Sex differences in cognition: a function of maturation rate?

Regardless of sex, early maturing adolescents performed better on tests of verbal than spatial abilities, the late maturing ones showed the opposite pattern. Those maturing late were more lateralized for speech than those maturing early. Sex differences in mental abilities, it is argued, reflect differences in the organization of cortical function that are related to differential rates of physical maturation.

An animal model to study toxicity of central nervous system therapy for childhood acute lymphoblastic leukemia: effects on behavior.

Central nervous system prophylactic therapy used in the treatment of acute lymphoblastic leukemia can reduce intelligence quotient scores and impair memory and attention in children. Cranial irradiation, intrathecal methotrexate, and steroids are commonly utilized in acute lymphoblastic leukemia therapy. How they induce neurotoxicity is unknown. This study employs an animal model to explore the induction of neurotoxicity. Male and female Sprague-Dawley rats at 17 and 18 days of age were administered 18 mg/kg prednisolone, 2 mg/kg methotrexate, and 1000 cGy cranial irradiation. Another 18-day-old group was administered 1000 cGy cranial irradiation but no drugs. Matching controls received saline and/or a sham exposure to radiation. All animals at 6 weeks and 4 months of age were tested for alterations in spontaneous behavior. A computer pattern recognition system automatically recorded and classified individual behavioral acts displayed during exploration of a novel environment. Measures of behavioral initiations, total time, and time structure were used to compare treated and control animals. A permanent sex-specific change in the time structure of behavior was induced by the prednisolone, methotrexate, and radiation treatment but not by radiation alone. Unlike hyperactivity, the effect consisted of abnormal clustering and dispersion of acts in a pattern indicative of disrupted development of sexually dimorphic behavior. This study demonstrates the feasibility of an animal model delineating the agent/agents responsible for the neurotoxicity of central nervous system prophylactic therapy.

The relationship of sex and treatment modality to neuropsychologic outcome in childhood acute lymphoblastic leukemia.

PURPOSE: Long-term adverse neurobehavioral sequelae frequently are observed in pediatric patients treated for acute lymphoblastic leukemia (ALL). To clarify the relative contribution of cranial irradiation (CRT) therapy and drug therapy to these outcomes, we evaluated neuropsychologic outcomes associated with different doses of CRT and intravenous (IV) methotrexate (MTX) in long-term survivors. PATIENTS AND METHODS: Fifty-one patients treated for ALL on Dana-Farber Cancer Institute protocol 81-01 were evaluated by standardized cognitive and academic achievement tests. These children had been assigned at diagnosis to a standard-risk (SR) or high-risk (HR) group and received 1,800 cGy or 2,800 cGy CRT, respectively. A subgroup of these patients was randomized to receive MTX during remission induction, either as a single low dose (LD; 40 mg/m2) or a single high dose (HD; 4 g/m2) with leucovorin rescue. RESULTS: Sex and MTX randomization jointly predicted the intelligence quotient (IQ). Fifty percent of girls versus 14% of boys exhibited low IQ (less than 90; P = .01); 80% of girls who received HD MTX versus 25% of girls who received LD MTX exhibited low IQ (P = .03). In contrast, risk group better predicted performance on tasks sensitive to verbal memory and/or coding. CONCLUSIONS: We conclude that (1) significant neurotoxicity occurred principally in girls; (2) increased dose intensity of IV MTX was associated with lower IQ, but only in girls; and (3) increased dose of CRT may have been associated with impairment of verbal memory and coding.

Cognitive sequelae of treatment in childhood acute lymphoblastic leukemia: cranial radiation requires an accomplice.

PURPOSE: We evaluated cognitive sequelae of treatment for childhood acute lymphoblastic leukemia (ALL). CNS therapy consisted of cranial irradiation (CRT) or no radiation. Children were also randomized to single intravenous high-dose methotrexate (HD-MTX) or conventional-dose methotrexate (CD-MTX) during induction, and all patients received intrathecal (IT) and systemic continuation chemotherapy. PATIENTS AND METHODS: Sixty-six patients treated for ALL on Dana-Farber Cancer Institute protocol 87-01 were evaluated by standardized cognitive and achievement tests. These children had been assigned at diagnosis to a standard-risk (SR) or high-risk (HR) group and received no CRT or 18 Gy CRT, respectively. All patients were randomized to receive MTX during remission induction, either as CD-MTX (40 mg/m2) or HD-MTX (4 g/m2) with leucovorin rescue. RESULTS: There was no difference in cognitive outcomes between radiated and unirradiated patients (P > .4). However, the HD-MTX/CRT combination was associated with decreased intelligence quotient (IQ estimate, 9.3 points) for girls only (P < .08). A specific deficit in verbal coding and memory was documented for all patients (P < .0001). CONCLUSION: We conclude the following: (1) 18 Gy CRT per se was not an independent toxic agent for cognitive outcome; (2) HD-MTX during induction was associated with IQ decline in girls, but only when it was followed by CRT; and (3) impairment of verbal memory and coding was a consistent finding that was independent of CRT, which implicates some component of chemotherapy, possibly prednisone, as a CNS toxin.

Nutritional supplementation, maternal education, and cognitive development of infants at risk of malnutrition.

Infants born to families at risk of malnutrition were studied prospectively from the beginning of the 3rd trimester of the mother's pregnancy until the child reached 3 yr of age to ascertain the effects of nutritional supplementation and/or a maternal education program on their cognitive development. Four hundred thirty-three families were assigned randomly to six groups: group A served as a control; group B received the supplement from the age of 6 months to 3 yr; group C received the supplement during the 3rd trimester of pregnancy and the first 6 months of the child's life; and group D received the supplement throughout the entire study period. In addition, group A1 was enrolled in a maternal education program but received no nutritional supplement and group B1 received both treatments. The Griffiths test of infant development was administered at 4, 6, 12, 18, 24, and 36 months of age, and the Corman-Escalona Einstein scale was administered at each age up to 18 months. Children who received food supplementation performed better than those who did not, especially on subtests that were primarily motoric. The effect of food supplementation on behavior appeared to be contemporaneous. In addition, the treatment effects were more pronounced for girls than for boys in this sample. Although these interventions reduced the gap in cognitive performance between lower and upper socioeconomic classes, a disparity nevertheless remained by the end of the study.

Motor correlates of dichotic listening asymmetries in children.

The purpose of this study was to determine the predictive relation between incidence of unintended motor overflow and degree of asymmetry on a dichotic word identification task in children. Seventy-eight third grade girls and 67 fifth grade boys were seen longitudinally over a 2-yr period. Among girls, incidence of overflow, primarily contralateral, accounted for nearly 20% of the variance in dichotic listening scores; but the results were not reliable for boys. The findings support the contention that suppression of the non-dominant hemisphere is an important mechanism underlying dichotic listening performance.

Neurobehavioral profiles of children with neurofibromatosis 1 referred for learning disabilities are sex-specific.

We compared neurobehavioral profiles of 10 children with neurofibromatosis 1 (NF-1) referred for evaluation of learning disabilities (NF/LD) to those to learning disabled children without known genetic disease (LD), matched for age, sex, and estimated IQ. It was hypothesized that the NF/LD children would exhibit a neurobehavioral profile diagnostic of compromise of frontal/subcortical brain systems while those of the case controls would be heterogeneous. Records from a clinical data base were reviewed retrospectively for the neurological and neuropsychological components of an interdisciplinary learning disabilities evaluation. Neurological abnormalities were more frequent in the NF/LD group, involving gross and fine motor coordination, praxis, and megencephaly. As predicted, clinical neuropsychological diagnostic ratings and composite neurobehavioral observation scores were consistent with compromise of frontal systems in the NF/LD group. An unanticipated finding was that outcomes in the NF/LD group were sex dependent: Megencephaly was observed in females only; and the frontal/subcortical neurobehavioral profile was more consistently observed in females. Females with NF-1 with megencephaly may be at increased risk for a neurobehavioral syndrome contributing to LD that is consistent with compromise of frontal/subcortical brain systems.

Memory deficits among children with craniopharyngiomas.

OBJECTIVE: To describe neuropsychological functioning (with a specific focus on cognition and memory) after surgical treatment of craniopharyngiomas. METHODS: Sixteen patients who were between 6 and 15 years of age at the time of surgery comprised the sample. Each child had been treated for a craniopharyngioma with surgery only, on Dana-Farber Cancer Institute Protocol 92-077. RESULTS: The overall level of cognitive functioning was well within the average range, with both language and visuospatial functioning being generally intact; however, specific memory problems, in both the language and visuospatial domains, were evident. CONCLUSION: Although general cognitive functioning was intact after the surgical treatment of craniopharyngiomas, difficulties in the retrieval of learned information were observed. Neuropsychological assessments, with a focus on memory recall, should be a component of the medical management plan for each child.

Children with adequate academic achievement scores referred for evaluation of school difficulties: information processing deficiencies.

Children (7-11 years old) with standardized academic achievement test scores in the normal range referred for evaluation of learning problems were compared to low-achieving children matched for age, sex, and nonverbal cognitive ability, and to children with no known history of learning difficulty matched for age, sex, and reading (all N = 65) on a battery of computerized tasks of nonverbal information processing. The normally achieving referred children performed similarly to the low-achieving group but worse than reading-matched nonreferred counterparts. These findings suggest that children who struggle in school yet perform adequately on standardized achievement measures can have heightened neurodevelopmental vulnerability. Implications are discussed with respect to the underlying substrate of learning disabilities, as well as their diagnosis, classification, and remediation.

Diminished motor timing control in children referred for diagnosis of learning problems.

Disabled readers exhibit motor timing control (MTC) deficits in bimanual coordination relative to average readers. This article evaluates to what extent poor MTC is specific to reading or if it is related to learning problems in general. Children (7 to 11 years of age) referred for learning impairment (LI; n = 100) and same-age children nonlearning impaired (NLI; n = 243) performed a paced finger-tapping task. Greater variability of interresponse intervals was associated with poorer reading, spelling, and arithmetic achievement. The LI group performed more poorly than the NLI group, a difference that persisted even after adjusting for reading skill. Poor MTC is associated with poor reading but may also be a characteristic of children referred for learning problems, possibly signaling increased vulnerability of underlying neural integrative processes relevant to the child's adaptation to academic demands, including reading.

Neurobehavioral and neurologic outcome in long-term survivors of posterior fossa brain tumors: role of age and perioperative factors.

We evaluated the neuropsychological and neurologic outcome of 15 long-term survivors of posterior fossa tumors who were treated between 1970 and 1984 with cranial irradiation (n = 15) and surgery (n = 14). The interval between diagnosis and evaluation ranged from 4 to 20 years (median = 10 years). Earlier age at diagnosis (< 6 years) was associated with an increased incidence of severe neurologic and neuropsychological sequelae. Hydrocephalus, obtundation, and tumor extension outside the vermis also were more prevalent in the younger group. Poor neurobehavioral outcomes in young children with posterior fossa tumors may be related to more aggressive tumor growth or complications of the initial therapy and not solely due to toxicity from craniospinal irradiation.

Auditory evoked response data reduction by PCA: development of variables sensitive to reading disability.

Long latency auditory evoked responses (AER) were formed on 232 healthy normal and learning impaired subjects to tone pairs of 50 msec inter-stimulus interval (TALAER) and also to the words "tight" and "tyke" (TTAER). Both evoked potential (EP) type have been used to demonstrate differences between good readers (WIAT Basic Reading score > 115, N = 42) and poor readers (Reading score < 85, N = 42). A largely automated, hands off approach was used to reduce artifact contamination, to develop canonical measures for discriminating good from poor readers, and to predict reading scores across the entire population including intermediate (average) readers. Eye and muscle artifact were diminished by multiple regression. Substantial EP data reduction was enabled by an unrestricted use of Principal Components Analysis (PCA). For each EP type, 40 factors encompassed 70-80% of initial variance, a meaningful data reduction of about 90:1. Factor interpretation was enhanced by mapping of the factor loadings. By discriminant analysis, resulting factors predicted reading group membership with over 80% jackknifed and also split--half replication accuracy. By multiple regression, they produced a canonical variate correlating significantly (p < 0.001) with the Basic Reading score (r = 0.39). The TTAER factors were more useful than the TALAER factors. The relevance of rapid auditory processing and phonemic discrimination measurements to dyslexia is discussed.

Auditory evoked responses to similar words with phonemic difference: comparison between children with good and poor reading scores.

Our previous study demonstrated a physiologic deficit in two-tone discrimination in poor readers. This was specific to the left parietal area suggesting that poor readers handled rapid tones differently. The current paper extends this finding in the same population, demonstrating that poor readers also have difficulty with phonemic discrimination. Long latency auditory evoked potentials (AEP) were formed using a phonemic discrimination task in a group of children with reading disabilities and controls. Measuring peak-to-peak amplitude of the waveforms, we found reduced N1-P2 amplitude in the Poor Reader group. Using the t-statistic significance probability map (SPM) technique, we also found a group difference, maximal over the mid-parietal area, from 584 msec to 626 msec after the stimulus onset. This difference was due to a lower amplitude on the Poor Reader group. We hypothesized that this late difference constitutes a P3 response and that the Poor Reader group generated smaller P3 waves. These auditory evoked response (AER) data support a discrimination deficit for close phonemes in the Poor Reader group as they had smaller N1-P2 absolute amplitude and developed smaller P3 waves. Based on these data we should be able to differentiate between Good and Poor readers based on long latency potentials created from phonemic stimuli.

Auditory evoked responses to single tones and closely spaced tone pairs in children grouped by reading or matrices abilities.

Long latency auditory evoked responses (AER) were formed to single tones and rapid tone pairs. Using the t-statistic SPM technique, children with poorer WIAT reading scores demonstrated group difference overlying the left parietal and frontal language regions but just for AER to tone pair stimuli. Variables derived from these regions were not significantly different when the same subjects were grouped by K-BIT Matrices scores. When the same children were regrouped by Matrices scores and compared using the SPM technique, differences were now seen over the right hemisphere, especially in the parietal and frontotemporal regions, for both single and two-tone derived AERs. Variables derived from these regions were not significantly different for children when grouped by reading score. AER data support a specific deficit in two-tone stimulation for poorer reading children over the left hemisphere and also a deficit to both single and two-tone stimulation over the right hemisphere for children with poorer Matrices scores.

Processing speed in children with attention deficit/hyperactivity disorder, inattentive type.

Attention Deficit/Hyperactivity Disorder (ADHD) is among the most common and most often reconceptualized neurobehavioral disorders of childhood. In the most recent DSM-IV, a primarily inattentive subtype of ADHD (AD) has again been identified. This study explores the neuropsychological profile of this group of children. Eighty-two children referred for school-related problems participated. Twenty-five met criteria for AD; 52 met criteria for reading disability (RD); 9 were comorbid for RD and AD. AD children performed poorly on measures of information processing speed. Children with comorbid AD/RD were distinguishable from those with RD on speed of processing measures only. Vulnerability to information processing load may be at the root of many of the behavioral manifestations of AD.

Rapid automatized naming in children referred for evaluation of heterogeneous learning problems: how specific are naming speed deficits to reading disability?

Because the Rapid Automatized Naming (RAN) test reliably predicts reading skill, it is typically viewed as a diagnostic indicator of risk for reading disability (RD). Since most of the work on naming speed has been undertaken within the framework of reading research, however, the extent to which poor RAN is specifically associated with RD or with learning impairment (LI) in general is uncertain. We tested the hypothesis that slow naming speed is specific to RD. Participants were 188 children (ages 7 to 11) referred for evaluation of learning problems. Receiver operating characteristic (ROC) analysis was used to evaluate the utility of the RAN task for classifying children in diagnostic groups. RAN was an excellent tool for detecting risk for learning problems in general, but it was much less effective at distinguishing LI children with and without RD from each other.

Characteristics of children referred for evaluation of school difficulties who have adequate academic achievement scores.

Forty children (7 to 11 years old) referred for evaluation of learning problems, who had scores within the normal range on standardized measures of academic achievement, were compared to 81 similarly referred children who had scored low (< 90) on at least one measure of academic achievement. We tested the hypothesis that children with normal achievement scores who are referred for evaluation of learning problems show neuropsychological profiles comparable to those of children with low achievement. Referral problems, school history, IQ, academic achievement, and neuropsychological function were evaluated. Referred children with normal achievement scores came from more advantaged backgrounds and had less intensive academic interventions, higher IQs, and better decoding skills. Nonetheless, the two groups showed similar neuropsychological profiles. Vulnerability to complexity and decreased automaticity were prominent. Normal-range achievement test scores among children referred for evaluation should not be regarded as indicating absence of neurodevelopmental vulnerability.

Speed of information processing in children referred for learning problems: performance on a visual filtering test.

Children referred for evaluation of learning impairment (LI, N =100) and a comparison group of nonreferred (NLI, N = 243) children were evaluated on a visual filtering task. The task was designed hierarchically to provide for evaluation of component operations-serial search, parallel search, decision, and response. With each additional processing demand, response times increased disproportionately for the LI group relative to the NLI group. Overall response time reliably predicted academic skills and cognitive ability, but was more strongly related to group membership. Thus, this nonverbal visual task is sensitive to a characteristic of children with learning problems over and above discrete academic and cognitive skills. Children with problems adapting to the demands of schooling may be distinguished by a disproportionate vulnerability to processing load.

Developmental fMRI study of episodic verbal memory encoding in children.

BACKGROUND: Understanding the maturation and organization of cognitive function in the brain is a central objective of both child neurology and developmental cognitive neuroscience. This study focuses on episodic memory encoding of verbal information by children, a cognitive domain not previously studied using fMRI. METHODS: Children from 7 to 19 years of age were scanned at 1.5-T field strength using event-related fMRI while performing a novel verbal memory encoding paradigm in which words were incidentally encoded. A subsequent memory analysis was performed. SPM2 was utilized for whole brain and region-of-interest analyses of data. Both whole-sample intragroup analyses and intergroup analyses of the sample divided into 2 subgroups by age were conducted. RESULTS: Importantly, behavioral memory performance was equal across the age range of children studied. Encoding-related activation in the left hippocampus and bilateral basal ganglia declined as age increased. In addition, while robust blood oxygen level-dependent signal was found in left prefrontal cortex with task performance, no encoding-related age-modulated prefrontal activation was observed in either hemisphere. CONCLUSION: These data are consistent with a developmental pattern of verbal memory encoding function in which left hippocampal and bilateral basal ganglionic activations are more robust earlier in childhood but then decline with age. No encoding-related activation was found in prefrontal cortex which may relate to this region's recognized delay in biologic maturation in humans. These data represent the first fMRI demonstration of verbal encoding function in children and are relevant developmentally and clinically.