Philip V. Bayly

Diffusion Tensor Imaging Reliably Detects Experimental Traumatic Axonal Injury and Indicates Approximate Time of Injury

Traumatic axonal injury (TAI) may contribute greatly to neurological impairments after traumatic brain injury, but it is difficult to assess with conventional imaging. We quantitatively compared diffusion tensor imaging (DTI) signal abnormalities with histological and electron microscopic characteristics of pericontusional TAI in a mouse model. Two DTI parameters, relative anisotropy and axial diffusivity, were significantly reduced 6 h to 4 d after trauma, corresponding to relatively isolated axonal injury. One to 4 weeks after trauma, relative anisotropy remained decreased, whereas axial diffusivity “pseudo-normalized” and radial diffusivity increased. These changes corresponded to demyelination, edema, and persistent axonal injury. At every time point, DTI was more sensitive to injury than conventional magnetic resonance imaging, and relative anisotropy distinguished injured from control mice with no overlap between groups. Remarkably, DTI changes strongly predicted the approximate time since trauma. These results provide an important validation of DTI for pericontusional TAI and suggest novel clinical and forensic applications.

Stability of Interrupted Cutting by Temporal Finite Element Analysis

Chatter in milling and other interrupted cutting operations occurs at different combinations of speed and depth of cut from chatter in continuous cutting. Prediction of stability in interrupted cutting is complicated by two facts: (1) the equation of motion when cutting is not the same as the equation when the tool is free; (2) no exact analytical solution is known when the tool is in the cut. These problems are overcome by matching the free response with an approximate solution that is valid white the tool is cutting. An approximate solution, not restricted to small times in the cut, is obtained by the application of finite elements in time. The complete, combined solution is cast in the form of a discrete map that relates position and velocity at the beginning and end of each element to the corresponding values one period earlier. The eigenvalues of the linearized map are used to determine stability. This method can be used to predict stability for arbitrary times in the cut; the current method is applicable only to a single degree of freedom. Predictions of stability for a 1-degree of freedom case are confirmed by experiment.

Detection of traumatic axonal injury with diffusion tensor imaging in a mouse model of traumatic brain injury

Traumatic axonal injury (TAI) is thought to be a major contributor to cognitive dysfunction following traumatic brain injury (TBI), however TAI is difficult to diagnose or characterize non-invasively. Diffusion tensor imaging (DTI) has shown promise in detecting TAI, but direct comparison to histologically-confirmed axonal injury has not been performed. In the current study, mice were imaged with DTI, subjected to a moderate cortical controlled impact injury, and re-imaged 4-6 h and 24 h post-injury. Axonal injury was detected by amyloid beta precursor protein (APP) and neurofilament immunohistochemistry in pericontusional white matter tracts. The severity of axonal injury was quantified using stereological methods from APP stained histological sections. Two DTI parameters--axial diffusivity and relative anisotropy--were significantly reduced in the injured, pericontusional corpus callosum and external capsule, while no significant changes were seen with conventional MRI in these regions. The contusion was easily detectable on all MRI sequences. Significant correlations were found between changes in relative anisotropy and the density of APP stained axons across mice and across subregions spanning the spatial gradient of injury. The predictive value of DTI was tested using a region with DTI changes (hippocampal commissure) and a region without DTI changes (anterior commissure). Consistent with DTI predictions, there was histological detection of axonal injury in the hippocampal commissure and none in the anterior commissure. These results demonstrate that DTI is able to detect axonal injury, and support the hypothesis that DTI may be more sensitive than conventional imaging methods for this purpose.

Estimation of conduction velocity vector fields from epicardial mapping data

An automated method to estimate vector fields of propagation velocity from observed epicardial extracellular potentials is introduced. The method relies on fitting polynomial surfaces T(x,y) to the space-time (x,y,t) coordinates of activity, Both speed and direction of propagation are computed from the gradient of the local polynomial surface. The components of velocity, which are total derivatives, are expressed in terms of the partial derivatives which comprise the gradient of T. The method was validated on two-dimensional (2-D) simulations of propagation and then applied to cardiac mapping data. Conduction velocity was estimated at multiple epicardial locations during sinus rhythm, pacing, and ventricular fibrillation (VF) in pigs. Data were obtained via a 528-channel mapping system from 23/spl times/22 and 24/spl times/21 arrays of unipolar electrodes sutured to the right ventricular epicardium. Velocity estimates are displayed as vector fields and are used to characterize propagation qualitatively and quantitatively during both simple and complex rhythms.

Stability of up-milling and down-milling, part 1: alternative analytical methods

Abstract The dynamic stability of the milling process is investigated through a single degree of freedom mechanical model. Two alternative analytical methods are introduced, both based on finite dimensional discrete map representations of the governing time periodic delay-differential equation. Stability charts and chatter frequencies are determined for partial immersion up- and down-milling, and for full immersion milling operations. A special duality property of stability regions for up- and down-milling is shown and explained.

Multiple chatter frequencies in milling processes

Analytical and experimental identifications of the chatter frequencies in milling processes are presented. In the case of milling, there are several frequency sets arising from the vibration signals, as opposed to the single well-defined chatter frequency of the unstable turning process. Frequency diagrams are constructed analytically and attached to the stability charts of mechanical models of high-speed milling. The corresponding quasiperiodic solutions of the governing time-periodic delay-differential equations are also identified with some milling experiments in the case of highly intermittent cutting.

Stability of up-milling and down-milling, part 2: experimental verification

The stability of interrupted cutting in a single degree of freedom milling process was studied experimentally. An instrumented flexure was used to provide a flexible workpiece with a natural frequency comparable to the tooth pass frequency, mimicking high speed milling dynamics. The displacement of the system was sampled continuously and periodically once per cutter revolution. These data samples were used to asses the stability of the system. Results confirm the theoretical predictions obtained in Part 1.

Axons Pull on the Brain, But Tension Does Not Drive Cortical Folding

During human brain development, the cerebral cortex undergoes substantial folding, leading to its characteristic highly convoluted form. Folding is necessary to accommodate the expansion of the cerebral cortex; abnormal cortical folding is linked to various neurological disorders, including schizophrenia, epilepsy, autism, and mental retardation. Although this process requires mechanical forces, the specific force-generating mechanisms that drive folding remain unclear. The two most widely accepted hypotheses are as follows: (1) Folding is caused by differential growth of the cortex and (2) folding is caused by mechanical tension generated in axons. Direct evidence supporting either theory, however, is lacking. Here we show that axons are indeed under considerable tension in the developing ferret brain, but the patterns of tissue stress are not consistent with a causal role for axonal tension. In particular, microdissection assays reveal that significant tension exists along axons aligned circumferentially in subcortical white matter tracts, as well as those aligned radially inside developing gyri (outward folds). Contrary to previous speculation, however, axonal tension is not directed across developing gyri, suggesting that axon tension does not drive folding. On the other hand, using computational (finite element) models, we show that differential cortical growth accompanied by remodeling of the subplate leads to outward folds and stress fields that are consistent with our microdissection experiments, supporting a mechanism involving differential growth. Local perturbations, such as temporal differences in the initiation of cortical growth, can ensure consistent folding patterns. This study shows that a combination of experimental and computational mechanics can be used to evaluate competing hypotheses of morphogenesis, and illuminate the biomechanics of cortical folding.

Measurements of mechanical anisotropy in brain tissue and implications for transversely isotropic material models of white matter

White matter in the brain is structurally anisotropic, consisting largely of bundles of aligned, myelin-sheathed axonal fibers. White matter is believed to be mechanically anisotropic as well. Specifically, transverse isotropy is expected locally, with the plane of isotropy normal to the local mean fiber direction. Suitable material models involve strain energy density functions that depend on the I4 and I5 pseudo-invariants of the Cauchy-Green strain tensor to account for the effects of relatively stiff fibers. The pseudo-invariant I4 is the square of the stretch ratio in the fiber direction; I5 contains contributions of shear strain in planes parallel to the fiber axis. Most, if not all, published models of white matter depend on I4 but not on I5. Here, we explore the small strain limits of these models in the context of experimental measurements that probe these dependencies. Models in which strain energy depends on I4 but not I5 can capture differences in Youngs (tensile) moduli, but will not exhibit differences in shear moduli for loading parallel and normal to the mean direction of axons. We show experimentally, using a combination of shear and asymmetric indentation tests, that white matter does exhibit such differences in both tensile and shear moduli. Indentation tests were interpreted through inverse fitting of finite element models in the limit of small strains. Results highlight that: (1) hyperelastic models of transversely isotropic tissues such as white matter should include contributions of both the I4 and I5 strain pseudo-invariants; and (2) behavior in the small strain regime can usefully guide the choice and initial parameterization of more general material models of white matter.

Whole-Exome Capture and Sequencing Identifies HEATR2 Mutation as a Cause of Primary Ciliary Dyskinesia

Motile cilia are essential components of the mucociliary escalator and are central to respiratory-tract host defenses. Abnormalities in these evolutionarily conserved organelles cause primary ciliary dyskinesia (PCD). Despite recent strides characterizing the ciliome and sensory ciliopathies through exploration of the phenotype-genotype associations in model organisms, the genetic bases of most cases of PCD remain elusive. We identified nine related subjects with PCD from geographically dispersed Amish communities and performed exome sequencing of two affected individuals and their unaffected parents. A single autosomal-recessive nonsynonymous missense mutation was identified in HEATR2, an uncharacterized gene that belongs to a family not previously associated with ciliary assembly or function. Airway epithelial cells isolated from PCD-affected individuals had markedly reduced HEATR2 levels, absent dynein arms, and loss of ciliary beating. MicroRNA-mediated silencing of the orthologous gene in Chlamydomonas reinhardtii resulted in absent outer dynein arms, reduced flagellar beat frequency, and decreased cell velocity. These findings were recapitulated by small hairpin RNA-mediated knockdown of HEATR2 in airway epithelial cells from unaffected donors. Moreover, immunohistochemistry studies in human airway epithelial cells showed that HEATR2 was localized to the cytoplasm and not in cilia, which suggests a role in either dynein arm transport or assembly. The identification of HEATR2 contributes to the growing number of genes associated with PCD identified in both individuals and model organisms and shows that exome sequencing in family studies facilitates the discovery of novel disease-causing gene mutations.