Sean C.L. Deoni

Rapid combined T1 and T2 mapping using gradient recalled acquisition in the steady state.

A novel, fully 3D, high‐resolution T1 and T2 relaxation time mapping method is presented. The method is based on steady‐state imaging with T1 and T2 information derived from either spoiling or fully refocusing the transverse magnetization following each excitation pulse. T1 is extracted from a pair of spoiled gradient recalled echo (SPGR) images acquired at optimized flip angles. This T1 information is combined with two refocused steady‐state free precession (SSFP) images to determine T2. T1 and T2 accuracy was evaluated against inversion recovery (IR) and spin‐echo (SE) results, respectively. Error within the T1 and T2 maps, determined from both phantom and in vivo measurements, is approximately 7% for T1 between 300 and 2000 ms and 7% for T2 between 30 and 150 ms. The efficiency of the method, defined as the signal‐to‐noise ratio (SNR) of the final map per voxel volume per square root scan time, was evaluated against alternative mapping methods. With an efficiency of three times that of multipoint IR and three times that of multiecho SE, our combined approach represents the most efficient of those examined. Acquisition time for a whole brain T1 map (25 × 25 × 10 cm) is less than 8 min with 1 mm3 isotropic voxels. An additional 7 min is required for an identically sized T2 map and postprocessing time is less than 1 min on a 1 GHz PIII PC. The method therefore permits real‐time clinical acquisition and display of whole brain T1 and T2 maps for the first time. Magn Reson Med 49:515–526, 2003.

High-resolution T1 and T2 mapping of the brain in a clinically acceptable time with DESPOT1 and DESPOT2.

Variations in the intrinsic T1 and T2 relaxation times have been implicated in numerous neurologic conditions. Unfortunately, the low resolution and long imaging time associated with conventional methods have prevented T1 and T2 mapping from becoming part of routine clinical evaluation. In this study, the clinical applicability of the DESPOT1 and DESPOT2 imaging methods for high‐resolution, whole‐brain, T1 and T2 mapping was investigated. In vivo, 1‐mm3 isotropic whole‐brain T1 and T2 maps of six healthy volunteers were acquired at 1.5 T with an imaging time of <17 min each. Isotropic maps (0.34 mm3) of one volunteer were also acquired (time <21 min). Average signal‐to‐noise within the 1‐mm3 T1 and T2 maps was ∼20 and ∼14, respectively, with average repeatability standard deviations of 46.7 ms and 6.7 ms. These results demonstrate the clinical feasibility of the methods in the study of neurologic disease. Magn Reson Med 53:237–241, 2005.

Gleaning Multicomponent T-1 and T-2 Information From Steady-State Imaging Data

The driven‐equilibrium single‐pulse observation of T1 (DESPOT1) and T2 (DESPOT2) are rapid, accurate, and precise methods for voxelwise determination of the longitudinal and transverse relaxation times. A limitation of the methods, however, is the inherent assumption of single‐component relaxation. In a variety of biological tissues, in particular human white matter (WM) and gray matter (GM), the relaxation has been shown to be more completely characterized by a summation of two or more relaxation components, or species, each believed to be associated with unique microanatomical domains or water pools. Unfortunately, characterization of these components on a voxelwise, whole‐brain basis has traditionally been hindered by impractical acquisition times. In this work we extend the conventional DESPOT1 and DESPOT2 approaches to include multicomponent relaxation analysis. Following numerical analysis of the new technique, renamed multicomponent driven equilibrium single pulse observation of T1/T2 (mcDESPOT), whole‐brain multicomponent T1 and T2 quantification is demonstrated in vivo with clinically realistic times of between 16 and 30 min. Results obtained from four healthy individuals and two primary progressive multiple sclerosis (MS) patients demonstrate the future potential of the approach for identifying and assessing tissue changes associated with several neurodegenerative conditions, in particular those associated with WM. Magn Reson Med 60:1372–1387, 2008.

Mapping Infant Brain Myelination with Magnetic Resonance Imaging

Myelination, the elaboration of myelin surrounding neuronal axons, is essential for normal brain function. The development of the myelin sheath enables rapid synchronized communication across the neural systems responsible for higher order cognitive functioning. Despite this critical role, quantitative visualization of myelination in vivo is not possible with current neuroimaging techniques including diffusion tensor and structural magnetic resonance imaging (MRI). Although these techniques offer insight into structural maturation, they reflect several different facets of development, e.g., changes in axonal size, density, coherence, and membrane structure; lipid, protein, and macromolecule content; and water compartmentalization. Consequently, observed signal changes are ambiguous, hindering meaningful inferences between imaging findings and metrics of learning, behavior or cognition. Here we present the first quantitative study of myelination in healthy human infants, from 3 to 11 months of age. Using a new myelin-specific MRI technique, we report a spatiotemporal pattern beginning in the cerebellum, pons, and internal capsule; proceeding caudocranially from the splenium of the corpus callosum and optic radiations (at 3–4 months); to the occipital and parietal lobes (at 4–6 months); and then to the genu of the corpus callosum and frontal and temporal lobes (at 6–8 months). Our results also offer preliminary evidence of hemispheric myelination rate differences. This work represents a significant step forward in our ability to appreciate the fundamental process of myelination, and provides the first ever in vivo visualization of myelin maturation in healthy human infancy.

Biological sex affects the neurobiology of autism

In autism, heterogeneity is the rule rather than the exception. One obvious source of heterogeneity is biological sex. Since autism was first recognized, males with autism have disproportionately skewed research. Females with autism have thus been relatively overlooked, and have generally been assumed to have the same underlying neurobiology as males with autism. Growing evidence, however, suggests that this is an oversimplification that risks obscuring the biological base of autism. This study seeks to answer two questions about how autism is modulated by biological sex at the level of the brain: (i) is the neuroanatomy of autism different in males and females? and (ii) does the neuroanatomy of autism fit predictions from the ‘extreme male brain’ theory of autism, in males and/or in females? Neuroanatomical features derived from voxel-based morphometry were compared in a sample of equal-sized high-functioning male and female adults with and without autism (n = 120, n = 30/group). The first question was investigated using a 2 × 2 factorial design, and by spatial overlap analyses of the neuroanatomy of autism in males and females. The second question was tested through spatial overlap analyses of specific patterns predicted by the extreme male brain theory. We found that the neuroanatomy of autism differed between adult males and females, evidenced by minimal spatial overlap (not different from that occurred under random condition) in both grey and white matter, and substantially large white matter regions showing significant sex × diagnosis interactions in the 2 × 2 factorial design. These suggest that autism manifests differently by biological sex. Furthermore, atypical brain areas in females with autism substantially and non-randomly (P < 0.001) overlapped with areas that were sexually dimorphic in neurotypical controls, in both grey and white matter, suggesting neural ‘masculinization’. This was not seen in males with autism. How differences in neuroanatomy relate to the similarities in cognition between males and females with autism remains to be understood. Future research should stratify by biological sex to reduce heterogeneity and to provide greater insight into the neurobiology of autism.

MRI characteristics of the substantia nigra in Parkinson's disease: a combined quantitative T1 and DTI study.

The substantia nigra contains dopaminergic cells that project to the striatum and are affected by the neurodegenerative process that appears in Parkinsons disease (PD). For accurate differential diagnosis and for disease monitoring the availability of a sensitive and non-invasive biomarker for Parkinsons disease would be essential. Although there has been notable progress in studying correlates of nigral degeneration by means of magnetic resonance imaging (MRI) in the past decade, MRI and analysis techniques that allow accurate high-resolution mapping of the SN within a clinically acceptable acquisition time are still elusive. The main purpose of the preliminary study was to evaluate the potential role of the driven equilibrium single pulse observation of T1 (DESPOT1) method for delineation of the SN and differentiation of PD patients from healthy control subjects (n=10 in each group). We also investigated whether additional measures that can be obtained with diffusion tensor imaging (DTI) can further improve the MRI-guided discrimination between PD patients and controls. Our results show that the DESPOT1 method allows for a clear visualisation of the SN as a whole. Volumetric comparisons between ten PD patients and ten healthy subjects revealed significantly smaller volumes in patients for both the left and the right sides when the whole SN was considered. Combining SN volumetry and its connectivity with the thalamus improved the classification sensitivity to 100% and specificity to 80% for PD (discriminant function analysis with leave-one-out cross validation). Combining DESPOT1 imaging and DTI could therefore serve as a diagnostic marker for idiopathic Parkinsons disease in the future.

Investigating white matter development in infancy and early childhood using myelin water faction and relaxation time mapping.

The elaboration of the myelinated white matter is essential for normal neurodevelopment, establishing and mediating rapid communication pathways throughout the brain. These pathways facilitate the synchronized communication required for higher order behavioral and cognitive functioning. Altered neural messaging (or ‘disconnectivity’) arising from abnormal white matter and myelin development may underlie a number of neurodevelopmental psychiatric disorders. Despite the vital role myelin plays, few imaging studies have specifically examined its maturation throughout early infancy and childhood. Thus, direct investigations of the relationship(s) between evolving behavioral and cognitive functions and the myelination of the supporting neural systems have been sparse. Further, without knowledge of the ‘normative’ developmental time-course, identification of early abnormalities associated with developmental disorders remains challenging. In this work, we examined the use of longitudinal (T1) and transverse (T2) relaxation time mapping, and myelin water fraction (MWF) imaging to investigate white matter and myelin development in 153 healthy male and female children, 3 months through 60 months in age. Optimized age-specific acquisition protocols were developed using the DESPOT and mcDESPOT imaging techniques; and mean T1, T2 and MWF trajectories were determined for frontal, temporal, occipital, parietal and cerebellar white matter, and genu, body and splenium of the corpus callosum. MWF results provided a spatio-temporal pattern in-line with prior histological studies of myelination. Comparison of T1, T2 and MWF measurements demonstrates dissimilar sensitivity to tissue changes associated with neurodevelopment, with each providing differential but complementary information.

Brain Differences in Infants at Differential Genetic Risk for Late-Onset Alzheimer Disease: A Cross-sectional Imaging Study

IMPORTANCE Converging evidence suggests brain structure alterations may precede overt cognitive impairment in Alzheimer disease by several decades. Early detection of these alterations holds inherent value for the development and evaluation of preventive treatment therapies. OBJECTIVE To compare magnetic resonance imaging measurements of white matter myelin water fraction (MWF) and gray matter volume (GMV) in healthy infant carriers and noncarriers of the apolipoprotein E (APOE) ε4 allele, the major susceptibility gene for late-onset AD. DESIGN, SETTING, AND PARTICIPANTS Quiet magnetic resonance imaging was performed at an academic research imaging center on 162 healthy, typically developing 2- to 25-month-old infants with no family history of Alzheimer disease or other neurological or psychiatric disorders. Cross-sectional measurements were compared in the APOE ε4 carrier and noncarrier groups. White matter MWF was compared in one hundred sixty-two 2- to 25-month-old sleeping infants (60 ε4 carriers and 102 noncarriers). Gray matter volume was compared in a subset of fifty-nine 6- to 25-month-old infants (23 ε4 carriers and 36 noncarriers), who remained asleep during the scanning session. The carrier and noncarrier groups were matched for age, gestational duration, birth weight, sex ratio, maternal age, education, and socioeconomic status. MAIN OUTCOMES AND MEASURES Automated algorithms compared regional white matter MWF and GMV in the carrier and noncarrier groups and characterized their associations with age. RESULTS Infant ε4 carriers had lower MWF and GMV measurements than noncarriers in precuneus, posterior/middle cingulate, lateral temporal, and medial occipitotemporal regions, areas preferentially affected by AD, and greater MWF and GMV measurements in extensive frontal regions and measurements were also significant in the subset of 2- to 6-month-old infants (MWF differences, P < .05, after correction for multiple comparisons; GMV differences, P < .001, uncorrected for multiple comparisons). Infant ε4 carriers also exhibited an attenuated relationship between MWF and age in posterior white matter regions. CONCLUSIONS AND RELEVANCE While our findings should be considered preliminary, this study demonstrates some of the earliest brain changes associated with the genetic predisposition to AD. It raises new questions about the role of APOE in normal human brain development, the extent to which these processes are related to subsequent AD pathology, and whether they could be targeted by AD prevention therapies.

High resolution diffusion-weighted imaging in fixed human brain using diffusion-weighted steady state free precession.

High resolution diffusion tensor imaging and tractography of ex vivo brain specimens has the potential to reveal detailed fibre architecture not visible on in vivo images. Previous ex vivo diffusion imaging experiments have focused on animal brains or small sections of human tissue since the unfavourable properties of fixed tissue (including short T(2) and low diffusion rates) demand the use of very powerful gradient coils that are too small to accommodate a whole, human brain. This study proposes the use of diffusion-weighted steady-state free precession (DW-SSFP) as a method of extending the benefits of ex vivo DTI and tractography to whole, human, fixed brains on a clinical 3 T scanner. DW-SSFP is a highly efficient pulse sequence; however, its complicated signal dependence precludes the use of standard diffusion tensor analysis and tractography. In this study, a method is presented for modelling anisotropy in the context of DW-SSFP. Markov Chain Monte Carlo sampling is used to estimate the posterior distributions of model parameters and it is shown that it is possible to estimate a tight distribution on the principal axis of diffusion at each voxel using DW-SSFP. Voxel-wise estimates are used to perform tractography in a whole, fixed human brain. A direct comparison between 3D diffusion-weighted spin echo EPI and 3D DW-SSFP-EPI reveals that the orientation of the principal diffusion axis can be inferred on with a higher degree of certainty using a 3D DW-SSFP-EPI even with a 68% shorter acquisition time.

Breastfeeding and early white matter development: A cross-sectional study.

Does breastfeeding alter early brain development? The prevailing consensus from large epidemiological studies posits that early exclusive breastfeeding is associated with improved measures of IQ and cognitive functioning in later childhood and adolescence. Prior morphometric brain imaging studies support these findings, revealing increased white matter and sub-cortical gray matter volume, and parietal lobe cortical thickness, associated with IQ, in adolescents who were breastfed as infants compared to those who were exclusively formula-fed. Yet it remains unknown when these structural differences first manifest and when developmental differences that predict later performance improvements can be detected. In this study, we used quiet magnetic resonance imaging (MRI) scans to compare measures of white matter microstructure (mcDESPOT measures of myelin water fraction) in 133 healthy children from 10 months through 4 years of age, who were either exclusively breastfed a minimum of 3 months; exclusively formula-fed; or received a mixture of breast milk and formula. We also examined the relationship between breastfeeding duration and white matter microstructure. Breastfed children exhibited increased white matter development in later maturing frontal and association brain regions. Positive relationships between white matter microstructure and breastfeeding duration are also exhibited in several brain regions, that are anatomically consistent with observed improvements in cognitive and behavioral performance measures. While the mechanisms underlying these structural differences remains unclear, our findings provide new insight into the earliest developmental advantages associated with breastfeeding, and support the hypothesis that breast milk constituents promote healthy neural growth and white matter development.