Lawrence R. Frank

Implementation of quantitative perfusion imaging techniques for functional brain mapping using pulsed arterial spin labeling

We describe here experimental considerations in the implementation of quantitative perfusion imaging techniques for functional MRI using pulsed arterial spin labeling. Three tagging techniques: EPISTAR, PICORE, and FAIR are found to give very similar perfusion results despite large differences in static tissue contrast. Two major sources of systematic error in the perfusion measurement are identified: the transit delay from the tagging region to the imaging slice; and the inclusion of intravascular tagged signal. A modified technique called QUIPSS II is described that decreases sensitivity to these effects by explicitly controlling the time width of the tag bolus and imaging after the bolus is entirely deposited into the slice. With appropriate saturation pulses the pulse sequence can be arranged so as to allow for simultaneous collection of perfusion and BOLD data that can be cleanly separated. Such perfusion and BOLD signals reveal differences in spatial location and dynamics that may be useful both for functional brain mapping and for study of the BOLD contrast mechanism. The implementation of multislice perfusion imaging introduces additional complications, primarily in the elimination of signal from static tissue. In pulsed ASL, this appears to be related to the slice profile of the inversion tag pulse in the presence of relaxation, rather than magnetization transfer effects as in continuous arterial spin labeling, and can be alleviated with careful adjustment of inversion pulse parameters.

A Model for the Coupling Between Cerebral Blood Flow and Oxygen Metabolism During Neural Stimulation

A general mathematical model for the delivery of O2 to the brain is presented, based on the assumptions that all of the brain capillaries are perfused at rest and that all of the oxygen extracted from the capillaries is metabolized. The model predicts that disproportionately large changes in blood flow are required in order to support small changes in the O2 metabolic rate. Interpreted in terms of this model, previous positron emission tomography (PET) studies of the human brain during neural stimulation demonstrating that cerebral blood flow (CBF) increases much more than the oxygen metabolic rate are consistent with tight coupling of flow and oxidative metabolism. The model provides a basis for the quantitative interpretation of functional magnetic resonance imaging (fMRI) studies in terms of changes in local CBF.

Characterization of anisotropy in high angular resolution diffusion-weighted MRI.

The methods of group theory are applied to the problem of characterizing the diffusion measured in high angular resolution MR experiments. This leads to a natural representation of the local diffusion in terms of spherical harmonics. In this representation, it is shown that isotropic diffusion, anisotropic diffusion from a single fiber, and anisotropic diffusion from multiple fiber directions fall into distinct and separable channels. This decomposition can be determined for any voxel without any prior information by a spherical harmonic transform, and for special cases the magnitude and orientation of the local diffusion may be determined. Moreover, non‐diffusion–related asymmetries produced by experimental artifacts fall into channels distinct from the fiber channels, thereby allowing their separation and a subsequent reduction in noise from the reconstructed fibers. In the case of a single fiber, the method reduces identically to the standard diffusion tensor method. The method is applied to normal volunteer brain data collected with a stimulated echo spiral high angular resolution diffusion‐weighted (HARD) acquisition. Magn Reson Med 47:1083–1099, 2002. Published 2002 Wiley‐Liss, Inc.

Anisotropy in high angular resolution diffusion-weighted MRI †

The diffusion in voxels with multidirectional fibers can be quite complicated and not necessarily well characterized by the standard diffusion tensor model. High angular resolution diffusion‐weighted acquisitions have recently been proposed as a method to investigate such voxels, but the reconstruction methods proposed require sophisticated estimation schemes. We present here a simple algorithm for the identification of diffusion anisotropy based upon the variance of the estimated apparent diffusion coefficient (ADC) as a function of measurement direction. The rationale for this method is discussed, and results in normal human subjects acquired with a novel diffusion‐weighted stimulated‐echo spiral acquisition are presented which distinguish areas of anisotropy that are not apparent in the relative anisotropy maps derived from the standard diffusion tensor model. Magn Reson Med 45:935–939, 2001. Published 2001 Wiley‐Liss, Inc.

Detection power, estimation efficiency, and predictability in event-related fMRI.

Experimental designs for event-related functional magnetic resonance imaging can be characterized by both their detection power, a measure of the ability to detect an activation, and their estimation efficiency, a measure of the ability to estimate the shape of the hemodynamic response. Randomized designs offer maximum estimation efficiency but poor detection power, while block designs offer good detection power at the cost of minimum estimation efficiency. Periodic single-trial designs are poor by both criteria. We present here a theoretical model of the relation between estimation efficiency and detection power and show that the observed trade-off between efficiency and power is fundamental. Using the model, we explore the properties of semirandom designs that offer intermediate trade-offs between efficiency and power. These designs can simultaneously achieve the estimation efficiency of randomized designs and the detection power of block designs at the cost of increasing the length of an experiment by less than a factor of 2. Experimental designs can also be characterized by their predictability, a measure of the ability to circumvent confounds such as habituation and anticipation. We examine the relation between detection power, estimation efficiency, and predictability and show that small increases in predictability can offer significant gains in detection power with only a minor decrease in estimation efficiency.

Behavioral and Functional Neuroimaging Evidence for Prefrontal Dysfunction in Methamphetamine-Dependent Subjects

Stimulant-dependent subjects show dysfunctions in decision-making similar to those seen in subjects with ventromedial prefrontal cortex lesions. Studies of drug craving, reward association, and decision-making have implicated dysfunctions of the dorsolateral and orbitofrontal cortex as a key neural substrate in subjects with stimulant dependence. Here, a functional magnetic resonance imaging (fMRI) study was carried out to determine the relationship between decision-making dysfunction and neural activation in different prefrontal areas. This investigation tested the behavioral hypothesis that methamphetamine-dependent subjects in early sustained remission show decision-making dysfunctions that are consistent with an increased reliance on stimulus-contingent response selection. It was hypothesized that these decision-making dysfunctions are due to differences in task-related activation in the dorsolateral and ventromedial prefrontal cortex. Ten methamphetamine-dependent subjects were compared with ten age- and education-matched controls performing a two-choice prediction task and a two-choice response task during a fMRI session. Response bias, latency, and mutual information measures assessing the underlying strategies of the decision-making sequences were obtained. First, methamphetamine-dependent subjects were more influenced by the immediately preceding outcome during the two-choice prediction task relative to normal comparison subjects. Second, methamphetamine-dependent subjects activated less dorsolateral prefrontal cortex (BA 9) and failed to activate ventromedial cortex (BA 10,11) during the two-choice prediction task compared with the two-choice response task. These results support the basic hypothesis that stimulant-dependent subjects exhibit fundamental cognitive deficits during decision-making that are consistent with both orbitofrontal and dorsolateral prefrontal dysfunction.

Decreased white matter integrity in late-myelinating fiber pathways in Alzheimer's disease supports retrogenesis.

The retrogenesis model of Alzheimers disease (AD) posits that white matter (WM) degeneration follows a pattern that is the reverse of myelogenesis. Using diffusion tensor imaging (DTI) to test this model, we predicted greater loss of microstructural integrity in late-myelinating WM fiber pathways in AD patients than in healthy older adults, whereas differences in early-myelinating WM fiber pathways were not expected. We compared 16 AD patients and 14 demographically-matched healthy older adults with a whole-brain approach via tract-based spatial statistics (TBSS), and a region of interest (ROI) approach targeting early-myelinating (posterior limb of internal capsule, cerebral peduncles) and late-myelinating (inferior longitudinal fasciculus [ILF], superior longitudinal fasciculus [SLF]) fiber pathways. Permutation-based voxelwise analysis supported the retrogenesis model. There was significantly lower fractional anisotropy (FA) in AD patients compared to healthy older adults in late-myelinating but not early-myelinating pathways. These group differences appeared to be driven by loss of myelin integrity based on our finding of greater radial diffusion in AD than in healthy elderly. ROI analyses were generally in agreement with whole-brain findings, with significantly lower FA and increased radial diffusion in the ILF in the AD group. Consistent with the retrogenesis model, AD patients showed demonstrable changes in late-myelinating WM fiber pathways. Given greater change in the ILF than the SLF, wallerian degeneration secondary to cortical atrophy may also be a contributing mechanism. Knowledge of the pattern of WM microstructural changes in AD and its underlying mechanisms may contribute to earlier detection and intervention in at-risk groups.

Discrepancies between BOLD and flow dynamics in primary and supplementary motor areas: application of the balloon model to the interpretation of BOLD transients.

The blood-oxygen-level-dependent (BOLD) signal measured in the brain with functional magnetic resonance imaging (fMRI) during an activation experiment often exhibits pronounced transients at the beginning and end of the stimulus. Such transients could be a reflection of transients in the underlying neural activity, or they could result from transients in cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), or cerebral blood volume (CBV). These transients were investigated using an arterial spin labeling (ASL) method that allows simultaneous measurements of BOLD and CBF responses. Responses to a finger-tapping task (40-s stimulus, 80-s rest) were measured in primary motor area (M1) and supplementary motor area (SMA) in five healthy volunteers. In SMA, the average BOLD response was pronounced near the beginning and end of the stimulus, while in M1, the BOLD response was nearly flat. However, CBF responses in the two regions were rather similar, and did not exhibit the same transient features as the BOLD response in SMA. Because this suggests a hemodynamic rather than a neural origin for the transients of the BOLD response in SMA, we used a generalization of the balloon model to test the degree of hemodynamic transients required to produce the measured curves. Both data sets could be approximated with modest differences in the shapes of the CMRO2 and CBV responses. This study illustrates the utility and the limitations of using theoretical models combined with ASL techniques to understand the dynamics of the BOLD response.

Altered White Matter Integrity in Adolescent Binge Drinkers

BACKGROUND White matter integrity has been found to be compromised in adult alcoholics, but it is unclear when in the course of alcohol exposure white matter abnormalities become apparent. This study assessed microstructural white matter integrity among adolescent binge drinkers with no history of an alcohol use disorder. METHODS We used diffusion tensor imaging to examine fractional anisotropy (FA), a measure of directional coherence of white matter tracts, among teens with (n = 14) and without (n = 14) histories of binge drinking but no history of alcohol use disorder, matched on age, gender, and education. RESULTS Binge drinkers had lower FA than controls in 18 white matter areas (clusters > or =27 contiguous voxels, each with p < 0.01) throughout the brain, including the corpus callosum, superior longitudinal fasciculus, corona radiata, internal and external capsules, and commissural, limbic, brainstem, and cortical projection fibers, while exhibiting no areas of higher FA. Among binge drinkers, lower FA in 6 of these regions was linked to significantly greater lifetime hangover symptoms and/or higher estimated peak blood alcohol concentrations. CONCLUSIONS Binge drinking adolescents demonstrated widespread reductions of FA in major white matter pathways. Although preliminary, these results could indicate that infrequent exposure to large doses of alcohol during youth may compromise white matter fiber coherence.

Hemispheric asymmetries in global and local processing: evidence from fMRI

FUNCTIONAL magnetic resonance imaging (fMRI) was used to explore the brain substrate associated with global and local processing of visuospatial patterns. Systematic differences in activation, consistent with differences observed in reaction time data collected under conditions of visual hemifield presentation, were found in occipitotemporal regions of the right and left hemispheres. Within the right hemisphere, area of activation and fractional signal changes were greater under conditions of global processing than under local processing conditions. In the left hemisphere, activation to global and local input was high and comparable.