The impact of physiological noise correction on fMRI at 7 T.

Cognitive neuroimaging studies typically require fast whole brain image acquisition with maximal sensitivity to small BOLD signal changes. To increase the sensitivity, higher field strengths are often employed, since they provide an increased image signal-to-noise ratio (SNR). However, as image SNR increases, the relative contribution of physiological noise to the total time series noise will be greater compared to that from thermal noise. At 7 T, we studied how the physiological noise contribution can be best reduced for EPI time series acquired at three different spatial resolutions (1.1 mm × 1.1 mm × 1.8 mm, 2 mm × 2 mm × 2 mm and 3 mm × 3 mm × 3 mm). Applying optimal physiological noise correction methods improved temporal SNR (tSNR) and increased the numbers of significantly activated voxels in fMRI visual activation studies for all sets of acquisition parameters. The most dramatic results were achieved for the lowest spatial resolution, an acquisition parameter combination commonly used in cognitive neuroimaging which requires high functional sensitivity and temporal resolution (i.e. 3mm isotropic resolution and whole brain image repetition time of 2s). For this data, physiological noise models based on cardio-respiratory information improved tSNR by approximately 25% in the visual cortex and 35% sub-cortically. When the time series were additionally corrected for the residual effects of head motion after retrospective realignment, the tSNR was increased by around 58% in the visual cortex and 71% sub-cortically, exceeding tSNR ~140. In conclusion, optimal physiological noise correction at 7 T increases tSNR significantly, resulting in the highest tSNR per unit time published so far. This tSNR improvement translates into a significant increase in BOLD sensitivity, facilitating the study of even subtle BOLD responses.

Estimating the transfer function from neuronal activity to BOLD using simultaneous EEG-fMRI.

Previous studies using combined electrical and hemodynamic measurements of brain activity, such as EEG and (BOLD) fMRI, have yielded discrepant results regarding the relationship between neuronal activity and the associated BOLD response. In particular, some studies suggest that this link, or transfer function, depends on the frequency content of neuronal activity, while others suggest that total neuronal power accounts for the changes in BOLD. Here we explored this dependency by comparing different frequency-dependent and -independent transfer functions, using simultaneous EEG-fMRI. Our results suggest that changes in BOLD are indeed associated with changes in the spectral profile of neuronal activity and that these changes do not arise from one specific spectral band. Instead they result from the dynamics of the various frequency components together, in particular, from the relative power between high and low frequencies. Understanding the nature of the link between neuronal activity and BOLD plays a crucial role in improving the interpretability of BOLD images as well as on the design of more robust and realistic models for the integration of EEG and fMRI.

The prefrontal cortex: response selection or maintenance within working memory?

It is controversial whether the dorsolateral prefrontal cortex is involved in the maintenance of items in working memory or in the selection of responses. We used event-related functional magnetic resonance imaging to study the performance of a spatial working memory task by humans. We distinguished the maintenance of spatial items from the selection of an item from memory to guide a response. Selection, but not maintenance, was associated with activation of prefrontal area 46 of the dorsal lateral prefrontal cortex. In contrast, maintenance was associated with activation of prefrontal area 8 and the intraparietal cortex. The results support a role for the dorsal prefrontal cortex in the selection of representations. This accounts for the fact that this area is activated both when subjects select between items on working memory tasks and when they freely select between movements on tasks of willed action.

Auditory processing across the sleep-wake cycle: simultaneous EEG and fMRI monitoring in humans.

We combined fMRI and EEG recording to study the neurophysiological responses associated with auditory stimulation across the sleep-wake cycle. We found that presentation of auditory stimuli produces bilateral activation in auditory cortex, thalamus, and caudate during both wakefulness and nonrapid eye movement (NREM) sleep. However, the left parietal and, bilaterally, the prefrontal and cingulate cortices and the thalamus were less activated during NREM sleep compared to wakefulness. These areas may play a role in the further processing of sensory information required to achieve conscious perception during wakefulness. Finally, during NREM sleep, the left amygdala and the left prefrontal cortex were more activated by stimuli having special affective significance than by neutral stimuli. These data suggests that the sleeping brain can process auditory stimuli and detect meaningful events.

Encoding of the temporal regularity of sound in the human brainstem.

We measured the neural activity associated with the temporal structure of sound in the human auditory pathway from cochlear nucleus to cortex. The temporal structure includes regularities at the millisecond level and pitch sequences at the hundreds-of-milliseconds level. Functional magnetic resonance imaging (fMRI) of the whole brain with cardiac triggering allowed simultaneous observation of activity in the brainstem, thalamus and cerebrum. This work shows that the process of recoding temporal patterns into a more stable form begins as early as the cochlear nucleus and continues up to auditory cortex.

Recollection and familiarity in recognition memory: an event-related functional magnetic resonance imaging study.

The question of whether recognition memory judgments with and without recollection reflect dissociable patterns of brain activity is unresolved. We used event-related, functional magnetic resonance imaging (fMRI) of 12 healthy volunteers to measure hemodynamic responses associated with both studying and recognizing words. Volunteers made one of three judgments to each word during recognition: whether they recollected seeing it during study (R judgments), whether they experienced a feeling of familiarity in the absence of recollection (K judgments), or whether they did not remember seeing it during study (N judgments). Both R and K judgments for studied words were associated with enhanced responses in left prefrontal and left parietal cortices relative to N judgments for unstudied words. The opposite pattern was observed in bilateral temporoccipital regions and amygdalae. R judgments for studied words were associated with enhanced responses in anterior left prefrontal, left parietal, and posterior cingulate regions relative to K judgments. At study, a posterior left prefrontal region exhibited an enhanced response to words subsequently given R versus K judgments, but the response of this region during recognition did not differentiate R and K judgments. K judgments for studied words were associated with enhanced responses in right lateral and medial prefrontal cortex relative to both R judgments for studied words and N judgments for unstudied words, a difference we attribute to greater monitoring demands when memory judgments are less certain. These results suggest that the responses of different brain regions do dissociate according to the phenomenology associated with memory retrieval.

Dissociable human perirhinal, hippocampal, and parahippocampal roles during verbal encoding.

The precise contribution of perirhinal cortex to human episodic memory is uncertain. Human intracranial recordings highlight a role in successful episodic memory encoding, but encoding-related perirhinal activation has not been observed with functional imaging. By adapting functional magnetic resonance imaging scanning parameters to maximize sensitivity to medial temporal lobe activity, we demonstrate that left perirhinal and hippocampal responses during word list encoding are greater for subsequently recalled than forgotten words. Although perirhinal responses predict memory for all words, successful encoding of initial words in a list, demonstrating a primacy effect, is associated with parahippocampal and anterior hippocampal activation. We conclude that perirhinal cortex and hippocampus participate in successful memory encoding. Encoding-related parahippocampal and anterior hippocampal responses for initial, remembered words most likely reflects enhanced attentional orienting to these positionally distinctive items.

Action selectivity in parietal and temporal cortex.

The sensory-action theory proposes that the neural substrates underlying action representations are related to a visuomotor action system encompassing the left ventral premotor cortex, the anterior intraparietal (AIP) and left posterior middle temporal gyrus (LPMT). Using fMRI, we demonstrate that semantic decisions on action, relative to non-action words, increased activation in the left AIP and LPMT irrespective of whether the words were presented in a written or spoken form. Left AIP and LPMT might thus play the role of amodal semantic regions that can be activated via auditory as well as visual input. Left AIP and LPMT did not distinguish between different types of actions such as hand actions and whole body movements, although a right STS region responded selectively to whole body movements.

Cortical and subcortical control of tongue movement in humans: a functional neuroimaging study using fMRI.

We have used voluntary tongue contraction to test whether we can image activation of the hypoglossal nuclei within the human brain stem by using functional magnetic resonance imaging (fMRI). Functional images of the whole brain were acquired in eight subjects by using T2-weighted echo planar imaging (blood oxygen level development) every 6.2 s. Sequences of images were acquired during 12 periods of 31-s "isometric" rhythmic tongue contraction alternated with 12 periods of 31-s tongue relaxation. Noise arising from cardiac- and respiratory-related movement was removed either by filtration (high pass; cutoff 120 s) or by inclusion in the statistical analysis as confounding effects of no interest. For the group, tongue contraction was associated with significant signal increases (P < 0.05 corrected for multiple comparisons) in the sensorimotor cortex, supplementary motor area, operculum, insula, thalamus, and cerebellum. For the group and for six of eight individuals, significant signal increases were also seen within the medulla (P < 0.001, predefined region of interest with no correction for multiple comparisons); this signal is most likely to reflect neuronal activation associated with the hypoglossal motor nuclei. The data demonstrate that fMRI can be used to detect, simultaneously, the cerebral and brain stem control of tongue movement.

Blood oxygenation level dependent signal time courses during prolonged visual stimulation.

Previous functional magnetic resonance imaging (MRI) studies using extended visual stimulation have reported disparate results. Two studies have shown that blood oxygen level dependent (BOLD) contrast decays over time which is cited as evidence of recoupling between oxygen utilisation and cerebral blood flow during stimulus presentation. These findings have serious implications for the design of functional MRI experiments because they raise the possibility that BOLD contrast may not accurately reflect neuronal activity. Another study reported no decay of BOLD contrast. These studies used different visual stimuli and imaging techniques. We have performed a series of experiments, using different MRI techniques (echo-planar imaging and fast low angle shot) and two different visual stimuli to assess which of these factors may explain the previous results. In all of our experiments the signal time course from areas of significant activation remained largely elevated throughout the duration of stimulation and this is not affected by the imaging method used. Our data, in accordance with that of Bandettini et al., suggest that recoupling between blood flow and oxygen extraction is not a general phenomenon in the human brain when visual stimuli are presented for an extended time.

Activity in human V1 follows multisensory perception.

When a single brief visual flash is accompanied by two auditory bleeps, it is frequently perceived incorrectly as two flashes. Such illusory multisensory perception is associated with increased activation of retinotopic human primary visual cortex (V1) suggesting that such activity reflects subjective perception [Watkins, S., Shams, L., Tanaka, S., Haynes, J.D., Rees, G., 2006. Sound alters activity in human V1 in association with illusory visual perception. Neuroimage. 31, 1247-1256]. However, an alternate possibility is that increased V1 activity reflects either fluctuating attention or auditory-visual perceptual matching on illusion trials. Here, we rule out these possibilities by studying the complementary illusion, where a double flash is accompanied by a single bleep and perceived incorrectly as a single flash. We replicate findings of increased activity in retinotopic V1 when a single flash is perceived incorrectly as two flashes, and now show that activity is decreased in retinotopic V1 when a double flash is perceived incorrectly as a single flash. Our findings provide strong support for the notion that human V1 activity reflects subjective perception in these multisensory illusions.

Event-related functional magnetic resonance imaging: modelling, inference and optimization.

Event-related functional magnetic resonance imaging is a recent and popular technique for detecting haemodynamic responses to brief stimuli or events. However, the design of event-related experiments requires careful consideration of numerous issues of measurement, modelling and inference. Here we review these issues, with particular emphasis on the use of basis functions within a general linear modelling framework to model and make inferences about the haemodynamic response. With these models in mind, we then consider how the properties of functional magnetic resonance imaging data determine the optimal experimental design for a specific hypothesis, in terms of stimulus ordering and interstimulus interval. Finally, we illustrate various event-related models with examples from recent studies.

Event-related f MRI.

We present a method for detecting event-related responses in functional magnetic resonance imaging (fMRI). The occurrence of time-locked activations is formulated in terms of the general linear model, i.e., multiple linear regression. This permits the use of established statistical techniques that correct for multiple comparisons in the context of spatially smooth and serially correlated data. Responses are modelled using event-related temporal basis functions. Inferences are then made about all components of the model, using the F-ratio at all voxels in the image, to produce a statistical parametric map (SPM{F}). This method allows for the experimental design to relate the timing of events to the acquisition of data to give a temporal resolution (with respect to the event-related response) far better than the scanning repeat time.

A method for removing imaging artifact from continuous EEG recorded during functional MRI.

Combined EEG/fMRI recording has been used to localize the generators of EEG events and to identify subject state in cognitive studies and is of increasing interest. However, the large EEG artifacts induced during fMRI have precluded simultaneous EEG and fMRI recording, restricting study design. Removing this artifact is difficult, as it normally exceeds EEG significantly and contains components in the EEG frequency range. We have developed a recording system and an artifact reduction method that reduce this artifact effectively. The recording system has large dynamic range to capture both low-amplitude EEG and large imaging artifact without distortion (resolution 2 microV, range 33.3 mV), 5-kHz sampling, and low-pass filtering prior to the main gain stage. Imaging artifact is reduced by subtracting an averaged artifact waveform, followed by adaptive noise cancellation to reduce any residual artifact. This method was validated in recordings from five subjects using periodic and continuous fMRI sequences. Spectral analysis revealed differences of only 10 to 18% between EEG recorded in the scanner without fMRI and the corrected EEG. Ninety-nine percent of spike waves (median 74 microV) added to the recordings were identified in the corrected EEG compared to 12% in the uncorrected EEG. The median noise after artifact reduction was 8 microV. All these measures indicate that most of the artifact was removed, with minimal EEG distortion. Using this recording system and artifact reduction method, we have demonstrated that simultaneous EEG/fMRI studies are for the first time possible, extending the scope of EEG/fMRI studies considerably.

Nonlinear event-related responses in fMRI.

This paper presents an approach to characterizing evoked hemodynamic responses in fMRI based on nonlinear system identification, in particular the use of Volterra series. The approach employed enables one to estimate Volterra kernels that describe the relationship between stimulus presentation and the hemodynamic responses that ensue. Volterra series are essentially high-order extensions of linear convolution or "smoothing." These kernels, therefore, represent a nonlinear characterization of the hemodynamic response function that can model the responses to stimuli in different contexts (in this work, different rates of word presentation) and interactions among stimuli. The nonlinear components of the responses were shown to be statistically significant, and the kernel estimates were validated using an independent event-related fMRI experiment. One important manifestation of these nonlinear effects is a modulation of stimulus-specific responses by preceding stimuli that are proximate in time. This means that responses at high-stimulus presentation rates saturate and, in some instances, show an inverted U behavior. This behavior appears to be specific to BOLD effects (as distinct from evoked changes in cerebral blood flow) and may represent a hemodynamic "refractoriness." The aim of this paper is to describe the theory and techniques upon which these conclusions were based and to discuss the implications for experimental design and analysis.

Functional magnetic resonance imaging of the human brain: data acquisition and analysis.

It is now feasible to create spatial maps of activity in the human brain completely non-invasively using magnetic resonance imaging. Magnetic resonance imaging (MRI) images in which the spin magnetization is refocussed by gradient switching are sensitive to local changes in magnetic susceptibility, which can occur when the oxygenation state of blood changes. Cortical neural activity causes increases in blood flow, which usually result in changes in blood oxygenation. Hence changes of image intensity can be observed, given rise to the so-called Blood Oxygenation Level Dependent (BOLD) contrast technique. Use of echo-planar imaging methods (EPI) allows the monitoring over the entire brain of such changes in real time. A temporal resolution of 1-3 s, and a spatial resolution of 2 mm in-plane, can thus be obtained. Generally in a brain mapping experiment hundred of brain image volumes are acquired at repeat times of 1-6 s, while brain tasks are performed. The data are transformed into statistical maps of image difference, using the technique known as statistical parametric mapping (SPM). This method, based on robust multilinear regression techniques, has become the method of reference for analysis of positron emission tomography (PET) image data. The special characteristics of functional MRI data require some modification of SPM algorithms and strategies, and the MRI data must be gaussianized in time and space to conform to the assumptions of the statistics of Gaussian random fields. The steps of analysis comprise: removal of head movement effects, spatial smoothing, and statistical interference, which includes temporal smoothing and removal by fitting of temporal variations slower than the experimental paradigm. By these means, activation maps can be generated with great flexibility and statistical power, giving probability estimates for activated brain regions based on intensity or spatial extent, or both combined. Recent studies have shown that patterns of activation obtained in human brain for a given stimulus are independent of the order and spatial orientation with which MRI images are acquired, and hence that inflow effects are not important for EPI data with a TR much longer than T1.

Learning-related neuronal responses in prefrontal cortex studied with functional neuroimaging.

We assessed time-dependent neuronal activity accompanying learning using functional magnetic resonance imaging (fMRI). An artificial grammar learning paradigm enabled us to dissociate activations associated with individual item learning from those involved in learning the underlying grammar system. We show that a localized region of right prefrontal cortex (PFC) is preferentially sensitive to individual item learning during the early stages of the experiment, while the left PFC region is sensitive to grammar learning which occurred across the entire course of the experiment. In addition to dissociating these two types of learning, we were able to characterize the effect of rule acquisition on neuronal responses associated with explicit learning of individual items. This effect was expressed as modulation of the time-dependent right PFC activations such that the early increase in activation associated with item learning was attenuated as the experiment progressed. In a further analysis we used structural equation modelling to explore time-dependent changes in inter-regional connectivity as a function of both item and grammar rule learning. Although there were no significant effects of item learning on the measured path strengths, rule learning was associated with a decrease in right fronto-parietal connectivity and an increase in connectivity between left and right PFC. Further fronto-parietal path strengths were observed to change, with an increase in left fronto-parietal and a decrease in right fronto-parietal connectivity path strength from right PFC to left parietal cortex. We interpret our findings in terms of a left frontal system mediating the semantic analysis of study items and directly influencing a right fronto-parietal system associated with episodic memory retrieval.

The critical relationship between the timing of stimulus presentation and data acquisition in blocked designs with fMRI.

This paper concerns the experimental design and statistical models employed by fMRI activation studies which block presentation of linguistic stimuli. In particular, we note that the relationship between the timing of stimulus presentation and data acquisition can have a substantial impact on the ability to detect activations in critical language areas, even when the stimuli are presented in blocks. Using a blocked word rhyming paradigm and repeated investigations on a single subject, activation was observed in Broca's area (left inferior frontal cortex) and Wernicke's area (left posterior temporoparietal cortex) when (i) the timing of data acquisition was distributed throughout the peristimulus time and (ii) an event-related analysis was used to model the phasic nature of the hemodynamic response within each block of repeated word stimuli. In contrast, when the timing of data acquisition relative to stimulus presentation was fixed, activation was detected in Broca's area but not consistently in Wernicke's area. Our results indicate that phasic responses to stimuli occur even in a blocked design and that the sampling and proper modeling of these responses can have profound effects on their detection. Specifically, distributed sampling over peristimulus time is essential in order to detect small activations particularly when they are transient. These findings are likely to generalize to the detection of transient signals in any cognitive paradigm.

Compensation of susceptibility-induced BOLD sensitivity losses in echo-planar fMRI imaging.

Gradient-echo echo-planar imaging is a standard technique in functional magnetic resonance imaging (fMRI) experiments based on the blood oxygenation level-dependent (BOLD) effect. A major problem is the occurrence of susceptibility gradients near air/tissue interfaces. As a consequence, the detection of neuronal activation may be greatly compromised in certain brain areas, especially in the temporal lobes and in the orbitofrontal cortex. Common approaches to overcome this problem, such as z-shimming or the use of tailored radio frequency pulses, usually compensate only for susceptibility gradients in the slice selection direction. In the present study, the influence of susceptibility gradients in the phase encoding direction is investigated both theoretically and experimentally. It is shown that these gradients influence the effective echo time TE and may reduce considerably the local BOLD sensitivity, even in the case of acceptable image intensities. A compensation method is proposed and tested in an fMRI experiment based on a hypercapnic challenge. The results suggest that the compensation method allows for the detection of activation in brain areas which are usually unavailable for BOLD studies.

Learning arbitrary visuomotor associations: temporal dynamic of brain activity.

Primates can give behavioral responses on the basis of arbitrary, context-dependent rules. When sensory instructions and behavioral responses are associated by arbitrary rules, these rules need to be learned. This study investigates the temporal dynamics of functional segregation at the basis of visuomotor associative learning in humans, isolating specific learning-related changes in neurovascular activity across the whole brain. We have used fMRI to measure human brain activity during performance of two tasks requiring the association of visual patterns with motor responses. Both tasks were learned by trial and error, either before (visuomotor control) or during (visuomotor learning) the scanning session. Epochs of tasks performance ( approximately 30 s) were alternated with a baseline period over the whole scanning session ( approximately 50 min). We have assessed both linear and nonlinear modulations in the differential signal between tasks, independently from overall task differences. The performance indices of the visuomotor learning task smoothly converged onto the values of a steady-state control condition, according to nonlinear timecourses. Specific visuomotor learning-related activity has been found over a distributed cortical network, centred on a temporo-prefrontal circuit. These cortical time-modulated activities were supported early in learning by the hippocampal/parahippocampal complex, and late in learning by the basal ganglia system. These findings suggest the inferior temporal and the ventral prefrontal cortex are critical neural nodes for integrating perceptual information with executive processes.