Cryo-EM Map Anisotropy Can Be Attenuated by Map Post-Processing and a New Method for Its Estimation.

One of the most important challenges in cryogenic electron microscopy (cryo-EM) is the substantial number of samples that exhibit preferred orientations, which leads to an uneven coverage of the projection sphere. As a result, the overall quality of the reconstructed maps can be severely affected, as manifested by the presence of anisotropy in the map resolution. Several methods have been proposed to measure the directional resolution of maps in tandem with experimental protocols to address the problem of preferential orientations in cryo-EM. Following these works, in this manuscript we identified one potential limitation that may affect most of the existing methods and we proposed an alternative approach to evaluate the presence of preferential orientations in cryo-EM reconstructions. In addition, we also showed that some of the most recently proposed cryo-EM map post-processing algorithms can attenuate map anisotropy, thus offering alternative visualization opportunities for cases affected by moderate levels of preferential orientations.

ECL cytosensor for sensitive and label-free detection of circulating tumor cells based on hierarchical flower-like gold microstructures.

The development of sensitive and efficient cell sensing strategies to detect circulating tumor cells (CTCs) in peripheral blood is crucial for the early diagnosis and prognostic assessment of cancer clinical treatment. Herein, an array of hierarchical flower-like gold microstructures (HFGMs) with anisotropic nanotips was synthesized by a simple electrodeposition method and used as a capture substrate to construct an ECL cytosensor based on the specific recognition of target cells by aptamers. The complex topography of the HFGMs array not only catalyzed the enhancement of ECL signals, but also induced the cells to generate more filopodia, improving the capture efficiency and shortening the capture time. The effect of topographic roughness on cell growth and adhesion propensity was also investigated, while the cell capture efficiency was proposed to be an important indicator affecting the accuracy of the ECL cytosensor. In addition, the capture of cells on the electrode surface increased the steric hindrance, which caused ECL signal changes in the Ru(bpy)32+ and TPrA system, realizing the quantitative detection of MCF-7 cells. The detection range of the sensor was from 102 to 106 cells mL-1 and the detection limit was 18 cells mL-1. The proposed detection method avoids the process of separation, labeling and counting, which has great potential for sensitive detection in clinical applications.

Diffusion tensor imaging in anisotropic tissues: application of reduced gradient vector schemes in peripheral nerves.

BACKGROUND: In contrast to the brain, fibers within peripheral nerves have distinct monodirectional structure questioning the necessity of complex multidirectional gradient vector schemes for DTI. This proof-of-concept study investigated the diagnostic utility of reduced gradient vector schemes in peripheral nerve DTI. METHODS: Three-Tesla magnetic resonance neurography of the tibial nerve using 20-vector DTI (DTI20) was performed in 10 healthy volunteers, 12 patients with type 2 diabetes, and 12 age-matched healthy controls. From the full DTI20 dataset, three reduced datasets including only two or three vectors along the x- and/or y- and z-axes were built to calculate major parameters. The influence of nerve angulation and intraneural connective tissue was assessed. The area under the receiver operating characteristics curve (ROC-AUC) was used for analysis. RESULTS: Simplified datasets achieved excellent diagnostic accuracy equal to DTI20 (ROC-AUC 0.847-0.868, p ≤ 0.005), but compared to DTI20, the reduced models yielded mostly lower absolute values of DTI scalars: median fractional anisotropy (FA) ≤ 0.12; apparent diffusion coefficient (ADC) ≤ 0.25; axial diffusivity ≤ 0.96, radial diffusivity ≤ 0.07). The precision of FA and ADC with the three-vector model was closest to DTI20. Intraneural connective tissue was negatively correlated with FA and ADC (r ≥ -0.49, p < 0.001). Small deviations of nerve angulation had little effect on FA accuracy. CONCLUSIONS: In peripheral nerves, bulk tissue DTI metrics can be approximated with only three predefined gradient vectors along the scanner's main axes, yielding similar diagnostic accuracy as a 20-vector DTI, resulting in substantial scan time reduction. RELEVANCE STATEMENT: DTI bulk tissue parameters of peripheral nerves can be calculated with only three predefined gradient vectors at similar diagnostic performance as a standard DTI but providing a substantial scan time reduction. KEY POINTS: • In peripheral nerves, DTI parameters can be approximated using only three gradient vectors. • The simplified model achieves a similar diagnostic performance as a standard DTI. • The simplified model allows for a significant acceleration of image acquisition. • This can help to introduce multi-b-value DTI techniques into clinical practice.

Engineering an artificial catch bond using mechanical anisotropy.

Catch bonds are a rare class of protein-protein interactions where the bond lifetime increases under an external pulling force. Here, we report how modification of anchor geometry generates catch bonding behavior for the mechanostable Dockerin G:Cohesin E (DocG:CohE) adhesion complex found on human gut bacteria. Using AFM single-molecule force spectroscopy in combination with bioorthogonal click chemistry, we mechanically dissociate the complex using five precisely controlled anchor geometries. When tension is applied between residue #13 on CohE and the N-terminus of DocG, the complex behaves as a two-state catch bond, while in all other tested pulling geometries, including the native configuration, it behaves as a slip bond. We use a kinetic Monte Carlo model with experimentally derived parameters to simulate rupture force and lifetime distributions, achieving strong agreement with experiments. Single-molecule FRET measurements further demonstrate that the complex does not exhibit dual binding mode behavior at equilibrium but unbinds along multiple pathways under force. Together, these results show how mechanical anisotropy and anchor point selection can be used to engineer artificial catch bonds.

Characterization of the layer, direction and time-dependent mechanical behaviour of the human oesophagus and the effects of formalin preservation.

The mechanical characterization of the oesophagus is essential for applications such as medical device design, surgical simulations and tissue engineering, as well as for investigating the organ's pathophysiology. However, the material response of the oesophagus has not been established ex vivo in regard to the more complex aspects of its mechanical behaviour using fresh, human tissue: as of yet, in the literature, only the hyperelastic response of the intact wall has been studied. Therefore, in this study, the layer-dependent, anisotropic, visco-hyperelastic behaviour of the human oesophagus was investigated through various mechanical tests. For this, cyclic tests, with increasing stretch levels, were conducted on the layers of the human oesophagus in the longitudinal and circumferential directions and at two different strain rates. Additionally, stress-relaxation tests on the oesophageal layers were carried out in both directions. Overall, the results show discrete properties in each layer and direction, highlighting the importance of treating the oesophagus as a multi-layered composite material with direction-dependent behaviour. Previously, the authors conducted layer-dependent cyclic experimentation on formalin-embalmed human oesophagi. A comparison between the fresh and embalmed tissue response was carried out and revealed surprising similarities in terms of anisotropy, strain-rate dependency, stress-softening and hysteresis, with the main difference between the two preservation states being the magnitude of these properties. As formalin fixation is known to notably affect the formation of cross-links between the collagen of biological materials, the differences may reveal the influence of cross-links on the mechanical behaviour of soft tissues.

17O Solid-State NMR Spectroscopy of Lipid Membranes.

Despite the limitations posed by poor sensitivity, studies have reported the unique advantages of 17O based NMR spectroscopy to study systems existing in liquid, solid, or semisolid states. 17O NMR studies have exploited the remarkable sensitivity of quadrupole coupling and chemical shift anisotropy tensors to the local environment in the characterization of a variety of intra- and intermolecular interactions and motion. Recent studies have considerably expanded the use of 17O NMR to study dynamic intermolecular interactions associated with some of the challenging biological systems under magic angle spinning (MAS) and aligned conditions. The very fast relaxing nature of 17O has been well utilized in cellular and in vivo MRS (magnetic resonance spectroscopy) and MRI (magnetic resonance imaging) applications. The main focus of this Review is to highlight the new developments in the biological solids with a detailed discussion for a few selected examples including membrane proteins and nanodiscs. In addition to the unique benefits and limitations, the remaining challenges to overcome, and the impacts of higher magnetic fields and sensitivity enhancement techniques are discussed.

In-Bath 3D Printing of Anisotropic Shape-Memory Cryogels Functionalized with Bone-Bioactive Nanoparticles.

Cryogels exhibit unique shape memory with full recovery and structural stability features after multiple injections. These constructs also possess enhanced cell permeability and nutrient diffusion when compared to typical bulk hydrogels. Volumetric processing of cryogels functionalized with nanosized units has potential to widen their biomedical applications, however this has remained challenging and relatively underexplored. In this study, we report a novel methodology that combines suspension 3D printing with directional freezing for the fabrication of nanocomposite cryogels with configurable anisotropy. When compared to conventional bulk or freeze-dried hydrogels, nanocomposite cryogel formulations exhibit excellent shape recovery (>95%) and higher pore connectivity. Suspension printing, assisted with a prechilled metal grid, was optimized to induce anisotropy. The addition of calcium- and phosphate-doped mesoporous silica nanoparticles into the cryogel matrix enhanced bioactivity toward orthopedic applications without hindering the printing process. Notably, the nanocomposite 3D printed cryogels exhibit injectable shape memory while also featuring a lamellar topography. The fabrication of these constructs was highly reproducible and exhibited potential for a cell-delivery injectable cryogel with no cytotoxicity to human-derived adipose stem cells. Hence, in this work, it was possible to combine a gravity defying 3D printed methodology with injectable and controlled anisotropic macroporous structures containing bioactive nanoparticles. This methodology ameliorates highly tunable injectable 3D printed anisotropic nanocomposite cryogels with a user-programmable degree of structural complexity.

Atypical brain structural connectivity and social cognition in childhood maltreatment and peer victimisation.

BACKGROUND: Childhood maltreatment (CM) is associated with neurobiological aberrations and atypical social cognition. Few studies have examined the neural effects of another common early-life interpersonal stressor, namely peer victimisation (PV). This study examines the associations between tract aberrations and childhood interpersonal stress from caregivers (CM) and peers (PV), and explores how the observed tract alterations are in turn related to affective theory of mind (ToM). METHODS: Data from 107 age-and gender-matched youths (34 CM [age = 19.9 ± 1.68; 36%male], 35 PV [age = 19.9 ± 1.65; 43%male], 38 comparison subjects [age = 20.0 ± 1.66; 42%male] were analysed using tractography and whole-brain tract-based spatial statistics (TBSS). RESULTS: At the whole-brain level using TBSS, the CM group had higher fractional anisotropy (FA) than the PV and comparison groups in a cluster of predominantly limbic and corpus callosal pathways. Segmented tractography indicated the CM group had higher FA in right uncinate fasciculus compared to both groups. They also had smaller right anterior thalamic radiation (ATR) tract volume than the comparison group and higher left ATR FA than the PV group, with these metrics associated with higher emotional abuse and enhanced affective ToM within the CM group, respectively. The PV group had lower inferior fronto-occipital fasciculus FA than the other two groups, which was related to lower affective ToM within the PV group. CONCLUSION: Findings suggest that exposure to early-life stress from caregivers and peers are differentially associated with alterations of neural pathways connecting the frontal, temporal and occipital cortices involved in cognitive and affective control, with possible links to their atypical social cognition.

Coupling dynamic response of saturated soil with anisotropic thermal conductivity under fractional order thermoelastic theory.

In this paper, a two-dimensional (2D) thermo-hydro-mechanical dynamic (THMD) coupling analysis in the presence of a half-space medium is studied using Ezzat's fractional order generalized theory of thermoelasticity. Using normal mode analysis (NMA), the influence of the anisotropy of the thermal conduction coefficient, fractional derivatives, and frequency on the THMD response of anisotropy, fully saturated, and poroelastic subgrade is then analyzed with a time-harmonic load including mechanical load and thermal source subjected to the surface. The general relationships among the dimensionless physical variables such as the vertical displacement, excess pore water pressure, vertical stress, and temperature distribution are graphically illustrated. The NMA method does not require the integration and inverse transformation, increases the decoupling speed, and eliminates the limitation of numerical inverse transformation. The obtained results can guide the geotechnical engineering construction according to different values of load frequency, fractional order coefficient, and anisotropy of thermal conduction coefficient. This improves the subgrade stability and enriches the theoretical studies on thermo-hydro-mechanical coupling.

Electronic, optical, and thermoelectric characteristics of (Ae)xFBiS2 (Ae=Sr, Ba, and x=1.7) layered materials useful in optical modulator devices.

The recent discovery of superconductivity behavior in the mother BiS2-layered compounds has captivated the attention of several physicists. The crystal structure of superconductors with alternate layers of BiS2 is homologous to that of cuprates and Fe-based superconductors. The full-potential linearized augmented plane-wave (FP-LAPW) technique was utilized to investigate the electronic structures and density of states in the vicinity of the Fermi energy of SrFBiS2 and BaFBiS2 compounds under the electron carriers doping. The introduction of electron doping (carries doping) reveals that the host compounds SrFBiS2 and BaFBiS2 exhibit features indicative of superconductivity. This carrier doping of SrFBiS2 and BaFBiS2 compounds (electron-doped) has a significant impact on the lowest conduction states near the Fermi level for the emergence of the superconducting aspect. The electron doping modifies and induces changes in the electronic structures with superconducting behavior in (Ae)1.7FBiS2(Ae=Sr,Ba) compounds. A Fermi surface nesting occurred under the modification of electrons (carriers) doping in the host compounds SrFBiS2 and BaFBiS2. Furthermore, the optical characteristics of the carrier-doped SrFBiS2 and BaFBiS2 compounds are simulated. Due to the anisotropic behavior, the optical properties of these materials based on BiS2 demonstrate a pronounced polarization dependency. The starting point at zero photon energy in the infrared region is elucidated by considering the Drude features in the optical conductivity spectra of SrFBiS2 and BaFBiS2 compounds, when the electron carriers doping is applied. It was clearly noticed that the spin-orbit coupling (SOC) influences the electronic band structures, density of states, Femi surface, and optical features because of the heavy Bismuth atom, which may disclose fascinating aspects. Further, we conducted simulations to assess the thermoelectric properties of these mother compounds. The two BiS2-layered compounds could be suitable for practical thermoelectric purposes and are highlighted through assessment of electrical conductivity, thermal conductivity, Seebeck coefficient, and power factor. As a result, we propose that the mechanisms of superconducting behavior in BiS2 family may pave new avenues for investigating the field of unconventional superconductivity. It may also provide new insights into the origin of high-Tc superconductivity nature.

Induction for Self-Propelled Motion of Artificial Objects with/without Shape Anisotropy.

Motion is an essential feature of living systems. Microorganisms autonomously change their nature in response to slight changes in the surrounding environment induced by external stimuli and exhibit unique motion modes. Various self-propelled objects have been constructed to understand these behaviors. Towards achievement of such purpose, the precise settings of experimental conditions including fabrication of objects with a shape anisotropy have been made attempts in the field of active matter and supramolecular chemistry. This review describes the recent progress in inducing the self-propelled motion of artificial objects. If life-like dynamic behavior such as self-propelled motion can be designed and experimentally induced from molecular properties, it will be easier to control functions expressed as outputs. This will lead to not only a better understanding of the complex functions in living systems, but also the fabrication of exotic materials with life-like properties.

Corpus callosum and cerebellum participate in semantic dysfunction of Parkinson's disease: a diffusion tensor imaging-based cross-sectional study.

Language dysfunction is common in Parkinson's disease (PD) patients, among which, the decline of semantic fluency is usually observed. This study aims to explore the relationship between white matter (WM) alterations and semantic fluency changes in PD patients. 127 PD patients from the Parkinson's Progression Markers Initiative cohort who received diffusion tensor imaging scanning, clinical assessment and semantic fluency test (SFT) were included. Tract-based special statistics, automated fiber quantification, graph-theoretical and network-based analyses were performed to analyze the correlation between WM structural changes, brain network features and semantic fluency in PD patients. Fractional anisotropy of corpus callosum, anterior thalamic radiation, inferior front-occipital fasciculus, and uncinate fasciculus, were positively correlated with SFT scores, while a negative correlation was identified between radial diffusion of the corpus callosum, inferior longitudinal fasciculus, and SFT scores. Automatic fiber quantification identified similar alterations with more details in these WM tracts. Brain network analysis positively correlated SFT scores with nodal efficiency of cerebellar lobule VIII, and nodal local efficiency of cerebellar lobule X. WM integrity and myelin integrity in the corpus callosum and several other language-related WM tracts may influence the semantic function in PD patients. Damage to the cerebellum lobule VIII and lobule X may also be involved in semantic dysfunction in PD patients.

Optical Sensor System for 3D Jones Matrix Reconstruction of Optical Anisotropy Maps of Self-Assembled Polycrystalline Soft Matter Films.

Our work uses a polarization matrix formalism to analyze and algorithmically represent optical anisotropy by open dehydration of blood plasma films. Analytical relations for Jones matrix reconstruction of optical birefringence maps of protein crystal networks of dehydrated biofluid films are found. A technique for 3D step-by-step measurement of the distributions of the elements of the Jones matrix or Jones matrix images (JMI) of the optically birefringent structure of blood plasma films (BPF) has been created. Correlation between JMI maps and corresponding birefringence images of dehydrated BPF and saliva films (SF) obtained from donors and prostate cancer patients was determined. Within the framework of statistical analysis of layer-by-layer optical birefringence maps, the parameters most sensitive to pathological changes in the structure of dehydrated films were found to be the central statistical moments of the 1st to 4th orders. We physically substantiated and experimentally determined the sensitivity of the method of 3D polarization scanning technique of BPF and SF preparations in the diagnosis of endometriosis of uterine tissue.

Investigating female versus male differences in white matter neuroplasticity associated with complex visuo-motor learning.

Magnetic resonance imaging (MRI) has increasingly been used to characterize structure-function relationships during white matter neuroplasticity. Biological sex differences may be an important factor that affects patterns of neuroplasticity, and therefore impacts learning and rehabilitation. The current study examined a participant cohort before and after visuo-motor training to characterize sex differences in microstructural measures. The participants (N = 27) completed a 10-session (4 week) complex visuo-motor training task with their non-dominant hand. All participants significantly improved movement speed and their movement speed variability over the training period. White matter neuroplasticity in females and males was examined using fractional anisotropy (FA) and myelin water fraction (MWF) along the cortico-spinal tract (CST) and the corpus callosum (CC). FA values showed significant differences in the middle portion of the CST tract (nodes 38-51) across the training period. MWF showed a similar cluster in the inferior portion of the tract (nodes 18-29) but did not reach significance. Additionally, at baseline, males showed significantly higher levels of MWF measures in the middle body of the CC. Combining data from females and males would have resulted in reduced sensitivity, making it harder to detect differences in neuroplasticity. These findings offer initial insights into possible female versus male differences in white matter neuroplasticity during motor learning. This warrants investigations into specific patterns of white matter neuroplasticity for females versus males across the lifespan. Understanding biological sex-specific differences in white matter neuroplasticity may have significant implications for the interpretation of change associated with learning or rehabilitation.

The use of NADH anisotropy to investigate mitochondrial cristae alignment.

Life may be expressed as the flow of electrons, protons, and other ions, resulting in large potential difference. It is also highly photo-sensitive, as a large proportion of the redox capable molecules it relies on are chromophoric. It is thus suggestive that a key organelle in eukaryotes, the mitochondrion, constantly adapt their morphology as part of the homeostatic process. Studying unstained in vivo nano-scale structure in live cells is technically very challenging. One option is to study a central electron carrier in metabolism, reduced nicotinamide adenine dinucleotide (NADH), which is fluorescent and mostly located within mitochondria. Using one and two-photon absorption (340-360 nm and 730 nm, respectively), fluorescence lifetime imaging and anisotropy spectroscopy of NADH in solution and in live cells, we show that mitochondria do indeed appear to be aligned and exhibit high anisotropy (asymmetric directionality). Aqueous solution of NADH showed an anisotropy of ~ 0.20 compared to fluorescein or coumarin of < 0.1 and 0.04 in water respectively and as expected for small organic molecules. The anisotropy of NADH also increased further to 0.30 in the presence of proteins and 0.42 in glycerol (restricted environment) following two-photon excitation, suggesting more ordered structures. Two-photon NADH fluorescence imaging of Michigan Cancer Foundation-7 (MCF7) also showed strong anisotropy of 0.25 to 0.45. NADH has a quantum yield of fluorescence of 2% compared to more than 40% for photoionisation (electron generation), when exposed to light at 360 nm and below. The consequence of such highly ordered and directional NADH patterns with respect to electron ejection upon ultra-violet (UV) excitation could be very informative-especially in relation to ascertaining the extent of quantum effects in biology, including electron and photonic cascade, communication and modulation of effects such as spin and tunnelling.

Anisotropic plates with architected tendon network.

We synthesize geometrically tailorable anisotropic plates by combining button shaped fish-scale like features on soft substrates, then lacing them with high-stiffness strings. This creates a new type of biomimetic architectured structure with multiple broken symmetries. First, the tendons and substrate together break the symmetry of the bending response between the concave and convex curvature. Next, the weave pattern of the tendons further breaks symmetry along the two directors of plates. The anisotropy is clearly evident in 3-point bending experiments. Motivated by these experiments and the need for design, we formulate an analytical energy-based model to quantify the anisotropic elasticity. The derived architecture-property relationships can be used to design architected tendon plates with desirable properties.

Janus microparticles-based targeted and spatially-controlled piezoelectric neural stimulation via low-intensity focused ultrasound.

Electrical stimulation is a fundamental tool in studying neural circuits, treating neurological diseases, and advancing regenerative medicine. Injectable, free-standing piezoelectric particle systems have emerged as non-genetic and wireless alternatives for electrode-based tethered stimulation systems. However, achieving cell-specific and high-frequency piezoelectric neural stimulation remains challenging due to high-intensity thresholds, non-specific diffusion, and internalization of particles. Here, we develop cell-sized 20 µm-diameter silica-based piezoelectric magnetic Janus microparticles (PEMPs), enabling clinically-relevant high-frequency neural stimulation of primary neurons under low-intensity focused ultrasound. Owing to its functionally anisotropic design, half of the PEMP acts as a piezoelectric electrode via conjugated barium titanate nanoparticles to induce electrical stimulation, while the nickel-gold nanofilm-coated magnetic half provides spatial and orientational control on neural stimulation via external uniform rotating magnetic fields. Furthermore, surface functionalization with targeting antibodies enables cell-specific binding/targeting and stimulation of dopaminergic neurons. Taking advantage of such functionalities, the PEMP design offers unique features towards wireless neural stimulation for minimally invasive treatment of neurological diseases.

Diffusion tensor imaging of white-matter structural features of maltreating mothers and their associations with intergenerational chain of childhood abuse.

Child abuse causes lifelong adverse outcomes for both physical and mental health, although many are resilient. Efforts to prevent this issue from the parental side require an understanding of the neurobiological basis that leads abusive parents to perpetrate abuse and the influence of the intergenerational chain of childhood abuse. Therefore, this study was conducted to compare the brain white-matter fiber structures between 11 maltreating mothers who had been recognized as having conducted child abuse prior to the intervention and 40 age-matched control mothers using tract-based spatial statistics. There was a significantly reduced axial diffusivity (AD) and a similar trend in fractional anisotropy (FA) in the right corticospinal tract in maltreating mothers compared to control mothers. Therefore, maltreating mothers may have excessive control over the forcefulness of voluntary movements. These features also decreased as the number of childhood abuse experiences increased, suggesting that an intergenerational chain of child abuse may also be involved. Other aspects observed were that the higher the current depressive symptoms, the lower the AD and FA values; however, they were not related to parental practice or empathy. These results corroborate the neurobiological features that perpetrate behaviors in abusive mothers.

An integrated model of the human cornea as a linear biaxial birefringent medium.

A novel model of human corneal birefringence is presented. The cornea is treated as a homogeneous biaxial linear birefringent medium in which the values of the binormal axes angle and organization of the main refractive indices vary continuously from the apex to the limbus. In its central part, the angle between binormal axes is 35°, and para centrally, it smoothly increases to 83.7°. The values of the main refractive indices (nx, ny, nz) change, as well as their order, from nx < nz < ny to nz < nx < ny. The transition between these two states was described with a normal distribution (µ = 0.45, σ = 0.1). The presented model corresponds with the experimental results presented in the literature. To our knowledge, it is the first model that presents the anisotropic properties' distributions of the entire cornea. The presented model facilitates a better understanding of the corneal birefringence phenomenon directly related to its lamellar structure.

Microstructural abnormality of white matter tracts in rheumatoid arthritis.

BACKGROUND: Structural and functional brain imaging studies have reported abnormalities of gray matter morphology and functional activities in patients with rheumatoid arthritis (RA). However, it is largely unknown whether patients with RA show alterations of white matter microstructural organization. OBJECTIVES: To automatically identify alteration of white matter microstructure in patients with RA and further examine how this alteration associates with clinical characteristics. METHODS: This single-institutional prospective study included 66 participants (33 patients with RA [52 ± 9 years, 29 women] and 33 sex/age-matched healthy controls [53 ± 12 years, 27 women]), who underwent diffusion MRI scan from January 2021 to December 2021. The white matter microstructure was assessed using fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity. Voxelwise analyses were conducted on white matter skeleton using an automated, observer-independent tract-based spatial statistics analysis. The relationship between white matter microstructural alterations and clinical and neuropsychological variables was evaluated using correlation analysis. RESULTS: Compared with healthy controls, patients with RA exhibited lower fractional anisotropy in several major white matter tracts (threshold-free cluster enhancement at P < 0.05 for multiple comparison correction, permutation test), involving the forceps minor, bilateral inferior fronto-occipital fasciculus, bilateral anterior thalamic radiation, and bilateral uncinate fasciculus. Lower fractional anisotropy values in the patients with RA were significantly associated with pain-related assessments, including tender joint count (r = -0.43, P = 0.015), Clinical Disease Activity Index score (r = -0.36, P = 0.049), pain severity rated through visual analogue scale (r = -0.45, P = 0.012), and Simplified Disease Activity Index score (r = -0.36, P = 0.045). No significant group difference was found in mean diffusivity, axial diffusivity, and radial diffusivity. CONCLUSIONS: We report the first anatomical evidence for aberrant microstructure organization of several major white matter tracts and its associations with pain processing in patients with rheumatoid arthritis.