Leveraging the Apple Ecosystem: Easy Viewing and Sharing of Three-dimensional Perforator Visualizations via iPad/iPhone-based Augmented Reality.

We introduce a novel technique using augmented reality (AR) on smartphones and tablets, making it possible for surgeons to review perforator anatomy in three dimensions on the go. Autologous breast reconstruction with abdominal flaps remains challenging due to the highly variable anatomy of the deep inferior epigastric artery. Computed tomography angiography has mitigated some but not all challenges. Previously, volume rendering and different headsets were used to enable better three-dimensional (3D) review for surgeons. However, surgeons have been dependent on others to provide 3D imaging data. Leveraging the ubiquity of Apple devices, our approach permits surgeons to review 3D models of deep inferior epigastric artery anatomy segmented from abdominal computed tomography angiography directly on their iPhone/iPad. Segmentation can be performed in common radiology software. The models are converted to the universal scene description zipped format, which allows immediate use on Apple devices without third-party software. They can be easily shared using secure, Health Insurance Portability and Accountability Act-compliant sharing services already provided by most hospitals. Surgeons can simply open the file on their mobile device to explore the images in 3D using "object mode" natively without additional applications or can switch to AR mode to pin the model in their real-world surroundings for intuitive exploration. We believe patient-specific 3D anatomy models are a powerful tool for intuitive understanding and communication of complex perforator anatomy and would be a valuable addition in routine clinical practice and education. Using this one-click solution on existing devices that is simple to implement, we hope to streamline the adoption of AR models by plastic surgeons.

Suture Packaging as a Marker for Intraoperative Image Alignment in Augmented Reality on Mobile Devices.

Preoperative vascular imaging has become standard practice in the planning of microsurgical breast reconstruction. Currently, translating perforator locations from radiological findings to a patient's abdomen is often not easy or intuitive. Techniques using three-dimensional printing or patient-specific guides have been introduced to superimpose anatomy onto the abdomen for reference. Augmented and mixed reality is currently actively investigated for perforator mapping by superimposing virtual models directly onto the patient. Most techniques have found only limited adoption due to complexity and price. Additionally, a critical step is aligning virtual models to patients. We propose repurposing suture packaging as an image tracking marker. Tracking markers allow quick and easy alignment of virtual models to the individual patient's anatomy. Current techniques are often complicated or expensive and limit intraoperative use of augmented reality models. Suture packs are sterile, readily available, and can be used to align abdominal models on the patients. Using an iPad, the augmented reality models automatically align in the correct position by using a suture pack as a tracking marker. Given the ubiquity of iPads, the combination of these devices with readily available suture packs will predictably lower the barrier to entry and utilization of this technology. Here, our workflow is presented along with its intraoperative utilization. Additionally, we investigated the accuracy of this technology.

The Reconstructive Metaverse - Collaboration in Real-Time Shared Mixed Reality Environments for Microsurgical Reconstruction.

Plastic surgeons routinely use 3D-models in their clinical practice, from 3D-photography and surface imaging to 3D-segmentations from radiological scans. However, these models continue to be viewed on flattened 2D screens that do not enable an intuitive understanding of 3D-relationships and cause challenges regarding collaboration with colleagues. The Metaverse has been proposed as a new age of applications building on modern Mixed Reality headset technology that allows remote collaboration on virtual 3D-models in a shared physical-virtual space in real-time. We demonstrate the first use of the Metaverse in the context of reconstructive surgery, focusing on preoperative planning discussions and trainee education. Using a HoloLens headset with the Microsoft Mesh application, we performed planning sessions for 4 DIEP-flaps in our reconstructive metaverse on virtual patient-models segmented from routine CT angiography. In these sessions, surgeons discuss perforator anatomy and perforator selection strategies whilst comprehensively assessing the respective models. We demonstrate the workflow for a one-on-one interaction between an attending surgeon and a trainee in a video featuring both viewpoints as seen through the headset. We believe the Metaverse will provide novel opportunities to use the 3D-models that are already created in everyday plastic surgery practice in a more collaborative, immersive, accessible, and educational manner.

Increasing DIEA Perforator Detail in 3D Photorealistic Volume Rendering Visualizations with Skin-masking and Cinematic Anatomy.

Preoperative CT angiography (CTA) is increasingly performed prior to perforator flap-based reconstruction. However, radiological 2D thin-slices do not allow for intuitive interpretation and translation to intraoperative findings. 3D volume rendering has been used to alleviate the need for mental 2D-to-3D abstraction. Even though volume rendering allows for a much easier understanding of anatomy, it currently has limited utility as the skin obstructs the view of critical structures. Using free, open-source software, we introduce a new skin-masking technique that allows surgeons to easily create a segmentation mask of the skin that can later be used to toggle the skin on and off. Additionally, the mask can be used in other rendering applications. We use Cinematic Anatomy for photorealistic volume rendering and interactive exploration of the CTA with and without skin. We present results from using this technique to investigate perforator anatomy in deep inferior epigastric perforator flaps and demonstrate that the skin-masking workflow is performed in less than 5 minutes. In Cinematic Anatomy, the view onto the abdominal wall and especially onto perforators becomes significantly sharper and more detailed when no longer obstructed by the skin. We perform a virtual, partial muscle dissection to show the intramuscular and submuscular course of the perforators. The skin-masking workflow allows surgeons to improve arterial and perforator detail in volume renderings easily and quickly by removing skin and could alternatively also be performed solely using open-source and free software. The workflow can be easily expanded to other perforator flaps without the need for modification.

Spatial Fidelity of Microvascular Perforating Vessels as Perceived by Augmented Reality Virtual Projections.

BACKGROUND: Autologous breast reconstruction yields improved long-term aesthetic results but requires increased resources of practitioners and hospital systems. Innovations in radiographic imaging have been increasingly used to improve the efficiency and success of free flap harvest. Augmented reality affords the opportunity to superimpose relevant imaging on a surgeon's native field of view, potentially facilitating dissection of anatomically variable structures. To validate the spatial fidelity of augmented reality projections of deep inferior epigastric perforator flap-relevant anatomy, comparisons of three-dimensional (3D) models and their virtual renderings were performed by four independent observers. Measured discrepancies between the real and holographic models were evaluated. METHODS: The 3D-printed models of deep inferior epigastric perforator flap-relevant anatomy were fabricated from computed tomographic angiography data from 19 de-identified patients. The corresponding computed tomographic angiography data were similarly formatted for the Microsoft HoloLens to generate corresponding projections. Anatomic points were initially measured on 3D models, after which the corresponding points were measured on the HoloLens projections from two separate vantage points (V1 and V2). Statistical analyses, including generalized linear modeling, were performed to characterize spatial fidelity regarding translation, rotation, and scale of holographic projections. RESULTS: Among all participants, the median translational displacement at corresponding points was 9.0 mm between the real-3D model and V1, 12.1 mm between the 3D model and V2, and 13.5 mm between V1 and V2. CONCLUSION: Corresponding points, including topography of perforating vessels, for the purposes of breast reconstruction can be identified within millimeters, but there remain multiple independent contributors of error, most notably the participant and location at which the projection is perceived.

The Impact of Occlusion on Depth Perception at Arm's Length.

This paper investigates the accuracy of Augmented Reality (AR) technologies, particularly commercially available optical see-through displays, in depicting virtual content inside the human body for surgical planning. Their inherent limitations result in inaccuracies in perceived object positioning. We examine how occlusion, specifically with opaque surfaces, affects perceived depth of virtual objects at arm's length working distances. A custom apparatus with a half-silvered mirror was developed, providing accurate depth cues excluding occlusion, differing from commercial displays. We carried out a study, contrasting our apparatus with a HoloLens 2, involving a depth estimation task under varied surface complexities and illuminations. In addition, we explored the effects of creating a virtual "hole" in the surface. Subjects' depth estimation accuracy and confidence were a ssessed. Results showed more depth estimation variation with HoloLens and significant depth error beneath complex occluding surfaces. However, creating a virtual hole significantly reduced depth errors and increased subjects' confidence, irrespective of accuracy enhancement. These findings have important implications for the design and use of mixed-reality technologies in surgical applications, and industrial applications such as using virtual content to guide maintenance or repair of components hidden beneath the opaque outer surface of equipment. A free copy of this paper and all supplemental materials are available at https://bit.ly/3YbkwjU.

An orexigenic subnetwork within the human hippocampus.

Only recently have more specific circuit-probing techniques become available to inform previous reports implicating the rodent hippocampus in orexigenic appetitive processing1-4. This function has been reported to be mediated at least in part by lateral hypothalamic inputs, including those involving orexigenic lateral hypothalamic neuropeptides, such as melanin-concentrating hormone5,6. This circuit, however, remains elusive in humans. Here we combine tractography, intracranial electrophysiology, cortico-subcortical evoked potentials, and brain-clearing 3D histology to identify an orexigenic circuit involving the lateral hypothalamus and converging in a hippocampal subregion. We found that low-frequency power is modulated by sweet-fat food cues, and this modulation was specific to the dorsolateral hippocampus. Structural and functional analyses of this circuit in a human cohort exhibiting dysregulated eating behaviour revealed connectivity that was inversely related to body mass index. Collectively, this multimodal approach describes an orexigenic subnetwork within the human hippocampus implicated in obesity and related eating disorders.

Stereoscopic calibration for augmented reality visualization in microscopic surgery.

PURPOSE: Middle and inner ear procedures target hearing loss, infections, and tumors of the temporal bone and lateral skull base. Despite the advances in surgical techniques, these procedures remain challenging due to limited haptic and visual feedback. Augmented reality (AR) may improve operative safety by allowing the 3D visualization of anatomical structures from preoperative computed tomography (CT) scans on real intraoperative microscope video feed. The purpose of this work was to develop a real-time CT-augmented stereo microscope system using camera calibration and electromagnetic (EM) tracking. METHODS: A 3D printed and electromagnetically tracked calibration board was used to compute the intrinsic and extrinsic parameters of the surgical stereo microscope. These parameters were used to establish a transformation between the EM tracker coordinate system and the stereo microscope image space such that any tracked 3D point can be projected onto the left and right images of the microscope video stream. This allowed the augmentation of the microscope feed of a 3D printed temporal bone with its corresponding CT-derived virtual model. Finally, the calibration board was also used for evaluating the accuracy of the calibration. RESULTS: We evaluated the accuracy of the system by calculating the registration error (RE) in 2D and 3D in a microsurgical laboratory setting. Our calibration workflow achieved a RE of 0.11 ± 0.06 mm in 2D and 0.98 ± 0.13 mm in 3D. In addition, we overlaid a 3D CT model on the microscope feed of a 3D resin printed model of a segmented temporal bone. The system exhibited small latency and good registration accuracy. CONCLUSION: We present the calibration of an electromagnetically tracked surgical stereo microscope for augmented reality visualization. The calibration method achieved accuracy within a range suitable for otologic procedures. The AR process introduces enhanced visualization of the surgical field while allowing depth perception.

Virtual Resection Specimen Interaction Using Augmented Reality Holograms to Guide Margin Communication and Flap Sizing.

Head and neck surgeons often have difficulty in relocating sites of positive margins due to the complex 3-dimensional (3D) anatomy of the head and neck. We introduce a new technique where resection specimens are 3D scanned with a smartphone, annotated in computer-assisted design software, and immediately visualized on augmented reality (AR) glasses. The 3D virtual specimen can be accurately superimposed onto surgical sites for orientation and sizing applications. During an operative workshop, a surgeon using AR glasses projected virtual, annotated specimen models back into the resection bed onto a cadaver within approximately 10 minutes. Colored annotations can correspond with pathologic annotations and guide the orientation of the virtual 3D specimen. The model was also overlayed onto a flap harvest site to aid in reconstructive planning. We present a new technique allowing interactive, sterile inspection of tissue specimens in AR that could facilitate communication among surgeons and pathologists and assist with reconstructive surgery.

Changes in the Cerebello-Thalamo-Cortical Network After Magnetic Resonance-Guided Focused Ultrasound Thalamotomy.

Objective: In recent years, transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS) has been established as a potential treatment option for movement disorders, including essential tremor (ET). So far, however, little is known about the impact of tcMRgFUS on structural connectivity. The objective of this study was to detect microstructural changes in tremor- and motor-related white matter tracts in ET patients treated with tcMRgFUS thalamotomy. Methods: Eleven patients diagnosed with ET were enrolled in this tcMRgFUS thalamotomy study. For each patient, 3 Tesla magnetic resonance imaging (3T MRI) including structural and diffusion MRI were acquired and the Clinical Rating Scale for Tremor was assessed before the procedure as well as 1 year after the treatment. Diffusion MRI tractography was performed to identify the cerebello-thalamo-cortical tract (CTCT), the medial lemniscus, and the corticospinal tract in both hemispheres on pre-treatment data. Pre-treatment tractography results were co-registered to post-treatment diffusion data. Diffusion tensor imaging (DTI) metrics, including fractional anisotropy (FA), mean diffusivity (MD) and radial diffusivity (RD), were averaged across the tracts in the pre- and post-treatment data. Results: The mean value of tract-specific DTI metrics changed significantly within the thalamic lesion and in the CTCT on the treated side (p < 0.05). Changes of DTI-derived indices within the CTCT correlated well with lesion overlap (FA: r = -0.54, p = 0.04; MD: r = 0.57, p = 0.04); RD: r = 0.67, p = 0.036). Further, a trend was seen for the correlation between changes of DTI-derived indices within the CTCT and clinical improvement (FA: r = 0.58; p = 0.062; MD: r = -0.52, p = 0.64; RD: r = -0.61 p = 0.090). Conclusions: Microstructural changes were detected within the CTCT after tcMRgFUS, and these changes correlated well with lesion-tract overlap. Our results show that diffusion MRI is able to detect the microstructural effects of tcMRgFUS, thereby further elucidating the treatment mechanism, and ultimately to improve targeting prospectively. Impact statement The results of this study demonstrate microstructural changes within the cerebello-thalamo-cortical pathways 1 year after MR-guided focused ultrasound thalamotomy. Even more, microstructural changes within the cerebello-thalamo-cortical pathways correlated significantly with clinical outcome. These findings do not only highly emphasize the need of new targeting strategies for MR-guided focused ultrasound thalamotomy but also help to elucidate the treatment mechanism of it.

Remote Training for Medical Staff in Low-Resource Environments Using Augmented Reality.

This work aims to leverage medical augmented reality (AR) technology to counter the shortage of medical experts in low-resource environments. We present a complete and cross-platform proof-of-concept AR system that enables remote users to teach and train medical procedures without expensive medical equipment or external sensors. By seeing the 3D viewpoint and head movements of the teacher, the student can follow the teacher's actions on the real patient. Alternatively, it is possible to stream the 3D view of the patient from the student to the teacher, allowing the teacher to guide the student during the remote session. A pilot study of our system shows that it is easy to transfer detailed instructions through this remote teaching system and that the interface is easily accessible and intuitive for users. We provide a performant pipeline that synchronizes, compresses, and streams sensor data through parallel efficiency.

Augmented Reality for Retrosigmoid Craniotomy Planning.

While medical imaging data have traditionally been viewed on two-dimensional (2D) displays, augmented reality (AR) allows physicians to project the medical imaging data on patient's bodies to locate important anatomy. We present a surgical AR application to plan the retrosigmoid craniotomy, a standard approach to access the posterior fossa and the internal auditory canal. As a simple and accurate alternative to surface landmarks and conventional surgical navigation systems, our AR application augments the surgeon's vision to guide the optimal location of cortical bone removal. In this work, two surgeons performed a retrosigmoid approach 14 times on eight cadaver heads. In each case, the surgeon manually aligned a computed tomography (CT)-derived virtual rendering of the sigmoid sinus on the real cadaveric heads using a see-through AR display, allowing the surgeon to plan and perform the craniotomy accordingly. Postprocedure CT scans were acquired to assess the accuracy of the retrosigmoid craniotomies with respect to their intended location relative to the dural sinuses. The two surgeons had a mean margin of d avg = 0.6 ± 4.7 mm and d avg = 3.7 ± 2.3 mm between the osteotomy border and the dural sinuses over all their cases, respectively, and only positive margins for 12 of the 14 cases. The intended surgical approach to the internal auditory canal was successfully achieved in all cases using the proposed method, and the relatively small and consistent margins suggest that our system has the potential to be a valuable tool to facilitate planning a variety of similar skull-base procedures.

Evaluation Challenges for the Application of Extended Reality Devices in Medicine.

Augmented and virtual reality devices are being actively investigated and implemented for a wide range of medical uses. However, significant gaps in the evaluation of these medical devices and applications hinder their regulatory evaluation. Addressing these gaps is critical to demonstrating the devices' safety and effectiveness. We outline the key technical and clinical evaluation challenges discussed during the US Food and Drug Administration's public workshop, "Medical Extended Reality: Toward Best Evaluation Practices for Virtual and Augmented Reality in Medicine" and future directions for evaluation method development. Evaluation challenges were categorized into several key technical and clinical areas. Finally, we highlight current efforts in the standards communities and illustrate connections between the evaluation challenges and the intended uses of the medical extended reality (MXR) devices. Participants concluded that additional research is needed to assess the safety and effectiveness of MXR devices across the use cases.

Phantom study of SPECT/CT augmented reality for intraoperative localization of sentinel lymph nodes in head and neck melanoma.

OBJECTIVE: To show that augmented reality (AR) visualization of single-photon emission computed tomography (SPECT)/computed tomography (CT) data in 3D can be used to accurately localize targets in the head and neck region. MATERIALS AND METHODS: Eight head and neck styrofoam phantoms were painted with a mixture of radioactive solution (Tc-99m) detectable with a handheld gamma probe and fluorescent ink visible only under ultraviolet (UV) light to create 10-20 simulated lymph nodes on their surface. After obtaining SPECT/CT images of these phantoms, virtual renderings of the nodes were generated from the SPECT/CT data and displayed using a commercially available AR headset. For each of three physician evaluators, the time required to localize lymph node targets was recorded (1) using the gamma probe alone and (2) using the gamma probe while wearing the AR headset. In addition, the surface localization accuracy when using the AR headset was evaluated by measuring the misalignment between the locations visually marked by the evaluators and the ground truth locations identified using UV stimulation of the ink at the site of the nodes. RESULTS: For all three evaluators, using the AR headset significantly reduced the time to detect targets (P = 0.012, respectively) compared to using the gamma probe alone. The average misalignment between the location marked by the evaluators and the ground truth location was 8.6 mm. CONCLUSION: AR visualization of SPECT/CT data in 3D allows for accurate localization of targets in the head and neck region, and may reduce the localization time of targets.

Nanostructure-specific X-ray tomography reveals myelin levels, integrity and axon orientations in mouse and human nervous tissue.

Myelin insulates neuronal axons and enables fast signal transmission, constituting a key component of brain development, aging and disease. Yet, myelin-specific imaging of macroscopic samples remains a challenge. Here, we exploit myelin's nanostructural periodicity, and use small-angle X-ray scattering tensor tomography (SAXS-TT) to simultaneously quantify myelin levels, nanostructural integrity and axon orientations in nervous tissue. Proof-of-principle is demonstrated in whole mouse brain, mouse spinal cord and human white and gray matter samples. Outcomes are validated by 2D/3D histology and compared to MRI measurements sensitive to myelin and axon orientations. Specificity to nanostructure is exemplified by concomitantly imaging different myelin types with distinct periodicities. Finally, we illustrate the method's sensitivity towards myelin-related diseases by quantifying myelin alterations in dysmyelinated mouse brain. This non-destructive, stain-free molecular imaging approach enables quantitative studies of myelination within and across samples during development, aging, disease and treatment, and is applicable to other ordered biomolecules or nanostructures.

Augmented reality visualization tool for the future of tactical combat casualty care.

ABSTRACT: The objective of this project was to identify and develop software for an augmented reality application that runs on the US Army Integrated Visual Augmentation System (IVAS) to support a medical caregiver during tactical combat casualty care scenarios. In this augmented reality tactical combat casualty care application, human anatomy of individual soldiers obtained predeployment is superimposed on the view of an injured war fighter through the IVAS. This offers insight into the anatomy of the injured war fighter to advance treatment in austere environments.In this article, we describe various software components required for an augmented reality tactical combat casualty care tool. These include a body pose tracking system to track the patient's body pose, a virtual rendering of a human anatomy avatar, speech input to control the application and rendering techniques to visualize the virtual anatomy, and treatment information on the augmented reality display. We then implemented speech commands and visualization for four common medical scenarios including injury of a limb, a blast to the pelvis, cricothyrotomy, and a pneumothorax on the Microsoft HoloLens 1 (Microsoft, Redmond, WA).The software is designed for a forward surgical care tool on the US Army IVAS, with the intention to provide the medical caregiver with a unique ability to quickly assess affected internal anatomy. The current software components still had some limitations with respect to speech recognition reliability during noise and body pose tracking. These will likely be improved with the improved hardware of the IVAS, which is based on a modified HoloLens 2.

Application of holographic augmented reality for external approaches to the frontal sinus.

BACKGROUND: External approaches to the frontal sinus such as osteoplastic flaps are challenging because they require blind entry into the sinus, posing risks of injury to the brain or orbit. Intraoperative computed tomography (CT)-based navigation is the current standard for planning the approach, but still necessitates blind entry into the sinus. The aim of this work was to describe a novel technique for external approaches to the frontal sinus using a holographic augmented reality (AR) application. METHODS: Our team developed an AR system to create a 3-dimensional (3D) hologram of key anatomical structures, based on CT scans images. Using Magic Leap AR goggles for visualization, the frontal sinus hologram was aligned to the surface anatomy in 6 fresh cadaveric heads' anatomic boundaries, and the boundaries of the frontal sinus were demarcated based on the margins of the fused image. Trephinations and osteoplastic flap approaches were performed. The specimens were re-scanned to assess the accuracy of the osteotomy with respect to the actual frontal sinus perimeter. RESULTS: Registration and surgery were completed successfully in all specimens. Registration required an average of 2 minutes. The postprocedure CT showed a mean difference of 1.4 ± 4.1 mm between the contour of the osteotomy and the contour of the frontal sinus. One surgical complication (posterior table perforation) occurred (16%). CONCLUSION: We describe proof of concept of a novel technique utilizing AR to enhance external approaches to the frontal sinus. Holographic AR-enhanced surgical navigation holds promise for enhanced visualization of target structures during surgical approaches to the sinuses.

Multimodal image registration and connectivity analysis for integration of connectomic data from microscopy to MRI.

3D histology, slice-based connectivity atlases, and diffusion MRI are common techniques to map brain wiring. While there are many modality-specific tools to process these data, there is a lack of integration across modalities. We develop an automated resource that combines histologically cleared volumes with connectivity atlases and MRI, enabling the analysis of histological features across multiple fiber tracts and networks, and their correlation with in-vivo biomarkers. We apply our pipeline in a murine stroke model, demonstrating not only strong correspondence between MRI abnormalities and CLARITY-tissue staining, but also uncovering acute cellular effects in areas connected to the ischemic core. We provide improved maps of connectivity by quantifying projection terminals from CLARITY viral injections, and integrate diffusion MRI with CLARITY viral tracing to compare connectivity maps across scales. Finally, we demonstrate tract-level histological changes of stroke through this multimodal integration. This resource can propel investigations of network alterations underlying neurological disorders.

Multimodal characterization of the human nucleus accumbens.

Dysregulation of the nucleus accumbens (NAc) is implicated in numerous neuropsychiatric disorders. Treatments targeting this area directly (e.g. deep brain stimulation) demonstrate variable efficacy, perhaps owing to non-specific targeting of a functionally heterogeneous nucleus. Here we provide support for this notion, first observing disparate behavioral effects in response to direct simulation of different locations within the NAc in a human patient. These observations motivate a segmentation of the NAc into subregions, which we produce from a diffusion-tractography based analysis of 245 young, unrelated healthy subjects. We further explore the mechanism of these stimulation-induced behavioral responses by identifying the most probable subset of axons activated using a patient-specific computational model. We validate our diffusion-based segmentation using evidence from several modalities, including MRI-based measures of function and microstructure, human post-mortem immunohistochemical staining, and cross-species comparison of cortical-NAc projections that are known to be conserved. Finally, we visualize the passage of individual axon bundles through one NAc subregion in a post-mortem human sample using CLARITY 3D histology corroborated by 7T tractography. Collectively, these findings extensively characterize human NAc subregions and provide insight into their structural and functional distinctions with implications for stereotactic treatments targeting this region.

Generalized diffusion spectrum magnetic resonance imaging (GDSI) for model-free reconstruction of the ensemble average propagator.

Diffusion spectrum MRI (DSI) provides model-free estimation of the diffusion ensemble average propagator (EAP) and orientation distribution function (ODF) but requires the diffusion data to be acquired on a Cartesian q-space grid. Multi-shell diffusion acquisitions are more flexible and more commonly acquired but have, thus far, only been compatible with model-based analysis methods. Here, we propose a generalized DSI (GDSI) framework to recover the EAP from multi-shell diffusion MRI data. The proposed GDSI approach corrects for q-space sampling density non-uniformity using a fast geometrical approach. The EAP is directly calculated in a preferable coordinate system by multiplying the sampling density corrected q-space signals by a discrete Fourier transform matrix, without any need for gridding. The EAP is demonstrated as a way to map diffusion patterns in brain regions such as the thalamus, cortex and brainstem where the tissue microstructure is not as well characterized as in white matter. Scalar metrics such as the zero displacement probability and displacement distances at different fractions of the zero displacement probability were computed from the recovered EAP to characterize the diffusion pattern within each voxel. The probability averaged across directions at a specific displacement distance provides a diffusion property based image contrast that clearly differentiates tissue types. The displacement distance at the first zero crossing of the EAP averaged across directions orthogonal to the primary fiber orientation in the corpus callosum is found to be larger in the body (5.65 ±â€¯0.09 µm) than in the genu (5.55 ±â€¯0.15 µm) and splenium (5.4 ±â€¯0.15 µm) of the corpus callosum, which corresponds well to prior histological studies. The EAP also provides model-free representations of angular structure such as the diffusion ODF, which allows estimation and comparison of fiber orientations from both the model-free and model-based methods on the same multi-shell data. For the model-free methods, detection of crossing fibers is found to be strongly dependent on the maximum b-value and less sensitive compared to the model-based methods. In conclusion, our study provides a generalized DSI approach that allows flexible reconstruction of the diffusion EAP and ODF from multi-shell diffusion data and data acquired with other sampling patterns.