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.

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.

Excellent therapeutic efficacy and minimal late neurotoxicity in children treated with 18 grays of cranial radiation therapy for high-risk acute lymphoblastic leukemia: a 7-year follow-up study of the Dana-Farber Cancer Institute Consortium Protocol 87-01.

BACKGROUND: In the current study, the authors evaluated late neuropsychologic effects 7 years after diagnosis and the long-term survival in a cohort of patients treated for high-risk childhood acute lymphoblastic leukemia (ALL) with cranial radiation therapy. Efficacy and toxicity were evaluated in relation to patient age at diagnosis (age < or > or = 36 months). METHODS: Two hundred and one patients treated for high-risk ALL on the Dana-Farber Cancer Institute Consortium Protocol 87-01 were included, 147 of whom were in continuous complete disease remission and were eligible for cognitive testing. Sixty-one patients consented to undergo testing. All patients received 18 grays (Gy) of cranial radiation as a component of central nervous system treatment. RESULTS: For all 201 patients, the 5-year overall survival (% +/- the standard error) was 82% +/- 2 and the 5-year event-free survival (% +/- the standard error) was 75% +/- 3. Only two patients developed a central nervous system recurrence. Intelligence quotient (IQ) and memory were at the expected mean for age, but performance on a complex figure drawing task was found to be reduced. Children who were age < 36 months at the time of diagnosis were found to have an IQ in the average range, but showed verbal deficits. CONCLUSIONS: The results of the current study demonstrate excellent efficacy of therapy and relatively limited late neurotoxicity on a childhood ALL therapy protocol in which all evaluated patients had received 18 Gy of cranial radiation. Efficacious therapy that includes cranial radiation does not appear to necessarily incur a heightened risk for significant cognitive impairment.

Processing of rapid auditory stimuli in school-age children referred for evaluation of learning disorders.

Tallal hypothesized that reading disabled children have a domain-general deficit in processing rapidly occurring auditory stimuli that degrades speech perception, thereby limiting phonologic awareness and thus reading acquisition. She predicted they would be disproportionately affected by rapidly presented auditory stimuli. In this study, one hundred 7- to 11-year-old children with learning impairment (LI) and 243 non-learning impaired (NLI) children were evaluated on a two-tone auditory discrimination paradigm. LI committed more errors, but effects of timing were comparable. The same result was obtained for a subsample of good and poor readers. Task performance predicted reading, spelling, and calculation. Neural processes underlying perception of speech and other auditory stimuli may be less effective in poor readers; however, contrary to Tallal's hypothesis, rate may not be specifically affected.

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.

Sources of poor performance on the Rey-Osterrieth Complex Figure Test among children with learning difficulties: a dynamic assessment approach.

A dynamic assessment approach was used to examine the source of poor performance on the Rey-Osterrieth Complex Figure Test (ROCF) among 202 school-age children referred for learning difficulties. The ROCF was administered in the standard format and then in a structured format that highlighted the design's organizational framework. Manipulating encoding in this way improved recall to at least age-level for the majority of children. Those children who did not benefit from the structured format had relatively poor visual organizational skills. For most children with learning problems, poor ROCF performance stems from metacognitive difficulties; for a minority, the source appears to be more perceptual. A dynamic assessment procedure can enhance the diagnostic utility of the ROCF for children.

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.

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.

Cognitive sequelae in children treated for acute lymphoblastic leukemia with dexamethasone or prednisone.

PURPOSE: The cognitive sequelae of treatment for childhood acute lymphoblastic leukemia (ALL) were compared in a group of patients who received dexamethasone during the intensification and maintenance phases of therapy with those in a historical control group for whom antileukemia therapy was similar, except that the corticosteroid component of therapy was prednisone. METHODS: Patients treated for ALL on Dana-Farber Cancer Institute protocols 87-01 (n = 44) and 91-01 (n = 23) were evaluated by standard cognitive and achievement tests. Corticosteroid therapy was delivered in 5-day pulses given every 3 weeks during intensification and continuation phases of therapy for a total of 2 years. RESULTS: Children treated on protocol 87-01 received prednisone at a dose of 40 mg/m2/d (standard risk, SR) or 120 mg/ m2/d (high risk, HR); those treated on protocol 91-01 received dexamethasone at a dose of 6 mg/m2 per day (SR) or 18 mg/m2 per day (HR). Children treated on protocol 91-01 performed less well on cognitive testing. Subsample analysis indicated that cranial radiation therapy and methotrexate dose did not account for differences in cognitive outcomes. CONCLUSIONS: The findings of this preliminary study are consistent with the hypothesis that dexamethasone therapy can increase risk for neurocognitive late effects in children treated for ALL and indicate that further investigation of this question is warranted.

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.

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.

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.

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.

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.

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.

Late neuropsychological outcomes in preterm infants of normal IQ: selective vulnerability of the visual system.

Evaluated neuropsychological outcomes in 635 children, ages 7 to 10 years, in relation to birth weight group: < or = 1,000 g; 1,001-1,500 g; 1,501-2,500 g, and > 2,500 g. The prevalence of low IQ (< 85) was related to birth weight. Among children with IQ > 84 (N = 475): (a) Birth weight was unrelated to Verbal IQ, Performance IQ, Full-scale IQ, or reading achievement; (b) extremely low birth weight (ELBW) children achieved more poorly in mathematics than did other birth weight groups (p < .05); (c) ELBW and very low birth weight children performed more poorly on the Rey-Osterrieth Complex Figure, a complex visual processing task, than did heavier birth weight children (p < .05), but performance on the Beery Test of Visuomotor Integration was not related to birth weight. Results are consistent with heightened neurobehavioral vulnerability of visual processing to preterm birth.

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.

The oral health of long-term survivors of acute lymphoblastic leukaemia: a comparison of three treatment modalities.

Sixty-eight children who were diagnosed with acute lymphoblastic leukaemia (ALL) prior to age 5 years and treated with chemotherapy alone, chemotherapy plus 1800 cGy cranial irradiation (RT), or chemotherapy plus 2400 cGy RT were assessed clinically for overall dental health. All patients were at least 60 months in continuous remission. Dental caries were assessed by NIDR diagnostic criteria, oral hygiene was assessed by the modified Oral Hygiene Index, and gingival health was assessed by the modified gingival index of Loe and Silness. There was no significant difference in caries experience between the three groups nor with the normal population. Those patients that received 2400 cGy RT had significantly higher plaque and periodontal index scores than patients in the other treatment groups. The results of this study suggest that: (1) children with ALL treated with any of the described modalities are at no greater risk of developing dental caries than the normal population; and (2) patients receiving 2400 cGy prior to age 5 years are at greater risk of developing periodontal disease than patients treated with other central nervous system prophylaxis regimens examined in this study.