Spatio-temporal coupling of the electric and hemodynamic brain responses in humans

Our comprehension of human brain functions and their dynamics has been dramatically improved by recent developments in non-invasive imaging techniques. These methods can be divided into two different categories, according to the nature of the measured signal: hemodynamic techniques, such as functional magnetic resonance imaging (fMRI) and positiron emission tomography (PET), and electromagnetic techniques, such as electroencephalography (EEG) and magnetoencephalography (MEG). These two categories are have complementary characteristics: hemodynamic techniques have a good spatial resolution (on a millimeter spatial scale) but have a poor temporal resolution, which is inherently limited by the rate changes in blood flow and oxygenation. Electromagnetic techniques have sub-millisecond temporal resolution but have a poor spatial resolution, since the analysis of intracranial generators requires the solution of an underdetermined inverse problem (i.e. there are infinite solutions that can explain equally well the same scalp-recorded distribution). The complementarity of the characteristics of these two families of methods allowed researchers to suppose that the understanding of spatio-temporal brain dynamics can be drastically improved by their combination (so-called multimodal imaging). Unfortunately some caveats hinder such combination. First, the nature of neurovascular coupling is still poorly understood. Second, analytical methods for multimodal imaging are largely in their infancy. The first part of this thesis focuses on the analysis of the temporal characteristics of the blood oxygenation level dependent (BOLD) signal and on how they are modulated by stimulus conditions. To analyze the BOLD dynamics, a novel method for synchronizing stimulus delivery and volume acquisition was developed. This method allows for estimating the BOLD signal with a high temporal resolution (in this thesis up to 125 ms) and for studying how the temporal characteristics (in this thesis mainly the BOLD peak latency and slope) are modulated by stimulus conditions (with an approach similar to that used in the analysis of the EEG evoked potentials). We applied this novel technique to a simple reaction time task to lateralized visual stimuli (the so-called Poffenberger paradigm) as well as to a multisensory auditory-visual reaction time task. In the first study (the Poffenberger paradigm) the analysis of BOLD dynamics supported the theory of a bilateral visuo-motor pathway even in the case of a visual stimulus ipsilateral to the responding hand. In the second study, (the auditory-visual multisensory reaction-time task), the analysis showed auditory-visual interactions within both primary auditory and visual cortices that could not be otherwise revealed by traditional fMRI analysis methods since it does not involve changes in signal amplitude. The second part of this thesis focuses on the comparison of the statistical results obtained by the analyses of fMRI and of the intracranial local field potentials (LFPs), estimated by the ELECTRA inverse solution. We first developed a new method for the analysis of EEG data. This method is based on the statistical comparison of the spectral characteristics of the estimated intracranial LFPs of the pre- and post- stimulus onset periods. Each single trial is analyzed independently, without including an averaging step, so that the information carried by high frequencies is preserved. We also propose a new metric, called resemblance, to investigate the relationship between fMRI and the estimated intracranial LFPs. Single-trial analysis and the resemblance metric were applied in an experiment involving separate EEG and fMRI acquisitions during the same passive visual stimulation protocol. This experiment revealed that only a limited set of LFP frequencies shows a spatial correlation with fMRI. This set of frequencies changes across brain areas, such that progression from lower to higher cortical levels of visual processing incorporates at each step new frequencies. In conclusion, in this thesis we show that the estimation and the analysis of the BOLD time course can give an important contribution to better understanding brain functions and brain organization. To fully understand the meaning of changes in BOLD dynamics, we need a better knowledge of the neuro-vascular coupling. To do that, we introduced a new method for evaluating the relationship between EEG and fMRI across frequencies and anatomical regions.

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