Effects of hypoxia, hyperoxia, and hypercapnia on baseline and stimulus-evoked BOLD, CBF, and CMRO2 in spontaneously breathing animals

Functional magnetic resonance imaging (fMRI) was used to investigate the effects of inspired hypoxic, hyperoxic, and hypercapnic gases on baseline and stimulus-evoked changes in blood oxygenation level-dependent (BOLD) signals, cerebral blood flow (CBF), and the cerebral metabolic rate of oxygen (CMRO2) in spontaneously breathing rats under isoflurane anesthesia. Each animal was subjected to a baseline period of six inspired gas conditions (9% O2, 12% O2, 21% O2, 100% O2, 5% CO2, and 10% CO2) followed by a superimposed period of forepaw stimulation. Significant stimulus-evoked fMRI responses were found in the primary somatosensory cortices. Relative fMRI responses to forepaw stimulation varied across gas conditions and were dependent on baseline physiology, whereas absolute fMRI responses were similar across moderate gas conditions (12% O2, 21% O2 100% O2, and 5% CO2) and were relatively independent of baseline physiology. Consistent with data obtained using well-established techniques, baseline and stimulus-evoked CMRO2 were invariant across moderate physiological perturbations thereby supporting a CMRO2-fMRI technique for non-invasive CMRO2 measurement. However, under 9% O2 and 10% CO2, stimulus-evoked CBF and BOLD were substantially reduced and the CMRO2 formalism appeared invalid, likely due to attenuated neurovascular coupling and/or a failure of the model under extreme physiological perturbations. These findings demonstrate that absolute fMRI measurements help distinguish neural from non-neural contributions to the fMRI signals and may lend a more accurate measure of brain activity during states of altered basal physiology. Moreover, since numerous pharmacologic agents, pathophysiological states, and psychiatric conditions alter baseline physiology independent of neural activity, these results have implications for neuroimaging studies using relative fMRI changes to map brain activity.     

BOLD study of stimulation-induced neural activity and resting-state connectivity in medetomidine-sedated rat

Functional magnetic resonance imaging (fMRI) in anesthetized-animals is critical in studying the mechanisms of fMRI and investigating animal models of various diseases. Medetomidine was recently introduced for independent anesthesia for longitudinal (survival) fMRI studies in rats. Since stimulation-induced fMRI signal is anesthesia-dependent and its characteristics in rats under medetomidine are not fully elucidated, the blood oxygenation level dependent (BOLD) fMRI response to electrical forepaw stimulation under medetomidine was systematically investigated at 9.4 T. Robust activations in contralateral primary somatosensory cortex (SI) and thalamus were observed and peaked at the stimulus frequency of 9 Hz. The response in SI saturates at the stimulus strength of 4 mA while that in thalamus monotonically increases. In addition to fMRI data acquired with the forepaw stimulation, data were also acquired during the resting-state to investigate the synchronization of low frequency fluctuations (LFF) in the BOLD signal (<0.08 Hz) in different brain regions. LFF during resting-state have been observed to be synchronized between functionally related brain regions in human subjects while its origin is not fully understood. LFF have not been extensively studied or widely reported in anesthetized-animals. In our data, synchronized LFF of BOLD signals are found in clustered, bilaterally symmetric regions, including SI and caudate-putamen and the magnitude of the LFF is approximately 1.5%, comparable to the stimulation-induced BOLD signals. Similar to resting-state data reported in human subjects, LFF in rats under medetomidine likely reflect functional connectivity of these brain regions.     

BOLD responses to visual stimulation in survivors of childhood cancer

Children surviving certain cancers have a high incidence of cognitive deficits caused by central nervous system (CNS) disease or treatments directed at the CNS. To establish the feasibility of using blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to study cognitive deficits in survivors of childhood cancer, we tested the hypothesis that this population has the same BOLD response to visual stimulation as healthy subjects. We used BOLD fMRI to measure spatial and temporal patterns of brain activity after brief visual stimulation in 16 survivors of childhood cancer, 11 age-similar healthy siblings of survivors, and 16 healthy adults. Functional data for the survivors were analyzed with two general linear models, one used a canonical hemodynamic response function (HRF) and the other used a Fourier set as basis functions. The measured BOLD signal and brain activation patterns were similar in the survivors with both models. The BOLD signal for survivors was qualitatively similar in timing and shape, but there were significant quantitative differences as compared with healthy subjects. The activation was normally located in the primary visual cortex in 13 survivors, but the activation volume was significantly smaller in brain tumor survivors than in other groups. These findings demonstrate the feasibility of using BOLD fMRI to investigate brain function in survivors of childhood cancer. However, fMRI studies in this population must take into account effects of quantitative differences in their BOLD responses as compared to healthy subjects.     

Investigating the post-stimulus undershoot of the BOLD signal--a simultaneous fMRI and fNIRS study

Measuring the hemodynamic response with functional magnetic resonance imaging (fMRI) together with functional near-infrared spectroscopy (fNIRS) may overcome limitations of single-method approaches. Accordingly, we measured the event-related hemodynamic response with both imaging methods simultaneously in young subjects during visual stimulation. An intertrial interval of 60 s was chosen to include the prolonged post-stimulus undershoot of the blood oxygenation level dependent (BOLD) signal. During visual stimulation, the BOLD signal, oxy-, and total hemoglobin (Hb) increased, whereas deoxy-Hb decreased. The post-stimulus period was characterized by an undershoot of the BOLD signal, oxy-Hb, and an overshoot of deoxy-Hb. Total Hb as measured by fNIRS returned to baseline immediately after the end of stimulation. Results suggest that the post-stimulus events as measured by fNIRS are dominated by a prolonged high-level oxygen consumption in the microvasculature. The contribution of a delayed return of blood volume to the BOLD post-stimulus undershoot in post-capillary veins as suggested by the Balloon and Windkessel models remains ambiguous. Temporal changes in the BOLD signal were highly correlated with deoxy-Hb, with lower correlation values for oxy- and total Hb. Furthermore, data show that fNIRS covers the outer 1 cm of the brain cortex. These results were confirmed by simultaneous fMRI/fNIRS measurements during rest. In conclusion, multimodal imaging approaches may contribute to the understanding of neurovascular coupling.     

Single-trial variability in event-related BOLD signals

Most current analysis methods for fMRI data assume a priori knowledge of the time course of the hemodynamic response (HR) to experimental stimuli or events in brain areas of interest. In addition, they typically assume homogeneity of both the HR and the non-HR "noise" signals, both across brain regions and across similar experimental events. When HRs vary unpredictably, from area to area or from trial to trial, an alternative approach is needed. Here, we use Infomax independent component analysis (ICA) to detect and visualize variations in single-trial HRs in event-related fMRI data. Six subjects participated in four fMRI sessions each in which ten bursts of 8-Hz flickering-checkerboard stimulation were presented for 0.5-s (short) or 3-s (long) durations at 30-s intervals. Five axial slices were acquired by a Bruker 3-T magnetic resonance imager at interscan intervals of 500 ms (TR). ICA decomposition of the resulting blood oxygenation level-dependent (BOLD) data from each session produced an independent component active in primary visual cortex (V1) and, in several sessions, another active in medial temporal cortex (MT/V5). Visualizing sets of BOLD response epochs with novel BOLD-image plots demonstrated that component HRs varied substantially and often systematically across trials as well as across sessions, subjects, and brain areas. Contrary to expectation, in four of the six subjects the V1 component HR contained two positive peaks in response to short-stimulus bursts, while components with nearly identical regions of activity in long-stimulus sessions from the same subjects were associated with single-peaked HRs. Thus, ICA combined with BOLD-image visualization can reveal dramatic and unforeseen HR variations not apparent to researchers analyzing their data with event-related response averaging and fixed HR templates.     

Top-down biases win against focal attention in the fusiform face area

Many studies have reported that BOLD activity in visual cortex is enhanced in the presence of selective attention. These reports are seemingly at odds with psychophysical data showing that observers are able to efficiently categorize natural stimuli in the near-absence of focal attention. To reconcile these two lines of evidence, we study the effects of attentional modulation on face-selective responses in the fusiform face area (FFA) using fMRI. Different from previous fMRI studies in which an "attended" condition (where subjects make a behavioral report on faces) is compared to an "unattended" condition (where the faces are task irrelevant), we included a third condition in which focal attention was not fully available to the faces yet they remained task relevant. Thus we were able to distinguish between the effects of spatial attention and a task-based component of attention. Whether or not subjects had to spatially attend to the faces made no difference to the amplitude of BOLD activity in the FFA provided the faces had to be discriminated. As expected, we observed a decrease in BOLD activity in the FFA when faces were task irrelevant. This pattern of modulation of the BOLD response as a function of the subject's behavior was region specific as it did not extend to the parahippocampal place area. These results point to a coherent picture of how spatial attention and top-down task-based attention interact in visual cortex.     

Nonlinear coupling between evoked rCBF and BOLD signals: a simulation study of hemodynamic responses

The aim of this work was to investigate the dependence of BOLD responses on different patterns of stimulus input/neuronal changes. In an earlier report, we described an input-state-output model that combined (i) the Balloon/Windkessel model of nonlinear coupling between rCBF and BOLD signals, and (ii) a linear model of how regional flow changes with synaptic activity. In the present investigation, the input-state-output model was used to explore the dependence of simulated PET (rCBF) and fMRI (BOLD) signals on various parameters pertaining to experimental design. Biophysical simulations were used to estimate rCBF and BOLD responses as functions of (a) a prior stimulus, (b) epoch length (for a fixed SOA), (c) SOA (for a fixed number of events), and (d) stimulus amplitude. We also addressed the notion that a single neuronal response may differ, in terms of the relative contributions of early and late neural components, and investigated the effect of (e) the relative size of the late or "endogenous" neural component. We were interested in the estimated average rCBF and BOLD responses per stimulus or event, not in the statistical efficiency with which these responses are detected. The BOLD response was underestimated relative to rCBF with a preceding stimulus, increasing epoch length, and increasing SOA. Furthermore, the BOLD response showed some highly nonlinear behaviour when varying stimulus amplitude, suggesting some form of hemodynamic "rectification." Finally, the BOLD response was underestimated in the context of large late neuronal components. The difference between rCBF and BOLD is attributed to the nonlinear transduction of rCBF to BOLD signal. Our simulations support the idea that varying parameters that specify the experimental design may have differential effects in PET and fMRI. Moreover, they show that fMRI can be asymmetric in its ability to detect deactivations relative to activations when an absolute baseline is stipulated. Finally, our simulations suggest that relative insensitivity to BOLD signal in specific regions, such as the temporal lobe, may be partly explained by higher cognitive functions eliciting a relatively large late endogenous neuronal component.     

The influence of simultaneous ratings on cortical BOLD effects during painful and non-painful stimulation

This fMRI study investigates the influence of a rating procedure on BOLD signals in common pain-activated cortical brain regions. Painful and non-painful mechanical impact stimuli were applied to the left hand of healthy volunteers. Subjects performed ratings of the perceived intensity during every second stimulation period by operating a visual analogue scale with the right hand. During every other stimulus period the subjects rested passively. Pain and touch stimuli were found to activate the same cortical areas previously defined as the "cortical pain matrix". General Linear Models were used to calculate contrasts between cortical activations during the "rating" and "non-rating" paradigm. In most brain regions activation following pain and touch was stronger during "rating" compared to "non-rating" conditions. Only the responses in the S1 projection field of the stimulated hand following pain were not influenced by the rating procedure. Furthermore, activations in the right and left posterior insular cortex and in the left superior frontal gyrus showed an opposite pattern, namely a stronger BOLD signal during "non-rating". We concluded: (1) Cortical areas regularly activated by painful stimuli may also be activated by touch stimulation. (2) Enhancement of the BOLD contrast by a rating procedure is probably an effect of closer stimulus evaluation and attention focussing. (3) In contrast to most other cortical regions, the posterior insular cortex, which is crucial for the integration of interoceptive afferent input, shows stronger responses in the absence of ratings, which points to a unique role of this region in the processing of somato-visceral information.     

Exploring resting-state functional connectivity with total interdependence

Resting-state fMRI has become a powerful tool for studying network mechanisms of normal brain functioning and its impairments by neurological and psychiatric disorders. Analytically, independent component analysis and seed-based cross correlation are the main methods for assessing the connectivity of resting-state fMRI time series. A feature common to both methods is that they exploit the covariation structures of contemporaneously (zero-lag) measured data but ignore temporal relations that extend beyond the zero-lag. To examine whether data covariations across different lags can contribute to our understanding of functional brain networks, a measure that can uncover the overall temporal relationship between two resting-state BOLD signals is needed. In this paper we propose such a measure referred as total interdependence (TI). Comparing TI with zero-lag cross correlation (CC) we report three results. First, when combined with a random permutation procedure, TI can reveal the amount of temporal relationship between two resting-state BOLD time series that is not captured by CC. Second, comparing resting-state data with task-state data recorded in the same scanning session, we demonstrate that the resting-state functional networks constructed with TI match more precisely the networks activated by the task. Third, TI is shown to be more statistically sensitive than CC and provides better feature vectors for network clustering analysis.     

Linear aspects of transformation from interictal epileptic discharges to BOLD fMRI signals in an animal model of occipital epilepsy

Epileptic disorders manifest with seizures and interictal epileptic discharges (IEDs). The hemodynamic changes that accompany IEDs are poorly understood and may be critical for understanding epileptogenesis. Despite a known linear coupling of the neurovascular elements in normal brain tissues, previous simultaneous electroencephalography (EEG)-functional magnetic resonance imaging (fMRI) studies have shown variable correlations between epileptic discharges and blood oxygenation level-dependent (BOLD) response, partly because most previous studies assumed particular hemodynamic properties in normal brain tissue. The occurrence of IEDs in human subjects is unpredictable. Therefore, an animal model with reproducible stereotyped IEDs was developed by the focal injection of penicillin into the right occipital cortex of rats anesthetized with isoflurane. Simultaneous EEG-fMRI was used to study the hemodynamic changes during IEDs. A hybrid of temporal independent component analysis (ICA) of EEG and spatial ICA of fMRI data was used to correlate BOLD fMRI signals with IEDs. A linear autoregression with exogenous input (ARX) model was used to estimate the hemodynamic impulse response function (HIRF) based on the data from simultaneous EEG-fMRI measurement. Changes in the measured BOLD signal from the right primary visual cortex and bilateral visual association cortices were consistently coupled to IEDs. The linear ARX model was applied here to confirm that a linear transform can be used to study the correlation between BOLD signal and its corresponding neural activity in this animal model of occipital epilepsy.     

Hypercapnic normalization of BOLD fMRI: comparison across field strengths and pulse sequences

The blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signal response to neural stimulation is influenced by many factors that are unrelated to the stimulus. These factors are physiological, such as the resting venous cerebral blood volume (CBV(v)) and vessel size, as well as experimental, such as pulse sequence and static magnetic field strength (B(0)). Thus, it is difficult to compare task-induced fMRI signals across subjects, field strengths, and pulse sequences. This problem can be overcome by normalizing the neural activity-induced BOLD fMRI response by a global hypercapnia-induced BOLD signal. To demonstrate the effectiveness of the BOLD normalization approach, gradient-echo BOLD fMRI at 1.5, 4, and 7 T and spin-echo BOLD fMRI at 4 T were performed in human subjects. For neural stimulation, subjects performed sequential finger movements at 2 Hz, while for global stimulation, subjects breathed a 5% CO(2) gas mixture. Under all conditions, voxels containing primarily large veins and those containing primarily active tissue (i.e., capillaries and small veins) showed distinguishable behavior after hypercapnic normalization. This allowed functional activity to be more accurately localized and quantified based on changes in venous blood oxygenation alone. The normalized BOLD signal induced by the motor task was consistent across different magnetic fields and pulse sequences, and corresponded well with cerebral blood flow measurements. Our data suggest that the hypercapnic normalization approach can improve the spatial specificity and interpretation of BOLD signals, allowing comparison of BOLD signals across subjects, field strengths, and pulse sequences. A theoretical framework for this method is provided.     

Improved spatial localization of post-stimulus BOLD undershoot relative to positive BOLD

The negative blood oxygenation level-dependent (BOLD) signal following the cessation of stimulation (post-stimulus BOLD undershoot) is observed in functional magnetic resonance imaging (fMRI) studies. However, its spatial characteristics are unknown. To investigate this, gradient-echo BOLD fMRI in response to visual stimulus was obtained in isoflurane-anesthetized cats at 9.4 T. Since the middle cortical layer (layer 4) is known to have the highest metabolic and cerebral blood volume (CBV) responses, images were obtained to view the cortical cross-section. Robust post-stimulus BOLD undershoot was observed in all studies, and lasted longer than 30 s after the cessation of 40-60 s stimulation. The magnitude of post-stimulus BOLD undershoot was linearly dependent on echo time with little intercept when extrapolating to TE = 0, indicating that the T2* change is the major cause of the BOLD undershoot. The post-stimulus BOLD undershoot was observed within the cortex and near the surface of the cortex, while the prolonged CBV elevation was observed only at the middle of the cortex. Within the cortex, the largest post-stimulus undershoot was detected at the middle of the cortex, similar to the CBV increase during the stimulation period. Our findings demonstrate that, even though there is significant contribution from pial vessel signals, the post-stimulus undershoot BOLD signal is useful to improve the spatial localization of fMRI to active cortical sites.     

Stimulus-Dependent BOLD and Perfusion Dynamics in Human V1

Blood oxygenation level-dependent (BOLD) fMRI signals often exhibit pronounced over- or undershoot upon changes in stimulation state. Current models postulate that this is due to the delayed onset or decay of perfusion-dependent attenuating responses such as increased cerebral blood volume or oxygen consumption, which are presumed to lag behind the rapid adjustment of blood flow rate to a new steady-state level. If this view is correct, then BOLD overshoot amplitudes in a specific tissue volume should be correlated with steady-state increases in perfusion, independent of stimulus type. To test this prediction, we simultaneously recorded BOLD and relative perfusion signals in primary visual cortex while inducing graded perfusion increases with three types of visual stimulus. Two of these, a diffuse chromatic stimulus with no luminance variation and a very high spatial frequency luminance grating, did not produce detectable BOLD overshoot (or undershoot) when an equal mean luminance baseline was used. Radial checkerboard stimuli, however, caused pronounced over/undershoot of both BOLD and perfusion signals even when temporal mean luminance was held constant and stimulus contrast was adjusted to produce the same steady-state blood flow increases evoked by the other stimuli. Transient amplitudes were relatively invariant in spite of large changes in steady-state response, demonstrating nonlinear BOLD and perfusion step responses in human V1. These findings suggest that, rather than a purely tissue-specific biomechanical or metabolic phenomenon, BOLD overshoot and undershoot represent transient features in the perfusion signal whose effects may be amplified by slowly evolving blood volume changes.     

Cerebral blood flow and BOLD responses to a memory encoding task: a comparison between healthy young and elderly adults

Functional magnetic resonance imaging (fMRI) studies of the medial temporal lobe have primarily made use of the blood oxygenation level dependent (BOLD) response to neural activity. The interpretation of the BOLD signal as a measure of medial temporal lobe function can be complicated, however, by changes in the cerebrovascular system that can occur with both normal aging and age-related diseases, such as Alzheimer's disease. Quantitative measures of the functional cerebral blood flow (CBF) response offer a useful complement to BOLD measures and have been shown to aid in the interpretation of fMRI studies. Despite these potential advantages, the application of ASL to fMRI studies of cognitive tasks and at-risk populations has been limited. In this study, we demonstrate the application of ASL fMRI to obtain measures of the CBF and BOLD responses to the encoding of natural scenes in healthy young (mean 25 years) and elderly (mean 74 years) adults. The percent CBF increase in the medial temporal lobe was significantly higher in the older adults, whereas the CBF levels during baseline and task conditions and during a separate resting-state scan were significantly lower in the older group. The older adults also showed slightly higher values for the BOLD response amplitude and the absolute change in CBF, but the age group differences were not significant. The percent CBF and BOLD responses are consistent with an age-related increase in the cerebral metabolic rate of oxygen metabolism (CMRO(2)) response to memory encoding.     

Comparison of BOLD fMRI and MEG characteristics to vibrotactile stimulation

The characteristics of blood oxygenation level-dependent (BOLD) fMRI and magnetoencephalographic (MEG) responses to vibrotactile stimuli in humans were studied and compared. The stimuli, presented with interstimulus intervals (ISIs) ranging from 1 to 5 s, yielded highly reproducible MEG responses, with current dipoles in the primary somatosensory (SI) cortex in all subjects. BOLD fMRI responses to similar stimuli showed substantial intrasubject variation in the activation sites around the SI cortex. BOLD responses were detected in all subjects in the secondary somatosensory (SII) cortices as well, with comparable BOLD response amplitudes to those in the SI cortex. Current dipoles, used to model the MEG signals, were stronger at longer ISIs than shorter ISIs. The BOLD response amplitudes did not show a similar dependence on ISI, but the activated brain area was larger when longer ISIs or longer stimuli were applied. Our results support the view that combined use of brain mapping methods provides complementary information and should be considered in functional brain examinations.     

Spatial relationship between neuronal activity and BOLD functional MRI

Despite the ubiquitous use of functional magnetic resonance imaging (fMRI), the extent to which the magnitude and spatial scale of the fMRI signal correlates with neuronal activity is poorly understood. In this study, we directly compared single and multiunit neuronal activity with blood oxygenation level-dependent (BOLD) fMRI responses across a large area of the cat area 18. Our data suggest that at the scale of several millimeters, the BOLD contrast correlates linearly with the underlying neuronal activity. At the level of individual electrode recording sites, however, the correlation between the two signals varied substantially. We conclude from our study that T(2)*-based positive BOLD signals are a robust predictor for neuronal activity only at supra-millimeter spatial scales.     

Coupling between simultaneously recorded BOLD response and neuronal activity in the rat somatosensory cortex

Understanding the link between the hemodynamic response and the underlying neuronal activity is important for interpreting functional magnetic resonance (fMRI) signals in human and animal studies. Simultaneous electrophysiological and functional imaging measurements provide a knowledge of information processing and communication in the brain with high spatial and temporal resolution. In this study, a range of neural and blood oxygenation level-dependent (BOLD) responses were elicited in the rat somatosensory cortex by changing the type of anesthesia (urethane or alpha-chloralose) and the electrical forepaw stimulus frequency (1-15 Hz). Duration of the stimulus was 30 s. Electrical local field potential and BOLD fMRI responses were recorded simultaneously. Under urethane anesthesia, integrated neural activity and BOLD responses increased with increasing stimulus frequency up to 11 Hz, after which both responses plateaued. In contrast, in alpha-chloralose-anesthetized rats both responses were measurable only at 1 and 3 Hz. Although neuronal and BOLD responses were nonlinear as a function of frequency over the 1 to 15 Hz stimulation range under both anesthetics, tight neural-hemodynamic coupling was observed independently of the anesthetic agent. Anesthetic agents influence neuronal activity in a different manner, but the relationship of neuronal activity and BOLD response remains the same.     

A BOLD signature of eyeblinks in the visual cortex

We are usually unaware of the brief but large illumination changes caused by blinks, presumably because of blink suppression mechanisms. In fMRI however, increase of the BOLD signal was reported in the visual cortex, e.g. during blocks of voluntary blinks (Bristow, Frith and Rees, 2005) or after spontaneous blinks recorded during the prolonged fixation of a static stimulus (Tse, Baumgartner and Greenlee, 2010). We tested whether such activation, possibly related to illumination changes, was also present during standard fMRI retinotopic and visual experiments and was large enough to contaminate the BOLD signal we are interested in. We monitored in a 3T scanner the eyeblinks of 14 subjects who observed three different types of visual stimuli, including periodic rotating wedges and contracting/expanding rings, event-related Mondrians and graphemes, while fixating. We performed event-related analyses on the set of detected spontaneous blinks. We observed large and widespread BOLD responses related to blinks in the visual cortex of every subject and whatever the visual stimulus. The magnitude of the modulation was comparable to visual stimulation. However, blink-related activations lay mostly in the anterior parts of retinotopic visual areas, coding the periphery of the visual field well beyond the extent of our stimuli. Blinks therefore represent an important source of BOLD variations in the visual cortex and a troublesome source of noise since any correlation, even weak, between the distribution of blinks and a tested protocol could trigger artifactual activities. However, the typical signature of blinks along the anterior calcarine and the parieto-occipital sulcus allows identifying, even in the absence of eyetracking, fMRI protocols possibly contaminated by a heterogeneous distribution of blinks.     

Caffeine increases the temporal variability of resting-state BOLD connectivity in the motor cortex

Correlations between spontaneous fluctuations in the blood oxygenation level dependent (BOLD) signal measured with functional MRI are finding increasing use as measures of functional connectivity in the brain, where differences can potentially predict cognitive performance and diagnose disease. Caffeine, which is a widely consumed neural stimulant and vasoactive agent, has been found to decrease the amplitude and correlation of resting-state BOLD fluctuations, and hence is an important factor to consider in functional connectivity studies. However, because the BOLD signal is sensitive to neural and vascular factors, the physiological mechanisms by which caffeine alters spontaneous BOLD fluctuations remain unclear. Resting-state functional connectivity has traditionally been assessed using stationary measures, such as the correlation coefficient between BOLD signals measured across the length of a scan. However, recent work has shown that the correlation of resting-state networks can vary considerably over time, with periods as short as 10 s. In this study, we used a sliding window correlation analysis to assess temporal variations in resting-state functional connectivity of the motor cortex before and after caffeine ingestion. We found that the temporal variability of BOLD correlation was significantly higher following a caffeine dose, with transient periods of strong correlation alternating with periods of low or negative correlation. This phenomenon was primarily due to increased variability in the phase difference between BOLD time courses in the left and right motor cortices. These results indicate that caffeine may cause underlying spontaneous neural fluctuations to go in and out of coherence more frequently, and emphasizes the need to consider non-stationary measures when studying changes in functional connectivity.     

Spatio-temporal information analysis of event-related BOLD responses

A new approach for analysis of event-related fMRI (BOLD) signals is proposed. The technique is based on measures from information theory and is used both for spatial localization of task-related activity, as well as for extracting temporal information regarding the task-dependent propagation of activation across different brain regions. This approach enables whole brain visualization of voxels (areas) most involved in coding of a specific task condition, the time at which they are most informative about the condition, as well as their average amplitude at that preferred time. The approach does not require prior assumptions about the shape of the hemodynamic response function (HRF) nor about linear relations between BOLD response and presented stimuli (or task conditions). We show that relative delays between different brain regions can also be computed without prior knowledge of the experimental design, suggesting a general method that could be applied for analysis of differential time delays that occur during natural, uncontrolled conditions. Here we analyze BOLD signals recorded during performance of a motor learning task. We show that, during motor learning, the BOLD response of unimodal motor cortical areas precedes the response in higher-order multimodal association areas, including posterior parietal cortex. Brain areas found to be associated with reduced activity during motor learning, predominantly in prefrontal brain regions, are informative about the task typically at significantly later times.