J. D. G. Watson

Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels

BACKGROUND In patients with coronary heart disease and a broad range of cholesterol levels, cholesterol-lowering therapy reduces the risk of coronary events, but the effects on mortality from coronary heart disease and overall mortality have remained uncertain. METHODS In a double-blind, randomized trial, we compared the effects of pravastatin (40 mg daily) with those of a placebo over a mean follow-up period of 6.1 years in 9014 patients who were 31 to 75 years of age. The patients had a history of myocardial infarction or hospitalization for unstable angina and initial plasma total cholesterol levels of 155 to 271 mg per deciliter. Both groups received advice on following a cholesterol-lowering diet. The primary study outcome was mortality from coronary heart disease. RESULTS Death from coronary heart disease occurred in 8.3 percent of the patients in the placebo group and 6.4 percent of those in the pravastatin group, a relative reduction in risk of 24 percent (95 percent confidence interval, 12 to 35 percent; P<0.001). Overall mortality was 14.1 percent in the placebo group and 11.0 percent in the pravastatin group (relative reduction in risk, 22 percent; 95 percent confidence interval, 13 to 31 percent; P<0.001). The incidence of all cardiovascular outcomes was consistently lower among patients assigned to receive pravastatin; these outcomes included myocardial infarction (reduction in risk, 29 percent; P<0.001), death from coronary heart disease or nonfatal myocardial infarction (a 24 percent reduction in risk, P<0.001), stroke (a 19 percent reduction in risk, P=0.048), and coronary revascularization (a 20 percent reduction in risk, P<0.001). The effects of treatment were similar for all predefined subgroups. There were no clinically significant adverse effects of treatment with pravastatin. CONCLUSIONS Pravastatin therapy reduced mortality from coronary heart disease and overall mortality, as compared with the rates in the placebo group, as well as the incidence of all prespecified cardiovascular events in patients with a history of myocardial infarction or unstable angina who had a broad range of initial cholesterol levels.

A direct demonstration of functional specialization in human visual cortex

We have used positron emission tomography (PET), which measures regional cerebral blood flow (rCBF), to demonstrate directly the specialization of function in the normal human visual cortex. A novel technique, statistical parametric mapping, was used to detect foci of significant change in cerebral blood flow within the prestriate cortex, in order to localize those parts involved in the perception of color and visual motion. For color, we stimulated the subjects with a multicolored abstract display containing no recognizable objects (Land color Mondrian) and contrasted the resulting blood flow maps with those obtained when subjects viewed an identical display consisting of equiluminous shades of gray. The comparison identified a unique area (area V4) located in the lingual and fusiform gyri of the prestriate cortex. For motion, blood flow maps when subjects viewed moving or stationary black and white random-square patterns were contrasted. The comparison identified a unique area located in the region of the temporo-parieto-occipital junction (area V5). We thus provide direct evidence to show that, just as in the macaque monkey, different areas of the human prestriate visual cortex are specialized for different attributes of vision. The striate cortex (V1) and the contiguous visual area (V2), which in the monkey brain feed both the homologous areas, were active in all 4 conditions. This pattern of activity allowed us to use an extension of the approach to assess the functional relationship between the 3 areas during color and motion stimulation. This is based on an hypothesis-led analysis of the covariance structure of the blood flow maps and promises to be a powerful tool for inferring anatomical pathways in the normal human brain.(ABSTRACT TRUNCATED AT 250 WORDS)

Automated image registration : II. Intersubject validation of Linear and nonlinear models

PURPOSE Our goal was to validate linear and nonlinear intersubject image registration using an automated method (AIR 3.0) based on voxel intensity. METHOD PET and MRI data from 22 normal subjects were registered to corresponding averaged PET or MRI brain atlases using several specific linear and nonlinear spatial transformation models with an automated algorithm. Validation was based on anatomically defined landmarks. RESULTS Automated registration produced results that were superior to a manual nine parameter variant of the Talairach registration method. Increasing the degrees of freedom in the spatial transformation model improved the accuracy of automated intersubject registration. CONCLUSION Linear or nonlinear automated intersubject registration based on voxel intensities is computationally practical and produces more accurate alignment of homologous landmarks than manual nine parameter Talairach registration. Nonlinear models provide better registration than linear models but are slower.

Nonparametric Analysis of Statistic Images from Functional Mapping Experiments

The analysis of functional mapping experiments in positron emission tomography involves the formation of images displaying the values of a suitable statistic, summarising the evidence in the data for a particular effect at each voxel. These statistic images must then be scrutinised to locate regions showing statistically significant effects. The methods most commonly used are parametric, assuming a particular form of probability distribution for the voxel values in the statistic image. Scientific hypotheses, formulated in terms of parameters describing these distributions, are then tested on the basis of the assumptions. Images of statistics are usually considered as lattice representations of continuous random fields. These are more amenable to statistical analysis. There are various shortcomings associated with these methods of analysis. The many assumptions and approximations involved may not be true. The low numbers of subjects and scans, in typical experiments, lead to noisy statistic images with low degrees of freedom, which are not well approximated by continuous random fields. Thus, the methods are only approximately valid at best and are most suspect in single-subject studies. In contrast to the existing methods, we present a nonparametric approach to significance testing for statistic images from activation studies. Formal assumptions are replaced by a computationally expensive approach. In a simple rest-activation study, if there is really no activation effect, the labelling of the scans as “active” or “rest” is artificial, and a statistic image formed with some other labelling is as likely as the observed one. Thus, considering all possible relabellings, a p value can be computed for any suitable statistic describing the statistic image. Consideration of the maximal statistic leads to a simple nonparametric single-threshold test. This randomisation test relies only on minimal assumptions about the design of the experiment, is (almost) exact, with Type I error (almost) exactly that specified, and hence is always valid. The absence of distributional assumptions permits the consideration of a wide range of test statistics, for instance, “pseudo” t statistic images formed with smoothed variance images. The approach presented extends easily to other paradigms, permitting nonparametric analysis of most functional mapping experiments. When the assumptions of the parametric methods are true, these new nonparametric methods, at worst, provide for their validation. When the assumptions of the parametric methods are dubious, the nonparametric methods provide the only analysis that can be guaranteed valid and exact.

Pravastatin Therapy and the Risk of Stroke

Background Several epidemiologic studies have concluded that there is no relation between total cholesterol levels and the risk of stroke. In some studies that classified strokes according to cause, there was an association between increasing cholesterol levels and the risk of ischemic stroke and a possible association between low cholesterol levels and the risk of hemorrhagic stroke. Recent reviews of trials of 3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors have suggested that these agents may reduce the risk of stroke. Methods In a double-blind trial (the Long-Term Intervention with Pravastatin in Ischaemic Disease study), we compared the effects of pravastatin on mortality due to coronary heart disease (the primary end point) with the effects of placebo among 9014 patients with a history of myocardial infarction or unstable angina and a total cholesterol level of 155 to 271 mg per deciliter (4.0 to 7.0 mmol per liter). Our goal in the present study was to assess effects on stroke from any c...

Going beyond the Information Given: The Relation of Illusory Visual Motion to Brain Activity

There are many instances in which human subjects perceive a component which is not physically present in a visual stimulus. To study the cerebral activity which correlates with the perception of such an illusory component, we chose Enigma, a static figure in which many subjects perceive illusory motion. By using the technique of positron emission tomography (pet) we recorded the relative regional cerebral blood flow (rCBF) in the brain of 13 subjects while they viewed it and reported seeing the illusory motion. We found that, when subjects perceived illusory motion, the increases in rCBF took place in regions of the brain closely related to, and perhaps identical with, area V5, as defined by the site of rCBF change that took place when the same subjects viewed a physically moving stimulus. In addition, there was activity in other cortical areas outside the visual cortex, not present when the subjects had been viewing objective motion. This suggests that the generation of illusory motion depends not only on a highly specific visual area but also on relative contributions from other parts of the brain that are not activated to the same extent when humans perceive objective motion.

High‐resolution MRI reflects myeloarchitecture and cytoarchitecture of human cerebral cortex

Maps of cytoarchitectonically defined cortical areas have proven to be a valuable tool for anatomic localization of activated brain regions revealed by functional imaging studies. However, architectonic data require observations in a sample of postmortem brains. They can only be used reliably for comparison with functional data as probabilistic maps after spatial normalization to a common reference space. The complete architectonic analysis of an individual living brain has not been achievable to date, because the relationship remains unclear between laminar gray value changes of cerebral cortex in magnetic resonance (MR) images and those of cyto‐ and myeloarchitectonic histologic sections. We examined intensity profiles through the cortex in five imaging modalities: in vivo T1 and postmortem T2 MRI, one cell body stain, and two myelin stains. After visualizing the dissimilarities in the shapes of these profiles using a canonical analysis, differences between the profiles from the different image modalities were compared quantitatively. Subsequently, the profiles extracted from the in vivo T1‐weighted images were estimated from profiles extracted from cyto‐ and myeloarchitectonic sections using linear combinations. We could verify statistically the mixed nature of the cortical T1 signal obtained in vivo: The MR intensity profiles were significantly more similar to myeloarchitectonic than to cytoarchitectonic profiles, but a weighted sum of both fitted the T1 profiles best. Hum. Brain Mapping 24:206–215, 2005.

Neuropsychological and neuropathological sequelae of cerebral anoxia: A critical review

Fifty-eight studies of the neuropathological and neuropsychological outcomes of cerebral anoxia were reviewed. Neuropathological reports were examined for the variety, extent, and specificity of lesions resulting from an anoxic event. While most attention has focused on damage to the hippocampus following anoxic brain injury, the review indicated that watershed cerebral cortex and the basal ganglia were both more frequently damaged than the hippocampus. The hippocampus was the sole affected structure in only 18% of reported cases. Neurological, neuropsychological and psychiatric studies were analyzed. Of 67 individual case reports, a memory disturbance was documented in 36 (54%), but a memory disturbance without report of additional cognitive deficits occurred in only 13 (19.4%). Changes in personality and behavior were noted in 31 (46.2%). Visuospatial or, less frequently, visual recognition problems were noted in 21 individual cases (31.3%) reviewed. Memory deficits were found in all 14 group studies reviewed, while in 9 papers changes in behavior or personality were also documented. Six studies also reported visuospatial deficits. Careful reading of the literature reveals a range of cognitive and behavioral changes that reflect very well the neuropathological outcomes of anoxic episodes.

The activity in human areas V1/V2, V3, and V5 during the perception of coherent and incoherent motion

We have used the technique of positron emission tomography to study and compare the cortical activity produced when humans view a pattern of small squares moving incoherently with respect to one another and when the same pattern moves coherently and unidirectionally. A stationary version of the stimulus acted as a control. Our choice of paradigm was inspired by psychophysical models and physiological studies in the macaque monkey which show that directionally selective cells in V5 respond optimally to unidirectional coherent motion, whereas those of V1 respond to motion within their receptive fields, regardless of the motion in surrounding parts. Our results show that human V1/V2, V3, and V5 are all activated by both types of motion stimuli. Incoherent motion, however, proved to be more effective than coherent motion in activating V1/V2 and V5. Thus the higher perceptual salience of unidirectional coherent motion in comparison to incoherent motion is not reflected by any increased activation of human area V5.

In vivo identification of human cortical areas using high-resolution MRI: An approach to cerebral structure–function correlation

Understanding the relationship between the structural and functional organization of the human brain is one of the most important goals of neuroscience. Individual variability in brain structure means that it is essential to obtain this information from the same subject. To date, this has been almost impossible. Even though noninvasive functional imaging techniques such as functional MRI (fMRI) are now commonplace, there is no complementary noninvasive structural technique. We present an in vivo method of examining the detailed neuroanatomy of any individual, which can then be correlated with that individuals own functional results. This method utilizes high-resolution structural MRI to identify distinct cortical regions based on cortical lamination structure. We demonstrate that the observed MR lamination patterns relate to myeloarchitecture through a correlation of histology with MRI. In vivo high-resolution MRI studies identify striate cortex, as well as visual area V5, in four individuals, as defined by using fMRI. The anatomical identification of a cortical area (V5/MT) outside of striate cortex is a significant advance, proving it possible to identify extra-striate cortical areas and demonstrating that in vivo structural mapping of the human cerebral cortex is possible.