Brain biomarkers and pre-injury cognition are associated with long-term cognitive outcome in children with traumatic brain injury.

BACKGROUND: Children with traumatic brain injury (TBI) are frequently at risk of long-term impairments of attention and executive functioning but these problems are difficult to predict. Although deficits have been reported to vary with injury severity, age at injury and sex, prognostication of outcome remains imperfect at a patient-specific level. The objective of this proof of principle study was to evaluate a variety of patient variables, along with six brain-specific and inflammatory serum protein biomarkers, as predictors of long-term cognitive outcome following paediatric TBI. METHOD: Outcome was assessed in 23 patients via parent-rated questionnaires related to attention deficit hyperactivity disorder (ADHD) and executive functioning, using the Conners 3rd Edition Rating Scales (Conners-3) and Behaviour Rating Inventory of Executive Function (BRIEF) at a mean time since injury of 3.1 years. Partial least squares (PLS) analyses were performed to identify factors measured at the time of injury that were most closely associated with outcome on (1) the Conners-3 and (2) the Behavioural Regulation Index (BRI) and (3) Metacognition Index (MI) of the BRIEF. RESULTS: Higher levels of neuron specific enolase (NSE) and lower levels of soluble neuron cell adhesion molecule (sNCAM) were associated with higher scores on the inattention, hyperactivity/impulsivity and executive functioning scales of the Conners-3, as well as working memory and initiate scales of the MI from the BRIEF. Higher levels of NSE only were associated with higher scores on the inhibit scale of the BRI. CONCLUSIONS: NSE and sNCAM show promise as reliable, early predictors of long-term attention-related and executive functioning problems following paediatric TBI.

Serum Biomarkers Help Predict Attention Problems in Critically Ill Children With Traumatic Brain Injury.

OBJECTIVE: To evaluate the association between acute serum biomarkers, and the changes in attention at 1 year following traumatic brain injury. DESIGN AND SETTING: A prospective observational and laboratory study conducted in PICUs at five Canadian children's hospitals. STUDY POPULATION AND MEASUREMENTS: Fifty-eight patients aged 5 to 17 years with traumatic brain injury were enrolled in the study. Nine brain-specific and inflammatory serum protein biomarkers were measured multiple times over the first week following injury. Attention was measured at "baseline" to represent pre-injury function and at 1 year following injury using the Conners Third Parent Rating Scale. RESULTS: Compared with baseline, there were significantly more clinical symptoms of inattention at 1 year post injury. The Glasgow Coma Scale score, age at injury, baseline levels of inattention, and highest levels of serum biomarkers were used to estimate the probability of developing inattention. These independent variables were first evaluated individually followed by combinations of the best predictors using area under the receiver operating characteristic curve analyses. A combination of high baseline levels of inattention and high serum levels of the biomarker neuron-specific enolase was the best predictor for inattention. Glasgow Coma Scale and age at injury were not associated with inattention at 1 year post injury. CONCLUSIONS: Combining baseline assessment of attention with measurement of serum biomarkers shows promise as reliable, early predictors of long-term attention after childhood traumatic brain injury.

Functional plasticity in childhood brain disorders: when, what, how, and whom to assess.

At every point in the lifespan, the brain balances malleable processes representing neural plasticity that promote change with homeostatic processes that promote stability. Whether a child develops typically or with brain injury, his or her neural and behavioral outcome is constructed through transactions between plastic and homeostatic processes and the environment. In clinical research with children in whom the developing brain has been malformed or injured, behavioral outcomes provide an index of the result of plasticity, homeostasis, and environmental transactions. When should we assess outcome in relation to age at brain insult, time since brain insult, and age of the child at testing? What should we measure? Functions involving reacting to the past and predicting the future, as well as social-affective skills, are important. How should we assess outcome? Information from performance variability, direct measures and informants, overt and covert measures, and laboratory and ecological measures should be considered. In whom are we assessing outcome? Assessment should be cognizant of individual differences in gene, socio-economic status (SES), parenting, nutrition, and interpersonal supports, which are moderators that interact with other factors influencing functional outcome.

Visuospatial, visuoperceptual, and visuoconstructive abilities in congenital hypothyroidism.

Individuals with congenital hypothyroidism (CH), even those diagnosed and treated early, experience selective cognitive deficits, the most striking of which involves the visuocognitive domain. However, the range and nature of their visuocognitive disturbances is not fully understood. We assessed a range of higher-order visuocognitive abilities in 19 children and adolescents with CH and 19 age- and sex-matched typically developing peers (TD) using a battery of neuropsychological tests and a novel self-report measure of sense of direction. CH scored lower than TD on direct tests of visuocognitive function (judging line orientation, parts-to-whole localization, copying three-dimensional block towers, discriminating designs, and matching unfamiliar faces in ¾ profile-view) as well as on self-reported problems in spatial ability. Visuocognitive problems were not global as CH and TD did not differ at copying two-dimensional block designs, mentally rotating and matching abstract shapes, or at matching unfamiliar front-view faces, design features, or designs that engaged either figure-ground segregation, visual constancy, or closure. Early and concurrent thyroid stimulating hormone (TSH) levels were associated with visuocognitive ability, although attention and working memory were not. Individuals with CH exhibit selective visuocognitive weaknesses, some of which are related to early and concurrent TSH levels.

Irony and empathy in children with traumatic brain injury.

Social communication involves influencing what other people think and feel about themselves. We use the term conative theory of mind (ToM) to refer to communicative interactions involving one person trying to influence the mental and emotional state of another, paradigmatic examples of which are irony and empathy. This study reports how children with traumatic brain injury (TBI) understand ironic criticism and empathic praise, on a task requiring them to identify speaker belief and intention for direct conative speech acts involving literal truth, and indirect speech acts involving either ironic criticism or empathic praise. Participants were 71 children in the chronic state of a single TBI and 57 age- and gender-matched children with orthopedic injuries (OI). Group differences emerged on indirect speech acts involving conation (i.e., irony and empathy), but not on structurally and linguistically identical direct speech acts, suggesting specific deficits in this aspect of social cognition in school-age children with TBI. Deficits in children with mild-moderate TBI were less widespread and more selective than those of children with more severe injuries. Deficits in understanding the social, conative function of indirect speech acts like irony and empathy have widespread and deep implications for social function in children with TBI.

Theory of mind in children with traumatic brain injury.

Theory of mind (ToM) involves thinking about mental states and intentions to understand what other people know and to predict how they will act. We studied ToM in children with traumatic brain injury (TBI) and age- and gender-matched children with orthopedic injuries (OI), using a new three-frame Jack and Jill cartoon task that measures intentional thinking separate from contingent task demands. In the key ToM trials, which required intentional thinking, Jack switched a black ball from one hat to another of a different color, but Jill did not witness the switch; in the otherwise identical non-ToM trials, the switch was witnessed. Overall accuracy was higher in children with OI than in those with TBI. Children with severe TBI showed a larger decline in accuracy on ToM trials, suggesting a specific deficit in ToM among children with severe TBI. Accuracy was significantly higher on trials following errors than on trials following correct responses, suggesting that all groups monitored performance and responded to errors with increased vigilance. TBI is associated with poorer intentional processing in school-age children and adolescents relative to peers with OI; furthermore, children with TBI are challenged specifically by intentional demands, especially when their injury is severe. (JINS, 2012, 19, 1-9).

Modified Atkins Diet with slow reduction of carbohydrate.

Typically, the amount of daily carbohydrate in the Modified Atkins diet (MAD) is restricted to 10-20 g from the beginning of the therapy. It is possible to gradually reduce the daily carbohydrate amount to this target to increase acceptability of the diet. We report the use of the MAD with slow carbohydrate reduction in a patient with Glucose Transporter 1 Deficiency, including results of neuropsychological assessments. Seizures were controlled at 45 g of carbohydrates daily. This case report illustrates that a liberalized form of MAD with slow reduction of carbohydrate may be a therapeutic option in some children with epilepsy. It is possible that other children with epilepsy could achieve seizure control at higher carbohydrate level than current MAD recommendations.

[Formula: see text]Dorsal and ventral visual streams: Typical and atypical development.

The literature on visuospatial processing describes two distinct pathways within the brain: a dorsal route extending from the visual cortex into the parietal lobes that is critical for spatial processing and a ventral route extending from the visual cortex into the temporal lobes that is critical for form perception. These visual streams appear to differ in their developmental trajectories and their vulnerabilities to diverse neurodevelopmental conditions. The present work aims to investigate development and vulnerability in two aspects of dorsal and ventral visual-stream function, namely attention to location and attention to identity. In Study 1, we compare typically-developing (TD) youth aged 9 to 16 years with young adults aged 18 to 22 years on computerized location and identity tasks. In Study 2, we compare children and adolescents who have congenital hypothyroidism (CH), a pediatric endocrine disorder, with age-matched TD controls on the same tasks. The results from Study 1 show that the youths were less accurate than the adults at judging identity, whereas both groups were equally accurate at judging location. The results from Study 2 show that the youths with CH were slower but not less accurate than the TD youths in making both identity and location judgments. The results are interpreted as signifying later development of ventral (identity) stream functions compared to dorsal (location) but equal vulnerability of both functions in CH.

White and grey matter relations to simple, choice, and cognitive reaction time in spina bifida.

Elevated reaction time (RT) is common in brain disorders. We studied three forms of RT in a neurodevelopmental disorder, spina bifida myelomeningocele (SBM), characterized by regional alterations of both white and grey matter, and typically developing individuals aged 8 to 48 years, in order to establish the nature of the lifespan-relations of RT and brain variables. Cognitive accuracy and RT speed and variability were all impaired in SBM relative to the typically developing group, but the most important effects of SBM on RT are seen on tasks that require a cognitive decision rule. Individuals with SBM are impaired not only in speeded performance, but also in the consistency of their performance on tasks that extend over time, which may contribute to poor performance on a range of cognitive tasks. The group with SBM showed smaller corrected corpus callosum proportions, larger corrected cerebellar white matter proportions, and larger corrected proportions for grey matter in the Central Executive and Salience networks. There were clear negative relations between RT measures and corpus callosum, Central Executive, and Default Mode networks in the group with SBM; relations were not observed in typically developing age peers. Statistical mediation analyses indicated that corpus callosum and Central Executive Network were important mediators. While RT is known to rely heavily on white matter under conditions of typical development and in individuals with adult-onset brain injury, we add the new information that additional involvement of grey matter may be important for a key neuropsychological function in a common neurodevelopmental disorder.

Heterogeneity of brain lesions in pediatric traumatic brain injury.

OBJECTIVE: Magnetic resonance imaging (MRI) provides a method to identify and quantify abnormalities resulting from traumatic brain injury (TBI). MRI abnormalities in children with TBI have not been fully characterized according to the frequency, location, and quantitative measurement of a range of pathologies critical for studies of neuropsychological outcome. Here, we report MRI findings from a large, multicenter study of childhood TBI, the Social Outcomes of Brain Injury in Kids (SOBIK) study, which compared qualitative and quantitative neuroimaging findings in 72 children with complicated mild-to-severe TBI to 52 children with orthopedic injury (OI). METHOD: Qualitative analyses of MRI scans coded white matter hyperintensities (WMHs), hemosiderin deposits reflecting prior hemorrhagic lesions, regions of encephalomalacia and/or atrophy, and corpus callosum atrophy and traumatic shear lesions. Two automated quantitative analyses were conducted: (a) FreeSurfer methods computed volumes for total brain, white matter (WM), gray matter (GM), corpus callosum, ventricles, amygdala, hippocampus, basal ganglia, and thalamus along with a ventricle-to-brain ratio (VBR); and (b) voxel-based morphometry (VBM) to identify WM, GM, and cerebrospinal fluid. We also examined performance on the Processing Speed Index (PSI) from the Wechsler Intelligence Scale for Children, Fourth Edition, in relation to the above-mentioned neuroimaging variables. RESULTS: WMHs, hemosiderin deposits, and focal areas of encephalomalacia or atrophy were common in children with TBI, were related to injury severity, and were mostly observed within a frontotemporal distribution. Quantitative analyses showed volumetric changes related to injury severity, especially ventricular enlargement and reduced corpus callosum volume. VBM demonstrated similar findings, but, in addition, GM reductions in the inferior frontal, basal forebrain region, especially in the severe TBI group. The complicated mild TBI group showed few differences from the OI group. PSI was significantly associated with global atrophy, as measured by VBR. CONCLUSION: MRI findings after childhood TBI are diverse and particularly influenced by injury severity, and they involve common features, group heterogeneity, and individual variability.

Cognitive, affective, and conative theory of mind (ToM) in children with traumatic brain injury.

We studied three forms of dyadic communication involving theory of mind (ToM) in 82 children with traumatic brain injury (TBI) and 61 children with orthopedic injury (OI): Cognitive (concerned with false belief), Affective (concerned with expressing socially deceptive facial expressions), and Conative (concerned with influencing another's thoughts or feelings). We analyzed the pattern of brain lesions in the TBI group and conducted voxel-based morphometry for all participants in five large-scale functional brain networks, and related lesion and volumetric data to ToM outcomes. Children with TBI exhibited difficulty with Cognitive, Affective, and Conative ToM. The perturbation threshold for Cognitive ToM is higher than that for Affective and Conative ToM, in that Severe TBI disturbs Cognitive ToM but even Mild-Moderate TBI disrupt Affective and Conative ToM. Childhood TBI was associated with damage to all five large-scale brain networks. Lesions in the Mirror Neuron Empathy network predicted lower Conative ToM involving ironic criticism and empathic praise. Conative ToM was significantly and positively related to the package of Default Mode, Central Executive, and Mirror Neuron Empathy networks and, more specifically, to two hubs of the Default Mode Network, the posterior cingulate/retrosplenial cortex and the hippocampal formation, including entorhinal cortex and parahippocampal cortex.

Visual abilities at 6 months in preterm infants: impact of thyroid hormone deficiency and neonatal medical morbidity.

BACKGROUND: Preterm infants are at risk for neonatal morbidity, transiently reduced thyroid hormone (TH) levels, and impaired visual abilities. To determine the interrelationship between these factors, we measured TH levels in the period ex utero and compared their visual abilities with those of term infants at 6 months (corrected) of age. METHODS: The preterm group consisted of 62 infants stratified by gestational age: Group A (23-26 weeks, n = 10), Group B (27-29 weeks, n = 23), Group C (30-32 weeks, n = 19), and Group D (33-35 weeks, n = 10). Controls were 31 healthy full-term infants. In the preterm group, free thyroxine, triiodothyronine, and thyroid-stimulating hormone levels were measured at 2 and 4 weeks of life and 40 weeks postconceptional age. All infants were assessed for visual acuity, contrast sensitivity, and color vision using electrophysiological techniques. RESULTS: Compared with controls, the preterm infants demonstrated reduced contrast sensitivity at low temporal frequencies and slower blue-yellow color processing. Groups did not differ from controls in visual acuity. In the preterm group, reduced contrast sensitivity and slow blue-yellow and red-green color vision processing were associated with low TH levels, low gestational age, and several medical morbidities. CONCLUSIONS: Our findings signify that some of the weak visual abilities in preterm infants can be accounted for, in part, by their reduced TH levels in the early postnatal period.

Impact of neonatal thyroid hormone insufficiency and medical morbidity on infant neurodevelopment and attention following preterm birth.

BACKGROUND: Infants born preterm are at risk of both transiently reduced thyroid hormone levels and impaired neurocognitive development, including attention deficits. The objective of this study was to examine the effects of reduced thyroid hormone levels on general neurodevelopment and attention at 3 months corrected age. METHODS: Sixty-four infants born 24 to 35 weeks gestation were stratified into four gestational age groups: Group A, 23-26 weeks (n = 10); Group B, 27-29 weeks (n = 23); Group C, 30-32 weeks (n = 20); Group D, 33-35 weeks (n = 11). Controls were 33 healthy infants born full-term (Group E). In preterm only, free thyroxine (FT(4)), triiodothyronine (T(3)), and thyrotropin (TSH) were measured at 2 and 4 weeks of life and at 40 weeks postconceptional age. At 3 months corrected age, all infants were assessed with the Bayley Scales of Infant Development-Second Edition (BSID-II), from which both mental development index (MDI) and psychomotor development index (PDI) scores and four indices of attention were derived: sustained attention, selective attention, attention shift, and total attention. RESULTS: Gestational age-stratified preterm groups differed significantly in T(3) and FT(4) levels at 2 and 4 weeks of life in infants born less than 27 weeks gestation. Preterm infants overall scored significantly below full-term on BSID-II MDI and PDI, selective, sustained, and total attention scales. In the preterm group, FT(4) levels were positively associated with PDI and selective, sustained, and total attention. CONCLUSIONS: Reduced levels of thyroid hormone in the neonatal period in preterm infants are associated with a reduced neurocognitive outcome in the attention domain at 3 months corrected age.

The role of transient hypothyroxinemia of prematurity in development of visual abilities.

Preterm birth is associated with an increased risk of visual impairment. However, not all visual deficits can be fully explained by the typical prematurity morbidity factors. In addition, children born preterm often exhibit transient hypothroxinemia of prematurity (THOP) due to premature severing of the maternal supply of thyroid hormones. Because thyroid hormone is critically needed for multiple facets of early brain development, including the structures needed for visual processing, and because the maternal thyroid supply is essential throughout pregnancy, it is possible that THOP contributes to the visual impairments seen in preterm children. To test this hypothesis, we used both clinical tests and visual-evoked potential techniques to assess visual abilities in two cohorts of preterm infants whose thyroid hormone levels were measured in the perinatal period. In the first cohort born 30 to 35 weeks gestation, we found associations between low thyroid hormone levels and reduced visual attention at 3 months corrected age (Study 1) and poor visuomotor abilities at 12 and 18 months corrected age (Study 2). In the second cohort born 23 to 35 weeks gestation, THOP severity was negatively correlated with attention at 3 months corrected age (Study 3) and contrast sensitivity and color vision at 6 months corrected age (Study 4). These findings therefore suggest that thyroid hormone is necessary for the development of early visual abilities and that THOP may partially explain the visual deficits of preterm infants.

Integration of visual and tactile stimuli: top-down influences require time.

In a visuotactile congruency task, a distracting flash of light presented near a tactile target can influence speeded judgments of tactile location. Localization of the tactile target is more rapid when the elevation of the visual distractor is congruent with the tactile stimulus than when it is incongruent. The goal of the present study was to examine the degree of control that can be exerted on the process proposed to integrate the visual and tactile stimuli. To this end, the proportion of spatially congruent items was manipulated across blocks of trials. A robust congruency effect was observed across three experiments. There was no effect of proportion congruency (varied between 75 and 11% congruent) when the visual event was presented only 30 ms prior to the tactile event. When this lead-time was increased to 100 ms there was a significant increase in the congruency effect, for errors, in the high proportion congruent conditions (experiment 3). We conclude that with sufficient lead-time, top-down influence can be exerted in this task, however, when presented at near simultaneity, visuotactile integration is independent of top-down effects.