Sónia I. Gonçalves

The hemodynamic response of the alpha rhythm: An EEG/fMRI study

EEG was recorded during fMRI scanning of 16 normal controls in resting condition with eyes closed. Time variations of the occipital alpha band amplitudes were correlated to the fMRI signal variations to obtain insight into the hemodynamic correlates of the EEG alpha activity. Contrary to earlier studies, no a priori assumptions were made on the expected shape of the alpha band response function (ARF). The ARF of different brain regions and subjects were explored and compared. It was found that: (1) the ARF of the thalamus is mainly positive. (2) The ARFs at the occipital and left and right parietal points are similar in amplitude and timing. (3) The peak time of the thalamus is a few seconds earlier than that of occipital and parietal cortex. (4) No systematic BOLD activity was found preceding the alpha band activity, although in the two subjects with the strongest alpha band power such correlation was present. (5) There is a strong and immediate positive correlation at the eyeball, and a strong negative correlation at the back of the eye. Furthermore, it was found that in one subject the cortical ARF was positive, contrary to the other subjects. Finally, a cluster analysis of the observed ARF, in combination with a Modulated Sine Model (MSM) fit to the estimated ARF, revealed that within the cortex the ARF peak time shows a spatial pattern that may be interpreted as a traveling wave. The spatial pattern of alpha band response function represents the combined effect of local differences in electrical alpha band activity and local differences in the hemodynamic response function (HRF) onto these electrical activities. To disentangle the contributions of both factors, more advanced integration of EEG inverse modeling and hemodynamic response modeling is required in future studies.

Novel artefact removal algorithms for co-registered EEG/fMRI based on selective averaging and subtraction.

Co-registered EEG and functional MRI (EEG/fMRI) is a potential clinical tool for planning invasive EEG in patients with epilepsy. In addition, the analysis of EEG/fMRI data provides a fundamental insight into the precise physiological meaning of both fMRI and EEG data. Routine application of EEG/fMRI for localization of epileptic sources is hampered by large artefacts in the EEG, caused by switching of scanner gradients and heartbeat effects. Residuals of the ballistocardiogram (BCG) artefacts are similarly shaped as epileptic spikes, and may therefore cause false identification of spikes. In this study, new ideas and methods are presented to remove gradient artefacts and to reduce BCG artefacts of different shapes that mutually overlap in time. Gradient artefacts can be removed efficiently by subtracting an average artefact template when the EEG sampling frequency and EEG low-pass filtering are sufficient in relation to MR gradient switching (Gonçalves et al., 2007). When this is not the case, the gradient artefacts repeat themselves at time intervals that depend on the remainder between the fMRI repetition time and the closest multiple of the EEG acquisition time. These repetitions are deterministic, but difficult to predict due to the limited precision by which these timings are known. Therefore, we propose to estimate gradient artefact repetitions using a clustering algorithm, combined with selective averaging. Clustering of the gradient artefacts yields cleaner EEG for data recorded during scanning of a 3T scanner when using a sampling frequency of 2048 Hz. It even gives clean EEG when the EEG is sampled with only 256 Hz. Current BCG artefacts-reduction algorithms based on average template subtraction have the intrinsic limitation that they fail to deal properly with artefacts that overlap in time. To eliminate this constraint, the precise timings of artefact overlaps were modelled and represented in a sparse matrix. Next, the artefacts were disentangled with a least squares procedure. The relevance of this approach is illustrated by determining the BCG artefacts in a data set consisting of 29 healthy subjects recorded in a 1.5 T scanner and 15 patients with epilepsy recorded in a 3 T scanner. Analysis of the relationship between artefact amplitude, duration and heartbeat interval shows that in 22% (1.5T data) to 30% (3T data) of the cases BCG artefacts show an overlap. The BCG artefacts of the EEG/fMRI data recorded on the 1.5T scanner show a small negative correlation between HBI and BCG amplitude. In conclusion, the proposed methodology provides a substantial improvement of the quality of the EEG signal without excessive computer power or additional hardware than standard EEG-compatible equipment.

Dynamics of epileptic activity in a peculiar case of childhood absence epilepsy and correlation with thalamic levels of GABA.

Objectives Childhood absence epilepsy (CAE) is a syndrome with well-defined electroclinical features but unknown pathological basis. An increased thalamic tonic GABA inhibition has recently been discovered on animal models (Cope et al., 2009), but its relevance for human CAE is unproven. Methods We studied an 11-year-old boy, presenting the typical clinical features of CAE, but spike–wave discharges (SWD) restricted to one hemisphere. Results High-resolution EEG failed to demonstrate independent contralateral hemisphere epileptic activity. Consistently, simultaneous EEG–fMRI revealed the typical thalamic BOLD activation, associated with caudate and default mode network deactivation, but restricted to the hemisphere with SWD. Cortical BOLD activations were localized on the ipsilateral pars transverse. Magnetic resonance spectroscopy, using MEGA-PRESS, showed that the GABA/creatine ratio was 2.6 times higher in the hemisphere with SWD than in the unaffected one, reflecting a higher GABA concentration. Similar comparisons for the patients occipital cortex and thalamus of a healthy volunteer yielded asymmetries below 25%. Significance In a clinical case of CAE with EEG and fMRI-BOLD manifestations restricted to one hemisphere, we found an associated increase in thalamic GABA concentration consistent with a role for this abnormality in human CAE.

Brain and behaviour phenotyping of a mouse model of neurofibromatosis type-1: an MRI/DTI study on social cognition

Neurofibromatosis type‐1 (NF1) is a common neurogenetic disorder and an important cause of intellectual disability. Brain‐behaviour associations can be examined in vivo using morphometric magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) to study brain structure. Here, we studied structural and behavioural phenotypes in heterozygous Nf1 mice (Nf1+/−) using T2‐weighted imaging MRI and DTI, with a focus on social recognition deficits. We found that Nf1+/− mice have larger volumes than wild‐type (WT) mice in regions of interest involved in social cognition, the prefrontal cortex (PFC) and the caudate‐putamen (CPu). Higher diffusivity was found across a distributed network of cortical and subcortical brain regions, within and beyond these regions. Significant differences were observed for the social recognition test. Most importantly, significant structure–function correlations were identified concerning social recognition performance and PFC volumes in Nf1+/− mice. Analyses of spatial learning corroborated the previously known deficits in the mutant mice, as corroborated by platform crossings, training quadrant time and average proximity measures. Moreover, linear discriminant analysis of spatial performance identified 2 separate sub‐groups in Nf1+/− mice. A significant correlation between quadrant time and CPu volumes was found specifically for the sub‐group of Nf1+/− mice with lower spatial learning performance, suggesting additional evidence for reorganization of this region. We found strong evidence that social and spatial cognition deficits can be associated with PFC/CPu structural changes and reorganization in NF1.

MR fat fraction mapping: a simple biomarker for liver steatosis quantification in nonalcoholic fatty liver disease patients.

RATIONALE AND OBJECTIVES To assess the performance, postprocessing time, and intra- and interobserver agreement of a simple magnetic resonance-based mapping technique to quantify liver fat. MATERIALS AND METHODS This prospective, single-center study included 26 patients who were overweight with type 2 diabetes and at risk for nonalcoholic fatty liver disease. Mapping of the liver was based on a triple echo gradient-echo sequence, and (1)H magnetic resonance spectroscopy was used as the reference standard. The nonparametric Spearman correlation coefficient and the Wilcoxon test were used for comparisons between mapping and spectroscopy. The mapping was assessed for its predictive performance using the area under the curve of a receiver operating characteristic curve. Intraclass correlation coefficients were used to calculate intra- and interobservers agreement for mapping measurements. RESULTS Patients had a mean fat percentage of 11.7% (range, 2-35.4%). A strong correlation was seen between mapping and spectroscopy (r = 0.89, P < .0001). A cutoff of 6.9% for fat fraction mapping was found to diagnose steatosis with 93% sensitivity and 100% specificity with an area under the curve of 0.99. Mapping of the liver had shorter acquisition and post-processing times than spectroscopy (5 min vs. 38 min; P < .0001). Mapping measurements had an intra- and interobserver agreement of 0.98 and 0.99, respectively. CONCLUSIONS The magnetic resonance-based liver mapping can accurately quantify liver fat with a cutoff value of 6.9% and excellent intra- and interobserver agreement. This mapping technique, with its simple methodology and short postprocessing time, has the potential to be included in routine abdominal protocols.

Signal processing aspects of simultaneously recorded EEG, PULSE and fMRI

Recording of EEG during fMRI scanning is a recent technique that provides new perspectives on the underlying generators of classical EEG phenomena appearing in spontaneous brain activity, such as the alpha rhythm, interictal spikes and sleep spindles. The theoretical principle, on which the method is based, is quite simple. By making a statistical comparison between fMRI scans in which the EEG-phenomenon is present and in which it is absent, and detecting the voxels in which this difference is significant, one can localize the brain regions involved in the generation of the EEG phenomenon under study. Furthermore, one can determine whether the phenomenon corresponds to an activation or a de-activation of the brain region. In practice, however, there are many bio-signal processing problems to be solved: the artifact removal in the EEG, the demodulation of the EEG, the extraction of an EEG reference from the multi-channels, the determination of a sensible correlation co-efficient (in which heart beat effects and breathing are eliminated) and its statistical significance. In this paper, several innovations concerning the signal processing of simultaneously recorded fMRI, PULSE and fMRI are presented and applied in a case study on the generators of the alpha-rhythm

A whole brain longitudinal study in the YAC128 mouse model of Huntington’s disease shows distinct trajectories of neurochemical, structural connectivity and volumetric changes

Huntingtons disease (HD) is a neurodegenerative disorder causing cognitive and motor impairments, evolving to death within 15-20 years after symptom onset. We previously established a mouse model with the entire human HD gene containing 128 CAG repeats (YAC128) which accurately recapitulates the natural history of the human disease. Defined time points in this natural history enable the understanding of longitudinal trajectories from the neurochemical and structural points of view using non-invasive high-resolution multi-modal imaging. Accordingly, we designed a longitudinal structural imaging (MRI and DTI) and spectroscopy (1H-MRS) study in YAC128, at 3, 6, 9 and 12 months of age, at 9.4 T. Structural analysis (MRI/DTI), confirmed that the striatum is the earliest affected brain region, but other regions were also identified through connectivity analysis (pre-frontal cortex, hippocampus, globus pallidus and thalamus), suggesting a striking homology with the human disease. Importantly, we found for the first time, a negative correlation between striatal and hippocampal changes only in YAC128. In fact, the striatum showed accelerated volumetric decay in HD, as opposed to the hippocampus. Neurochemical analysis of the HD striatum suggested early neurometabolic alterations in neurotransmission and metabolism, with a significant increase in striatal GABA levels, and specifically anticorrelated levels of N-acetyl aspartate and taurine, suggesting that the later is homeostatically adjusted for neuroprotection, as neural loss, indicated by the former, is progressing. These results provide novel insights into the natural history of HD and prove a valuable role for longitudinal multi-modal panels of structural and metabolite/neurotransmission in the YAC128 model.

Methylglyoxal-induced glycation changes adipose tissue vascular architecture, flow and expansion, leading to insulin resistance

Microvascular dysfunction has been suggested to trigger adipose tissue dysfunction in obesity. This study investigates the hypothesis that glycation impairs microvascular architecture and expandability with an impact on insulin signalling. Animal models supplemented with methylglyoxal (MG), maintained with a high-fat diet (HFD) or both (HFDMG) were studied for periepididymal adipose (pEAT) tissue hypoxia and local and systemic insulin resistance. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to quantify blood flow in vivo, showing MG-induced reduction of pEAT blood flow. Increased adipocyte size and leptin secretion were observed only in rats feeding the high-fat diet, without the development of hypoxia. In turn, hypoxia was only observed when MG was combined (HFDMG group), being associated with impaired activation of the insulin receptor (Tyr1163), glucose intolerance and systemic and muscle insulin resistance. Accordingly, the adipose tissue angiogenic assay has shown decreased capillarization after dose-dependent MG exposure and glyoxalase-1 inhibition. Thus, glycation impairs adipose tissue capillarization and blood flow, hampering its expandability during a high-fat diet challenge and leading to hypoxia and insulin resistance. Such events have systemic repercussions in glucose metabolism and may lead to the onset of unhealthy obesity and progression to type 2 diabetes.