Dynamic spatiotemporal variability of alpha-BOLD relationships during the resting-state and task-evoked responses.

Accurate characterization of the spatiotemporal relationship between two of the most prominent neuroimaging measures of neuronal activity, the 8-13Hz, occipito-parietal EEG alpha oscillation and the BOLD fMRI signal, must encompass the intrinsically dynamic nature of both alpha power and brain function. Here, during the eyes-open resting state, we use a 16s sliding-window analysis and demonstrate that the mean spatial network of dynamic alpha-BOLD correlations is highly comparable to the static network calculated over six minutes. However, alpha-BOLD correlations showed substantial spatiotemporal variability within-subjects and passed through many different configurations such that the static network was fully represented in only ~10% of 16s epochs, with visual and parietal regions (coherent on average) often opposingly correlated with each other or with alpha. We find that the common assumption of static-alpha BOLD correlations greatly oversimplifies temporal variation in brain network dynamics. Fluctuations in alpha-BOLD coupling significantly depended upon the instantaneous amplitude of alpha power, and primary and lateral visual areas were most strongly negatively correlated with alpha during different alpha power states, possibly suggesting the action of multiple alpha mechanisms. Dynamic alpha-BOLD correlations could not be explained by eye-blinks/movements, head motion or non-neuronal physiological variability. Individual's mean alpha power and frequency were found to contribute to between-subject variability in alpha-BOLD correlations. Additionally, application to a visual stimulation dataset showed that dynamic alpha-BOLD correlations provided functional information pertaining to the brain's response to stimulation by exhibiting spatiotemporal fluctuations related to variability in the trial-by-trial BOLD response magnitude. Significantly weaker visual alpha-BOLD correlations were found both preceding and following small amplitude BOLD response trials compared to large response trials.

Global signal modulation of single-trial fMRI response variability: Effect on positive vs negative BOLD response relationship.

In functional magnetic resonance imaging (fMRI), the relationship between positive BOLD responses (PBRs) and negative BOLD responses (NBRs) to stimulation is potentially informative about the balance of excitatory and inhibitory brain responses in sensory cortex. In this study, we performed three separate experiments delivering visual, motor or somatosensory stimulation unilaterally, to one side of the sensory field, to induce PBR and NBR in opposite brain hemispheres. We then assessed the relationship between the evoked amplitudes of contralateral PBR and ipsilateral NBR at the level of both single-trial and average responses. We measure single-trial PBR and NBR peak amplitudes from individual time-courses, and show that they were positively correlated in all experiments. In contrast, in the average response across trials the absolute magnitudes of both PBR and NBR increased with increasing stimulus intensity, resulting in a negative correlation between mean response amplitudes. Subsequent analysis showed that the amplitude of single-trial PBR was positively correlated with the BOLD response across all grey-matter voxels and was not specifically related to the ipsilateral sensory cortical response. We demonstrate that the global component of this single-trial response modulation could be fully explained by voxel-wise vascular reactivity, the BOLD signal standard deviation measured in a separate resting-state scan (resting state fluctuation amplitude, RSFA). However, bilateral positive correlation between PBR and NBR regions remained. We further report that modulations in the global brain fMRI signal cannot fully account for this positive PBR-NBR coupling and conclude that the local sensory network response reflects a combination of superimposed vascular and neuronal signals. More detailed quantification of physiological and noise contributions to the BOLD signal is required to fully understand the trial-by-trial PBR and NBR relationship compared with that of average responses.

Investigating intrinsic connectivity networks using simultaneous BOLD and CBF measurements.

When the sensory cortex is stimulated and directly receiving afferent input, modulations can also be observed in the activity of other brain regions comprising spatially distributed, yet intrinsically connected networks, suggesting that these networks support brain function during task performance. Such networks can exhibit subtle or unpredictable task responses which can pass undetected by conventional general linear modelling (GLM). Additionally, the metabolic demand of these networks in response to stimulation remains incompletely understood. Here, we recorded concurrent BOLD and CBF measurements during median nerve stimulation (MNS) and compared GLM analysis with independent component analysis (ICA) for identifying the spatial, temporal and metabolic properties of responses in the primary sensorimotor cortex (S1/M1), and in the default mode (DMN) and fronto-parietal (FPN) networks. Excellent spatial and temporal agreement was observed between the positive BOLD and CBF responses to MNS detected by GLM and ICA in contralateral S1/M1. Values of the change in cerebral metabolic rate of oxygen consumption (Δ%CMRO2) and the Δ%CMRO2/Δ%CBF coupling ratio were highly comparable when using either GLM analysis or ICA to extract the contralateral S1/M1 responses, validating the use of ICA for estimating changes in CMRO2. ICA identified DMN and FPN network activity that was not detected by GLM analysis. Using ICA, spatially coincident increases/decreases in both BOLD and CBF signals to MNS were found in the FPN/DMN respectively. Calculation of CMRO2 changes in these networks during MNS showed that the Δ%CMRO2/Δ%CBF ratio is comparable between the FPN and S1/M1 but is larger in the DMN than in the FPN, assuming an equal value of the parameter M in the DMN, FPN and S1/M1. This work suggests that metabolism-flow coupling may differ between these two fundamental brain networks, which could originate from differences between task-positive and task-negative fMRI responses, but might also be due to intrinsic differences between the two networks.

Evidence that the negative BOLD response is neuronal in origin: a simultaneous EEG-BOLD-CBF study in humans.

Unambiguous interpretation of changes in the BOLD signal is challenging because of the complex neurovascular coupling that translates changes in neuronal activity into the subsequent haemodynamic response. In particular, the neurophysiological origin of the negative BOLD response (NBR) remains incompletely understood. Here, we simultaneously recorded BOLD, EEG and cerebral blood flow (CBF) responses to 10 s blocks of unilateral median nerve stimulation (MNS) in order to interrogate the NBR. Both negative BOLD and negative CBF responses to MNS were observed in the same region of the ipsilateral primary sensorimotor cortex (S1/M1) and calculations showed that MNS induced a decrease in the cerebral metabolic rate of oxygen consumption (CMRO2) in this NBR region. The ∆CMRO2/∆CBF coupling ratio (n) was found to be significantly larger in this ipsilateral S1/M1 region (n=0.91±0.04, M=10.45%) than in the contralateral S1/M1 (n=0.65±0.03, M=10.45%) region that exhibited a positive BOLD response (PBR) and positive CBF response, and a consequent increase in CMRO2 during MNS. The fMRI response amplitude in ipsilateral S1/M1 was negatively correlated with both the power of the 8-13 Hz EEG mu oscillation and somatosensory evoked potential amplitude. Blocks in which the largest magnitude of negative BOLD and CBF responses occurred therefore showed greatest mu power, an electrophysiological index of cortical inhibition, and largest somatosensory evoked potentials. Taken together, our results suggest that a neuronal mechanism underlies the NBR, but that the NBR may originate from a different neurovascular coupling mechanism to the PBR, suggesting that caution should be taken in assuming the NBR simply represents the neurophysiological inverse of the PBR.

Concordance between distributed EEG source localization and simultaneous EEG-fMRI studies of epileptic spikes.

In order to analyze where epileptic spikes are generated, we assessed the level of concordance between EEG source localization using distributed source models and simultaneous EEG-fMRI which measures the hemodynamic correlates of EEG activity. Data to be compared were first estimated on the same cortical surface and two comparison strategies were used: (1) MEM-concordance: a comparison between EEG sources localized with the Maximum Entropy on the Mean (MEM) method and fMRI clusters showing a significant hemodynamic response. Minimal geodesic distances between local extrema and overlap measurements between spatial extents of EEG sources and fMRI clusters were used to quantify MEM-concordance. (2) fMRI-relevance: estimation of the fMRI-relevance index alpha quantifying if sources located in an fMRI cluster could explain some scalp EEG data, when this fMRI cluster was used to constrain the EEG inverse problem. Combining MEM-concordance and fMRI-relevance (alpha) indexes, each fMRI cluster showing a significant hemodynamic response (p<0.05 corrected) was classified according to its concordance with EEG data. Nine patients with focal epilepsy who underwent EEG-fMRI examination followed by EEG recording outside the scanner were selected for this study. Among the 62 fMRI clusters analyzed (7 patients), 15 (24%) found in 6 patients were highly concordant with EEG according to both MEM-concordance and fMRI-relevance. EEG concordance was found for 5 clusters (8%) according to alpha only, suggesting sources missed by the MEM. No concordance with EEG was found for 30 clusters (48%) and for 10 clusters (16%) alpha was significantly negative, suggesting EEG-fMRI discordance. We proposed two complementary strategies to assess and classify EEG-fMRI concordance. We showed that for most patients, part of the hemodynamic response to spikes was highly concordant with EEG sources, whereas other fMRI clusters in response to the same spikes were found distant or discordant with EEG sources.

Cortical and thalamic fMRI responses in partial epilepsy with focal and bilateral synchronous spikes.

OBJECTIVE: To determine the blood oxygen level-dependent (BOLD) responses to epileptic discharges in the thalamus and cerebral cortex in patients with partial epilepsy. METHODS: Among 64 tested patients, 40 had EEG spikes during scanning and were divided in two groups: unilateral or bilateral independent spikes (29 patients) and bilaterally synchronous spikes (11 patients). Each spike topography was analyzed separately, yielding 40 studies in the first group and 17 in the second. RESULTS: Forty-five percent of focal spike studies showed significant BOLD responses. Cortical activation (positive BOLD) represented the dominant response and had a better correlation with spike location than cortical deactivation (negative BOLD). In the second group, all patients had significant BOLD responses; they were more widespread compared to the first group, and deactivated areas were as important as activated regions. A thalamic response was seen in 12.5% of studies in the first group and 55% in the second. CONCLUSIONS: The thalamus is involved in partial epilepsy during interictal discharges. This involvement and also cortical deactivation are more commonly seen with bilateral spikes than focal discharges. SIGNIFICANCE: These findings show evidence for a role for the thalamus and a more important role for inhibition in secondary bilateral synchrony.

Intrinsic epileptogenicity in polymicrogyric cortex suggested by EEG-fMRI BOLD responses.

Polymicrogyria (PMG) is a widespread cortical malformation frequently associated with seizures and EEG spikes. Its epileptogenicity is poorly understood. Nine patients with simultaneous EEG and fMRI were studied to assess the blood oxygenation level-dependent response to spikes. Sixteen of 18 studies showed responses, with maximum activation involving the lesion in 61.5%, but often limited to a small fraction of that lesion, suggesting intrinsic epileptogenicity in small areas of the PMG cortex.

fMRI activation during spike and wave discharges in idiopathic generalized epilepsy.

The objectives of this study were to evaluate the haemodynamic response of the cerebral cortex and thalamus during generalized spike and wave or polyspike and wave (GSW) bursts in patients with idiopathic generalized epilepsy (IGE). The haemodynamic response is measured by fMRI [blood oxygenation level-dependent (BOLD) effect]. We used combined EEG-functional MRI, a method that allows the unambiguous measurement of the BOLD effect during bursts, compared with measurements during the inter-burst interval. Fifteen patients with IGE had GSW bursts during scanning and technically acceptable studies. fMRI cortical changes as a result of GSW activity were present in 14 patients (93%). Changes in the form of activation (increased BOLD) or deactivation (decreased BOLD) occurred symmetrically in the cortex of both hemispheres, involved anterior as much as posterior head regions, but were variable across patients. Bilateral thalamic changes were also found in 12 patients (80%). Activation predominated over deactivation in the thalamus, whereas the opposite was seen in the cerebral cortex. These results bring a new light to the pathophysiolocal mechanisms generating GSW. The spatial distribution of BOLD responses to GSW was unexpected: it involved as many posterior as anterior head regions, contrary to the usual fronto-central predominance seen in EEG. The presence of a thalamic BOLD response in most patients provided, for the first time in a group of human patients, confirmation of the evidence of thalamic involvement seen in animal models. The possible mechanisms underlying these phenomena are discussed.

A comparison of headnet electrode arrays for electrical impedance tomography of the human head.

Three types of commercially available headnet electrode arrays, designed for use in EEG, and conventional EEG Ag/AgCl cup electrodes were tested on human subjects, and a realistic, saline-filled head-shaped tank was prepared with vegetable skin to simulate human skin in order to determine the optimum electrode system for electrical impedance tomography (EIT) of the human head. Impedance changes during EIT acquisition were produced in healthy volunteers during a finger-thumb apposition task and in tanks by the insertion of a Perspex rod. Signal-to-baseline noise, measured from raw EIT data, was 2.3 +/- 0.3 and 2.3 +/- 0.2 for the human and tank data, respectively. In both the human and tank experiments, a commercial hydrogel elasticated electrode headnet produced the least amount of baseline noise, and was the only headnet in the human data with noise levels acceptable for EIT imaging. Image quality measured in the tank was similar for most of the headnets tested, except that the EEG electrodes produced a higher positional error and electrodes in a geodesic elasticated net produced images with worse subjective image quality. Overall, the hydrogel elasticated headnet was judged to be the most suitable for human neuroimaging with EIT.

The use of skin Fe levels as a surrogate marker for organ Fe levels, to monitor treatment in cases of iron overload.

A system based on the detection of K-shell x-ray fluorescence (XRF) has been used to investigate whether a correlation exists between the concentration of iron in the skin and the concentration of iron in the liver, as the degree of iron loading increases. The motivation behind this work is to develop a non-invasive method of determining the extent of the body's iron stores via measurements on the skin, in order to monitor the efficacy of chelation therapy administered to patients with beta-thalassaemia. Sprague-Dawley rats were iron loaded via injections of iron dextran and subsequently treated with the iron chelator CP94. The non-haem iron concentrations of the liver, heart and spleen were determined using bathophenanthroline sulphonate as the chromogen reagent. Samples of abdominal skin were taken and the iron concentrations determined using XRF. A strong correlation between the skin iron concentration and the liver iron concentration has been demonstrated (R2 = 0.86). Similar correlations exist for the heart and the spleen. These results show that this method holds great potential as a tool in the diagnosis and treatment of hereditary haemochromatosis and beta-thalassaemia.