Key properties of D-optimal designs for event-related functional MRI experiments with application to nonlinear models.

To properly formulate functional magnetic resonance imaging (fMRI) experiments with complex mental activity, it is advantageous to permit great flexibility in the statistical components of the design of these studies. The length of an experiment, the placement of various stimuli and the modeling approach used all affect the ability to detect mental activity. Major advances in understanding the implications of various designs of fMRI experiments have taken place over the last decade. Nevertheless, new and increasingly difficult issues relating to the modeling of hemodynamic responses and the detection of activated brain regions continue to arise because of the increasing complexity of the experiments. In this article, the D-optimality criterion is used in conjunction with a genetic algorithm to create probability-based design generators for the selection of designs in event-related fMRI experiments where the hemodynamic response function is modeled with a function that is nonlinear in the parameters. The designs produced by these generators are shown to perform well compared with locally D-optimal designs and provide insight into optimal design characteristics that investigators can utilize in the selection of interstimulus intervals. Designs with these characteristics are shown to be applicable to fMRI studies involving one or two stimulus types. The designs are also shown to be robust with respect to misspecification of an AR(1) error autocorrelation and compare favorably with a maximin procedure.

Hippocampal dysfunction in Gulf War veterans: investigation with ASL perfusion MR imaging and physostigmine challenge.

PURPOSE: To determine, with arterial spin labeling (ASL) perfusion magnetic resonance (MR) imaging and physostigmine challenge, if abnormal hippocampal blood flow in ill Gulf War veterans persists 11 years after initial testing with single photon emission computed tomography and nearly 20 years after the 1991 Gulf War. MATERIALS AND METHODS: The local institutional review board approved this HIPAA-compliant study. Veterans were screened for contraindications and gave written informed consent before the study. In a semiblinded retrospective protocol, veterans in three Gulf War illness groups-syndrome 1 (impaired cognition), syndrome 2 (confusion-ataxia), and syndrome 3 (central neuropathic pain)-and a control group received intravenous infusions of saline in an initial session and physostigmine in a second session, 48 hours later. Each infusion was followed by measurement of hippocampal regional cerebral blood flow (rCBF) with pulsed ASL. A mixed-effects linear model adjusted for age was used to test for differences in rCBF after the cholinergic challenge across the four groups. RESULTS: Physostigmine significantly decreased hippocampal rCBF in control subjects (P < .0005) and veterans with syndrome 1 (P < .05) but significantly increased hippocampal rCBF in veterans with syndrome 2 (P < .005) and veterans with syndrome 3 (P < .002). The abnormal increase in rCBF was found to have progressed to the left hippocampus of the veterans with syndrome 2 and to both hippocampi of the veterans with syndrome 3. CONCLUSION: Chronic hippocampal perfusion dysfunction persists or worsens in veterans with certain Gulf War syndromes. ASL MR imaging examination of hippocampal rCBF in a cholinergic challenge experiment may be useful as a diagnostic test for this condition.

Abnormal brain response to cholinergic challenge in chronic encephalopathy from the 1991 Gulf War.

Several case definitions of chronic illness in veterans of the 1991 Persian Gulf War have been linked epidemiologically with environmental exposure to cholinesterase-inhibiting chemicals, which cause chronic changes in cholinergic receptors in animal models. Twenty-one chronically ill Gulf War veterans (5 with symptom complex 1, 11 with complex 2, and 5 with complex 3) and 17 age-, sex- and education-matched controls, underwent an 99mTc-HMPAO-SPECT brain scan following infusion of saline and >48 h later a second scan following infusion of physostigmine in saline. From each SPECT image mean normalized regional cerebral blood flow (nrCBF) from 39 small blocks of correlated voxels were extracted with geostatistical spatial modeling from eight deep gray matter structures in each hemisphere. Baseline nrCBF in symptom complex 2 was lower than controls throughout deep structures. The change in nrCBF after physostigmine (challenge minus baseline) was negative in complexes 1 and 3 and controls but positive in complex 2 in some structures. Since effects were opposite in different groups, no finding typified the entire patient sample. A hold-out discriminant model of nrCBF from 17 deep brain blocks predicted membership in the clinical groups with sensitivity of 0.95 and specificity of 0.82. Gulf War-associated chronic encephalopathy in a subset of veterans may be due to neuronal dysfunction, including abnormal cholinergic response, in deep brain structures.

Using a white matter reference to remove the dependency of global signal on experimental conditions in SPECT analyses.

Proportional scaling models are often used in functional imaging studies to remove confounding of local signals by global effects. It is generally assumed that global effects are uncorrelated with experimental conditions. However, when the global effect is estimated by the global signal, defined as the intracerebral average, incorrect inference may result from the dependency of the global signal on preexisting conditions or experimental manipulations. In this paper, we propose a simple alternative method of estimating the global effect to be used in a proportional scaling model. Specifically, by defining the global signal with reference strictly to a white matter region within the centrum semiovale, the dependency is removed in experiments where white matter is unaffected by the disease effect or experimental treatments. The increase in the ability to detect changes in regional blood flow is demonstrated in a SPECT study of healthy and ill Gulf War veterans in whom it is suspected that brain abnormalities influence the traditional calculation of the global signal. Controlling for the global effect, ill veterans have significantly lower intracerebral averages than healthy controls (P = 0.0038), evidence that choice of global signal has an impact on inference. Scaling by the modified global signal proposed here results in an increase in sensitivity leading to the identification of several regions in the insula and frontal cortex where ill veterans have significantly lower SPECT emissions. Scaling by the traditional global signal results in the loss of sensitivity to detect these regional differences. Advantages of this alternative method are its computational simplicity and its ability to be easily integrated into existing analysis frameworks such as SPM.

Improved agreement between Talairach and MNI coordinate spaces in deep brain regions.

Disagreement between the Talairach atlas and the stereotaxic space commonly used in software like SPM is a widely recognized problem. Others have proposed affine transformations to improve agreement in surface areas such as Brodmann's areas. This article proposes a similar transformation with the goal of improving agreement specifically in the deep brain region. The task is accomplished by finding an affine transformation that minimizes the mean distance between the surface coordinates of the lateral ventricles in the Talairach atlas and the MNI templates. The result is a transformation that improves deep brain agreement over both the untransformed Talairach coordinates and the surface-oriented transformation. While the transformation improves deep brain agreement, surface agreement is generally made worse. For areas near the lateral ventricle, the transformation presented herein is valuable for applications such as region of interest (ROI) modeling.