Wiring and Molecular Features of Prefrontal Ensembles Representing Distinct Experiences.

A major challenge in understanding the cellular diversity of the brain has been linking activity during behavior with standard cellular typology. For example, it has not been possible to determine whether principal neurons in prefrontal cortex active during distinct experiences represent separable cell types, and it is not known whether these differentially active cells exert distinct causal influences on behavior. Here, we develop quantitative hydrogel-based technologies to connect activity in cells reporting on behavioral experience with measures for both brain-wide wiring and molecular phenotype. We find that positive and negative-valence experiences in prefrontal cortex are represented by cell populations that differ in their causal impact on behavior, long-range wiring, and gene expression profiles, with the major discriminant being expression of the adaptation-linked gene NPAS4. These findings illuminate cellular logic of prefrontal cortex information processing and natural adaptive behavior and may point the way to cell-type-specific understanding and treatment of disease-associated states.

Bundle-specific tractogram distribution estimation using higher-order streamline differential equation.

Streamline tractography locally traces peak directions extracted from fiber orientation distribution (FOD) functions, lacking global information about the trend of the whole fiber bundle. Therefore, it is prone to producing erroneous tracks while missing true positive connections. In this work, we propose a new bundle-specific tractography (BST) method based on a bundle-specific tractogram distribution (BTD) function, which directly reconstructs the fiber trajectory from the start region to the termination region by incorporating the global information in the fiber bundle mask. A unified framework for any higher-order streamline differential equation is presented to describe the fiber bundles with disjoint streamlines defined based on the diffusion vectorial field. At the global level, the tractography process is simplified as the estimation of BTD coefficients by minimizing the energy optimization model, and is used to characterize the relations between BTD and diffusion tensor vector under the prior guidance by introducing the tractogram bundle information to provide anatomic priors. Experiments are performed on simulated Hough, Sine, Circle data, ISMRM 2015 Tractography Challenge data, FiberCup data, and in vivo data from the Human Connectome Project (HCP) for qualitative and quantitative evaluation. Results demonstrate that our approach reconstructs complex fiber geometry more accurately. BTD reduces the error deviation and accumulation at the local level and shows better results in reconstructing long-range, twisting, and large fanning tracts.

The effects of axonal beading and undulation on axonal diameter estimation from diffusion MRI: Insights from simulations in human axons segmented from three-dimensional electron microscopy.

The increasing availability of high-performance gradient systems in human MRI scanners has generated great interest in diffusion microstructural imaging applications such as axonal diameter mapping. Practically, sensitivity to axon diameter in diffusion MRI is attained at strong diffusion weightings b , where the deviation from the expected 1 / b scaling in white matter yields a finite transverse diffusivity, which is then translated into an axon diameter estimate. While axons are usually modeled as perfectly straight, impermeable cylinders, local variations in diameter (caliber variation or beading) and direction (undulation) are known to influence axonal diameter estimates and have been observed in microscopy data of human axons. In this study, we performed Monte Carlo simulations of diffusion in axons reconstructed from three-dimensional electron microscopy of a human temporal lobe specimen using simulated sequence parameters matched to the maximal gradient strength of the next-generation Connectome 2.0 human MRI scanner ( ≲ 500 mT/m). We show that axon diameter estimation is accurate for nonbeaded, nonundulating fibers; however, in fibers with caliber variations and undulations, the axon diameter is heavily underestimated due to caliber variations, and this effect overshadows the known overestimation of the axon diameter due to undulations. This unexpected underestimation may originate from variations in the coarse-grained axial diffusivity due to caliber variations. Given that increased axonal beading and undulations have been observed in pathological tissues, such as traumatic brain injury and ischemia, the interpretation of axon diameter alterations in pathology may be significantly confounded.

Role of articulatory motor networks in perceptual categorization of speech signals: a 7T fMRI study.

Speech and language processing involve complex interactions between cortical areas necessary for articulatory movements and auditory perception and a range of areas through which these are connected and interact. Despite their fundamental importance, the precise mechanisms underlying these processes are not fully elucidated. We measured BOLD signals from normal hearing participants using high-field 7 Tesla fMRI with 1-mm isotropic voxel resolution. The subjects performed 2 speech perception tasks (discrimination and classification) and a speech production task during the scan. By employing univariate and multivariate pattern analyses, we identified the neural signatures associated with speech production and perception. The left precentral, premotor, and inferior frontal cortex regions showed significant activations that correlated with phoneme category variability during perceptual discrimination tasks. In addition, the perceived sound categories could be decoded from signals in a region of interest defined based on activation related to production task. The results support the hypothesis that articulatory motor networks in the left hemisphere, typically associated with speech production, may also play a critical role in the perceptual categorization of syllables. The study provides valuable insights into the intricate neural mechanisms that underlie speech processing.

Artificial intelligence for neuro MRI acquisition: a review.

OBJECT: To review recent advances of artificial intelligence (AI) in enhancing the efficiency and throughput of the MRI acquisition workflow in neuroimaging, including planning, sequence design, and correction of acquisition artifacts. MATERIALS AND METHODS: A comprehensive analysis was conducted on recent AI-based methods in neuro MRI acquisition. The study focused on key technological advances, their impact on clinical practice, and potential risks associated with these methods. RESULTS: The findings indicate that AI-based algorithms have a substantial positive impact on the MRI acquisition process, improving both efficiency and throughput. Specific algorithms were identified as particularly effective in optimizing acquisition steps, with reported improvements in workflow efficiency. DISCUSSION: The review highlights the transformative potential of AI in neuro MRI acquisition, emphasizing the technological advances and clinical benefits. However, it also discusses potential risks and challenges, suggesting areas for future research to mitigate these concerns and further enhance AI integration in MRI acquisition.

High-fidelity mesoscale in-vivo diffusion MRI through gSlider-BUDA and circular EPI with S-LORAKS reconstruction.

PURPOSE: To develop a high-fidelity diffusion MRI acquisition and reconstruction framework with reduced echo-train-length for less T2* image blurring compared to typical highly accelerated echo-planar imaging (EPI) acquisitions at sub-millimeter isotropic resolution. METHODS: We first proposed a circular-EPI trajectory with partial Fourier sampling on both the readout and phase-encoding directions to minimize the echo-train-length and echo time. We then utilized this trajectory in an interleaved two-shot EPI acquisition with reversed phase-encoding polarity, to aid in the correction of off-resonance-induced image distortions and provide complementary k-space coverage in the missing partial Fourier regions. Using model-based reconstruction with structured low-rank constraint and smooth phase prior, we corrected the shot-to-shot phase variations across the two shots and recover the missing k-space data. Finally, we combined the proposed acquisition/reconstruction framework with an SNR-efficient RF-encoded simultaneous multi-slab technique, termed gSlider, to achieve high-fidelity 720 µm and 500 µm isotropic resolution in-vivo diffusion MRI. RESULTS: Both simulation and in-vivo results demonstrate the effectiveness of the proposed acquisition and reconstruction framework to provide distortion-corrected diffusion imaging at the mesoscale with markedly reduced T2*-blurring. The in-vivo results of 720 µm and 500 µm datasets show high-fidelity diffusion images with reduced image blurring and echo time using the proposed approaches. CONCLUSIONS: The proposed method provides high-quality distortion-corrected diffusion-weighted images with ∼40% reduction in the echo-train-length and T2* blurring at 500µm-isotropic-resolution compared to standard multi-shot EPI.

3D-EPI blip-up/down acquisition (BUDA) with CAIPI and joint Hankel structured low-rank reconstruction for rapid distortion-free high-resolution T 2 * mapping.

PURPOSE: This work aims to develop a novel distortion-free 3D-EPI acquisition and image reconstruction technique for fast and robust, high-resolution, whole-brain imaging as well as quantitative T 2 * $$ {\mathrm{T}}_2^{\ast } $$ mapping. METHODS: 3D Blip-up and -down acquisition (3D-BUDA) sequence is designed for both single- and multi-echo 3D gradient recalled echo (GRE)-EPI imaging using multiple shots with blip-up and -down readouts to encode B0 field map information. Complementary k-space coverage is achieved using controlled aliasing in parallel imaging (CAIPI) sampling across the shots. For image reconstruction, an iterative hard-thresholding algorithm is employed to minimize the cost function that combines field map information informed parallel imaging with the structured low-rank constraint for multi-shot 3D-BUDA data. Extending 3D-BUDA to multi-echo imaging permits T 2 * $$ {\mathrm{T}}_2^{\ast } $$ mapping. For this, we propose constructing a joint Hankel matrix along both echo and shot dimensions to improve the reconstruction. RESULTS: Experimental results on in vivo multi-echo data demonstrate that, by performing joint reconstruction along with both echo and shot dimensions, reconstruction accuracy is improved compared to standard 3D-BUDA reconstruction. CAIPI sampling is further shown to enhance image quality. For T 2 * $$ {\mathrm{T}}_2^{\ast } $$ mapping, parameter values from 3D-Joint-CAIPI-BUDA and reference multi-echo GRE are within limits of agreement as quantified by Bland-Altman analysis. CONCLUSIONS: The proposed technique enables rapid 3D distortion-free high-resolution imaging and T 2 * $$ {\mathrm{T}}_2^{\ast } $$ mapping. Specifically, 3D-BUDA enables 1-mm isotropic whole-brain imaging in 22 s at 3T and 9 s on a 7T scanner. The combination of multi-echo 3D-BUDA with CAIPI acquisition and joint reconstruction enables distortion-free whole-brain T 2 * $$ {\mathrm{T}}_2^{\ast } $$ mapping in 47 s at 1.1 × 1.1 × 1.0 mm3 resolution.

High-fidelity, high-spatial-resolution diffusion magnetic resonance imaging of ex vivo whole human brain at ultra-high gradient strength with structured low-rank echo-planar imaging ghost correction.

Diffusion magnetic resonance imaging (dMRI) of whole ex vivo human brain specimens enables three-dimensional (3D) mapping of structural connectivity at the mesoscopic scale, providing detailed evaluation of fiber architecture and tissue microstructure at a spatial resolution that is difficult to access in vivo. To account for the short T2 and low diffusivity of fixed tissue, ex vivo dMRI is often acquired using strong diffusion-sensitizing gradients and multishot/segmented 3D echo-planar imaging (EPI) sequences to achieve high spatial resolution. However, the combination of strong diffusion-sensitizing gradients and multishot/segmented EPI readout can result in pronounced ghosting artifacts incurred by nonlinear spatiotemporal variations in the magnetic field produced by eddy currents. Such ghosting artifacts cannot be corrected with conventional correction solutions and pose a significant roadblock to leveraging human MRI scanners with ultrahigh gradients for ex vivo whole-brain dMRI. Here, we show that ghosting-correction approaches that correct for either polarity-related ghosting or shot-to-shot variations in a separate manner are suboptimal for 3D multishot diffusion-weighted EPI experiments in fixed human brain specimens using strong diffusion-sensitizing gradients on the 3-T Connectom MRI scanner, resulting in orientationally biased dMRI estimates. We apply a recently developed advanced k-space reconstruction method based on structured low-rank matrix (SLM) modeling that handles both polarity-related ghosting and shot-to-shot variation simultaneously, to mitigate artifacts in high-angular resolution multishot dMRI data acquired in several fixed human brain specimens at 0.7-0.8-mm isotropic spatial resolution using b-values up to 10,000 s/mm2 and gradient strengths up to 280 mT/m. We demonstrate the improved mapping of diffusion tensor imaging and fiber orientation distribution functions in key neuroanatomical areas distributed across the whole brain using SLM-based EPI ghost correction compared with alternative techniques.

SDnDTI: Self-supervised deep learning-based denoising for diffusion tensor MRI.

Diffusion tensor magnetic resonance imaging (DTI) is a widely adopted neuroimaging method for the in vivo mapping of brain tissue microstructure and white matter tracts. Nonetheless, the noise in the diffusion-weighted images (DWIs) decreases the accuracy and precision of DTI derived microstructural parameters and leads to prolonged acquisition time for achieving improved signal-to-noise ratio (SNR). Deep learning-based image denoising using convolutional neural networks (CNNs) has superior performance but often requires additional high-SNR data for supervising the training of CNNs, which reduces the feasibility of supervised learning-based denoising in practice. In this work, we develop a self-supervised deep learning-based method entitled "SDnDTI" for denoising DTI data, which does not require additional high-SNR data for training. Specifically, SDnDTI divides multi-directional DTI data into many subsets of six DWI volumes and transforms DWIs from each subset to along the same diffusion-encoding directions through the diffusion tensor model, generating multiple repetitions of DWIs with identical image contrasts but different noise observations. SDnDTI removes noise by first denoising each repetition of DWIs using a deep 3-dimensional CNN with the average of all repetitions with higher SNR as the training target, following the same approach as normal supervised learning based denoising methods, and then averaging CNN-denoised images for achieving higher SNR. The denoising efficacy of SDnDTI is demonstrated in terms of the similarity of output images and resultant DTI metrics compared to the ground truth generated using substantially more DWI volumes on two datasets with different spatial resolutions, b-values and numbers of input DWI volumes provided by the Human Connectome Project (HCP) and the Lifespan HCP in Aging. The SDnDTI results preserve image sharpness and textural details and substantially improve upon those from the raw data. The results of SDnDTI are comparable to those from supervised learning-based denoising and outperform those from state-of-the-art conventional denoising algorithms including BM4D, AONLM and MPPCA. By leveraging domain knowledge of diffusion MRI physics, SDnDTI makes it easier to use CNN-based denoising methods in practice and has the potential to benefit a wider range of research and clinical applications that require accelerated DTI acquisition and high-quality DTI data for mapping of tissue microstructure, fiber tracts and structural connectivity in the living human brain.

Estimating axial diffusivity in the NODDI model.

To estimate microstructure-related parameters from diffusion MRI data, biophysical models make strong, simplifying assumptions about the underlying tissue. The extent to which many of these assumptions are valid remains an open research question. This study was inspired by the disparity between the estimated intra-axonal axial diffusivity from literature and that typically assumed by the Neurite Orientation Dispersion and Density Imaging (NODDI) model (d∥=1.7µm2/ms). We first demonstrate how changing the assumed axial diffusivity results in considerably different NODDI parameter estimates. Second, we illustrate the ability to estimate axial diffusivity as a free parameter of the model using high b-value data and an adapted NODDI framework. Using both simulated and in vivo data we investigate the impact of fitting to either real-valued or magnitude data, with Gaussian and Rician noise characteristics respectively, and what happens if we get the noise assumptions wrong in this high b-value and thus low SNR regime. Our results from real-valued human data estimate intra-axonal axial diffusivities of ∼2-2.5µm2/ms, in line with current literature. Crucially, our results demonstrate the importance of accounting for both a rectified noise floor and/or a signal offset to avoid biased parameter estimates when dealing with low SNR data.

Mapping the human connectome using diffusion MRI at 300 mT/m gradient strength: Methodological advances and scientific impact.

Tremendous efforts have been made in the last decade to advance cutting-edge MRI technology in pursuit of mapping structural connectivity in the living human brain with unprecedented sensitivity and speed. The first Connectom 3T MRI scanner equipped with a 300 mT/m whole-body gradient system was installed at the Massachusetts General Hospital in 2011 and was specifically constructed as part of the Human Connectome Project. Since that time, numerous technological advances have been made to enable the broader use of the Connectom high gradient system for diffusion tractography and tissue microstructure studies and leverage its unique advantages and sensitivity to resolving macroscopic and microscopic structural information in neural tissue for clinical and neuroscientific studies. The goal of this review article is to summarize the technical developments that have emerged in the last decade to support and promote large-scale and scientific studies of the human brain using the Connectom scanner. We provide a brief historical perspective on the development of Connectom gradient technology and the efforts that led to the installation of three other Connectom 3T MRI scanners worldwide - one in the United Kingdom in Cardiff, Wales, another in continental Europe in Leipzig, Germany, and the latest in Asia in Shanghai, China. We summarize the key developments in gradient hardware and image acquisition technology that have formed the backbone of Connectom-related research efforts, including the rich array of high-sensitivity receiver coils, pulse sequences, image artifact correction strategies and data preprocessing methods needed to optimize the quality of high-gradient strength diffusion MRI data for subsequent analyses. Finally, we review the scientific impact of the Connectom MRI scanner, including advances in diffusion tractography, tissue microstructural imaging, ex vivo validation, and clinical investigations that have been enabled by Connectom technology. We conclude with brief insights into the unique value of strong gradients for diffusion MRI and where the field is headed in the coming years.

Highly accelerated EPI with wave encoding and multi-shot simultaneous multislice imaging.

PURPOSE: To introduce wave-encoded acquisition and reconstruction techniques for highly accelerated EPI with reduced g-factor penalty and image artifacts. THEORY AND METHODS: Wave-EPI involves application of sinusoidal gradients during the EPI readout, which spreads the aliasing in all spatial directions, thereby taking better advantage of 3D coil sensitivity profiles. The amount of voxel spreading that can be achieved by the wave gradients during the short EPI readout period is constrained by the slew rate of the gradient coils and peripheral nerve stimulation monitor. We propose to use a "half-cycle" sinusoidal gradient to increase the amount of voxel spreading that can be achieved while respecting the slew and stimulation constraints. Extending wave-EPI to multi-shot acquisition minimizes geometric distortion and voxel blurring at high in-plane resolutions, while structured low-rank regularization mitigates shot-to-shot phase variations. To address gradient imperfections, we propose to use different point spread functions for the k-space lines with positive and negative polarities, which are calibrated with a FLEET-based reference scan. RESULTS: Wave-EPI enabled whole-brain single-shot gradient-echo (GE) and multi-shot spin-echo (SE) EPI acquisitions at high acceleration factors at 3T and was combined with g-Slider encoding to boost the SNR level in 1 mm isotropic diffusion imaging. Relative to blipped-CAIPI, wave-EPI reduced average and maximum g-factors by up to 1.21- and 1.37-fold at Rin × Rsms  = 3 × 3, respectively. CONCLUSION: Wave-EPI allows highly accelerated single- and multi-shot EPI with reduced g-factor and artifacts and may facilitate clinical and neuroscientific applications of EPI by improving the spatial and temporal resolution in functional and diffusion imaging.

Improving in vivo human cerebral cortical surface reconstruction using data-driven super-resolution.

Accurate and automated reconstruction of the in vivo human cerebral cortical surface from anatomical magnetic resonance (MR) images facilitates the quantitative analysis of cortical structure. Anatomical MR images with sub-millimeter isotropic spatial resolution improve the accuracy of cortical surface and thickness estimation compared to the standard 1-millimeter isotropic resolution. Nonetheless, sub-millimeter resolution acquisitions require averaging multiple repetitions to achieve sufficient signal-to-noise ratio and are therefore long and potentially vulnerable to subject motion. We address this challenge by synthesizing sub-millimeter resolution images from standard 1-millimeter isotropic resolution images using a data-driven supervised machine learning-based super-resolution approach achieved via a deep convolutional neural network. We systematically characterize our approach using a large-scale simulated dataset and demonstrate its efficacy in empirical data. The super-resolution data provide improved cortical surfaces similar to those obtained from native sub-millimeter resolution data. The whole-brain mean absolute discrepancy in cortical surface positioning and thickness estimation is below 100 µm at the single-subject level and below 50 µm at the group level for the simulated data, and below 200 µm at the single-subject level and below 100 µm at the group level for the empirical data, making the accuracy of cortical surfaces derived from super-resolution sufficient for most applications.

Improved cortical surface reconstruction using sub-millimeter resolution MPRAGE by image denoising.

Automatic cerebral cortical surface reconstruction is a useful tool for cortical anatomy quantification, analysis and visualization. Recently, the Human Connectome Project and several studies have shown the advantages of using T1-weighted magnetic resonance (MR) images with sub-millimeter isotropic spatial resolution instead of the standard 1-mm isotropic resolution for improved accuracy of cortical surface positioning and thickness estimation. Nonetheless, sub-millimeter resolution images are noisy by nature and require averaging multiple repetitions to increase the signal-to-noise ratio for precisely delineating the cortical boundary. The prolonged acquisition time and potential motion artifacts pose significant barriers to the wide adoption of cortical surface reconstruction at sub-millimeter resolution for a broad range of neuroscientific and clinical applications. We address this challenge by evaluating the cortical surface reconstruction resulting from denoised single-repetition sub-millimeter T1-weighted images. We systematically characterized the effects of image denoising on empirical data acquired at 0.6 mm isotropic resolution using three classical denoising methods, including denoising convolutional neural network (DnCNN), block-matching and 4-dimensional filtering (BM4D) and adaptive optimized non-local means (AONLM). The denoised single-repetition images were found to be highly similar to 6-repetition averaged images, with a low whole-brain averaged mean absolute difference of ~0.016, high whole-brain averaged peak signal-to-noise ratio of ~33.5 dB and structural similarity index of ~0.92, and minimal gray matter-white matter contrast loss (2% to 9%). The whole-brain mean absolute discrepancies in gray matter-white matter surface placement, gray matter-cerebrospinal fluid surface placement and cortical thickness estimation were lower than 165 µm, 155 µm and 145 µm-sufficiently accurate for most applications. These discrepancies were approximately one third to half of those from 1-mm isotropic resolution data. The denoising performance was equivalent to averaging ~2.5 repetitions of the data in terms of image similarity, and 1.6-2.2 repetitions in terms of the cortical surface placement accuracy. The scan-rescan variability of the cortical surface positioning and thickness estimation was lower than 170 µm. Our unique dataset and systematic characterization support the use of denoising methods for improved cortical surface reconstruction at sub-millimeter resolution.

Scan-rescan repeatability of axonal imaging metrics using high-gradient diffusion MRI and statistical implications for study design.

Axon diameter mapping using diffusion MRI in the living human brain has attracted growing interests with the increasing availability of high gradient strength MRI systems. A systematic assessment of the consistency of axon diameter estimates within and between individuals is needed to gain a comprehensive understanding of how such methods extend to quantifying differences in axon diameter index between groups and facilitate the design of neurobiological studies using such measures. We examined the scan-rescan repeatability of axon diameter index estimation based on the spherical mean technique (SMT) approach using diffusion MRI data acquired with gradient strengths up to 300 mT/m on a 3T Connectom system in 7 healthy volunteers. We performed statistical power analyses using data acquired with the same protocol in a larger cohort consisting of 15 healthy adults to investigate the implications for study design. Results revealed a high degree of repeatability in voxel-wise restricted volume fraction estimates and tract-wise estimates of axon diameter index derived from high-gradient diffusion MRI data. On the region of interest (ROI) level, across white matter tracts in the whole brain, the Pearson's correlation coefficient of the axon diameter index estimated between scan and rescan experiments was r = 0.72 with an absolute deviation of 0.18 µm. For an anticipated 10% effect size in studies of axon diameter index, most white matter regions required a sample size of less than 15 people to observe a measurable difference between groups using an ROI-based approach. To facilitate the use of high-gradient strength diffusion MRI data for neuroscientific studies of axonal microstructure, the comprehensive multi-gradient strength, multi-diffusion time data used in this work will be made publicly available, in support of open science and increasing the accessibility of such data to the greater scientific community.

A 48-channel receive array coil for mesoscopic diffusion-weighted MRI of ex vivo human brain on the 3 T connectome scanner.

In vivo diffusion-weighted magnetic resonance imaging is limited in signal-to-noise-ratio (SNR) and acquisition time, which constrains spatial resolution to the macroscale regime. Ex vivo imaging, which allows for arbitrarily long scan times, is critical for exploring human brain structure in the mesoscale regime without loss of SNR. Standard head array coils designed for patients are sub-optimal for imaging ex vivo whole brain specimens. The goal of this work was to design and construct a 48-channel ex vivo whole brain array coil for high-resolution and high b-value diffusion-weighted imaging on a 3T Connectome scanner. The coil was validated with bench measurements and characterized by imaging metrics on an agar brain phantom and an ex vivo human brain sample. The two-segment coil former was constructed for a close fit to a whole human brain, with small receive elements distributed over the entire brain. Imaging tests including SNR and G-factor maps were compared to a 64-channel head coil designed for in vivo use. There was a 2.9-fold increase in SNR in the peripheral cortex and a 1.3-fold gain in the center when compared to the 64-channel head coil. The 48-channel ex vivo whole brain coil also decreases noise amplification in highly parallel imaging, allowing acceleration factors of approximately one unit higher for a given noise amplification level. The acquired diffusion-weighted images in a whole ex vivo brain specimen demonstrate the applicability and advantage of the developed coil for high-resolution and high b-value diffusion-weighted ex vivo brain MRI studies.

Connectome 2.0: Developing the next-generation ultra-high gradient strength human MRI scanner for bridging studies of the micro-, meso- and macro-connectome.

The first phase of the Human Connectome Project pioneered advances in MRI technology for mapping the macroscopic structural connections of the living human brain through the engineering of a whole-body human MRI scanner equipped with maximum gradient strength of 300 mT/m, the highest ever achieved for human imaging. While this instrument has made important contributions to the understanding of macroscale connectional topology, it has also demonstrated the potential of dedicated high-gradient performance scanners to provide unparalleled in vivo assessment of neural tissue microstructure. Building on the initial groundwork laid by the original Connectome scanner, we have now embarked on an international, multi-site effort to build the next-generation human 3T Connectome scanner (Connectome 2.0) optimized for the study of neural tissue microstructure and connectional anatomy across multiple length scales. In order to maximize the resolution of this in vivo microscope for studies of the living human brain, we will push the diffusion resolution limit to unprecedented levels by (1) nearly doubling the current maximum gradient strength from 300 mT/m to 500 mT/m and tripling the maximum slew rate from 200 T/m/s to 600 T/m/s through the design of a one-of-a-kind head gradient coil optimized to minimize peripheral nerve stimulation; (2) developing high-sensitivity multi-channel radiofrequency receive coils for in vivo and ex vivo human brain imaging; (3) incorporating dynamic field monitoring to minimize image distortions and artifacts; (4) developing new pulse sequences to integrate the strongest diffusion encoding and highest spatial resolution ever achieved in the living human brain; and (5) calibrating the measurements obtained from this next-generation instrument through systematic validation of diffusion microstructural metrics in high-fidelity phantoms and ex vivo brain tissue at progressively finer scales with accompanying diffusion simulations in histology-based micro-geometries. We envision creating the ultimate diffusion MRI instrument capable of capturing the complex multi-scale organization of the living human brain - from the microscopic scale needed to probe cellular geometry, heterogeneity and plasticity, to the mesoscopic scale for quantifying the distinctions in cortical structure and connectivity that define cyto- and myeloarchitectonic boundaries, to improvements in estimates of macroscopic connectivity.

RUN-UP: Accelerated multishot diffusion-weighted MRI reconstruction using an unrolled network with U-Net as priors.

PURPOSE: To accelerate and improve multishot diffusion-weighted MRI reconstruction using deep learning. METHODS: An unrolled pipeline containing recurrences of model-based gradient updates and neural networks was introduced for accelerating multishot DWI reconstruction with shot-to-shot phase correction. The network was trained to predict results of jointly reconstructed multidirection data using single-direction data as input. In vivo brain and breast experiments were performed for evaluation. RESULTS: The proposed method achieves a reconstruction time of 0.1 second per image, over 100-fold faster than a shot locally low-rank reconstruction. The resultant image quality is comparable to the target from the joint reconstruction with a peak signal-to-noise ratio of 35.3 dB, a normalized root-mean-square error of 0.0177, and a structural similarity index of 0.944. The proposed method also improves upon the locally low-rank reconstruction (2.9 dB higher peak signal-to-noise ratio, 29% lower normalized root-mean-square error, and 0.037 higher structural similarity index). With training data from the brain, this method also generalizes well to breast diffusion-weighted imaging, and fine-tuning further reduces aliasing artifacts. CONCLUSION: A proposed data-driven approach enables almost real-time reconstruction with improved image quality, which improves the feasibility of multishot DWI in a wide range of clinical and neuroscientific studies.

Distortion-free, high-isotropic-resolution diffusion MRI with gSlider BUDA-EPI and multicoil dynamic B0 shimming.

PURPOSE: We combine SNR-efficient acquisition and model-based reconstruction strategies with newly available hardware instrumentation to achieve distortion-free in vivo diffusion MRI of the brain at submillimeter-isotropic resolution with high fidelity and sensitivity on a clinical 3T scanner. METHODS: We propose blip-up/down acquisition (BUDA) for multishot EPI using interleaved blip-up/blip-down phase encoding and incorporate B0 forward-modeling into structured low-rank reconstruction to enable distortion-free and navigator-free diffusion MRI. We further combine BUDA-EPI with an SNR-efficient simultaneous multislab acquisition (generalized slice-dithered enhanced resolution ["gSlider"]), to achieve high-isotropic-resolution diffusion MRI. To validate gSlider BUDA-EPI, whole-brain diffusion data at 860-µm and 780-µm data sets were acquired. Finally, to improve the conditioning and minimize noise penalty in BUDA reconstruction at very high resolutions where B0 inhomogeneity can have a detrimental effect, the level of B0 inhomogeneity was reduced by incorporating slab-by-slab dynamic shimming with a 32-channel AC/DC coil into the acquisition. Whole-brain 600-µm diffusion data were then acquired with this combined approach of gSlider BUDA-EPI with dynamic shimming. RESULTS: The results of 860-µm and 780-µm datasets show high geometry fidelity with gSlider BUDA-EPI. With dynamic shimming, the BUDA reconstruction's noise penalty was further alleviated. This enables whole-brain 600-µm isotropic resolution diffusion imaging with high image quality. CONCLUSIONS: The gSlider BUDA-EPI method enables high-quality, distortion-free diffusion imaging across the whole brain at submillimeter resolution, where the use of multicoil dynamic B0 shimming further improves reconstruction performance, which can be particularly useful at very high resolutions.

Resting-state "physiological networks".

Slow changes in systemic brain physiology can elicit large fluctuations in fMRI time series, which manifest as structured spatial patterns of temporal correlations between distant brain regions. Here, we investigated whether such "physiological networks"-sets of segregated brain regions that exhibit similar responses following slow changes in systemic physiology-resemble patterns associated with large-scale networks typically attributed to remotely synchronized neuronal activity. By analyzing a large group of subjects from the 3T Human Connectome Project (HCP) database, we demonstrate brain-wide and noticeably heterogenous dynamics tightly coupled to either respiratory variation or heart rate changes. We show, using synthesized data generated from physiological recordings across subjects, that these physiologically-coupled fluctuations alone can produce networks that strongly resemble previously reported resting-state networks, suggesting that, in some cases, the "physiological networks" seem to mimic the neuronal networks. Further, we show that such physiologically-relevant connectivity estimates appear to dominate the overall connectivity observations in multiple HCP subjects, and that this apparent "physiological connectivity" cannot be removed by the use of a single nuisance regressor for the entire brain (such as global signal regression) due to the clear regional heterogeneity of the physiologically-coupled responses. Our results challenge previous notions that physiological confounds are either localized to large veins or globally coherent across the cortex, therefore emphasizing the necessity to consider potential physiological contributions in fMRI-based functional connectivity studies. The rich spatiotemporal patterns carried by such "physiological" dynamics also suggest great potential for clinical biomarkers that are complementary to large-scale neuronal networks.