Predicting neurocognitive and behavioural outcome after early brain insult.

AIMS: The aims of the study were to investigate (1) the impact of age at brain insult on functional outcome and (2) the influence of insult and environmental factors on cognitive and behavioural outcomes. METHOD: The study was a cross-sectional, retrospective observational study, involving 138 children (76 males, 62 females; mean age 13y 1mo, SD 1y 11mo, range 10­16y) with magnetic resonance imaging (MRI) evidence of focal brain insult sustained from the first trimester of pregnancy to adolescence. Children underwent MRI and intellectual, executive, behavioural, and social evaluation. Outcome predictors were insult (lesion location, laterality, and extent, history of seizures, age at insult) and environmental (social risk and family function) factors. RESULTS: Focal insult before the age of 3 years was associated with poorer outcomes than insult after the age of 3 years across all domains. For IQ outcomes, insult characteristics and seizures were highly predictive. For executive and behavioural domains, family function and social risk had the greatest impact. Earlier age at insult predicted poorer social competence. INTERPRETATION Focal brain insult before age 3 years has devastating consequences for children's development. Findings suggest that greater emphasis should be placed on providing early intervention for children who sustain early focal brain insults.

Childhood brain insult: can age at insult help us predict outcome?

Until recently, the impact of early brain insult (EBI) has been considered to be less significant than for later brain injuries, consistent with the notion that the young brain is more flexible and able to reorganize in the context of brain insult. This study aimed to evaluate this notion by comparing cognitive and behavioural outcomes for children sustaining EBI at different times from gestation to late childhood. Children with focal brain insults were categorized according to timing of brain insult, represented by six developmental periods: (i) Congenital (n = 38): EBI: first-second trimester; (ii) Perinatal (n = 33); EBI: third trimester to 1 month post-natal; (iii) Infancy (n = 23): EBI: 2 months-2 years post-birth; (iv) Preschool (n = 19): EBI: 3-6 years; (v) Middle Childhood (n = 31): EBI: 7-9 years; and (vi) Late Childhood (n = 19): EBI: after age 10. Groups were similar with respect to injury and demographic factors. Children were assessed for intelligence, academic ability, everyday executive function and behaviour. Results showed that children with EBI were at increased risk for impairment in all domains assessed. Furthermore, children sustaining EBI before age 2 years recorded global and significant cognitive deficits, while children with later EBI performed closer to normal expectations, suggesting a linear association between age at insult and outcome. In contrast, for behaviour, children with EBI from 7 to 9 years performed worse than those with EBI from 3 to 6 years, and more like those with younger insults, suggesting that not all functions share the same pattern of vulnerability with respect to age at insult.

Does early age at brain insult predict worse outcome? Neuropsychological implications.

OBJECTIVE: Traditionally early brain insult (EBI) has been argued to have better outcome than later injury, consistent with the notion that the young brain is flexible and able to reorganize. This view was investigated by comparing neurobehavioral outcomes of children sustaining EBI at different developmental stages (gestation to late childhood). METHODS: One hundred and sixty four children who had sustained focal brain insult (confirmed by MRI) formed six groups, based on age at EBI, (a) Congenital; (b) Peri-natal; (c) Infancy; (d) Preschool; (e) Middle Childhood; (f) Late Childhood, and were compared on a range of standardized neurobehavioral measures. Groups were matched for lesion characteristics and demographics. RESULTS: Children sustaining EBI before age 2 recorded global deficits, while children with later EBI performed closer to average. CONCLUSION: These results question the advantages of early brain plasticity, demonstrating poorer outcome from very early insults, and increasingly better function with lesions later in childhood.

Neuropsychological profile of children with subcortical band heterotopia.

AIM: Subcortical band heterotopia (SBH) or 'double cortex' is a malformation of cortical development resulting from impaired neuronal migration. So far, research has focused on the neurological, neuroimaging, and genetic correlates of SBH. More recently, clinical reports and small sample studies have documented neuropsychological dysfunction in patients with this malformation. This study aimed to characterize further the phenotype of patients with SBH by describing the neuropsychological profiles of children. METHOD: Seven children (six females) aged 4 to 15 years were assessed for cognitive functioning (intellectual ability, processing speed, attention, working memory) and academic achievement (reading, spelling, arithmetic). Parents completed questionnaires examining their child's social skills and problem behaviours. Magnetic resonance images (MRI) conducted for routine clinical follow-up were coded by a paediatric neurologist. Genetic and seizure history were obtained from medical records. RESULTS: There was variation in the neurological, neuroimaging, and genetic presentation of children in the sample. Impairments were observed in all areas of neuropsychological functioning examined. Intellectual ability was generally within the 'extremely low' range (full-scale IQ 44-74; performance IQ 45-72; verbal IQ 57-80). Generalized impairments in cognitive skills were typical, with severe impairments (scores greater than 2SD below the test mean) reported in processing speed, working memory, and arithmetic. Impairments in academic, social, and behavioural functioning were less generalized. No clear relationship between neuroimaging and neuropsychological impairments was found. INTERPRETATION: Children with SBH demonstrate cognitive, academic, social, and behavioural problems, with the greatest difficulties in processing speed and complex cognitive skills.

Electroencephalographic abnormalities during sleep in children with developmental speech-language disorders: a case-control study.

Earlier research has suggested a link between epileptiform activity in the electroencephalogram (EEG) and developmental speech-language disorder (DSLD). This study investigated the strength of this association by comparing the frequency of EEG abnormalities in 45 language-normal children (29 males, 16 females; mean age 6y 11mo, SD 1y 10mo, range 4y-9y 10mo) and 54 community-ascertained children (35 males, 19 females; mean age 5y 7mo, SD 1y 6mo, range 4y-9y 11mo) with a diagnosis of severe DSLD, defined as a score at least 2 SD below the mean on at least one speech-language measure, and a performance IQ of at least 80 points. All participants underwent sleep EEGs after sedation. Children with DSLD also had detailed speech-language, hearing, and psychological assessments. Results failed to support the previously identified strong association between abnormal EEG and DSLD. There was a weak, non-significant relationship between DSLD and epileptiform EEG. Epileptiform EEG was significantly associated with low performance IQ (p=0.04). This study draws into question previously reported associations between epileptiform activity and DSLD probably because it examined a purer cohort of children with more severe language difficulties who did not have seizures.

Executive function following focal frontal lobe lesions: impact of timing of lesion on outcome.

While it is generally agreed that outcome following cerebral insult during childhood differs from that seen following similar pathology in adulthood, the specific relationship between timing of cerebral lesion and outcome, and the mechanism associated with observed neurobehavioral changes, remains controversial. Data from children with focal lesions suggests a non-linear relationship between age at injury and language function (e.g., Bates et al., 1999). With respect to executive function, animal models also demonstrate a non-linear relationship, and suggest that outcome is tightly linked to underlying neuronal changes (e.g., Kolb et al., 2000). Whether these models easily translate to humans, where brain morphology, cognitive function and environmental influences are more complex, is not clear. To date, focal lesion research in children has been restricted to individual case studies or, to samples of children with lesions to regions subsuming language function, or those who have undergone hemispherectomy for the treatment of intractable epilepsy. This study aimed to build on current knowledge, investigating executive function in 38 children with focal lesions involving prefrontal cortex. Aetiology and timing of lesions was diverse. Results are consistent with animal research suggesting a non-linear relationship between age at injury and outcome, with "critical periods" during development when the frontal lobes are particularly vulnerable to insult, and others when outcome is more optimal. Our findings indicate that children with prenatal lesions are at greatest risk of neurobehavioral deficits. Children with lesions sustained in middle childhood demonstrate least severe impairments across executive domains, possibly due to a period of peak synaptogenesis and dendritic arborization during this developmental stage, in keeping with animal models and research investigating frontal lobe development.

The Object Classification Task for Children (OCTC): a measure of concept generation and mental flexibility in early childhood.

In this study, the development of concept generation and mental flexibility was investigated in 84 Australian children between 3 and 7 years of age, using the Object Classification Task for Children (OCTC), a newly developed executive function test for use with young children. On this task, which was adapted from the Concept Generation Test (Levine, Stuss, & Milberg, 1995) and the Concept Generation Test for Children (Jacobs, Anderson, & Harvey, 2001), children were asked to categorize 6 plastic toys according to 3 predetermined groupings (i.e., color, size, and function). The test included 3 performance levels, each providing increasing levels of structure for the child. Findings from the OCTC show meaningful age-related changes in performance across age groups, with older children being less dependent on additional structure to complete the task, in comparison to younger children. Furthermore, findings from this study suggest that the ability to generate concepts emerges between 3 and 4 years of age, continuing to develop beyond the age of 7 years. A developmental spurt in cognitive flexibility was observed around 4 to 5 years of age, with refinement of this capacity occurring between 5 and 7 years of age. Results suggest that the OCTC is a useful measure of conceptual reasoning skills in early childhood.

Differential functional magnetic resonance imaging language activation in twins discordant for a left frontal tumor.

Eight-year-old twins, one with a left frontal tumor and aphasic seizures, the other neurologically normal, underwent serial assessment of expressive language with functional magnetic resonance imaging and neuropsychology. The affected twin showed a significant amount of right hemisphere activation coincident with behavioral deterioration in expressive language and late growth in the tumor. This pattern of language dysfunction and the left language dominance of her co-twin suggested that the affected twin was also left dominant for language, and the significance of her right activation is discussed. We postulate that the right hemisphere activation represents a stabilizing mechanism in the context of a developmental and progressive lesion in language cortex rather than language transfer per se.

Neuropsychological outcome after acute disseminated encephalomyelitis: impact of age at illness onset.

Recovery from acute disseminated encephalomyelitis in childhood appears relatively uneventful, at least when looking at functional recovery parameters such as neurologic outcome. However, neuropsychology literature suggests that relatively transient illnesses affecting the central nervous system are associated with cognitive and social sequelae, particularly when the illness occurs during the preschool years. This study investigated the impact of timing of acute disseminated encephalomyelitis on intellectual, educational, and social functioning in children. Nineteen children (10 with acute disseminated encephalomyelitis before the age of 5 years), who had been admitted to the Royal Children's Hospital, Melbourne Australia, in the past 6 years underwent a brief neuropsychologic assessment. Performance was compared with 19 control subjects, stratified for age and socioeconomic status with the acute disseminated encephalomyelitis group. Children who sustained their illness before 5 years of age were particularly vulnerable to impairments in both cognitive and social domains. In particular, a higher incidence of severe behavioral and emotional problems was reported by parents of children who had experienced acute disseminated encephalomyelitis before 5 years of age. This finding suggests that there may be long-term complications in early childhood. A multidisciplinary approach to management post-illness is warranted in this age group.

Planning and problem solving skills following focal frontal brain lesions in childhood: analysis using the Tower of London.

Problem solving skills were investigated in children with focal lesions using the Tower of London test (TOL; Shallice, 1982). The scoring procedure was elaborated from previous studies to delineate separate processes contributing to overall performance in children. Thirty-one children with focal frontal pathology, 18 children with focal pathology in other brain regions (extra-frontal), 17 children with generalized pathology and 38 healthy children participated in the study. Results suggest a distributed network for problem solving skills, particularly cognitive flexibility and goal setting skills. Within the frontal group, children with lesions involving the right pre-frontal cortex had greatest problems with self-regulation, with rule breaks most common among this group. As these skills develop relatively early in comparison to other aspects of executive function, right pre-frontal regions may play a particularly important role in the development of executive skills in childhood, with damage to these regions rendering children vulnerable to a range of cognitive and social deficits.

Relationships between cognitive and behavioral measures of executive function in children with brain disease.

This study addressed the clinical and construct validity of the Behavior Rating Inventory of Executive Function. (BRIEF: Gioia, Isquith, Guy, & Kenworthy, 2000), a questionnaire designed to tap behavioral aspects of executive functions in children. BRIEF profiles in early treated phenylketonuria (PKU; n=44), early treated hydrocephalus (n=45), frontal focal lesions (n=20) and controls (n=80) were examined. Clinical validity was supported through significant between-group comparisons, especially between the frontal focal lesion group and other groups. To examine construct validity, raw scores on cognitive executive function measures including the Contingency Naming Test (CNT), Rey Complex Figure (RCF), Tower of London (TOL), and Controlled Oral Word Association Test (COWAT), were correlated with BRIEF scale scores. Few significant correlations were found, indicating cognitive and behavioral measures appear to tap different constructs within the executive function domain. A dissociation was found between behavioral and cognitive impairments in the frontal as opposed to PKU and hydrocephalus groups. This is discussed in relation to underlying pathology, the cognitive measures used, and possible limitations in the BRIEF's usefulness for measuring behavioral executive dysfunction in groups only mildly affected by neurological compromise.

Attention and social functioning in children with malformations of cortical development and stroke.

Attention and social functioning and their interrelationships have not been routinely examined in children with early brain insult (EBI). This study aimed to describe attention and social functioning in children with two types of EBI: malformations of cortical development (MCD) and stroke. Children diagnosed with MCD (n = 14, 6 males) or stroke (n = 14, 8 males) aged 8 to 14 years (M = 12 years 11 months) completed neuropsychological assessments to examine attention processes. Primary caregivers completed a questionnaire to assess executive components of children's attention and teachers completed a questionnaire to measure children's social functioning. Brain scans (MRI or CT) were coded by a pediatric neuroradiologist. Higher rates of impairments in attention and social function were found in children with EBI compared with normative expectations. Children with MCD experienced more global and clinically significant levels of impairment than children with stroke; though impairments were present in both groups. A strong association between executive components of attention and social function was observed. In addition, complex attention processes were associated with social function. The findings emphasize the reciprocity between attention, behavior and social outcomes, and the vulnerability of social function following EBI.

Are executive skills primarily mediated by the prefrontal cortex in childhood? Examination of focal brain lesions in childhood.

INTRODUCTION: Based on the study of adults with brain insult, traditional localizationist views have argued that executive skills are primarily mediated by prefrontal cortex. It remains unclear whether a similar pattern of localization exists in childhood. METHODS: To investigate this hypothesis, we compared the performance of children, aged 7-16 years, with radiological evidence of brain pathology. The sample was divided according to lesion location as follows: frontal pathology (n=38), extra-frontal pathology (n=20), generalized pathology (n=21) and healthy controls (n=40). Using a multidimensional model of executive function described by Anderson (2002) and Anderson (1998; Anderson et al., 2001c, 2001d), these groups were compared on a range of executive function domains including: attentional control, goal setting, cognitive flexibility, and information processing. Additional, non-executive measures were also administered. RESULTS: Contrary to adult lesion-based studies, there was little differentiation in executive processes between frontal and extra-frontal groups. CONCLUSIONS: These results provide support for contemporary models which propose a distributed, but integrated neural network for executive skills, suggesting that the integrity of the entire brain is necessary for adequate executive functions in childhood. Further, focal lesions to any brain region during development may render children vulnerable to a range of executive deficits that would not normally be expected following similar pathology in adulthood.

Does timing of brain lesion have an impact on children's attention?

This study examined developmental timing of brain lesion effects on children's attention skills. The sample of 138 children, 10-16 years at assessment, were grouped based on developmental timing of brain lesion: (1) Congenital; (2) Perinatal; (3) Infancy; (4) Preschool; (5) Middle Childhood; (6) Late Childhood. Children with lesions in infancy or earlier demonstrated global attention problems, while children with lesions in middle childhood performed closer to normal expectations. This pattern of results was particularly evident for encoding and shifting attention. Findings highlight vulnerability of the immature brain to lesions and identify critical periods in development for attention skills.

Executive function following child stroke: the impact of lesion size.

Childhood stroke is increasingly recognized as a major cause of childhood morbidity and mortality; however, limited information exists regarding neurobehavioral sequelae. Executive function (EF), important for problem solving, reasoning, social awareness, and adaptive behavior, may be particularly vulnerable to early brain lesions such as stroke, due to its protracted development. This study investigated: (i) the impact of childhood stroke on EF; and (ii) the impact of lesion size on EF outcome. Twenty-eight children diagnosed with stroke at least 12 months prior to assessment were recruited. Neurobehavioral assessment focused on cognitive and behavioral aspects of EF. Lesion volume was determined from standard ratings of brain pathology based on magnetic resonance imaging (MRI) scans. Deficits in cognitive aspects of EF were detected in attentional control, cognitive flexibility and information processing. Difficulties in behavioral aspects of EF were most striking, with problems identified across a wide range of behaviors. Lesion size impacted on EF, with large lesions (greater than 25% of brain volume) proving the most detrimental.

Executive function following child stroke: the impact of lesion location.

Child stroke is a major cause of death in children, although limited information exists on neurobehavioral functioning of stroke survivors. Executive function (important for goal-directed behavior) is thought to be vulnerable to early insults such as stroke because of its widespread representation in the immature brain. This study investigated the impact of lesion location on executive skills. Twenty-eight children diagnosed with stroke at least 18 months before assessment were recruited. Lesion characteristics were coded from magnetic resonance imaging (MRI) scans. Neurobehavioral assessment focused on cognitive and everyday executive skills. Deficits were found in the context of overall normal intellectual functioning (M = 91.60; SD = 19.40). Generally, insults involving frontal and extra-frontal regions impacted equally on cognitive performance. Everyday deficits were marginally more prominent following frontal insult. Subcortical frontal lesions were associated with impairments in everyday executive skills. Results provide further support for the diffuse representation of executive function in the immature brain.

Childhood MS and ADEM: investigation and comparison of neurocognitive features in children.

Cognitive deficits in adult multiple sclerosis (MS) are well documented; however, little is known regarding cognitive impairments in similar childhood conditions. This study compared cognitive profiles of children aged 7-18 years with MS (N = 9) to those with acute disseminated encephalomyelitis (ADEM) (N = 9), a similar but monophasic condition. Individual profiles showed clinically relevant impairments across all cognitive domains evaluated. Differences in severity and spread were also found. Results suggest a gradient effect, with the transient white matter disruption in ADEM resulting in subtle cognitive impairments, while the multiple insults to white matter in childhood MS are associated with more severe sequelae.

Children's executive functions: are they poorer after very early brain insult.

Traditionally early brain insult (EBI) has been considered to have better outcome than later injury, consistent with the notion that the young brain is flexible and able to reorganize. Recent research findings question this view, suggesting that EBI might lead to poorer outcome than brain insult at any other age. Exploring this early vulnerability perspective, we investigated whether skills developing later in childhood, for example, executive functions (EF), would be at greater risk of disruption from EBI. The aim of this study was to investigate EF in children sustaining EBI at different developmental stages. We expected that brain insult during gestation and infancy, before the emergence of EF, would lead to global EF deficits. In contrast, we predicted that brain injury in late childhood would have fewer consequences. Using a cross-sectional, retrospective, group design we compared six groups of children (Total N=164), with a history of brain insult and documented focal brain pathology, aged 10-16 years on a range of measures of EF. Groups were based on age of EBI: (1) Congenital; (2) Peri-natal; (3) Infancy; (4) Preschool; (5) Middle Childhood; and (6) Late Childhood. Children with EBI were at increased risk for impairment across all aspects of EF. Presence of seizures and/or frontal pathology were not predictive of outcome, but age at insult was. Children sustaining EBI before age 3 recorded more global and severe EF deficits, while children with later EBI performed closer to normal expectations. With the exception of attentional control, skills emerging at time of insult were found to be more vulnerable to disruption than those previously established, supporting the 'early vulnerability' model for EBI.