Nan-kuei Chen

Diffusion tensor imaging of cerebral white matter integrity in cognitive aging

In this article we review recent research on diffusion tensor imaging (DTI) of white matter (WM) integrity and the implications for age-related differences in cognition. Neurobiological mechanisms defined from DTI analyses suggest that a primary dimension of age-related decline in WM is a decline in the structural integrity of myelin, particularly in brain regions that myelinate later developmentally. Research integrating behavioral measures with DTI indicates that WM integrity supports the communication among cortical networks, particularly those involving executive function, perceptual speed, and memory (i.e., fluid cognition). In the absence of significant disease, age shares a substantial portion of the variance associated with the relation between WM integrity and fluid cognition. Current data are consistent with one model in which age-related decline in WM integrity contributes to a decreased efficiency of communication among networks for fluid cognitive abilities. Neurocognitive disorders for which older adults are at risk, such as depression, further modulate the relation between WM and cognition, in ways that are not as yet entirely clear. Developments in DTI technology are providing a new insight into both the neurobiological mechanisms of aging WM and the potential contribution of DTI to understanding functional measures of brain activity. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.

Magnetic Resonance Imaging of Iron Deposition in Neurological Disorders

Deposition of iron in the brain is proposed to play a role in the pathophysiology of the normal aging process and neurodegenerative diseases. Whereas iron is required for normal neuronal metabolism, excessive levels can contribute to the formation of free radicals, leading to lipid peroxidation and neurotoxicity. Magnetic resonance imaging (MRI) is a powerful tool to detect excessive iron in the brain and longitudinally monitor changes in iron levels. Iron deposition is associated with a reduction in the T2 relaxation time, leading to hypointensity on spin-echo and gradient-echo T2-weighted images. The MRI changes associated with iron deposition have been observed both in normal aging and in various chronic neurological diseases, including multiple sclerosis, Alzheimer disease, and Parkinson disease. Magnetic resonance imaging metrics providing information about iron concentrations include R2, R2&vprime;, and R2*. The purpose of this review is to discuss the role of iron and its detection by MRI in various neurological disorders. We will review the basic biochemical properties of iron and its influence on MRI signal. We will also summarize the sensitivity and specificity of MRI techniques in detecting iron. The MRI and pathological findings pertaining to brain iron will be reviewed with respect to normal aging and a variety of neurological disorders. Finally, the biochemistry and pathophysiology surrounding iron, oxidative stress, free radicals, and lipid peroxidation in the brain will be discussed, including therapeutic implications. The potential role of iron deposition and its assessment by MRI provides exciting potential applications to the diagnosis, longitudinal monitoring, and therapeutic development for disorders of the brain.

Correction for EPI Distortions Using Multi-Echo Gradient-Echo Imaging

A novel and effective technique is described for distortion correction in echo planar imaging (EPI) utilizing the field maps derived from multi‐echo gradient‐echo images. The distortions from different off‐resonance related factors such as field inhomogeneity, eddy current effect, radiofrequency pulse frequency offset, and chemical shift effect can be simultaneously reduced to a great extent. With the proposed post‐processing algorithm of multi‐channel modulation, distortions may be corrected without unwrapping the phase discontinuities in the derived field map, a process that usually restricts the application of other field map‐based correction methods. Results from phantom and animal experiments at 4.7 T demonstrate the efficiency of the method in reducing the geometrical distortions in gradient‐echo EPI. Magn Reson Med 41:1206–1213, 1999.

PROPELLER EPI: An MRI technique suitable for diffusion tensor imaging at high field strength with reduced geometric distortions†

A technique suitable for diffusion tensor imaging (DTI) at high field strengths is presented in this work. The method is based on a periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) k‐space trajectory using EPI as the signal readout module, and hence is dubbed PROPELLER EPI. The implementation of PROPELLER EPI included a series of correction schemes to reduce possible errors associated with the intrinsically higher sensitivity of EPI to off‐resonance effects. Experimental results on a 3.0 Tesla MR system showed that the PROPELLER EPI images exhibit substantially reduced geometric distortions compared with single‐shot EPI, at a much lower RF specific absorption rate (SAR) than the original version of the PROPELLER fast spin‐echo (FSE) technique. For DTI, the self‐navigated phase‐correction capability of the PROPELLER EPI sequence was shown to be effective for in vivo imaging. A higher signal‐to‐noise ratio (SNR) compared to single‐shot EPI at an identical total scan time was achieved, which is advantageous for routine DTI applications in clinical practice. Magn Reson Med, 2005.

A robust multi-shot scan strategy for high-resolution diffusion weighted MRI enabled by multiplexed sensitivity-encoding (MUSE)

Diffusion weighted magnetic resonance imaging (DWI) data have been mostly acquired with single-shot echo-planar imaging (EPI) to minimize motion induced artifacts. The spatial resolution, however, is inherently limited in single-shot EPI, even when the parallel imaging (usually at an acceleration factor of 2) is incorporated. Multi-shot acquisition strategies could potentially achieve higher spatial resolution and fidelity, but they are generally susceptible to motion-induced phase errors among excitations that are exacerbated by diffusion sensitizing gradients, rendering the reconstructed images unusable. It has been shown that shot-to-shot phase variations may be corrected using navigator echoes, but at the cost of imaging throughput. To address these challenges, a novel and robust multi-shot DWI technique, termed multiplexed sensitivity-encoding (MUSE), is developed here to reliably and inherently correct nonlinear shot-to-shot phase variations without the use of navigator echoes. The performance of the MUSE technique is confirmed experimentally in healthy adult volunteers on 3Tesla MRI systems. This newly developed technique should prove highly valuable for mapping brain structures and connectivities at high spatial resolution for neuroscience studies.

Selection of voxel size and slice orientation for fMRI in the presence of susceptibility field gradients: application to imaging of the amygdala.

The impact of voxel geometry on the blood oxygenation level-dependent (BOLD) signal detectability in the presence of field inhomogeneity is assessed and a quantitative approach to selecting appropriate voxel geometry is developed in this report. Application of the developed technique to BOLD sensitivity improvement of the human amygdala is presented. Field inhomogeneity was measured experimentally at 1.5 T and 3 T and the dominant susceptibility field gradient in the human amygdala was observed approximately along the superior-inferior direction. Based on the field mapping studies, an optimal selection for the slice orientation would be an oblique pseudo-coronal plane with its frequency-encoding direction parallel to the field gradient measured from each subject. Experimentally this was confirmed by comparing the normalized standard deviation of time-series echo-planar imaging signals acquired with different slice orientations, in the absence of a functional stimulus. A further confirmation with a carefully designed functional magnetic resonance imaging study is needed. Although the BOLD sensitivity may generally be improved by a voxel size commensurable with the activation volume, our quantitative analysis shows that the optimal voxel size also depends on the susceptibility field gradient and is usually smaller than the activation volume. The predicted phenomenon is confirmed with a hybrid simulation, in which the functional activation was mathematically added to the experimentally acquired rest-period echo-planar imaging data.

Optimized distortion correction technique for echo planar imaging

A new phase‐shifted EPI pulse sequence is described that encodes EPI phase errors due to all off‐resonance factors, including Bo field inhomogeneity, eddy current effects, and gradient waveform imperfections. Combined with the previously proposed multichannel modulation postprocessing algorithm (Chen and Wyrwicz, MRM 1999;41:1206–1213), the encoded phase error information can be used to effectively remove geometric distortions in subsequent EPI scans. The proposed EPI distortion correction technique has been shown to be effective in removing distortions due to gradient waveform imperfections and phase gradient‐induced eddy current effects. In addition, this new method retains advantages of the earlier method, such as simultaneous correction of different off‐resonance factors without use of a complicated phase unwrapping procedure. The effectiveness of this technique is illustrated with EPI studies on phantoms and animal subjects. Implementation to different versions of EPI sequences is also described. Magn Reson Med 45:525–528, 2001.

Removal of EPI Nyquist ghost artifacts with two-dimensional phase correction

Odd–even echo inconsistencies result in Nyquist ghost artifacts in the reconstructed EPI images. The ghost artifacts reduce the image signal‐to‐noise ratio and make it difficult to correctly interpret the EPI data. In this article a new 2D phase mapping protocol and a postprocessing algorithm are presented for an effective Nyquist ghost artifacts removal. After an appropriate k‐space data regrouping, a 2D map accurately encoding low‐ and high‐order phase errors is derived from two phase‐encoded reference scans, which were originally proposed by Hu and Le (Magn Reson Med 36:166–171;1996) for their 1D nonlinear correction method. The measured phase map can be used in the postprocessing algorithm developed to remove ghost artifacts in subsequent EPI experiments. Experimental results from phantom, animal, and human studies suggest that the new technique is more effective than previously reported methods and has a better tolerance to signal intensity differences between reference and actual EPI scans. The proposed method may potentially be applied to repeated EPI measurements without subject movements, such as functional MRI and diffusion coefficient mapping. Magn Reson Med 51:1247–1253, 2004.

Investigation of long-term reproducibility of intrinsic connectivity network mapping: a resting-state fMRI study.

BACKGROUND AND PURPOSE: Connectivity mapping based on resting-state fMRI is rapidly developing, and this methodology has great potential for clinical applications. However, before resting-state fMRI can be applied for diagnosis, prognosis, and monitoring treatment for an individual patient with neurologic or psychiatric diseases, it is essential to assess its long-term reproducibility and between-subject variations among healthy individuals. The purpose of the study was to quantify the long-term test-retest reproducibility of ICN measures derived from resting-state fMRI and to assess the between-subject variation of ICN measures across the whole brain. MATERIALS AND METHODS: Longitudinal resting-state fMRI data of 6 healthy volunteers were acquired from 9 scan sessions during >1 year. The within-subject reproducibility and between-subject variation of ICN measures, across the whole brain and major nodes of the DMN, were quantified with the ICC and COV. RESULTS: Our data show that the long-term test-retest reproducibility of ICN measures is outstanding, with >70% of the connectivity networks showing an ICC > 0.60. The COV across 6 healthy volunteers in this sample was >0.2, suggesting significant between-subject variation. CONCLUSIONS: Our data indicate that resting-state ICN measures (eg, the correlation coefficients between fMRI signal-intensity profiles from 2 different brain regions) are potentially suitable as biomarkers for monitoring disease progression and treatment effects in clinical trials and individual patients. Because between-subject variation is significant, it may be difficult to use quantitative ICN measures in their current state as a diagnostic tool.

Effects of Repetitive Transcranial Magnetic Stimulation on Motor Symptoms in Parkinson Disease: A Systematic Review and Meta-analysis

IMPORTANCE Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation technique that has been closely examined as a possible treatment for Parkinson disease (PD). However, results evaluating the effectiveness of rTMS in PD are mixed, mostly owing to low statistical power or variety in individual rTMS protocols. OBJECTIVES To determine the rTMS effects on motor dysfunction in patients with PD and to examine potential factors that modulate the rTMS effects. DATA SOURCES Databases searched included PubMed, EMBASE, Web of Knowledge, Scopus, and the Cochrane Library from inception to June 30, 2014. STUDY SELECTION Eligible studies included sham-controlled, randomized clinical trials of rTMS intervention for motor dysfunction in patients with PD. DATA EXTRACTION AND SYNTHESIS Relevant measures were extracted independently by 2 investigators. Standardized mean differences (SMDs) were calculated with random-effects models. MAIN OUTCOMES AND MEASURES Motor examination of the Unified Parkinsons Disease Rating Scale. RESULTS Twenty studies with a total of 470 patients were included. Random-effects analysis revealed a pooled SMD of 0.46 (95% CI, 0.29-0.64), indicating an overall medium effect size favoring active rTMS over sham rTMS in the reduction of motor symptoms (P<.001). Subgroup analysis showed that the effect sizes estimated from high-frequency rTMS targeting the primary motor cortex (SMD, 0.77; 95% CI, 0.46-1.08; P<.001) and low-frequency rTMS applied over other frontal regions (SMD, 0.50; 95% CI, 0.13-0.87; P=.008) were significant. The effect sizes obtained from the other 2 combinations of rTMS frequency and rTMS site (ie, high-frequency rTMS at other frontal regions: SMD, 0.23; 95% CI, -0.02 to 0.48, and low primary motor cortex: SMD, 0.28; 95% CI, -0.23 to 0.78) were not significant. Meta-regression revealed that a greater number of pulses per session or across sessions is associated with larger rTMS effects. Using the Grading of Recommendations, Assessment, Development, and Evaluation criteria, we characterized the quality of evidence presented in this meta-analysis as moderate quality. CONCLUSIONS AND RELEVANCE The pooled evidence suggests that rTMS improves motor symptoms for patients with PD. Combinations of rTMS site and frequency as well as the number of rTMS pulses are key modulators of rTMS effects. The findings of our meta-analysis may guide treatment decisions and inform future research.