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The purpose of this investigation was to elucidate the association between microvascular blood volume and glucose uptake and to link these measures with tumor angiogenesis. We demonstrate a regionally specific correlation between tumor relative microvascular blood volume (CBV), determined in vivo with functional magnetic resonance imaging techniques, and tumor glucose uptake determined with fluorodeoxyglucose positron emission tomography. Regions of maximum glucose uptake were well matched with maximum CBV across all patients (n = 21; r = 0.572; P = 0.023). High-grade gliomas showed significantly elevated CBV and glucose uptake compared with low-grade gliomas, (P = 0.009 and 0.008, respectively). Correlations between CBV and glucose uptake were then determined on a voxel-by-voxel basis within each patient's glioma. Correlation indices varied widely, but in 16 of 21 cases of human glioma, CBV and glucose uptake were correlated (r > 0.150). These measures were well correlated in all cases when comparing healthy brain tissue in these same patients. Tumor vascularity, as determined immunohistochemically and morphometrically on clinical samples, revealed statistically significant relationships with functional imaging characteristics in vivo. Regional heterogeneities in glucose uptake were well matched with functional magnetic resonance imaging CBV maps. Our findings support the concept that there is an association of microvascular density and tumor energy metabolism in most human gliomas. In addition, the findings are likely to have important clinical applications in the initial evaluation, treatment, and longitudinal monitoring of patients with malignant gliomas.

Although it is well known that there is considerable variation among individuals in the size of the human brain, the etiology of less extreme individual differences in brain size is largely unknown. We present here data from the first large twin sample (N=132 individuals) in which the size of brain structures has been measured. As part of an ongoing project examining the brain correlates of reading disability (RD), whole brain morphometric analyses of structural magnetic response image (MRI) scans were performed on a sample of adolescent twins. Specifically, there were 25 monozygotic (MZ) and 23 dizygotic (DZ) pairs in which at least one member of each pair had RD and 9 MZ and 9 DZ pairs in which neither member had RD. We first factor-analyzed volume data for 13 individual brain structures, comprising all of the neocortex and most of the subcortex. This analysis yielded two factors ("cortical" and "subcortical") that accounted for 64% of the variance. We next tested whether genetic and environmental influences on brain size variations varied for these two factors or by hemisphere. We computed intraclass correlations within MZ and DZ pairs in each sample for the cortical and subcortical factor scores, for left and right neocortex, and for the total cerebral volume. All five MZ correlations were substantial (r's=.78 to.98) and significant in both samples, as well as being larger than the corresponding DZ correlations, (r's=0.32 to 0.65) in both samples. The MZ-DZ difference was significant for 3 variables in the RD sample and for one variable in the smaller control sample. These results indicate significant genetic influences on these variables. The magnitude of genetic influence did not vary markedly either for the 2 factors or the 2 hemispheres. There was also a positive correlation between brain size and full-scale IQ, consistent with the results of earlier studies. The total cerebral volume was moderately correlated (r=.42, p<.01, two-tailed) with full-scale IQ in the RD sample; there was a similar trend in the smaller control sample (r=.31, p<.07, two-tailed). Corrections of similar magnitude were found between the subcortical factor and full-scale IQ, whereas the results for the cortical factor (r=.16 and.13) were smaller and not significant. In sum, these results provide evidence for the heritability of individual differences in brain size which do not vary markedly by hemisphere or for neocortex relative to subcortex. Since there are also correlations between brain size and full-scale IQ in this sample, it is possible that genetic influences on brain size partly contribute to individual differences in IQ.

Acupuncture, an ancient therapeutic technique, is emerging as an important modality of complementary medicine in the United States. The use and efficacy of acupuncture treatment are not yet widely accepted in Western scientific and medical communities. Demonstration of regionally specific, quantifiable acupuncture effects on relevant structures of the human brain would facilitate acceptance and integration of this therapeutic modality into the practice of modern medicine. Research with animal models of acupuncture indicates that many of the beneficial effects may be mediated at the subcortical level in the brain. We used functional magnetic resonance imaging (fMRI) to investigate the effects of acupuncture in normal subjects and to provide a foundation for future studies on mechanisms of acupuncture action in therapeutic interventions. Acupuncture needle manipulation was performed at Large Intestine 4 (LI 4, Hegu) on the hand in 13 subjects [Stux, 1997]. Needle manipulation on either hand produced prominent decreases of fMRI signals in the nucleus accumbens, amygdala, hippocampus, parahippocampus, hypothalamus, ventral tegmental area, anterior cingulate gyrus (BA 24), caudate, putamen, temporal pole, and insula in all 11 subjects who experienced acupuncture sensation. In marked contrast, signal increases were observed primarily in the somatosensory cortex. The two subjects who experienced pain instead of acupuncture sensation exhibited signal increases instead of decreases in the anterior cingulate gyrus (BA 24), caudate, putamen, anterior thalamus, and posterior insula. Superficial tactile stimulation to the same area elicited signal increases in the somatosensory cortex as expected, but no signal decreases in the deep structures. These preliminary results suggest that acupuncture needle manipulation modulates the activity of the limbic system and subcortical structures. We hypothesize that modulation of subcortical structures may be an important mechanism by which acupuncture exerts its complex multisystem effects.

Changes in species composition in two 4-ha plots of lowland dipterocarp rainforest at Danum, Sabah, were measured over ten years (1986-1996) for trees > or = 10 cm girth at breast height (gbh). Each included a lower-slope to ridge gradient. The period lay between two drought events of moderate intensity but the forest showed no large lasting responses, suggesting that its species were well adapted to this regime. Mortality and recruitment rates were not unusual in global or regional comparisons. The forest continued to aggrade from its relatively (for Sabah) low basal area in 1986 and, together with the very open upper canopy structure and an abundance of lianas, this suggests a forest in a late stage of recovery from a major disturbance, yet one continually affected by smaller recent setbacks. Mortality and recruitment rates were not related to population size in 1986, but across subplots recruitment was positively correlated with the density and basal area of small trees (10-< 50cm gbh) forming the dense understorey. Neither rate was related to topography. While species with larger mean gbh had greater relative growth rates (rgr) than smaller ones, subplot mean recruitment rates were correlated with rgr among small trees. Separating understorey species (typically the Euphorbiaceae) from the overstorey (Dipterocarpaceae) showed marked differences in change in mortality with increasing gbh: in the former it increased, in the latter it decreased. Forest processes are centred on this understorey quasi-stratum. The two replicate plots showed a high correspondence in the mortality, recruitment, population changes and growth rates of small trees for the 49 most abundant species in common to both. Overstorey species had higher rgrs than understorey ones, but both showed considerable ranges in mortality and recruitment rates. The supposed trade-off in traits, viz slower rgr, shade tolerance and lower population turnover in the understorey group versus faster potential growth rate, high light responsiveness and high turnover in the overstorey group, was only partly met, as some understorey species were also very dynamic. The forest at Danum, under such a disturbance-recovery regime, can be viewed as having a dynamic equilibrium in functional and structural terms. A second trade-off in shade-tolerance versus drought-tolerance is suggested for among the understorey species. A two-storey (or vertical component) model is proposed where the understorcy-overstorey species' ratio of small stems (currently 2:1) is maintained by a major feedback process. The understorey appears to be an important part of this forest, giving resilience against drought and protecting the overstorey saplings in the long term. This view could be valuable for understanding forest responses to climate change where drought frequency in Borneo is predicted to intensify in the coming decades.

Objective: To determine whether individuals with situs inversus totalis (SI), a condition in which there is a mirror-image reversal of asymmetric visceral organs, have alterations in brain asymmetries., Background: The human brain is asymmetric in structure and function. Although correlations between anatomic asymmetries and functional lateralization in human brain have been demonstrated, it has been difficult to further analyze them. Characterization of asymmetries of brain structure and function in SI might advance the understanding of these relationships., Methods: Using anatomic and functional MRI techniques, we analyzed asymmetries in the brains of three individuals with SI., Results: Two major anatomic asymmetries of the cerebral hemispheres, the frontal and occipital petalia, were reversed in individuals with SI. In contrast, SI subjects had left cerebral hemisphere language dominance on functional MRI analysis as well as strong right-handedness., Conclusion: These observations suggest that the developmental factors determining anatomic asymmetry of the cerebral petalia and viscera are distinct from those producing the functional lateralization of language.

Objective: To test for brain structure differences in reading disability (RD) by means of MRI-based morphometry., Background: Consensus is lacking on the brain structural correlates of RD. The current study reports on a wider set of structures in the largest sample yet studied, controlling for age, gender, IQ, and attention deficit hyperactivity disorder (ADHD)., Methods: A case-control study was performed that was comprised of 75 individuals with RD (mean age, 17.43+/-4.29 years) and 22 control subjects without RD (mean age, 18.69+/-3.75 years), each a single member of a twin pair. The two groups were similar in age, gender, and handedness, but differed in full-scale IQ (FSIQ), with the RD group having a lower mean FSIQ (101.8+/-9.9 versus 118.3+/-10.3). Using three group-by-structure analyses of covariance, groups were compared in terms of volume (in cubic centimeters) of major neocortical subdivisions, subcortical structures, and midsagittal areas (in square millimeters) of three subdivisions of the corpus callosum., Results: Controlling for age, gender, and IQ, the authors found a significant group-by-structure interaction for the major neocortical subdivisions (p = 0.002), reflecting a different developmental pattern in the RD group, with the insula and anterior superior neocortex being smaller and the retrocallosal cortex being larger in the RD group. In contrast, they found no group main or interaction effects for the subcortical or callosal structures. The pattern of results was essentially the same in subjects without ADHD., Conclusions: Most brain structures do not differ in size in RD, but cortical development is altered subtly. This study replicates in a larger sample previous findings of insular differences in RD and demonstrates further that those differences are not attributable to comorbid ADHD.

MRI-based brain volumetrics is an established methodology of great versatility and reliability with a broad range of potential applications in medicine and basic human brain science. We consider here, more theoretical implications of brain tissue volumes. Specifically, we suggest that volume is an evolutionarily and developmentally regulated fundamental property of tissue, in this instance the brain and its component structures. Within this framework (1), regularities in relative variation of volumes with respect to mean volume of a structure are viewed as systematic manifestations of the rules of histogenetic process (2), regularities in the relative strength of correlation of volumes of structures are suggested to reflect constraints which serve systematically the requirements of neural systems operation. These hypotheses, if supported by extensive observation, may guide the design of applications of MRI based volumetric analysis of the human brain.

Background: Relatively few magnetic resonance imaging studies of schizophrenia have investigated the entire cerebral cortex. Most focus on only a few areas within a lobe or an entire lobe. To assess expected regional alterations in cortical volumes, we used a new method to segment the entire neocortex into 48 topographically defined brain regions. We hypothesized, based on previous empirical and theoretical work, that dorsolateral prefrontal and paralimbic cortices would be significantly volumetrically reduced in patients with schizophrenia compared with normal controls., Methods: Twenty-nine patients with DSM-III-R schizophrenia were systematically sampled from 3 public outpatient service networks in the Boston, Mass, area. Healthy subjects, recruited from catchment areas from which the patients were drawn, were screened for psychopathologic disorders and proportionately matched to patients by age, sex, ethnicity, parental socioeconomic status, reading ability, and handedness. Analyses of covariance of the volumes of brain regions, adjusted for age- and sex-corrected head size, were used to compare patients and controls., Results: The greatest volumetric reductions and largest effect sizes were in the middle frontal gyrus and paralimbic brain regions, such as the frontomedial and frontoorbital cortices, anterior cingulate and paracingulate gyri, and the insula. In addition, the supramarginal gyrus, which is densely connected to prefrontal and cingulate cortices, was also significantly reduced in patients. Patients also had subtle volumetric increases in other cortical areas with strong reciprocal connections to the paralimbic areas that were volumetrically reduced., Conclusion: Findings using our methods have implications for understanding brain abnormalities in schizophrenia and suggest the importance of the paralimbic areas and their connections with prefrontal brain regions.

Background: Functional MRI (fMRI) is of potential value in determining hemisphere dominance for language in epileptic patients., Objective: To develop and validate an fMRI-based method of determining language dominance for patients with a wide range of potentially operable brain lesions in addition to epilepsy., Methods: Initially, a within-subjects design was used with 19 healthy volunteers (11 strongly right-handed, 8 left-handed) to determine the relative lateralizing usefulness of three different language tasks in fMRI. An automated, hemispheric analysis of laterality was used to analyze whole brain fMRI data sets. To evaluate the clinical usefulness of this method, we compared fMRI-determined laterality with laterality determined by Wada testing or electrocortical stimulation mapping, or both, in 23 consecutive patients undergoing presurgical evaluation of language dominance., Results: Only the verb generation task was reliably lateralizing. fMRI, using the verb generation task and an automated hemispheric analysis method, was concordant with invasive measures in 22 of 23 patients (12 Wada, 11 cortical stimulation). For the single patient who was discordant, in whom a tumor involved one-third of the left hemisphere, fMRI became concordant when the tumor and its reflection in the right hemisphere were excluded from laterality analysis. No significant negative correlation was obtained between lesion size and strength of laterality for the patients with lesions involving the dominant hemisphere., Conclusion: This fMRI method shows potential for evaluating language dominance in patients with a variety of brain lesions.

Several groups have developed methods for registering an individual's 3D MRI by deforming a standard template. This achievement leads to many possibilities for segmentation and morphology that will impact nuclear medical research in areas such as activation and receptor studies. Accordingly, there is a need for methods that can assess the accuracy of intersubject registration. We have developed a method based on a set of 128 anatomic landmarks per hemisphere, both cortical and subcortical, that allows assessment of both global and local transformation accuracy. We applied our method to compare the accuracy of two standard methods of intersubject registration, AIR 3.0 with fifth-order polynomial warping and the Talairach stereotaxic transformation (Talairach and Tournoux, 1988). SPGR MRI's (256 x 256 x 160) of six normal subjects (age 18-24 years) were derformed to match a standard template volume. To assess registration accuracy the landmarks were located on both the template volume and the transformed volumes by an experienced neuroanatomist. The resulting list of coordinates was analyzed graphically and by ANOVA to compare the accuracy of the two methods and the results of the manual analysis. ANOVA performed over all 128 landmarks showed that the Woods method was more accurate than Talairach (left hemisphere F = 2.8, P < 0.001 and right hemisphere F =2.4, P < 0.006). The Woods method provided a better brain surface transformation than did Talairach (F = 18.0, P < 0.0001), but as expected there was a smaller difference for subcortical structures and both had an accuracy <1 mm for the majority of subcortical landmarks. Overall, both the Woods and Talairach method located about 70% of landmarks with an error of 3 mm or less. More striking differences were noted for landmark accuracy

The number of physiologic and metabolic phenomena amenable to analysis using magnetic resonance (MR) techniques is increasing every year. MR techniques can now evaluate tissue parameters relevant to TCA cyclemetabolism, anerobic glycolysis, ATP levels, blood-brain barrier permeability, macrophage infiltration, cytotoxic edema, spreading depression, cerebral blood flow and volume, and neurotransmitter function. The paramagnetic nature of certain oxidation states of iron leads to the ability to map out brain function using deoxyhemoglobin as an endogenous contrast agent, and also allows for mapping of local tissue iron concentrations. In addition to these metabolic parameters, the number of ways to generate anatomic contrast using MR is also expanding; and in addition to conventional anatomic scans, mapping of axonal fiber tracts can also be performed using the anisotropy of water diffusion. A strategy for integration of these multifarious parameters in a comprehensive neurofunctional exam in neurodegenerative illness is outlined in this paper. The goals of the integrated exam, as applied to a given neurodegenerative illness, can be subdivided into three categories: etiology, natural history, and therapeutic end points. The consequences of oxidative stress and/or mitochondrial dysfunction are explored in the context of the various parameters that can be measured using the integrated MR exam.

We describe a system for parcellation of the human cerebral white matter and nuclei, based upon magnetic resonance images. An algorithm for subdivision of the cerebral central white matter according to topographic criteria is developed in the companion manuscript. In the present paper we provide a rationale for this system of parcellation of the central white matter and we extend the system of cerebral parcellation to include principal subcortical gray structures such as the thalamus and the basal ganglia. The volumetric measures of the subcortical gray and white matter parcellation units in 20 young adult brains are computed and reported here as well. In addition, with the comprehensive system for cerebral gray and white matter structure parcellation as reference, we formulate a systematics of forebrain connectivity. The degree to which functionally specific brain areas correspond to topographically specific areas is an open empirical issue. The resolution of this issue requires the development of topographically specific anatomic analyses, such as presented in the current system, and the application of such systems to a comprehensive set of functional-anatomic correlation studies in order to establish the degree of structural-functional correspondence. This system is expected to be applied in both cognitive and clinical neuroscience as an MRI-based topographic systematics of human forebrain anatomy with normative volumetric reference and also as a system of reference for the anatomic organization of specific neural systems as disrupted by focal lesions in lesion-deficit correlations., (Copyright 1999 Academic Press.)

We describe a virtually automatic comprehensive parcellation of the human cerebral central white matter, which is based upon T1-weighted MRI scans. The system, which is "rule-based," is developed from prior anatomic studies of the human brain and experimental studies of connectivity in animals as elaborated in the companion manuscript. Boundaries which delineate anatomic subregions of the white matter are computed from the geometric features of anatomic landmarks visible in the imaging data. The fiber systems of the central white matter are ordered topographically into three compartments, reflecting the inferred arrangements of principal neural systems pathways. These include an outer radiate (fibers principally radially aligned), an intermediate sagittal (fibers principally sagittally aligned), and deep bridging (fibers bridging hemispheres or cortex and deep structures) compartments. Each of these compartments is secondarily parcellated into smaller units to increase the anatomic specificity and spatial resolution of the system. The principal intended uses for this system of anatomic subdivision are for the volumetric characterization of forebrain white matter in normal and abnormal brains and for precision and specificity of localization in focal lesion-deficit correlation studies., (Copyright 1999 Academic Press.)

This work demonstrates encouraging results for increasing the automation of a practical and precise magnetic resonance brain image segmentation method. The intensity threshold for segmenting the brain exterior is determined automatically by locating the choroid plexus. This is done by finding peaks in a series of histograms taken over regions specified using anatomical knowledge. Intensity inhomogeneities are accounted for by adjusting the global intensity to match the white matter peak intensity in local regions. Automated results are incorporated into the established manually guided segmentation method by providing a trained expert with the automated threshold. The results from 20 different brain scans (over 1000 images) obtained under different conditions are presented to validate the method which was able to determine the appropriate threshold in approximately 80% of the data.

This magnetic resonance imaging (MRI)-based morphometric analysis of cortical topography in the human brain is based upon the segmentation and parcellation of volumetric T1-weighted MRI data for a set of 20 young adult brains including 10 males and 10 females. For the most part, each parcellation unit (PU) of the neocortex corresponds to a single or a portion of a single gyrus. The volumes of each PU were computed for each brain. Subsets of PUs were also grouped so as to represent the neocortex for the frontal, temporal, parietal and occipital lobes. The coefficient of variation of the mean volume of total neocortex and that of the neocortex assigned to individual lobes cluster around 10%, whereas that of neocortex assigned to the individual gyri (PU) is more than twice that value. Approximately 80% of the total variance in gyral volume arises from determinants interactive for individual and specific gyri, while only approximately 10% of the total variance appears to be a reflection of uniform scaling to total neocortical volume. Sexual dimorphism contributes a pervasive though relatively small component of this variance. These results have implications for the study of structure-function correlation, and the proper statistical methods of handling volumetric data in morphometric studies. In addition, the nature of the covariance structure of the data will lead to future hypotheses regarding the relationships between the various potential genetic and epigenetic gyral influencing factors.

The precise characterization of cortical connectivity is important for the understanding of brain morphological and functional organization. Such connectivity is conveyed by specific pathways or tracts in the white matter. Diffusion-weighted magnetic resonance imaging detects the diffusivity of water molecules in three dimensions. Diffusivity is anisotropic in oriented tissues such as fiber tracts. In the present study, we used this method to map (in terms of orientation, location, and size) the "stem" (compact portion) of the principal association, projection, and commissural white matter pathways of the human brain in vivo, in 3 normal subjects. In addition, its use in clinical neurology is illustrated in a patient with left inferior parietal lobule embolic infarction in whom a significant reduction in relative size of the stem of the left superior longitudinal fasciculus was observed. This represents an important method for the characterization of major association pathways in the living human that are not discernible by conventional magnetic resonance imaging. In the clinical domain, this method will have a potential impact on the understanding of the diseases that involve white matter such as stroke, multiple sclerosis, amyotrophic lateral sclerosis, head injury, and spinal cord injury.

Background and Purpose: Stroke recovery mechanisms remain incompletely understood, particularly for subjects with cortical stroke, in whom limited data are available. We used functional magnetic resonance imaging to compare brain activations in normal controls and subjects who recovered from hemiparetic stroke., Methods: Functional magnetic resonance imaging was performed in ten stroke subjects with good recovery, five with deep, and five with cortical infarcts. Brain activation was achieved by index finger-tapping. Statistical parametric activation maps were obtained using a t test and a threshold of P < .001. In five bilateral motor regions, the volume of activated brain for each stroke subject was compared with the distribution of activation volumes among nine controls., Results: Control subjects activated several motor regions. During recovered hand finger-tapping, stroke subjects activated the same regions as controls, often in a larger brain volume. In the unaffected hemisphere, sensorimotor cortex activation was increased in six of nine stroke subjects compared with controls. Cerebellar hemisphere contralateral and premotor cortex ipsilateral to this region, as well as supplementary motor areas, also had increased activation. In the stroke hemisphere, activation exceeding controls was uncommon, except that three of five cortical strokes showed peri-infarct activation foci. During unaffected hand finger-tapping, increased activation by stroke subjects compared with controls was uncommon; however, decreased activation was seen in unaffected sensorimotor cortex, suggesting that this region's responsiveness increased to the ipsilateral hand and decreased to contralateral hand movements. Use of a different threshold for defining activation (P < .01) did not change the overall findings (kappa = .75)., Conclusions: Recovered finger-tapping by stroke subjects activated the same motor regions as controls but to a larger extent, particularly in the unaffected hemisphere. Increased reliance on these motor areas may represent an important component of motor recovery. Functional magnetic resonance imaging studies of subjects who recovered from stroke provide evidence for several processes that may be related to restoration of neurologic function.

We investigated brain circuitry mediating cocaine-induced euphoria and craving using functional MRI (fMRI). During double-blind cocaine (0.6 mg/kg) and saline infusions in cocaine-dependent subjects, the entire brain was imaged for 5 min before and 13 min after infusion while subjects rated scales for rush, high, low, and craving. Cocaine induced focal signal increases in nucleus accumbens/subcallosal cortex (NAc/SCC), caudate, putamen, basal forebrain, thalamus, insula, hippocampus, parahippocampal gyrus, cingulate, lateral prefrontal and temporal cortices, parietal cortex, striate/extrastriate cortices, ventral tegmentum, and pons and produced signal decreases in amygdala, temporal pole, and medial frontal cortex. Saline produced few positive or negative activations, which were localized to lateral prefrontal cortex and temporo-occipital cortex. Subjects who underwent repeat studies showed good replication of the regional fMRI activation pattern following cocaine and saline infusions, with activations on saline retest that might reflect expectancy. Brain regions that exhibited early and short duration signal maxima showed a higher correlation with rush ratings. These included the ventral tegmentum, pons, basal forebrain, caudate, cingulate, and most regions of lateral prefrontal cortex. In contrast, regions that demonstrated early but sustained signal maxima were more correlated with craving than with rush ratings; such regions included the NAc/SCC, right parahippocampal gyrus, and some regions of lateral prefrontal cortex. Sustained negative signal change was noted in the amygdala, which correlated with craving ratings. Our data demonstrate the ability of fMRI to map dynamic patterns of brain activation following cocaine infusion in cocaine-dependent subjects and provide evidence of dynamically changing brain networks associated with cocaine-induced euphoria and cocaine-induced craving.

A morphometric magnetic resonance imaging (MRI) study compared volumes of brain structures in 10 female subjects with trichotillomania (repetitive hair-pulling) versus 10 normal controls matched for sex, age, handedness, and education. Three-dimensional MRI scans were blindly normalized and segmented using well-characterized semiautomated intensity and differential contour algorithms by signal intensity-frequency histograms. Consistent with one a priori hypothesis, left putamen volume was found to be significantly smaller in trichotillomania subjects as compared with normal matched controls. This is the first report of a structural brain abnormality in trichotillomania. Results are discussed in terms of putative relationships between trichotillomania, Tourette's syndrome, and obsessive-compulsive disorder.

Objective: To test by MRI-based morphometry the a priori hypotheses that developmental anomalies exist in attention-deficit hyperactivity disorder (ADHD) in left caudate and right prefrontal/frontal/ and/or posterior parietal hemispheric regions, in accord with neurochemical, neuronal circuitry and attentional network hypotheses, and prior imaging studies., Design: Case-control study., Setting: Academic medical center., Participants: Fifteen male subjects with ADHD without comorbid diagnoses (aged 12.4 +/- 3.4 years) and 15 male normal controls (aged 14.4 +/- 3.4), group-matched for age, IQ, and handedness., Main Outcome Measures: Global and hemispheric regional volumes (in cm3) of cerebral hemispheres, cortex, white matter, ventricles, caudate, lenticulate, central gray nuclei, insula, amygdala, and hippocampus., Results: Despite similar hemispheric volumes, ADHD subjects had smaller volumes of (1) left total caudate and caudate head (p < 0.04), with reversed asymmetry (p < 0.03); (2) right anterior-superior (frontal) region en bloc (p < 0.03) and white matter (p < 0.01); (3) bilateral anterior-inferior region en bloc (p < 0.04); and (4) bilateral retrocallosal (parietal-occipital) region white matter (p < 0.03). Possible structural correlates of ADHD response to stimulants were noted in an exploratory analysis, with the smallest and symmetric caudate, and smallest left anterior-superior cortex volumes found in the responders, but reversed caudate asymmetry and the smallest retrocallosal white matter volumes noted in the nonresponders., Conclusions: This study is the first to report localized hemispheric structural anomalies in ADHD, which are concordant with theoretical models of abnormal frontal-striatal and parietal function, and with possible differing morphologic substrates of response to stimulant medication.

Abstract We describe a system of parcellation of the human neocortex, based upon magnetic resonance images, that conserves the topographic uniqueness of the individual brain. Subdivision of the neocortex, according to this system, is based entirely upon the configuration of a specified set of cerebral landmarks, principally neocortical fissures. These are present but unique in the details of their configurations in each individual brain. We introduce here a computer-assisted algorithm that ensures that a skilled investigator can execute the parcellation routine in a manageable period of time. Secondly, we outline a comprehensive set of conventions that specify how the boundaries of parcellation units are defined by anatomic landmarks. The average interobserver agreement in voxel assignment to parcellation units within the overall neocortex was 80.2%.

Volumetric magnetic resonance image (MRI)-based morphometry was performed on the brains of 30 normal children (15 males and 15 males) with a mean age of 9 years (range 7-11 years). This age range lies in a late but critical phase of brain growth where not volumetric increment will be small but when the details of brain circuity are being fine-tuned to support the operations of the adult brain. The brain at this age is 95% the volume of the adult brain. The brain of the female child is 93% the volume of the male child. For more than 95% of brain structures, the volumetric differences in male and female child brain are uniformly scaled to the volume difference of the total brain in the two sexes. Exceptions to this pattern of uniform scaling are the caudate, hippocampus and pallidum, which are disproportionately larger in female than male child brain, and the amygdala, which is disproportionately smaller in the female child brain. The patterns of uniform scaling are generally sustained during the final volumetric increment in overall brain size between age 7-11 and adulthood. There are exceptions to this uniform scaling of child to adult brain, and certain of these exceptions are sexually dimorphic. Thus, with respect to major brain regions, the cerebellum in the female but not the male child is already at adult volume while the brainstem in both sexes must enlarge more than the brain as a whole. The collective subcortical gray matter structures of the forebrain of the female child are already at their adult volumes. The volumes of these same structures in the male child, by contrast, are greater than their adult volumes and, by implication, must regress in volume before adulthood. The volume of the central white matter, on the other hand, is disproportionately smaller in female than male child brain with respect to the adult volumes of cerebral central white matter. By implication, relative volumetric increase of cerebral central white matter by adulthood must be greater in the female than male brain. The juxtaposed progressive and regressive patterns of growth of brain structures implied by these observations in the human brain have a soundly established precedent in the developing rhesus brain. There is emerging evidence that sexually dimorphic abnormal regulation of these terminal patterns of brain development are associated with gravely disabling human disorders of obscure etiology.

Background: The new technique of functional magnetic resonance imaging was used to investigate the mediating neuroanatomy of obsessive-compulsive disorder symptoms., Methods: Ten patients with obsessive-compulsive disorder and 5 normal subjects were studied via functional magnetic resonance imaging during control and provoked conditions. Data analysis entailed parametric and nonparametric statistical mapping., Results: Statistical maps (nonparametric; P < 10(-3)) showed activation for 70% or more of patients with obsessive-compulsive disorder in medial orbitofrontal, lateral frontal, anterior temporal, anterior cingulate, and insular cortex, as well as caudate, lenticulate, and amygdala. No normal subjects exhibited activation in any brain region., Conclusions: Results of functional magnetic resonance imaging were consistent with past studies of obsessive-compulsive disorder that used other functional neuroimaging modalities. However, paralimbic and limbic activations were more prominent in the present study.

Background: A previous pilot study of only posterior brain regions found lower white-matter volume in patients with obsessive-compulsive disorder than in normal control subjects. We used new cohorts of patients and matched normal control subjects to study whole-brain volume differences between these groups with magnetic resonance imaging-based morphometry., Methods: Ten female patients with obsessive-compulsive disorder and 10 female control subjects, matched for handedness, age, weight, education, and verbal IQ, underwent magnetic resonance imaging with a 3-dimensional volumetric protocol. Scans were blindly normalized and segmented by means of well-characterized semiautomated intensity contour mapping and differential intensity contour algorithms. Brain structures investigated included the cerebral hemispheres, cerebral cortex, diencephalon, caudate, putamen, globus pallidus, hippocampus amygdala, third and fourth ventricles, corpus callosum, operculum, cerebellum, and brain stem. Anterior to posterior neocortical regions, including precallosum, anterior pericallosum, posterior pericallosum, and retrocallosum, with adjacent white matter were also measured. Volumes found different between groups were correlated with Yale-Brown Obsessive Compulsive Scale score and Rey-Osterieth Complex Figure Test measures., Results: Confirming results of our earlier pilot study and expanding the findings to the whole brain, patients with obsessive-compulsive disorder had significantly less total white matter but, in addition, significantly greater total cortex and opercular volumes. Severity of obsessive-compulsive disorder and nonverbal immediate memory correlated with opercular volume., Conclusions: Replication of volumetric white-matter differences suggests a widely distributed structural brain abnormality in obsessive-compulsive disorder. Whereas determining the etiogenesis may require research at a microscopic level, understanding its functional significance can be further explored via functional neuroimaging and neuropsychological studies.

Magnetic resonance imaging (MRI) has revolutionized the practical demands of clinical neurology. This technology promises now to advance neurology in theoretical and applied realms of fundamental human brain science. We emphasize here two domains in which these advances will occur. The first is volumetric morphometry of the human brain. With MRI the multiple levels of processing of the brain may be characterized in terms of their absolute volumes and their relative sizes, perspectives indispensable for our understanding of the development and operation of neural systems. Volumetric morphometry also promises substantial increases in the specificity and sensitivity of neurological diagnosis, particularly where applied to disorders where structural abnormalities will be reflected only in volumetric abnormalities. The second direction of advance considered here is application of MRI in cortical mapping in support of cognitive neuroscience. In this application MRI provides means to map at high resolution the distribution of subcomponents of neural systems activated by behavioral paradigms. This line of investigation will carry forward rapidly our understanding of how the information processing algorithms of the brain are mapped upon the coordinates of the various gray matter structures of the brain. Among the practical consequences of this application will be a reasoned design of surgical field in tumor and epilepsy surgery.

Morphometric analysis was performed on three-dimensional MRI scans of 10 male and 10 female young adults with four principal objectives: (1) to characterize in vivo volumes of whole brain and substructures, (2) to explore volumetric symmetry in bilateral structures, (3) to consider the extent to which volumetric measures are dimorphic in the male and female brain, and (4) to provide a normal volumetric database for the young adult brain. Total brain volumes ranged between 1173 and 1626 cm3. All bilateral structures were symmetric or nearly symmetric in volume, with the exception of a slightly larger right neocortex and amygdala, and larger left lateral ventricle. Male brains were larger in volume than female brains, a difference that reached significance for cerebellar but not for cerebral hemisphere volume. In females, there was less cerebral white matter while caudate volume was larger than in the male brains. The proportions of caudate and hippocampus relative to total cerebral volumes were larger in females than in males. These four measures accurately predicted gender in 85% of the subjects by discriminant analysis. No gender differences were noted in the structural symmetry analysis. These results represent the first step in establishing a comprehensive database of morphometric parameters, with unexpected findings relative to brain symmetry and sexual dimorphism.

This study had three general points. First, it examined possible visual consequences of frontal lesions. A patient with focal damage to the subcortical regions of the left frontal lobe, and a small amount of damage near Broca's area, was predicted to have impaired brain function in posterior regions that are anatomically connected to the damaged site. Second, it showed the utility of using positron emission tomography (PET) in conjunction with magnetic resonance imaging to characterize "functional lesions." PET revealed reduced metabolism in posterior cortical loci that are innervated by fibers from the damaged regions. Some of the affected areas are hypothesized to be involved in visual functions, specifically the encoding of lines and edges. Third, a series of tests was designed to document that the patient had difficulty encoding visual stimuli, and then to distinguish among alternative possible causes of this deficit. The results suggested that the patient encoded shapes as sets of filled locations if possible, which allowed him to use intact processes subserved by brain areas that were not affected by the damage. The data were best explained if the lesion slowed processing in the ventral system (which encodes object properties), allowing the dorsal system (which encodes spatial properties) to produce a response more quickly than the ventral system.

Magnetic resonance imaging (MRI) studies of human brain activity are described. Task-induced changes in brain cognitive state were measured using high-speed MRI techniques sensitive to changes in cerebral blood volume (CBV), blood flow (CBF), and blood oxygenation. These techniques were used to generate the first functional MRI maps of human task activation, by using a visual stimulus paradigm. The methodology of MRI brain mapping and results from the investigation of the functional organization and frequency response of human primary visual cortex (V1) are presented.

We describe a system of parcellation of the human brain that is based on the functional anatomy of the cerebral cortex and that is applied to the analysis of magnetic resonance images. This system is designed to support investigations of hemispheric asymmetries and quantitative lesion localization studies in cognitive neuroscience. The system of cortical subdivision is a neural systems oriented model that approximates subdivisions supported by previous architectonic and functional analyses. It is based primarily on boundaries determined by "limiting fissures." It is completed by a set of coronal planes, keyed to visible anatomic landmarks, which "close" the borders of the parcellation subdivisions. The method depends on computational reconstruction of the primary image data in multiple planes so as to allow the observed pattern of limiting fissures in a given brain to be digitized. In this presentation, the method is applied in order to define the surface anatomy of the cerebral hemispheres in a normal subject. Volumetric measurements of individual cortical regions are compared as hemispheric percentiles to areal perceniiles derived from the analysis of Jouandet et al. (1989), a conceptually related though methodologically different approach. We specifically address the approach to the study of interhemispheric differences and interindividual variations in cortical anatomy.

Neuronal activity causes local changes in cerebral blood flow, blood volume, and blood oxygenation. Magnetic resonance imaging (MRI) techniques sensitive to changes in cerebral blood flow and blood oxygenation were developed by high-speed echo planar imaging. These techniques were used to obtain completely noninvasive tomographic maps of human brain activity, by using visual and motor stimulus paradigms. Changes in blood oxygenation were detected by using a gradient echo (GE) imaging sequence sensitive to the paramagnetic state of deoxygenated hemoglobin. Blood flow changes were evaluated by a spin-echo inversion recovery (IR), tissue relaxation parameter T1-sensitive pulse sequence. A series of images were acquired continuously with the same imaging pulse sequence (either GE or IR) during task activation. Cine display of subtraction images (activated minus baseline) directly demonstrates activity-induced changes in brain MR signal observed at a temporal resolution of seconds. During 8-Hz patterned-flash photic stimulation, a significant increase in signal intensity (paired t test; P less than 0.001) of 1.8% +/- 0.8% (GE) and 1.8% +/- 0.9% (IR) was observed in the primary visual cortex (V1) of seven normal volunteers. The mean rise-time constant of the signal change was 4.4 +/- 2.2 s for the GE images and 8.9 +/- 2.8 s for the IR images. The stimulation frequency dependence of visual activation agrees with previous positron emission tomography observations, with the largest MR signal response occurring at 8 Hz. Similar signal changes were observed within the human primary motor cortex (M1) during a hand squeezing task and in animal models of increased blood flow by hypercapnia. By using intrinsic blood-tissue contrast, functional MRI opens a spatial-temporal window onto individual brain physiology.

The Rett syndrome is a progressive disorder which is associated with regression of psychomotor development and precipitous deceleration of brain growth during the first year of life. General histopathological surveys in postmortem specimens have identified degeneration of subpopulations of neurons of the nigrostriatal system but no other evidence of degenerative process. Magnetic resonance imaging-based morphometry may usefully guide application of rigorous but demanding quantitative histologic search for evidence of neuronal degeneration. The volumes of the principal set of cortical and nuclear structures of principal interest in the disorder may be measured by currently available MRI-based methods. Optimized levels of precision now allow detection of volumetric changes over time in the same brain of approximately 10% at the 95% confidence level.

Knowledge of regional cerebral hemodynamics has widespread application for both physiological research and clinical assessment because of the well-established interrelation between physiological function, energy metabolism, and localized blood supply. A magnetic resonance technique was developed for quantitative imaging of cerebral hemodynamics, allowing for measurement of regional cerebral blood volume during resting and activated cognitive states. This technique was used to generate the first functional magnetic resonance maps of human task activation, by using a visual stimulus paradigm. During photic stimulation, localized increases in blood volume (32 +/- 10 percent, n = 7 subjects) were detected in the primary visual cortex. Center-of-mass coordinates and linear extents of brain activation within the plane of the calcarine fissure are reported.

Morphometric analyses were performed using an objective semiautomated algorithm on 5 sequential three-dimensional T1-weighted magnetic resonance imaging scans of a metastatic choroid plexus carcinoma, concurrent with a course of chemotherapy. The 5 scans were positionally normalized in a three-dimensional coordinate system for uniform definition of the borders of the mass. Volumes were calculated for the gadolinium-DTPA enhancing and nonenhancing cystic-appearing regions. Volumetric changes of up to 145% were measured using this method which were associated with changes in the calculated (spherical) radii of only up to 2.7 mm. Volumetric changes of up to 59% were not appreciated by visual inspection, most probably due to irregular borders and positional variability across the scans. Volumetric analyses were also performed on the right cerebellar hemisphere, producing a 1.83% coefficient of variability across the 5 scans. The growth rates of this mass were estimated from the sequential computations, permitting in vivo observations on tumor behavior otherwise not obtainable. These analyses demonstrate the potential of this morphometric method to detect significant volumetric changes, and illustrate its use to define in vivo the growth properties of central nervous system tumors in response to therapeutic interventions.

Overall body fat and its distribution in different regions are important predispositions to known aberrations in lipid and glucose metabolism. The accuracy of MR imaging in estimating overall body fatness and regional fat distribution at individual landmarks was determined by comparing it with well-accepted measures by deuterium-oxide (D2O) dilution and bioimpedance analysis. Fourteen normal young women (athletes and control subjects) were studied. A total of 308 axial, T1-weighted, spin-echo MR images over a specific region in the trunk (21-24 scans per subject) were obtained. Morphometric computer image analysis was performed to determine the subcutaneous, internal, and total fat volumes in each image. The data were analyzed in two ways: data from all slices were summed to assess overall body fatness, and six anatomic landmarks were chosen for regional comparisons. MR-determined estimates of overall body fatness strongly correlated with total body fat measures by D2O dilution in both total fat (r = .91) and subcutaneous fat (r = .92) determinations. Athletes in both the low- and high-intensity training phases had significantly lower values of MR-determined total body fatness than did control subjects. Parallel to total body fatness, athletes had significantly lower MR-determined ratios of total fat/total volume in four of six individual landmarks compared with control subjects. Our experience suggests that MR is an accurate method to quantify overall body fatness, when compared with D2O dilution and bioimpedance analysis. MR could also discriminate regional components of subcutaneous and internal body fat at individual landmarks.

Contrast-enhanced magnetic resonance imaging of regional cerebral hemodynamics is discussed. Techniques for measuring cerebral blood volume (CBV) have been validated in animal models and have recently been applied to human studies. Factors affecting CBV measurement in pathologic tissue are addressed. Extension of these techniques to the measurement of cerebral blood flow is presented.

In vivo measurement of cerebral physiology by dynamic contrast-enhanced NMR is demonstrated. Time-resolved images of the cerebral transit of paramagnetic contrast agent were acquired using a new ultrafast NMR imaging technique and a novel mechanism of image contrast based on microscopic changes in tissue magnetic susceptibility. Global hypercapnia in dogs was used to establish the relationship between susceptibility-induced signal change and brain blood volume, and the response of gray and white matter to this microvascular stimulus was measured.

A comprehensive methodology for image segmentation is presented. Tools for differential and intensity contouring, and outline optimization are discussed, as well as the methods for automating such procedures. After segmentation, regional volumes and image intensity distributions can be determined. The methodology is applied to nuclear magnetic resonance images of the brain. Examples of the results of volumetric calculations for the cerebral cortex, white matter, cerebellum, ventricular system, and caudate nucleus are presented. An image intensity distribution is demonstrated for the cerebral cortex.

A semiautomated computerized method of in vivo morphometric analysis that is based upon high-resolution three-dimensional magnetic resonance imaging has been developed. This morphometric method is efficient and is of greater analytical precision than any other morphometric method currently applied to living human tissue. Including error inherent in image data acquisition, the aggregate error of the methodology, as estimated by the phantom studies, ranges from 4.5 to 9.6%, with incremental error above 4.5% a function of magnetic resonance slice thickness. This method was applied to magnetic resonance scans of 7 normal volunteers. The derived volumes of whole brain and of individual substructures were closely concordant with previously published volumes of normal fresh (unfixed) brains obtained post mortem. This morphometric methodology is potentially applicable to any structure or lesion that can be visualized by magnetic resonance imaging.

A system has been developed to facilitate three-dimensional visualizations of tomographic image data. Tomographic techniques yield parallel planes of data at discrete locations; thus, a series of images comprises a three-dimensional database. From this database, a system has been developed to perform three-dimensional calculations, measurements, and display. The system consists of a conventional two-dimensional video monitor, a digitizing tablet for user interaction and region-of-interest (ROI) definition, application-oriented computational software, and an image display system for true three-dimensional database visualization. The three-dimensional display makes use of a varifocal mirror system with vector graphics capability. Through the use of specialized contouring software, we illustrate the utility of this system in the specific examples of displays prepared from magnetic resonance (MR) images of the brain and carotid arteries. It can be concluded that this system will provide valuable diagnostic and physiologic information that will provide added insight into normal and abnormal structure and its relationship to function.

Magnetic resonance images provide a comprehensiveness of analysis of the human brain and levels of resolution never achieved by other modes of pathoanatomic analysis. We review a strategy and technology of MRI-based image analysis which extracts independent measures of brain volumes, shape and position. These parameters are readily correlated with behavioral as well as physiological measures derived from PET and the emerging technology of MRI-based in vivo spectroscopy. A coordinate program which draws upon these methods will have wide applications in human brain science and the study of dynamic properties of human brain disease.