Antoine Lutti

Confirmation of functional zones within the human subthalamic nucleus: Patterns of connectivity and sub-parcellation using diffusion weighted imaging

The subthalamic nucleus (STN) is a small, glutamatergic nucleus situated in the diencephalon. A critical component of normal motor function, it has become a key target for deep brain stimulation in the treatment of Parkinsons disease. Animal studies have demonstrated the existence of three functional sub-zones but these have never been shown conclusively in humans. In this work, a data driven method with diffusion weighted imaging demonstrated that three distinct clusters exist within the human STN based on brain connectivity profiles. The STN was successfully sub-parcellated into these regions, demonstrating good correspondence with that described in the animal literature. The local connectivity of each sub-region supported the hypothesis of bilateral limbic, associative and motor regions occupying the anterior, mid and posterior portions of the nucleus respectively. This study is the first to achieve in-vivo, non-invasive anatomical parcellation of the human STN into three anatomical zones within normal diagnostic scan times, which has important future implications for deep brain stimulation surgery.

Using high-resolution quantitative mapping of R1 as an index of cortical myelination

A fundamental tenet of neuroscience is that cortical functional differentiation is related to the cross-areal differences in cyto-, receptor-, and myeloarchitectonics that are observed in ex-vivo preparations. An ongoing challenge is to create noninvasive magnetic resonance (MR) imaging techniques that offer sufficient resolution, tissue contrast, accuracy and precision to allow for characterization of cortical architecture over an entire living human brain. One exciting development is the advent of fast, high-resolution quantitative mapping of basic MR parameters that reflect cortical myeloarchitecture. Here, we outline some of the theoretical and technical advances underlying this technique, particularly in terms of measuring and correcting for transmit and receive radio frequency field inhomogeneities. We also discuss new directions in analytic techniques, including higher resolution reconstructions of the cortical surface. We then discuss two recent applications of this technique. The first compares individual and group myelin maps to functional retinotopic maps in the same individuals, demonstrating a close relationship between functionally and myeloarchitectonically defined areal boundaries (as well as revealing an interesting disparity in a highly studied visual area). The second combines tonotopic and myeloarchitectonic mapping to localize primary auditory areas in individual healthy adults, using a similar strategy as combined electrophysiological and post-mortem myeloarchitectonic studies in non-human primates.

Quantitative multi-parameter mapping of R1, PD*, MT, and R2* at 3T: a multi-center validation

Multi-center studies using magnetic resonance imaging facilitate studying small effect sizes, global population variance and rare diseases. The reliability and sensitivity of these multi-center studies crucially depend on the comparability of the data generated at different sites and time points. The level of inter-site comparability is still controversial for conventional anatomical T1-weighted MRI data. Quantitative multi-parameter mapping (MPM) was designed to provide MR parameter measures that are comparable across sites and time points, i.e., 1 mm high-resolution maps of the longitudinal relaxation rate (R1 = 1/T1), effective proton density (PD*), magnetization transfer saturation (MT) and effective transverse relaxation rate (R2* = 1/T2*). MPM was validated at 3T for use in multi-center studies by scanning five volunteers at three different sites. We determined the inter-site bias, inter-site and intra-site coefficient of variation (CoV) for typical morphometric measures [i.e., gray matter (GM) probability maps used in voxel-based morphometry] and the four quantitative parameters. The inter-site bias and CoV were smaller than 3.1 and 8%, respectively, except for the inter-site CoV of R2* (<20%). The GM probability maps based on the MT parameter maps had a 14% higher inter-site reproducibility than maps based on conventional T1-weighted images. The low inter-site bias and variance in the parameters and derived GM probability maps confirm the high comparability of the quantitative maps across sites and time points. The reliability, short acquisition time, high resolution and the detailed insights into the brain microstructure provided by MPM makes it an efficient tool for multi-center imaging studies.

In Vivo Functional and Myeloarchitectonic Mapping of Human Primary Auditory Areas

In contrast to vision, where retinotopic mapping alone can define areal borders, primary auditory areas such as A1 are best delineated by combining in vivo tonotopic mapping with postmortem cyto- or myeloarchitectonics from the same individual. We combined high-resolution (800 μm) quantitative T1 mapping with phase-encoded tonotopic methods to map primary auditory areas (A1 and R) within the “auditory core” of human volunteers. We first quantitatively characterize the highly myelinated auditory core in terms of shape, area, cortical depth profile, and position, with our data showing considerable correspondence to postmortem myeloarchitectonic studies, both in cross-participant averages and in individuals. The core region contains two “mirror-image” tonotopic maps oriented along the same axis as observed in macaque and owl monkey. We suggest that these two maps within the core are the human analogs of primate auditory areas A1 and R. The core occupies a much smaller portion of tonotopically organized cortex on the superior temporal plane and gyrus than is generally supposed. The multimodal approach to defining the auditory core will facilitate investigations of structure–function relationships, comparative neuroanatomical studies, and promises new biomarkers for diagnosis and clinical studies.

Unified segmentation based correction of R1 brain maps for RF transmit field inhomogeneities (UNICORT)

Quantitative mapping of the longitudinal relaxation rate (R1 = 1/T1) in the human brain enables the investigation of tissue microstructure and macroscopic morphology which are becoming increasingly important for clinical and neuroimaging applications. R1 maps are now commonly estimated from two fast high-resolution 3D FLASH acquisitions with variable excitation flip angles, because this approach is fast and does not rely on special acquisition techniques. However, these R1 maps need to be corrected for bias due to RF transmit field (B1+) inhomogeneities, requiring additional B1+ mapping which is usually time consuming and difficult to implement. We propose a technique that simultaneously estimates the B1+ inhomogeneities and R1 values from the uncorrected R1 maps in the human brain without need for B1+ mapping. It employs a probabilistic framework for unified segmentation based correction of R1 maps for B1+ inhomogeneities (UNICORT). The framework incorporates a physically informed generative model of smooth B1+ inhomogeneities and their multiplicative effect on R1 estimates. Extensive cross-validation with the established standard using measured B1+ maps shows that UNICORT yields accurate B1+ and R1 maps with a mean deviation from the standard of less than 4.3% and 5%, respectively. The results of different groups of subjects with a wide age range and different levels of atypical brain anatomy further suggest that the method is robust and generalizes well to wider populations. UNICORT is easy to apply, as it is computationally efficient and its basic framework is implemented as part of the tissue segmentation in SPM8.

Widespread age-related differences in the human brain microstructure revealed by quantitative magnetic resonance imaging

A pressing need exists to disentangle age-related changes from pathologic neurodegeneration. This study aims to characterize the spatial pattern and age-related differences of biologically relevant measures in vivo over the course of normal aging. Quantitative multiparameter maps that provide neuroimaging biomarkers for myelination and iron levels, parameters sensitive to aging, were acquired from 138 healthy volunteers (age range: 19–75 years). Whole-brain voxel-wise analysis revealed a global pattern of age-related degeneration. Significant demyelination occurred principally in the white matter. The observed age-related differences in myelination were anatomically specific. In line with invasive histologic reports, higher age-related differences were seen in the genu of the corpus callosum than the splenium. Iron levels were significantly increased in the basal ganglia, red nucleus, and extensive cortical regions but decreased along the superior occipitofrontal fascicle and optic radiation. This whole-brain pattern of age-associated microstructural differences in the asymptomatic population provides insight into the neurobiology of aging. The results help build a quantitative baseline from which to examine and draw a dividing line between healthy aging and pathologic neurodegeneration.

Optimization and validation of methods for mapping of the radiofrequency transmit field at 3T.

MRI techniques such as quantitative imaging and parallel transmit require precise knowledge of the radio‐frequency transmit field (B  1+ ). Three published methods were optimized for robust B  1+ mapping at 3T in the human brain: three‐dimensional (3D) actual flip angle imaging (AFI), 3D echo‐planar imaging (EPI), and two‐dimensional (2D) stimulated echo acquisition mode (STEAM). We performed a comprehensive comparison of the methods, focusing on artifacts, reproducibility, and accuracy compared to a reference 2D double angle method. For the 3D AFI method, the addition of flow‐compensated gradients for diffusion damping reduced the level of physiological artifacts and improved spoiling of transverse coherences. Correction of susceptibility‐induced artifacts alleviated image distortions and improved the accuracy of the 3D EPI imaging method. For the 2D STEAM method, averaging over multiple acquisitions reduced the impact of physiological noise and a new calibration method enhanced the accuracy of the B  1+ maps. After optimization, all methods yielded low noise B  1+ maps (below 2 percentage units), of the nominal flip angle value (p.u.) with a systematic bias less than 5 p.u. units. Full brain coverage was obtained in less than 5 min. The 3D AFI method required minimal postprocessing and showed little sensitivity to off‐resonance and physiological effects. The 3D EPI method showed the highest level of reproducibility. The 2D STEAM method was the most time‐efficient technique. Magn Reson Med, 2010.

Robust and Fast Whole Brain Mapping of the RF Transmit Field B1 at 7T

In-vivo whole brain mapping of the radio frequency transmit field B1 + is a key aspect of recent method developments in ultra high field MRI. We present an optimized method for fast and robust in-vivo whole-brain B1 + mapping at 7T. The method is based on the acquisition of stimulated and spin echo 3D EPI images and was originally developed at 3T. We further optimized the method for use at 7T. Our optimization significantly improved the robustness of the method against large B1 + deviations and off-resonance effects present at 7T. The mean accuracy and precision of the optimized method across the brain was high with a bias less than 2.6 percent unit (p.u.) and random error less than 0.7 p.u. respectively.

High-resolution functional MRI at 3 T: 3D/2D echo-planar imaging with optimized physiological noise correction

High‐resolution functional MRI (fMRI) offers unique possibilities for studying human functional neuroanatomy. Although high‐resolution fMRI has proven its potential at 7 T, most fMRI studies are still performed at rather low spatial resolution at 3 T. We optimized and compared single‐shot two‐dimensional echo‐planar imaging (EPI) and multishot three‐dimensional EPI high‐resolution fMRI protocols. We extended image‐based physiological noise correction from two‐dimensional EPI to multishot three‐dimensional EPI. The functional sensitivity of both acquisition schemes was assessed in a visual fMRI experiment. The physiological noise correction increased the sensitivity significantly, can be easily applied, and requires simple recordings of pulse and respiration only. The combination of three‐dimensional EPI with physiological noise correction provides exceptional sensitivity for 1.5 mm high‐resolution fMRI at 3 T, increasing the temporal signal‐to‐noise ratio by more than 25% compared to two‐dimensional EPI. Magn Reson Med, 2013.

Advances in MRI-based computational neuroanatomy: from morphometry to in-vivo histology

PURPOSE OF REVIEW Current computational neuroanatomy based on MRI focuses on morphological measures of the brain. We present recent methodological developments in quantitative MRI (qMRI) that provide standardized measures of the brain, which go beyond morphology. We show how biophysical modelling of qMRI data can provide quantitative histological measures of brain tissue, leading to the emerging field of in-vivo histology using MRI (hMRI). RECENT FINDINGS qMRI has greatly improved the sensitivity and specificity of computational neuroanatomy studies. qMRI metrics can also be used as direct indicators of the mechanisms driving observed morphological findings. For hMRI, biophysical models of the MRI signal are being developed to directly access histological information such as cortical myelination, axonal diameters or axonal g-ratio in white matter. Emerging results indicate promising prospects for the combined study of brain microstructure and function. SUMMARY Non-invasive brain tissue characterization using qMRI or hMRI has significant implications for both research and clinics. Both approaches improve comparability across sites and time points, facilitating multicentre/longitudinal studies and standardized diagnostics. hMRI is expected to shed new light on the relationship between brain microstructure, function and behaviour, both in health and disease, and become an indispensable addition to computational neuroanatomy.