Biomedical subjects

P M Thompson

Publications and source records attributed to P M Thompson.

At least 19 recordsLinked to original sources

PubMed2003

Relationships between sulcal asymmetries and corpus callosum size: gender and handedness effects.

Magnetic resonance imaging was used to establish the presence and nature of relationships between sulcal asymmetries and mid-sagittal callosal size in neurologically intact subjects, and to determine the influences of sex and handedness. Against a background of long-standing disputes, effects of gender and handedness on callosal size, shape, and variability were additionally examined. Both positive and negative correlations between sulcal asymmetry and callosal size were observed, with effects influenced by sex and handedness. The direction of relationships, however, were dependent on the regional asymmetry measured and on whether real or absolute values were used to quantify sulcal asymmetries. Callosal measurements showed no significant effects of sex or handedness, although subtle differences in callosal shape were observed in anterior and posterior regions between males and females and surface variability was increased in males. Individual variations in callosal size appear to outrange any detectable divergences in size between groups. Relationships between sulcal asymmetries and callosal size, however, are influenced by both sex and handedness. Whether magnitudes of asymmetry are related to increases or decreases in callosal size appears dependent on the chosen indicators of asymmetry. It is an oversimplification, therefore, to assume a single relationship exists between cerebral asymmetries and callosal connections.

Adult↗

PubMed2003

Cortical sulcal maps in autism.

This study presents the first three-dimensional mapping of cortical sulcal patterns in autism, a pervasive developmental disorder, the underlying neurobiology of which remains unknown. High-resolution T(1)-weighted MRI scans were acquired in 21 autistic (age 10.7 +/- 3.1 years) and 20 normal control (age 11.3 +/- 2.9) children and adolescents. Using parametric mesh-based analytic techniques, we created three-dimensional models of the cerebral cortex and detailed maps of 22 major sulci in stereotaxic space. These average maps revealed anatomic shifting of major sulci primarily in frontal and temporal areas. Specifically, we found anterior and superior shifting of the superior frontal sulci bilaterally (P < or = 0.0003), anterior shifting of the right Sylvian fissure (P = 0.0002), the superior temporal sulcus (P = 0.0006 right, P = 0.02 left) and the left inferior frontal sulcus (P < or = 0.002) in the autistic group relative to the normal group. Less significant sulcal shifts occurred in the intraparietal and collateral sulci. These findings may indicate delayed maturation in autistic subjects in these brain regions involved in functions including working memory, emotion processing, language and eye gaze.

Autistic Disorder↗

PubMed2001

Mapping continued brain growth and gray matter density reduction in dorsal frontal cortex: Inverse relationships during postadolescent brain maturation.

Recent in vivo structural imaging studies have shown spatial and temporal patterns of brain maturation between childhood, adolescence, and young adulthood that are generally consistent with postmortem studies of cellular maturational events such as increased myelination and synaptic pruning. In this study, we conducted detailed spatial and temporal analyses of growth and gray matter density at the cortical surface of the brain in a group of 35 normally developing children, adolescents, and young adults. To accomplish this, we used high-resolution magnetic resonance imaging and novel computational image analysis techniques. For the first time, in this report we have mapped the continued postadolescent brain growth that occurs primarily in the dorsal aspects of the frontal lobe bilaterally and in the posterior temporo-occipital junction bilaterally. Notably, maps of the spatial distribution of postadolescent cortical gray matter density reduction are highly consistent with maps of the spatial distribution of postadolescent brain growth, showing an inverse relationship between cortical gray matter density reduction and brain growth primarily in the superior frontal regions that control executive cognitive functioning. Inverse relationships are not as robust in the posterior temporo-occipital junction where gray matter density reduction is much less prominent despite late brain growth in these regions between adolescence and adulthood. Overall brain growth is not significant between childhood and adolescence, but close spatial relationships between gray matter density reduction and brain growth are observed in the dorsal parietal and frontal cortex. These results suggest that progressive cellular maturational events, such as increased myelination, may play as prominent a role during the postadolescent years as regressive events, such as synaptic pruning, in determining the ultimate density of mature frontal lobe cortical gray matter.

Adolescent↗

PubMed2001

Lagged effects of ocean climate change on fulmar population dynamics.

Environmental variation reflected by the North Atlantic Oscillation affects breeding and survival in terrestrial vertebrates, and climate change is predicted to have an impact on population dynamics by influencing food quality or availability. The North Atlantic Oscillation also affects the abundance of marine fish and zooplankton, but it is unclear whether this filters up trophic levels to long-lived marine top predators. Here we show by analysis of data from a 50-year study of the fulmar that two different indices of ocean climate variation may have lagged effects on population dynamics in this procellariiform seabird. Annual variability in breeding performance is influenced by the North Atlantic Oscillation, whereas cohort differences in recruitment are related to temperature changes in the summer growing season in the year of birth. Because fulmars exhibit delayed reproduction, there is a 5-year lag in the population's response to these effects of environmental change. These data show how interactions between different climatic factors result in complex dynamics, and that the effects of climate change may take many years to become apparent in long-lived marine top predators.

Animals↗

PubMed2001

Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia.

Neurodevelopmental models for the pathology of schizophrenia propose both polygenetic and environmental risks, as well as early (pre/perinatal) and late (usually adolescent) developmental brain abnormalities. With the use of brain mapping algorithms, we detected striking anatomical profiles of accelerated gray matter loss in very early-onset schizophrenia; surprisingly, deficits moved in a dynamic pattern, enveloping increasing amounts of cortex throughout adolescence. Early-onset patients were rescanned prospectively with MRI, at 2-year intervals at three time points, to uncover the dynamics and timing of disease progression during adolescence. The earliest deficits were found in parietal brain regions, supporting visuospatial and associative thinking, where adult deficits are known to be mediated by environmental (nongenetic) factors. Over 5 years, these deficits progressed anteriorly into temporal lobes, engulfing sensorimotor and dorsolateral prefrontal cortices, and frontal eye fields. These emerging patterns correlated with psychotic symptom severity and mirrored the neuromotor, auditory, visual search, and frontal executive impairments in the disease. In temporal regions, gray matter loss was completely absent early in the disease but became pervasive later. Only the latest changes included dorsolateral prefrontal cortex and superior temporal gyri, deficit regions found consistently in adult studies. These emerging dynamic patterns were (i) controlled for medication and IQ effects, (ii) replicated in independent groups of males and females, and (iii) charted in individuals and groups. The resulting mapping strategy reveals a shifting pattern of tissue loss in schizophrenia. Aspects of the anatomy and dynamics of disease are uncovered, in a changing profile that implicates genetic and nongenetic patterns of deficits.

Adolescent↗

PubMed2001

Mapping callosal morphology and cognitive correlates: effects of heavy prenatal alcohol exposure.

BACKGROUND: Abnormalities of the corpus callosum (CC) have been documented in fetal alcohol syndrome (FAS), ranging from subtle decrements in its size to partial and even complete agenesis. Prenatal exposure to alcohol is also known to result in neurocognitive deficits. OBJECTIVE: To 1) investigate abnormalities in size, shape, and location of the CC within the brain in individuals with FAS and in those exposed to high amounts of alcohol prenatally but without FAS (PEA group); and 2) determine if there is a relationship between callosal dysmorphology and cognitive test performance. METHODS: MRI and novel surface-based image analytic methods were used. Twenty alcohol-exposed subjects (8 to 22 years) along with 21 normal controls (8 to 25 years) were studied with high-resolution MRI and measures of verbal learning and visuospatial abilities. RESULTS: In addition to callosal area reductions, most severe in the splenium, the CC is significantly displaced in patients exposed to alcohol prenatally. In the alcohol-exposed group, this structure lies more anterior and inferior in posterior regions with relatively normal localization of anterior regions. These findings are significant in the FAS group, and a similar but less severe pattern is observed in the PEA patients. The authors show that the amount of CC displacement is correlated with impairment in verbal learning ability and that CC displacement is a better predictor of verbal learning than regional CC area. The brain-behavior relationship is only significant within the alcohol-exposed group, and the effect is not solely mediated by overall impaired verbal intellectual functioning. CONCLUSIONS: These results further emphasize the vulnerability of midline brain structures to prenatal alcohol exposure.

Adolescent↗

PubMed2001

Three-dimensional mapping of temporo-limbic regions and the lateral ventricles in schizophrenia: gender effects.

BACKGROUND: Local alterations in morphological parameters are poorly characterized in several brain regions widely implicated in schizophrenia neuropathology. METHODS: Surface-based anatomical modeling was applied to magnetic resonance data to obtain three-dimensional (3D) average anatomical maps and measures of location, shape, asymmetry, and volume for the lateral ventricles, hippocampus, amygdala, and superior temporal gyrus in schizophrenic (n = 25; 15 male) and normal subjects (n = 28; 15 male) matched for demographic variables. For all regions, intra-group variability was visualized and group differences assessed statistically to discriminate local alterations in anatomy across sex and diagnosis. RESULTS: Posterior hippocampal volumes, lengths, and widths were reduced in patients. The right amygdala showed volume increases in schizophrenia patients versus controls. Ventricular enlargements, pronounced in the left hemisphere, occurred in the superior and lateral dimensions in patients, and these effects interacted with gender. Superior horn anterior extremes, inferior horn volumes, and hippocampal asymmetries exhibited gender effects. Significant group differences were absent in superior temporal gyrus parameters. Finally, regional variability profiles differed across groups. CONCLUSIONS: Clear morphometric differences of the lateral ventricles, hippocampus, and amygdala indicate regional displacements and shape distortions in several functional systems in schizophrenia. Alterations in these structures as mapped in 3D may provide the foundation for establishing brain abnormalities not previously defined at such a local level.

Adult↗

PubMed2001

Mapping cortical asymmetry and complexity patterns in normal children.

This study reports the first comprehensive three-dimensional (3D) maps of cortical patterns in children. Using a novel parametric mesh-based analytic technique applied to high-resolution T1-weighted MRI scans, we examined age (6-16 years) and gender differences in cortical complexity (the fractal dimension or complexity of sulcal/gyral convolutions) and asymmetry of 24 primary cortical sulci in normally developing children (N=24). Three-dimensional models of the cerebral cortex were extracted and major sulci mapped in stereotaxic space. Given the documented age-related changes in frontal lobe functions and several neuroimaging studies that have reported accompanying volumetric changes in these regions, we hypothesized that, with age, we would find continued modifications of the cerebrum in frontal cortex. We also predicted that phylogenetically older regions of the cerebrum, such as olfactory cortex, would be less variable in anatomic location across subjects and with age. Age-related increases in cortical complexity were found in both left and right inferior frontal and left superior frontal regions, possibly indicating an increase in secondary branching with age in these regions. Moreover, a significant increase in the length of the left inferior frontal sulcus and a posterior shifting of the left pre-central sulcus was associated with age. Three-dimensional asymmetry and anatomic variability maps revealed a significant left-greater-than-right asymmetry of the Sylvian fissures and superior temporal sulci, and increased variance in dorsolateral frontal and perisylvian areas relative to ventral regions of the cortex. These results suggest increases in cortical complexity and subtle modifications of sulcal topography of frontal lobe regions, likely reflecting ongoing processes such as myelination and synaptic remodeling that continue into the second decade of life. More studies in a larger sample set and/or longitudinal design are needed to address the issues of normal individual variation and sulcal development.

Adolescent↗

PubMed2001

Voxel-based morphometric analyses of the brain in children and adolescents prenatally exposed to alcohol.

Children of mothers who abuse alcohol during pregnancy can suffer varying degrees of neurological abnormality, cognitive impairment, and behavioral problems, and in the worst case, are diagnosed with fetal alcohol syndrome (FAS). The purpose of the present study was to localize brain abnormalities in a group of children and adolescents prenatally exposed to alcohol using high resolution, 3D structural MRI data and whole-brain voxel-based morphometry (VBM). Data were collected for 21 children and adolescents with histories of prenatal alcohol exposure (ALC) and 21 normally developing individuals. Statistical parametric maps revealed abnormalities most prominent in the left hemisphere perisylvian cortices of the temporal and parietal lobes where the ALC patients tended to have too much gray matter and not enough white matter. These results provide further support for dysmorphology in temporo-parietal cortices above and beyond the overall microcephaly that results from severe prenatal alcohol exposure.

Adolescent↗

PubMed2001

Homozygous deletion of CDKN2A (p16INK4a/p14ARF) but not within 1p36 or at other tumor suppressor loci in neuroblastoma.

Loss of heterozygosity of several specific genomic regions is frequently observed in neuroblastoma tumors and cell lines, but homozygous deletion (HD) is rare, and no neuroblastoma tumor suppressor gene (TSG) has yet been identified. We performed a systematic search for HD, indicative of a disrupted TSG, in a panel of 46 neuroblastoma cell lines. An initial search focused on a well-characterized consensus region of hemizygous deletion at 1p36.3, which occurs in 35% of primary neuroblastomas. Each cell line was screened with 162 1p36 markers, for a resolution of 13 kb within the consensus 1p36.3 deletion region and 350 kb throughout the remainder of 1p36. No HDs were detected. This approach was expanded to survey 21 known TSGs, specifically targeting intragenic regions frequently inactivated in other malignancies. HD was detected only at the CDKN2A (p16INK4a/p14ARF) gene at 9p21 and was observed in 4 of 46 cell lines. The observed region of HD included all exons of both CDKN2A and the closely linked CDKN2B (p15INK4b) gene for cell lines LA-N-6 and CHLA-174, all exons of CDKN2A but none of CDKN2B for CHLA-179, and only 104 bp within CDKN2A exon 2 for CHLA-101. All four deletions are predicted to inactivate the coding regions of both p16INK4a and p14ARF. HD was observed in corresponding primary tumor samples for CHLA-101 and CHLA-174 but was not present in constitutional samples. These results suggest that for neuroblastoma, large HDs do not occur within 1p36, most known TSGs are not homozygously deleted, and biallelic inactivation of CDKN2A may contribute to tumorigenicity in a subset of cases.

Blotting, Southern↗

PubMed2001

Allelic deletion at chromosome bands 11q14-23 is common in neuroblastoma.

BACKGROUND: Neuroblastoma tumorigenesis may involve the differential inactivation of multiple tumor suppressor genes. Recent data have suggested that a neuroblastoma suppressor gene may be located on the long arm of chromosome 11 (11q). PROCEDURE: We therefore analyzed 295 primary neuroblastomas from a representative group of patients for loss of heterozygosity (LOH) at 25 polymorphic markers spanning 11q. RESULTS: LOH was observed in 129 primary neuroblastomas (44%), and a common region of LOH mapped to 11q14-23. No correlation was found between 11q LOH and adverse prognostic variables, but a strong inverse relationship between 11q LOH and MYCN amplification (P < 0.001) was observed. There was no difference in overall survival when patients were stratified by 11q LOH status. However, 11q LOH was associated with a decreased overall survival probability when patients whose tumors had a single copy of MYCN were analyzed separately (P = 0.008). CONCLUSION: These data support the hypothesis that a tumor suppressor gene mapping within 11q14-23 is frequently inactivated during the malignant evolution of neuroblastoma.

Alleles↗

PubMed2001

Loss of heterozygosity for chromosome 14q in neuroblastoma.

BACKGROUND: Neuroblastoma is a genetically heterogeneous disease, with subsets of tumors demonstrating rearrangements of several genomic regions. Preliminary studies from several groups have identified loss of heterozygosity (LOH) for the long arm of chromosome 14 (14q) in 20-25% of primary neuroblastomas. PROCEDURE: To determine precisely the frequency and extent of 14q deletions, we performed LOH analysis for a large series of primary neuroblastomas using a panel of 11 highly polymorphic markers. RESULTS: LOH was detected in 83 of 372 tumors (22%). Although the majority of tumors with allelic loss demonstrated allelic loss for all informative markers, 13 cases showed LOH for only a portion of 14q. A single consensus region of deletion, which was shared by all tumors with 14q LOH, was defined within 14q23-q32 between D14S588 and the 14q telomere. Allelic loss for 14q was strongly correlated with the presence of 11q LOH (P < 0.001 ) and inversely correlated with MYCN amplification (P= 0.04). CONCLUSIONS: LOH for 14q was evident in all clinical risk groups, indicating that this abnormality may be a universal feature of neuroblastoma tumor development. These findings suggest that a tumor suppressor gene involved in the initiation or progression of neuroblastoma is located within distal 14q.

Child↗

PubMed2001

Comprehensive analysis of chromosome 1p deletions in neuroblastoma.

BACKGROUND: Chromosome 1p deletions are common in advanced neuroblastomas, but the biological and clinical implications of this clonal rearrangement remain controversial. Previous studies of chromosome 1p loss of heterozygosity (LOH) have been limited by analyses of relatively small number of tumors derived from heterogeneously assessed and treated patient populations. Therefore, a strictly representative cohort of 288 Children's Cancer Group neuroblastoma patients treated on the most recent phase III therapeutic trials was identified. PROCEDURE: Primary tumors from these patients were analyzed for LOH at precisely mapped and highly informative 1p polymorphic loci located from 1p32 to 1p36.3 by multiplex PCR. RESULTS: Ninety-three primary tumor specimens (32%) had LOH at multiple 1p36 marker loci. All 1p deletions overlapped the previously determined smallest region of overlap (SRO). One tumor had a small terminal deletion completely within 1p36.3, allowing for further refinement of the 1p36 SRO. We found no evidence to support an additional, nonoverlapping region of LOH within 1p32-36. We confirmed the strong correlation of 1p36 LOH with MYCN amplification (P < 0.001), advanced disease stage (P < 0.001), and decreased both 3-year event-free survival and overall survival probabilities (P< 0.001). When stratified for MYCN amplification status or entered into a multivariate analysis, 1p36 LOH remained predictive for decreased event-free survival, but not overall survival probability. CONCLUSIONS: These data support the hypothesis that inactivation of a tumor suppressor gene within 1p36.3 is associated with an increased risk for disease relapse.

Alleles↗

PubMed2001

Detailed molecular analysis of 1p36 in neuroblastoma.

BACKGROUND: Several lines of evidence es tablish that chromosome band 1p36 is frequently deleted in neuroblastoma primary tumors and cell lines, suggesting that a tumor suppressor gene within this region is involved in the development of this tumor. PROCEDURE: We analyzed the status of 1p36 in primary neuroblastomas and cell lines to define the region of consistent rearrangement. RESULTS: Loss of heterozygosity (LOH) studies of primary neuro blastomas identified allelic loss in 135 of 503 tumors (27%), with the smallest region of overlap (SRO) defined distal to D15214 (1p36.3). No homozygous deletions were detected at 120 loci mapping to 1p36.1-p36.3 in a panel of 46 neuroblastoma cell lines. A recently identified patient with neuroblastoma was found to have a constitutional deletion within 1p36.2-p36.3, and this deletion, when combined with the LOH results, defined a smaller SRO of one megabase within 1p36.3. We constructed a comprehensive integrated map of chromosome 1 containing 11,000 markers and large-insert clones, a high-resolution radiation hybrid (RH) map of 1p36, and a P1-artificial chromosome (PAC) contig spanning the SRO, to further characterize the region of interest. Over 768 kb (75%) of the SRO has been sequenced to completion. Further analysis of distal 1p identified 113 transcripts localizing to 1p36, 21 of which were mapped within the SRO. CONCLUSION: This analysis will identify suitable positional candidate transcripts for mutational screening and subsequent identification of the 1p36.3 neuroblastoma suppressor gene.

Alleles↗

PubMed2001

Maps of the brain.

We review recent developments in brain mapping and computational anatomy that have greatly expanded our ability to analyze brain structure and function. The enormous diversity of brain maps and imaging methods has spurred the development of population-based digital brain atlases. These atlases store information on how the brain varies across age and gender, across time, in health and disease, and in large human populations. We describe how brain atlases, and the computational tools that align new datasets with them, facilitate comparison of brain data across experiments, laboratories, and from different imaging devices. The major methods are presented for the construction of probabilistic atlases, which store information on anatomic and functional variability in a population. Algorithms are reviewed that create composite brain maps and atlases based on multiple subjects. We show that group patterns of cortical organization, asymmetry, and disease-specific trends can be resolved that may not be apparent in individual brain maps. Finally, we describe the creation of four-dimensional (4D) maps that store information on the dynamics of brain change in development and disease. Digital atlases that correlate these maps show considerable promise in identifying general patterns of structural and functional variation in human populations, and how these features depend on demographic, genetic, cognitive, and clinical parameters.

Algorithms↗

PubMed2001

Unfolding the human hippocampus with high resolution structural and functional MRI.

The hippocampus is a region of the brain that is crucial to memory function. Functional neuroimaging allows for the noninvasive investigation of the neurophysiology of human memory by observing changes in blood flow in the brain. We have developed a technique that employs high-resolution functional magnetic resonance imaging (fMRI) in combination with cortical unfolding to provide activation maps of the hippocampal region that surpass in anatomic and functional detail other methods of in vivo human brain mapping of the medial temporal lobe. We explain the principles behind this method and illustrate its application to a novelty-encoding paradigm.

Brain Mapping↗

PubMed2001

Probabilistic approaches for atlasing normal and disease-specific brain variability.

The extreme variability in the structural conformation of the human brain poses significant challenges for the creation of population-based atlases. The ability to statistically and visually compare and contrast brain image data from multiple individuals is essential to understanding normal variability within a particular population as well as differentiating normal from diseased populations. This paper introduces the application of probabilistic atlases that describe specific subpopulations, measures their variability and characterizes the structural differences between them. Utilizing data from structural MRI, we have built atlases with defined coordinate systems creating a framework for mapping data from functional, histological and other studies of the same population. This paper describes the basic approach and a brief description of the underlying mathematical constructs that enable the calculation of probabilistic atlases and examples of their results from several different normal and diseased populations.

Brain↗

PubMed2001

Genetic influences on brain structure.

Here we report on detailed three-dimensional maps revealing how brain structure is influenced by individual genetic differences. A genetic continuum was detected in which brain structure was increasingly similar in subjects with increasing genetic affinity. Genetic factors significantly influenced cortical structure in Broca's and Wernicke's language areas, as well as frontal brain regions (r2(MZ) > 0.8, p < 0.05). Preliminary correlations were performed suggesting that frontal gray matter differences may be linked to Spearman's g, which measures successful test performance across multiple cognitive domains (p < 0.05). These genetic brain maps reveal how genes determine individual differences, and may shed light on the heritability of cognitive and linguistic skills, as well as genetic liability for diseases that affect the human cortex.

Adult↗