Functional Brain Hyperactivations Are Linked to an Electrophysiological Measure of Slow Interhemispheric Transfer Time after Pediatric Moderate/Severe Traumatic Brain Injury.

Increased task-related blood oxygen level dependent (BOLD) activation is commonly observed in functional magnetic resonance imaging (fMRI) studies of moderate/severe traumatic brain injury (msTBI), but the functional relevance of these hyperactivations and how they are linked to more direct measures of neuronal function remain largely unknown. Here, we investigated how working memory load (WML)-dependent BOLD activation was related to an electrophysiological measure of interhemispheric transfer time (IHTT) in a sample of 18 msTBI patients and 26 demographically matched controls from the UCLA RAPBI (Recovery after Pediatric Brain Injury) study. In the context of highly similar fMRI task performance, a subgroup of TBI patients with slow IHTT had greater BOLD activation with higher WML than both healthy control children and a subgroup of msTBI patients with normal IHTT. Slower IHTT treated as a continuous variable was also associated with BOLD hyperactivation in the full TBI sample and in controls. Higher WML-dependent BOLD activation was related to better performance on a clinical cognitive performance index, an association that was more pronounced within the patient group with slow IHTT. Our previous work has shown that a subgroup of children with slow IHTT after pediatric msTBI has increased risk for poor white matter organization, long-term neurodegeneration, and poor cognitive outcome. BOLD hyperactivations after msTBI may reflect neuronal compensatory processes supporting higher-order capacity demanding cognitive functions in the context of inefficient neuronal transfer of information. The link between BOLD hyperactivations and slow IHTT adds to the multi-modal validation of this electrophysiological measure as a promising biomarker.

Executive function changes before memory in preclinical Alzheimer's pathology: a prospective, cross-sectional, case control study.

BACKGROUND: Early treatment of Alzheimer's disease may reduce its devastating effects. By focusing research on asymptomatic individuals with Alzheimer's disease pathology (the preclinical stage), earlier indicators of disease may be discovered. Decreasing cerebrospinal fluid beta-amyloid42 is the first indicator of preclinical disorder, but it is not known which pathology causes the first clinical effects. Our hypothesis is that neuropsychological changes within the normal range will help to predict preclinical disease and locate early pathology. METHODS AND FINDINGS: We recruited adults with probable Alzheimer's disease or asymptomatic cognitively healthy adults, classified after medical and neuropsychological examination. By logistic regression, we derived a cutoff for the cerebrospinal fluid beta amyloid42/tau ratios that correctly classified 85% of those with Alzheimer's disease. We separated the asymptomatic group into those with (n = 34; preclinical Alzheimer's disease) and without (n = 36; controls) abnormal beta amyloid42/tau ratios; these subgroups had similar distributions of age, gender, education, medications, apolipoprotein-ε genotype, vascular risk factors, and magnetic resonance imaging features of small vessel disease. Multivariable analysis of neuropsychological data revealed that only Stroop Interference (response inhibition) independently predicted preclinical pathology (OR = 0.13, 95% CI = 0.04-0.42). Lack of longitudinal and post-mortem data, older age, and small population size are limitations of this study. CONCLUSIONS: Our data suggest that clinical effects from early amyloid pathophysiology precede those from hippocampal intraneuronal neurofibrillary pathology. Altered cerebrospinal fluid beta amyloid42 with decreased executive performance before memory impairment matches the deposits of extracellular amyloid that appear in the basal isocortex first, and only later involve the hippocampus. We propose that Stroop Interference may be an additional important screen for early pathology and useful to monitor treatment of preclinical Alzheimer's disease; measures of executive and memory functions in a longitudinal design will be necessary to more fully evaluate this approach.

Metabolic levels in the corpus callosum and their structural and behavioral correlates after moderate to severe pediatric TBI.

Diffuse axonal injury (DAI) secondary to traumatic brain injury (TBI) contributes to long-term functional morbidity. The corpus callosum (CC) is particularly vulnerable to this type of injury. Magnetic resonance spectroscopy (MRS) was used to characterize the metabolic status of two CC regions of interest (ROIs) (anterior and posterior), and their structural (diffusion tensor imaging; DTI) and neurobehavioral (neurocognitive functioning, bimanual coordination, and interhemispheric transfer time [IHTT]) correlates. Two groups of moderate/severe TBI patients (ages 12-18 years) were studied: post-acute (5 months post-injury; n = 10), and chronic (14.7 months post-injury; n = 8), in addition to 10 age-matched healthy controls. Creatine (energy metabolism) did not differ between groups across both ROIs and time points. In the TBI group, choline (membrane degeneration/inflammation) was elevated for both ROIs at the post-acute but not chronic period. N-acetyl aspartate (NAA) (neuronal/axonal integrity) was reduced initially for both ROIs, with partial normalization at the chronic time point. Posterior, not anterior, NAA was positively correlated with DTI fractional anisotropy (FA) (r = 0.88), and most domains of neurocognition (r range 0.22-0.65), and negatively correlated with IHTT (r = -0.89). Inverse corerlations were noted between creatine and posterior FA (r = -0.76), neurocognition (r range -0.22 to -0.71), and IHTT (r = 0.76). Multimodal studies at distinct time points in specific brain structures are necessary to delineate the course of the degenerative and reparative processes following TBI, which allows for preliminary hypotheses about the nature and course of the neural mechanisms of subsequent functional morbidity. This will help guide the future development of targeted therapeutic agents.

Bimanual motor coordination in agenesis of the corpus callosum.

The nature and extent of deficiencies in bimanual motor coordination in individuals with agenesis of the corpus callosum (ACC) was studied using the computerized Bimanual Coordination Test (cBCT). Compared with previous bimanual tasks, the cBCT is more specifically reliant on interhemispheric interactions of lateralized motor control, allows more precise measurement, and permits examination of performance over a wider range of bimanual challenges. The cBCT performance of 13 high-functioning individuals with complete ACC was compared to 21 age- and IQ-matched controls. The groups did not differ in unimanual response speed. On trials involving angled paths that require bimanual coordination, the ACC group performed significantly slower and less accurately across all angles. The largest group differences in speed occurred on trials where the hands must respond symmetrically, while mirror-image (vs. parallel) responding produced the greatest deficits in accuracy. These data confirm previous findings of deficits in bimanual coordination in callosal absence, but using significantly improved measurement technology. Deficits in bimanual coordination in ACC are present across different demands for interhand interactions in the speed and direction of movement.

Bimanual coordination in alcohol-exposed children: role of the corpus callosum.

The corpus callosum (CC) is one of several brain structures affected in children prenatally exposed to alcohol. This structure plays a major role in coordinating motor activity from opposite sides of the body, and deficits in bimanual coordination have been documented in individuals with agenesis of or damage to the CC, particularly when the task is performed without visual feedback. The Bimanual Coordination Test was used to assess speed and accuracy on a task where both hands must coordinate to guide a cursor through angled pathways providing measures of interhemispheric interaction or the ability of the two hemispheres to coordinate activity via the corpus callosum. Twenty-one children with fetal alcohol spectrum disorders (FASD) and 17 non-exposed control children (CON), matched closely in age, sex, and ethnicity were tested. For trials with visual feedback (WV), children with FASD were slower than CON children but were equally accurate. Although statistically significant group differences were not observed on most trials completed without visual feedback (WOV), accuracy of the FASD group on WOV trials was highly variable. Group differences in accuracy on WOV angles approached significance after accounting for performance on the WV angles, and children with FASD were significantly less accurate on an individual angle believed to be particularly sensitive to interhemispheric interaction. These results indicate that children with FASD are slower than CON children but equally accurate on basic visuomotor tasks. However, as task complexity and reliance on interhemispheric interaction increases, children with FASD demonstrate variable and inaccurate performance.

Sequential analysis reveals a unique structure for self-injurious behavior.

Conditional probability, calculated using sequential analysis techniques in four time conditions (2, 10, 30, and 60 seconds), provided evidence that successive episodes of self-injury were sequentially dependent. This unique distribution of sequential association for self-injurious behavior (SIB) was not related to frequency or rate of occurrence. Compared with other environmental and behavioral events, the best predictor of SIB was an earlier SIB episode, consistent with a contagious distribution. This study is one of the few in which sequential analysis techniques were applied to data derived from a large group of individuals with severe behavior disorders. It may be the first in which this analytic tool was used to investigate systematically successive occurrences of SIB as it takes place in vivo.

Normal development of bimanual coordination: visuomotor and interhemispheric contributions.

The corpus callosum is one of the last cortical pathways to develop, continuing to myelinate through the end of the first decade of life. However, the functional consequences of this late development are not entirely known. The importance of callosal development for bimanual motor coordination is suggested by the fact that bimanual coordination in younger children is similar to that of persons with commissurotomy or callosal agenesis. This study focused on the development of bimanual coordination in 67 normally developing children between 6 and 15 years of age using the computerized Bimanual Coordination Test (cBCT). Results indicated that right- and left-hand unimanual motor speed was significantly correlated with age (r = -.26 and -.44, respectively). Age was also significantly associated with accuracy of performance on trials demanding both symmetric (r = -.46) and asymmetric (r = -.50) bi-manual responding. The correlation with asymmetric bimanual responding (requiring greater interhand coordination) remained significant when covarying performance on symmetric response trials. Accuracy on asymmetric bimanual trials requiring greater left- than right-hand speed accounted for the largest portion of this unique, age-related variance. Thus, cBCT performance reveals child development in motor speed and visuomotor processing, as well as the unique contributions of interhemispheric interactions to bimanually coordinated motor activity.