Janice E. Brunstrom

Two modes of radial migration in early development of the cerebral cortex.

Layer formation in the developing cerebral cortex requires the movement of neurons from their site of origin to their final laminar position. We demonstrate, using time-lapse imaging of acute cortical slices, that two distinct forms of cell movement, locomotion and somal translocation, are responsible for the radial migration of cortical neurons. These modes are distinguished by their dynamic properties and morphological features. Locomotion and translocation are not cell-type specific; although at early ages some cells may move by translocation only, locomoting cells also translocate once their leading process reaches the marginal zone. The existence of two modes of radial migration may account for the differential effects of certain genetic mutations on cortical development.

Promotion of Physical Fitness and Prevention of Secondary Conditions for Children With Cerebral Palsy: Section on Pediatrics Research Summit Proceedings

Inadequate physical fitness is a major problem affecting the function and health of children with cerebral palsy (CP). Lack of optimal physical activity may contribute to the development of secondary conditions associated with CP such as chronic pain, fatigue, and osteoporosis. The purpose of this article is to highlight the content and recommendations of a Pediatrics Research Summit developed to foster collaborative research in this area. Two components of physical fitness—muscle strength and cardiorespiratory fitness—were emphasized. Although there is evidence to support the use of physical fitness interventions, there are many gaps in our current knowledge. Additional research of higher quality and rigor is needed in order to make definitive recommendations regarding the mode, intensity, frequency, and duration of exercise. Outcome measurements have focused on the body functions and structures level of the International Classification of Functioning, Disability and Health (ICF), and much less is known about effects at the activities and participation levels. Additionally, the influence of nutritional and growth factors on physical fitness has not been studied in this population, in which poor growth and skeletal fragility have been identified as serious health issues. Current intervention protocols and outcome measurements were critically evaluated, and recommendations were made for future research.

Neuronal Heterotopias in the Developing Cerebral Cortex Produced by Neurotrophin-4

The marginal zone (MZ) of embryonic neocortex is crucial to its normal development. We report that neurotrophin-4 (but not NT3 or NGF), applied to embryonic rodent cortex in vitro or in vivo, produces heterotopic accumulations of neurons in the MZ. Although heterotopia production is TrkB mediated, BDNF is >10-fold less effective than NT4. Heterotopic neurons have the same birth date and phenotype as normal MZ neurons; they are not the result of NT4-induced proliferation or rescue from apoptosis. We suggest that NT4 causes excess neurons to migrate into the MZ and thus may play a role in normal MZ formation as well as in the pathogenesis of certain human cortical dysplasias.

New directions for neuronal migration

Analysis of genetic mutations that lead to abnormal migration and layer formation in the developing cerebral cortex of mice and humans has led to important new discoveries regarding the molecular mechanisms that underlie these processes. Genetic manipulation and experimental analysis have demonstrated significant tangential migrations of cortical neurons, some arriving from very distant noncortical sites.

Joint-Position Sense and Kinesthesia in Cerebral Palsy

OBJECTIVES To examine joint-position sense and kinesthesia in all extremities in participants with diplegic or hemiplegic cerebral palsy (CP). DESIGN Survey of joint-position sense and kinesthesia differences between aged-matched controls and 2 groups with CP. SETTING University movement assessment laboratory. PARTICIPANTS Population-based sample of participants with CP, diplegia (n=21), hemiplegia (n=17), and age-matched volunteers (n=21) without neurologic disease. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Joint-position sense and kinesthesia were measured in the transverse plane (forearm pronation/supination and hip internal/external rotation) using a custom-built device. For joint-position sense, participants actively rotated the tested limb to align the distal end with 10 target positions first with the limb and targets visible to assess their ability to perform the task motorically. The task was then repeated with vision of the limb occluded, with targets remaining visible. Joint-position sense error was determined by the magnitude and direction of the rotation errors for each limb in the vision and no vision conditions. Kinesthesia was evaluated by the ability to detect passive limb rotation without vision. RESULTS No group differences were detected in the vision condition. Indicative of joint-position sense deficits, a significant increase in errors was found in the no vision condition in all limbs except the dominant upper limb for both groups with CP. Joint-position sense errors were systematically biased toward the direction of internal rotation. Kinesthesia deficits were evident on the nondominant upper limb in diplegia and hemiplegia, and bilaterally in the lower limbs in hemiplegia. In hemiplegia, joint-position sense and kinesthesia deficits were noted on the dominant limbs, but were significantly worse on the nondominant limbs. CONCLUSIONS These results indicate that people with CP have proprioception deficits in all limbs.

Inhibitory Control Following Perinatal Brain Injury

Evidence from developmental, lesion, and neuroimaging studies indicates that the prefrontal cortex plays a major role in executive abilities, including inhibitory control. Proficient executive performance, however, relies not only on the integrity of the prefrontal cortex but also on its interactions with other brain regions. In the current study, the authors focused on the effect that early damage to the white matter tracts interconnecting prefrontal and other brain regions has on inhibitory control. Data were collected from 13 children with bilateral spastic cerebral palsy and from a control group of 20 children with no history of neurologic compromise. Converging evidence from 3 separate paradigms is presented that strongly suggests these children experience impairments in inhibitory control. Findings are discussed within the context of current cognitive and neuroanatomical models of inhibition.

Tactile sensory abilities in cerebral palsy: deficits in roughness and object discrimination

Motor deficits in cerebral palsy (CP) have been well documented; however, associated sensory impairment in CP remains poorly understood. We examined tactile object recognition in the hands using geometric shapes, common objects, and capital letters. Discrimination of tactile roughness was tested using paired horizontal gratings of varied groove widths passively translated across the index finger. We tested 17 individuals with hemiplegia (mean 13y 9mo [SD 5y 2mo]; 6 males, 11 females), 21 with diplegia (mean 14y 10mo [SD 7y]; 10 males, 11 females), and 21 without disabilities (mean 14y 10mo [SD 5y 1mo]; 11 males, 10 females). All participants with CP fell within level I or II of the Gross Motor Function Classification System and level I or II of the Manual Abilities Classification System. Individuals with CP were significantly less accurate compared with those without disabilities on all tactile object‐recognition tasks using their non‐dominant hand. Both groups of patients also had significantly higher thresholds for groove‐width differences with both hands compared with those without disabilities. Within the group with diplegia, only roughness discrimination differed between hands, whereas within the group with hemiplegia, significant between‐limb differences were present for all tasks. Despite mild motor deficits compared with the entire population of individuals with CP, this sample demonstrated ubiquitous tactile deficits.

High dose botulinum toxin A for the treatment of lower extremity hypertonicity in children with cerebral palsy

The aim of this study was to determine the safety profile of high dose (15‐25 units/kg) of botulinum toxin A (BTX‐A) in children with cerebral palsy (CP) and increased lower extremity muscle tone. We performed a retrospective review of 929 patient encounters at the Movement Disorders Center at Washington University. A total of 261 patients (105 females; 156 males) were treated during these visits, ages 6 months to 21 years (mean 8y 4mo [SD 4y 8mo]). Ambulatory ability at the time of BTX‐A injection was independent ambulation (36.4%, n=95), ambulation with a walker (27.6%, n=72), and non‐ambulatory (31.8%, n=83). A few patients (4.2%, n=11) were able to ambulate with a cane or crutch at the time of injection. Participants were characterized according to BTX‐A dose, CP etiology, motor involvement pattern, muscles injected, ambulatory ability, and use of oral tone medications. Follow‐up records were searched for reported adverse events (AEs), with a mean time to AE assessment of 6.5 weeks (SD 3.38). The AE occurrence was determined for doses of 0 to 4.9 units/kg, 5 to 9.9 units/kg, 10 to 14.9 units/kg, 15 to 19.9 units/kg, and 20 to 25 units/kg. The overall AE occurrence was 4.2%. Standard doses of BTX‐A had side‐effect occurrences of 3.9% for 5 to 10 units/kg and 7.6% for 10 to 15 units/kg. Among higher doses (15‐20 units/kg and 20–25 units/kg) the AE occurrence was 3.5% and 8.6% respectively. No patient developed botulism. AEs were randomly distributed across dosing groups, CP etiologies, clinical phenotypes, ambulatory status, and treatment duration. All doses were associated with a significant increase in passive range of motion using the Tardieu scale. We conclude that higher dose BTX‐A is safe in children with a spectrum of CP phenotypes and are well tolerated over time.

Clinical considerations in cerebral palsy and spasticity.

The ultimate goal for management of patients with cerebral palsy is to help them grow up to become as independent as possible, learn to make their own choices in life, and pursue their own dreams. Optimal mobility is crucial to achieving independence and is also necessary for better health and quality of life in these patients. This article discusses the treatment of spasticity in cerebral palsy, addresses tone management issues in relationship to mobility and physical fitness, and introduces the reader to a comprehensive approach to the management of patients with cerebral palsy. (J Child Neurol 2001;16:10-15).

Growth factor influences on the production and migration of cortical neurons.

Production of neurons from progenitor cells is the first step in building the complex, six-layered cerebral cortex. The neurons that will populate the mature cortex are produced during development in an active proliferative neuroepithelium, the ventricular zone (VZ), adjacent to the cerebral ventricle (Rakic 1975; McConnell 1995; Caviness et al. 1996; Ross 1996). The first postmitotic neurons move out of the ventricular zone to form the preplate, just beneath the pia. Subsequent neuronal cohorts, generated in the neo-cortical ventricular zone, move into the preplate to form the cortical plate, which will eventually become layers 2 through 6 of cortex. At the earliest stages of cortical plate formation, preplate neurons are divided into two layers, the marginal zone, above the cortical plate, and the subplate, below it (Marin-Padilla 1971; Luskin and Shatz 1985; Allendoerfer and Shatz 1994). Many neurons move into the cortical plate under the guidance of the processes of radial glia (Hatten 1990; Rakic et al. 1994), but others, arising in distant proliferative zones, migrate tangentially into cortex, guided by cues that have not been defined (reviewed in Pearlman et al. 1998).