John P. Phillips

A Baseline for the Multivariate Comparison of Resting-State Networks

As the size of functional and structural MRI datasets expands, it becomes increasingly important to establish a baseline from which diagnostic relevance may be determined, a processing strategy that efficiently prepares data for analysis, and a statistical approach that identifies important effects in a manner that is both robust and reproducible. In this paper, we introduce a multivariate analytic approach that optimizes sensitivity and reduces unnecessary testing. We demonstrate the utility of this mega-analytic approach by identifying the effects of age and gender on the resting-state networks (RSNs) of 603 healthy adolescents and adults (mean age: 23.4 years, range: 12–71 years). Data were collected on the same scanner, preprocessed using an automated analysis pipeline based in SPM, and studied using group independent component analysis. RSNs were identified and evaluated in terms of three primary outcome measures: time course spectral power, spatial map intensity, and functional network connectivity. Results revealed robust effects of age on all three outcome measures, largely indicating decreases in network coherence and connectivity with increasing age. Gender effects were of smaller magnitude but suggested stronger intra-network connectivity in females and more inter-network connectivity in males, particularly with regard to sensorimotor networks. These findings, along with the analysis approach and statistical framework described here, provide a useful baseline for future investigations of brain networks in health and disease.

A prospective diffusion tensor imaging study in mild traumatic brain injury

Objectives: Only a handful of studies have investigated the nature, functional significance, and course of white matter abnormalities associated with mild traumatic brain injury (mTBI) during the semi-acute stage of injury. The present study used diffusion tensor imaging (DTI) to investigate white matter integrity and compared the accuracy of traditional anatomic scans, neuropsychological testing, and DTI for objectively classifying mTBI patients from controls. Methods: Twenty-two patients with semi-acute mTBI (mean = 12 days postinjury), 21 matched healthy controls, and a larger sample (n = 32) of healthy controls were studied with an extensive imaging and clinical battery. A subset of participants was examined longitudinally 3–5 months after their initial visit. Results: mTBI patients did not differ from controls on clinical imaging scans or neuropsychological performance, although effect sizes were consistent with literature values. In contrast, mTBI patients demonstrated significantly greater fractional anisotropy as a result of reduced radial diffusivity in the corpus callosum and several left hemisphere tracts. DTI measures were more accurate than traditional clinical measures in classifying patients from controls. Longitudinal data provided preliminary evidence of partial normalization of DTI values in several white matter tracts. Conclusions: Current findings of white matter abnormalities suggest that cytotoxic edema may be present during the semi-acute phase of mild traumatic brain injury (mTBI). Initial mechanical damage to axons disrupts ionic homeostasis and the ratio of intracellular and extracellular water, primarily affecting diffusion perpendicular to axons. Diffusion tensor imaging measurement may have utility for objectively classifying mTBI, and may serve as a potential biomarker of recovery.

Endurance and gait in children with cerebral palsy after intensive body weight-supported treadmill training.

Purpose: This study was designed to investigate changes in endurance, functional gait, and balance after intensive body weight-supported treadmill training in children with CP who were ambulatory. Methods: Six school-aged children with CP (four boys, two girls; age range: six to 14 years) participated in an intensive program of body weight-supported treadmill training 30 minutes twice daily for two weeks. Results: Statistically significant improvement in walking velocity and energy expenditure were observed. Variability of individual outcomes was observed with some children showing positive changes, and others no change or a decline in performance. Four children showed minimal detectable changes in a positive direction on both an endurance measure and a functional gait measure. Each endurance and functional gait measure included at least one child with a positive minimal detectable change. Conclusion: Intensive body weight-supported treadmill training may be an effective intervention for some children with CP who are ambulatory.

Auditory Orienting and Inhibition of Return in Mild Traumatic Brain Injury: A FMRI Study

The semiacute phase of mild traumatic brain injury (mTBI) is associated with deficits in the cognitive domains of attention, memory, and executive function, which previous work suggests may be related to a specific deficit in disengaging attentional focus. However, to date, there have only been a few studies that have employed dynamic imaging techniques to investigate the potential neurological basis of these cognitive deficits during the semiacute stage of injury. Therefore, event‐related functional magnetic resonance imaging was used to investigate the neurological correlates of attentional dysfunction in a clinically homogeneous sample of 16 patients with mTBI during the semiacute phase of injury (<3 weeks). Behaviorally, patients with mTBI exhibited deficits in disengaging and reorienting auditory attention following invalid cues as well as a failure to inhibit attentional allocation to a cued spatial location compared to a group of matched controls. Accordingly, patients with mTBI also exhibited hypoactivation within thalamus, striatum, midbrain nuclei, and cerebellum across all trials as well as hypoactivation in the right posterior parietal cortex, presupplementary motor area, bilateral frontal eye fields, and right ventrolateral prefrontal cortex during attentional disengagement. Finally, the hemodynamic response within several regions of the attentional network predicted response times better for controls than for patients with mTBI. These objective neurological findings represent a potential biomarker for the behavioral deficits in spatial attention that characterize the initial recovery phase of mTBI. Hum Brain Mapp, 2009.

Ankle dorsiflexion fMRI in children with cerebral palsy undergoing intensive body‐weight‐supported treadmill training: a pilot study

This pilot study investigated the feasibility of using functional magnetic resonance imaging (fMRI) as a physiological marker of brain plasticity before and after an intensive body‐weight‐supported treadmill training (BWSTT) program in children with cerebral palsy (CP). Six ambulatory children (four males, two females; mean age 10y 6mo, age range 6–14y) with spastic CP (four hemiplegia, two asymmetric diplegia, all Gross Motor Function Classification System Level I) received BWSTT twice daily for 2 weeks. All children tolerated therapy; only one therapy session was aborted due to fatigue. With training, over ground mean walking speed increased from 1.47 to 1.66m/s (p=0.035). There was no change in distance walked for 6 minutes (pre‐: 451m; post‐: 458m;p 0.851). In three children, reliable fMRIs were taken of cortical activation pre‐ and post‐intervention. Post‐intervention increases in cortical activation during ankle dorsiflexion were observed in all three children. This study demonstrates that children with CP between 6 and 14 years of age can tolerate intensive locomotor training and, with appropriate modifications, can complete an fMRI series. This study supports further studies designed to investigate training‐dependent plasticity in children with CP.

Hypoxic-ischemic encephalopathy in areas of primary myelination: a neuroimaging and PET study

The stage of regional structural and biochemical development of the central nervous system appears as a critical factor determining the distribution of hypoxic-ischemic lesions during the perinatal period. We describe the brain lesions in 12 patients who suffered hypoxia-ischemia during the perinatal period. The gestational age ranged from 35 to 42 weeks and the age at death from 2 to 16 weeks. There is one patient alive at age 18 years and a second patient at age 1 year. The cerebral cortical damage is mainly restricted to areas of primary myelination and adjacent subcortical white matter. In addition, there is thalamic, basal ganglia, brainstem, and spinal cord damage. It is postulated that selective damage occurs in those areas which at the moment of the hypoxic-ischemic insult had achieved higher rates of oxygen-glucose utilization. This hypothesis is supported by studies utilizing positron emission tomography which indicates that glucose utilization in the normal human neonatal brain follows a phylogenetic order. Regions that achieved higher levels of glucose consumption are those that suffered the brunt of the damage in our term neonates.

Functional connectivity in the developing brain: A longitudinal study from 4 to 9months of age

We characterize the development of intrinsic connectivity networks (ICNs) from 4 to 9months of age with resting state magnetic resonance imaging performed on sleeping infants without sedative medication. Data is analyzed with independent component analysis (ICA). Using both low (30 components) and high (100 components) ICA model order decompositions, we find that the functional network connectivity (FNC) map is largely similar at both 4 and 9months. However at 9months the connectivity strength decreases within local networks and increases between more distant networks. The connectivity within the default-mode network, which contains both local and more distant nodes, also increases in strength with age. The low frequency power spectrum increases with age only in the posterior cingulate cortex and posterior default mode network. These findings are consistent with a general developmental pattern of increasing longer distance functional connectivity over the first year of life and raise questions regarding the developmental importance of the posterior cingulate at this age.

Prematurity Affects Cortical Maturation in Early Childhood

Cortical development in the first years of age for children with very low birth weight is not well characterized. We obtained high-resolution structural magnetic resonance images from children aged 18-22 months (16 very low birth weight/7 term) and 3-4 years (12 very low birth weight/8 term). Cortical surface area and thickness of the brain were assessed using the FreeSurfer data analysis program, and manually inspected for accuracy. For children with very low birth weight, a negative correlation was evident between birth weight and cortical thickness at 18-22 months (P = 0.04), and a positive correlation with cortical surface area at 3-4 years (P = 0.02). Between groups, children with very low birth weight demonstrated a consistent trend for thicker cortices and reduced surface area, compared with control term children (18-22 month surface area, P = 0.08; thickness, P = 0.11; 3-4 year surface area, P = 0.73; thickness, P = 0.14). The normal processes of cortical thinning and surface area expansion in the first several years of age may be delayed by premature delivery, a potentially more prominent effect with greater degrees of prematurity.

Effects of constraint-induced movement therapy on hand skills and muscle recruitment of children with spastic hemiplegic cerebral palsy.

BACKGROUND Constraint-Induced Movement Therapy (CIMT) is a therapeutic intervention using constraint of the less-affected limb and intensive use of the hemiplegic extremity in individuals with hemiplegia. The purpose of this study was to determine whether children with cerebral palsy (CP) who have undergone a 2-week function-based CIMT show improved hand function and underlying muscle activation changes associated with functional gains. METHODS Six children with hemiplegic CP participated in the study, receiving 4 hours of therapy 5 days a week coupled with bi-valve casts worn 8-12 hours for 14 days. Outcome measures of grip strength, pinch strength, dexterity tests and electromyography (EMG) were compared before, immediately post- and 3 months post-intervention. RESULTS Repeated measures ANOVA and post hoc paired t-tests showed significant group improvements in all strength and dexterity measures (p < 0.05). EMG analysis showed significant increases in muscle activation on pinch measures (p = 0.05). Visual inspection of the EMG data suggested increased muscle activation during grip and a decrease in the muscle activation required during dexterity tasks. CONCLUSIONS Our preliminary results support CIMT for improving strength and dexterity in children with hemiplegic CP. Further studies with greater sample sizes and longer study periods are recommended to determine muscle activation changes post CIMT.

Mother–infant mutual eye gaze supports emotion regulation in infancy during the Still-Face paradigm

This study was designed to examine the sequential relationship between mother-infant synchrony and infant affect using multilevel modeling during the Still Face paradigm. We also examined self-regulatory behaviors that infants use during the Still-Face paradigm to modulate their affect, particularly during stressors where their mothers are not available to help them co-regulate. There were 84 mother-infant dyads, of healthy full term 4 month old infants. Second-by-second coding of infant self-regulation and infant affect was done, in addition to mother-infant mutual eye gaze. Using multilevel modeling, we found that infant affect became more positive when mutual gaze had occurred the previous second, suggesting that the experience of synchronicity was associated with observable shifts in affect. We also found a positive association between self-regulatory behaviors and increases in positive affect only during the Still-Face episode (episode 2). Our study provides support for the role of mother-infant synchronicity in emotion regulation as well as support for the role of self-regulatory behaviors in emotion regulation that can have important implication for intervention.