Andrew K. Knutsen

A Surface-Based Analysis of Hemispheric Asymmetries and Folding of Cerebral Cortex in Term-Born Human Infants

We have established a population average surface-based atlas of human cerebral cortex at term gestation and used it to compare infant and adult cortical shape characteristics. Accurate cortical surface reconstructions for each hemisphere of 12 healthy term gestation infants were generated from structural magnetic resonance imaging data using a novel segmentation algorithm. Each surface was inflated, flattened, mapped to a standard spherical configuration, and registered to a target atlas sphere that reflected shape characteristics of all 24 contributing hemispheres using landmark constrained surface registration. Population average maps of sulcal depth, depth variability, three-dimensional positional variability, and hemispheric depth asymmetry were generated and compared with previously established maps of adult cortex. We found that cortical structure in term infants is similar to the adult in many respects, including the pattern of individual variability and the presence of statistically significant structural asymmetries in lateral temporal cortex, including the planum temporale and superior temporal sulcus. These results indicate that several features of cortical shape are minimally influenced by the postnatal environment.

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.

Regional Patterns of Cerebral Cortical Differentiation Determined by Diffusion Tensor MRI

The morphology of axonal and dendritic arbors in the immature cerebral cortex influences the degree of anisotropy in water diffusion. This enables cortical maturation to be monitored by the noninvasive technique of diffusion tensor magnetic resonance imaging (DTI). Herein, we utilized DTI of postmortem ferret brain to quantify regional and temporal patterns in cortical maturation. We found that diffusion anisotropy within the isocortex decreases over the first month of life, coinciding closely in time with expansion of axonal and dendritic cellular processes of pyramidal neurons. Regional patterns consist of differences between allocortex and isocortex, a regional anisotropy gradient that closely parallels the transverse neurogenetic gradient, and differences between primary and nonprimary isocortical areas. By combining the temporal and regional factors, the isocortical developmental gradient magnitude corresponds to a 5-day difference in maturity between relatively developed rostral/caudal isocortex at the gradient source and less mature isocortex at the occipital pole. Additionally, the developmental trajectory of primary areas precedes nonprimary areas by 2.7 days. These quantitative estimates coincide with previous histological studies of ferret development. Similarities in cerebral cortical diffusion anisotropy observed between ferret and other species suggest the framework developed here is of general potential relevance.

Characterization of brain development in the ferret via MRI.

Animal models with complex cortical development are useful for improving our understanding of the wide spectrum of neurodevelopmental challenges facing human preterm infants. MRI techniques can define both cerebral injury and alterations in cerebral development with translation between animal models and the human infant. We hypothesized that the immature ferret would display a similar sequence of brain development [both gray (GM) and white matter (WM)] to that of the preterm human infant. We describe postnatal ferret neurodevelopment with conventional and diffusion MRI. The ferret is born lissencephalic with a thin cortical plate and relatively large ventricles. Cortical folding and WM maturation take place during the first month of life. From the mid-second through the third week of postnatal life, the ferret brain undergoes a similar, though less complex, pattern of maturational changes to those observed in the human brain during the second half of gestation. GM anisotropy decreases rapidly in the first 3 wks of life, followed by an upward surge of surface folding and WM anisotropy over the next 2 wks.

Magnetic resonance imaging detects significant sex differences in human myocardial strain

BackgroundThe pathophysiology responsible for the significant outcome disparities between men and women with cardiac disease is largely unknown. Further investigation into basic cardiac physiological differences between the sexes is needed. This study utilized magnetic resonance imaging (MRI)-based multiparametric strain analysis to search for sex-based differences in regional myocardial contractile function.MethodsEnd-systolic strain (circumferential, longitudinal, and radial) was interpolated from MRI-based radiofrequency tissue tagging grid point displacements in each of 60 normal adult volunteers (32 females).ResultsThe average global left ventricular (LV) strain among normal female volunteers (n = 32) was significantly larger in absolute value (functionally better) than in normal male volunteers (n = 28) in both the circumferential direction (Male/Female = -0.19 ± 0.02 vs. -0.21 ± 0.02; p = 0.025) and longitudinal direction (Male/Female = -0.14 ± 0.03 vs. -0.16 ± 0.02; p = 0.007).ConclusionsThe finding of significantly larger circumferential and longitudinal LV strain among normal female volunteers suggests that baseline contractile differences between the sexes may contribute to the well-recognized divergence in cardiovascular disease outcomes. Further work is needed in order to determine the pathologic changes that occur in LV strain between women and men with the onset of cardiovascular disease.

A New Method for Measuring Deformation of Folding Surfaces During Morphogenesis

During morphogenesis, epithelia (cell sheets) undergo complex deformations as they stretch, bend, and twist to form the embryo. Often these changes in shape create multivalued surfaces that can be problematic for strain measurements. This paper presents a method for quantifying deformation of such surfaces. The method requires four-dimensional spatiotemporal coordinates of a finite number of surface markers, acquired using standard imaging techniques. From the coordinates of the markers, various deformation measures are computed as functions of time and space using straightforward matrix algebra. This method accommodates sparse randomly scattered marker arrays, with reasonable errors in marker locations. The accuracy of the method is examined for some sample problems with exact solutions. Then, the utility of the method is illustrated by using it to measure surface stretch ratios and shear in the looping heart and developing brain of the early chick embryo. In these examples, microspheres are tracked using optical coherence tomography. This technique provides a new tool that can be used in studies of the mechanics of morphogenesis.

Spatial and Temporal Variations of Cortical Growth during Gyrogenesis in the Developing Ferret Brain

Spatial and temporal variations in cortical growth were studied in the neonatal ferret to illuminate the mechanisms of folding of the cerebral cortex. Cortical surface representations were created from magnetic resonance images acquired between postnatal day 4 and 35. Global measures of shape (e.g., surface area, normalized curvature, and sulcal depth) were calculated. In 2 ferrets, relative cortical growth was calculated between surfaces created from in vivo images acquired at P14, P21, and P28. The isocortical surface area transitions from a slower (12.7 mm(2)/day per hemisphere) to a higher rate of growth (36.7 mm(2)/day per hemisphere) approximately 13 days after birth, which coincides with the time of transition from neuronal proliferation to cellular morphological differentiation. Relative cortical growth increases as a function of relative geodesic distance from the origin of the transverse neurogenetic gradient and is related to the change in fractional diffusion anisotropy over the same time period. The methods presented here can be applied to study cortical growth during development in other animal models or human infants. Our results provide a quantitative spatial and temporal description of folding in cerebral cortex of the developing ferret brain, which will be important to understand the underlying mechanisms that drive folding.

Improved measurement of brain deformation during mild head acceleration using a novel tagged MRI sequence

In vivo measurements of human brain deformation during mild acceleration are needed to help validate computational models of traumatic brain injury and to understand the factors that govern the mechanical response of the brain. Tagged magnetic resonance imaging is a powerful, noninvasive technique to track tissue motion in vivo which has been used to quantify brain deformation in live human subjects. However, these prior studies required from 72 to 144 head rotations to generate deformation data for a single image slice, precluding its use to investigate the entire brain in a single subject. Here, a novel method is introduced that significantly reduces temporal variability in the acquisition and improves the accuracy of displacement estimates. Optimization of the acquisition parameters in a gelatin phantom and three human subjects leads to a reduction in the number of rotations from 72 to 144 to as few as 8 for a single image slice. The ability to estimate accurate, well-resolved, fields of displacement and strain in far fewer repetitions will enable comprehensive studies of acceleration-induced deformation throughout the human brain in vivo.

Three-dimensional regional strain computation method with displacement encoding with stimulated echoes (DENSE) in non-ischemic, non-valvular dilated cardiomyopathy patients and healthy subjects validated by tagged MRI

Fast cine displacement encoding with stimulated echoes (DENSE) MR has higher spatial resolution and enables rapid postprocessing. Thus we compared the accuracy of regional strains computation by DENSE with tagged MR in healthy and non‐ischemic, non‐valvular dilated cardiomyopathy (DCM) subjects.

Heterogeneous Distribution of Left Ventricular Contractile Injury in Chronic Aortic Insufficiency

BACKGROUND Global systolic strain has been described previously in patients with chronic aortic insufficiency (AI). This study explored regional differences in contractile injury. METHODS Tagged magnetic resonance images of the left ventricle (LV) were acquired and analyzed to calculate systolic strain in 42 patients with chronic AI. Multiparametric systolic strain analysis was applied to relate cardiac function in AI patients to a normal strain database (N = 60). AI patients were classified as having normal or poor function based on their results. A two-way repeated-measures analysis of variance was applied to analyze regional differences in injury. RESULTS The mean and standard deviation of raw strain values (circumferential strain, longitudinal strain, and minimum principal strain angle) are presented over the entire LV in our normal strain database. Of the 42 patients with AI, 15 could be defined as having poor function by multiparametric systolic strain analysis. In AI patients with poor function, statistical analysis showed significant differences in injury between standard LV regions (F(3.69,44.33) = 3.47, p = 0.017) and levels (F(1.49,17.88) = 4.41, p = 0.037) of the LV, whereas no significant differences were seen in the group with normal cardiac function. CONCLUSIONS Patients with poor function, as defined by multiparametric systolic strain z scores, exhibit a consistent, heterogeneous pattern of contractile injury in which the septum and posterior regions at the base are most injured.