Evidence for cerebellar-frontal subsystem changes in children treated with intrathecal chemotherapy for leukemia: enhanced data analysis using an effect size model.

BACKGROUND: Following brain insult in early childhood, the later maturing neocerebellum and frontal lobes frequently show abnormalities. OBJECTIVE: To investigate the morphologic characteristics and function of a proposed cerebellar-frontal subsystem in children treated for acute lymphoblastic leukemia (ALL) with intrathecal methotrexate using quantitative magnetic resonance imaging, neuropsychological measures, nonlinear multiple regression analysis, and a statistical effect size model that augments interpretive validity of nonsignificant statistical findings, particularly from small sample size studies. DESIGN: Comparison and relationship of magnetic resonance imaging morphometry of cerebellar lobuli I-V and VI-VII and prefrontal cortices, and performance on 5 neuropsychological tests assessing visual-spatial attention, short-term memory, and visuomotor organization and coordination between childhood survivors of ALL and a matched control group. PARTICIPANTS: Ten childhood survivors of ALL treated between 1982 and 1989 with standard 3-year intrathecal chemotherapy, and matched control subjects. MAIN OUTCOME MEASURES: Morphometric results of cerebellar lobuli I-V and VI-VII and prefrontal cortices, and results of Trail-Making Tests, Rey-Osterreith Complex Figure Test, WISC-III Coding. RESULTS: Significant effect size model values for outcome measures in the ALL group support deficits in lobuli VI-VII and prefrontal cortices, and neuropsychological performance. Multiple regression analysis results were consistent with hypothesized involvement of a cerebellar-frontal brain subsystem. CONCLUSION: Treatment of children with ALL with intrathecal methotrexate before 5 years of age has structural and functional effects on the developing neocerebellar-frontal subsystem.

Hypoplasia of the cerebellar vermis and cognitive deficits in survivors of childhood leukemia.

BACKGROUND: Neurodevelopmental evidence of the cerebellum's protracted course of postnatal development suggests that it is particularly sensitive to early toxic insult from cancer therapy. If this is the case, one would expect that there is a relationship between the pattern of neuropsychological and magnetic resonance imaging deficits and that both may indicate cerebellar abnormalities. OBJECTIVE: To investigate the profiles of neuropsychological functions and the morphologic features of the cerebellum, using in vivo magnetic resonance imaging planimetry in survivors of acute lymphoblastic leukemia (ALL) treated with radiation and chemotherapy. DESIGN: Thirteen survivors of childhood ALL with onset at age 2 to 5 years and a uniform protocol of treatment involving cranial radiation of 24 Gy and five doses of intrathecal methotrexate sodium participated in the study. Ten controls matched the patients in age and socioeconomic status. Each child was assessed with a comprehensive battery of neuropsychological tests and with magnetic resonance imaging of the brain. MEASUREMENTS: The neuropsychological scores were transformed into z scores and clustered into right and left hemisphere measures. Planimetric measures of the cerebellar vermis and pons were collected in the midsagittal plane. RESULTS: Consistently observed in survivors of ALL were the following: (1) significant cognitive deficits in visual-spatial-motor coordination and figural memory, functions commonly related to the right side of the brain; and (2) hypoplasia of the cerebellar vermis, lobuli I through V and particularly VI to VII. Lateralization of the neurobehavioral deficits was not reflected in structural brain abnormalities. CONCLUSIONS: Coexistence of the cerebellar hypoplasia and visual-motor coordination and memory deficits supports the neurodevelopmental approach to brain sequelae in survivors of ALL; it also suggests significance of the cerebellum for both motor and complex nonmotor cognitive processing.

Event-related potentials in children with specific visual cognitive disability.

Event-related potentials (ERPs) elicited by novel and well memorized non-verbal visual patterns were recorded over the right and left hemispheres from ten children with Specific Visual Cognitive Disability (SVCD) and ten matched Control subjects (C). ERPs of SVCD children were generally longer in latency (particularly N2) and decreased in amplitude (particularly P3) relative to the ERPs of Cs. No hemisphere differences were observed in the SVCD group, while the latency of N2 in the C group tended to be slightly shorter and the amplitude of P3 was significantly larger over the right than over the left hemisphere. The results are discussed in terms of deficits in visual learning and visual pattern analysis. The different hemispheric pattern in SVCD children as compared to Cs is suggested to be a symptom secondary to basic visual cognitive deficits.

Event-related potentials in cross-modal divided attention in autism.

The behavior and event-related potentials (ERPs) of high functioning subjects with autism (Autism group) were contrasted with the results of normal controls (Control group) during a focused visual attention, a focused auditory attention and a visual/auditory divided attention task. Detecting targets by the Autism group in the cross-modal divided attention condition was more difficult (longer RTs, lower % of correct detections) than attending to one modality. However, both the Autism and Control groups performed all tasks above chance level. The slow negative wave (SNW) was the only negative component which reflected Focused vs Divided task effect in Controls, being largest to stimuli in single channel-focused attention, intermediate when attention was divided between targets of two modalities and smallest to unattended stimuli. Task effects were more evident in the positive peaks for the Autism group. No significant divided attention task effect was noted for P3b, although it was larger for attended than ignored stimuli, of normal morphology and only slightly decreased in size in the Autism group as compared to the Control group. The failure of the Autism group to modulate the slow negative wave in response to Focused/Divided/Ignored conditions in a normal manner, the presence of relatively normal morphology despite the reduced amplitude of the P3b and other positive components, together with the high level of correct target detections are discussed in the context of a selective inhibition deficit and an alternative mechanism of selective attention in autism.

Cerebellar hypoplasia and frontal lobe cognitive deficits in disorders of early childhood.

A developmental chronometry hypothesis of early brain damage is suggested in which regions of the brain with a protracted course of postnatal development will be more vulnerable than earlier maturing areas to deleterious effects of early insult and, therefore, may become common sites of abnormality across many disorders originating in early childhood. Initial investigations of the cerebellum and frontal lobes are presented using MRI and neuropsychological measures. Planimetric measures of the cerebellar vermis (lobuli I-V and VI-VII) and pons, and neuropsychological frontal lobe measures were obtained from high functioning individuals with autism (A), survivors of acute lymphoblastic leukemia (ALL) with brain sequelae following radiation and chemotherapy, and from rigorously selected healthy controls (C). The neuropsychological results were clustered according to functions commonly related to frontal brain, posterior brain, and left and right hemispheres. The A and ALL groups, as compared to C, yielded modest but consistently reduced MRI measures for vermal lobuli I-V and VI-VII. Hypoplasia of lobuli VI-VII was more marked than I-V. Performance on neuropsychological tests for frontal lobe functions was generally depressed in both groups, with more severe deficits in A. Between-group differences in verbal, visual-spatial, and emotional-social skills are discussed. The cerebellar and frontal brain deficits that are present in both clinical groups (A and ALL) may be common to other developmental and acquired disorders of early childhood. Such joint manifestation of cerebellar and frontal lobe abnormalities is in agreement with the concept of cerebellar significance for the development of higher cognitive functions.

MRI morphometry of mamillary bodies, caudate nuclei, and prefrontal cortices after chemotherapy for childhood leukemia: multivariate models of early and late developing memory subsystems.

Neurotoxic intrathecal chemotherapy for childhood acute lymphoblastic leukemia (ALL) affects developing structures and functions of memory and learning subsystems selectively. Results show significant reductions in magnetic resonance imaging morphometry of mamillary bodies, components of the corticolimbic-diencephalic subsystem subserving functionally later developing, single-trial memory, nonsignificant changes in bilateral heads of the caudate nuclei, components of the corticostriatal subsystem subserving functionally earlier developing, multitrial learning, significant reductions in prefrontal cortical volume, visual and verbal single-trial memory deficits, and visuospatial, but not verbal, multitrial learning deficits. Multiple regression models provide evidence for partial dissociation and connectivity between the subsystems, and suggest that greater involvement of caudate may compensate for inefficient corticolimbic-diencephalic components.

Lateralization of visual cognitive potentials.

Pairs of stimuli containing either the same or different visual patterns were presented separately to the right and left brain hemispheres. Ten adult males were trained before the formal experiment to perform the task automatically and without verbal control. A verbal control task was arranged at the end of the experiment. Reaction times and P3P4, C3C4 brain evoked potentials were recorded. The N2 (180-290 msecs) and P3 (290-380 msecs) components were found to be lateralized over the right side of the scalp for nonverbal conditions. Slightly larger P3 was found over the left side for the verbal control test. The results are discussed in relation to the present evidence about the nature of N2 and P3 in the single act of perception and in the ontogenetic development.

Event-related potentials before and after training: chronometry and lateralization of visual N1 and N2.

Event-related potentials (ERPs) were recorded from normal right-handed males in visual-matching tasks before and after training to a high level of automaticity. The amplitude and latency of the left and right hemispheric N1 and N2 components were analyzed. While changes of N1 "after training" relative to "before training" were statistically non-significant, the N2 component appeared to be a sensitive indicator of the variability in chronometry and lateralization of cerebral processes modified by training. The N2 results suggest that with practice the physiological processes underlying performance in a visual-cognitive task become more efficient, selective and localized.

Cerebellar abnormality in autism: a nonspecific effect of early brain damage?

Cerebellum may be a common site of developmental abnormalities due to its protracted course of maturation. Recent studies have implicated morphological deviations of the cerebellum as responsible for specific behavioral and cognitive manifestations of autism. We investigated neuropsychology and quantitative MRI of the cerebellum in both high functioning subjects with autism and survivors of childhood leukemia treated with radiation and intrathecal chemotherapy. The results of neuropsychological testing revealed different patterns of cognitive deficits for the two groups, while the abnormal cerebellar morphology was similar for both groups. Since it is suggested that the cerebellum contributes to motor-attentional subsystems, the present data provide support for a cerebellar role in the governance of higher cognitive functions, found to be abnormal in both groups. However, the abnormal macromorphology of the cerebellar vermis described here appears to be non-specific to autism.

Anterior brain deficits in chronic alcoholism. Cause or effect?

To investigate the hypothesis of anterior brain involvement in alcoholism, nonfamilial short-term drinkers (STD) and long-term drinkers (LTD) were assessed using neuropsychological tests commonly related to frontal lobe functions. Both STDs and LTDs were similarly impaired on measures of visually mediated concept formation and flexibility of thinking. Results from other time-constrained tests that required good concentration and immediate memory, visual scanning, and visual-motor coordination were significantly lower in the LTD group as compared with STDs. The data suggest a dual-factor hypothesis of anterior cerebral dysfunctions in alcoholism: a preexisting deficit in conceptual thinking and consequential CNS abnormality (psychomotor slowing, decreased attentiveness, and immediate memory) associated with prolonged alcohol intake, and resembling signs of premature aging.

Some electrophysiological observations in obsessional states.

Averaged evoked potentials were recorded from a group of obsessional patients and matched normal controls for three types of visual stimulation: passive monitoring of a light flash, a pattern consisting of gratings and a cognitive task involving discrimination of two similar shapes. As the complexity of information processing required by the tasks increased, differences in the evoked potentials of obsessionals became more marked. The main finding was of faster latency and reduced amplitude of the N220 component in the cognitive task. The relevance of this finding to a theory of obsessional disorder is discussed.

Effects of focused selective attention tasks on event-related potentials in autistic and normal individuals.

Event-related potentials (ERPs) and behavioral responses were recorded from autistic and normal subjects under two focused selective attention conditions. In each condition, subjects were presented with an identical stimulus paradigm--a random sequence of 50 msec sounds and flashes occurring at interstimulus intervals ranging between 0.5 and 1.5 sec. The sequence consisted of rare auditory (12.5%), rare visual (12.5%), standard auditory (37.5%) and standard visual (37.5%) stimuli. In the focal auditory condition, subjects pressed a button to the rare auditory target, and in a focal visual condition, they pressed a button to the rare visual stimuli. When normal subjects detected target stimuli in a given attended modality, all stimuli in the attended modality produced enhanced negative ERP responses at frontal electrode sites (i.e., auditory Nde, Ndl, and Nc; visual N270 and Nc) and enhanced positive ERP responses at posterior electrode sites (i.e., P3b and visual P400). In the autistic subjects, in contrast, all auditory and visual attention-related negativities recorded in the auditory and visual focused attention tasks were not in evidence. P3b was significantly diminished in size. The results suggest that abnormalities in the neurophysiological mechanisms of selective attention may underlie the cognitive deficits in autism. The present report and its companion papers are the first reports of the neurophysiological correlates of selective attention in autism.

Further observations of evoked potentials in obsessional patients.

This study was designed to replicate and extend earlier findings. Evoked potentials (EP) were recorded, using a task of varying complexity involving shape discrimination, with matched groups of obsessional and normal subjects. Results confirmed previous findings that obsessional patients are characterized by reduced amplitudes and decreased latencies of late EP components; divergences between the groups were more marked for tasks of increased complexity.

Visual and verbal short-term memory deficits in childhood leukemia survivors after intrathecal chemotherapy.

Assessed survivors of childhood lymphoblastic leukemia (ALL) treated with intrathecal chemotherapy, using the Wide Range Assessment of Memory and Learning (WRAML), compared to controls without cancer, matched as closely as possible in age, SES, and gender. Mild, but consistent, deficits were found in both visual-spatial and verbal single-trial memory tasks. In multitrial learning, only visual-spatial tasks resulted in deficient scores, while verbal learning was within the normal range. IQ results indicated scores 10-20 points lower in the ALL group. Memory results are related to deficits in strategic planning and attentional distractiveness. The WRAML may be a useful clinical tool to evaluate differential memory deficits in children with ALL.

Long-term brain impairment in chronic alcoholics: N2-P3 cognitive potentials in a template-matching memory task.

Neuropsychological measurements and N2-P3 visual cognitive potentials evoked by a template-matching visual-memory task were collected from seemingly intact chronic alcoholics and normal controls. Psychometric results were not significantly different between alcoholics and controls, but the N2-P3 cognitive potentials of the alcoholic population showed a decreased amplitude and an atypical interhemispheric pattern of latencies that point to alcohol-related deficits. The different functional nature and possibly separate intracranial origin of N2 and P3 suggest respective cortical and hippocampal localisation of these deficits. Cognitive brain potentials were a more sensitive indicator of cerebral impairment than psychometric data.