peak and contact velocity. Preterm toddlers demonstrated substantial differences in temporal-spatial reach parameters compared to TD toddlers, and evidence indicated several reach parameters were revealing of function and may be useful as a clinical assessment.

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.

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.

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.

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 children's 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.

Temporal-spatial gait parameters and neurodevelopment in very-low-birth-weight preterm toddlers at 18-22 months.

Children born preterm with very-low birth-weight (VLBW) have increased risk of motor impairment. Early identification of impairment guides treatment to improve long-term function. Temporal-spatial gait parameters are an easily-recorded assessment of gross motor function. The objective of this study was to characterize preterm toddlers' gait and its relationship with neurodevelopment. Velocity, cycle time, step width, step length and time asymmetry, %stance, %single-limb support, and %double-limb support were calculated for 81 VLBW preterm and 43 typically-developing (TD) toddlers. Neurodevelopment was assessed with Bayley Scales of Infant Development-3rd Edition (BSID-III) motor composite and gross motor scores. Mean step width (p=.009) was wider in preterm compared to TD toddlers. Preterm toddlers with <85 BSID-III motor composite scores, indicating mild-to-moderate delay, had significantly increased step width, step length asymmetry, and step time compared to TD toddlers. Step time was also significantly longer for lower-scoring compared to higher-scoring (≥85 BSID-III motor composite scores) preterm toddlers, suggesting that step time may be particularly sensitive to gradations of motor performance. Velocity, cycle time, step length asymmetry, %stance, step length, and step time significantly correlated with BSID-III gross motor scores, suggesting that these parameters may be revealing of gross motor function. The differences in gait between lower-scoring preterm toddlers and TD toddlers, together with the correlations between gait and BSID-III motor scores, suggest that temporal-spatial gait parameters may be useful in building a clinically-relevant, easily-conducted assessment of toddler gross motor development.

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

OBJECTIVE: 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. DESIGN: Retrospective analysis of gait kinematics and clinical data collected from 2010-2013. SETTING: Motion & Gait Analysis Laboratory at Lucile Packard Children's Hospital, Stanford, CA. PARTICIPANTS: Gait analysis data from persons with spastic CP (Gross Motor Function Classification System [GMFCS] I-III) who had no prior surgery were analyzed. Participants exhibiting KF ≥20° at IC were included; the more-involved limb was analyzed. METHODS: Outcome measures were analyzed with respect to clinical findings, including passive range of motion, Selective Motor Control Assessment for the Lower Extremity (SCALE), gait kinematics, and musculoskeletal models of muscle-tendon lengths during gait. MAIN OUTCOME MEASURES: KF at IC (KFIC) and minimum KF during single-limb support (KFSLS) were investigated. RESULTS: Thirty-four participants met the inclusion criteria, and their data were analyzed (20 males and 14 females, mean age 10.1 years, range 5-20 years). Mean KFIC was 34.4 ± 8.4 degrees and correlated with lower SCALE score (ρ = -0.530, P = .004), later peak KF during swing (ρ = 0.614, P < .001), and shorter maximal muscle length of the semimembranosus (ρ = -0.359, P = .037). Mean KFSLS was 18.7 ± 14.9 and correlated to KF contracture (ρ = 0.605, P < .001) and shorter maximal muscle length of the semimembranosus (ρ = -0.572, P < .001) and medial gastrocnemius (ρ = -0.386, P = .024). GMFCS correlated more strongly to KFIC (ρ = 0.502, P = .002) than to KFSLS (ρ = 0.371, P = .031). Linear regression found that both the SCALE score (P = .001) and delayed timing of peak KF during swing (P = .001) independently predicted KFIC. KF contracture (P = .026) and maximal length of the semimembranosus (P = .043) independently predicted KFSLS. CONCLUSION: Correlates of KFIC differed from those for KFSLS and suggest that impaired selective motor control and later timing of swing-phase KF influence knee position at IC, whereas KF contracture and muscle lengths influence minimal KF in single-limb support, findings with important treatment implications.

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.

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 r(2) = 0.247; P = 0.002) and motor score (adjusted r(2) = 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 swing-phase knee flexion in individuals with spastic cerebral palsy who walk with flexed-knee gait.

OBJECTIVE: To identify clinical and biomechanical parameters that influence swing-phase knee flexion and contribute to stiff-knee gait in individuals with spastic cerebral palsy (CP) and flexed-knee gait. DESIGN: Retrospective analysis of clinical data and gait kinematics collected from 2010 to 2013. SETTING: Motion and gait analysis laboratory at a children's hospital. PARTICIPANTS: Individuals with spastic CP (N=34; 20 boys, 14 girls; mean age ± SD, 10.1±4.1y [range, 5-20y]; Gross Motor Function Classification System I-III) who walked with flexed-knee gait ≥20° at initial contact and had no prior surgery were included; the more-involved limb was analyzed. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: The magnitude and timing of peak knee flexion (PKF) during swing were analyzed with respect to clinical data, including passive range of motion and Selective Control Assessment of the Lower Extremity, and biomechanical data, including joint kinematics and hamstring, rectus femoris, and gastrocnemius muscle-tendon length during gait. RESULTS: Data from participants demonstrated that achieving a higher magnitude of PKF during swing correlated with a higher maximum knee flexion velocity in swing (ρ=.582, P<0.001) and a longer maximum length of the rectus femoris (ρ=.491, P=.003). In contrast, attaining earlier timing of PKF during swing correlated with a higher knee flexion velocity at toe-off (ρ=-.576, P<.001), a longer maximum length of the gastrocnemius (ρ=-.355, P=.039), and a greater peak knee extension during single-limb support phase (ρ=-.354, P=.040). CONCLUSIONS: Results indicate that the magnitude and timing of PKF during swing were independent, and their biomechanical correlates differed, suggesting important treatment implications for both stiff-knee and flexed-knee gait.

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 Children's 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.

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.

Functional task kinematics of the thumb carpometacarpal joint.

BACKGROUND: Abnormal biomechanical loading has been identified as an associated risk factor of osteoarthritis in the wrist and hand. Empirical data to date are insufficient to describe the role of altered biomechanics in thumb carpometacarpal (CMC) arthritis. QUESTIONS/PURPOSES: This is a pilot study to evaluate motion analysis of the upper extremity while performing functional tasks. We wished to describe the in vivo kinematics of the thumb and hand in relation to the larger joints of the upper extremity in subjects without arthritis in functional positions at rest and while loading the CMC joint. If reproducible, we then planned to compare kinematics between these subjects and a subject with advanced thumb CMC arthritis. METHODS: In vivo kinematics of the hand and upper extremity during the functional tasks of grasp, jar opening, and pinch with and without loading of the CMC joint were evaluated using cameras and a motion-capture system in four asymptomatic female subjects and one female subject with advanced radiographic (Eaton Stage IV) osteoarthritis. RESULTS: Kinematics of the hand and upper extremity can be reliably quantified. Loading of the CMC joint did not alter the hand and forearm kinematics in control subjects. In the subject with osteoarthritis, the adduction-extension deformity at the CMC joint resulted in kinematic alterations as compared with the four control subjects. CONCLUSIONS: This study represents preliminary steps in defining thumb CMC position, motion, and loading associated with activities of daily living. These findings enhance our understanding of motion at the CMC joint and how it differs in arthritic patients. LEVEL OF EVIDENCE: Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence.

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.