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There is substantial variation between healthy individuals in the number of retinal ganglion cells (RGC) in the eye, with commensurate variation in the number of axons in the optic tracts. Fixel-based analysis of diffusion MR produces estimates of fiber density (FD) and cross section (FC). Using these fixel measurements along with retinal imaging, we asked if individual differences in RGC tissue volume are correlated with individual differences in FD and FC measurements obtained from the optic tracts, and subsequent structures along the cortical visual pathway. We find that RGC endowment is correlated with optic tract FC, but not with FD. RGC volume had a decreasing relationship with measurements from subsequent regions of the visual system (LGN volume, optic radiation FC/FD, and V1 surface area). However, we also found that the variations in each visual area were correlated with the variations in its immediately adjacent visual structure. We only observed these serial correlations when FC is used as the measure of interest for the optic tract and radiations, but no significant relationship was found when FD represented these white matter structures. From these results, we conclude that the variations in RGC endowment, LGN volume, and V1 surface area are better predicted by the overall cross section of the optic tract and optic radiations as compared to the intra-axonal restricted signal component of these white matter pathways. Additionally, the presence of significant correlations between adjacent, but not distant, anatomical structures suggests that there are multiple, local sources of anatomical variation along the visual pathway., Competing Interests: Conflicts of Interest The authors declare that they have no relevant financial interests that relate to the research described in this paper., (Copyright © 2022. Published by Elsevier Inc.)

Objective: Strong magnetic fields from magnetic resonance (MR) scanners induce a Lorentz force that contributes to vertigo and persistent nystagmus. Prior studies have reported a predominantly horizontal direction for healthy subjects in a 7 Tesla (T) MR scanner, with slow phase velocity (SPV) dependent on head orientation. Less is known about vestibular signal behavior for subjects in a weaker, 3T magnetic field, the standard strength used in the Human Connectome Project (HCP). The purpose of this study is to characterize the form and magnitude of nystagmus induced at 3T., Methods: Forty-two subjects were studied after being introduced head-first, supine into a Siemens Prisma 3T scanner. Eye movements were recorded in four separate acquisitions over 20 min. A biometric eye model was fitted to the recordings to derive rotational eye position and then SPV. An anatomical template of the semi-circular canals was fitted to the T2 anatomical image from each subject, and used to derive the angle of the B 0 magnetic field with respect to the vestibular apparatus., Results: Recordings from 37 subjects yielded valid measures of eye movements. The population-mean SPV ± SD for the horizontal component was -1.38 ± 1.27 deg/sec, and vertical component was -0.93 ± 1.44 deg/sec, corresponding to drift movement in the rightward and downward direction. Although there was substantial inter-subject variability, persistent nystagmus was present in half of subjects with no significant adaptation over the 20 min scanning period. The amplitude of vertical drift was correlated with the roll angle of the vestibular system, with a non-zero vertical SPV present at a 0 degree roll., Interpretation: Non-habituating vestibular signals of varying amplitude are present in resting state data collected at 3T., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022. Published by Elsevier Inc.)

Human behavior and cognition result from a complex pattern of interactions between brain regions. The flexible reconfiguration of these patterns enables behavioral adaptation, such as the acquisition of a new motor skill. Yet, the degree to which these reconfigurations depend on the brain's baseline sensorimotor integration is far from understood. Here, we asked whether spontaneous fluctuations in sensorimotor networks at baseline were predictive of individual differences in future learning. We analyzed functional MRI data from 19 participants prior to six weeks of training on a new motor skill. We found that visual-motor connectivity was inversely related to learning rate: sensorimotor autonomy at baseline corresponded to faster learning in the future. Using three additional scans, we found that visual-motor connectivity at baseline is a relatively stable individual trait. These results suggest that individual differences in motor skill learning can be predicted from sensorimotor autonomy at baseline prior to task execution., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

The early years of BOLD fMRI coincided with the rapid growth of both the internet and the open-source software movement. This environment encouraged the creation and dissemination of many neuroimaging software projects, only some of which survived. I tell the story of two of these open-source projects, FIASCO and VoxBo, as well as the interesting links between the commercial MedX software deployed at the NIH and satellite reconnaissance., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Arterial spin labeled (ASL), perfusion fMRI was developed nearly simultaneously with BOLD fMRI. The application of this technique in studies of human brain activity has grown slowly over the last twenty years, primarily because of the need to meet technical challenges in data acquisition and analysis. Even within these constraints, perfusion fMRI has been identified as a tool that is well suited to measure slow changes in neural activity and to examine individual differences in brain-behavior relationships. Major advances have been made in acquisition and analysis techniques during this time. With further, anticipated technical improvements, perfusion fMRI studies in humans are poised to gain the improved cortical spatial resolution that has been observed in animal studies. If achieved, these advances portend surprising future applications of perfusion fMRI, including multi-voxel pattern analysis., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Separate neuroscience experiments have examined two properties of neural coding for perceptual stimuli. Adaptation studies seek a graded recovery from neural adaptation with ever greater dissimilarity between pairs of stimuli. Studies of prototype effects test for a larger absolute response to a stimulus which is distant from the center of a stimulus space. While intellectually distinct, these effects are confounded in measurement in standard neuroscience paradigms and can be mistaken for one another. Stimuli which are more distinctive are less subject to adaptation from perceptual neighbors. Therefore, a putative prototype effect may simply result from greater adaptation of prototypical stimuli by other stimuli in the experiment. Conversely, stimulus pairs which are the most perceptually distant from one another, and therefore expected to show the greatest recovery from adaptation, disproportionately draw from the extremes of the stimulus space. Thus, an apparent neural similarity effect may be created by an underlying prototype representation. We simulate BOLD fMRI results driven by each possible effect and demonstrate spurious results in support of the complementary effect. We then present an example fMRI experiment that demonstrates the confound and how it may be minimized. Finally, we discuss the implications of this intrinsic confound for studies of perceptual representation, neural coding, and category learning., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Stimulus counterbalance is critical for studies of neural habituation, bias, anticipation, and (more generally) the effect of stimulus history and context. We introduce de Bruijn cycles, a class of combinatorial objects, as the ideal source of pseudo-random stimulus sequences with arbitrary levels of counterbalance. Neuro-vascular imaging studies (such as BOLD fMRI) have an additional requirement imposed by the filtering and noise properties of the method: only some temporal frequencies of neural modulation are detectable. Extant methods of generating counterbalanced stimulus sequences yield neural modulations that are weakly (or not at all) detected by BOLD fMRI. We solve this limitation using a novel "path-guided" approach for the generation of de Bruijn cycles. The algorithm encodes a hypothesized neural modulation of specific temporal frequency within the seemingly random order of events. By positioning the modulation between the signal and noise bands of the neuro-vascular imaging method, the resulting sequence markedly improves detection power. These sequences may be used to study stimulus context and history effects in a manner not previously possible., (Copyright © 2011 Elsevier Inc. All rights reserved.)

This paper describes continuous carry-over fMRI experiments. In these studies, stimuli are presented in an unbroken, sequential manner, and can be used to estimate simultaneously the mean difference in neural activity between stimuli as well as the effect of one stimulus upon another (carry-over effects). Neural adaptation, which has been the basis of many recent fMRI studies, is shown to be a specific form of carry-over effect. With this approach, the adapting effects of stimuli may be studied in a continuous sequence, as opposed to within isolated pairs or blocks. Additionally, the average, direct effect of a stimulus upon neural response can form the basis of a simultaneously obtained distributed pattern analysis, allowing comparison of neural population coding on focal (within voxel) and distributed (across voxel) spatial scales. These studies are ideally conducted with serially balanced sequences, in which every stimulus precedes and follows every other stimulus. While m-sequences can provide this stimulus order, the type 1 index 1 sequence of Finney and Outhwaite may be used in fMRI studies for those experimental designs for which an m-sequence solution does not exist. Continuous carry-over designs with serially balanced sequences are argued to be particularly well suited to the characterization of "similarity spaces," in which the perceptual similarity of stimuli is related to the structure of neural representation both within and across voxels. These concepts are illustrated with a worked example involving the neural representation of color. It is shown that data from a single scanning session are sufficient to detect direct and carry-over effects, as well as demonstrate the correspondence of the similarity structure of distributed patterns of neural firing and the perceptual similarity of a set of colors.

Behavioral and neuroimaging studies of cognition frequently test hypotheses regarding mental processing of different stimulus categories (e.g. verbs, faces, animals, scenes, etc.). The conclusions of such studies hinge upon the generalizability of their findings from the specific stimuli used in the experiment to the category as a whole. This type of generalizability is explicitly tested in behavioral studies, using "item analysis". However, generalizability to stimulus categories has up until now been assumed in neuroimaging studies, without employing item analysis for statistical validation. Here we apply item analysis to a functional magnetic resonance imaging study of nouns and verbs, demonstrating its theoretical importance and feasibility. In the subject-wise analysis, a left prefrontal and a left posterior-temporal region of interest showed putative grammatical class effects. An item-wise analysis revealed, however, that only the left posterior-temporal effect was generalizable to the stimulus categories of nouns and verbs. Taken together, the findings of the subject- and item-wise analyses suggest that grammatical-class effects in the left prefrontal cortex depend on the particular word stimuli used, rather than reflecting categorical differences between nouns and verbs. This empirical example illustrates that item analysis not only is sufficiently powered to detect task relevant changes in BOLD signal but also can make theoretically important distinctions between findings that generalize to the item populations, and those that do not.

In this study, we examine the suitability of a relatively new imaging technique, arterial spin labeled perfusion imaging, for the study of continuous, gradual changes in neural activity. Unlike BOLD imaging, the perfusion signal is stable over long time-scales, allowing for accurate assessment of continuous performance. In addition, perfusion fMRI provides an absolute measure of blood flow so signal changes can be interpreted without reference to a baseline. The task we used was the serial response time task, a sequence learning task. Our results show reliable correlations between performance improvements and decreases in blood flow in premotor cortex and the inferior parietal lobe, supporting the model that learning procedures that increase efficiency of processing will be reflected in lower metabolic needs in tissues that support such processes. More generally, our results show that perfusion fMRI may be applied to the study of mental operations that produce gradual changes in neural activity.

Functional magnetic resonance imaging (fMRI) based on arterial spin labeling (ASL) perfusion contrast is an emergent methodology for visualizing brain function both at rest and during task performance. Because of the typical pairwise subtraction approach in generating perfusion images, ASL contrast manifests different noise properties and offers potential advantages for some experimental designs as compared with blood oxygenation-level-dependent (BOLD) contrast. We studied the noise properties and statistical power of ASL contrast, with a focus on temporal autocorrelation and spatial coherence, at both 1.5- and 4.0-T field strengths. Perfusion fMRI time series were found to be roughly independent in time, and voxelwise statistical analysis assuming independence of observations yielded false-positive rates compatible with theoretical values using appropriate analysis methods. Unlike BOLD fMRI data, perfusion data were not found to have spatial coherence that varied across temporal frequency. This finding has implications for the application of spatial smoothing to perfusion data. It was also found that the spatial coherence of the ASL data is greater at high magnetic field than low field, and including the global signal as a covariate in the general linear model improves the central tendency of test statistic as well as reduces the noise level in perfusion fMRI, especially at high magnetic field.

This paper compares the statistical power of BOLD and arterial spin labeling perfusion fMRI for a variety of experimental designs within and across subjects. Based on theory and simulations, we predict that perfusion data are composed of independent observations in time under the null hypothesis, in contrast to BOLD data, which possess marked autocorrelation. We also present a method (sinc subtraction) of generating perfusion data from its raw source signal that minimizes the presence of oxygen-sensitive signal changes and can be used with any experimental design. Empirically, we demonstrate the absence of autocorrelation in perfusion noise, examine the shape of the hemodynamic response function for BOLD and perfusion, and obtain a measure of signal to noise for each method. This information is then used to generate a model of relative sensitivity of the BOLD and perfusion methods for within-subject experimental designs of varying temporal frequency. It is determined that perfusion fMRI provides superior sensitivity for within-subject experimental designs that concentrate their power at or below approximately 0.009 Hz (corresponding to a "blocked" experimental design of 60-s epochs). Additionally, evidence is presented that across-subject hypothesis tests may be more sensitive when conducted using perfusion imaging, despite the better within-subject signal to noise obtained in some cases with BOLD., (©2002 Elsevier Science (USA).)

Delayed-response tasks are behavioral paradigms in which subjects must remember stimulus attributes across a delay to subsequently perform the appropriate motor response. Quintana and Fuster (1992), reported that there exist subpopulations of neurons in monkey lateral prefrontal cortex (PFC) whose firing rates during the delay are tuned to either sensorial attributes of the stimulus (i.e., involved in sensory memory) or the direction of a postdelay motor response associated with the stimulus (i.e., involved in motor preparation). We studied human subjects with an event-related fMRI method that would allow us to test the hypothesis that there are regions within the PFC that are recruited during both motor preparation and sensory memory. Subjects performed a delayed-response task with two types of trials that either (1) allowed subjects to prepare during a delay period for a specific motor response or (2) required that subjects maintain a sensory attribute (specifically, color) during a delay period for correct performance postdelay. It was assumed that during the delay periods, the delayed-response trials would engage motor preparation while delayed-match trials would engage sensory memory. Behavioral data supported this assumption. Imaging results support the hypothesis that the PFC is involved in both motor preparation and sensory memory. Furthermore, no selectivity (in terms of intensity of neural representation on the spatial scale of the voxel size <5 mm(3)) for motor preparation over sensory memory (or vice-versa) was detected within the PFC. This latter result fails to support a gross anatomical segregation within the PFC with respect to involvement in these two cognitive processes., (Copyright 2000 Academic Press.)

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., (Copyright 1999 Academic Press.)

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., (Copyright 1998 Academic Press.)

Lesion studies in monkeys have provided evidence that lateral prefrontal cortex is necessary for working memory, the cognitive processes involved in the temporary maintenance and manipulation of information. Monkey electrophysiological studies, however, have also observed prefrontal neuronal activity associated with cognitive processes that are nonmnemonic. We tested the hypothesis that the same regions of human prefrontal cortex that demonstrate activity during working memory tasks would also demonstrate activity during tasks without working memory demands. During echoplanar fMRI imaging, subjects performed a three-condition experiment (working memory task, nonworking memory task, rest). In the working memory task, subjects observed serially presented stimuli and determined if each stimulus was the same as that presented two stimuli back. The nonworking memory task in Experiment 1 required subjects to identify a single predetermined stimulus; in Experiment 2, subjects were required to make a button press to every stimulus. In all subjects in both experiments, the working memory task exhibited greater prefrontal cortical activity compared to either nonworking memory task. In these same prefrontal regions, greater activation was also observed during both nonworking memory tasks compared to rest. We conclude that human lateral prefrontal cortex supports processes in addition to working memory. Thus, reverse inference of the form "if prefrontal cortex is active, working memory is engaged" is not supported., (Copyright 1998 Academic Press.)

Neuroimaging activation studies typically observe signals during two or more periods of differing cognitive activity which are then analyzed by a subtraction to test for localized neuroanatomical dissociations between cognitive tasks. Significant activity found between task conditions is frequently assumed to reflect a novel cognitive process present in one task and not the other. We present a conceptual framework that considers the neural mechanisms underlying such observed neuroimaging changes. We propose that neuroimaging experiments which present stimuli at a fixed pace (where each trial takes the same amount of time) will be sensitive to changes in both duration and intensity of neural processing. In contrast, the signal observed during a self-paced design is derived from neural processing averaged over the reaction time and hence could be less sensitive to differences in duration of neural processing. As an empirical demonstration of these ideas, we studied normal subjects using echoplanar functional MRI during two visuospatial tasks (matching of either ROTATED or NONROTATED stimuli) performed using FIXED and SELF-PACED designs. In both pacing designs, reaction times were greater in the ROTATED than NONROTATED task, interpreted as a greater duration of neural processing during the ROTATED compared to the NONROTATED task. In the FIXED-PACED design, significantly greater signal was present within a parieto-occipital cortical region during the ROTATED task compared to the NONROTATED task. This difference was not observed during the SELF-PACED design. This result illustrates the importance of considering trial pacing in the interpretation of functional neuroimaging activation studies., (Copyright 1997 Academic Press.)

Temporal autocorrelation, spatial coherency, and their effects on voxel-wise parametric statistics were examined in BOLD fMRI null-hypothesis, or "noise," datasets. Seventeen normal, young subjects were scanned using BOLD fMRI while not performing any time-locked experimental behavior. Temporal autocorrelation in these datasets was described well by a 1/frequency relationship. Voxel-wise statistical analysis of these noise datasets which assumed independence (i.e., ignored temporal autocorrelation) rejected the null hypothesis at a higher rate than specified by the nominal alpha. Temporal smoothing in conjunction with the use of a modified general linear model (Worsley and Friston, 1995, NeuroImage 2: 173-182) brought the false-positive rate closer to the nominal alpha. It was also found that the noise fMRI datasets contain spatially coherent time signals. This observed spatial coherence could not be fully explained by a continuously differentiable spatial autocovariance function and was much greater for lower temporal frequencies. Its presence made voxel-wise test statistics in a given noise dataset dependent, and thus shifted their distributions to the right or left of 0. Inclusion of a "global signal" covariate in the general linear model reduced this dependence and consequently stabilized (i.e., reduced the variance of) dataset false-positive rates.

In the companion to this paper (E. Zarahn, G. K. Aguirre, and M. D'Esposito, 1997, NeuroImage, 179-197), we describe an implementation of a general linear model for autocorrelated observations in which the voxel-wise false-positive rates in fMRI "noise" datasets were stabilized and brought close to theoretical values. Here, implementations of the model are tested for use with statistical parametric mapping analysis of spatially smoothed fMRI data. Analyses using varying models of intrinsic temporal autocorrelation and either including or excluding a global signal covariate were conducted upon human subject data collected under null hypothesis as well as under experimental conditions. We found that smoothing with an empirically derived impulse response function (IRF), combined with a model of the intrinsic temporal autocorrelation in spatially smoothed fMRI data, resulted in a map-wise false-positive rate which did not exceed a 5% level when a nominal alpha = 0.05 tabular threshold was applied. Use of other models of intrinsic temporal autocorrelation resulted in map-wise false-positive rates that significantly exceeded this level. fMRI data collected while subjects performed a behavioral task were used to examine (a) task-dependent global signal changes and (b) the dependence of sensitivity on the temporal smoothing kernel and inclusion/exclusion of a global signal covariate. The global signal changes within an fMRI dataset were shown to be influenced by the performance of a behavioral task. However, the inclusion of this measure as a covariate did not have an adverse affect upon our measure of sensitivity. Finally, use of an empirically derived estimate of the IRF of the system was shown to result in greater map-wise sensitivity for signal changes than the use of a broader (in time) Poisson (parameter = 8 s) kernel.