Cortical Geometry Research Articles

7140 Assessing Bone Mineral Density and Cortical Geometry Using High-resolution Peripheral Quantitative Computed Tomography and Dual Energy X-ray Absorptiometry in Pediatric Survivors of High-risk Neuroblastoma with Growth Failure

Abstract Disclosure: S. Gera: None. M. Guo: None. N. Pollock: None. I. Hampton: None. M. Song: None. D. Weber: None. M. Denburg: None. S. Mostoufi-Moab: None. Introduction: Survival of children with high-risk neuroblastoma (HR-NBL) has increased with multimodal therapy. Cis-retinoic acid (cis-RA), cornerstone of HR-NBL therapy, can cause osteoporosis and premature physeal closure, posing a threat to skeletal structure. HR-NBL survivors demonstrate profound growth failure. DXA measures areal bone mineral density (aBMD). DXA is confounded by short stature and fails to distinguish between trabecular and cortical bone. We previously reported no significant difference in height-per-age adjusted aBMD-Z in HR-NBL survivors compared to healthy controls[1]. However, aBMD-Z in severe short stature may attenuate bone density deficits. High-resolution peripheral quantitative computed tomography (HRpQCT) yields 3D measures of volumetric BMD and bone architecture. Objectives: Assess volumetric BMD (vBMD) and cortical structure using distal tibia HRpQCT and leg lean mass by DXA in HR-NBL survivors compared to healthy controls in a cross-sectional study. Methods: We prospectively enrolled 20 HR-NBL survivors (median age 12.2 yrs, range 9.5 to 15.8, 7 female) treated with cis-RA (median age 2.6 yrs at start of therapy, range 0.3-9.1), and 20 age-, sex-, and race-matched healthy controls. We assessed leg lean mass adjusted for leg length by DXA. For HRpQCT, we compared tibia length (cm), cortical and trabecular vBMD (mg HA/cm3), geometry parameters (cortical and trabecular area [mm2]), and structural parameters (cortical thickness [μm] and porosity, trabecular number [mm-[1]] and separation [μm]). Outcomes were compared using Student’s t-test or Mann-Whitney U test. Linear regression models assessed difference in outcomes of bone microarchitecture and leg lean mass between both groups. Results: Compared to controls, tibia length was significantly shorter in HR-NBL survivors (32.3 ± 0.8 vs. 35.7 ± 0.6, P<0.005). HR-NBL survivors demonstrated lower cortical area (187.6 ± 43.8 vs. 218.7 ± 42.3, P<0.05), cortical perimeter (62.4 ± 7.71 vs. 69.5 ± 8.1, P<0.01), and leg lean mass Z-score (-1.47 ± 1.34 vs. -0.20 ± 0.84, P<0.001) compared to controls. Cortical geometry deficits were explained by muscle deficits (P<0.001). Trabecular area, BMC, areal and volumetric BMD, and measures of bone structure were not significantly different in HR-NBL survivors compared to controls. IGF-1 and 25-OH D levels had no significant effects on DXA or HRpQCT parameters. Conclusion: Bone density is not severely impacted in HR-NBL survivors. Muscle deficits persist years after treatment and explain cortical geometry deficits. HRpQCT substantiates prior DXA evaluation in HR-NBL survivors with significant short stature, demonstrating preserved bone density and structure. 1.Guo et al. Sarcopenia and preserved bone mineral density in pediatric survivors of high-risk neuroblastoma with growth failure. J Cachexia Sarcopenia Muscle. 2021 Aug;12(4):1024-1033. Presentation: 6/3/2024

QCT-based spatio-temporal aging atlas of the proximal femur BMD and cortical geometry

Aging is associated with an increased risk of fragility fractures at the hip, resulting from a loss of bone mass. While this loss is typically reported as a decreased mean areal bone mineral density (aBMD) in the proximal femur or the femoral neck, its evolution is spatially inhomogeneous, which might also contribute to the increased risk of fractures. Yet, little is known about the evolution of BMD distribution and cortical thickness with age in the proximal femur. We propose a 3D spatio-temporal atlas of the proximal femur to identify regions with high BMD losses and cortical thinning. The atlas is based on 532 post-mortem QCT scans from donors aged 20 to 94, including 179 female subjects. A point cloud with anatomically corresponding positions was defined for each femur based on a personalized coordinate system. The evolution of BMD and cortical thickness was computed as a multiple linear regression with age and BMI, for female and male subjects separately. The average BMD decrease with age was significant in all subregions for both sexes but higher in females. High BMD losses were observed in the superior and middle neck regions, in the medial part of the head, and in the trochanteric trabecular bone. BMD was well preserved in the inferior neck and, for males, in cortical regions. In both sexes, the cortical thickness decreased significantly in the superior and posterior neck cortex and increased significantly in the inferior neck. Higher BMI was associated with increased BMD in the inferior neck and medial shaft cortex, as well as with increased cortical thickness in all neck and shaft regions for both sexes. The spatio-temporal atlas showed the evolution of BMD distribution and cortical thickness in the proximal femur, with high losses in typical fracture locations, such as the femoral neck and pertrochanteric regions.

Tibial Bone Co-Morbidities Following Volumetric Muscle Loss Injury and Physical Inactivity

Volumetric muscle loss (VML) injuries are a traumatic loss of muscle, limiting regenerative potential and resulting in chronic loss of function. In isolation the bone adjacent to the VML injury is often overlooked, but known association between the tissues are important to long-term health and function. Recent work suggests decrements in both bones and muscles of VML-injured limbs, as well as a distinct relationship between VML and bone health. The clinically injured VML population is expected to undergo considerable periods of physical inactivity or a long-term sedentary lifestyle, and thus decreased loading, after VML. Our objective was to investigate the concomitant impact of VML on the adjacent bone, with and without the restriction of physical activity (reduced ~50% of daily ambulation). We hypothesized that with restriction of physical activity, the tibia adjacent to the VML would have functional impairments greater than those with normal physical activity (daily ambulation >1km). Adult male C57BI/6J mice (n=41) underwent unilateral VML to the posterior hindlimb compartment or served as uninjured age-matched controls, then were randomized to standard or restricted activity cages for 8-wks. Terminally (age 20-wks), mice underwent in vivo muscle function testing. Adjacent tibia were assessed for strength, mid‐diaphysis cortical geometry, and intrinsic material properties, and the metaphyseal trabecular bone structure was evaluated by microcomputed tomography and three‐point bending. A subset of tibias was saved for histologic staining (H&E, TRAP). Data were evaluated by two-way ANOVA. There were no absolute or normalized functional muscle deficits following 8-wks of inactivity. That said, there were significant VML-functional deficits (~42% of uninjured) that are not exacerbated by inactivity (p<0.001). Cortical geometric changes in the bone were primarily a result of physical inactivity, with thickness and cross-sectional moment of inertia both diminished independent of injury (p≤0.018). However, there were no differences in cortical bone volume, diameter, or cross-sectional area (p≥0.056). Trabecular bone mineral density was lower in all VML-injured tibias compared to uninjured (p=0.003). While there was no difference across groups for trabecular spacing (p>0.397), there was a reduction in bone mineral density across all VML-injured, compared to uninjured tibias (p=0.003). The functional capacity of the tibia to resist fracture (i.e., ultimate load during 3‐point bending) was ~21% lower with inactivity (p=0.018), while there was only a trend for VML injury to impact resistance to fracture. Stiffness was calculated during the onset to ultimate load and ~15% less in the VML injured and inactivity VML tibias (p=0.016). Tibia of VML injured and inactive groups appear to have greater lipid accumulation compared to uninjured tibias. While discordant with muscle function, physical activity restriction with and without VML injury impairs adjacent tibia. Inactivity alone had the greatest impact on the cortical bone properties, while VML with and without physical inactivity impacted trabecular tibia properties. This study demonstrates the impact of VML with and without physical inactivity on the tibia, furthering the complexity of traumatic injury on the musculoskeletal system. W81XWH‐20‐10885 (JAC & SMG); S10OD025177. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Combining raloxifene and mechanical loading improves bone composition and mechanical properties in a murine model of chronic kidney disease (CKD)

IntroductionPatients with chronic kidney disease (CKD) are at an alarming risk of fracture compared to age and sex-matched non-CKD individuals. Clinical and preclinical data highlight two key factors in CKD-induced skeletal fragility: cortical porosity and reduced matrix-level properties including bone hydration. Thus, strategies are needed to address these concerns to improve mechanical properties and ultimately lower fracture risk in CKD. We sought to evaluate the singular and combined effects of mechanical and pharmacological interventions on modulating porosity, bone hydration, and mechanical properties in CKD. MethodsSixteen-week-old male C57BL/6J mice underwent a 10-week CKD induction period via a 0.2 % adenine-laced casein-based diet (n = 48) or remained as non-CKD littermate controls (Con, n = 48). Following disease induction (26 weeks of age), n = 7 CKD and n = 7 Con were sacrificed (baseline cohort) to confirm a steady-state CKD state was achieved prior to the initiation of treatment. At 27 weeks of age, all remaining mice underwent right tibial loading to a maximum tensile strain of 2050 μƐ 3× a week for five weeks with the contralateral limb as a non-loaded control. Half of the mice (equal number CKD and Con) received subcutaneous injections of 0.5 mg/kg raloxifene (RAL) 5× a week, and the other half remained untreated (UN). Mice were sacrificed at 31 weeks of age. Serum biochemistries were performed, and bi-lateral tibiae were assessed for microarchitecture, whole bone and tissue level mechanical properties, and composition including bone hydration. ResultsRegardless of intervention, BUN and PTH were higher in CKD animals throughout the study. In CKD, the combined effects of loading and RAL were quantified as lower cortical porosity and improved mechanical, material, and compositional properties, including higher matrix-bound water. Loading was generally responsible for positive impacts in cortical geometry and structural mechanical properties, while RAL treatment improved some trabecular outcomes and material-level mechanical properties and was responsible for improvements in several compositional parameters. While control animals responded positively to loading, their bones were less impacted by the RAL treatment, showing no deformation, toughness, or bound water improvements which were all evident in CKD. Serum PTH levels were negatively correlated with matrix-bound water. DiscussionAn effective treatment program to improve fracture risk in CKD ideally focuses on the cortical bone and considers both cortical porosity and matrix properties. Loading-induced bone formation and mechanical improvements were observed across groups, and in the CKD cohort, this included lower cortical porosity. This study highlights that RAL treatment superimposed on active bone formation may be ideal for reducing skeletal complications in CKD by forming new bone with enhanced matrix properties.

Sex-specific effects of Fat-1 transgene on bone material properties, size, and shape in mice.

Western diets are becoming increasingly common around the world. Western diets have high omega 6 (ω-6) and omega 3 (ω-3) fatty acids and are linked to bone loss in humans and animals. Dietary fats are not created equal; therefore, it is vital to understand the effects of specific dietary fats on bone. We aimed to determine how altering the endogenous ratios of ω-6:ω-3 fatty acids impacts bone accrual, strength, and fracture toughness. To accomplish this, we used the Fat-1 transgenic mice, which carry a gene responsible for encoding a ω-3 fatty acid desaturase that converts ω-6 to ω-3 fatty acids. Male and female Fat-1 positive mice (Fat-1) and Fat-1 negative littermates (WT) were given either a high-fat diet (HFD) or low-fat diet (LFD) at 4wk of age for 16wk. The Fat-1 transgene reduced fracture toughness in males. Additionally, male BMD, measured from DXA, decreased over the diet duration for HFD mice. In males, neither HFD feeding nor the presence of the Fat-1 transgene impacted cortical geometry, trabecular architecture, or whole-bone flexural properties, as detected by main group effects. In females, Fat-1-LFD mice experienced increases in BMD compared to WT-LFD mice; however, cortical area, distal femur trabecular thickness, and cortical stiffness were reduced in Fat-1 mice compared to pooled WT controls. However, reductions in stiffness were caused by a decrease in bone size and were not driven by changes in material properties. Together, these results demonstrate that the endogenous ω-6:ω-3 fatty acid ratio influences bone material properties in a sex-dependent manner. In addition, Fat-1 mediated fatty acid conversion was not able to mitigate the adverse effects of HFD on bone strength and accrual.

Transcranial MEP threshold voltages and current densities simulated with finite element modelling

ObjectiveThe aim of this study was to compare stimulation thresholds and current densities in the brain for transcranial motor evoked potentials (tcMEPs) from the hands and feet with linked quadripolar (LQP), M3-M4 and C1-C2 electrode montages. MethodsTwenty-five patients underwent cerebral vascular surgery with tcMEP monitoring. tcMEP voltage thresholds were compared between LQP (C1, M3, C2, M4), C1-C2, and M3-M4 montages. In a finite element model (FEM), hand, arm, and leg regions of interest (ROIs) on the cortical motor homunculus were segmented. Current densities in these ROIs at tcMEP thresholds were compared across tcMEP electrode montages. ResultsLQP tcMEP thresholds were 61.5 volts for hands and 95.2 volts for feet. Thresholds were higher for M3-M4 (hands, 89.4 V; feet, 141.3 V) and C1-C2 (hands: 137.3 V; feet: 194.7 V). Total current at threshold voltage was greater for LQP (hands, 210.9 mA; feet, 311.3 mA) compared to M3-M4 (hands, 166.8 mA; feet, 256.6 mA), but similar to C1-C2 (hands, 246.7 mA; feet, 341.1 mA). In FEM simulations, current density and local current density topography in the hand ROI at threshold were very similar for LQP, M3-M4 and C1-C2. ConclusionsTcMEP voltage thresholds were least for LQP, and lesser for M3-M4 compared to C1-C2. In FEM simulations, resistance to current to hand ROI was ordered the same (LQP < M3-M4 < C1-C2). The local distribution of current density in motor cortex with tcMEP was mainly determined by cortical geometry. SignificanceCurrent densities and resistance to current simulated with FEM may explain threshold requirements for tcMEP electrode montages.

Tibial bone strength is negatively affected by volumetric muscle loss injury to the adjacent muscle in male mice.

This study's objective was to investigate how contractile strength loss associated with a volumetric muscle loss (VML) injury affects the adjacent tibial bone structural and functional properties in male C57BL/6J mice. Mice were randomized into one of two experimental groups: VML-injured mice that were injured at age 12 weeks and aged to 20 weeks (8 weeks postinjury, VML) and 20-week-old age-matched uninjured mice (Uninjured-20). Tibial bone strength, mid-diaphysis cortical geometry, intrinsic material properties, and metaphyseal trabecular bone structure were assessed by three-point bending and microcomputed tomography (µCT). The plantar flexor muscle group (gastrocnemius, soleus, plantaris) was analyzed for its functional capacities, that is, peak-isometric torque and peak-isokinetic power. VML-injured limbs had 25% less peak-isometric torque and 31% less peak-isokinetic power compared to those of Uninjured-20 mice (p < 0.001). Ultimate load, but not stiffness, was significantly less (10%) in tibias of VML-injured limbs compared to those from Uninjured-20 (p = 0.014). µCT analyses showed cortical bone thickness was 6% less in tibias of VML-injured limbs compared to Uninjured-20 (p = 0.001). Importantly, tibial bone cross-section moment of inertia, the primary determinant of bone ultimate load, was 16% smaller in bones of VML-injured limbs compared to bones from Uninjured-20 (p = 0.046). Metaphyseal trabecular bone structure was also altered up to 23% in tibias of VML-injured limbs (p < 0.010). These changes in tibial bone structure and function after a VML injury occur during a natural maturation phase between the age of 12 and 20 weeks, as evidenced by Uninjured-20 mice having greater tibial bone size and strength compared to uninjured-aged 12-week mice.

Germ-Free C57BL/6 Mice Have Increased Bone Mass and Altered Matrix Properties but Not Decreased Bone Fracture Resistance.

The gut microbiome impacts bone mass, which implies a disruption to bone homeostasis. However, it is not yet clear how the gut microbiome affects the regulation of bone mass and bone quality. We hypothesized that germ-free (GF) mice have increased bone mass and decreased bone toughness compared with conventionally housed mice. We tested this hypothesis using adult (20- to 21-week-old) C57BL/6J GF and conventionally raised female and male mice (n = 6-10/group). Trabecular microarchitecture and cortical geometry were measured from micro-CT of the femur distal metaphysis and cortical midshaft. Whole-femur strength and estimated material properties were measured using three-point bending and notched fracture toughness. Bone matrix properties were measured for the cortical femur by quantitative back-scattered electron imaging and nanoindentation, and, for the humerus, by Raman spectroscopy and fluorescent advanced glycation end product (fAGE) assay. Shifts in cortical tissue metabolism were measured from the contralateral humerus. GF mice had reduced bone resorption, increased trabecular bone microarchitecture, increased tissue strength and decreased whole-bone strengththat was not explained by differences in bone size, increased tissue mineralization and fAGEs, and altered collagen structure that did not decrease fracture toughness. We observed several sex differences in GF mice, most notably for bone tissue metabolism. Male GF mice had a greater signature of amino acid metabolism, and female GF mice had a greater signature of lipid metabolism, exceeding the metabolic sex differences of the conventional mice. Together, these data demonstrate that the GF state in C57BL/6J mice alters bone mass and matrix properties but does not decrease bone fracture resistance. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Ex vivo exposure to calcitonin or raloxifene improves mechanical properties of diseased bone through non-cell mediated mechanisms

Raloxifene (RAL) reduces clinical fracture risk despite modest effects on bone mass and density. This reduction in fracture risk may be due to improved material level-mechanical properties through a non-cell mediated increase in bone hydration. Synthetic salmon calcitonin (CAL) has also demonstrated efficacy in reducing fracture risk with only modest bone mass and density improvements. This study aimed to determine if CAL could modify healthy and diseased bone through cell-independent mechanisms that alter hydration similar to RAL.26-week-old male C57BL/6 mice induced with chronic kidney disease (CKD) beginning at 16 weeks of age via 0.2 % adenine-laced casein-based (0.9 % P, 0.6 % C) chow, and their non-CKD control littermates (Con), were utilized. Upon sacrifice, right femora were randomly assigned to the following ex vivo experimental groups: RAL (2 μM, n = 10 CKD, n = 10 Con), CAL (100 nM, n = 10 CKD, n = 10 Con), or Vehicle (VEH; n = 9 CKD, n = 9 Con). Bones were incubated in PBS + drug solution at 37 °C for 14 days using an established ex vivo soaking methodology. Cortical geometry (μCT) was used to confirm a CKD bone phenotype, including porosity and cortical thinning, at sacrifice. Femora were assessed for mechanical properties (3-point bending) and bone hydration (via solid state nuclear magnetic resonance spectroscopy with magic angle spinning (ssNMR)). Data were analyzed by two-tailed t-tests (μCT) or 2-way ANOVA for main effects of disease, treatment, and their interaction. Tukey's post hoc analyses followed a significant main effect of treatment to determine the source of the effect.Imaging confirmed a cortical phenotype reflective of CKD, including lower cortical thickness (p < 0.0001) and increased cortical porosity (p = 0.02) compared to Con. In addition, CKD resulted in weaker, less deformable bones. In CKD bones, ex vivo exposure to RAL or CAL improved total work (+120 % and +107 %, respectively; p < 0.05), post-yield work (+143 % and +133 %), total displacement (+197 % and +229 %), total strain (+225 % and +243 %), and toughness (+158 % and +119 %) vs. CKD VEH soaked bones. Ex vivo exposure to RAL or CAL did not impact any mechanical properties in Con bone. Matrix-bound water by ssNMR showed CAL treated bones had significantly higher bound water compared to VEH treated bones in both CKD and Con cohorts (p = 0.001 and p = 0.01, respectively). RAL positively modulated bound water in CKD bone compared to VEH (p = 0.002) but not in Con bone. There were no significant differences between bones soaked with CAL vs. RAL for any outcomes measured.RAL and CAL improve important post-yield properties and toughness in a non-cell mediated manner in CKD bone but not in Con bones. While RAL treated CKD bones had higher matrix-bound water content in line with previous reports, both Con and CKD bones exposed to CAL had higher matrix-bound water. Therapeutic modulation of water, specifically the bound water fraction, represents a novel approach to improving mechanical properties and potentially reducing fracture risk.

Evolution of cortical geometry and its link to function, behaviour and ecology

Studies in comparative neuroanatomy and of the fossil record demonstrate the influence of socio-ecological niches on the morphology of the cerebral cortex, but have led to oftentimes conflicting theories about its evolution. Here, we study the relationship between the shape of the cerebral cortex and the topography of its function. We establish a joint geometric representation of the cerebral cortices of ninety species of extant Euarchontoglires, including commonly used experimental model organisms. We show that variability in surface geometry relates to species’ ecology and behaviour, independent of overall brain size. Notably, ancestral shape reconstruction of the cortical surface and its change during evolution enables us to trace the evolutionary history of localised cortical expansions, modal segregation of brain function, and their association to behaviour and cognition. We find that individual cortical regions follow different sequences of area increase during evolutionary adaptations to dynamic socio-ecological niches. Anatomical correlates of this sequence of events are still observable in extant species, and relate to their current behaviour and ecology. We decompose the deep evolutionary history of the shape of the human cortical surface into spatially and temporally conscribed components with highly interpretable functional associations, highlighting the importance of considering the evolutionary history of cortical regions when studying their anatomy and function.

Relationship between risk factors for impaired bone health and HR-pQCT in young adults with type 1 diabetes.

In type 1 diabetes, risk factors associated with impaired bone health contribute to increased risk of fracture. The aim of this study was to (1): compare the high-resolution peripheral quantitative computed tomography (HR-pQCT) parameters of young adults with type 1 diabetes with those of healthy controls (2), identify sex differences, and (3) evaluate the association between diabetes and bone health risk factors, with HR-pQCT. This is a cross-sectional study in young Canadian adults with childhood onset type 1 diabetes. Z-scores were generated for HR-pQCT parameters using a large healthy control database. Diet, physical activity, BMI, hemoglobin A1C (A1C) and bone health measures were evaluated, and associations were analyzed using multivariate regression analysis. Eighty-eight participants (age 21 ± 2.2 years; 40 males, 48 females, diabetes duration 13.9 ± 3.4 years) with type 1 diabetes were studied. Low trabecular thickness and elevated cortical geometry parameters were found suggesting impaired bone quality. There were no sex differences. Significant associations were found: Vitamin D (25(OH)D) with trabecular parameters with possible synergy with A1C, parathyroid hormone with cortical parameters, BMI with cortical bone and failure load, and diabetes duration with trabecular area. Our data suggests impairment of bone health as assessed by HR-pQCT in young adults with type 1 diabetes. Modifiable risk factors were associated with trabecular and cortical parameters. These findings imply that correction of vitamin D deficiency, prevention and treatment of secondary hyperparathyroidism, and optimization of metabolic control may reduce incident fractures.

Longitudinal changes in surface based brain morphometry measures in amnestic mild cognitive impairment and Alzheimer’s Disease

BackgroundAlzheimer’s disease (AD) is associated with marked brain atrophy. While commonly used structural MRI imaging methods do not account for the complexity of human brain morphology, little is known about the longitudinal changes of cortical geometry and their relationship with cognitive decline in subjects with AD. MethodsData from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were used to perform two-sample t-tests to investigate longitudinal changes of cortical thickness (CTh) and three surface-based morphometry measures: fractal dimension (i.e. cortical complexity; FD), gyrification index (GI), and sulcal depth (SD) in subjects with AD, amnestic mild cognitive impairment (aMCI) in comparison to cognitively unimpaired controls (CU) in baseline and 2-year follow-up sMRI scans. In addition, correlations of the morphological measures with two-year cognitive decline as assessed by the modified AD Assessment Scale-Cognitive Subscale (ADAS-Cog 11) were calculated via regression analyses. ResultsCompared to CU, both AD and aMCI showed marked decreases in CTh. In contrast, analyses of FD and GI yielded a more nuanced decline of the respective measures with some areas showing increases in FD and GI. Overall changes in FD and GI were more pronounced in AD as compared to aMCI. Analyses of SD yielded widespread decreases. Interestingly, cognitive decline corresponded well with CTh declines in aMCI but not AD, whereas changes in FD corresponded with AD only but not aMCI, whereas GI and SD were associated with cognitive decline in aMCI and AD. ConclusionPatterns of longitudinal changes in FD, GI and SD were only partially overlapping with CTh reductions. In AD, surface-based morphometry measures for brain-surface complexity showed better correspondence than CTh with cognitive decline over a two-year period of time. Being drawn from measures reflecting changes in more intricate aspects of human brain morphology, these data provide new insight into the complexity of AD-related brain atrophy and its relationship with cognitive decline.

Impact of Alcohol on Bone Health in People Living With HIV: Integrating Clinical Data From Serum Bone Markers With Morphometric Analysis in a Non-Human Primate Model.

People living with HIV (PLWH) represent a vulnerable population to adverse musculoskeletal outcomes due to HIV infection, antiretroviral therapy (ART), and at-risk alcohol use. Developing measures to prevent skeletal degeneration in this group requires a grasp of the relationship between alcohol use and low bone mass in both the PLWH population and its constituents as defined by sex, age, and race. We examined the association of alcohol use with serum biochemical markers of bone health in a diverse cohort of PLWH enrolled in the New Orleans Alcohol Use in HIV (NOAH) study. To explore the effects of alcohol on bone in the context of HIV and ART and the role of estrogen, we conducted a parallel, translational study using simian immunodeficiency virus (SIV)+/ART+ female rhesus macaques divided into four groups: vehicle (Veh)/Sham; chronic binge alcohol (CBA)/Sham; Veh/ovariectomy (OVX); and CBA/OVX. Clinical data showed that both osteocalcin (Ocn) and procollagen type I N-propeptide (PINP) levels were inversely associated with multiple measures of alcohol consumption. Age (>50 years) significantly increased susceptibility to alcohol-associated suppression of bone formation in both female and male PLWH, with postmenopausal status appearing as an additional risk factor in females. Serum sclerostin (Scl) levels correlated positively with measures of alcohol use and negatively with Ocn. Micro-CT analysis of the macaque tibias revealed that although both CBA and OVX independently decreased trabecular number and bone mineral density, only OVX decreased trabecular bone volume fraction and impacted cortical geometry. The clinical data implicate circulating Scl in the pathogenesis of alcohol-induced osteopenia and suggest that bone morphology can be significantly altered in the absence of net change in osteoblast function as measured by serum markers. Inclusion of sophisticated tools to evaluate skeletal strength in clinical populations will be essential to understand the impact of alcohol-induced changes in bone microarchitecture. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Caring for the injured: Exploring the immediate and long-term consequences of injury in medieval Cambridge, England

ObjectiveTo combine paleopathological and biomechanical analysis to reconstruct the impact that a severe skeletal injury had on an individual’s ability to function and participate in medieval society. MaterialsThree medieval individuals from Cambridge, England with ante-mortem fractures to the lower limb were analyzed. MethodsPlain X-rays were used to determine the degree of malunion, rotation and overlap of each fracture. Cortical bone architecture of the injured individuals and 28 uninjured controls were analyzed using micro-computed tomography (µCT). Clinical and functional consequences were examined using the Bioarcheology of Care framework. ResultsThe mechanism of injury, the secondary complications, and the extent of the care received was reconstructed for each individual. Bilateral asymmetry in the cortical bone architecture revealed the long-term alterations to each individual’s gait. ConclusionEach of these individuals survived a severe injury resulting in chronic physical impairment, though not all would have been considered ‘disabled’. SignificanceThis research contributes to the discussion about medieval care provision and social constructions of disability by illustrating how an interdisciplinary approach provides insight into the experiences of those with physical impairments. The integration of µCT imaging within the Bioarcheology of Care model is a novel approach with great potential for application across the field. LimitationsBiomechanical analysis was restricted to cortical geometry. Suggestions for future researchFurther study of bilateral asymmetry in trabecular architecture could complement our understanding of altered loading modalities in past societies.

Mapping Inter-individual Functional Connectivity Variability in TMS Targets for Major Depressive Disorder.

Transcranial magnetic stimulation (TMS) is an emerging alternative to existing treatments for major depressive disorder (MDD). The effects of TMS on both brain physiology and therapeutic outcomes are known to be highly variable from subject to subject, however. Proposed reasons for this variability include individual differences in neurophysiology, in cortical geometry, and in brain connectivity. Standard approaches to TMS target site definition tend to focus on coordinates or landmarks within the individual brain regions implicated in MDD, such as the dorsolateral prefrontal cortex (dlPFC) and orbitofrontal cortex (OFC). Additionally considering the network connectivity of these sites (i.e., the wider set of brain regions that may be mono- or poly-synaptically activated by TMS stimulation) has the potential to improve subject-specificity of TMS targeting and, in turn, improve treatment outcomes. In this study, we looked at the functional connectivity (FC) of dlPFC and OFC TMS targets, based on induced electrical field (E-field) maps, estimated using the SimNIBS library. We hypothesized that individual differences in spontaneous functional brain dynamics would contribute more to downstream network engagement than individual differences in cortical geometry (i.e., E-field variability). We generated individualized E-field maps on the cortical surface for 121 subjects (67 female) from the Human Connectome Project database using tetrahedral head models generated from T1- and T2-weighted MR images. F3 and Fp1 electrode positions were used to target the left dlPFC and left OFC, respectively. We analyzed inter-subject variability in the shape and location of these TMS target E-field patterns, their FC, and the major functional networks to which they belong. Our results revealed the key differences in TMS target FC between the dlPFC and OFC, and also how this connectivity varies across subjects. Three major functional networks were targeted across the dlPFC and OFC: the ventral attention, fronto-parietal and default-mode networks in the dlPFC, and the fronto-parietal and default mode networks in the OFC. Inter-subject variability in cortical geometry and in FC was high. Our analyses showed that the use of normative neuroimaging reference data (group-average or representative FC and subject E-field) allows prediction of which networks are targeted, but fails to accurately quantify the relative loading of TMS targeting on each of the principal networks. Our results characterize the FC patterns of canonical therapeutic TMS targets, and the key dimensions of their variability across subjects. The high inter-individual variability in cortical geometry and FC, leading to high variability in distributions of targeted brain networks, may account for the high levels of variability in physiological and therapeutic TMS outcomes. These insights should, we hope, prove useful as part of the broader effort by the psychiatry, neurology, and neuroimaging communities to help improve and refine TMS therapy, through a better understanding of the technology and its neurophysiological effects.

Translationally Relevant Magnetic Resonance Imaging Markers in a Ferret Model of Closed Head Injury.

Pre-clinical models of traumatic brain injury (TBI) have been the primary experimental tool for understanding the potential mechanisms and cellular alterations that follow brain injury, but the human relevance and translational value of these models are often called into question. Efforts to better recapitulate injury biomechanics and the use of non-rodent species with neuroanatomical similarities to humans may address these concerns and promise to advance experimental studies toward clinical impact. In addition to improving translational aspects of animal models, it is also advantageous to establish pre-clinical outcomes that can be directly compared with the same outcomes in humans. Non-invasive imaging and particularly MRI is promising for this purpose given that MRI is a primary tool for clinical diagnosis and at the same time increasingly available at the pre-clinical level. The objective of this study was to identify which commonly used radiologic markers of TBI outcomes can be found also in a translationally relevant pre-clinical model of TBI. The ferret was selected as a human relevant species for this study with folded cortical geometry and relatively high white matter content and the closed head injury model of engineered rotation and acceleration (CHIMERA) TBI model was selected for biomechanical similarities to human injury. A comprehensive battery of MRI protocols based on common data elements (CDEs) for human TBI was collected longitudinally for the identification of MRI markers and voxelwise analysis of T2, contrast enhancement and diffusion tensor MRI values. The most prominent MRI findings were consistent with focal hemorrhage and edema in the brain stem region following high severity injury as well as vascular and meningeal injury evident by contrast enhancement. While conventional MRI outcomes were not highly conspicuous in less severe cases, quantitative voxelwise analysis indicated diffusivity and anisotropy alterations in the acute and chronic periods after TBI. The main conclusions of this study support the translational relevance of closed head TBI models in intermediate species and identify brain stem and meningeal vulnerability. Additionally, the MRI findings highlight a subset of CDEs with promise to bridge pre-clinical studies with human TBI outcomes.

Similarities and differences between bone quality parameters, trabecular bone score and femur geometry.

Bone quality is a critical factor that, along with bone quantity, determines bone strength. Image-based parameters are used for assessing bone quality non-invasively. The trabecular bone score (TBS) is used to assess quality of trabecular bone and femur geometry for cortical bone. Little is known about the associations between these two bone quality parameters and whether they show differences in the relationships with age and body mass index (BMI). We investigated the associations between the trabecular bone score (TBS) and femur cortical geometry. Areal bone mineral density (BMD) was assessed using dual energy X-ray absorptiometry (DXA) and the TBS was assessed using iNsight software and, femur geometry using APEX (Hologic). A total of 452 men and 517 women aged 50 years and older with no medical history of a condition affecting bone metabolism were included. Z-scores for TBS and cortical thickness were calculated using the age-specific mean and SD for each parameter. A ‘discrepancy group’ was defined as patients whose absolute Z-score difference between TBS and cortical thickness was > 1 point. TBS and cortical thickness correlated negatively with age both in men and women, but the associations were stronger in women. Regarding the associations with BMI, TBS provided significant negative correlation with BMI in the range of BMI > 25 kg/m2. By contrast, cortical thickness correlated positively with BMI for all BMI ranges. These bone quality-related parameters, TBS and cortical thickness, significantly correlated, but discordance between these two parameters was observed in about one-third of the men and women (32.7% and 33.4%, respectively). Conclusively, image-based bone quality parameters for trabecular and cortical bone exhibit both similarities and differences in terms of their associations with age and BMI. These different profiles in TBS and FN cortical thickness might results in different risk profiles for the vertebral fractures or hip fractures in a certain percentage of people.

White matter volume loss drives cortical reshaping after thalamic infarcts

ObjectiveThe integration of somatosensory, ocular motor and vestibular signals is necessary for self-location in space and goal-directed action. We aimed to detect remote changes in the cerebral cortex after thalamic infarcts to reveal the thalamo-cortical connections necessary for multisensory processing and ocular motor control. MethodsThirteen patients with unilateral ischemic thalamic infarcts presenting with vestibular, somatosensory, and ocular motor symptoms were examined longitudinally in the acute phase and after six months. Voxel- and surface-based morphometry were used to detect changes in vestibular and multisensory cortical areas and known hubs of central ocular motor processing. The results were compared with functional connectivity data in 50 healthy volunteers. ResultsPatients with paramedian infarcts showed impaired saccades and vestibular perception, i.e., tilts of the subjective visual vertical (SVV). The most common complaint in these patients was double vision or vertigo / dizziness. Posterolateral thalamic infarcts led to tilts of the SVV and somatosensory deficits without vertigo. Tilts of the SVV were higher in paramedian compared to posterolateral infarcts (median 11.2° vs 3.8°). Vestibular and ocular motor symptoms recovered within six months. Somatosensory deficits persisted. Structural longitudinal imaging showed significant volume reduction in subcortical structures connected to the infarcted thalamic nuclei (vestibular nuclei region, dentate nucleus region, trigeminal root entry zone, medial lemniscus, superior colliculi). Volume loss was evident in connections to the frontal, parietal and cingulate lobes. Changes were larger in the ipsilesional hemisphere but were also detected in homotopical regions contralesionally. The white matter volume reduction led to deformation of the cortical projection zones of the infarcted nuclei. ConclusionsWhite matter volume loss after thalamic infarcts reflects sensory input from the brainstem as well the cortical projections of the main affected nuclei for sensory and ocular motor processing. Changes in the cortical geometry seem not to reflect gray matter atrophy but rather reshaping of the cortical surface due to the underlying white matter atrophy.

Multi-Frequency Image Completion via a Biologically-Inspired Sub-Riemannian Model with Frequency and Phase.

We present a novel cortically-inspired image completion algorithm. It uses five-dimensional sub-Riemannian cortical geometry, modeling the orientation, spatial frequency and phase-selective behavior of the cells in the visual cortex. The algorithm extracts the orientation, frequency and phase information existing in a given two-dimensional corrupted input image via a Gabor transform and represents those values in terms of cortical cell output responses in the model geometry. Then, it performs completion via a diffusion concentrated in a neighborhood along the neural connections within the model geometry. The diffusion models the activity propagation integrating orientation, frequency and phase features along the neural connections. Finally, the algorithm transforms the diffused and completed output responses back to the two-dimensional image plane.

Gestational and lactational exposure to BPA, but not BPS, negatively impacts trabecular microarchitecture and cortical geometry in adult male offspring

Bisphenol-A (BPA) and bisphenol-S (BPS) are endocrine disrupting chemicals (EDCs) found primarily in plastics. Estrogen is a primary hormonal regulator of skeletal growth and development; however, the impact of gestational BPA or BPS exposure on skeletal health of offspring remains relatively unknown. Here, adult female mice were randomized into three treatment groups: 200 μg BPA/kg BW (BPA), 200 μg BPS/kg BW (BPS) or control (CON). Animals were then further randomized to exercising (EX) or sedentary (SED) groups. Treatment continued through mating, gestation, and lactation. One male offspring from each dam (n = 6–8/group) was assessed at 16 weeks of age to evaluate effects of EDC exposure on the adult skeleton. Cortical geometry of the mid-diaphysis and trabecular microarchitecture of the distal femur were assessed via micro-CT. Biomechanical strength and mineral apposition rate of the femoral diaphysis were assessed via three-point bending and dynamic histomorphometry, respectively. Two-factor ANOVA or ANCOVA were used to determine the effects of maternal EX and BPA or BPS on trabecular and cortical bone outcomes. Maternal EX led to a significant decrease in body fat percentage and bone stiffness, independent of EDC exposure. Offspring exposed to BPA had significantly lower trabecular bone volume, trabecular number, connectivity density, cortical thickness, and greater trabecular spacing compared to BPS or CON animals. In conclusion, gestational BPA, but not BPS, exposure negatively impacted trabecular microarchitecture and cortical geometry in adult male offspring. If these findings translate to humans, this could have significant public health impacts on expecting women or those seeking to become pregnant.