Noninvasive fMRI investigation of interaural level difference processing the rat auditory subcortex

published_or_final_versio

Resting-state fMRI using passband balanced steady-state free precession

OBJECTIVE: Resting-state functional MRI (rsfMRI) has been increasingly used for understanding brain functional architecture. To date, most rsfMRI studies have exploited blood oxygenation level-dependent (BOLD) contrast using gradient-echo (GE) echo planar imaging (EPI), which can suffer from image distortion and signal dropout due to magnetic susceptibility and inherent long echo time. In this study, the feasibility of passband balanced steady-state free precession (bSSFP) imaging for distortion-free and high-resolution rsfMRI was investigated. METHODS: rsfMRI was performed in humans at 3 T and in rats at 7 T using bSSFP with short repetition time (TR = 4/2.5 ms respectively) in comparison with conventional GE-EPI. Resting-state networks (RSNs) were detected using independent component analysis. RESULTS AND SIGNIFICANCE: RSNs derived from bSSFP images were shown to be spatially and spectrally comparable to those derived from GE-EPI images with considerable intra- and inter-subject reproducibility. High-resolution bSSFP images corresponded well to the anatomical images, with RSNs exquisitely co-localized to the gray matter. Furthermore, RSNs at areas of severe susceptibility such as human anterior prefrontal cortex and rat piriform cortex were proved accessible. These findings demonstrated for the first time that passband bSSFP approach can be a promising alternative to GE-EPI for rsfMRI. It offers distortion-free and high-resolution RSNs and is potentially suited for high field studies.published_or_final_versio

Brain resting-state functional MRI connectivity: Morphological foundation and plasticity

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Early Stage Alterations in White Matter and Decreased Functional Interhemispheric Hippocampal Connectivity in the 3xTg Mouse Model of Alzheimer’s Disease

Alzheimer’s disease (AD) is characterized in the late stages by amyloid-β (Aβ) plaques and neurofibrillary tangles. Nevertheless, recent evidence has indicated that early changes in cerebral connectivity could compromise cognitive functions even before the appearance of the classical neuropathological features. Diffusion tensor imaging (DTI), resting-state functional magnetic resonance imaging (rs-fMRI) and volumetry were performed in the triple transgenic mouse model of AD (3xTg-AD) at 2 months of age, prior to the development of intraneuronal plaque accumulation. We found the 3xTg-AD had significant fractional anisotropy (FA) increase and radial diffusivity (RD) decrease in the cortex compared with wild-type controls, while axial diffusivity (AD) and mean diffusivity (MD) were similar. Interhemispheric hippocampal connectivity was decreased in the 3xTg-AD while connectivity in the caudate putamen (CPu) was similar to controls. Most surprising, ventricular volume in the 3xTg-AD was four times larger than controls. The results obtained in this study characterize the early stage changes in interhemispheric hippocampal connectivity in the 3xTg-AD mouse that could represent a translational biomarker to human models in preclinical stages of the AD

Methodological considerations for fMRI studies of pitch processing

Four functional magnetic resonance imaging (fMRI) studies of pitch processing in auditory cortex were designed to reduce the impact of a number of methodological issues that have hitherto limited previous research findings. Due to adaptation effects, it is necessary to repeatedly present short stimulus bursts rather than long-duration stimuli. Thus, conventionally, in neuroimaging studies of pitch perception, a number of short bursts of the pitch stimulus, separated by silent intervals, are compared to a Gaussian noise presented in the same way. The results of the first experiment indicate that replacing the silent intervals with an energetically matched noise context increases the pitch-specific response by removing the 'energy-onset response' that saturates the overall response if silent intervals are used. In the second experiment, a particular pitch-evoking stimulus, iterated ripple noise (IRN), which is commonly used in neuroimaging studies of pitch perception, was examined. Hall and Plack (Cerebral Cortex 2009;19:576-585) showed that IRN contains slowly varying spectro-temporal features unrelated to pitch, and suggested that these features could account for at least some of the cortical activation produced by IRN. The results support this hypothesis, but also suggest that there is an additional pitch-dependent effect in the same region of auditory cortex.The third experiment assessed the effect of using a different control stimulus to the usual Gaussian noise. The new matched controls were a pulse train with randomly jittered inter-pulse intervals and a random-phase unresolved harmonic complex tone. These low-pitch-salience controls were compared to a regular interval pulse train, which is identical to a cosine-phase unresolved harmonic complex tone. The third experiment did not provide evidence for sensitivity to pitch-salience in pitch-responsive regions of auditory cortex. The fourth and final experiment was a factorial design seeking to answer two main questions: 1) Is the pitch-sensitive region of auditory cortex responsive to the salience of other sound features (e.g. modulation)? 2) Are the responses to pitch and to modulation within this region co-located? Two different pitch-evoking stimuli with different levels of pitch salience were used, presented in a noise context. Results indicate that the pitch-sensitive region contains representations for both pitch and modulation. Furthermore, there was no evidence for an interaction between pitch and modulation, suggesting that the two responses are independent. Overall, the results suggest that careful stimulus design, and appropriate experimental control, is necessary to obtain reliable information on the cortical response to pitch. In addition, the results have shed further light on the likely neural substrates of pitch processing in the cortex.EThOS - Electronic Theses Online ServiceMRC Institute of Hearing ResearchGBUnited Kingdo

Form in Darkness: Linking Visual Cortex Structure With Spontaneous Neural Function

Spontaneous neural activity within visual cortex is synchronized at varying spatial scales, from the cytoarchitecural level of individual neurons to the coarse scale of whole regions. The neural basis of this synchronicity remains ambiguous. In this thesis, we focus on the role visual experience plays in organizing the spontaneous activity within the visual system. We start in Chapter 2 by creating a means by which to analyze homologous patches of cortex between sighted and blind individuals, as lack of vision precludes the use of traditional stimulus-driven mapping techniques. We find that anatomy alone could indeed predict the retinotopic organization of an individual\u27s striate cortex with an accuracy equivalent to the length of a typical mapping experiment. Chapter 3 applies this approach to analyze the organization of spontaneous signals within the striate cortex of blind and sighted subjects. We find that lack of visual experience produces a subtle change in the pattern of corticocortico correlations only between the hemispheres, and that these correlations are best modeled as function of cortical distance, not retinotopy. Chapter 4 expands our analysis to include areas V2 and V3. Here, we find that persistent visual experience supports network-level neural synchrony between spatially distributed cortical visual areas at both a coarse (regional) and fine (topographic) scale. Together, these results allow us model the organization of spontaneous activity in visual cortex as a combination of network signals linked to visual function and intrinsic signals coupled to structural connections. In the final chapter, we examine possible top-down mediators that may further modulate this network-level correlation. Minimal change in synchronicity is observed in a subject with a corpus callosotomy, suggesting the preeminence of bottom-up inputs. Taken together, this work advances our understanding of the origins of coherent spontaneous neural activity within visual cortex

Mechanisms of spatial and non-spatial auditory selective attention

Selective attention is a crucial function that encompasses all perceptual modalities and which enables us to focus on the behaviorally relevant information and ignore the rest. The main goal of the thesis is to test well-established hypotheses about the mechanisms of visual selective attention in the auditory domain using behavioral and neuroimaging methods. Two fMRI studies (Experiments 1 and 2) test the hypothesis of feature-specific attentional enhancement. This hypothesis states that when attending to an object or a feature, there should be an enhancement of the response in the sensory region that is sensitive to that object or feature. Experiment 1 investigated feature-specific attentional modulation mainly within the tonotopic fields around primary auditory cortex. Experiment 2 investigated feature-specific attentional modulation mainly around non-primary auditory cortex, when attending to frequency modulation or motion of the same auditory object. Experiment 1 showed evidence for feature-specific enhancement, while Experiment 2 did not. The role of competition among concurrent auditory objects as a necessary factor in driving feature-specific enhancement is discussed. A second hypothesis from vision research is that spatial perception and attention is much more precise in the centre than in the periphery. Experiment 3 used a masking release paradigm to investigate whether the acuity of auditory spatial attention was similarly increased in the midline. Although location discrimination of sounds segregated by inter-aural time differences was more precise at the midline than at the periphery, spatial attention was not. Therefore for this task at least there was no effect of eccentricity on auditory spatial attention. The results of these three studies are discussed in view of selective attention as a flexible process that operates in different ways according to the specifics of the task

DEVELOPEMENT OF WIDEFIELD MULTI-CONTRAST OPTICAL METHODS FOR IN VIVO MICROVASCULAR SCALE IMAGING

Traditional in vivo optical imaging methods rely on a single contrast mechanism, thereby limiting one’s ability to characterize more than one biological variable. However, most biological systems are complex and are comprised of multiple variables. Therefore, optical methods that employ multiple contrast mechanisms and are capable of visualizing multiple biological variables would permit a more comprehensive understanding of biological systems. Multi-contrast optical imaging, therefore, has great potential for both fundamental and applied biomedical research. The goal of this dissertation is to develop optical methods to enable multi-contrast imaging in vivo over a wide field of view while retaining a microvascular scale spatial resolution. We present the integration of three types of optical imaging contrast mechanisms: fluorescence (FL), intrinsic optical signals (IOS) and laser speckle contrast (LSC). Fluorescence enables tracking pre-labelled molecules and cells, IOS allow quantification of blood volume and/or intravascular oxygen saturation, and LSC permits assessment of tissue perfusion. Together, these contrast mechanisms can be harnessed to provide a more complete picture of the underlying physiology at the microvascular spatial scale. We developed two such microvascular resolution optical multi-contrast imaging methods, and demonstrated their utility in multiple biomedical applications. First, we developed a multi-contrast imaging system that can interrogate in vivo both neural activity and its corresponding microvascular scale hemodynamics in the brain of a freely moving rodent. To do this, we miniaturized an entire benchtop optical imaging system that would typically occupy 5 x 5 x 5 feet, into just 5 cm3. Our miniaturized microscope weighs only 9 g. The miniature size and light weight permitted us to mount our microscope on a rodent’s head and image brain activity in vivo with multiple contrast mechanisms. We used our microscope to study the functional activation of the mouse auditory cortex, and to investigate the alteration of brain function during arousal from deep anesthesia. Our miniaturized microscope is the world’s first rodent head-mountable imaging system capable of interrogating both neural and hemodynamic brain activity. We envision our microscope to usher an exciting new era in neuroscience research. Second, we developed an optical imaging system to extensively characterize microvascular scale hemodynamics in vivo in an orthotopic breast tumor model. We specifically designed it as a benchtop based system to allow ample space for surgical preparation and small animal manipulation. Using it, we continuously monitored in vivo microvascular scale changes in tissue perfusion, blood volume and intravascular oxygen saturation of an orthotopic breast tumor microenvironment for multiple hours over a field of view encompassing the entire tumor extent. This unique dataset enabled us for the first time to characterize the temporal relationship between different tumor hemodynamic variables at the scale of individual microvessels. We envision our work to inspire a whole new avenue of experimental cancer research where the role of a tumor’s hemodynamic microenvironment is extensively characterized at its native (i.e. microvascular) spatial scale. In summary, this dissertation describes the design, implementation and demonstration of two microvascular resolution, wide-field, multi-contrast optical imaging systems. We believe these methods to be a new tool for broadening our understanding of biology