The brain stands as the most powerful processor in the known universe. It generates a continuous stream of electrical and chemical signals that underpin every thought, sensation, and action. Our past efforts in decoding these signals have made it possible to diagnose and treat many neurological disorders, helped us gain a deeper understanding of cognitive processes and consciousness, and paved the way for brain-computer interfaces. To take another step forward in our long but rewarding journey of discovering the brain's complex organization, we rely on advances in imaging technologies and signal processing.

Functional ultrasound is a neuroimaging technique that has emerged in the last decade, and has gained remarkable attention since then. The popularity of this technique stems from its portability, high resolution and affordability. Functional ultrasound can detect subtle fluctuations in local blood dynamics, which serve as delayed indicators of the underlying changes in neuronal activity. The goal of this thesis is to develop novel signal models and processing algorithms that can reveal the spatial and temporal characteristics of hemodynamic activity induced by external stimuli using functional ultrasound.

Existing techniques that explore how the brain reacts in response to stimuli model the design variables using a linear time-invariant system with binarized input representations, marking when a stimulus is on or off. However, experimental evidence suggests that the brain reacts in a more intricate manner. While some regions exhibit consistent responses to repeated stimuli, others can show substantial variation even when exposed to the same stimulus seconds apart. In our in-vivo experiments, we particularly focus on key regions within the mouse visual processing pathway, which are analogous to those in the human brain. We track how visual information flows across these areas, and propose methods that can incorporate the spatiotemporal variability of brain responses when identifying evoked activity. Using these methods, we show that functional ultrasound can capture the dynamic nature of brain responses with high spatial and temporal resolution, and provide us with further insights into the functional organization of the brain. Future directions of this dissertation include multimodal processing of the functional ultrasound signal together with neuronal activity, aiming to enhance our understanding of neurovascular coupling.@en

Analysis of functional neuroimaging data aims to unveil spatial and temporal patterns of interest. Existing analysis methods fall into two categories: fully data-driven approaches and those reliant on prior information, e.g. the stimulus time course. While using the stimulus signal directly can help identify the activated brain areas, it is known that the relationship between stimuli and the brain's response exhibits nonlinear and time-varying characteristics. As such, relying completely on the stimulus signal to describe the brain's temporal response leads to a restricted interpretation of the brain function. In this paper, we present a new technique called Evoked Component Analysis (ECA), which leverages prior information up to a defined extent. This is achieved by including the general linear model (GLM) design matrix as a regulatory term and estimating the factor matrices in both space and time through an alternating minimization approach. We apply ECA to 2D and swept-3D functional ultrasound (fUS) experiments conducted with mice. When decomposing 2D fUS data, we employ GLM regularization at various intensities to emphasize the role of prior information. Furthermore, we show that incorporating multiple hemodynamic response functions within the design matrix can provide valuable insights into region-specific characteristics of evoked activity. Finally, we use ECA to analyze swept-3D fUS data recorded from five mice engaged in two distinct visual tasks. Swept-3D fUS images the 3D brain sequentially using a moving probe, resulting in different slice acquisition time instants. We show that ECA can estimate factor matrices with a fine resolution at each slice acquisition time instant and yield higher t-statistics compared to GLM and correlation analysis for all subjects.

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Functional ultrasound (fUS) is a high-sensitivity neuroimaging technique that images cerebral blood volume changes, which reflect neuronal activity in the corresponding brain area. fUS measures hemodynamic changes which are typically modeled as the output of a linear time-invariant system, characterized by an impulse response known as the hemodynamic response function (HRF), and a binary representation of the stimulus signal as input. In this work, we quantify the difference between a linear and a nonlinear time-invariant HRF model in terms of data fitting and prediction performance. Our results on fUS data obtained from two mice reveal that: (a) including nonlinearities in the HRF achieves a significantly more precise modeling of the fUS signal compared to the linear assumption under certain stimulus conditions and (b) a second-order Volterra series approximation can be used to characterize the nonlinear model and predict responses to stimuli.

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Functional ultrasound (fUS) is an emerging neuroimaging modality that indirectly measures neural activity by detecting fluctuations in local blood dynamics. fUS acquisitions typically rely on the use of a 1D array transducer, which records hemodynamic activity in a single plane. A new technique named swept-3D fUS imaging obtains a full 3D volume of the brain by continuously moving a 1D array back-and-forth over the volume of interest. The standard procedure in fUS imaging involves filtering and averaging a number of ultrasound frames obtained at a single location to compute power-Doppler images, yet, in case of swept-3D fUS, the location of the recorded slice shifts at each time instant due to probe motion. In this work, we aim at discovering task-relevant components from 3D fUS data while taking into account the spatiotemporal differences in adjacent slices. We propose an alternating optimization scheme with general liner model-based regularization, and validate our method on swept-3D fUS data by identifying active regions and time traces within the mouse brain during a visual experiment.

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Functional ultrasound (fUS) indirectly measures brain activity by detecting changes in cerebral blood volume following neural activation. Conventional approaches model such functional neuroimaging data as the convolution between an impulse response, known as the hemodynamic response function (HRF), and a binarized representation of the input signal based on the stimulus onsets, the so-called experimental paradigm (EP). However, the EP may not characterize the whole complexity of the activity-inducing signals that evoke the hemodynamic changes. Furthermore, the HRF is known to vary across brain areas and stimuli. To achieve an adaptable framework that can capture such dynamics of the brain function, we model the multivariate fUS time-series as convolutive mixtures and apply block-term decomposition on a set of lagged fUS autocorrelation matrices, revealing both the region-specific HRFs and the source signals that induce the hemodynamic responses. We test our approach on two mouse-based fUS experiments. In the first experiment, we present a single type of visual stimulus to the mouse, and deconvolve the fUS signal measured within the mouse brain’s lateral geniculate nucleus, superior colliculus and visual cortex. We show that the proposed method is able to recover back the time instants at which the stimulus was displayed, and we validate the estimated region-specific HRFs based on prior studies. In the second experiment, we alter the location of the visual stimulus displayed to the mouse, and aim at differentiating the various stimulus locations over time by identifying them as separate sources.

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The original version of this article was revised to update the Figure 8 (panel B) image. The correct image should have a yellow shape as presented below. (Figure presented.). The original article has been corrected.

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Neuroimaging techniques are used to image the structure and function of the nervous system for medicine, psychology, and neuroscience research. Brain data are inherently multidimensional and complex, and the recent advances in neuroimaging allow the acquisition of brain signals at an increasing spatiotemporal resolution. Being able to process the resulting large-scale data and capturing the multiway structure of the brain, tensor-based analyses are well suited for a variety of neuroimaging applications. In this review, we provide a comprehensive overview of successful tensor-based solutions used in the field of neuroimaging discuss practical challenges and the future of tensors in medical technology.

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Functional ultrasound (fUS) is an exciting new neuroimaging technique that is able to record brain activity similar to functional magnetic resonance imaging, yet with higher spatiotemporal resolution and at lower cost. We consider the problem of jointly estimating the underlying neural sources and the hemodynamic response function (HRF) from fUS recordings. We propose to model the measured voxel time-series as a convolutive mixture of multiple source signals and solve the blind deconvolution problem via block-term decomposition. This allows us to estimate both the source time courses and a different HRF for each voxel and source combination, which accounts for the variability of HRF across different brain regions and events respectively. The proposed approach is proven to be robust against noise via simulations and further validated on real fUS data by performing a visual experiment on a mouse. The obtained results show that the proposed method is able to recover the timings of the visual paradigm.@en