Geoffrey K. Aguirre

The Variability of Human, BOLD Hemodynamic Responses

Cerebral hemodynamic responses to brief periods of neural activity are delayed and dispersed in time. The specific shape of these responses is of some importance to the design and analysis of blood oxygenation level-dependent (BOLD), functional magnetic resonance imaging (fMRI) experiments. Using fMRI scanning, we examine here the characteristics and variability of hemodynamic responses from the central sulcus in human subjects during an event-related, simple reaction time task. Specifically, we determine the contribution of subject, day, and scanning session (within a day) to variability in the shape of evoked hemodynamic response. We find that while there is significant and substantial variability in the shape of responses collected across subjects, responses collected during multiple scans within a single subject are less variable. The results are discussed in terms of the impact of response variability upon sensitivity and specificity of analyses of event-related fMRI designs.

Functional MRI studies of spatial and nonspatial working memory

Single-unit recordings in monkeys have revealed neurons in the lateral prefrontal cortex that increase their firing during a delay between the presentation of information and its later use in behavior. Based on monkey lesion and neurophysiology studies, it has been proposed that a dorsal region of lateral prefrontal cortex is necessary for temporary storage of spatial information whereas a more ventral region is necessary for the maintenance of nonspatial information. Functional neuroimaging studies, however, have not clearly demonstrated such a division in humans. We present here an analysis of all reported human functional neuroimaging studies plotted onto a standardized brain. This analysis did not find evidence for a dorsal/ventral subdivision of prefrontal cortex depending on the type of material held in working memory, but a hemispheric organization was suggested (i.e., left-nonspatial; right-spatial). We also performed functional MRI studies in 16 normal subjects during two tasks designed to probe either nonspatial or spatial working memory, respectively. A group and subgroup analysis revealed similarly located activation in right middle frontal gyrus (Brodmanns area 46) in both spatial and nonspatial [working memory-control] subtractions. Based on another model of prefrontal organization [M. Petrides, Frontal lobes and behavior, Cur. Opin. Neurobiol., 4 (1994) 207-211], a reconsideration of the previous imaging literature data suggested that a dorsal/ventral subdivision of prefrontal cortex may depend upon the type of processing performed upon the information held in working memory.

The Effect of Normal Aging on the Coupling of Neural Activity to the Bold Hemodynamic Response

The use of functional neuroimaging to test hypotheses regarding age-related changes in the neural substrates of cognitive processes relies on assumptions regarding the coupling of neural activity to neuroimaging signal. Differences in neuroimaging signal response between young and elderly subjects can be mapped directly to differences in neural response only if such coupling does not change with age. Here we examined spatial and temporal characteristics of the BOLD fMRI hemodynamic response in primary sensorimotor cortex in young and elderly subjects during the performance of a simple reaction time task. We found that 75% of elderly subjects (n = 20) exhibited a detectable voxel-wise relationship with the behavioral paradigm in this region as compared to 100% young subjects (n = 32). The median number of suprathreshold voxels in the young subjects was greater than four times that of the elderly subjects. Young subjects had a slightly greater signal:noise per voxel than the elderly subjects that was attributed to a greater level of noise per voxel in the elderly subjects. The evidence did not support the idea that the greater head motion observed in the elderly was the cause of this greater voxel-wise noise. There were no significant differences between groups in either the shape of the hemodynamic response or in its the within-group variability, although the former evidenced a near significant trend. The overall finding that some aspects of the hemodynamic coupling between neural activity and BOLD fMRI signal change with age cautions against simple interpretations of the results of imaging studies that compare young and elderly subjects.

An Area within Human Ventral Cortex Sensitive to “Building” Stimuli: Evidence and Implications

Isolated, ventral brain lesions in humans occasionally produce specific impairments in the ability to use landmarks, particularly buildings, for way-finding. Using functional MRI, we tested the hypothesis that there exists a cortical region specialized for the perception of buildings. Across subjects, a region straddling the right lingual sulcus was identified that possessed the functional correlates predicted for a specialized building area. A series of experiments discounted several alternative explanations for the behavior of this site. These results are discussed in terms of their impact upon our understanding of the functional structure of visual processing, disorders of topographical disorientation, and the influence of environmental conditions upon neural organization.

Arterial spin labeling perfusion fMRI with very low task frequency

Functional magnetic resonance imaging (fMRI) has become the most widely used modality for visualizing regional brain activation in response to sensorimotor or cognitive tasks. While the majority of fMRI studies have used blood oxygenation level‐dependent (BOLD) contrast as a marker for neural activation, baseline drift effects result in poor sensitivity for detecting slow variations in neural activity. By contrast, drift effects are minimized in arterial spin labeling (ASL) perfusion contrast, primarily as a result of successive pairwise subtraction between images acquired with and without labeling. Recent data suggest that ASL contrast shows stable noise characteristics over the entire frequency spectrum, which makes it suitable for studying low‐frequency events in brain function. The present study investigates the relative sensitivities of ASL and BOLD contrast in detecting changes in motor cortex activation over a spectrum of frequencies of experimental design, where the alternating period between the resting state and activation is varied from 30 s up to 24 hr. The results demonstrate that 1) ASL contrast can detect differences in motor cortex activation over periods of minutes, hours, and even days; 2) the functional sensitivity of ASL contrast becomes superior to that of BOLD contrast when the alternating period between the resting state and activation is greater than a few minutes; and 3) task activation measured by ASL tends to have less intersubject variability than BOLD contrast. The improved sensitivity of the ASL contrast for low task frequency and longitudinal studies, along with its superior power in group analysis, is expected to extend the range of experimental designs that can be studied using fMRI. Magn Reson Med 49:796–802, 2003.

Neural Specialization for Letter Recognition

Functional magnetic resonance imaging (fMRI) was used to estimate neural activity while subjects viewed strings of consonants, digits, and shapes. An area on or near the left fusiform gyrus was found that responded significantly more to letters than digits. Similar results were obtained when consonants were used whose visual features were matched with the digits and when an active matching task was used, suggesting that the results cannot be easily attributed to artifacts of the stimuli or task. These results demonstrate that neural specialization in the human brain can extend to a category of stimuli that is culturally defined and that is acquired many years postnatally.

A neural basis for category and modality specificity of semantic knowledge

Prevalent theories hold that semantic memory is organized by sensorimotor modality (e.g., visual knowledge, motor knowledge). While some neuroimaging studies support this idea, it cannot account for the category specific (e.g., living things) knowledge impairments seen in some brain damaged patients that cut across modalities. In this article we test an alternative model of how damage to interactive, modality-specific neural regions might give rise to these categorical impairments. Functional MRI was used to examine a cortical area with a known modality-specific function during the retrieval of visual and non-visual knowledge about living and non-living things. The specific predictions of our model regarding the signal observed in this area were confirmed, supporting the notion that semantic memory is functionally segregated into anatomically discrete, but highly interactive, modality-specific regions.

Functional MRI lateralization of memory in temporal lobe epilepsy

Objective: To determine the feasibility of using functional magnetic resonance imaging (fMRI) to detect asymmetries in the lateralization of memory activation in patients with temporal lobe epilepsy (TLE). Background: Assessment of mesial temporal lobe function is a critical aspect of the preoperative evaluation for epilepsy surgery, both for predicting postoperative memory deficits and for seizure lateralization. fMRI offers several potential advantages over the current gold standard, intracarotid amobarbital testing (IAT). fMRI has already been successfully applied to language lateralization in TLE. Methods: fMRI was carried out in eight normal subjects and 10 consecutively recruited patients with TLE undergoing preoperative evaluation for epilepsy surgery. A complex visual scene encoding task known to activate mesial temporal structures was used during fMRI. Asymmetry ratios for mesial temporal activation were calculated, using regions of interest defined in normals. Patient findings were compared with the results of IAT performed as part of routine clinical evaluation. Results: Task activation was nearly symmetric in normal subjects, whereas in patients with TLE, significant asymmetries were observed. In all nine patients in whom the IAT result was interpretable, memory asymmetry by fMRI concurred with the findings of IAT including two patients with paradoxical IAT memory lateralization ipsilateral to seizure focus. Conclusions: fMRI can be used to detect asymmetries in memory activation in patients with TLE. Because fMRI studies are noninvasive and provide excellent spatial resolution for functional activation, these preliminary results suggest a promising role for fMRI in improving the preoperative evaluation for epilepsy surgery.

Modulation of task-related neural activity in task-switching: an fMRI study

Task-switching paradigms, in which subjects are typically asked to switch between different S-R mappings, can be considered operationalizations of executive control. Such paradigms are therefore potentially useful in investigating the neural bases of control functions. Here, we present the results of an fMRI study intended to examine two separable components of task-switching: preparation, and the residual shift cost identified by Rogers and Monsell [13]. In analyses restricted to functionally identified regions of interest, we found robust evidence of greater activity for switch trials, compared to repeat trials. This pattern was present both at the time of stimulus presentation and prior to the switch trial. In analyses of the entire brain, we were able to identify one area in the superior parietal lobule that was active during switching but was not part of the apparent network of task-related regions. We conclude that switch trials are neurally distinct from repeat trials in eliciting generally greater neural activity both before and during the performance of a trial.

The Inferential Impact of Global Signal Covariates in Functional Neuroimaging Analyses

Neuroimaging techniques, such as PET and fMRI, are used to test hypotheses regarding local changes in neural activity in response to experimental manipulations. These changes are indirectly measured using raw counts or blood flow in the case of PET (Arndt et al., 1996) or susceptibility in the case of BOLD fMRI (Ogawa et al., 1993). Typically, data are acquired from the entire brain volume and analyses undertaken to identify subcomponents of this volume—voxels or regions of interest—in which significant signal changes have occurred (Friston et al., 1995c). Because neuroimaging experiments often test hypotheses regarding local changes in neuronal activity, variations in signal that are common to the entire brain volume (i.e., global blood flow in PET or global signal in fMRI) have been considered nuisance effects to be eliminated (Ramsay et al., 1993). Therefore, the bulk of discussion to date concerning global signals has regarded the appropriate method of their removal (Fox et al., 1988; Friston et al., 1990; Arndt et al., 1996). Specifically, the question of whether regional ‘‘activations’’ are proportional or additive to global signals has been debated at length, with the outcome of importance for scaling versus covariate approaches (Friston et al., 1990). Using one or another of these techniques, numerous PET and fMRI studies in which the effects of the global signal have been removed have been reported (e.g., Cabeza et al., 1997; Courtney et al., 1996; Jonides et al., 1993; Poline et al., 1996; Schacter et al., 1995; Vandenberghe et al., 1996). Relatively unaddressed, however, is the underlying validity of adjusting for the effects of global signal changes in the first place. Specifically, it must be asked if global signals behave as confounds or simple nuisance variables in additive models (Friston et al., 1995c). Formally, confounding exists if ‘‘meaningfully different interpretations of the relationship of interest result when an extraneous variable is ignored or included in the data analysis’’ (Kleinbaum et al., 1988). Confounding may be contrasted with a simple nuisance variable in that inclusion or exclusion of a confound will affect the expected relationship between the data and an independent variable of interest. In contrast, inclusion or exclusion of a simple nuisance variable will only affect the error variance of the model. In other words, covarying for confounds could change interpretation of statistical results both qualitatively (by changing the sign of relationships) and quantitatively (by either increasing or decreasing the significance of relationships), while covarying for simple nuisance variables could only quantitatively impact interpretation by increasing the significance of relationships (while preserving the sign). This difference in behavior between confounds and nuisance variables is due to correlation of the former with the independent variable(s) of interest. As global signals are spatial averages of the local signals of interest, which are themselves hypothesized to correlate with experimental treatments, it is reasonable to hypothesize that global changes would correlate with behavioral manipulations. If true, global signals will act as confounds, and hence interpretation of statistical results would be contingent upon whether a global signal covariate is either included or excluded. PET count data reported by Friston and colleagues (1990) demonstrated a relationship of global flow with experimental condition that was large with respect to the magnitude of the adjusted local effect (see Fig. 6 from that report). Similarly, Aguirre and colleagues (1997) reported that there was a significant correlation between observed global fMRI signals and an experimental paradigm. These two results suggest that global neuroimaging signals can be correlated with the experimental manipulation and are thus not necessarily simple nuisance variables. The implication is that covarying for global signal in PET and fMRI analyses is not simply, or necessarily, increasing power, but meaningfully changing the results and hence interpretation of these studies. To further address the issue of whether global neuroimaging signals could act as confounds, we analyzed an NEUROIMAGE 8, 302–306 (1998) ARTICLE NO. NI980367