Mapping Short Association Fibers in the Early Cortical Visual Processing Stream Using In Vivo Diffusion Tractography

Short association fibers (U-fibers) connect proximal cortical areas and constitute the majority of white matter connections in the human brain. U-fibers play an important role in brain development, function, and pathology but are underrepresented in current descriptions of the human brain connectome, primarily due to methodological challenges in diffusion magnetic resonance imaging (dMRI) of these fibers. High spatial resolution and dedicated fiber and tractography models are required to reliably map the U-fibers. Moreover, limited quantitative knowledge of their geometry and distribution makes validation of U-fiber tractography challenging. Submillimeter resolution diffusion MRI-facilitated by a cutting-edge MRI scanner with 300 mT/m maximum gradient amplitude-was used to map U-fiber connectivity between primary and secondary visual cortical areas (V1 and V2, respectively) in vivo. V1 and V2 retinotopic maps were obtained using functional MRI at 7T. The mapped V1-V2 connectivity was retinotopically organized, demonstrating higher connectivity for retinotopically corresponding areas in V1 and V2 as expected. The results were highly reproducible, as demonstrated by repeated measurements in the same participants and by an independent replication group study. This study demonstrates a robust U-fiber connectivity mapping in vivo and is an important step toward construction of a more complete human brain connectome

Neural Representations of Visual Motion Processing in the Human Brain Using Laminar Imaging at 9.4 Tesla

During natural behavior, much of the motion signal falling into our eyes is due to our own movements. Therefore, in order to correctly perceive motion in our environment, it is important to parse visual motion signals into those caused by self-motion such as eye- or head-movements and those caused by external motion. Neural mechanisms underlying this task, which are also required to allow for a stable perception of the world during pursuit eye movements, are not fully understood. Both, perceptual stability as well as perception of real-world (i.e. objective) motion are the product of integration between motion signals on the retina and efference copies of eye movements. The central aim of this thesis is to examine whether different levels of cortical depth or distinct columnar structures of visual motion regions are differentially involved in disentangling signals related to self-motion, objective, or object motion. Based on previous studies reporting segregated populations of voxels in high level visual areas such as V3A, V6, and MST responding predominantly to either retinal or extra- retinal (‘real’) motion, we speculated such voxels to reside within laminar or columnar functional units. We used ultra-high field (9.4T) fMRI along with an experimental paradigm that independently manipulated retinal and extra-retinal motion signals (smooth pursuit) while controlling for effects of eye-movements, to investigate whether processing of real world motion in human V5/MT, putative MST (pMST), and V1 is associated to differential laminar signal intensities. We also examined motion integration across cortical depths in human motion areas V3A and V6 that have strong objective motion responses. We found a unique, condition specific laminar profile in human area V6, showing reduced mid-layer responses for retinal motion only, suggestive of an inhibitory retinal contribution to motion integration in mid layers or alternatively an excitatory contribution in deep and superficial layers. We also found evidence indicating that in V5/MT and pMST, processing related to retinal, objective, and pursuit motion are either integrated or colocalized at the scale of our resolution. In contrast, in V1, independent functional processes seem to be driving the response to retinal and objective motion on the one hand, and to pursuit signals on the other. The lack of differential signals across depth in these regions suggests either that a columnar rather than laminar segregation governs these functions in these areas, or that the methods used were unable to detect differential neural laminar processing. Furthermore, the thesis provides a thorough analysis of the relevant technical modalities used for data acquisition and data analysis at ultra-high field in the context of laminar fMRI. Relying on our technical implementations we were able to conduct two high-resolution fMRI experiments that helped us to further investigate the laminar organization of self-induced and externally induced motion cues in human high-level visual areas and to form speculations about the site and the mechanisms of their integration

Hybrid-space reconstruction with add-on distortion correction for simultaneous multi-slab diffusion MRI

Purpose: This study aims to propose a model-based reconstruction algorithm for simultaneous multi-slab diffusion MRI acquired with blipped-CAIPI gradients (blipped-SMSlab), which can also incorporate distortion correction. Methods: We formulate blipped-SMSlab in a 4D k-space with kz gradients for the intra-slab slice encoding and km (blipped-CAIPI) gradients for the inter-slab encoding. Because kz and km gradients share the same physical axis, the blipped-CAIPI gradients introduce phase interference in the z-km domain while motion induces phase variations in the kz-m domain. Thus, our previous k-space-based reconstruction would need multiple steps to transform data back and forth between k-space and image space for phase correction. Here we propose a model-based hybrid-space reconstruction algorithm to correct the phase errors simultaneously. Moreover, the proposed algorithm is combined with distortion correction, and jointly reconstructs data acquired with the blip-up/down acquisition to reduce the g-factor penalty. Results: The blipped-CAIPI-induced phase interference is corrected by the hybrid-space reconstruction. Blipped-CAIPI can reduce the g-factor penalty compared to the non-blipped acquisition in the basic reconstruction. Additionally, the joint reconstruction simultaneously corrects the image distortions and improves the 1/g-factors by around 50%. Furthermore, through the joint reconstruction, SMSlab acquisitions without the blipped-CAIPI gradients also show comparable correction performance with blipped-SMSlab. Conclusion: The proposed model-based hybrid-space reconstruction can reconstruct blipped-SMSlab diffusion MRI successfully. Its extension to a joint reconstruction of the blip-up/down acquisition can correct EPI distortions and further reduce the g-factor penalty compared with the separate reconstruction.Comment: 10 figures+tables, 8 supplementary figure

Expanding the role of functional mri in rehabilitation research

Functional magnetic resonance imaging (fMRI) based on blood oxygenation level dependent (BOLD) contrast has become a universal methodology in functional neuroimaging. However, the BOLD signal consists of a mix of physiological parameters and has relatively poor reproducibility. As fMRI becomes a prominent research tool for rehabilitation studies involving repeated measures of the human brain, more quantitative and stable fMRI contrasts are needed. This dissertation enhances quantitative measures to complement BOLD fMRI. These additional markers, cerebral blood flow (CBF) and cerebral blood volume (CBV) (and hence cerebral metabolic rate of oxygen (CMRO₂) modeling) are more specific imaging markers of neuronal activity than BOLD. The first aim of this dissertation assesses feasibility of complementing BOLD with quantitative fMRI measures in subjects with central visual impairment. Second, image acquisition and analysis are developed to enhance quantitative fMRI by quantifying CBV while simultaneously acquiring CBF and BOLD images. This aim seeks to relax assumptions related to existing methods that are not suitable for patient populations. Finally, CBF acquisition using a low-cost local labeling coil, which improves image quality, is combined with simultaneous acquisition of two types of traditional BOLD contrast. The demonstrated enhancement of CBF, CBV and CMRO₂measures can lead to better characterization of pathophysiology and treatment effects.Ph.D.Committee Chair: Hu, Xiaoping; Committee Member: Benkeser, Paul; Committee Member: Keilholz, Shella; Committee Member: Sathian, Krish; Committee Member: Schuchard, Ronal

Imaging the subthalamic nucleus in Parkinson’s disease

This thesis is comprised of a set of work that aims to visualize and quantify the anatomy, structural variability, and connectivity of the subthalamic nucleus (STN) with optimized neuroimaging methods. The study populations include both healthy cohorts and individuals living with Parkinson's disease (PD). PD was chosen specifically due to the involvement of the STN in the pathophysiology of the disease. Optimized neuroimaging methods were primarily obtained using ultra-high field (UHF) magnetic resonance imaging (MRI). An additional component of this thesis was to determine to what extent UHF-MRI can be used in a clinical setting, specifically for pre-operative planning of deep brain stimulation (DBS) of the STN for patients with advanced PD. The thesis collectively demonstrates that i, MRI research, and clinical applications must account for the different anatomical and structural changes that occur in the STN with both age and PD. ii, Anatomical connections involved in preparatory motor control, response inhibition, and decision-making may be compromised in PD. iii. The accuracy of visualizing and quantifying the STN strongly depends on the type of MR contrast and voxel size. iv, MRI at a field strength of 3 Tesla (T) can under certain circumstances be optimized to produce results similar to that of 7 T at the expense of increased acquisition time

Phase imaging for reducing macrovascular signal contributions in high-resolution fMRI

High resolution functional MRI allows for the investigation of neural activity within the cortical sheet. One consideration in high resolution fMRI is the choice of which sequence to use during imaging, as all methods come with sensitivity and specificity tradeoffs. The most used fMRI sequence is gradient-echo echo planar imaging (GE-EPI) which has the highest sensitivity but is not specific to microvasculature. GE-EPI results in a signal with pial vessel bias which increases complexity of performing studies targeted at structures within the cortex. This work seeks to explore the use of MRI phase signal as a macrovascular filter to correct this bias. First, an in-house phase combination method was designed and tested on the 7T MRI system. This method, the fitted SVD method, uses a low-resolution singular value decomposition and fitting to a polynomial basis to provide computationally efficient, phase sensitive, coil combination that is insensitive to motion. Second, a direct comparison of GE-EPI, GE-EPI with phase regression (GE-EPI-PR), and spin echo EPI (SE-EPI) was performed in humans completing a visual task. The GE-EPI-PR activation showed higher spatial similarity with SE-EPI than GE-EPI across the cortical surface. GE-EPI-PR produced a similar laminar profile to SE-EPI while maintaining a higher contrast-to-noise ratio across layers, making it a useful method in low SNR studies such as high-resolution fMRI. The final study extended this work to a resting state macaque experiment. Macaques are a common model for laminar fMRI as they allow for simultaneous imaging and electrophysiology. We hypothesized that phase regression could improve spatial specificity of the resting state data. Further analysis showed the phase data contained both system and respiratory artifacts which prevented the technique performing as expected under two physiological cleaning strategies. Future work will have to examine on-scanner physiology correction to obtain a phase timeseries without artifacts to allow for the phase regression technique to be used in macaques. This work demonstrates that phase regression reduces signal contributions from pial vessels and will improve specificity in human layer fMRI studies. This method can be completed easily with complex fMRI data which can be created using our fitted SVD method

Magnetic Resonance Imaging of the Rat Retina

The retina is a thin layer of tissue lining the back of the eye and is primarily responsible for sight in vertebrates. The neural retina has a distinct layered structure with three dense nuclear layers, separated by plexiform layers comprising of axons and dendrites, and a layer of photoreceptor segments. The retinal and choroidal vasculatures nourish the retina from either side, with an avascular layer comprised largely of photoreceptor cells. Diseases that directly affect the neural retina like retinal degeneration as well as those of vascular origin like diabetic retinopathy can lead to partial or total blindness. Early detection of these diseases can potentially pave the way for a timely intervention and improve patient prognosis. Current techniques of retinal imaging rely mainly on optical techniques, which have limited depth resolution and depend mainly on the clarity of visual pathway. Magnetic resonance imaging is a versatile tool that has long been used for anatomical and functional imaging in humans and animals, and can potentially be used for retinal imaging without the limitations of optical methods. The work reported in this thesis involves the development of high resolution magnetic resonance imaging techniques for anatomical and functional imaging of the retina in rats. The rats were anesthetized using isoflurane, mechanically ventilated and paralyzed using pancuronium bromide to reduce eye motion during retinal MRI. The retina was imaged using a small, single-turn surface coil placed directly over the eye. The several physiological parameters, like rectal temperature, fraction of inspired oxygen, end-tidal CO2, were continuously monitored in all rats. MRI parameters like T1, T2, and the apparent diffusion coefficient of water molecules were determined from the rat retina at high spatial resolution and found to be similar to those obtained from the brain at the same field strength. High-resolution MRI of the retina detected the three layers in wild-type rats, which were identified as the retinal vasculature, the avascular layer and the choroidal vasculature. Anatomical MRI performed 24 hours post intravitreal injection of MnCl2, an MRI contrast agent, revealed seven distinct layers within the retina. These layers were identified as the various nuclear and plexiform layers, the photoreceptor segment layer and the choroidal vasculature using Mn54Cl2 emulsion autoradiography. Blood-oxygenlevel dependent (BOLD) functional MRI (fMRI) revealed layer-specific vascular responses to hyperoxic and hypercapnic challenges. Relative blood volume of the retina calculated by using microcrystalline iron oxide nano-colloid, an intravascular contrast agent, revealed high blood-volume in the choroidal vasculature. Fractional changes to blood volume during systemic challenges revealed a higher degree of autoregulation in the retinal vasculature compared to the choroidal vasculature, corroborating the BOLD fMRI data. Finally, the retinal MRI techniques developed were applied to detect structural and vascular changes in a rat model of retinal dystrophy. We conclude that retinal MRI is a powerful investigative tool to resolve layer-specific structure and function in the retina and to probe for changes in retinal diseases. We expect the anatomical and functional retinal MRI techniques developed herein to contribute towards the early detection of diseases and longitudinal evaluation of treatment options without interference from overlying tissue or opacity of the visual pathway

Magnetic Resonance Imaging of the Rat Retina: a Dissertation

The retina is a thin layer of tissue lining the back of the eye and is primarily responsible for sight in vertebrates. The neural retina has a distinct layered structure with three dense nuclear layers, separated by plexiform layers comprising of axons and dendrites, and a layer of photoreceptor segments. The retinal and choroidal vasculatures nourish the retina from either side, with an avascular layer comprised largely of photoreceptor cells. Diseases that directly affect the neural retina like retinal degeneration as well as those of vascular origin like diabetic retinopathy can lead to partial or total blindness. Early detection of these diseases can potentially pave the way for a timely intervention and improve patient prognosis. Current techniques of retinal imaging rely mainly on optical techniques, which have limited depth resolution and depend mainly on the clarity of visual pathway. Magnetic resonance imaging is a versatile tool that has long been used for anatomical and functional imaging in humans and animals, and can potentially be used for retinal imaging without the limitations of optical methods. The work reported in this thesis involves the development of high resolution magnetic resonance imaging techniques for anatomical and functional imaging of the retina in rats. The rats were anesthetized using isoflurane, mechanically ventilated and paralyzed using pancuronium bromide to reduce eye motion during retinal MRI. The retina was imaged using a small, single-turn surface coil placed directly over the eye. The several physiological parameters, like rectal temperature, fraction of inspired oxygen, end-tidal CO2, were continuously monitored in all rats. MRI parameters like T1, T2, and the apparent diffusion coefficient of water molecules were determined from the rat retina at high spatial resolution and found to be similar to those obtained from the brain at the same field strength. High-resolution MRI of the retina detected the three layers in wild-type rats, which were identified as the retinal vasculature, the avascular layer and the choroidal vasculature. Anatomical MRI performed 24 hours post intravitreal injection of MnCl2, an MRI contrast agent, revealed seven distinct layers within the retina. These layers were identified as the various nuclear and plexiform layers, the photoreceptor segment layer and the choroidal vasculature using Mn54Cl2emulsion autoradiography. Blood-oxygenlevel dependent (BOLD) functional MRI (fMRI) revealed layer-specific vascular responses to hyperoxic and hypercapnic challenges. Relative blood volume of the retina calculated by using microcrystalline iron oxide nano-colloid, an intravascular contrast agent, revealed a superfluous choroidal vasculature. Fractional changes to blood volume during systemic challenges revealed a higher degree of autoregulation in the retinal vasculature compared to the choroidal vasculature, corroborating the BOLD fMRI data. Finally, the retinal MRI techniques developed were applied to detect structural and vascular changes in a rat model of retinal dystrophy. We conclude that retinal MRI is a powerful investigative tool to resolve layerspecific structure and function in the retina and to probe for changes in retinal diseases. We expect the anatomical and functional retinal MRI techniques developed herein to contribute towards the early detection of diseases and longitudinal evaluation of treatment options without interference from overlying tissue or opacity of the visual pathway

The Correlation between Astrocytic Calcium and fMRI Signals is Related to the Thalamic Regulation of Cortical States

BOLD fMRI has been wildly used for mapping brain activity, but the cellular contribution of BOLD signals is still controversial. In this study, we investigated the correlation between neuronal/astrocytic calcium and the BOLD signal using simultaneous GCaMP-mediated calcium and BOLD signal recording, in the event-related state and in resting state, in anesthetized and in free-moving rats. To our knowledge, the results provide the first demonstration that evoked and intrinsic astrocytic calcium signals could occur concurrently accompanied by opposite BOLD signals which are associated with vasodilation and vasoconstriction. We show that the intrinsic astrocytic calcium is involved in brain state changes and is related to the activation of central thalamus. First, by simultaneous LFP and fiber optic calcium recording, the results show that the coupling between LFP and calcium indicates that neuronal activity is the basis of the calcium signal in both neurons and astrocytes. Second, we found that evoked neuronal and astrocytic calcium signals are always positively correlated with BOLD responses. However, intrinsic astrocytic calcium signals are accompanied by the activation of the central thalamus followed by a striking negative BOLD signal in cortex, which suggests that central thalamus may be involved in the initiation of the intrinsic astrocytic calcium signal. Third, we confirmed that the intrinsic astrocytic calcium signal is preserved in free moving rats. Moreover, the occurrences of intrinsic astrocytic calcium spikes are coincident with the transition between different sleep stages, which suggests intrinsic astrocytic calcium spikes reflect brain state transitions. These results demonstrate that the correlation between astrocytic calcium and fMRI signals is related to the thalamic regulation of cortical states. On the other hand, by studying the relationship between vessel–specific BOLD signals and spontaneous calcium activity from adjacent neurons, we show that low frequency spontaneous neuronal activity is the cellular mechanism of the BOLD signal during resting state