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.

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 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.

Understanding neural system dynamics through task modulation and measurement of functional MRI amplitude, latency, and width.

Estimates of hemodynamic amplitude, delay, and width were combined to investigate system dynamics involved in lexical decision making. Subjects performed a lexical decision task using word and nonword stimuli rotated 0 degrees, 60 degrees, or 120 degrees. Averaged hemodynamic responses to repeated stimulation were fit to a Gamma-variate function convolved with a heavyside function of varying onset and duration to estimate each voxel's activation delay and width. Consistent with prolonged reaction times for the rotated stimuli and nonwords, the motor cortex showed delayed hemodynamic onset for both conditions. Language areas such as the lingual gyrus, middle temporal gyrus, fusiform gyrus, and precuneus all showed delayed hemodynamic onsets to rotated stimuli but not to nonword stimuli. The inferior frontal gyrus showed both increased onset latency for rotated stimuli and a wider hemodynamic response to nonwords, consistent with prolonged processing in this area during the lexical decision task. Phonological processing areas such as superior temporal and angular gyrus showed no delay or width difference for rotated stimuli. These results suggest that phonological routes but not semantic routes to the lexicon can proceed regardless of stimulus orientation. This study demonstrates the utility of estimating hemodynamic delay and width in addition to amplitude allowing for more quantitative measures of brain function such as mental chronometry.

Spatial heterogeneity of the nonlinear dynamics in the FMRI BOLD response.

Recent studies of blood oxygenation level dependent (BOLD) signal responses averaged over a region of interest have demonstrated that the response is nonlinear with respect to stimulus duration. Specifically, shorter duration stimuli produce signal changes larger than expected from a linear system. The focus of this study is to characterize the spatial heterogeneity of this nonlinear effect. A series of MR images of the visual and motor cortexes were acquired during visual stimulation and finger tapping, respectively, at five different stimulus durations (SD). The nonlinearity was assessed by fitting ideal linear responses to the responses at each SD. This amplitude, which is constant for different SD in a linear system, was normalized by the amplitude of the response to a blocked design, thus describing the amount by which the stimulus is larger than predicted from a linear extrapolation of the response to the long duration stimulus. The amplitude of the BOLD response showed a nonlinear behavior that varied considerably and consistently over space, ranging from almost linear to 10 times larger than a linear prediction at short SD. In the motor cortex different nonlinear behavior was found in the primary and supplementary motor cortexes.

Comparison of simultaneously measured perfusion and BOLD signal increases during brain activation with T(1)-based tissue identification.

Perfusion and blood oxygenation level-dependent (BOLD) signals were simultaneously measured during a finger-tapping task at 3T using QUIPSS II with thin-slice TI(1) periodic saturation, a modified pulsed arterial spin labeling technique that provides quantitative measurement of perfusion. Perfusion and BOLD signal changes due to motor activation were obtained and correlated with the T(1) values estimated from echo-planar imaging (EPI)-based T(1) maps on a voxel-by-voxel basis. The peak perfusion signal occurs in voxels with a T(1) of brain parenchyma while the peak BOLD signal occurs in voxels with a T(1) characteristic of blood and cerebrospinal fluid. The locations of the peak signals of functional BOLD and perfusion only partially overlap on the order of 40%. Perfusion activation maps will likely represent the sites of neuronal activity better than do BOLD activation maps. Magn Reson Med 44:137-143, 2000.

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.

QUIPSS II with thin-slice TI1 periodic saturation: a method for improving accuracy of quantitative perfusion imaging using pulsed arterial spin labeling.

Quantitative imaging of perfusion using a single subtraction, second version (QUIPSS II) is a pulsed arterial spin labeling (ASL) technique for improving the quantitation of perfusion imaging by minimizing two major systematic errors: the variable transit delay from the distal edge of the tagged region to the imaging slices, and the contamination by intravascular signal from tagged blood that flows through the imaging slices. However, residual errors remain due to incomplete saturation of spins over the slab-shaped tagged region by the QUIPSS II saturation pulse, and spatial mismatch of the distal edge of the saturation and inversion slice profiles. By replacing the original QUIPSS II saturation pulse with a train of thin-slice periodic saturation pulses applied at the distal end of the tagged region, the accuracy of perfusion quantitation is improved. Results of single and multislice studies are reported.

Event-related fMRI of tasks involving brief motion.

The assessment of brain function by blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) for tasks involving motion near the field of view is compromised by artifacts arising from the motion. The aim of this study is to demonstrate that these artifacts can be reduced by acquiring the average response from a brief stimulus (a "single-trial," or "event-related," paradigm) as opposed to alternating blocks of repeated task with rest (a "block-trial" paradigm). The basis of this technique is that the NMR signal changes from neuronal activation are delayed relative to the motion due to a slow hemodynamic response. By acquiring the average response from a brief stimulus, motion-induced signal changes occur prior to neuronal activation-induced signal changes, and the two can thus be distinguished. This technique is applied to the tasks of speaking out loud, swallowing, jaw clenching, and tongue movement. Functional activation maps derived from the single-trial paradigm contain significantly less artifact than functional activation maps derived from a more traditional block-trial paradigm.

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.

Simultaneous gradient-echo/spin-echo EPI of graded ischemia in human skeletal muscle.

The goal of this study was to evaluate the usefulness of blood oxygenation level-dependent (BOLD) methodologies to provide temporal and spatial information about skeletal muscle perfusion. A simultaneous gradient echo (GE) and spin-echo (SE) imaging sequence (GE/SE) with alternating TE was used to acquire images of leg skeletal muscle throughout a stepped reactive hyperemia paradigm. The change in both the GE and SE relaxation rates (deltaR2*, deltaR2) measured during ischemia and reactive hyperemia scaled with the duration of cuff inflation (the ischemic period) plateaued for cuff inflations lasting longer than 120 seconds and were greater in soleus muscle than in gastrocnemius. The ratio deltaR2*/deltaR2 was found to be less during the reactive hyperemia period relative to ischemia. Considering that a greater proportion of capillary vessels are perfused during reactive hyperemia than during ischemia, this finding suggests that magnetic susceptibility methodologies, with their dependence on compartment size, may provide a measure of the relative distribution of small and large vessels in skeletal muscle.

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.

Magnetic field changes in the human brain due to swallowing or speaking.

Variations in the magnetic field in the human brain caused by the processes of swallowing or speaking are measured. In both processes, motion of the pharyngeal muscles, especially the tongue and jaw, alter the susceptibility-induced magnetic field distribution at the brain slice being imaged. This leads to image warping, compromising the analysis of a time series of images, such as in functional magnetic resonance imaging (fMRI). These dynamic changes are assessed by acquiring a time series of images using a gradient-echo asymmetric-spin-echo sequence (GREASE), a technique in which two images are acquired for each excitation--one during the gradient echo, and one during the latter part of the spin echo. The NMR phase difference between the two images is a measure of the magnetic field distribution. A series of brain images, acquired with this sequence while the subject either swallows or speaks, indicated negative magnetic field changes of up to 0.087 ppm in the inferior region of the brain for both speaking and swallowing, and in some speech, additional positive changes of up to 0.056 ppm in the frontal region of the brain were indicated.

Functional MRI of brain activation induced by scanner acoustic noise.

A method is introduced by which brain activation caused by the acoustic noise associated with echo planar imaging (EPI) is mapped. Two types of time series were compared. The first time series, considered the "task," involved applying only EPI gradients for 20 s without the application of RF pulses, then, without pause, starting image collection. The second, considered the "control," involved typical sequential image acquisition without the prior gradient pulses. Subtraction of the first 5 s of the two time series revealed signal enhancement mainly in the primary auditory cortex. The technique was validated using a motor cortex task that mimicked the hypothesized scanner noise induced activation.

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.

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.