Zoë A. Englander

Diffuse reduction of white matter connectivity in cerebral palsy with specific vulnerability of long range fiber tracts.

Cerebral palsy (CP) is a heterogeneous group of non-progressive motor disorders caused by injury to the developing fetal or infant brain. Although the defining feature of CP is motor impairment, numerous other neurodevelopmental disabilities are associated with CP and contribute greatly to its morbidity. The relationship between brain structure and neurodevelopmental outcomes in CP is complex, and current evidence suggests that motor and developmental outcomes are related to the spatial pattern and extent of brain injury. Given that multiple disabilities are frequently associated with CP, and that there is increasing burden of neurodevelopmental disability with increasing motor severity, global white matter (WM) connectivity was examined in a cohort of 17 children with bilateral CP to test the hypothesis that increased global WM damage will be seen in the group of severely affected (Gross Motor Function Classification Scale (GMFCS) level of IV) as compared to moderately affected (GMFCS of II or III) individuals. Diffusion tensor tractography was performed and the resulting fibers between anatomically defined brain regions were quantified and analyzed in relation to GMFCS levels. Overall, a reduction in total WM connectivity throughout the brain in severe versus moderate CP was observed, including but not limited to regions associated with the sensorimotor system. Our results also show a diffuse and significant reduction in global inter-regional connectivity between severity groups, represented by inter-regional fiber count, throughout the brain. Furthermore, it was also observed that there is a significant difference (p = 0.02) in long-range connectivity in patients with severe CP as compared to those with moderate CP, whereas short-range connectivity was similar between groups. This new finding, which has not been previously reported in the CP literature, demonstrates that CP may involve distributed, network-level structural disruptions.

Brain structural connectivity increases concurrent with functional improvement: Evidence from diffusion tensor MRI in children with cerebral palsy during therapy

Cerebral Palsy (CP) refers to a heterogeneous group of permanent but non-progressive movement disorders caused by injury to the developing fetal or infant brain (Bax et al., 2005). Because of its serious long-term consequences, effective interventions that can help improve motor function, independence, and quality of life are critically needed. Our ongoing longitudinal clinical trial to treat children with CP is specifically designed to meet this challenge. To maximize the potential for functional improvement, all children in this trial received autologous cord blood transfusions (with order randomized with a placebo administration over 2 years) in conjunction with more standard physical and occupational therapies. As a part of this trial, magnetic resonance imaging (MRI) is used to improve our understanding of how these interventions affect brain development, and to develop biomarkers of treatment efficacy. In this report, diffusion tensor imaging (DTI) and subsequent brain connectome analyses were performed in a subset of children enrolled in the clinical trial (n = 17), who all exhibited positive but varying degrees of functional improvement over the first 2-year period of the study. Strong correlations between increases in white matter (WM) connectivity and functional improvement were demonstrated; however no significant relationships between either of these factors with the age of the child at time of enrollment were identified. Thus, our data indicate that increases in brain connectivity reflect improved functional abilities in children with CP. In future work, this potential biomarker can be used to help differentiate the underlying mechanisms of functional improvement, as well as to identify treatments that can best facilitate functional improvement upon un-blinding of the timing of autologous cord blood transfusions at the completion of this study.

Reduced delta power and synchrony and increased gamma power during the P3 time window in schizophrenia

BACKGROUND Event-related potential studies in schizophrenia have demonstrated amplitude reduction of the P3 in oddball tasks. The P3 has been linked to attention and memory brain functions. METHODS In 24 schizophrenia patients and 28 control subjects, wavelet transform was used to reveal event-related modulations of the EEG signal during target trials in delta, theta, alpha, beta, and gamma frequency bands. RESULTS Patients showed reductions in P3 amplitude accompanied by reduced low frequency delta-theta and increased beta-gamma band EEG activity. CONCLUSIONS These results indicate abnormalities in the synchronization and/or efficiency of neural processes involved in memory and attention networks in schizophrenia.

Identification of potential therapeutic targets in a model of neuropathic pain.

Neuropathic pain (NP) is caused by damage to the nervous system, resulting in dysfunction and aberrant pain. The cellular functions (e.g., peripheral neuron spinal cord innervation, neuronal excitability) associated with NP often develop over time and are likely associated with gene expression changes. Gene expression studies on the cells involved in NP (e.g., sensory dorsal root ganglion neurons) are publically available; the mining of these studies may enable the identification of novel targets and the subsequent development of therapies that are essential for improving quality of life for the millions of individuals suffering with NP. Here we analyzed a publically available microarray dataset (GSE30165) in order to identify new RNAs (e.g., messenger RNA (mRNA) isoforms and non-coding RNAs) underlying NP. GSE30165 profiled gene expression in dorsal root ganglion neurons (DRG) and in sciatic nerve (SN) after resection, a NP model. Gene ontological analysis shows enrichment for sensory and neuronal processes. Protein network analysis demonstrates DRG upregulated genes typical to an injury and NP response. Of the top changing genes, 34 and 36% are associated with more than one protein coding isoform in the DRG and SN, respectively. The majority of genes are receptor and enzymes. We identified 15 long non-coding RNAs (lncRNAs) targeting these genes in LNCipedia.org, an online comprehensive lncRNA database. These RNAs represent new therapeutic targets for preventing NP development and this approach demonstrates the feasibility of data reanalysis for their identification.

A comparison of patellofemoral cartilage morphology and deformation in anterior cruciate ligament deficient versus uninjured knees

Anterior cruciate ligament (ACL) deficient patients have an increased rate of patellofemoral joint (PFJ) osteoarthritis (OA) as compared to the general population. Although the cause of post-injury OA is multi-factorial, alterations in joint biomechanics may predispose patients to cartilage degeneration. This study aimed to compare in vivo PFJ morphology and mechanics between ACL deficient and intact knees in subjects with unilateral ACL ruptures. Eight male subjects underwent baseline MRI scans of both knees. They then performed a series of 60 single-legged hops, followed by a post-exercise MRI scan. This process was repeated for the contralateral knee. The MR images were converted into three-dimensional surface models of cartilage and bone in order to assess cartilage thickness distributions and strain following exercise. Prior to exercise, patellar cartilage was significantly thicker in intact knees as compared to ACL deficient knees by 1.8%. In response to exercise, we observed average patellar cartilage strains of 5.4 ± 1.1% and 2.5 ± 1.4% in the ACL deficient and intact knees, respectively. Importantly, the magnitude of patellar cartilage strain in the ACL deficient knees was significantly higher than in the intact knees. However, while trochlear cartilage experienced a mean strain of 2.4 ± 1.6%, there was no difference in trochlear cartilage strain between the ACL deficient and uninjured knees. In summary, we found that ACL deficiency was associated with decreased patellar cartilage thickness and increased exercise-induced patellar cartilage strain when compared to the uninjured contralateral knees.

Frontal Hypoactivation During a Working Memory Task in Children With 22q11 Deletion Syndrome.

Impairments in executive function, such as working memory, are almost universal in children with chromosome 22q11.2 deletion syndrome. Delineating the neural underpinnings of these functions would enhance understanding of these impairments. In this study, children and adolescents with 22q11 deletion syndrome were compared with healthy control participants in a functional magnetic resonance imaging (MRI) study of working memory. When the 2-back condition was contrasted with the 1-back and 0-back conditions, the participants with 22q11 deletion syndrome showed lower activation in several brain areas involved in working memory—notably dorsolateral prefrontal cortex, anterior cingulate, and precuneus. This hypoactivation may be due to reduced gray matter volumes or white matter connectivity in the frontal and parietal regions, differences that have previously been documented in children with 22q11 deletion syndrome. Understanding differences in brain function will provide a foundation for future interventions to address the wide range of neurodevelopmental deficits observed in 22q11 deletion syndrome.

Determination of the Position of the Knee at the Time of an Anterior Cruciate Ligament Rupture for Male Versus Female Patients by an Analysis of Bone Bruises

Background: The incidence of anterior cruciate ligament (ACL) ruptures is 2 to 4 times higher in female athletes as compared with their male counterparts. As a result, a number of recent studies have addressed the hypothesis that female and male patients sustain ACL injuries via different mechanisms. The efficacy of prevention programs may be improved by a better understanding of whether there are differences in the injury mechanism between sexes. Hypothesis/Purpose: To compare knee positions at the time of a noncontact ACL injury between sexes. It was hypothesized that there would be no differences in the position of injury. Study Design: Controlled laboratory study. Methods: Clinical T2-weighted magnetic resonance imaging (MRI) scans from 30 participants (15 male and 15 female) with a noncontact ACL rupture were reviewed retrospectively. MRI scans were obtained within 1 month of injury. Participants had contusions associated with an ACL injury on both the medial and lateral articular surfaces of the femur and tibia. Three-dimensional models of the femur, tibia, and associated bone bruises were created via segmentation on MRI. The femur was positioned relative to the tibia to maximize bone bruise overlap, thereby predicting the bone positions near the time of the injury. Flexion, valgus, internal tibial rotation, and anterior tibial translation were measured in the predicted position of injury. Results: No statistically significant differences between male and female patients were detected in the position of injury with regard to knee flexion (P = .66), valgus (P = .87), internal tibial rotation (P = .26), or anterior tibial translation (P = .18). Conclusion: These findings suggest that a similar mechanism results in an ACL rupture in both male and female athletes with this pattern of bone bruising. Clinical Relevance: This study provides a novel comparison of male and female knee positions at the time of an ACL injury that may offer information to improve injury prevention strategies.

How to Predict Knee Kinematics During an ACL Injury

The factors that ultimately lead to an anterior cruciate ligament (ACL) injury are complex. The type of sports activity, population segment, posture, bone morphology, and the internal biomechanics of the knee each play a role in risk of injury. A multitude of studies have been performed in these individual areas, which have provided information to form a prediction algorithm for ACL injury. Sports activities, such as soccer, that place a premium on jumping and landing appear to have an increased incidence of these injuries. Female athletes appear to be at a higher risk, potentially due to differences in lower extremity shape or motion patterns. Bone morphology may contribute to the likelihood of ACL injury (i.e., posterior slope and relative tibial size), and the dimensions of the “joint play envelope” may help determine the amount of force necessary to cause injury. While there is no absolute consensus on the biomechanical mechanisms leading to non-contact ACL injury, there is extensive evidence to indicate that ACL injury results from a combination of these factors. Clinicians should consider these factors when mapping out a safe return to play for sports such as soccer. Those athletes more at risk for injury may benefit from more intensive or specific physical training.

Automatic registration of MRI-based joint models to high-speed biplanar radiographs for precise quantification of in vivo anterior cruciate ligament deformation during gait

Understanding in vivo joint mechanics during dynamic activity is crucial for revealing mechanisms of injury and disease development. To this end, laboratories have utilized computed tomography (CT) to create 3-dimensional (3D) models of bone, which are then registered to high-speed biplanar radiographic data captured during movement in order to measure in vivo joint kinematics. In the present study, we describe a system for measuring dynamic joint mechanics using 3D surface models of the joint created from magnetic resonance imaging (MRI) registered to high-speed biplanar radiographs using a novel automatic registration algorithm. The use of MRI allows for modeling of both bony and soft tissue structures. Specifically, the attachment site footprints of the anterior cruciate ligament (ACL) on the femur and tibia can be modeled, allowing for measurement of dynamic ACL deformation. In the present study, we demonstrate the precision of this system by tracking the motion of a cadaveric porcine knee joint. We then utilize this system to quantify in vivo ACL deformation during gait in four healthy volunteers.

Effects of Anterior Cruciate Ligament Deficiency on Tibiofemoral Cartilage Thickness and Strains in Response to Hopping

Background: Changes in knee kinematics after anterior cruciate ligament (ACL) injury may alter loading of the cartilage and thus affect its homeostasis, potentially leading to the development of posttraumatic osteoarthritis. However, there are limited in vivo data to characterize local changes in cartilage thickness and strain in response to dynamic activity among patients with ACL deficiency. Purpose/Hypothesis: The purpose was to compare in vivo tibiofemoral cartilage thickness and cartilage strain resulting from dynamic activity between ACL-deficient and intact contralateral knees. It was hypothesized that ACL-deficient knees would show localized reductions in cartilage thickness and elevated cartilage strains. Study Design: Controlled laboratory study. Methods: Magnetic resonance images were obtained before and after single-legged hopping on injured and uninjured knees among 8 patients with unilateral ACL rupture. Three-dimensional models of the bones and articular surfaces were created from the pre- and postactivity scans. The pre- and postactivity models were registered to each other, and cartilage strain (defined as the normalized difference in cartilage thickness pre- and postactivity) was calculated in regions across the tibial plateau, femoral condyles, and femoral cartilage adjacent to the medial intercondylar notch. These measurements were compared between ACL-deficient and intact knees. Differences in cartilage thickness and strain between knees were tested with multiple analysis of variance models with alpha set at P < .05. Results: Compressive strain in the intercondylar notch was elevated in the ACL-deficient knee relative to the uninjured knee. Furthermore, cartilage in the intercondylar notch and adjacent medial tibia was significantly thinner before activity in the ACL-deficient knee versus the intact knee. In these 2 regions, thinning was significantly influenced by time since injury, with patients with more chronic ACL deficiency (>1 year since injury) experiencing greater thinning. Conclusion: Among patients with ACL deficiency, the medial femoral condyle adjacent to the intercondylar notch in the ACL-deficient knee exhibited elevated cartilage strain and loss of cartilage thickness, particularly with longer time from injury. It is hypothesized that these changes may be related to posttraumatic osteoarthritis development. Clinical Relevance: This study suggests that altered mechanical loading is related to localized cartilage thinning after ACL injury.