In-Scanner Thoughts shape Resting-state Functional Connectivity: how participants "rest" matters.

Resting-state fMRI (rs-fMRI) scans-namely those lacking experimentally-controlled stimuli or cognitive demands-are often used to identify aberrant patterns of functional connectivity (FC) in clinical populations. To minimize interpretational uncertainty, researchers control for across-cohort disparities in age, gender, co-morbidities, and head motion. Yet, studies rarely, if ever, consider the possibility that systematic differences in inner experience (i.e., what subjects think and feel during the scan) may directly affect FC measures. Here we demonstrate that is the case using a rs-fMRI dataset comprising 471 scans annotated with experiential data. Wide-spread significant differences in FC are observed between scans that systematically differ in terms of reported in-scanner experience. Additionally, we show that FC can successfully predict specific aspects of in-scanner experience in a manner similar to how it predicts demographics, cognitive abilities, clinical outcomes and labels. Together, these results highlight the key role of in-scanner experience in shaping rs-fMRI estimates of FC.

The danger of systematic bias in group-level FMRI-lag-based causality estimation.

Schippers, Renken and Keysers (NeuroImage, 2011) present a simulation of multi-subject lag-based causality estimation. We fully agree that single-subject evaluations (e.g., Smith et al., 2011) need to be revisited in the context of multi-subject studies, and Schippers' paper is a good example, including detailed multi-level simulation and cross-subject statistical modelling. The authors conclude that "the average chance to find a significant Granger causality effect when no actual influence is present in the data stays well below the p-level imposed on the second level statistics" and that "when the analyses reveal a significant directed influence, this direction was accurate in the vast majority of the cases". Unfortunately, we believe that the general meaning that may be taken from these statements is not supported by the paper's results, as there may in reality be a systematic (group-average) difference in haemodynamic delay between two brain areas. While many statements in the paper (e.g., the final two sentences) do refer to this problem, we fear that the overriding message that many readers may take from the paper could cause misunderstanding.

Physiological noise effects on the flip angle selection in BOLD fMRI.

This work addresses the choice of imaging flip angle in blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI). When noise of physiological origin becomes the dominant noise source in fMRI timeseries, it causes a nonlinear dependence of the temporal signal-to-noise ratio (TSNR) versus signal-to-noise ratio (SNR) that can be exploited to perform BOLD fMRI at angles well below the Ernst angle without any detrimental effect on our ability to detect sites of neuronal activation. We show, both experimentally and theoretically, that for situations where available SNR is high and physiological noise dominates over system/thermal noise, although TSNR still reaches it maximum for the Ernst angle, reduction of imaging flip angle well below this angle results in negligible loss in TSNR. Moreover, we provide a way to compute a suggested imaging flip angle, which constitutes a conservative estimate of the minimum flip angle that can be used under given experimental SNR and physiological noise levels. For our experimental conditions, this suggested angle equals 7.63° for the grey matter compartment, while the Ernst angle=77°. Finally, using data from eight subjects with a combined visual-motor task we show that imaging at angles as low as 9° introduces no significant differences in observed hemodynamic response time-course, contrast-to-noise ratio, voxel-wise effect size or statistical maps of activation as compared to imaging at 75° (an angle close to the Ernst angle). These results suggest that using low flip angles in BOLD fMRI experimentation to obtain benefits such as (1) reduction of RF power, (2) limitation of apparent T(1)-related inflow effects, (3) reduction of through-plane motion artifacts, (4) lower levels of physiological noise, and (5) improved tissue contrast is feasible when physiological noise dominates and SNR is high.

A general mechanism for perceptual decision-making in the human brain.

Findings from single-cell recording studies suggest that a comparison of the outputs of different pools of selectively tuned lower-level sensory neurons may be a general mechanism by which higher-level brain regions compute perceptual decisions. For example, when monkeys must decide whether a noisy field of dots is moving upward or downward, a decision can be formed by computing the difference in responses between lower-level neurons sensitive to upward motion and those sensitive to downward motion. Here we use functional magnetic resonance imaging and a categorization task in which subjects decide whether an image presented is a face or a house to test whether a similar mechanism is also at work for more complex decisions in the human brain and, if so, where in the brain this computation might be performed. Activity within the left dorsolateral prefrontal cortex is greater during easy decisions than during difficult decisions, covaries with the difference signal between face- and house-selective regions in the ventral temporal cortex, and predicts behavioural performance in the categorization task. These findings show that even for complex object categories, the comparison of the outputs of different pools of selectively tuned neurons could be a general mechanism by which the human brain computes perceptual decisions.

Relationship between finger movement rate and functional magnetic resonance signal change in human primary motor cortex.

Functional magnetic resonance imaging (FMRI) is a noninvasive technique for mapping regional brain changes in response to sensory, motor, or cognitive activation tasks. Interpretation of these activation experiments may be confounded by more elementary task parameters, such as stimulus presentation or movement rates. We examined the effect of movement rate on the FMRI response recorded from the contralateral primary motor cortex. Four right-handed healthy subjects performed flexion-extension movements of digits 2-5 of the right hand at rates of 1, 2, 3, 4, or 5 Hz. Results of this study indicated a positive linear relationship between movement rate and FMRI signal change. Additionally, the number of voxels demonstrating functional activity increased significantly with faster movement rates. The magnitude of the signal change at each movement rate remained constant over the course of three 8-min scanning series. These findings are similar to those of previous rate studies of the visual and auditory system performed with positron emission tomography (PET) and FMRI.

Nicotine-induced limbic cortical activation in the human brain: a functional MRI study.

OBJECTIVE: Nicotine is a highly addictive substance, and cigarette smoking is a major cause of premature death among humans. Little is known about the neuropharmacology and sites of action of nicotine in the human brain. Such knowledge might help in the development of new behavioral and pharmacological therapies to aid in treating nicotine dependence and to improve smoking cessation success rates. METHOD: Functional magnetic resonance imaging, a real-time imaging technique, was used to determine the acute CNS effects of intravenous nicotine in 16 active cigarette smokers. An injection of saline followed by injections of three doses of nicotine (0.75, 1.50, and 2.25 mg/70 kg of weight) were each administered intravenously over 1-minute periods in an ascending, cumulative-dosing paradigm while whole brain gradient-echo, echo-planar images were acquired every 6 seconds during consecutive 20-minute trials. RESULTS: Nicotine induced a dose-dependent increase in several behavioral parameters, including feelings of "rush" and "high" and drug liking. Nicotine also induced a dose-dependent increase in neuronal activity in a distributed system of brain regions, including the nucleus accumbens, amygdala, cingulate, and frontal lobes. Activation in these structures is consistent with nicotine's behavior-arousing and behavior-reinforcing properties in humans. CONCLUSIONS: The identified brain regions have been previously shown to participate in the reinforcing, mood-elevating, and cognitive properties of other abused drugs such as cocaine, amphetamine, and opiates, suggesting that nicotine acts similarly in the human brain to produce its reinforcing and dependence properties.

Lateralized human brain language systems demonstrated by task subtraction functional magnetic resonance imaging.

OBJECTIVE: To develop a procedure for noninvasive measurement of language lateralization with functional magnetic resonance imaging (MRI). DESIGN: Functional neuroimaging using time-series echo-planar MRI. SETTING: University medical center research facility. SUBJECTS: Five healthy, right-handed, young adults. MAIN OUTCOME MEASURES: Number of MRI voxels in left and right hemispheres showing task-related signal increases during two contrasting auditory processing tasks. The nonlinguistic task involved processing of pure tones, while the linguistic task involved processing of single words based on semantic content. RESULTS: The pure-tone processing task activated temporal lobe auditory areas and dorsolateral frontal regions bilaterally. Using this task as a control condition, the semantic processing task resulted in lateralized activity in distributed regions of the left hemisphere. A significant effect of task on intrahemispheric activity pattern was demonstrated in every subject. Results were reproduced in preliminary studies of test-retest reliability. CONCLUSIONS: The results demonstrate the lateralized anatomy of semantic linguistic systems in contrast to non-linguistic auditory sensory processors and introduce a task subtraction technique adapted for functional MRI as a noninvasive measure of language lateralization.

Somatotopic mapping of the human primary motor cortex with functional magnetic resonance imaging.

We applied functional magnetic resonance imaging (FMRI) to map the somatotopic organization of the primary motor cortex using voluntary movements of the hand, arm, and foot. Eight right-handed healthy subjects performed self-paced, repetitive, flexion/extension movements of the limbs while undergoing echo-planar imaging. Four subjects performed movements of the right fingers and toes, while the remaining subjects performed movements of the right fingers and elbow joint. There was statistically significant functional activity in the left primary motor cortex in all subjects. The pattern of functional activity followed a topographic representation: finger movements resulted in signal intensity changes over the convexity of the left motor cortex, whereas toe movements produced changes either at the interhemispheric fissure or on the dorsolateral surface adjacent to the interhemispheric fissure. Elbow movements overlapped the more medial signal intensity changes observed with finger movements. Functionally active regions were confined to the cortical ribbon and followed the gyral anatomy closely. These findings indicate that FMRI is capable of generating somatotopic maps of the primary motor cortex in individual subjects.

Functional magnetic resonance imaging of complex human movements.

Functional magnetic resonance imaging (FMRI) is a new, noninvasive imaging tool thought to measure changes related to regional cerebral blood flow (rCBF). Previous FMRI studies have demonstrated functional changes within the primary cerebral cortex in response to simple activation tasks, but it is unknown whether FMRI can also detect changes within the nonprimary cortex in response to complex mental activities. We therefore scanned six right-handed healthy subjects while they performed self-paced simple and complex finger movements with the right and left hands. Some subjects also performed the tasks at a fixed rate (2 Hz) or imagined performing the complex task. Functional changes occurred (1) in the contralateral primary motor cortex during simple, self-paced movements; (2) in the contralateral (and occasionally ipsilateral) primary motor cortex, the supplementary motor area (SMA), the premotor cortex of both hemispheres, and the contralateral somatosensory cortex during complex, self-paced movements; (3) with less intensity during paced movements, presumably due to the slower movement rates associated with the paced (relative to self-paced) condition; and (4) in the SMA and, to a lesser degree, the premotor cortex during imagined complex movements. These preliminary results are consistent with hierarchical models of voluntary motor control.

Effects of stimulus rate on signal response during functional magnetic resonance imaging of auditory cortex.

Functional magnetic resonance imaging (FMRI) detects focal MRI signal changes in brain tissue that are believed to result from changes in neuronal activity. We describe the dependence of this response in auditory cortex on the rate of presentation of simple speech stimuli. Speech syllables were presented to five normal subjects at rates ranging from 0.17 to 2.5 Hz, while the subjects performed a phoneme discrimination task. Regions studied with FMRI during this task included the lateral aspect of both temporal lobes. All subjects showed bilateral superior temporal lobe MRI signal increases that were coincident with stimulus presentation and performance of the task. The magnitude of this response increased in a monotonic, non-linear manner with increasing stimulus rate. This rate-response relationship was nearly identical in right and left hemispheres. The relationship may reflect metabolic activity integrated over time and subject to non-linear characteristics of neuronal recovery or blood flow regulation. The dependence of response magnitude on stimulation rate supports the hypothesis that the FMRI phenomenon indirectly reflects neuronal metabolic activity. The measures provided here should assist in the design of optimal activation strategies for the human auditory cortex.

Modulation of auditory and visual cortex by selective attention is modality-dependent.

Using functional magnetic resonance imaging (fMRI), we investigated whether the response of auditory and visual cortex was modulated by attending selectively to either heard or seen numbers presented simultaneously. Alternating attention between modalities modulated fMRI signal within the corresponding sensory cortex. This study provides evidence that attention acts locally during early auditory cognitive sensory processing, and that modulation of auditory and visual sensory cortex by attention is modality-dependent.

Synthetic images by subspace transforms. I. Principal components images and related filters.

The principal component (PC) approach offers compressions of an image sequence into fewer images and noise suppressing filters. Multiple MR images of the same tomographic slice obtained with different acquisition parameters (i.e., with different TR, TE, and flip angles), time sequences of images in nuclear medicine, and cardiac ultrasound image sequences are examples of such input image sets. In this paper noise relationships of original and linearly transformed image sequences in general, and specifically of original, PC, and PC-filtered images are discussed. As the spinoff, it introduces locally weighted PC transforms and filters, nonlinear PC's, and a single-image based filter for suppression of noise. Examples illustrate increased perceptibility of anatomical/functional structures in PC images and PC-filtered images, including extraction of physiological functional information by PC loading curves. Generally, the more correlated the original images are, the more effective is the PC approach.

Magnetic resonance imaging of human brain function. Principles, practicalities, and possibilities.

This article presents a review of functional magnetic resonance (fMR) imaging. Included are four sections that address the principles, practicalities, and potentials of fMR imaging. The current types of hemodynamic contrast available with fMR imaging, including blood volume, perfusion, and oxygenation, are discussed. Technical issues of fMR imaging, including interpretability and sensitivity, are described, and several currently unresolved issues are addressed. Also reviewed are commonly used fMR imaging platforms and clinical and research applications.

Mapping the MRI voxel volume in which thermal noise matches physiological noise--implications for fMRI.

This work addresses the choice of the imaging voxel volume in blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI). Noise of physiological origin that is present in the voxel time course is a prohibitive factor in the detection of small activation-induced BOLD signal changes. If the physiological noise contribution dominates over the temporal fluctuation contribution in the imaging voxel, further increases in the voxel signal-to-noise ratio (SNR) will have diminished corresponding increases in temporal signal-to-noise (TSNR), resulting in reduced corresponding increases in the ability to detect activation induced signal changes. On the other hand, if the thermal and system noise dominate (suggesting a relatively low SNR) further decreases in SNR can prohibit detection of activation-induced signal changes. Here we have proposed and called the "suggested" voxel volume for fMRI the volume where thermal plus system-related and physiological noise variances are equal. Based on this condition we have created maps of fMRI suggested voxel volume from our experimental data at 3T, since this value will spatially vary depending on the contribution of physiologic noise in each voxel. Based on our fast EPI segmentation technique we have found that for gray matter (GM), white matter (WM), and cerebral spinal fluid (CSF) brain compartments the mean suggested cubical voxel volume is: (1.8 mm)3, (2.1 mm)3 and (1.4 mm)3, respectively. Serendipitously, (1.8 mm)3 cubical voxel volume for GM approximately matches the cortical thickness, thus optimizing BOLD contrast by minimizing partial volume averaging. The introduced suggested fMRI voxel volume can be a useful parameter for choice of imaging volume for functional studies.

Involvement of human left dorsolateral prefrontal cortex in perceptual decision making is independent of response modality.

Perceptual decision making typically entails the processing of sensory signals, the formation of a decision, and the planning and execution of a motor response. Although recent studies in monkeys and humans have revealed possible neural mechanisms for perceptual decision making, much less is known about how the decision is subsequently transformed into a motor action and whether or not the decision is represented at an abstract level, i.e., independently of the specific motor response. To address this issue, we used functional MRI to monitor changes in brain activity while human subjects discriminated the direction of motion in random-dot visual stimuli that varied in coherence and responded with either button presses or saccadic eye movements. We hypothesized that areas representing decision variables should respond more to high- than to low-coherence stimuli independent of the motor system used to express a decision. Four areas were found that fulfilled this condition: left posterior dorsolateral prefrontal cortex (DLPFC), left posterior cingulate cortex, left inferior parietal lobule, and left fusifom/parahippocampal gyrus. We previously found that, when subjects made categorical decisions about degraded face and house stimuli, left posterior DLPFC showed a greater response to high- relative to low-coherence stimuli. Furthermore, the left posterior DLPFC appears to perform a comparison of signals from sensory processing areas during perceptual decision making. These data suggest that the involvement of left posterior DLPFC in perceptual decision making transcends both task and response specificity, thereby enabling a flexible link among sensory evidence, decision, and action.

Noise reduction in multi-slice arterial spin tagging imaging.

Attenuating the static signal in arterial spin tagging (ASSIST) was initially developed for 3D imaging of cerebral blood flow. To enable the simultaneous collection of cerebral blood flow and BOLD data, a multi-slice version of ASSIST is proposed. As with the 3D version, this sequence uses multiple inversion pulses during the tagging period to suppress the static signal. To maintain background suppression in all slices, the multi-slice sequence applies additional inversion pulses between slice acquisitions. The utility of the sequence was demonstrated by simultaneously acquiring ASSIST and BOLD data during a functional task and by collecting resting-state ASSIST data over a large number of slices. In addition, the temporal stability of the perfusion signal was found to be 60% greater at 3 T compared to 1.5 T, which was attributed to the insensitivity of ASSIST to physiologic noise.

A hypercapnia-based normalization method for improved spatial localization of human brain activation with fMRI.

An issue in blood oxygenation level dependent contrast-based functional MRI is the accurate interpretation of the activation-induced signal changes. Hemodynamic factors other than activation-induced changes in blood oxygenation are known to contribute to the signal change magnitudes and dynamics, and therefore need to be accounted for or removed. In this paper, a general method for removal of effects other than activation-induced blood oxygenation changes from fMRI brain activation maps by the use of hypercapnic stress normalization is introduced. First, the effects of resting blood volume distribution across voxels on activation-induced BOLD-based fMRI signal changes are shown to be significant. Second, the effects of hypercapnia and hypoxia on resting and activation-induced signal changes are demonstrated. These results suggest that global hemodynamic stresses may be useful for non-invasive mapping of blood volume. Third, the normalization technique is demonstrated.

Event-related fMRI contrast when using constant interstimulus interval: theory and experiment.

Event-related functional magnetic resonance imaging (ER-fMRI) involves the mapping of averaged hemodynamic changes resulting from repeated, brief (<3 sec) brain activation episodes. In this paper, two issues regarding constant-interstimulus interval ER-fMRI were addressed. First, the optimal interstimulus interval (ISI), given a stimulus duration (SD), was determined. Second, the statistical power of ER-fMRI relative to that of a blocked-design paradigm was determined. Experimentally, it was found that with a 2-sec SD, the optimal ISI is 12 to 14 sec. Theoretically, the optimal repetition interval (T(opt) = ISI + SD) is 12 to 14 sec for stimuli of 2 sec or less. For longer stimuli, T(opt) is 8 + 2 x SD. At the optimal ISI for SD = 2 sec, the experimentally determined functional contrast of ER-fMRI was only -35% lower than that of blocked-design fMRI. Simulations that assumed a linear system demonstrated an event-related functional contrast that was -65% lower than that of the blocked design. These differences between simulated and experimental contrast suggest that the ER-fMRI amplitude is greater than that predicted by a linear shift-invariant system.

Single-shot half k-space high-resolution gradient-recalled EPI for fMRI at 3 Tesla.

Half k-space gradient-recalled echo-planar imaging (GR-EPI) is discussed in detail. T2* decay during full k-space GR-EPI gives rise to unequal weighting of the lines of k-space, loss of signal intensity at the center of k-space, and a point-spread function that limits resolution. In addition, the long readout time for high-resolution full k-space acquisition gives rise to severe susceptibility effects. These problems are substantially reduced by acquiring only half of k-space and filling the empty side by Hermitian conjugate formation. Details of the pulse sequence and image reconstruction are presented. The point-spread function is 3(1/2) times narrower for half than full k-space acquisition. Experiments as well as theoretical considerations were carried out in a context of fMRI using a whole-brain local gradient and an RF coil at 3 Tesla. Using a bandwidth of +/-83 kHz, well-resolved single-shot images of the human brain, as well as good quality fMRI data sets were obtained with a matrix of 192 x 192 over 16 x 16 cm2 FOV using half k-space techniques. The combination of high spatial resolution using the methods presented in this article and the high temporal resolution of EPI opens opportunities for research into fMRI contrast mechanisms. Increase of percent signal change as the resolution increases is attributed to reduction of partial volume effects of activated voxels. Histograms of fMRI pixel responses are progressively weighted to higher percent signal changes as the resolution increases. The conclusion has been reached that half k-space GR-EPI is generally superior to full k-space GR-EPI and should be used even for low-resolution (64 x 64) EPI.