Variational principle to regularize machine-learned density functionals: The non-interacting kinetic-energy functional.

Practical density functional theory (DFT) owes its success to the groundbreaking work of Kohn and Sham that introduced the exact calculation of the non-interacting kinetic energy of the electrons using an auxiliary mean-field system. However, the full power of DFT will not be unleashed until the exact relationship between the electron density and the non-interacting kinetic energy is found. Various attempts have been made to approximate this functional, similar to the exchange-correlation functional, with much less success due to the larger contribution of kinetic energy and its more non-local nature. In this work, we propose a new and efficient regularization method to train density functionals based on deep neural networks, with particular interest in the kinetic-energy functional. The method is tested on (effectively) one-dimensional systems, including the hydrogen chain, non-interacting electrons, and atoms of the first two periods, with excellent results. For atomic systems, the generalizability of the regularization method is demonstrated by training also an exchange-correlation functional, and the contrasting nature of the two functionals is discussed from a machine-learning perspective.

libMBD: A general-purpose package for scalable quantum many-body dispersion calculations.

Many-body dispersion (MBD) is a powerful framework to treat van der Waals (vdW) dispersion interactions in density-functional theory and related atomistic modeling methods. Several independent implementations of MBD with varying degree of functionality exist across a number of electronic structure codes, which both limits the current users of those codes and complicates dissemination of new variants of MBD. Here, we develop and document libMBD, a library implementation of MBD that is functionally complete, efficient, easy to integrate with any electronic structure code, and already integrated in FHI-aims, DFTB+, VASP, Q-Chem, CASTEP, and Quantum ESPRESSO. libMBD is written in modern Fortran with bindings to C and Python, uses MPI/ScaLAPACK for parallelization, and implements MBD for both finite and periodic systems, with analytical gradients with respect to all input parameters. The computational cost has asymptotic cubic scaling with system size, and evaluation of gradients only changes the prefactor of the scaling law, with libMBD exhibiting strong scaling up to 256 processor cores. Other MBD properties beyond energy and gradients can be calculated with libMBD, such as the charge-density polarization, first-order Coulomb correction, the dielectric function, or the order-by-order expansion of the energy in the dipole interaction. Calculations on supramolecular complexes with MBD-corrected electronic structure methods and a meta-review of previous applications of MBD demonstrate the broad applicability of the libMBD package to treat vdW interactions.

Ab initio quantum chemistry with neural-network wavefunctions.

Deep learning methods outperform human capabilities in pattern recognition and data processing problems and now have an increasingly important role in scientific discovery. A key application of machine learning in molecular science is to learn potential energy surfaces or force fields from ab initio solutions of the electronic Schrödinger equation using data sets obtained with density functional theory, coupled cluster or other quantum chemistry (QC) methods. In this Review, we discuss a complementary approach using machine learning to aid the direct solution of QC problems from first principles. Specifically, we focus on quantum Monte Carlo methods that use neural-network ansatzes to solve the electronic Schrödinger equation, in first and second quantization, computing ground and excited states and generalizing over multiple nuclear configurations. Although still at their infancy, these methods can already generate virtually exact solutions of the electronic Schrödinger equation for small systems and rival advanced conventional QC methods for systems with up to a few dozen electrons.

Image-Based Planning of Minimally Traumatic Inner Ear Access for Robotic Cochlear Implantation.

Objective: During robotic cochlear implantation, an image-guided robotic system provides keyhole access to the scala tympani of the cochlea to allow insertion of the cochlear implant array. To standardize minimally traumatic robotic access to the cochlea, additional hard and soft constraints for inner ear access were proposed during trajectory planning. This extension of the planning strategy aims to provide a trajectory that preserves the anatomical and functional integrity of critical intra-cochlear structures during robotic execution and allows implantation with minimal insertion angles and risk of scala deviation. Methods: The OpenEar dataset consists of a library with eight three-dimensional models of the human temporal bone based on computed tomography and micro-slicing. Soft constraints for inner ear access planning were introduced that aim to minimize the angle of cochlear approach, minimize the risk of scala deviation and maximize the distance to critical intra-cochlear structures such as the osseous spiral lamina. For all cases, a solution space of Pareto-optimal trajectories to the round window was generated. The trajectories satisfy the hard constraints, specifically the anatomical safety margins, and optimize the aforementioned soft constraints. With user-defined priorities, a trajectory was parameterized and analyzed in a virtual surgical procedure. Results: In seven out of eight cases, a solution space was found with the trajectories safely passing through the facial recess. The solution space was Pareto-optimal with respect to the soft constraints of the inner ear access. In one case, the facial recess was too narrow to plan a trajectory that would pass the nerves at a sufficient distance with the intended drill diameter. With the soft constraints introduced, the optimal target region was determined to be in the antero-inferior region of the round window membrane. Conclusion: A trend could be identified that a position between the antero-inferior border and the center of the round window membrane appears to be a favorable target position for cochlear tunnel-based access through the facial recess. The planning concept presented and the results obtained therewith have implications for planning strategies for robotic surgical procedures to the inner ear that aim for minimally traumatic cochlear access and electrode array implantation.

Robotic Milling of Electrode Lead Channels During Cochlear Implantation in an ex-vivo Model.

Objective: Robotic cochlear implantation is an emerging surgical technique for patients with sensorineural hearing loss. Access to the middle and inner ear is provided through a small-diameter hole created by a robotic drilling process without a mastoidectomy. Using the same image-guided robotic system, we propose an electrode lead management technique using robotic milling that replaces the standard process of stowing excess electrode lead in the mastoidectomy cavity. Before accessing the middle ear, an electrode channel is milled robotically based on intraoperative planning. The goal is to further standardize cochlear implantation, minimize the risk of iatrogenic intracochlear damage, and to create optimal conditions for a long implant life through protection from external trauma and immobilization in a slight press fit to prevent mechanical fatigue and electrode migrations. Methods: The proposed workflow was executed on 12 ex-vivo temporal bones and evaluated for safety and efficacy. For safety, the difference between planned and resulting channels were measured postoperatively in micro-computed tomography, and the length outside the planned safety margin of 1.0 mm was determined. For efficacy, the channel width and depth were measured to assess the press fit immobilization and the protection from external trauma, respectively. Results: All 12 cases were completed with successful electrode fixations after cochlear insertions. The milled channels stayed within the planned safety margins and the probability of their violation was lower than one in 10,000 patients. Maximal deviations in lateral and depth directions of 0.35 and 0.29 mm were measured, respectively. The channels could be milled with a width that immobilized the electrode leads. The average channel depth was 2.20 mm, while the planned channel depth was 2.30 mm. The shallowest channel depth was 1.82 mm, still deep enough to contain the full 1.30 mm diameter of the electrode used for the experiments. Conclusion: This study proposes a robotic electrode lead management and fixation technique and verified its safety and efficacy in an ex-vivo study. The method of image-guided robotic bone removal presented here with average errors of 0.2 mm and maximal errors below 0.5 mm could be used for a variety of other otologic surgical procedures.

Quantum Chemistry Common Driver and Databases (QCDB) and Quantum Chemistry Engine (QCEngine): Automation and interoperability among computational chemistry programs.

Community efforts in the computational molecular sciences (CMS) are evolving toward modular, open, and interoperable interfaces that work with existing community codes to provide more functionality and composability than could be achieved with a single program. The Quantum Chemistry Common Driver and Databases (QCDB) project provides such capability through an application programming interface (API) that facilitates interoperability across multiple quantum chemistry software packages. In tandem with the Molecular Sciences Software Institute and their Quantum Chemistry Archive ecosystem, the unique functionalities of several CMS programs are integrated, including CFOUR, GAMESS, NWChem, OpenMM, Psi4, Qcore, TeraChem, and Turbomole, to provide common computational functions, i.e., energy, gradient, and Hessian computations as well as molecular properties such as atomic charges and vibrational frequency analysis. Both standard users and power users benefit from adopting these APIs as they lower the language barrier of input styles and enable a standard layout of variables and data. These designs allow end-to-end interoperable programming of complex computations and provide best practices options by default.

Anisotropic Interlayer Force Field for Transition Metal Dichalcogenides: The Case of Molybdenum Disulfide.

An anisotropic interlayer force field that describes the interlayer interactions in molybdenum disulfide (MoS2) is presented. The force field is benchmarked against density functional theory calculations for both bilayer and bulk systems within the Heyd-Scuseria-Ernzerhof hybrid density functional approximation, augmented by a nonlocal many-body dispersion treatment of long-range correlation. The parametrization yields good agreement with the reference calculations of binding energy curves and sliding potential energy surfaces for both bilayer and bulk configurations. Benchmark calculations for the phonon spectra of bulk MoS2 provide good agreement with experimental data, and the calculated bulk modulus falls in the lower part of experimentally measured values. This indicates the accuracy of the interlayer force field near equilibrium. Under external pressures up to 20 GPa, the developed force field provides a good description of compression curves. At higher pressures, deviations from experimental data grow, signifying the validity range of the developed force field.

In Silico Assessment of Safety and Efficacy of Screw Placement for Pediatric Image-Guided Otologic Surgery.

Introduction: Current high-accuracy image-guided systems for otologic surgery use fiducial screws for patient-to-image registration. Thus far, these systems have only been used in adults, and the safety and efficacy of the fiducial screw placement has not yet been investigated in the pediatric population. Materials and Methods: In a retrospective study, CT image data of the temporal region from 11 subjects meeting inclusion criteria (8-48 months at the time of surgery) were selected, resulting in n = 20 sides. These datasets were investigated with respect to screw stability efficacy in terms of the cortical layer thickness, and safety in terms of the distance of potential fiducial screws to the dura mater or venous sinuses. All of these results are presented as distributions, thickness color maps, and with descriptive statistics. Seven regions within the temporal bone were analyzed individually. In addition, four fiducial screws per case with 4 mm thread-length were placed in an additively manufactured model according to the guidelines for robotic cochlear implantation surgery. For all these screws, the minimal distance to the dura mater or venous sinuses was measured, or if applicable how much they penetrated these structures. Results: The cortical layer has been found to be mostly between 0.7-3.3 mm thick (from the 5th to the 95th percentile), while even thinner areas exist. The distance from the surface of the temporal bone to the dura mater or the venous sinuses varied considerably between the subjects and ranged mostly from 1.1-9.3 mm (from the 5th to the 95th percentile). From all 80 placed fiducial screws of 4 mm thread length in the pediatric subject younger than two years old, 22 touched or penetrated either the dura or the sigmoid sinus. The best regions for fiducial placement would be the mastoid area and along the petrous pyramid in terms of safety. In terms of efficacy, the parietal followed by the petrous pyramid, and retrosigmoid regions are most suited. Conclusion: The current fiducial screws and the screw placement guidelines for adults are insufficiently safe or effective for pediatric patients.

Freehand Stereotactic Image-Guidance Tailored to Neurotologic Surgery.

Hypothesis: The use of freehand stereotactic image-guidance with a target registration error (TRE) of µTRE + 3σTRE < 0.5 mm for navigating surgical instruments during neurotologic surgery is safe and useful. Background: Neurotologic microsurgery requires work at the limits of human visual and tactile capabilities. Anatomy localization comes at the expense of invasiveness caused by exposing structures and using them as orientation landmarks. In the absence of more-precise and less-invasive anatomy localization alternatives, surgery poses considerable risks of iatrogenic injury and sub-optimal treatment. There exists an unmet clinical need for an accurate, precise, and minimally-invasive means for anatomy localization and instrument navigation during neurotologic surgery. Freehand stereotactic image-guidance constitutes a solution to this. While the technology is routinely used in medical fields such as neurosurgery and rhinology, to date, it is not used for neurotologic surgery due to insufficient accuracy of clinically available systems. Materials and Methods: A freehand stereotactic image-guidance system tailored to the needs of neurotologic surgery-most importantly sub-half-millimeter accuracy-was developed. Its TRE was assessed preclinically using a task-specific phantom. A pilot clinical trial targeting N = 20 study participants was conducted (ClinicalTrials.gov ID: NCT03852329) to validate the accuracy and usefulness of the developed system. Clinically, objective assessment of the TRE is impossible because establishing a sufficiently accurate ground-truth is impossible. A method was used to validate accuracy and usefulness based on intersubjectivity assessment of surgeon ratings of corresponding image-pairs from the microscope/endoscope and the image-guidance system. Results: During the preclinical accuracy assessment the TRE was measured as 0.120 ± 0.05 mm (max: 0.27 mm, µTRE + 3σTRE = 0.27 mm, N = 310). Due to the COVID-19 pandemic, the study was terminated early after N = 3 participants. During an endoscopic cholesteatoma removal, a microscopic facial nerve schwannoma removal, and a microscopic revision cochlear implantation, N = 75 accuracy and usefulness ratings were collected from five surgeons each grading 15 image-pairs. On a scale from 1 (worst rating) to 5 (best rating), the median (interquartile range) accuracy and usefulness ratings were assessed as 5 (4-5) and 4 (4-5) respectively. Conclusion: Navigating surgery in the tympanomastoid compartment and potentially in the lateral skull base with sufficiently accurate freehand stereotactic image-guidance (µTRE + 3σTRE < 0.5 mm) is feasible, safe, and useful. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03852329.

Coulomb interactions between dipolar quantum fluctuations in van der Waals bound molecules and materials.

Mutual Coulomb interactions between electrons lead to a plethora of interesting physical and chemical effects, especially if those interactions involve many fluctuating electrons over large spatial scales. Here, we identify and study in detail the Coulomb interaction between dipolar quantum fluctuations in the context of van der Waals complexes and materials. Up to now, the interaction arising from the modification of the electron density due to quantum van der Waals interactions was considered to be vanishingly small. We demonstrate that in supramolecular systems and for molecules embedded in nanostructures, such contributions can amount to up to 6 kJ/mol and can even lead to qualitative changes in the long-range van der Waals interaction. Taking into account these broad implications, we advocate for the systematic assessment of so-called Dipole-Correlated Coulomb Singles in large molecular systems and discuss their relevance for explaining several recent puzzling experimental observations of collective behavior in nanostructured materials.

Deep-neural-network solution of the electronic Schrödinger equation.

The electronic Schrödinger equation can only be solved analytically for the hydrogen atom, and the numerically exact full configuration-interaction method is exponentially expensive in the number of electrons. Quantum Monte Carlo methods are a possible way out: they scale well for large molecules, they can be parallelized and their accuracy has, as yet, been only limited by the flexibility of the wavefunction ansatz used. Here we propose PauliNet, a deep-learning wavefunction ansatz that achieves nearly exact solutions of the electronic Schrödinger equation for molecules with up to 30 electrons. PauliNet has a multireference Hartree-Fock solution built in as a baseline, incorporates the physics of valid wavefunctions and is trained using variational quantum Monte Carlo. PauliNet outperforms previous state-of-the-art variational ansatzes for atoms, diatomic molecules and a strongly correlated linear H10, and matches the accuracy of highly specialized quantum chemistry methods on the transition-state energy of cyclobutadiene, while being computationally efficient.

Recent developments in the PySCF program package.

PySCF is a Python-based general-purpose electronic structure platform that supports first-principles simulations of molecules and solids as well as accelerates the development of new methodology and complex computational workflows. This paper explains the design and philosophy behind PySCF that enables it to meet these twin objectives. With several case studies, we show how users can easily implement their own methods using PySCF as a development environment. We then summarize the capabilities of PySCF for molecular and solid-state simulations. Finally, we describe the growing ecosystem of projects that use PySCF across the domains of quantum chemistry, materials science, machine learning, and quantum information science.

Density Functional Model for van der Waals Interactions: Unifying Many-Body Atomic Approaches with Nonlocal Functionals.

Noncovalent van der Waals (vdW) interactions are responsible for a wide range of phenomena in matter. Popular density-functional methods that treat vdW interactions use disparate physical models for these intricate forces, and as a result the applicability of these methods is often restricted to a subset of relevant molecules and materials. Aiming towards a general-purpose density functional model of vdW interactions, here we unify two complementary approaches: nonlocal vdW functionals for polarization and interatomic methods for many-body interactions. The developed nonlocal many-body dispersion method (MBD-NL) increases the accuracy and efficiency of existing vdW functionals and is shown to be broadly applicable to molecules, soft and hard materials including ionic and metallic compounds, as well as interfaces between organic molecules and inorganic materials.

Nonlocal Electronic Correlations in the Cohesive Properties of High-Pressure Hydrogen Solids.

High-pressure hydrogen exhibits remarkable phenomena including the insulator-to-metal (IM) transition; however, a complete resolution of its phase diagram is still an elusive goal despite many efforts and much controversy. Theoretical modeling is typically based on density functional theory (DFT) with a mean-field description of electronic correlations, which is known to be rather limited in describing IM transitions. Herein, we show that nonlocal electron correlations play a central role in the relative stability of solid hydrogen phases, and that DFT-correcting for these correlations by the many-body dispersion (MBD) model reaches the accuracy of quantum Monte Carlo (QMC) simulations and predicts the same C2/c-24 → Cmca-12 → Cs(IV) IM transition. In contrast with the conventional assumption that many-body electronic correlations become localized in metallic systems because of exponential screening with interelectronic distance, we find that the anisotropy of the electronic response of hydrogen solids under pressure leads to longer-ranged many-body effects in metallic phases relative to insulating ones. This refines our understanding of phase diagram of hydrogen solids as well as anisotropic many-body correlations.

Evolution and Stagnation of Image Guidance for Surgery in the Lateral Skull: A Systematic Review 1989-2020.

Objective: Despite three decades of pre-clinical and clinical research into image guidance solutions as a more accurate and less invasive alternative for instrument and anatomy localization, translation into routine clinical practice for surgery in the lateral skull has not yet happened. The aim of this review is to identify challenges that need to be solved in order to provide image guidance solutions that are safe and beneficial for use during lateral skull surgery and to synthesize factors that facilitate the development of such solutions. Methods: Literature search was conducted via PubMed using terms relating to image guidance and the lateral skull. Data extraction included the following variables: image guidance error, imaging resolution, image guidance system, tracking technology, registration method, study endpoints, clinical target application, and publication year. A subsequent search of FDA 510(k) database for identified image guidance systems and extraction of the year of approval, intended use, and indications for use was performed. The study objectives and endpoints were subdivided in three time phases and summarized. Furthermore, it was analyzed which factors correlated with the image guidance error. Factor values for which an error ≤0.5 mm (µerror + 3σerror) was measured in more than one study were identified and inspected for time trends. Results: A descriptive statistics-based summary of study objectives and findings separated in three time intervals is provided. The literature provides qualitative and quantitative evidence that image guidance systems must provide an accuracy ≤0.5 mm (µerror + 3σerror) for their safe and beneficial application during surgery in the lateral skull. Spatial tracking accuracy and precision and medical image resolution both correlate with the image guidance accuracy, and all of them improved over the years. Tracking technology with accuracy ≤0.05 mm, computed tomography imaging with slice thickness ≤0.2 mm, and registration based on bone-anchored titanium fiducials are components that provide a sufficient setting for the development of sufficiently accurate image guidance. Conclusion: Image guidance systems must reliably provide an accuracy ≤0.5 mm (µerror + 3σerror) for their safe and beneficial use during surgery in the lateral skull. Advances in tracking and imaging technology contribute to the improvement of accuracy, eventually enabling the development and wide-scale adoption of image guidance solutions that can be used safely and beneficially during lateral skull surgery.

Feasibility of Pediatric Robotic Cochlear Implantation in Phantoms.

OBJECTIVE: To demonstrate the feasibility of robotic cochlear implant surgery in subject specific pediatric phantoms. STUDY DESIGN: Pilot study. MATERIALS AND METHODS: Computed tomographic preoperative encrypted data of 10 pediatric subjects (total of 20 sides) between 8 months and 48 months old, who underwent cochlear implant surgery were studied. Four datasets (n = 8 sides) were selected for investigation of the complete robotic procedure including middle and inner ear access and electrode insertion. RESULTS: The planning of the safe trajectory for the robotic approach was possible in 17 of the cases. In three sides, planning the trajectory was not possible due to the small size of the facial recess. Bone thickness study demonstrated average sufficient bone thickness at the site of screw implantation in general. The complete robotic procure including the drilling and insertion was successfully carried out on all the created phantoms. CONCLUSION: With this work we have demonstrated the feasibility of planning and performing a robotic middle and inner ear access and cochlear implantation (CI) in phantom models of pediatric subjects. To develop and validate the proposed procedure for use in children, next stage optimization of the current surgical workflow and adaptation of the surgical material to pediatric population is necessary.

Impact of nuclear vibrations on van der Waals and Casimir interactions at zero and finite temperature.

Recent advances in measuring van der Waals (vdW) interactions have probed forces on molecules at nanometric separations from metal surfaces and demonstrated the importance of infrared nonlocal polarization response and temperature effects, yet predictive theories for these systems remain lacking. We present a theoretical framework for computing vdW interactions among molecular structures, accounting for geometry, short-range electronic delocalization, dissipation, and collective nuclear vibrations (phonons) at atomic scales, along with long-range electromagnetic interactions in arbitrary macroscopic environments. We primarily consider experimentally relevant low-dimensional carbon allotropes, including fullerenes, carbyne, and graphene, and find that phonons couple strongly with long-range electromagnetic fields depending on molecular dimensionality and dissipation, especially at nanometric scales, creating delocalized phonon polaritons that substantially modify infrared molecular response. These polaritons, in turn, alter vdW interaction energies between molecular and macroscopic structures, producing nonmonotonic power laws and nontrivial temperature variations at nanometric separations feasible in current experiments.

Robotic middle ear access for cochlear implantation: First in man.

To demonstrate the feasibility of robotic middle ear access in a clinical setting, nine adult patients with severe-to-profound hearing loss indicated for cochlear implantation were included in this clinical trial. A keyhole access tunnel to the tympanic cavity and targeting the round window was planned based on preoperatively acquired computed tomography image data and robotically drilled to the level of the facial recess. Intraoperative imaging was performed to confirm sufficient distance of the drilling trajectory to relevant anatomy. Robotic drilling continued toward the round window. The cochlear access was manually created by the surgeon. Electrode arrays were inserted through the keyhole tunnel under microscopic supervision via a tympanomeatal flap. All patients were successfully implanted with a cochlear implant. In 9 of 9 patients the robotic drilling was planned and performed to the level of the facial recess. In 3 patients, the procedure was reverted to a conventional approach for safety reasons. No change in facial nerve function compared to baseline measurements was observed. Robotic keyhole access for cochlear implantation is feasible. Further improvements to workflow complexity, duration of surgery, and usability including safety assessments are required to enable wider adoption of the procedure.

Robotic cochlear implantation: feasibility of a multiport approach in an ex vivo model.

PURPOSE: A recent clinical trial has shown the feasibility of robotic cochlear implantation. The electrode was inserted through the robotically drilled tunnel and an additional access through the external auditory canal was created to provide for means of visualization and manipulation. To obviate the need for this additional access, the utilization of multiple robotically drilled tunnels targeting the round window has been proposed. The objective of this study was to assess the feasibility of electrode insertion through a robotic multiport approach. METHODS: In four ex vivo human head specimens (left side), four trajectories through the facial recess (2x) and the retrofacial and suprameatal region were planned and robotically drilled. Optimal three-port configurations were determined for each specimen by analyzing combinations of three of the four trajectories, where the three trajectories were used for the electrode, endoscopic visualization and manipulative assistance. Finally, electrode insertions were conducted through the optimal configurations. RESULTS: The electrodes could successfully be inserted, and the procedure sufficiently visualized through the facial recess drill tunnels in all specimens. Effective manipulative assistance for sealing the round window could be provided through the retrofacial tunnel. CONCLUSIONS: Electrode insertion through a robotic three-port approach is feasible. Drill tunnels through the facial recess for the electrode and endoscope allow for optimized insertion angles and sufficient visualization. Through a retrofacial tunnel effective manipulation for sealing is possible.

Noninvasive Registration Strategies and Advanced Image Guidance Technology for Submillimeter Surgical Navigation Accuracy in the Lateral Skull Base.

HYPOTHESIS: Combining novel registration strategies and advanced image guidance technology enable submillimeter accurate and noninvasive navigation for middle ear and lateral skull base surgery. BACKGROUND: Surgery in the internal auditory canal and the petrous apex present a cognitive and motoric challenge for the surgeon. To date, image guidance rarely assists these procedures, mainly due to the lack of navigation solutions providing submillimeter accuracy associated with low cost in terms of invasiveness, radiation, and time. METHODS: This study proposes an approach to clinically viable image guidance by using a combination of advanced image guidance technology and noninvasive registration strategies. Based on accuracy-optimized optical tracking hardware (accuracy: 0.05 ±â€Š0.025 mm), 14 novel registration strategies were investigated. In human cadaveric temporal bone specimens n = 36 registration attempts per strategy were conducted. Target registration errors at 10 anatomical targets were measured. RESULTS: The most accurate registration strategies were identified as paired-point-matching using eight landmarks located in the external auditory canal and middle ear and surface matching using combined surfaces of the middle ear, the external auditory canal and the mastoid cortex yielding target registration errors of 0.51 ±â€Š0.28 mm and 0.36 ±â€Š0.13 mm respectively. CONCLUSIONS: This study demonstrates submillimeter TREs achieved with noninvasive, anatomy-based registration strategies in combination with advanced image guidance technology. Clinically viable LSB and ME navigation is realized without additional invasiveness, radiation and time associated with artificial fiducials. The appropriate registration strategy can be chosen by the surgeon depending on the pathology and surgical approach.