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Cerebrovascular reactivity (CVR) reflects the capacity of blood vessels to adjust their caliber in order to maintain a steady supply of brain perfusion, and it may provide a sensitive disease biomarker. Measurement of the blood oxygen level dependent (BOLD) response to a hypercapnia-inducing breath-hold (BH) task has been frequently used to map CVR noninvasively using functional magnetic resonance imaging (fMRI). However, the best modeling approach for the accurate quantification of CVR maps remains an open issue. Here, we compare and optimize Fourier models of the BOLD response to a BH task with a preparatory inspiration, and assess the test-retest reproducibility of the associated CVR measurements, in a group of 10 healthy volunteers studied over two fMRI sessions. Linear combinations of sine-cosine pairs at the BH task frequency and its successive harmonics were added sequentially in a nested models approach, and were compared in terms of the adjusted coefficient of determination and corresponding variance explained (VE) of the BOLD signal, as well as the number of voxels exhibiting significant BOLD responses, the estimated CVR values, and their test-retest reproducibility. The brain average VE increased significantly with the Fourier model order, up to the 3rd order. However, the number of responsive voxels increased significantly only up to the 2nd order, and started to decrease from the 3rd order onwards. Moreover, no significant relative underestimation of CVR values was observed beyond the 2nd order. Hence, the 2nd order model was concluded to be the optimal choice for the studied paradigm. This model also yielded the best test-retest reproducibility results, with intra-subject coefficients of variation of 12 and 16% and an intra-class correlation coefficient of 0.74. In conclusion, our results indicate that a Fourier series set consisting of a sine-cosine pair at the BH task frequency and its two harmonics is a suitable model for BOLD-fMRI CVR measurements based on a BH task with preparatory inspiration, yielding robust estimates of this important physiological parameter.

Several strategies have been proposed to model and remove physiological noise from resting-state fMRI (rs-fMRI) data, particularly at ultrahigh fields (7 Tesla), including contributions from respiratory volume (RV) and heart rate (HR) signal fluctuations. Recent studies suggest that these contributions are highly variable across subjects and that physiological noise correction may thus benefit from optimization at the subject or even voxel level. Here, we systematically investigated the impact of the degree of spatial specificity (group, subject, newly proposed cluster, and voxel levels) on the optimization of RV and HR models. For each degree of spatial specificity, we measured the fMRI signal variance explained (VE) by each model, as well as the functional connectivity underlying three well-known resting-state networks (RSNs) obtained from the fMRI data after removal of RV+HR contributions. Whole-brain, high-resolution rs-fMRI data were acquired from twelve healthy volunteers at 7 Tesla, while simultaneously recording their cardiac and respiratory signals. Although VE increased with spatial specificity up to the voxel level, the accuracy of functional connectivity measurements improved only up to the cluster level, and subsequently decreased at the voxel level. This suggests that voxelwise modeling over-fits to local fluctuations with no physiological meaning. In conclusion, our results indicate that 7 Tesla rs-fMRI connectivity measurements improve if a cluster-based physiological noise correction approach is employed in order to take into account the individual spatial variability in the HR and RV contributions.

The study of spontaneous brain activity based on BOLD-fMRI may be seriously compromised by the presence of signal fluctuations of non-neuronal origin, most prominently due to cardiac and respiratory mechanisms. Methods used for modeling and correction of the so-called physiological noise usually rely on the concurrent measurement of cardiac and respiratory signals. In simultaneous EEG-fMRI recordings, which are primarily aimed at the study of spontaneous brain activity, the electrocardiogram (ECG) is typically measured as part of the EEG setup but respiratory data are not generally available. Here, we propose to use the ECG-derived respiratory (EDR) signal estimated by Empirical Mode Decomposition (EMD) as a surrogate of the respiratory signal, for retrospective physiological noise correction of typical simultaneous EEG-fMRI data. A physiological noise model based on these physiological signals (P-PNM) complemented with fMRI-derived noise regressors was generated, and evaluated, for 17 simultaneous EEG-fMRI datasets acquired from a group of seven epilepsy patients imaged at 3T. The respiratory components of P-PNM were found to explain BOLD variance significantly in addition to the cardiac components, suggesting that the EDR signal was successfully extracted from the ECG, and P-PNM outperformed an image-based model (I-PNM) in terms of total BOLD variance explained. Further, the impact of the correction using P-PNM on fMRI mapping of patient-specific epileptic networks and the resting-state default mode network (DMN) was assessed in terms of sensitivity and specificity and, when compared with an ICA-based procedure and a standard pre-processing pipeline, P-PNM achieved the best performance. Overall, our results support the feasibility and utility of extracting physiological noise models of the BOLD signal resorting to ECG data exclusively, with substantial impact on the simultaneous EEG-fMRI mapping of resting-state networks, and, most importantly, epileptic networks where sensitivity and specificity are still limited.

The ballistocardiogram (BCG) artifact is currently one of the most challenging in the EEG acquired concurrently with fMRI, with correction invariably yielding residual artifacts and/or deterioration of the physiological signals of interest. In this paper, we propose a family of methods whereby the EEG is decomposed using Independent Component Analysis (ICA) and a novel approach for the selection of BCG-related independent components (ICs) is used (PROJection onto Independent Components, PROJIC). Three ICA-based strategies for BCG artifact correction are then explored: 1) BCG-related ICs are removed from the back-reconstruction of the EEG (PROJIC); and 2-3) BCG-related ICs are corrected for the artifact occurrences using an Optimal Basis Set (OBS) or Average Artifact Subtraction (AAS) framework, before back-projecting all ICs onto EEG space (PROJIC-OBS and PROJIC-AAS, respectively). A novel evaluation pipeline is also proposed to assess the methods performance, which takes into account not only artifact but also physiological signal removal, allowing for a flexible weighting of the importance given to physiological signal preservation. This evaluation is used for the group-level parameter optimization of each algorithm on simultaneous EEG-fMRI data acquired using two different setups at 3T and 7T. Comparison with state-of-the-art BCG correction methods showed that PROJIC-OBS and PROJIC-AAS outperformed the others when priority was given to artifact removal or physiological signal preservation, respectively, while both PROJIC-AAS and AAS were in general the best choices for intermediate trade-offs. The impact of the BCG correction on the quality of event-related potentials (ERPs) of interest was assessed in terms of the relative reduction of the standard error (SE) across trials: 26/66%, 32/62% and 18/61% were achieved by, respectively, PROJIC, PROJIC-OBS and PROJIC-AAS, for data collected at 3T/7T. Although more significant improvements were achieved at 7T, the results were qualitatively comparable for both setups, which indicate the wide applicability of the proposed methodologies and recommendations.

The simultaneous recording of scalp electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) can provide unique insights into the dynamics of human brain function, and the increased functional sensitivity offered by ultra-high field fMRI opens exciting perspectives for the future of this multimodal approach. However, simultaneous recordings are susceptible to various types of artifacts, many of which scale with magnetic field strength and can seriously compromise both EEG and fMRI data quality in recordings above 3T. The aim of the present study was to implement and characterize an optimized setup for simultaneous EEG-fMRI in humans at 7 T. The effects of EEG cable length and geometry for signal transmission between the cap and amplifiers were assessed in a phantom model, with specific attention to noise contributions from the MR scanner coldheads. Cable shortening (down to 12 cm from cap to amplifiers) and bundling effectively reduced environment noise by up to 84% in average power and 91% in inter-channel power variability. Subject safety was assessed and confirmed via numerical simulations of RF power distribution and temperature measurements on a phantom model, building on the limited existing literature at ultra-high field. MRI data degradation effects due to the EEG system were characterized via B0 and B1(+) field mapping on a human volunteer, demonstrating important, although not prohibitive, B1 disruption effects. With the optimized setup, simultaneous EEG-fMRI acquisitions were performed on 5 healthy volunteers undergoing two visual paradigms: an eyes-open/eyes-closed task, and a visual evoked potential (VEP) paradigm using reversing-checkerboard stimulation. EEG data exhibited clear occipital alpha modulation and average VEPs, respectively, with concomitant BOLD signal changes. On a single-trial level, alpha power variations could be observed with relative confidence on all trials; VEP detection was more limited, although statistically significant responses could be detected in more than 50% of trials for every subject. Overall, we conclude that the proposed setup is well suited for simultaneous EEG-fMRI at 7 T.

It has recently been proposed that hypocapnic cerebrovascular reactivity (CVR) can be assessed by measuring the blood oxygenation level dependent (BOLD) response to paced deep breathing (PDB) tasks inducing mild hypocapnia and vasoconstriction. In this work, we aim to assess the test–retest reproducibility and inter-subject variability of BOLD CVR measurements obtained using a PDB task and different methods to analyse the associated BOLD signal. The respiratory protocol consisted of alternating 40 s of PDB with normal free breathing; expired CO 2 pressure levels (P ET CO 2 ) were continuously monitored. CVR was quantified using either a timecourse curve analysis (TCA) approach, where the magnitude of response peaks is emphasized, or general linear modelling (GLM) including optimisation of the BOLD response latencies. The GLM fit was carried out using two types of response regressors: one that was computed as the convolution of P ET CO 2 traces with a gamma function and another that consisted of the convolution of PDB paradigm blocks with a physiological model of the respiratory response. Haemodynamic response latencies were optimised either on a voxel basis or for the whole imaging region. We found that the GLM method based on PDB task or P ET CO 2 traces and voxelwise optimisation of response latencies provided the most reproducible measures of CVR. For the average grey matter CVR, the inter-subject coefficient of variation (CV inter ) / intra-subject coefficient of variation (CV intra ) / intra-class correlation coefficient (ICC) were 20%/8%/0.8 and 27%/8%/0.9, using the task and P ET CO 2 timecourses, respectively. In terms of the spatial reproducibility, the group mean (± standard deviation) of the spatial ICC (ICC spatial ) was 1.04 ± 0.23 and 1.02 ± 0.26, for the task and P ET CO 2 timecourses, respectively. These results indicate generally good reproducibility of the hypocapnic CVR maps obtained using the proposed PDB task and analysis methodology. This suggests that such protocol may therefore offer a promising alternative to conventional vasoactive challenges, which avoids their discomfort and difficulty.

Electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) have proved to be extremely valuable tools for the non-invasive study of human brain function. Moreover, due to a notable degree of complementarity between the two modalities, the combination of EEG and fMRI data has been actively sought in the last two decades. Although initially focused on epilepsy, EEG-fMRI applications were rapidly extended to the study of healthy brain function, yielding new insights into its underlying mechanisms and pathways. Nevertheless, EEG and fMRI have markedly different spatial and temporal resolutions, and probe neuronal activity through distinct biophysical processes, many aspects of which are still poorly understood. The remarkable conceptual and methodological challenges associated with EEG-fMRI integration have motivated the development of a wide range of analysis approaches over the years, each relying on more or less restrictive assumptions, and aiming to shed further light on the mechanisms of brain function along with those of the EEG-fMRI coupling itself. Here, we present a review of the most relevant EEG-fMRI integration approaches yet proposed for the study of brain function, supported by a general overview of our current understanding of the biophysical mechanisms coupling the signals obtained from the two modalities.