Increased intra-cortical porosity reduces bone stiffness and strength in pediatric patients with osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a heritable disease occurring in one out of every 20,000 births. Although it is known that Type I collagen mutation in OI leads to increased bone fragility, the mechanism of this increased susceptibility to fracture is not clear. The aim of this study was to assess the microstructure of cortical bone fragments from patients with osteogenesis imperfecta (OI) using polarized light microscopy, and to correlate microstructural observations with the results of previously performed mechanical compression tests on bone from the same source. Specimens of cortical bone were harvested from the lower limbs of three (3) OI patients at the time of surgery, and were divided into two groups. Group 1 had been subjected to previous micro-mechanical compression testing, while Group 2 had not been subjected to any prior testing. Polarized light microscopy revealed disorganized bone collagen architecture as has been previously observed, as well as a large increase in the areal porosity of the bone compared to typical values for healthy cortical bone, with large (several hundred micron sized), asymmetrical pores. Importantly, the areal porosity of the OI bone samples in Group 1 appears to correlate strongly with their previously measured apparent Young's modulus and compressive strength. Taken together with prior nanoindentation studies on OI bone tissue, the results of this study suggest that increased intra-cortical porosity is responsible for the reduction in macroscopic mechanical properties of OI cortical bone, and therefore that in vivo imaging modalities with resolutions of ~ 100 μm or less could potentially be used to non-invasively assess bone strength in OI patients. Although the number of subjects in this study is small, these results highlight the importance of further studies in OI bone by groups with access to human OI tissue in order to clarify the relationship between increased porosity and reduced macroscopic mechanical integrity.

4D deformation modeling of cortical disease progression in Alzheimer's dementia

This work describes the development of a model of cerebral atrophic changes associated with the progression of Alzheimer's disease (AD). Linear registration, region-of-interest analysis, and voxel-based morphometry methods have all been employed to elucidate the changes observed at discrete intervals during a disease process. In addition to describing the nature of the changes, modeling disease-related changes via deformations can also provide information on temporal characteristics. In order to continuously model changes associated with AD, deformation maps from 21 patients were averaged across a novel z-score disease progression dimension based on Mini Mental State Examination (MMSE) scores. The resulting deformation maps are presented via three metrics: local volume loss (atrophy), volume (CSF) increase, and translation (interpreted as representing collapse of cortical structures). Inspection of the maps revealed significant perturbations in the deformation fields corresponding to the entorhinal cortex (EC) and hippocampus, orbitofrontal and parietal cortex, and regions surrounding the sulci and ventricular spaces, with earlier changes predominantly lateralized to the left hemisphere. These changes are consistent with results from post-mortem studies of AD.

A genetic analysis of cortical thickness in 372 twins

Imaging genetics is a new field of neuroscience that blends methods from computational anatomy and quantitative genetics to identify genetic influences on brain structure and function. Here we analyzed brain MRI data from 372 young adult twins to identify cortical regions in which gray matter volume is influenced by genetic differences across subjects. Thickness maps, reconstructed from surface models of the cortical gray/white and gray/CSF interfaces, were smoothed with a 25 mm FWHM kernel and automatically parcellated into 34 regions of interest per hemisphere. In structural equation models fitted to volume values at each surface vertex, we computed components of variance due to additive genetic (A), shared (C) and unique (E) environmental factors, and tested their significance. Cortical regions in the vicinity of the perisylvian language cortex, and at the frontal and temporal poles, showed significant additive genetic variance, suggesting that volume measures from these regions may provide quantitative phenotypes to narrow the search for quantitative trait loci that influence brain structure.

The contribution of genes to cortical thickness and volume

We analyzed brain MRI data from 372 young adult twins toidentify cortical regions in which gray matter thickness and volume are influenced by genetics. This was achieved using an A/C/E structural equation model that divides the variance of these traits, at each point on the cortex, into additive genetic (A), shared (C), and unique environmental (E) components. A strong genetic influencewas found in frontal and parietal regions. Inaddition, we correlated cortical thickness with full-scale intelligence quotient for comparison with the A/C/E maps, and several regions where cortical structure was correlated with intelligence quotient are under genetic control. These cortical measures may be useful phenotypes to narrow the searchfor quantitative trait lociinfluencing brain structure.

Identifying rate-limiting nodes in large-scale cortical networks for visuospatial processing: An illustration using fMRI

With the advent of functional neuroimaging techniques, in particular functional magnetic resonance imaging (fMRI), we have gained greater insight into the neural correlates of visuospatial function. However, it may not always be easy to identify the cerebral regions most specifically associated with performance on a given task. One approach is to examine the quantitative relationships between regional activation and behavioral performance measures. In the present study, we investigated the functional neuroanatomy of two different visuospatial processing tasks, judgement of line orientation and mental rotation. Twenty-four normal participants were scanned with fMRI using blocked periodic designs for experimental task presentation. Accuracy and reaction time (RT) to each trial of both activation and baseline conditions in each experiment was recorded. Both experiments activated dorsal and ventral visual cortical areas as well as dorsolateral prefrontal cortex. More regionally specific associations with task performance were identified by estimating the association between (sinusoidal) power of functional response and mean RT to the activation condition; a permutation test based on spatial statistics was used for inference. There was significant behavioral-physiological association in right ventral extrastriate cortex for the line orientation task and in bilateral (predominantly right) superior parietal lobule for the mental rotation task. Comparable associations were not found between power of response and RT to the baseline conditions of the tasks. These data suggest that one region in a neurocognitive network may be most strongly associated with behavioral performance and this may be regarded as the computationally least efficient or rate-limiting node of the network.

Progressive dysgraphia in a case of posterior cortical atrophy

Dysgraphia (agraphia) is a common feature of posterior cortical atrophy (PCA). However, detailed analyses of these spelling and writing impairments are infrequently conducted. LM is a 59-year-old woman with dysgraphia associated with PCA. She presented with a two-year history of decline in her writing and dressmaking skills. A 3D T1-weighted MRI scan confirmed selective bi-parietal atrophy, with relative sparing of the hippocampi and other cortical regions. Analyses of LM's preserved and impaired spelling abilities indicated mild physical letter distortions and a significant spelling deficit characterised by letter substitutions, insertions, omissions, and transpositions that was systematically sensitive to word length while insensitive to real word versus nonword category, word frequency, regularity, imagery, grammatical class and ambiguity. Our findings suggest a primary graphemic buffer disorder underlies LM's spelling errors, possibly originating from disruption to the operation of a fronto-parietal network implicated in verbal working memory.

Mapping cortical change in Alzheimer's disease, brain development, and schizophrenia

This paper describes algorithms that can identify patterns of brain structure and function associated with Alzheimer's disease, schizophrenia, normal aging, and abnormal brain development based on imaging data collected in large human populations. Extraordinary information can be discovered with these techniques: dynamic brain maps reveal how the brain grows in childhood, how it changes in disease, and how it responds to medication. Genetic brain maps can reveal genetic influences on brain structure, shedding light on the nature-nurture debate, and the mechanisms underlying inherited neurobehavioral disorders. Recently, we created time-lapse movies of brain structure for a variety of diseases. These identify complex, shifting patterns of brain structural deficits, revealing where, and at what rate, the path of brain deterioration in illness deviates from normal. Statistical criteria can then identify situations in which these changes are abnormally accelerated, or when medication or other interventions slow them. In this paper, we focus on describing our approaches to map structural changes in the cortex. These methods have already been used to reveal the profile of brain anomalies in studies of dementia, epilepsy, depression, childhood- and adult-onset schizophrenia, bipolar disorder, attention-deficit/hyperactivity disorder, fetal alcohol syndrome, Tourette syndrome, Williams syndrome, and in methamphetamine abusers. Specifically, we describe an image analysis pipeline known as cortical pattern matching that helps compare and pool cortical data over time and across subjects. Statistics are then defined to identify brain structural differences between groups, including localized alterations in cortical thickness, gray matter density (GMD), and asymmetries in cortical organization. Subtle features, not seen in individual brain scans, often emerge when population-based brain data are averaged in this way. Illustrative examples are presented to show the profound effects of development and various diseases on the human cortex. Dynamically spreading waves of gray matter loss are tracked in dementia and schizophrenia, and these sequences are related to normally occurring changes in healthy subjects of various ages.

WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk

We aimed to identify genetic variants associated with cortical bone thickness (CBT) and bone mineral density (BMD) by performing two separate genome-wide association study (GWAS) meta-analyses for CBT in 3 cohorts comprising 5,878 European subjects and for BMD in 5 cohorts comprising 5,672 individuals. We then assessed selected single-nucleotide polymorphisms (SNPs) for osteoporotic fracture in 2,023 cases and 3,740 controls. Association with CBT and forearm BMD was tested for ~2.5 million SNPs in each cohort separately, and results were meta-analyzed using fixed effect meta-analysis. We identified a missense SNP (Thr>Ile; rs2707466) located in the WNT16 gene (7q31), associated with CBT (effect size of -0.11 standard deviations [SD] per C allele, P = 6.2×10-9). This SNP, as well as another nonsynonymous SNP rs2908004 (Gly>Arg), also had genome-wide significant association with forearm BMD (-0.14 SD per C allele, P = 2.3×10-12, and -0.16 SD per G allele, P = 1.2×10-15, respectively). Four genome-wide significant SNPs arising from BMD meta-analysis were tested for association with forearm fracture. SNP rs7776725 in FAM3C, a gene adjacent to WNT16, was associated with a genome-wide significant increased risk of forearm fracture (OR = 1.33, P = 7.3×10-9), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9×10-6 and rs2707466: OR = 1.22, P = 7.2×10-6). We next generated a homozygous mouse with targeted disruption of Wnt16. Female Wnt16-/- mice had 27% (P<0.001) thinner cortical bones at the femur midshaft, and bone strength measures were reduced between 43%-61% (6.5×10-13<P<5.9×10-4) at both femur and tibia, compared with their wild-type littermates. Natural variation in humans and targeted disruption in mice demonstrate that WNT16 is an important determinant of CBT, BMD, bone strength, and risk of fracture. © 2012 Zheng et al.

Effects of increasing neuromuscular electrical stimulation current intensity on cortical sensorimotor network activation: A time domain fNIRS study

Neuroimaging studies have shown neuromuscular electrical stimulation (NMES)-evoked movements activate regions of the cortical sensorimotor network, including the primary sensorimotor cortex (SMC), premotor cortex (PMC), supplementary motor area (SMA), and secondary somatosensory area (S2), as well as regions of the prefrontal cortex (PFC) known to be involved in pain processing. The aim of this study, on nine healthy subjects, was to compare the cortical network activation profile and pain ratings during NMES of the right forearm wrist extensor muscles at increasing current intensities up to and slightly over the individual maximal tolerated intensity (MTI), and with reference to voluntary (VOL) wrist extension movements. By exploiting the capability of the multi-channel time domain functional near-infrared spectroscopy technique to relate depth information to the photon time-of-flight, the cortical and superficial oxygenated (O₂Hb) and deoxygenated (HHb) hemoglobin concentrations were estimated. The O₂Hb and HHb maps obtained using the General Linear Model (NIRS-SPM) analysis method, showed that the VOL and NMES-evoked movements significantly increased activation (i.e., increase in O₂Hb and corresponding decrease in HHb) in the cortical layer of the contralateral sensorimotor network (SMC, PMC/SMA, and S2). However, the level and area of contralateral sensorimotor network (including PFC) activation was significantly greater for NMES than VOL. Furthermore, there was greater bilateral sensorimotor network activation with the high NMES current intensities which corresponded with increased pain ratings. In conclusion, our findings suggest that greater bilateral sensorimotor network activation profile with high NMES current intensities could be in part attributable to increased attentional/pain processing and to increased bilateral sensorimotor integration in these cortical regions.

Heritability analysis of surface-based cortical thickness estimation on a large twin cohort

The aim of this paper is to assess the heritability of cerebral cortex, based on measurements of grey matter (GM) thickness derived from structural MR images (sMRI). With data acquired from a large twin cohort (328 subjects), an automated method was used to estimate the cortical thickness, and EM-ICP surface registration algorithm was used to establish the correspondence of cortex across the population. An ACE model was then employed to compute the heritability of cortical thickness. Heritable cortical thickness measures various cortical regions, especially in frontal and parietal lobes, such as bilateral postcentral gyri, superior occipital gyri, superior parietal gyri, precuneus, the orbital part of the right frontal gyrus, right medial superior frontal gyrus, right middle occipital gyrus, right paracentral lobule, left precentral gyrus, and left dorsolateral superior frontal gyrus.

Quantitative electroencephalographic comodulation : an investigation of patterns in chronic fatigue syndrome

Introduction. This is a pilot study of quantitative electro-encephalographic (QEEG) comodulation analysis, which is used to assist in identifying regional brain differences in those people suffering from chronic fatigue syndrome (CFS) compared to a normative database. The QEEG comodulation analysis examines spatial-temporal cross-correlation of spectral estimates in the resting dominant frequency band. A pattern shown by Sterman and Kaiser (2001) and referred to as the anterior posterior dissociation (APD) discloses a significant reduction in shared functional modulation between frontal and centro-parietal areas of the cortex. This research attempts to examine whether this pattern is evident in CFS. Method. Eleven adult participants, diagnosed by a physician as having CFS, were involved in QEEG data collection. Nineteen-channel cap recordings were made in five conditions: eyes-closed baseline, eyes-open, reading task one, math computations task two, and a second eyes-closed baseline. Results. Four of the 11 participants showed an anterior posterior dissociation pattern for the eyes-closed resting dominant frequency. However, seven of the 11 participants did not show this pattern. Examination of the mean 8-12 Hz amplitudes across three cortical regions (frontal, central and parietal) indicated a trend of higher overall alpha levels in the parietal region in CFS patients who showed the APD pattern compared to those who did not have this pattern. All patients showing the pattern were free of medication, while 71% of those absent of the pattern were using antidepressant medications. Conclusions. Although the sample is small, it is suggested that this method of evaluating the disorder holds promise. The fact that this pattern was not consistently represented in the CFS sample could be explained by the possibility of subtypes of CFS, or perhaps co-morbid conditions. Further, the use of antidepressant medications may mask the pattern by altering the temporal characteristics of the EEG. The results of this pilot study indicate that further research is warranted to verify that the pattern holds across the wider population of CFS sufferers.

Lateral bone density variations in the scoliotic spine

Adolescent Idiopathic Scoliosis (AIS) is the most common deformity of the spine, affecting 2-4% of the population. Previous studies have shown that the vertebrae in scoliotic spines undergo abnormal shape changes, however there has been little exploration of how scoliosis affects bone density distribution within the vertebrae. In this study, existing CT scans of 53 female idiopathic scoliosis patients with right-sided main thoracic curves were used to measure the lateral (right to left) bone density profile at mid-height through each vertebral body. Five key bone density profile measures were identified from each normalised bone density distribution, and multiple regression analysis was performed to explore the relationship between bone density distribution and patient demographics (age, height, weight, body mass index (BMI), skeletal maturity, time since Menarche, vertebral level, and scoliosis curve severity). Results showed a marked convex/concave asymmetry in bone density for vertebral levels at or near the apex of the scoliotic curve. At the apical vertebra, mean bone density at the left side (concave) cortical shell was 23.5% higher than for the right (convex) cortical shell, and cancellous bone density along the central 60% of the lateral path from convex to concave increased by 13.8%. The centre of mass of the bone density profile at the thoracic curve apex was located 53.8% of the distance along the lateral path, indicating a shift of nearly 4% toward the concavity of the deformity. These lateral bone density gradients tapered off when moving away from the apical vertebra. Multi-linear regressions showed that the right cortical shell peak bone density is significantly correlated with skeletal maturity, with each Risser increment corresponding to an increase in mineral equivalent bone density of 4-5%. There were also statistically significant relationships between patient height, weight and BMI, and the gradient of cancellous bone density along the central 60% of the lateral path. Bone density gradient is positively correlated with weight, and negatively correlated with height and BMI, such that at the apical vertebra, a unit decrease in BMI corresponds to an almost 100% increase in bone density gradient.

The role of periosteum : a neglected aspect of osteoporosis

Most current studies on the pathogenesis of osteoporosis emphasize the bone metabolic activities occurring on endosteal surfaces, whereas the periosteal aspect is somewhat neglected. In terms of bone physiology, periosteum plays a determining role in de novo cortical bone formation and cortical bone expansion through periosteum is the most efficient way of increasing bone strength against fractures. Despite the important role of periosteum in the pathogenesis and treatment of osteoporosis, little is known about the structural and cellular features of periosteum in osteoporosis. This chapter will focus on the major changes occurring in the periosteum of osteoporosis and possible implications of these changes in the pathogenesis of osteoporosis. The changes identified in the periosteum of osteoporosis are mainly located in the metaphyseal compartment, which include: (a) much thicker and more cellular cambial layer; (b) increased number of TRAP (tartrate resistant acid phosphatase), VEGF (vascular endothelial growth factor) cells and the degree of vascularization; and (c) enhanced expression of sympathetic nerve fibers. The structural and cellular changes of osteoporotic periosteum indicate that periosteum plays an important role in the cortical bone resorption in metaphyseal areas and this pathological process may be regulated by the sympathetic nervous system.

Sensitivity of proximal femoral stiffness and areal bone mineral density to changes in bone geometry and density

Areal bone mineral density (aBMD) is the most common surrogate measurement for assessing the bone strength of the proximal femur associated with osteoporosis. Additional factors, however, contribute to the overall strength of the proximal femur, primarily the anatomical geometry. Finite element analysis (FEA) is an effective and widely used computerbased simulation technique for modeling mechanical loading of various engineering structures, providing predictions of displacement and induced stress distribution due to the applied load. FEA is therefore inherently dependent upon both density and anatomical geometry. FEA may be performed on both three-dimensional and two-dimensional models of the proximal femur derived from radiographic images, from which the mechanical stiffness may be redicted. It is examined whether the outcome measures of two-dimensional FEA, two-dimensional, finite element analysis of X-ray images (FEXI), and three-dimensional FEA computed stiffness of the proximal femur were more sensitive than aBMD to changes in trabecular bone density and femur geometry. It is assumed that if an outcome measure follows known trends with changes in density and geometric parameters, then an increased sensitivity will be indicative of an improved prediction of bone strength. All three outcome measures increased non-linearly with trabecular bone density, increased linearly with cortical shell thickness and neck width, decreased linearly with neck length, and were relatively insensitive to neck-shaft angle. For femoral head radius, aBMD was relatively insensitive, with two-dimensional FEXI and threedimensional FEA demonstrating a non-linear increase and decrease in sensitivity, respectively. For neck anteversion, aBMD decreased non-linearly, whereas both two-dimensional FEXI and three dimensional FEA demonstrated a parabolic-type relationship, with maximum stiffness achieved at an angle of approximately 15o. Multi-parameter analysis showed that all three outcome measures demonstrated their highest sensitivity to a change in cortical thickness. When changes in all input parameters were considered simultaneously, three and twodimensional FEA had statistically equal sensitivities (0.41±0.20 and 0.42±0.16 respectively, p = ns) that were significantly higher than the sensitivity of aBMD (0.24±0.07; p = 0.014 and 0.002 for three-dimensional and two-dimensional FEA respectively). This simulation study suggests that since mechanical integrity and FEA are inherently dependent upon anatomical geometry, FEXI stiffness, being derived from conventional two-dimensional radiographic images, may provide an improvement in the prediction of bone strength of the proximal femur than currently provided by aBMD.

Biomechanical force displacement analysis of strength of fixation of tracker holding devices to bone in computer aided joint replacement

Computer aided joint replacement surgery has become very popular during recent years and is being done in increasing numbers all over the world. The accuracy of the system depends to a major extent, on accurate registration and immobility of the tracker attachment devices to the bone. This study was designed to asses the forces needed to displace the tracker attachment devices in the bone simulators. Bone simulators were used to maintain the uniformity of the bone structure during the study. The fixation devices tested were 3mm diameter self drilling, self tapping threaded pin, 4mm diameter self tapping cortical threaded pin, 5mm diameter self tapping cancellous threaded pin and a triplanar fixation device ‘ortholock’ used with three 3mm pins. All the devices were tested for pull out, translational and rotational forces in unicortical and bicortical fixation modes. Also tested was the normal bang strength and forces generated by leaning on the devices. The forces required to produce translation increased with the increasing diameter of the pins. These were 105N, 185N, and 225N for the unicortical fixations and 130N, 200N, 225N for the bicortical fixations for 3mm, 4mm and 5mm diameter pins respectively. The forces required to pull out the pins were 1475N, 1650N, 2050N for the unicortical, 1020N, 3044N and 3042N for the bicortical fixated 3mm, 4mm and 5mm diameter pins. The ortholock translational and pull out strength was tested to 900N and 920N respectively and still it did not fail. Rotatory forces required to displace the tracker on pins was to the magnitude of 30N before failure. The ortholock device had rotational forces applied up to 135N and still did not fail. The manual leaning forces and the sudden bang forces generated were of the magnitude of 210N and 150N respectively. The strength of the fixation pins increases with increasing diameter from three to five mm for the translational forces. There is no significant difference in pull out forces of four mm and five mm diameter pins though it is more that the three mm diameter pins. This is because of the failure of material at that stage rather than the fixation device. The rotatory forces required to displace the tracker are very small and much less that that can be produced by the surgeon or assistants in single pins. Although the ortholock device was tested to 135N in rotation without failing, one has to be very careful not to put any forces during the operation on the tracker devices to ensure the accuracy of the procedure.