Biomedical subjects

A W Toga

Publications and source records attributed to A W Toga.

At least 37 records · Page 2Linked to original sources

PubMed2001

Medial temporal lobe in childhood-onset schizophrenia.

The majority of anatomic and neuroimaging studies in adult-onset schizophrenia demonstrate decreased volumes of the medial temporal lobe when compared with findings in normal individuals. The goal of this study was to investigate the hypothesis that subjects with childhood-onset schizophrenia would show decreased volumes of the medial temporal lobe when compared to normal children. Thirteen children meeting DSM-III-R criteria for schizophrenia (mean age 14.2+/-3.8 years) and 20 normal children (mean age 12.0+/-2.8 years) were investigated. MRI scans were performed on a 1.5-T GE Signa MR scanner using a coronal plane SPGR at 1.4-mm slice thickness. Volumes were assessed by manually tracing bilateral hippocampus, amygdala and temporal lobes. After adjustment for age and total brain volume, the amygdala was significantly larger in the schizophrenics than in the control subjects, and this volume increase was more pronounced on the left side. Hippocampus volumes did not differ significantly across groups. There was a nearly significant left-greater-than-right asymmetry of the amygdala in the schizophrenic group but not in the normal group. A nearly significant right-greater-than-left asymmetry was found in the anterior hippocampus for both schizophrenic and control groups. These findings are consistent with previous reports of at least initial sparing of temporal lobe regions in childhood-onset schizophrenia.

Adolescent↗

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

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

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↗

PubMed2001

Cortical change in Alzheimer's disease detected with a disease-specific population-based brain atlas.

We report the first detailed population-based maps of cortical gray matter loss in Alzheimer's disease (AD), revealing prominent features of early structural change. New computational approaches were used to: (i) distinguish variations in gray matter distribution from variations in gyral patterns; (ii) encode these variations in a brain atlas (n = 46); (iii) create detailed maps localizing gray matter differences across groups. High resolution 3D magnetic resonance imaging (MRI) volumes were acquired from 26 subjects with mild to moderate AD (age 75.8+/-1.7 years, MMSE score 20.0+/-0.9) and 20 normal elderly controls (72.4+/-1.3 years) matched for age, sex, handedness and educational level. Image data were aligned into a standardized coordinate space specifically developed for an elderly population. Eighty-four anatomical models per brain, based on parametric surface meshes, were created for all 46 subjects. Structures modeled included: cortical surfaces, all major superficial and deep cortical sulci, callosal and hippocampal surfaces, 14 ventricular regions and 36 gyral boundaries. An elastic warping approach, driven by anatomical features, was then used to measure gyral pattern variations. Measures of gray matter distribution were made in corresponding regions of cortex across all 46 subjects. Statistical variations in cortical patterning, asymmetry, gray matter distribution and average gray matter loss were then encoded locally across the cortex. Maps of group differences were generated. Average maps revealed complex profiles of gray matter loss in disease. Greatest deficits (20-30% loss, P<0.001-0.0001) were mapped in the temporo-parietal cortices. The sensorimotor and occipital cortices were comparatively spared (0-5% loss, P>0.05). Gray matter loss was greater in the left hemisphere, with different patterns in the heteromodal and idiotypic cortex. Gyral pattern variability also differed in cortical regions appearing at different embryonic phases. 3D mapping revealed profiles of structural deficits consistent with the cognitive, metabolic and histological changes in early AD. These deficits can therefore be (i) charted in a living population and (ii) compared across individuals and groups, facilitating longitudinal, genetic and interventional studies of dementia.

Aged↗

PubMed2001

Temporal spatial differences observed by functional MRI and human intraoperative optical imaging.

Pre-operative functional magnetic resonance imaging (fMRI), cortical evoked potentials (EPs) and intraoperative optical imaging of intrinsic signals (iOIS) were employed to relate the temporal-spatial characteristics of sensorimotor responses in human brain. Peripheral somasthetic stimulation (2 s) was provided either by a 110 Hz finger vibrator or transcutaneous median nerve stimulation in eight patients undergoing neurosurgical procedures. Each technique provided unique spatial patterns and temporal response profiles. EPs and iOIS activities were observed over the surface of pre- and post-central gyri (at the level of the superior genu) with very similar spatial distributions. In contrast, fMRI spatial distributions depended upon the model used for statistical correlation analysis. Using a monophasic response model, fMRI primarily localized within the central sulcus and did not demonstrate large signal changes over the pre- and post-central gyri (areas with iOIS/EP activity). However, as initial negative responses were incorporated into the response model, fMRI progressively localized closer to the iOIS and somatosensory EP maps. Temporally, responses to single stimuli differed between the fMRI and iOIS techniques. Using a monophasic model for fMRI analysis, the total fMRI response was delayed by 2--3 s relative to iOIS. As initial negative responses were incorporated in the analysis, the fMRI time course developed temporal characteristics similar to iOIS. Ultimately, when fMRI time courses were examined over pixels co-localizing with iOIS activation (without using statistical correlation analysis), the fMRI temporal profile included an initial decrease in signal (an initial dip) that closely resembled the time course of iOIS response. This is the first study to experimentally co-localize (temporally and spatially) iOIS and fMRI signals in human subjects. The spatial/temporal differences in this study likely reflect the capillary versus venous contributions of iOIS and fMRI, respectively. The temporal/spatial co-localization of the iOIS signal and the fMRI initial dip suggests the initial fMRI dip and the iOIS signal may result from similar physiologic events.

Algorithms↗

PubMed2001

Tracking tumor growth rates in patients with malignant gliomas: a test of two algorithms.

BACKGROUND AND PURPOSE: Two 3D image analysis algorithms, nearest-neighbor tissue segmentation and surface modeling, were applied separately to serial MR images in patients with glioblastoma multiforme (GBM). Rates of volumetric change were tracked for contrast-enhancing tumor tissue. Our purpose was to compare the two image analysis algorithms in their ability to track tumor volume relative to a manually defined standard of reference. METHODS: Three-dimensional T2-weighted and contrast-enhanced T1-weighted spoiled gradient-echo MR volumes were acquired in 10 patients with GBM. One of two protocols was observed: 1) a nearest-neighbor algorithm, which used manually determined or propagated tags and automatically segmented tissues into specific classes to determine tissue volume; or 2) a surface modeling algorithm, which used operator-defined contrast-enhancing boundaries to convert traced points into a parametric mesh model. Volumes were automatically calculated from the mesh models. Volumes determined by each algorithm were compared with the standard of reference, generated by manual segmentation of contrast-enhancing tissue in each cross section of a scan. RESULTS: Nearest-neighbor algorithm enhancement volumes were highly correlated with manually segmented volumes, as were growth rates, which were measured in terms of halving and doubling times. Enhancement volumes generated by the surface modeling algorithm were also highly correlated with the standard of reference, although growth rates were not. CONCLUSION: The nearest-neighbor tissue segmentation algorithm provides significant power in quantifying tumor volume and in tracking growth rates of contrast-enhancing tissue in patients with GBM. The surface modeling algorithm is able to quantify tumor volume reliably as well.

Adolescent↗

PubMed2001

Cognitive and metabolic responses to metrifonate therapy in Alzheimer disease.

OBJECTIVE: The objective of this study was to identify the relation between the cognitive benefit seen with the cholinesterase inhibitor metrifonate and changes in brain metabolism as visualized with [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET). BACKGROUND: The regional metabolic correlates of treatment with cholinesterase inhibitors are poorly understood. METHODS: Six patients with mild to moderate Alzheimer disease (AD) were evaluated before and after treatment with the long-lasting cholinesterase inhibitor metrifonate. Patients were given 60 or 80 mg of metrifonate per day (based on weight) for 6 to 12 weeks. Clinical evaluations included the cognitive portion of the Alzheimer's Disease Assessment Scale (ADAS-cog), the Mini-Mental State Examination (MMSE), and the Neuropsychiatric Inventory. Imaging was carried out using FDG-PET. The PET studies, registered to a probabilistic anatomic atlas, were normalized across the group's mean intensity levels and subjected to voxel-by-voxel subtraction of the posttreatment minus pretreatment studies. Subvolume thresholding corrected random lobar noise to produce a three-dimensional functional significance map. RESULTS: The criteria for cognitive improvement with treatment were met for the MMSE (>2 points improvement from baseline), and the drawing subscale of the ADAS-cog was significantly improved with treatment. The three-dimensional significance map revealed a significant metabolic increase of the dorsolateral frontoparietal network on the left and bilateral temporal cortex with metrifonate treatment. CONCLUSION: The clinical benefits observed in AD with cholinesterase inhibitor therapy are associated with a metabolic increase of heteromodal cognitive and medial temporal networks.

Aged↗

PubMed2000

Optical intrinsic signal imaging in a rodent seizure model.

The authors studied seizure activity with optical intrinsic signal (OIS) imaging in a rat seizure model. OIS, which measures vascular and metabolic effects associated with neuronal activity, showed significant cortical reflectance changes from penicillin-induced seizures, and correlated well with EEG epileptiform discharges. Furthermore, OIS changes often preceded initial EEG spikes. These observations suggest that OIS is well coupled with seizure activity, and may provide sensitive cues for seizure detection.

Animals↗

PubMed2000

Characterization of optical intrinsic signals and blood volume during cortical spreading depression.

Cortical spreading depression (CSD) was imaged in vivo in a rodent model with optical intrinsic signals (OIS). This is the first study to identify a triphasic OIS response and to characterize the rate and timing of the response. The initial OIS phase had a highly uniform wavefront, which spread at a rate characteristic of CSD, 3.5 mm/min. Later phases were more diffuse and inhomogeneous. Blood volume changes, measured with intravascular fluorescent dye, correlated in time and location with the later phases of OIS response. This suggests that the inhomogeneity of the late OIS response may be due to complex residual hemodynamic contributions, as opposed to underlying cortical circuitry.

Animals↗

PubMed2000

Growth patterns in the developing brain detected by using continuum mechanical tensor maps.

The dynamic nature of growth and degenerative disease processes requires the design of sensitive strategies to detect, track and quantify structural change in the brain in its full spatial and temporal complexity. Although volumes of brain substructures are known to change during development, detailed maps of these dynamic growth processes have been unavailable. Here we report the creation of spatially complex, four-dimensional quantitative maps of growth patterns in the developing human brain, detected using a tensor mapping strategy with greater spatial detail and sensitivity than previously obtainable. By repeatedly scanning children (aged 3-15 years) across time spans of up to four years, a rostro-caudal wave of growth was detected at the corpus callosum, a fibre system that relays information between brain hemispheres. Peak growth rates, in fibres innervating association and language cortices, were attenuated after puberty, and contrasted sharply with a severe, spatially localized loss of subcortical grey matter. Conversely, at ages 3-6 years, the fastest growth rates occurred in frontal networks that regulate the planning of new actions. Local rates, profiles, and principal directions of growth were visualized in each individual child.

Adolescent↗

PubMed2000

Mathematical/computational challenges in creating deformable and probabilistic atlases of the human brain.

Striking variations in brain structure, especially in the gyral patterns of the human cortex, present fundamental challenges in human brain mapping. Probabilistic brain atlases, which encode information on structural and functional variability in large human populations, are powerful research tools with broad applications. Knowledge-based imaging algorithms can also leverage atlased information on anatomic variation. Applications include automated image labeling, pathology detection in individuals or groups, and investigating how regional anatomy is altered in disease, and with age, gender, handedness and other clinical or genetic factors. In this report, we illustrate some of the mathematical challenges involved in constructing population-based brain atlases. A disease-specific atlas is constructed to represent the human brain in Alzheimer's disease (AD). Specialized strategies are developed for population-based averaging of anatomy. Sets of high-dimensional elastic mappings, based on the principles of continuum mechanics, reconfigure the anatomy of a large number of subjects in an anatomic image database. These mappings generate a local encoding of anatomic variability and are used to create a crisp anatomical image template with highly resolved structures in their mean spatial location. Specialized approaches are also developed to average cortical topography. Since cortical patterns are altered in a variety of diseases, gyral pattern matching is used to encode the magnitude and principal directions of local cortical variation. In the resulting cortical templates, subtle features emerge. Regional asymmetries appear that are not apparent in individual anatomies. Population-based maps of cortical variation reveal a mosaic of variability patterns that segregate sharply according to functional specialization and cytoarchitectonic boundaries.

Aged↗

PubMed2000

Brain abnormalities observed in childhood-onset schizophrenia: a review of the structural magnetic resonance imaging literature.

Childhood-onset schizophrenia (COS) is a rare, severe form of schizophrenia in which there are structural brain abnormalities that may be related to the psychotic symptomatology and neurocognitive deficits found in these patients. While there are numerous structural imaging studies of the adult-onset variant of schizophrenia (with many conflicting findings), relatively few brain imaging studies of COS have been conducted. This paper summarizes the extant literature of magnetic resonance imaging (MRI) studies of structural brain abnormalities in COS, and compares findings to similar studies of adult-onset patients. Volumetric MRI studies of COS patients have consistently shown evidence for increased ventricular volume, reduced cerebral gray matter, and increased caudate volume, consistent with findings from adult-onset studies. Other volumetric brain abnormalities are observed in COS patients, such as reduced total brain volume, but not consistently across all studies. Voxel-based morphometric analyses have revealed abnormalities in the shape and spatial location of structures in COS such as the corpus callosum, caudate, and thalamus that could not be observed in the more traditional volumetric assessments. Similar findings also are observed in adult-onset patients. Progressive degenerative changes, such as ventricular enlargement, appear to occur in COS only until young adulthood where there is an apparent asymptote with no further degenerative changes. This is consistent with the lack of progressive changes noted in most longitudinal studies of adult-onset schizophrenia.

Age of Onset↗