Nan-kuei Chen

Interests

Research

1) Development of high-throughput and motion-immune clinical MRI for imaging challenging patient populations2) Imaging of neuronal connectivity networks for studies of neurological diseases3) High-fidelity and multi-contrast MRI guided intervention4) Characterization and correction of MRI artifacts5) Signal processing and algorithm development6) MRI studies of human development

Teaching

Medical Imaging; Magnetic Resonance Imaging;

Courses

Scholarly Contributions

Chapters

• Chen, N. (2014). A Unified Machine Learning Method for Task-related and Resting State fMRI data Analysis. In 2014 36th Annual International Conference of the Ieee Engineering in Medicine and Biology Society (Embc).
• Chen, N. (2005). 76-space analysis of grey matter diffusivity: Methods and applications. In Medical Image Computing and Computer-Assisted Intervention - Miccai 2005, Pt 1.
• Chen, N. (2004). MRI intensity nonuniformity correction using simultaneously spatial and gray-level histogram information. In Medical Imaging 2004: Image Processing, Pts 1-3.

Journals/Publications

• Bell, R. P., Meade, C. S., Gadde, S., Towe, S. L., Hall, S. A., & Chen, N. K. (2022). Principal component analysis denoising improves sensitivity of MR diffusion to detect white matter injury in neuroHIV. Journal of neuroimaging : official journal of the American Society of Neuroimaging.
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  Diffusion-weighted imaging is able to capture important information about cerebral white matter (WM) structure. However, diffusion data can suffer from MRI and biological noise that degrades the quality of the images and makes finding important features difficult. We investigated how effectively local and nonlocal denoising increased the sensitivity to detect differences in cerebral WM in neuroHIV.
• Chen, N. K., Bell, R. P., & Meade, C. S. (2021). On the down-sampling of diffusion MRI data along the angular dimension. Magnetic resonance imaging, 82, 104-110.
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  It has been established that the diffusion gradient directions in diffusion MRI should be uniformly distributed in 3D spherical space, so that orientation-dependent diffusion properties (e.g., fractional anisotropy or FA) can be properly quantified. Sometimes the acquired data need to be down-sampled along the angular dimension before computing diffusion properties (e.g., to exclude data points corrupted by motion artifact; to harmonize data obtained with different protocols). It is important to quantitatively assess the impact of data down-sampling on measurement of diffusion properties.
• Haugg, A., Renz, F. M., Nicholson, A. A., Lor, C., Götzendorfer, S. J., Sladky, R., Skouras, S., McDonald, A., Craddock, C., Hellrung, L., Kirschner, M., Herdener, M., Koush, Y., Papoutsi, M., Keynan, J., Hendler, T., Cohen Kadosh, K., Zich, C., Kohl, S. H., , Hallschmid, M., et al. (2021). Predictors of real-time fMRI neurofeedback performance and improvement - A machine learning mega-analysis. NeuroImage, 237, 118207.
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  Real-time fMRI neurofeedback is an increasingly popular neuroimaging technique that allows an individual to gain control over his/her own brain signals, which can lead to improvements in behavior in healthy participants as well as to improvements of clinical symptoms in patient populations. However, a considerably large ratio of participants undergoing neurofeedback training do not learn to control their own brain signals and, consequently, do not benefit from neurofeedback interventions, which limits clinical efficacy of neurofeedback interventions. As neurofeedback success varies between studies and participants, it is important to identify factors that might influence neurofeedback success. Here, for the first time, we employed a big data machine learning approach to investigate the influence of 20 different design-specific (e.g. activity vs. connectivity feedback), region of interest-specific (e.g. cortical vs. subcortical) and subject-specific factors (e.g. age) on neurofeedback performance and improvement in 608 participants from 28 independent experiments. With a classification accuracy of 60% (considerably different from chance level), we identified two factors that significantly influenced neurofeedback performance: Both the inclusion of a pre-training no-feedback run before neurofeedback training and neurofeedback training of patients as compared to healthy participants were associated with better neurofeedback performance. The positive effect of pre-training no-feedback runs on neurofeedback performance might be due to the familiarization of participants with the neurofeedback setup and the mental imagery task before neurofeedback training runs. Better performance of patients as compared to healthy participants might be driven by higher motivation of patients, higher ranges for the regulation of dysfunctional brain signals, or a more extensive piloting of clinical experimental paradigms. Due to the large heterogeneity of our dataset, these findings likely generalize across neurofeedback studies, thus providing guidance for designing more efficient neurofeedback studies specifically for improving clinical neurofeedback-based interventions. To facilitate the development of data-driven recommendations for specific design details and subpopulations the field would benefit from stronger engagement in open science research practices and data sharing.
• Howard, C. M., Jain, S., Cook, A. D., Packard, L. E., Mullin, H. A., Chen, N. K., Liu, C., Song, A. W., & Madden, D. J. (2022). Cortical iron mediates age-related decline in fluid cognition. Human brain mapping, 43(3), 1047-1060.
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  Brain iron dyshomeostasis disrupts various critical cellular functions, and age-related iron accumulation may contribute to deficient neurotransmission and cell death. While recent studies have linked excessive brain iron to cognitive function in the context of neurodegenerative disease, little is known regarding the role of brain iron accumulation in cognitive aging in healthy adults. Further, previous studies have focused primarily on deep gray matter regions, where the level of iron deposition is highest. However, recent evidence suggests that cortical iron may also contribute to cognitive deficit and neurodegenerative disease. Here, we used quantitative susceptibility mapping (QSM) to measure brain iron in 67 healthy participants 18-78 years of age. Speed-dependent (fluid) cognition was assessed from a battery of 12 psychometric and computer-based tests. From voxelwise QSM analyses, we found that QSM susceptibility values were negatively associated with fluid cognition in the right inferior temporal gyrus, bilateral putamen, posterior cingulate gyrus, motor, and premotor cortices. Mediation analysis indicated that susceptibility in the right inferior temporal gyrus was a significant mediator of the relation between age and fluid cognition, and similar effects were evident for the left inferior temporal gyrus at a lower statistical threshold. Additionally, age and right inferior temporal gyrus susceptibility interacted to predict fluid cognition, such that brain iron was negatively associated with a cognitive decline for adults over 45 years of age. These findings suggest that iron may have a mediating role in cognitive decline and may be an early biomarker of neurodegenerative disease.
• Zhuang, J., Madden, D. J., Cunha, P., Badea, A., Davis, S. W., Potter, G. G., Lad, E. M., Cousins, S. W., Chen, N. K., Allen, K., Maciejewski, A. J., Fernandez, X. D., Diaz, M. T., & Whitson, H. E. (2021). Cerebral white matter connectivity, cognition, and age-related macular degeneration. NeuroImage. Clinical, 30, 102594.
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  Age-related macular degeneration (AMD) is a common retina disease associated with cognitive impairment in older adults. The mechanism(s) that account for the link between AMD and cognitive decline remain unclear. Here we aim to shed light on this issue by investigating whether relationships between cognition and white matter in the brain differ by AMD status. In a direct group comparison of brain connectometry maps from diffusion weighted images, AMD patients showed significantly weaker quantitative anisotropy (QA) than healthy controls, predominantly in the splenium and left optic radiation. The QA of these tracts, however, did not correlate with the visual acuity measure, indicating that this group effect is not directly driven by visual loss. The AMD and control groups did not differ significantly in cognitive performance.Across all participants, better cognitive performance (e.g. verbal fluency) is associated with stronger connectivity strength in white matter tracts including the splenium and the left inferior fronto-occipital fasciculus/inferior longitudinal fasciculus. However, there were significant interactions between group and cognitive performance (verbal fluency, memory), suggesting that the relation between QA and cognitive performance was weaker in AMD patients than in controls.This may be explained by unmeasured determinants of performance that are more common or impactful in AMD or by a recruitment bias whereby the AMD group had higher cognitive reserve. In general, our findings suggest that neural degeneration in the brain might occur in parallel to AMD in the eyes, although the participants studied here do not (yet) exhibit overt cognitive declines per standard assessments.
• Haugg, A., Sladky, R., Skouras, S., McDonald, A., Craddock, C., Kirschner, M., Herdener, M., Koush, Y., Papoutsi, M., Keynan, J. N., Hendler, T., Cohen Kadosh, K., Zich, C., MacInnes, J., Adcock, R. A., Dickerson, K., Chen, N. K., Young, K., Bodurka, J., , Yao, S., et al. (2020). Can we predict real-time fMRI neurofeedback learning success from pretraining brain activity?. Human brain mapping.
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  Neurofeedback training has been shown to influence behavior in healthy participants as well as to alleviate clinical symptoms in neurological, psychosomatic, and psychiatric patient populations. However, many real-time fMRI neurofeedback studies report large inter-individual differences in learning success. The factors that cause this vast variability between participants remain unknown and their identification could enhance treatment success. Thus, here we employed a meta-analytic approach including data from 24 different neurofeedback studies with a total of 401 participants, including 140 patients, to determine whether levels of activity in target brain regions during pretraining functional localizer or no-feedback runs (i.e., self-regulation in the absence of neurofeedback) could predict neurofeedback learning success. We observed a slightly positive correlation between pretraining activity levels during a functional localizer run and neurofeedback learning success, but we were not able to identify common brain-based success predictors across our diverse cohort of studies. Therefore, advances need to be made in finding robust models and measures of general neurofeedback learning, and in increasing the current study database to allow for investigating further factors that might influence neurofeedback learning.
• Kuo, P. H., Zhang, X., Stuehm, C., Chou, Y., & Chen, N. (2020). Functional Magnetic Resonance Imaging Reveals Taiji’s Real-time Effects on Neuronal Networks of the Brain. The Journal of Chinese Health Practices, 1(1).
• Kuo, P. H., Zhang, X., Stuehm, C., Chou, Y., & Chen, N. (2020). Functional Magnetic Resonance Imaging Reveals Taiji’s Real-time Effects on Neuronal Networks of the Brain. The Journal of the International Society of Chinese Health Practices, 1.
• Sui, J., Li, X., Bell, R. P., Towe, S. L., Gadde, S., Chen, N. K., & Meade, C. S. (2020). Structural and functional brain abnormalities in HIV disease revealed by multimodal MRI fusion: association with cognitive function. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.
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  HIV-associated neurocognitive impairment remains a prevalent comorbidity that impacts daily functioning and increases morbidity. While HIV infection is known to cause widespread disruptions in the brain, different MRI modalities have not been effectively integrated. This study applied 3-way supervised fusion to investigate how structural and functional co-alterations affect cognitive function.
• Sundman, M. H., Lim, K., Ton That, V., Mizell, J. M., Ugonna, C., Rodriguez, R., Chen, N. K., Fuglevand, A. J., Liu, Y., Wilson, R. C., Fellous, J. M., Rapcsak, S., & Chou, Y. H. (2020). Transcranial magnetic stimulation reveals diminished homoeostatic metaplasticity in cognitively impaired adults. Brain communications, 2(2), fcaa203.
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  Homoeostatic metaplasticity is a neuroprotective physiological feature that counterbalances Hebbian forms of plasticity to prevent network destabilization and hyperexcitability. Recent animal models highlight dysfunctional homoeostatic metaplasticity in the pathogenesis of Alzheimer's disease. However, the association between homoeostatic metaplasticity and cognitive status has not been systematically characterized in either demented or non-demented human populations, and the potential value of homoeostatic metaplasticity as an early biomarker of cognitive impairment has not been explored in humans. Here, we report that, through pre-conditioning the synaptic activity prior to non-invasive brain stimulation, the association between homoeostatic metaplasticity and cognitive status could be established in a population of non-demented human subjects (older adults across cognitive spectrums; all within the non-demented range). All participants ( = 40; age range, 65-74, 47.5% female) underwent a standardized neuropsychological battery, magnetic resonance imaging and a transcranial magnetic stimulation protocol. Specifically, we sampled motor-evoked potentials with an input/output curve immediately before and after repetitive transcranial magnetic stimulation to assess neural plasticity with two experimental paradigms: one with voluntary muscle contraction (i.e. modulated synaptic activity history) to deliberately introduce homoeostatic interference, and one without to serve as a control condition. From comparing neuroplastic responses across these experimental paradigms and across cohorts grouped by cognitive status, we found that (i) homoeostatic metaplasticity is diminished in our cohort of cognitively impaired older adults and (ii) this neuroprotective feature remains intact in cognitively normal participants. This novel finding suggests that (i) future studies should expand their scope beyond just Hebbian forms of plasticity that are traditionally assessed when using non-invasive brain stimulation to investigate cognitive ageing and (ii) the potential value of homoeostatic metaplasticity in serving as a biomarker for cognitive impairment should be further explored.
• Zuo, X., Zhuang, J., Chen, N., Cousins, S., Cunha, P., Lad, E. M., Madden, D. J., Potter, G., & Whitson, H. E. (2020). Relationship between neural functional connectivity and memory performance in age-related macular degeneration. Neurobiology of aging, 95, 176-185.
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  Age-related macular degeneration (AMD) has been linked to memory deficits, with no established neural mechanisms. We collected resting-state brain functional magnetic resonance imaging and standardized verbal recall tests from 42 older adults with AMD and 41 age-matched controls. We used seed-based whole brain analysis to quantify the strength of functional connectivity between hubs of the default mode network and a network of medial temporal regions relevant for memory. Our results indicated neither memory performance nor network connectivity differed by AMD status. However, the AMD participants exhibited stronger relationships than the controls between memory performance and connectivity from the memory network hub (left parahippocampal) to 2 other regions: the left temporal pole and the right superior/middle frontal gyri. Also, the connectivity between the medial prefrontal cortex and posterior cingulate cortex of default mode network correlated more strongly with memory performance in AMD compared to control. We concluded that stronger brain-behavior correlation in AMD may suggest a role for region-specific connectivity in supporting memory in the context of AMD.
• Chen, N. (2019). Bootstrap analysis of diffusion tensor and mean apparent propagator parameters derived from multiband diffusion MRI. Magnetic Resonance in Medicine.
• Chen, N. (2019). Synergistic effects of marijuana abuse and HIV infection on neural activation during a cognitive interference task. Addiction Biology.
• Chen, N. (2019). The use of Fourier‐domain analyses for unwrapping phase images of low SNR. Magnetic Resonance in Medicine.
• Bell, R. P., Barnes, L. L., Towe, S. L., Chen, N. K., Song, A. W., & Meade, C. S. (2018). Structural connectome differences in HIV infection: brain network segregation associated with nadir CD4 cell count. Journal of neurovirology, 24(4), 454-463.
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  This study investigated structural brain organization using diffusion tensor imaging (DTI) in 35 HIV-positive and 35 HIV-negative individuals. We used global and nodal graph theory metrics to investigate whether HIV was associated with differences in brain network organization based on fractional anisotropy (FA) and mean diffusivity (MD). Participants also completed a comprehensive neuropsychological testing battery. For global network metrics, HIV-positive individuals displayed a lower FA clustering coefficient relative to HIV-negative individuals. For nodal network metrics, HIV-positive individuals had less MD nodal degree in the left thalamus. Within HIV-positive individuals, the FA global clustering coefficient was positively correlated with nadir CD4 cell count. Across the sample, cognitive performance was negatively correlated with characteristic path length and positively correlated with global efficiency for FA. These results suggest that, despite management with combination antiretroviral therapy, HIV infection is associated with altered structural brain network segregation and thalamic centrality and that low nadir CD4 cell count may be a risk factor. These graph theory metrics may serve as neural biomarkers to identify individuals at risk for HIV-related neurological complications.
• Chen, N. (2018). A diffusion-matched principal component analysis (DM-PCA) based two-channel denoising procedure for high-resolution diffusion-weighted MRI. PLOS ONE.
• Chen, N. (2018). Cocaine and HIV are independently associated with neural activation in response to gain and loss valuation during economic risky choice.. Addiction biology.
• Chen, N. (2018). Free-breathing abdominal MRI improved by repeated k-t-subsampling and artifact-minimization (ReKAM).. Medical physics.
• Chen, N. (2018). Language processing in age-related macular degeneration associated with unique functional connectivity signatures in the right hemisphere.. Neurobiology of aging.
• Chen, N. K., Chang, H. C., Bilgin, A., Bernstein, A., & Trouard, T. P. (2018). A diffusion-matched principal component analysis (DM-PCA) based two-channel denoising procedure for high-resolution diffusion-weighted MRI. PloS one, 13(4), e0195952.
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  Over the past several years, significant efforts have been made to improve the spatial resolution of diffusion-weighted imaging (DWI), aiming at better detecting subtle lesions and more reliably resolving white-matter fiber tracts. A major concern with high-resolution DWI is the limited signal-to-noise ratio (SNR), which may significantly offset the advantages of high spatial resolution. Although the SNR of DWI data can be improved by denoising in post-processing, existing denoising procedures may potentially reduce the anatomic resolvability of high-resolution imaging data. Additionally, non-Gaussian noise induced signal bias in low-SNR DWI data may not always be corrected with existing denoising approaches. Here we report an improved denoising procedure, termed diffusion-matched principal component analysis (DM-PCA), which comprises 1) identifying a group of (not necessarily neighboring) voxels that demonstrate very similar magnitude signal variation patterns along the diffusion dimension, 2) correcting low-frequency phase variations in complex-valued DWI data, 3) performing PCA along the diffusion dimension for real- and imaginary-components (in two separate channels) of phase-corrected DWI voxels with matched diffusion properties, 4) suppressing the noisy PCA components in real- and imaginary-components, separately, of phase-corrected DWI data, and 5) combining real- and imaginary-components of denoised DWI data. Our data show that the new two-channel (i.e., for real- and imaginary-components) DM-PCA denoising procedure performs reliably without noticeably compromising anatomic resolvability. Non-Gaussian noise induced signal bias could also be reduced with the new denoising method. The DM-PCA based denoising procedure should prove highly valuable for high-resolution DWI studies in research and clinical uses.
• Chen, N. K., Chou, Y. H., Sundman, M., Hickey, P., Kasoff, W. S., Bernstein, A., Trouard, T. P., Lin, T., Rapcsak, S. Z., Sherman, S. J., & Weingarten, C. P. (2018). Alteration of Diffusion-Tensor Magnetic Resonance Imaging Measures in Brain Regions Involved in Early Stages of Parkinson's Disease. Brain connectivity, 8(6), 343-349.
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  Many nonmotor symptoms (e.g., hyposmia) appear years before the cardinal motor features of Parkinson's disease (PD). It is thus desirable to be able to use noninvasive brain imaging methods, such as magnetic resonance imaging (MRI), to detect brain abnormalities in early PD stages. Among the MRI modalities, diffusion-tensor imaging (DTI) is suitable for detecting changes in brain tissue structure due to neurological diseases. The main purpose of this study was to investigate whether DTI signals measured from brain regions involved in early stages of PD differ from those of healthy controls. To answer this question, we analyzed whole-brain DTI data of 30 early-stage PD patients and 30 controls using improved region of interest-based analysis methods. Results showed that (i) the fractional anisotropy (FA) values in the olfactory tract (connected with the olfactory bulb: one of the first structures affected by PD) are lower in PD patients than healthy controls; (ii) FA values are higher in PD patients than healthy controls in the following brain regions: corticospinal tract, cingulum (near hippocampus), and superior longitudinal fasciculus (temporal part). Experimental results suggest that the tissue property, measured by FA, in olfactory regions is structurally modulated by PD with a mechanism that is different from other brain regions.
• Chu, M. L., Chang, H. C., Chung, H. W., Bashir, M. R., Cai, J., Zhang, L., Sun, D., & Chen, N. K. (2018). Free-breathing abdominal MRI improved by repeated k-t-subsampling and artifact-minimization (ReKAM). Medical physics, 45(1), 178-190.
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  PURPOSE:We report an approach, termed Repeated k-t-subsampling and artifact-minimization (ReKAM), for removing motion artifacts in free-breathing abdominal MRI. The method is particularly valuable for challenging patients who may not hold their breath for a long time or have irregular respiratory rate.METHODS:The ReKAM framework comprises one acquisition module and two reconstruction modules. A fast MRI sequence is used to repeatedly acquire multiple sets of k-t space data. Motion artifacts are then minimized by two reconstruction modules: (a) a bootstrapping module in k-t-space is used to identify a low-artifact image; (b) a constrained reconstruction module that integrates projection onto convex set (POCS) and multiplexed sensitivity encoding (MUSE), termed POCSMUSE, is applied to further remove residual artifact. The ReKAM framework is compatible with different pulse sequences, and generally applicable to irregular data sampling patterns in k-space. Free-breathing fast spin-echo MRI data, acquired from healthy volunteers and patients, were used to evaluate the developed ReKAM method.RESULTS:Experimental results show that the ReKAM technique can produce high-quality free-breathing images with the artifact levels comparable to that of breath-holding MRI.CONCLUSION:The ReKAM framework improves the quality of free-breathing abdominal MRI data, and is compatible with various MRI pulse sequences.
• Chu, M. L., Chang, H. C., Oshio, K., & Chen, N. K. (2018). A single-shot T2 mapping protocol based on echo-split gradient-spin-echo acquisition and parametric multiplexed sensitivity encoding based on projection onto convex sets reconstruction. Magnetic resonance in medicine, 79(1), 383-393.
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  PURPOSE:To develop a high-speed T2 mapping protocol that is capable of accurately measuring T2 relaxation time constants from a single-shot acquisition.THEORY:A new echo-split single-shot gradient-spin-echo (GRASE) pulse sequence is developed to acquire multicontrast data while suppressing signals from most nonprimary echo pathways in Carr-Purcell-Meiboom-Gill (CPMG) echoes. Residual nonprimary pathway signals are taken into consideration when performing T2 mapping using a parametric multiplexed sensitivity encoding based on projection onto convex sets (parametric-POCSMUSE) reconstruction method that incorporates extended phase graph modeling of GRASE signals.METHODS:The single-shot echo-split GRASE-based T2 mapping procedure was evaluated in human studies at 3 Tesla. The acquired data were compared with reference data obtained with a more time-consuming interleaved spin-echo echo planar imaging protocol. T2 maps derived from conventional single-shot GRASE scans, in which nonprimary echo pathways were not appropriately addressed, were also evaluated.RESULTS:Using the developed single-shot T2 mapping protocol, quantitatively accurate T2 maps can be obtained with a short scan time (
• Horne, A. J., Chiew, K. S., Zhuang, J., George, L. K., Adcock, R. A., Potter, G. G., Lad, E. M., Cousins, S. W., Lin, F. R., Mamo, S. K., Chen, N. K., Maciejewski, A. J., Duong Fernandez, X., & Whitson, H. E. (2018). Relating Sensory, Cognitive, and Neural Factors to Older Persons' Perceptions about Happiness: An Exploratory Study. Journal of aging research, 2018, 4930385.
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  Despite increased rates of disease, disability, and social losses with aging, seniors consistently report higher levels of subjective well-being (SWB), a construct closely related to happiness, than younger adults. In this exploratory study, we utilized an available dataset to investigate how aspects of health commonly deteriorating with age, including sensory (i.e., vision and hearing) and cognitive status, relate to variability in self-described contributors to happiness. Community-dwelling seniors ( = 114) responded to a single-item prompt: "name things that make people happy." 1731 responses were categorized into 13 domains of SWB via structured content analysis. Sensory health and cognition were assessed by Snellen visual acuity, pure-tone audiometry, and in-person administration of the Brief Test of Adult Cognition by Telephone (BTACT) battery. A subset of eligible participants ( = 57) underwent functional magnetic resonance imaging (fMRI) to assess resting state functional connectivity (FC) within a previously described dopaminergic network associated with reward processing. SWB response patterns were relatively stable across gender, sensory status, and cognitive performance with few exceptions. For example, hearing-impaired participants listed fewer determinants of SWB (13.59 vs. 17.16; < 0.001) and were less likely to name things in the "special events" category. Participants with a higher proportion of responses in the "accomplishments" domain (e.g., winning, getting good grades) demonstrated increased FC between the ventral tegmental area and nucleus accumbens, regions implicated in reward and motivated behavior. While the framework for determinants of happiness among seniors was largely stable across the factors assessed here, our findings suggest that subtle changes in this construct may be linked to sensory loss. The possibility that perceptions about determinants of happiness might relate to differences in intrinsic connectivity within reward-related brain networks also warrants further investigation.
• Meade, C. S., Addicott, M., Hobkirk, A. L., Towe, S. L., Chen, N. K., Sridharan, S., & Huettel, S. A. (2018). Cocaine and HIV are independently associated with neural activation in response to gain and loss valuation during economic risky choice. Addiction biology, 23(2), 796-809.
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  Stimulant abuse is disproportionately common in HIV-positive persons. Both HIV and stimulants are independently associated with deficits in reward-based decision making, but their interactive and/or additive effects are poorly understood despite their prevalent co-morbidity. Here, we examined the effects of cocaine dependence and HIV infection in 69 adults who underwent functional magnetic resonance imaging while completing an economic loss aversion task. We identified two neural networks that correlated with the evaluation of the favorable characteristics of the gamble (i.e. higher gains/lower losses: ventromedial prefrontal cortex, anterior cingulate, anterior and posterior precuneus and visual cortex) versus unfavorable characteristics of the gamble (i.e. lower gains/higher losses: dorsal prefrontal, lateral orbitofrontal, posterior parietal cortex, anterior insula and dorsal caudate). Behaviorally, cocaine and HIV had additive effects on loss aversion scores, with HIV-positive cocaine users being the least loss averse. Cocaine users had greater activation in brain regions that tracked the favorability of gamble characteristics (i.e. increased activation to gains, but decreased activation to losses). In contrast, HIV infection was independently associated with lesser activation in regions that tracked the unfavorability of gamble characteristics. These results suggest that cocaine is associated with an overactive reward-seeking system, while HIV is associated with an underactive cognitive control system. Together, these alterations may leave HIV-positive cocaine users particularly vulnerable to making unfavorable decisions when outcomes are uncertain.
• Meade, C. S., Bell, R. P., Towe, S. L., Chen, N. K., Hobkirk, A. L., & Huettel, S. A. (2018). Synergistic effects of marijuana abuse and HIV infection on neural activation during a cognitive interference task. Addiction biology.
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  Marijuana use, which is disproportionately prevalent among human immunodeficiency virus (HIV)-infected persons, can alter activity in fronto-parietal regions during cognitively demanding tasks. While HIV is also associated with altered neural activation, it is not known how marijuana may further affect brain function in this population. Our study examined the independent and additive effects of HIV infection and regular marijuana use on neural activation during a cognitive interference task. The sample included 93 adults who differed on marijuana (MJ) and HIV statuses (20 MJ+/HIV+, 19 MJ+/HIV-, 29 MJ-/HIV+, 25 MJ-/HIV-). Participants completed a counting Stroop task during a functional magnetic resonance imaging scan. Main and interactive effects on neural activation during interference versus neutral blocks were examined using a mixed-effects analysis. The sample showed the expected Stroop effect for both speed and accuracy. There were main effects of MJ in the right and left inferior parietal lobules, with the left cluster extending into the posterior middle temporal gyrus and a main effect of HIV in the dorsal anterior cingulate cortex. There was an interaction in the left fronto-insular cortex, such that the MJ+/HIV+ group had the largest increase in activation compared with other groups. Among MJ+, signal change in this cluster correlated positively with cumulative years of regular marijuana use. These results suggest that comorbid HIV and marijuana use is associated with complex neural alterations in multiple brain regions during cognitive interference. Follow-up research is needed to determine how marijuana-related characteristics may moderate HIV neurologic disease and impact real-world functioning.
• Sonderer, C. M., & Chen, N. K. (2018). Improving the Accuracy, Quality, and Signal-To-Noise Ratio of MRI Parametric Mapping Using Rician Bias Correction and Parametric-Contrast-Matched Principal Component Analysis (PCM-PCA). The Yale journal of biology and medicine, 91(3), 207-214.
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  MRI parametric mapping, including T2 mapping, can quantitatively characterize tissue properties and is an important MRI procedure in biomedical research and studies of diseases [1-3]. However, the accuracy, quality, and signal-to-noise ratio (SNR) of MRI parametric mapping may be negatively impacted by Rician noise in multi-contrast MRI data [4]. As such, it is important to develop a post-processing method to minimize the negative impact of Rician noise. In this study, we report a new parametric-contrast-matched principal component analysis (PCM-PCA) denoising method that involves 1) identifying voxels with similar T2 decay characteristics and 2) using the principal component analysis (PCA) to denoise multi-contrast MRI data along the echo time (TE) dimension. We additionally evaluated the effects of integrating Rician bias correction and the new PCM-PCA method. In this study, we mathematically added Rician noise at various levels to human brain MRI data and performed different combinations of denoising and Rician bias correction on the magnitude-valued images. We found that MRI denoising using the PCM-PCA method resulted in improved image quality, SNR, and accuracy of the measured T2 relaxation time constants. Additionally, we found that for data with low SNR (., 1.5 or lower), Rician bias correction further improved image quality and T2 mapping accuracy. In summary, our experimental results demonstrated that the new PCM-PCA denoising method and Rician bias correction adequately improve multi-contrast MRI quality and T2 parametric mapping accuracy.
• Zhuang, J., Madden, D. J., Duong-Fernandez, X., Chen, N. K., Cousins, S. W., Potter, G. G., Diaz, M. T., & Whitson, H. E. (2018). Language processing in age-related macular degeneration associated with unique functional connectivity signatures in the right hemisphere. Neurobiology of aging, 63, 65-74.
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  Age-related macular degeneration (AMD) is a retinal disease associated with significant vision loss among older adults. Previous large-scale behavioral studies indicate that people with AMD are at increased risk of cognitive deficits in language processing, particularly in verbal fluency tasks. The neural underpinnings of any relationship between AMD and higher cognitive functions, such as language processing, remain unclear. This study aims to address this issue using independent component analysis of spontaneous brain activity at rest. In 2 components associated with visual processing, we observed weaker functional connectivity in the primary visual cortex and lateral occipital cortex in AMD patients compared with healthy controls, indicating that AMD might lead to differences in the neural representation of vision. In a component related to language processing, we found that increasing connectivity within the right inferior frontal gyrus was associated with better verbal fluency performance across all older adults, and the verbal fluency effect was greater in AMD patients than controls in both right inferior frontal gyrus and right posterior temporal regions. As the behavioral performance of our patients is as good as that of controls, these findings suggest that preservation of verbal fluency performance in AMD patients might be achieved through higher contribution from right hemisphere regions in bilateral language networks. If that is the case, there may be an opportunity to promote cognitive resilience among seniors with AMD or other forms of late-life vision loss.
• Bruce, I. P., Chang, H. C., Petty, C., Chen, N. K., & Song, A. W. (2017). 3D-MB-MUSE: A robust 3D multi-slab, multi-band and multi-shot reconstruction approach for ultrahigh resolution diffusion MRI. NeuroImage, 159, 46-56.
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  Recent advances in achieving ultrahigh spatial resolution (e.g. sub-millimeter) diffusion MRI (dMRI) data have proven highly beneficial in characterizing tissue microstructures in organs such as the brain. However, the routine acquisition of in-vivo dMRI data at such high spatial resolutions has been largely prohibited by factors that include prolonged acquisition times, motion induced artifacts, and low SNR. To overcome these limitations, we present here a framework for acquiring and reconstructing 3D multi-slab, multi-band and interleaved multi-shot EPI data, termed 3D-MB-MUSE. Through multi-band excitations, the simultaneous acquisition of multiple 3D slabs enables whole brain dMRI volumes to be acquired in-vivo on a 3 T clinical MRI scanner at high spatial resolution within a reasonably short amount of time. Representing a true 3D model, 3D-MB-MUSE reconstructs an entire 3D multi-band, multi-shot dMRI slab at once while simultaneously accounting for coil sensitivity variations across the slab as well as motion induced artifacts commonly associated with both 3D and multi-shot diffusion imaging. Such a reconstruction fully preserves the SNR advantages of both 3D and multi-shot acquisitions in high resolution dMRI images by removing both motion and aliasing artifacts across multiple dimensions. By enabling ultrahigh resolution dMRI for routine use, the 3D-MB-MUSE framework presented here may prove highly valuable in both clinical and research applications.
• Chang, H. C., Hui, E. S., Chiu, P. W., Liu, X., & Chen, N. K. (2017). Phase correction for three-dimensional (3D) diffusion-weighted interleaved EPI using 3D multiplexed sensitivity encoding and reconstruction (3D-MUSER). Magnetic resonance in medicine.
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  PURPOSE:Three-dimensional (3D) multiplexed sensitivity encoding and reconstruction (3D-MUSER) algorithm is proposed to reduce aliasing artifacts and signal corruption caused by inter-shot 3D phase variations in 3D diffusion-weighted echo planar imaging (DW-EPI).THEORY AND METHODS:3D-MUSER extends the original framework of multiplexed sensitivity encoding (MUSE) to a hybrid k-space-based reconstruction, thereby enabling the correction of inter-shot 3D phase variations. A 3D single-shot EPI navigator echo was used to measure inter-shot 3D phase variations. The performance of 3D-MUSER was evaluated by analyses of point-spread function (PSF), signal-to-noise ratio (SNR), and artifact levels. The efficacy of phase correction using 3D-MUSER for different slab thicknesses and b-values were investigated.RESULTS:Simulations showed that 3D-MUSER could eliminate artifacts because of through-slab phase variation and reduce noise amplification because of SENSE reconstruction. All aliasing artifacts and signal corruption in 3D interleaved DW-EPI acquired with different slab thicknesses and b-values were reduced by our new algorithm. A near-whole brain single-slab 3D DTI with 1.3-mm isotropic voxel acquired at 1.5T was successfully demonstrated.CONCLUSION:3D phase correction for 3D interleaved DW-EPI data is made possible by 3D-MUSER, thereby improving feasible slab thickness and maximum feasible b-value.
• Chen, N. (2017). 3D-MB-MUSE: A robust 3D multi-slab, multi-band and multi-shot reconstruction approach for ultrahigh resolution diffusion MRI.. NeuroImage.
• Chen, N. (2017). Cocaine dependence does not contribute substantially to white matter abnormalities in HIV infection.. Journal of neurovirology.
• Chen, N. (2017). Cocaine dependence modulates the effect of HIV infection on brain activation during intertemporal decision making.. Drug and alcohol dependence.
• Chen, N. (2017). Frontoparietal activation during visual conjunction search: Effects of bottom-up guidance and adult age.. Human brain mapping.
• Chen, N. (2017). Maintenance and Representation of Mind Wandering during Resting-State fMRI.. Scientific reports.
• Chen, N. (2017). Phase correction for three-dimensional (3D) diffusion-weighted interleaved EPI using 3D multiplexed sensitivity encoding and reconstruction (3D-MUSER).. Magnetic resonance in medicine.
• Chen, N. (2017). Sources of disconnection in neurocognitive aging: cerebral white-matter integrity, resting-state functional connectivity, and white-matter hyperintensity volume.. Neurobiology of aging.
• Chen, N. (2017). The bidirectional gut-brain-microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease.. Brain, behavior, and immunity.
• Cordero, D. M., Towe, S. L., Chen, N. K., Robertson, K. R., Madden, D. J., Huettel, S. A., & Meade, C. S. (2017). Cocaine dependence does not contribute substantially to white matter abnormalities in HIV infection. Journal of neurovirology, 23(3), 441-450.
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  This study investigated the association of HIV infection and cocaine dependence with cerebral white matter integrity using diffusion tensor imaging (DTI). One hundred thirty-five participants stratified by HIV and cocaine status (26 HIV+/COC+, 37 HIV+/COC-, 37 HIV-/COC+, and 35 HIV-/COC-) completed a comprehensive substance abuse assessment, neuropsychological testing, and MRI with DTI. Among HIV+ participants, all were receiving HIV care and 46% had an AIDS diagnosis. All COC+ participants were current users and met criteria for cocaine use disorder. We used tract-based spatial statistics (TBSS) to assess the relation of HIV and cocaine to fractional anisotropy (FA) and mean diffusivity (MD). In whole-brain analyses, HIV+ participants had significantly reduced FA and increased MD compared to HIV- participants. The relation of HIV and FA was widespread throughout the brain, whereas the HIV-related MD effects were restricted to the corpus callosum and thalamus. There were no significant cocaine or HIV-by-cocaine effects. These DTI metrics correlated significantly with duration of HIV disease, nadir CD4+ cell count, and AIDS diagnosis, as well as some measures of neuropsychological functioning. These results suggest that HIV is related to white matter integrity throughout the brain, and that HIV-related effects are more pronounced with increasing duration of infection and greater immune compromise. We found no evidence for independent effects of cocaine dependence on white matter integrity, and cocaine dependence did not appear to exacerbate the effects of HIV.
• Madden, D. J., Parks, E. L., Tallman, C. W., Boylan, M. A., Hoagey, D. A., Cocjin, S. B., Packard, L. E., Johnson, M. A., Chou, Y. H., Potter, G. G., Chen, N. K., Siciliano, R. E., Monge, Z. A., Honig, J. A., & Diaz, M. T. (2017). Sources of disconnection in neurocognitive aging: cerebral white-matter integrity, resting-state functional connectivity, and white-matter hyperintensity volume. Neurobiology of aging, 54, 199-213.
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  Age-related decline in fluid cognition can be characterized as a disconnection among specific brain structures, leading to a decline in functional efficiency. The potential sources of disconnection, however, are unclear. We investigated imaging measures of cerebral white-matter integrity, resting-state functional connectivity, and white-matter hyperintensity volume as mediators of the relation between age and fluid cognition, in 145 healthy, community-dwelling adults 19-79 years of age. At a general level of analysis, with a single composite measure of fluid cognition and single measures of each of the 3 imaging modalities, age exhibited an independent influence on the cognitive and imaging measures, and the imaging variables did not mediate the age-cognition relation. At a more specific level of analysis, resting-state functional connectivity of sensorimotor networks was a significant mediator of the age-related decline in executive function. These findings suggest that different levels of analysis lead to different models of neurocognitive disconnection, and that resting-state functional connectivity, in particular, may contribute to age-related decline in executive function.
• Meade, C. S., Hobkirk, A. L., Towe, S. L., Chen, N. K., Bell, R. P., & Huettel, S. A. (2017). Cocaine dependence modulates the effect of HIV infection on brain activation during intertemporal decision making. Drug and alcohol dependence, 178, 443-451.
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  Both HIV infection and chronic cocaine use alter the neural circuitry of decision making, but the interactive effects of these commonly comorbid conditions have not been adequately examined. This study tested how cocaine moderates HIV-related neural activation during an intertemporal decision-making task.
• Sundman, M. H., Chen, N. K., Subbian, V., & Chou, Y. H. (2017). The bidirectional gut-brain-microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease. Brain, behavior, and immunity, 66, 31-44.
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  As head injuries and their sequelae have become an increasingly salient matter of public health, experts in the field have made great progress elucidating the biological processes occurring within the brain at the moment of injury and throughout the recovery thereafter. Given the extraordinary rate at which our collective knowledge of neurotrauma has grown, new insights may be revealed by examining the existing literature across disciplines with a new perspective. This article will aim to expand the scope of this rapidly evolving field of research beyond the confines of the central nervous system (CNS). Specifically, we will examine the extent to which the bidirectional influence of the gut-brain axis modulates the complex biological processes occurring at the time of traumatic brain injury (TBI) and over the days, months, and years that follow. In addition to local enteric signals originating in the gut, it is well accepted that gastrointestinal (GI) physiology is highly regulated by innervation from the CNS. Conversely, emerging data suggests that the function and health of the CNS is modulated by the interaction between 1) neurotransmitters, immune signaling, hormones, and neuropeptides produced in the gut, 2) the composition of the gut microbiota, and 3) integrity of the intestinal wall serving as a barrier to the external environment. Specific to TBI, existing pre-clinical data indicates that head injuries can cause structural and functional damage to the GI tract, but research directly investigating the neuronal consequences of this intestinal damage is lacking. Despite this void, the proposed mechanisms emanating from a damaged gut are closely implicated in the inflammatory processes known to promote neuropathology in the brain following TBI, which suggests the gut-brain axis may be a therapeutic target to reduce the risk of Chronic Traumatic Encephalopathy and other neurodegenerative diseases following TBI. To better appreciate how various peripheral influences are implicated in the health of the CNS following TBI, this paper will also review the secondary biological injury mechanisms and the dynamic pathophysiological response to neurotrauma. Together, this review article will attempt to connect the dots to reveal novel insights into the bidirectional influence of the gut-brain axis and propose a conceptual model relevant to the recovery from TBI and subsequent risk for future neurological conditions.
• Chang, H., & Chen, N. (2016). Joint correction of Nyquist artifact and minuscule motion-induced aliasing artifact in interleaved diffusion weighted EPI data using a composite two-dimensional phase correction procedure. Magnetic resonance imaging, 34(7), 974-9.
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  Diffusion-weighted imaging (DWI) obtained with interleaved echo-planar imaging (EPI) pulse sequence has great potential of characterizing brain tissue properties at high spatial-resolution. However, interleaved EPI based DWI data may be corrupted by various types of aliasing artifacts. First, inconsistencies in k-space data obtained with opposite readout gradient polarities result in Nyquist artifact, which is usually reduced with 1D phase correction in post-processing. When there exist eddy current cross terms (e.g., in oblique-plane EPI), 2D phase correction is needed to effectively reduce Nyquist artifact. Second, minuscule motion induced phase inconsistencies in interleaved DWI scans result in image-domain aliasing artifact, which can be removed with reconstruction procedures that take shot-to-shot phase variations into consideration. In existing interleaved DWI reconstruction procedures, Nyquist artifact and minuscule motion-induced aliasing artifact are typically removed subsequently in two stages. Although the two-stage phase correction generally performs well for non-oblique plane EPI data obtained from well-calibrated system, the residual artifacts may still be pronounced in oblique-plane EPI data or when there exist eddy current cross terms. To address this challenge, here we report a new composite 2D phase correction procedure, which effective removes Nyquist artifact and minuscule motion induced aliasing artifact jointly in a single step. Our experimental results demonstrate that the new 2D phase correction method can much more effectively reduce artifacts in interleaved EPI based DWI data as compared with the existing two-stage artifact correction procedures. The new method robustly enables high-resolution DWI, and should prove highly valuable for clinical uses and research studies of DWI.
• Chen, N. (2016). Cognitive Neurostimulation: Learning to Volitionally Sustain Ventral Tegmental Area Activation. Neuron.
• Chen, N. (2016). Compensatory activation in fronto-parietal cortices among HIV-infected persons during a monetary decision-making task. Hum Brain Mapp.
• Chen, N. (2016). Data-Driven and Predefined ROI-Based Quantification of Long-Term Resting-State fMRI Reproducibility. Brain Connect.
• Chen, N. (2016). Hippocampal and Insular Response to Smoking-Related Environments: Neuroimaging Evidence for Drug-Context Effects in Nicotine Dependence. Neuropsychopharmacology.
• Chen, N. (2016). Joint 2D and 3D phase processing for quantitative susceptibility mapping: application to 2D echo-planar imaging. NMR Biomed.
• Chen, N. (2016). Joint correction of Nyquist artifact and minuscule motion-induced aliasing artifact in interleaved diffusion weighted EPI data using a composite two-dimensional phase correction procedure. Magnetic Resonance Imaging.
• Chen, N. (2016). Motion Immune Diffusion Imaging Using Augmented MUSE for High-Resolution Multi-Shot EPI. Magnetic Resonance in Medicine.
• Chou, Y. H., Sundman, M., Whitson, H. E., Gaur, P., Chu, M. L., Weingarten, C. P., Madden, D. J., Wang, L., Kirste, I., Joliot, M., Diaz, M. T., Li, Y. J., Song, A. W., & Chen, N. K. (2017). Maintenance and Representation of Mind Wandering during Resting-State fMRI. Scientific reports, 7, 40722.
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  Major advances in resting-state functional magnetic resonance imaging (fMRI) techniques in the last two decades have provided a tool to better understand the functional organization of the brain both in health and illness. Despite such developments, characterizing regulation and cerebral representation of mind wandering, which occurs unavoidably during resting-state fMRI scans and may induce variability of the acquired data, remains a work in progress. Here, we demonstrate that a decrease or decoupling in functional connectivity involving the caudate nucleus, insula, medial prefrontal cortex and other domain-specific regions was associated with more sustained mind wandering in particular thought domains during resting-state fMRI. Importantly, our findings suggest that temporal and between-subject variations in functional connectivity of above-mentioned regions might be linked with the continuity of mind wandering. Our study not only provides a preliminary framework for characterizing the maintenance and cerebral representation of different types of mind wandering, but also highlights the importance of taking mind wandering into consideration when studying brain organization with resting-state fMRI in the future.
• Guhaniyogi, S., Chu, M., Chang, H., Song, A. W., & Chen, N. (2016). Motion immune diffusion imaging using augmented MUSE for high-resolution multi-shot EPI. Magnetic resonance in medicine, 75(2), 639-52.
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  To develop new techniques for reducing the effects of microscopic and macroscopic patient motion in diffusion imaging acquired with high-resolution multishot echo-planar imaging.
• MacInnes, J. J., Dickerson, K. C., Chen, N., & Adcock, R. A. (2016). Cognitive Neurostimulation: Learning to Volitionally Sustain Ventral Tegmental Area Activation. Neuron, 89(6), 1331-42.
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  Activation of the ventral tegmental area (VTA) and mesolimbic networks is essential to motivation, performance, and learning. Humans routinely attempt to motivate themselves, with unclear efficacy or impact on VTA networks. Using fMRI, we found untrained participants' motivational strategies failed to consistently activate VTA. After real-time VTA neurofeedback training, however, participants volitionally induced VTA activation without external aids, relative to baseline, Pre-test, and control groups. VTA self-activation was accompanied by increased mesolimbic network connectivity. Among two comparison groups (no neurofeedback, false neurofeedback) and an alternate neurofeedback group (nucleus accumbens), none sustained activation in target regions of interest nor increased VTA functional connectivity. The results comprise two novel demonstrations: learning and generalization after VTA neurofeedback training and the ability to sustain VTA activation without external reward or reward cues. These findings suggest theoretical alignment of ideas about motivation and midbrain physiology and the potential for generalizable interventions to improve performance and learning.
• Madden, D. J., Parks, E. L., Tallman, C. W., Boylan, M. A., Hoagey, D. A., Cocjin, S. B., Johnson, M. A., Chou, Y. H., Potter, G. G., Chen, N. K., Packard, L. E., Siciliano, R. E., Monge, Z. A., & Diaz, M. T. (2017). Frontoparietal activation during visual conjunction search: Effects of bottom-up guidance and adult age. Human brain mapping.
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  We conducted functional magnetic resonance imaging (fMRI) with a visual search paradigm to test the hypothesis that aging is associated with increased frontoparietal involvement in both target detection and bottom-up attentional guidance (featural salience). Participants were 68 healthy adults, distributed continuously across 19 to 78 years of age. Frontoparietal regions of interest (ROIs) were defined from resting-state scans obtained prior to task-related fMRI. The search target was defined by a conjunction of color and orientation. Each display contained one item that was larger than the others (i.e., a size singleton) but was not informative regarding target identity. Analyses of search reaction time (RT) indicated that bottom-up attentional guidance from the size singleton (when coincident with the target) was relatively constant as a function of age. Frontoparietal fMRI activation related to target detection was constant as a function of age, as was the reduction in activation associated with salient targets. However, for individuals 35 years of age and older, engagement of the left frontal eye field (FEF) in bottom-up guidance was more prominent than for younger individuals. Further, the age-related differences in left FEF activation were a consequence of decreasing resting-state functional connectivity in visual sensory regions. These findings indicate that age-related compensatory effects may be expressed in the relation between activation and behavior, rather than in the magnitude of activation, and that relevant changes in the activation-RT relation may begin at a relatively early point in adulthood. Hum Brain Mapp, 2017. © 2017 Wiley Periodicals, Inc.
• McClernon, F. J., Conklin, C. A., Kozink, R. V., Adcock, R. A., Sweitzer, M. M., Addicott, M. A., Chou, Y., Chen, N., Hallyburton, M. B., & DeVito, A. M. (2016). Hippocampal and Insular Response to Smoking-Related Environments: Neuroimaging Evidence for Drug-Context Effects in Nicotine Dependence. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 41(3), 877-85.
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  Environments associated with prior drug use provoke craving and drug taking, and set the stage for lapse/relapse. Although the neurobehavioral bases of environment-induced drug taking have been investigated with animal models, the influence of drug-environments on brain function and behavior in clinical populations of substance users is largely unexplored. Adult smokers (n=40) photographed locations personally associated with smoking (personal smoking environments; PSEs) or personal nonsmoking environment (PNEs). Following 24-h abstinence, participants underwent fMRI scanning while viewing PSEs, PNEs, standard smoking and nonsmoking environments, as well as proximal smoking (eg, lit cigarette) and nonsmoking (eg, pencil) cues. Finally, in two separate sessions following 6-h abstinence they viewed either PSEs or PNEs while cue-induced self-reported craving and smoking behavior were assessed. Viewing PSEs increased blood oxygen level-dependent signal in right posterior hippocampus (pHPC; F(2,685)=3.74, p
• Meade, C. S., Cordero, D. M., Hobkirk, A. L., Metra, B. M., Chen, N., & Huettel, S. A. (2016). Compensatory activation in fronto-parietal cortices among HIV-infected persons during a monetary decision-making task. Human brain mapping, 37(7), 2455-67.
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  HIV infection can cause direct and indirect damage to the brain and is consistently associated with neurocognitive disorders, including impairments in decision-making capacities. The tendency to devalue rewards that are delayed (temporal discounting) is relevant to a range of health risk behaviors. Making choices about delayed rewards engages the executive control network of the brain, which has been found to be affected by HIV. In this case-control study of 18 HIV-positive and 17 HIV-negative adults, we examined the effects of HIV on brain activation during a temporal discounting task. Functional MRI (fMRI) data were collected while participants made choices between smaller, sooner rewards and larger, delayed rewards. Choices were individualized based on participants' unique discount functions, so each participant experienced hard (similarly valued), easy (disparately valued), and control choices. fMRI data were analyzed using a mixed-effects model to identify group-related differences associated with choice difficulty. While there was no difference between groups in behavioral performance, the HIV-positive group demonstrated significantly larger increases in activation within left parietal regions and bilateral prefrontal regions during easy trials and within the right prefrontal cortex and anterior cingulate during hard trials. Increasing activation within the prefrontal regions was associated with lower nadir CD4 cell count and risk-taking propensity. These results support the hypothesis that HIV infection can alter brain functioning in regions that support decision making, providing further evidence for HIV-associated compensatory activation within fronto-parietal cortices. A history of immunosuppression may contribute to these brain changes. Hum Brain Mapp 37:2455-2467, 2016. © 2016 Wiley Periodicals, Inc.
• Song, X., Panych, L. P., & Chen, N. (2016). Data-Driven and Predefined ROI-Based Quantification of Long-Term Resting-State fMRI Reproducibility. Brain connectivity, 6(2), 136-51.
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  Resting-state functional magnetic resonance imaging (fMRI) is a promising tool for neuroscience and clinical studies. However, there exist significant variations in strength and spatial extent of resting-state functional connectivity over repeated sessions in a single or multiple subjects with identical experimental conditions. Reproducibility studies have been conducted for resting-state fMRI where the reproducibility was usually evaluated in predefined regions-of-interest (ROIs). It was possible that reproducibility measures strongly depended on the ROI definition. In this work, this issue was investigated by comparing data-driven and predefined ROI-based quantification of reproducibility. In the data-driven analysis, the reproducibility was quantified using functionally connected voxels detected by a support vector machine (SVM)-based technique. In the predefined ROI-based analysis, all voxels in the predefined ROIs were included when estimating the reproducibility. Experimental results show that (1) a moderate to substantial within-subject reproducibility and a reasonable between-subject reproducibility can be obtained using functionally connected voxels identified by the SVM-based technique; (2) in the predefined ROI-based analysis, an increase in ROI size does not always result in higher reproducibility measures; (3) ROI pairs with high connectivity strength have a higher chance to exhibit high reproducibility; (4) ROI pairs with high reproducibility do not necessarily have high connectivity strength; (5) the reproducibility measured from the identified functionally connected voxels is generally higher than that measured from all voxels in predefined ROIs with typical sizes. The findings (2) and (5) suggest that conventional ROI-based analyses would underestimate the resting-state fMRI reproducibility.
• Song, X., Panych, L. P., & Chen, N. (2016). Spatially regularized machine learning for task and resting-state fMRI. Journal of neuroscience methods, 257, 214-28.
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  Reliable mapping of brain function across sessions and/or subjects in task- and resting-state has been a critical challenge for quantitative fMRI studies although it has been intensively addressed in the past decades.
• Wei, H., Zhang, Y., Gibbs, E., Chen, N., Wang, N., & Liu, C. (2016). Joint 2D and 3D phase processing for quantitative susceptibility mapping: application to 2D echo-planar imaging. NMR in biomedicine.
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  Quantitative susceptibility mapping (QSM) measures tissue magnetic susceptibility and typically relies on time-consuming three-dimensional (3D) gradient-echo (GRE) MRI. Recent studies have shown that two-dimensional (2D) multi-slice gradient-echo echo-planar imaging (GRE-EPI), which is commonly used in functional MRI (fMRI) and other dynamic imaging techniques, can also be used to produce data suitable for QSM with much shorter scan times. However, the production of high-quality QSM maps is difficult because data obtained by 2D multi-slice scans often have phase inconsistencies across adjacent slices and strong susceptibility field gradients near air-tissue interfaces. To address these challenges in 2D EPI-based QSM studies, we present a new data processing procedure that integrates 2D and 3D phase processing. First, 2D Laplacian-based phase unwrapping and 2D background phase removal are performed to reduce phase inconsistencies between slices and remove in-plane harmonic components of the background phase. This is followed by 3D background phase removal for the through-plane harmonic components. The proposed phase processing was evaluated with 2D EPI data obtained from healthy volunteers, and compared against conventional 3D phase processing using the same 2D EPI datasets. Our QSM results were also compared with QSM values from time-consuming 3D GRE data, which were taken as ground truth. The experimental results show that this new 2D EPI-based QSM technique can produce quantitative susceptibility measures that are comparable with those of 3D GRE-based QSM across different brain regions (e.g. subcortical iron-rich gray matter, cortical gray and white matter). This new 2D EPI QSM reconstruction method is implemented within STI Suite, which is a comprehensive shareware for susceptibility imaging and quantification. Copyright © 2016 John Wiley & Sons, Ltd.
• Carpenter, K. L., Angold, A., Chen, N., Copeland, W. E., Gaur, P., Pelphrey, K., Song, A. W., & Egger, H. L. (2015). Preschool anxiety disorders predict different patterns of amygdala-prefrontal connectivity at school-age. PloS one, 10(1), e0116854.
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  In this prospective, longitudinal study of young children, we examined whether a history of preschool generalized anxiety, separation anxiety, and/or social phobia is associated with amygdala-prefrontal dysregulation at school-age. As an exploratory analysis, we investigated whether distinct anxiety disorders differ in the patterns of this amygdala-prefrontal dysregulation.
• Chang, H., Guhaniyogi, S., & Chen, N. (2015). Interleaved diffusion-weighted improved by adaptive partial-Fourier and multiband multiplexed sensitivity-encoding reconstruction. Magnetic resonance in medicine, 73(5), 1872-84.
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  We report a series of techniques to reliably eliminate artifacts in interleaved echo-planar imaging (EPI) based diffusion-weighted imaging (DWI).
• Chang, H., Sundman, M., Petit, L., Guhaniyogi, S., Chu, M., Petty, C., Song, A. W., & Chen, N. (2015). Human brain diffusion tensor imaging at submillimeter isotropic resolution on a 3Tesla clinical MRI scanner. NeuroImage, 118, 667-75.
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  The advantages of high-resolution diffusion tensor imaging (DTI) have been demonstrated in a recent post-mortem human brain study (Miller et al., NeuroImage 2011;57(1):167-181), showing that white matter fiber tracts can be much more accurately detected in data at a submillimeter isotropic resolution. To our knowledge, in vivo human brain DTI at a submillimeter isotropic resolution has not been routinely achieved yet because of the difficulty in simultaneously achieving high resolution and high signal-to-noise ratio (SNR) in DTI scans. Here we report a 3D multi-slab interleaved EPI acquisition integrated with multiplexed sensitivity encoded (MUSE) reconstruction, to achieve high-quality, high-SNR and submillimeter isotropic resolution (0.85×0.85×0.85mm(3)) in vivo human brain DTI on a 3Tesla clinical MRI scanner. In agreement with the previously reported post-mortem human brain DTI study, our in vivo data show that the structural connectivity networks of human brains can be mapped more accurately and completely with high-resolution DTI as compared with conventional DTI (e.g., 2×2×2mm(3)).
• Chen, N. (2015). Comparison of Acoustic Radiation Force Impulse Imaging Derived Carotid Plaque Stiffness With Spatially Registered MRI Determined Composition. Ieee Transactions on Medical Imaging.
• Chen, N. (2015). Correction for Eddy Current-Induced Echo-Shifting Effect in Partial-Fourier Diffusion Tensor Imaging. Biomed Research International.
• Chen, N. (2015). Effect of Repetitive Transcranial Magnetic Stimulation on fMRI Resting-State Connectivity in Multiple System Atrophy. Brain Connect.
• Chen, N. (2015). Effects of Repetitive Transcranial Magnetic Stimulation on Motor Symptoms in Parkinson Disease A Systematic Review and Meta-analysis. Jama Neurology.
• Chen, N. (2015). Efficient imaging of midbrain nuclei using inverse double-echo steady-state acquisition. Medical Physics.
• Chen, N. (2015). Four dimensional magnetic resonance imaging with retrospective k-space reordering: A feasibility study. Medical Physics.
• Chen, N. (2015). Human brain diffusion tensor imaging at submillimeter isotropic resolution on a 3 Tesla clinical MRI scanner. Neuroimage.
• Chen, N. (2015). Interleaved Diffusion-Weighted EPI Improved by Adaptive Partial-Fourier and Multiband Multiplexed Sensitivity-Encoding Reconstruction. Magnetic Resonance in Medicine.
• Chen, N. (2015). Neuroimaging of Parkinson's disease: Expanding views. Neuroscience and Biobehavioral Reviews.
• Chen, N. (2015). POCS-based reconstruction of multiplexed sensitivity encoded MRI (POCSMUSE): A general algorithm for reducing motion-related artifacts. Magnetic Resonance in Medicine.
• Chen, N. (2015). Phonemic fluency and brain connectivity in age-related macular degeneration: a pilot study. Brain Connect.
• Chen, N. (2015). Preschool Anxiety Disorders Predict Different Patterns of Amygdala-Prefrontal Connectivity at School-Age. Plos One.
• Chou, Y., Hickey, P. T., Sundman, M., Song, A. W., & Chen, N. (2015). Effects of repetitive transcranial magnetic stimulation on motor symptoms in Parkinson disease: a systematic review and meta-analysis. JAMA neurology, 72(4), 432-40.
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  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.
• Chou, Y., You, H., Wang, H., Zhao, Y., Hou, B., Chen, N., & Feng, F. (2015). Effect of Repetitive Transcranial Magnetic Stimulation on fMRI Resting-State Connectivity in Multiple System Atrophy. Brain connectivity, 5(7), 451-9.
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  Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation technique that has been used to treat neurological and psychiatric conditions. Although results of rTMS intervention are promising, so far, little is known about the rTMS effect on brain functional networks in clinical populations. In this study, we used a whole-brain connectivity analysis of resting-state functional magnetic resonance imaging data to uncover changes in functional connectivity following rTMS intervention and their association with motor symptoms in patients with multiple system atrophy (MSA). Patients were randomized to active rTMS or sham rTMS groups and completed a 10-session 5-Hz rTMS treatment over the left primary motor area. The results showed significant rTMS-related changes in motor symptoms and functional connectivity. Specifically, (1) significant improvement of motor symptoms was observed in the active rTMS group, but not in the sham rTMS group; and (2) several functional links involving the default mode, cerebellar, and limbic networks exhibited positive changes in functional connectivity in the active rTMS group. Moreover, the positive changes in functional connectivity were associated with improvement in motor symptoms for the active rTMS group. The present findings suggest that rTMS may improve motor symptoms by modulating functional links connecting to the default mode, cerebellar, and limbic networks, inferring a future therapeutic candidate for patients with MSA.
• Chu, M., Chang, H., Chung, H., Truong, T., Bashir, M. R., & Chen, N. (2015). POCS-based reconstruction of multiplexed sensitivity encoded MRI (POCSMUSE): A general algorithm for reducing motion-related artifacts. Magnetic resonance in medicine, 74(5), 1336-48.
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  A projection onto convex sets reconstruction of multiplexed sensitivity encoded MRI (POCSMUSE) is developed to reduce motion-related artifacts, including respiration artifacts in abdominal imaging and aliasing artifacts in interleaved diffusion-weighted imaging.
• Doherty, J. R., Dahl, J. J., Kranz, P. G., El Husseini, N., Chang, H., Chen, N., Allen, J. D., Ham, K. L., & Trahey, G. E. (2015). Comparison of Acoustic Radiation Force Impulse Imaging Derived Carotid Plaque Stiffness With Spatially Registered MRI Determined Composition. IEEE transactions on medical imaging, 34(11), 2354-65.
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  Measurements of plaque stiffness may provide important prognostic and diagnostic information to help clinicians distinguish vulnerable plaques containing soft lipid pools from more stable, stiffer plaques. In this preliminary study, we compare in vivo ultrasonic Acoustic Radiation Force Impulse (ARFI) imaging derived measures of carotid plaque stiffness with composition determined by spatially registered Magnetic Resonance Imaging (MRI) in five human subjects with stenosis > 50%. Ultrasound imaging was implemented on a commercial diagnostic scanner with custom pulse sequences to collect spatially registered 2D longitudinal B-mode and ARFI images. A standardized, multi-contrast weighted MRI sequence was used to obtain 3D Time of Flight (TOF), T1 weighted (T1W), T2 weighted (T2W), and Proton Density Weighted (PDW) transverse image stacks of volumetric data. The MRI data was segmented to identify lipid, calcium, and normal loose matrix components using commercially available software. 3D MRI segmented plaque models were rendered and spatially registered with 2D B-mode images to create fused ultrasound and MRI volumetric images for each subject. ARFI imaging displacements in regions of interest (ROIs) derived from MRI segmented contours of varying composition were compared. Regions of calcium and normal loose matrix components identified by MRI presented as homogeneously stiff regions of similarly low (typically ≈ 1 μm) displacement in ARFI imaging. MRI identified lipid pools > 2 mm(2), found in three out of five subjects, presented as softer regions of increased displacement that were on average 1.8 times greater than the displacements in adjacent regions of loose matrix components in spatially registered ARFI images. This work provides early evidence supporting the use of ARFI imaging to noninvasively identify lipid regions in carotid artery plaques in vivo that are believed to increase the propensity of a plaque to rupture. Additionally, the results provide early training data for future studies and aid in the interpretation and possible clinical utility of ARFI imaging for identifying the elusive vulnerable plaque.
• Liu, Y., Yin, F., Chen, N., Chu, M., & Cai, J. (2015). Four dimensional magnetic resonance imaging with retrospective k-space reordering: a feasibility study. Medical physics, 42(2), 534-41.
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  Current four dimensional magnetic resonance imaging (4D-MRI) techniques lack sufficient temporal/spatial resolution and consistent tumor contrast. To overcome these limitations, this study presents the development and initial evaluation of a new strategy for 4D-MRI which is based on retrospective k-space reordering.
• Truong, T., Song, A. W., & Chen, N. (2015). Correction for Eddy Current-Induced Echo-Shifting Effect in Partial-Fourier Diffusion Tensor Imaging. BioMed research international, 2015, 185026.
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  In most diffusion tensor imaging (DTI) studies, images are acquired with either a partial-Fourier or a parallel partial-Fourier echo-planar imaging (EPI) sequence, in order to shorten the echo time and increase the signal-to-noise ratio (SNR). However, eddy currents induced by the diffusion-sensitizing gradients can often lead to a shift of the echo in k-space, resulting in three distinct types of artifacts in partial-Fourier DTI. Here, we present an improved DTI acquisition and reconstruction scheme, capable of generating high-quality and high-SNR DTI data without eddy current-induced artifacts. This new scheme consists of three components, respectively, addressing the three distinct types of artifacts. First, a k-space energy-anchored DTI sequence is designed to recover eddy current-induced signal loss (i.e., Type 1 artifact). Second, a multischeme partial-Fourier reconstruction is used to eliminate artificial signal elevation (i.e., Type 2 artifact) associated with the conventional partial-Fourier reconstruction. Third, a signal intensity correction is applied to remove artificial signal modulations due to eddy current-induced erroneous T2(∗) -weighting (i.e., Type 3 artifact). These systematic improvements will greatly increase the consistency and accuracy of DTI measurements, expanding the utility of DTI in translational applications where quantitative robustness is much needed.
• Weingarten, C. P., Sundman, M. H., Hickey, P., & Chen, N. (2015). Neuroimaging of Parkinson's disease: Expanding views. Neuroscience and biobehavioral reviews, 59, 16-52.
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  Advances in molecular and structural and functional neuroimaging are rapidly expanding the complexity of neurobiological understanding of Parkinson's disease (PD). This review article begins with an introduction to PD neurobiology as a foundation for interpreting neuroimaging findings that may further lead to more integrated and comprehensive understanding of PD. Diverse areas of PD neuroimaging are then reviewed and summarized, including positron emission tomography, single photon emission computed tomography, magnetic resonance spectroscopy and imaging, transcranial sonography, magnetoencephalography, and multimodal imaging, with focus on human studies published over the last five years. These included studies on differential diagnosis, co-morbidity, genetic and prodromal PD, and treatments from L-DOPA to brain stimulation approaches, transplantation and gene therapies. Overall, neuroimaging has shown that PD is a neurodegenerative disorder involving many neurotransmitters, brain regions, structural and functional connections, and neurocognitive systems. A broad neurobiological understanding of PD will be essential for translational efforts to develop better treatments and preventive strategies. Many questions remain and we conclude with some suggestions for future directions of neuroimaging of PD.
• Whitson, H. E., Chou, Y., Potter, G. G., Diaz, M. T., Chen, N., Lad, E. M., Johnson, M. A., Cousins, S. W., Zhuang, J., & Madden, D. J. (2015). Phonemic fluency and brain connectivity in age-related macular degeneration: a pilot study. Brain connectivity, 5(2), 126-35.
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  Age-related macular degeneration (AMD), the leading cause of blindness in developed nations, has been associated with poor performance on tests of phonemic fluency. This pilot study sought to (1) characterize the relationship between phonemic fluency and resting-state functional brain connectivity in AMD patients and (2) determine whether regional connections associated with phonemic fluency in AMD patients were similarly linked to phonemic fluency in healthy participants. Behavior-based connectivity analysis was applied to resting-state, functional magnetic resonance imaging data from seven patients (mean age=79.9±7.5 years) with bilateral AMD who completed fluency tasks prior to imaging. Phonemic fluency was inversely related to the strength of functional connectivity (FC) among six pairs of brain regions, representing eight nodes: left opercular portion of inferior frontal gyrus (which includes Broca's area), left superior temporal gyrus (which includes part of Wernicke's area), inferior parietal lobe (bilaterally), right superior parietal lobe, right supramarginal gyrus, right supplementary motor area, and right precentral gyrus. The FC of these reference links was not related to phonemic fluency among 32 healthy individuals (16 younger adults, mean age=23.5±4.6 years and 16 older adults, mean age=68.3±3.4 years). Compared with healthy individuals, AMD patients exhibited higher mean connectivity within the reference links and within the default mode network, possibly reflecting compensatory changes to support performance in the setting of reduced vision. These findings are consistent with the hypothesis that phonemic fluency deficits in AMD reflect underlying brain changes that develop in the context of AMD.
• Wu, M., Chang, H., Chao, T., & Chen, N. (2015). Efficient imaging of midbrain nuclei using inverse double-echo steady-state acquisition. Medical physics, 42(7), 4367-74.
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  Imaging of midbrain nuclei using T2- or T2*-weighted MRI often entails long echo time, leading to long scan time. In this study, an inverse double-echo steady-state (iDESS) technique is proposed for efficiently depicting midbrain nuclei.
• Chang, H., Gaur, P., Chou, Y., Chu, M., & Chen, N. (2014). Interleaved EPI based fMRI improved by multiplexed sensitivity encoding (MUSE) and simultaneous multi-band imaging. PloS one, 9(12), e116378.
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  Functional magnetic resonance imaging (fMRI) is a non-invasive and powerful imaging tool for detecting brain activities. The majority of fMRI studies are performed with single-shot echo-planar imaging (EPI) due to its high temporal resolution. Recent studies have demonstrated that, by increasing the spatial-resolution of fMRI, previously unidentified neuronal networks can be measured. However, it is challenging to improve the spatial resolution of conventional single-shot EPI based fMRI. Although multi-shot interleaved EPI is superior to single-shot EPI in terms of the improved spatial-resolution, reduced geometric distortions, and sharper point spread function (PSF), interleaved EPI based fMRI has two main limitations: 1) the imaging throughput is lower in interleaved EPI; 2) the magnitude and phase signal variations among EPI segments (due to physiological noise, subject motion, and B0 drift) are translated to significant in-plane aliasing artifact across the field of view (FOV). Here we report a method that integrates multiple approaches to address the technical limitations of interleaved EPI-based fMRI. Firstly, the multiplexed sensitivity-encoding (MUSE) post-processing algorithm is used to suppress in-plane aliasing artifacts resulting from time-domain signal instabilities during dynamic scans. Secondly, a simultaneous multi-band interleaved EPI pulse sequence, with a controlled aliasing scheme incorporated, is implemented to increase the imaging throughput. Thirdly, the MUSE algorithm is then generalized to accommodate fMRI data obtained with our multi-band interleaved EPI pulse sequence, suppressing both in-plane and through-plane aliasing artifacts. The blood-oxygenation-level-dependent (BOLD) signal detectability and the scan throughput can be significantly improved for interleaved EPI-based fMRI. Our human fMRI data obtained from 3 Tesla systems demonstrate the effectiveness of the developed methods. It is expected that future fMRI studies requiring high spatial-resolvability and fidelity will largely benefit from the reported techniques.
• Chen, N. (2014). A Study of Long-Term fMRI Reproducibility Using Data-Driven Analysis Methods. International Journal of Imaging Systems and Technology.
• Chen, N. (2014). Age mediation of frontoparietal activation during visual feature search. Neuroimage.
• Chen, N. (2014). Cocaine-induced Functional Hyper-connectivity at Rest Between Fronto-striate Regions and Structural Hypo-connectivity Between Frontal-limbic Regions. Neuropsychopharmacology.
• Chen, N. (2014). Interleaved EPI Based fMRI Improved by Multiplexed Sensitivity Encoding (MUSE) and Simultaneous Multi-Band Imaging. Plos One.
• Madden, D. J., Parks, E. L., Davis, S. W., Diaz, M. T., Potter, G. G., Chou, Y., Chen, N., & Cabeza, R. (2014). Age mediation of frontoparietal activation during visual feature search. NeuroImage, 102 Pt 2, 262-74.
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  Activation of frontal and parietal brain regions is associated with attentional control during visual search. We used fMRI to characterize age-related differences in frontoparietal activation in a highly efficient feature search task, detection of a shape singleton. On half of the trials, a salient distractor (a color singleton) was present in the display. The hypothesis was that frontoparietal activation mediated the relation between age and attentional capture by the salient distractor. Participants were healthy, community-dwelling individuals, 21 younger adults (19-29 years of age) and 21 older adults (60-87 years of age). Top-down attention, in the form of target predictability, was associated with an improvement in search performance that was comparable for younger and older adults. The increase in search reaction time (RT) associated with the salient distractor (attentional capture), standardized to correct for generalized age-related slowing, was greater for older adults than for younger adults. On trials with a color singleton distractor, search RT increased as a function of increasing activation in frontal regions, for both age groups combined, suggesting increased task difficulty. Mediational analyses disconfirmed the hypothesized model, in which frontal activation mediated the age-related increase in attentional capture, but supported an alternative model in which age was a mediator of the relation between frontal activation and capture.
• Song, A. W., Chang, H., Petty, C., Guidon, A., & Chen, N. (2014). Improved delineation of short cortical association fibers and gray/white matter boundary using whole-brain three-dimensional diffusion tensor imaging at submillimeter spatial resolution. Brain connectivity, 4(9), 636-40.
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  Recent emergence of human connectome imaging has led to a high demand on angular and spatial resolutions for diffusion magnetic resonance imaging (MRI). While there have been significant growths in high angular resolution diffusion imaging, the improvement in spatial resolution is still limited due to a number of technical challenges, such as the low signal-to-noise ratio and high motion artifacts. As a result, the benefit of a high spatial resolution in the whole-brain connectome imaging has not been fully evaluated in vivo. In this brief report, the impact of spatial resolution was assessed in a newly acquired whole-brain three-dimensional diffusion tensor imaging data set with an isotropic spatial resolution of 0.85 mm. It was found that the delineation of short cortical association fibers is drastically improved as well as the definition of fiber pathway endings into the gray/white matter boundary-both of which will help construct a more accurate structural map of the human brain connectome.
• Song, X., & Chen, N. (2014). A SVM-based quantitative fMRI method for resting-state functional network detection. Magnetic resonance imaging, 32(7), 819-31.
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  Resting-state functional magnetic resonance imaging (fMRI) aims to measure baseline neuronal connectivity independent of specific functional tasks and to capture changes in the connectivity due to neurological diseases. Most existing network detection methods rely on a fixed threshold to identify functionally connected voxels under the resting state. Due to fMRI non-stationarity, the threshold cannot adapt to variation of data characteristics across sessions and subjects, and generates unreliable mapping results. In this study, a new method is presented for resting-state fMRI data analysis. Specifically, the resting-state network mapping is formulated as an outlier detection process that is implemented using one-class support vector machine (SVM). The results are refined by using a spatial-feature domain prototype selection method and two-class SVM reclassification. The final decision on each voxel is made by comparing its probabilities of functionally connected and unconnected instead of a threshold. Multiple features for resting-state analysis were extracted and examined using an SVM-based feature selection method, and the most representative features were identified. The proposed method was evaluated using synthetic and experimental fMRI data. A comparison study was also performed with independent component analysis (ICA) and correlation analysis. The experimental results show that the proposed method can provide comparable or better network detection performance than ICA and correlation analysis. The method is potentially applicable to various resting-state quantitative fMRI studies.
• Song, X., & Chen, N. (2014). A unified machine learning method for task-related and resting state fMRI data analysis. Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2014, 6426-9.
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  Functional magnetic resonance imaging (fMRI) aims to localize task-related brain activation or resting-state functional connectivity. Most existing fMRI data analysis techniques rely on fixed thresholds to identify active voxels under a task condition or functionally connected voxels in the resting state. Due to fMRI non-stationarity, a fixed threshold cannot adapt to intra- and inter-subject variation and provide a reliable mapping of brain function. In this work, a machine learning method is proposed for a unified analysis of both task-related and resting state fMRI data. Specifically, the mapping of brain function in a task condition or resting state is formulated as an outlier detection process. Support vector machines are used to provide an initial mapping and refine mapping results. The method does not require a fixed threshold for the final decision, and can adapt to fMRI non-stationarity. The proposed method was evaluated using experimental data acquired from multiple human subjects. The results indicate that the proposed method can provide reliable mapping of brain function, and is applicable to various quantitative fMRI studies.
• Song, X., Chen, N., & Gaur, P. (2014). A kernel machine-based fMRI physiological noise removal method. Magnetic resonance imaging, 32(2), 150-62.
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  Functional magnetic resonance imaging (fMRI) technique with blood oxygenation level dependent (BOLD) contrast is a powerful tool for noninvasive mapping of brain function under task and resting states. The removal of cardiac- and respiration-induced physiological noise in fMRI data has been a significant challenge as fMRI studies seek to achieve higher spatial resolutions and characterize more subtle neuronal changes. The low temporal sampling rate of most multi-slice fMRI experiments often causes aliasing of physiological noise into the frequency range of BOLD activation signal. In addition, changes of heartbeat and respiration patterns also generate physiological fluctuations that have similar frequencies with BOLD activation. Most existing physiological noise-removal methods either place restrictive limitations on image acquisition or utilize filtering or regression based post-processing algorithms, which cannot distinguish the frequency-overlapping BOLD activation and the physiological noise. In this work, we address the challenge of physiological noise removal via the kernel machine technique, where a nonlinear kernel machine technique, kernel principal component analysis, is used with a specifically identified kernel function to differentiate BOLD signal from the physiological noise of the frequency. The proposed method was evaluated in human fMRI data acquired from multiple task-related and resting state fMRI experiments. A comparison study was also performed with an existing adaptive filtering method. The results indicate that the proposed method can effectively identify and reduce the physiological noise in fMRI data. The comparison study shows that the proposed method can provide comparable or better noise removal performance than the adaptive filtering approach.
• Song, X., Panych, L. P., Chou, Y., & Chen, N. (2014). A Study of Long-Term fMRI Reproducibility Using Data-Driven Analysis Methods. International journal of imaging systems and technology, 24(4), 339-349.
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  The reproducibility of functional magnetic resonance imaging (fMRI) is important for fMRI-based neuroscience research and clinical applications. Previous studies show considerable variation in amplitude and spatial extent of fMRI activation across repeated sessions on individual subjects even using identical experimental paradigms and imaging conditions. Most existing fMRI reproducibility studies were typically limited by time duration and data analysis techniques. Particularly, the assessment of reproducibility is complicated by a fact that fMRI results may depend on data analysis techniques used in reproducibility studies. In this work, the long-term fMRI reproducibility was investigated with a focus on the data analysis methods. Two spatial smoothing techniques, including a wavelet-domain Bayesian method and the Gaussian smoothing, were evaluated in terms of their effects on the long-term reproducibility. A multivariate support vector machine (SVM)-based method was used to identify active voxels, and compared to a widely used general linear model (GLM)-based method at the group level. The reproducibility study was performed using multisession fMRI data acquired from eight healthy adults over 1.5 years' period of time. Three regions-of-interest (ROI) related to a motor task were defined based upon which the long-term reproducibility were examined. Experimental results indicate that different spatial smoothing techniques may lead to different reproducibility measures, and the wavelet-based spatial smoothing and SVM-based activation detection is a good combination for reproducibility studies. On the basis of the ROIs and multiple numerical criteria, we observed a moderate to substantial within-subject long-term reproducibility. A reasonable long-term reproducibility was also observed from the inter-subject study. It was found that the short-term reproducibility is usually higher than the long-term reproducibility. Furthermore, the results indicate that brain regions with high contrast-to-noise ratio do not necessarily exhibit high reproducibility. These findings may provide supportive information for optimal design/implementation of fMRI studies and data interpretation.
• Sundman, M. H., Hall, E. E., & Chen, N. (2014). Examining the relationship between head trauma and neurodegenerative disease: A review of epidemiology, pathology and neuroimaging techniques. Journal of Alzheimer's disease & Parkinsonism, 4.
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  Traumatic brain injuries (TBI) are induced by sudden acceleration-deceleration and/or rotational forces acting on the brain. Diffuse axonal injury (DAI) has been identified as one of the chief underlying causes of morbidity and mortality in head trauma incidents. DAIs refer to microscopic white matter (WM) injuries as a result of shearing forces that induce pathological and anatomical changes within the brain, which potentially contribute to significant impairments later in life. These microscopic injuries are often unidentifiable by the conventional computed tomography (CT) and magnetic resonance (MR) scans employed by emergency departments to initially assess head trauma patients and, as a result, TBIs are incredibly difficult to diagnose. The impairments associated with TBI may be caused by secondary mechanisms that are initiated at the moment of injury, but often have delayed clinical presentations that are difficult to assess due to the initial misdiagnosis. As a result, the true consequences of these head injuries may go unnoticed at the time of injury and for many years thereafter. The purpose of this review is to investigate these consequences of TBI and their potential link to neurodegenerative disease (ND). This review will summarize the current epidemiological findings, the pathological similarities, and new neuroimaging techniques that may help delineate the relationship between TBI and ND. Lastly, this review will discuss future directions and propose new methods to overcome the limitations that are currently impeding research progress. It is imperative that improved techniques are developed to adequately and retrospectively assess TBI history in patients that may have been previously undiagnosed in order to increase the validity and reliability across future epidemiological studies. The authors introduce a new surveillance tool (Retrospective Screening of Traumatic Brain Injury Questionnaire, RESTBI) to address this concern.
• Chen, N. (2013). A robust multi-shot scan strategy for high-resolution diffusion weighted MRI enabled by multiplexed sensitivity-encoding (MUSE). Neuroimage.
• Chen, N. (2013). Accelerating EPI Distortion Correction by Utilizing a Modern GPU-Based Parallel Computation. Journal of Neuroimaging.
• Chen, N., Guidon, A., Chang, H., & Song, A. W. (2013). A robust multi-shot scan strategy for high-resolution diffusion weighted MRI enabled by multiplexed sensitivity-encoding (MUSE). NeuroImage, 72, 41-7.
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  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.
• Chou, Y., Chen, N., & Madden, D. J. (2013). Functional brain connectivity and cognition: effects of adult age and task demands. Neurobiology of aging, 34(8), 1925-34.
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  Previous neuroimaging research has documented that patterns of intrinsic (resting state) functional connectivity (FC) among brain regions covary with individual measures of cognitive performance. Here, we examined the relation between intrinsic FC and a reaction time (RT) measure of performance, as a function of age group and task demands. We obtained filtered, event-related functional magnetic resonance imaging data, and RT measures of visual search performance, from 21 younger adults (19-29 years old) and 21 healthy, older adults (60-87 years old). Age-related decline occurred in the connectivity strength in multiple brain regions, consistent with previous findings. Among 8 pairs of regions, across somatomotor, orbitofrontal, and subcortical networks, increasing FC was associated with faster responding (lower RT). Relative to younger adults, older adults exhibited a lower strength of this RT-connectivity relation and greater disruption of this relation by a salient but irrelevant display item (color singleton distractor). Age-related differences in the covariation of intrinsic FC and cognitive performance vary as a function of task demands.
• Yang, Y., Huang, T., Wang, F., Chuang, T., & Chen, N. (2013). Accelerating EPI distortion correction by utilizing a modern GPU-based parallel computation. Journal of neuroimaging : official journal of the American Society of Neuroimaging, 23(2), 202-6.
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  The combination of phase demodulation and field mapping is a practical method to correct echo planar imaging (EPI) geometric distortion. However, since phase dispersion accumulates in each phase-encoding step, the calculation complexity of phase modulation is Ny-fold higher than conventional image reconstructions. Thus, correcting EPI images via phase demodulation is generally a time-consuming task.
• Chen, N. (2012). Alterations in Brain Transition Metals in Huntington Disease An Evolving and Intricate Story. Archives of Neurology.
• Chen, N. (2012). Diffusion tensor imaging of cerebral white matter integrity in cognitive aging. Biochimica Et Biophysica Acta-Molecular Basis of Disease.
• Chen, N. (2012). Investigation of Long-Term Reproducibility of Intrinsic Connectivity Network Mapping: A Resting-State fMRI Study. American Journal of Neuroradiology.
• Chen, N. (2012). Investigation of the PSF-choice method for reduced lipid contamination in prostate MR spectroscopic imaging. Magnetic Resonance in Medicine.
• Chen, N. (2012). Meditation-State Functional Connectivity (msFC): Strengthening of the Dorsal Attention Network and Beyond. Evidence-Based Complementary and Alternative Medicine.
• Chen, N. (2012). Ultrafast 1D MR thermometry using phase or frequency mapping. Magnetic Resonance Materials in Physics Biology and Medicine.
• Chou, Y., Panych, L. P., Dickey, C. C., Petrella, J. R., & Chen, N. (2012). Investigation of long-term reproducibility of intrinsic connectivity network mapping: a resting-state fMRI study. AJNR. American journal of neuroradiology, 33(5), 833-8.
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  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.
• Froeliger, B., Garland, E. L., Kozink, R. V., Modlin, L. A., Chen, N., McClernon, F. J., Greeson, J. M., & Sobin, P. (2012). Meditation-State Functional Connectivity (msFC): Strengthening of the Dorsal Attention Network and Beyond. Evidence-based complementary and alternative medicine : eCAM, 2012, 680407.
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  Meditation practice alters intrinsic resting-state functional connectivity (rsFC) in the default mode network (DMN). However, little is known regarding the effects of meditation on other resting-state networks. The aim of current study was to investigate the effects of meditation experience and meditation-state functional connectivity (msFC) on multiple resting-state networks (RSNs). Meditation practitioners (MPs) performed two 5-minute scans, one during rest, one while meditating. A meditation naïve control group (CG) underwent one resting-state scan. Exploratory regression analyses of the relations between years of meditation practice and rsFC and msFC were conducted. During resting-state, MP as compared to CG exhibited greater rsFC within the Dorsal Attention Network (DAN). Among MP, meditation, as compared to rest, strengthened FC between the DAN and DMN and Salience network whereas it decreased FC between the DAN, dorsal medial PFC, and insula. Regression analyses revealed positive correlations between the number of years of meditation experience and msFC between DAN, thalamus, and anterior parietal sulcus, whereas negative correlations between DAN, lateral and superior parietal, and insula. These findings suggest that the practice of meditation strengthens FC within the DAN as well as strengthens the coupling between distributed networks that are involved in attention, self-referential processes, and affective response.
• Madden, D. J., Bennett, I. J., Burzynska, A., Potter, G. G., Chen, N., & Song, A. W. (2012). Diffusion tensor imaging of cerebral white matter integrity in cognitive aging. Biochimica et biophysica acta, 1822(3), 386-400.
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  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.
• Mei, C., Mulkern, R. V., Oshio, K., Chen, N., Madore, B., Panych, L. P., Hynynen, K., & McDannold, N. J. (2012). Ultrafast 1D MR thermometry using phase or frequency mapping. Magma (New York, N.Y.), 25(1), 5-14.
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  To develop an ultrafast MRI-based temperature monitoring method for application during rapid ultrasound exposures in moving organs.
• Panych, L. P., Roebuck, J. R., Chen, N., Tang, Y., Madore, B., Tempany, C. M., & Mulkern, R. V. (2012). Investigation of the PSF-choice method for reduced lipid contamination in prostate MR spectroscopic imaging. Magnetic resonance in medicine, 68(5), 1376-82.
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  The purpose of this work was to evaluate a previously proposed approach that aims to improve the point spread function (PSF) of MR spectroscopic imaging (MRSI) to avoid corruption by lipid signal arising from neighboring voxels. Retrospective spatial filtering can be used to alter the PSF; however, this either reduces spatial resolution or requires extending the acquisition in k-space at the cost of increased imaging time. Alternatively, the method evaluated here, PSF-choice, can modify the PSF localization to reduce the contamination from adjacent lipids by conforming the signal response more closely to the desired MRSI voxel grid. This is done without increasing scan time or degrading SNR of important metabolites. PSF-choice achieves improvements in spatial localization through modifications to the radiofrequency excitation pulses. An implementation of this method is reported for MRSI of the prostate, where it is demonstrated that, in 13 of 16 pilot prostate MRSI scans, intravoxel spectral contamination from lipid was significantly reduced when using PSF-choice. Phantom studies were also performed that demonstrate, compared with MRSI with standard Fourier phase encoding, out-of-voxel signal contamination of spectra was significantly reduced in MRSI with PSF-choice.
• Rosas, H. D., Chen, Y. I., Doros, G., Salat, D. H., Chen, N., Kwong, K. K., Bush, A., Fox, J., & Hersch, S. M. (2012). Alterations in brain transition metals in Huntington disease: an evolving and intricate story. Archives of neurology, 69(7), 887-93.
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  Aberrant accumulation of transition metals in the brain may have an early and important role in the pathogenesis of several neurodegenerative disorders, including Huntington disease (HD).
• Truong, T., Chen, N., & Song, A. W. (2012). Inherent correction of motion-induced phase errors in multishot spiral diffusion-weighted imaging. Magnetic resonance in medicine, 68(4), 1255-61.
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  Multishot spiral imaging is a promising alternative to echo-planar imaging for high-resolution diffusion-weighted imaging and diffusion tensor imaging. However, subject motion in the presence of diffusion-weighting gradients causes phase inconsistencies among different shots, resulting in signal loss and aliasing artifacts in the reconstructed images. Such artifacts can be reduced using a variable-density spiral trajectory or a navigator echo, however at the cost of a longer scan time. Here, a novel iterative phase correction method is proposed to inherently correct for the motion-induced phase errors without requiring any additional scan time. In this initial study, numerical simulations and in vivo experiments are performed to demonstrate that the proposed method can effectively and efficiently correct for spatially linear phase errors caused by rigid-body motion in multishot spiral diffusion-weighted imaging of the human brain.
• Chen, N. (2011). Identification and Attenuation of Physiological Noise in fMRI Using Kernel Techniques. 2011 Annual International Conference of the Ieee Engineering in Medicine and Biology Society (Embc).
• Chen, N. (2011). Phenotype Based Connectivity Analysis (PBCA) for Characterization of Intrinsic Functional Connectivity Networks in Familial Risk and Schizophrenia. Biological Psychiatry.
• Chen, N. (2011). Two-Dimensional Phase Cycled Reconstruction for Inherent Correction of Echo-Planar Imaging Nyquist Artifacts. Magnetic Resonance in Medicine.
• Chen, N., Avram, A. V., & Song, A. W. (2011). Two-dimensional phase cycled reconstruction for inherent correction of echo-planar imaging Nyquist artifacts. Magnetic resonance in medicine, 66(4), 1057-66.
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  The inconsistency of k-space trajectories results in Nyquist artifacts in echo-planar imaging (EPI). Traditional techniques often only correct for phase errors along the frequency-encoding direction (one-dimensional correction), which may leave significant residual artifacts, particularly for oblique-plane EPI or in the presence of cross-term eddy currents. As compared with one-dimensional correction, two-dimensional (2D) phase correction can be much more effective in suppressing Nyquist artifacts. However, most existing 2D correction methods require reference scans and may not be generally applicable to different imaging protocols. Furthermore, EPI reconstruction with these 2D phase correction methods is susceptible to error amplification due to subject motion. To address these limitations, we report an inherent and general 2D phase correction technique for EPI Nyquist removal. First, a series of images are generated from the original dataset, by cycling through different possible values of phase errors using a 2D reconstruction framework. Second, the image with the lowest artifact level is identified from images generated in the first step using criteria based on background energy in sorted and sigmoid-weighted signals. In this report, we demonstrate the effectiveness of our new method in removing Nyquist ghosts in single-shot, segmented and parallel EPI without acquiring additional reference scans and the subsequent error amplifications.
• Song, X., Chen, N., & Gaur, P. (2011). Identification and attenuation of physiological noise in fMRI using kernel techniques. Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference, 2011, 4852-5.
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  Functional magnetic resonance imaging (fMRI) techniques enable noninvasive studies of brain functional activity under task and resting states. However, the analysis of brain activity could be significantly affected by the cardiac- and respiration-induced physiological noise in fMRI data. In most multi-slice fMRI experiments, the temporal sampling rates are not high enough to critically sample the physiological noise, and the noise is aliased into frequency bands where useful brain functional signal exists, compromising the analysis. Most existing approaches cannot distinguish between the aliased noise and signal if they overlap in the frequency domain. In this work, we further developed a kernel principal component analysis based physiological removal method based on our previous work. Specifically, two kernel functions were evaluated based on a newly proposed criterion that can measure the capability of a kernel to separate the aliased physiological noise from fMRI signal. In addition, a mutual information based criterion was designed to select principal components for noise removal. The method was evaluated by human experimental fMRI studies, and the results demonstrate that the proposed method can effectively identify and attenuate the aliased physiological noise in fMRI data.
• Truong, T., Chen, N., & Song, A. W. (2011). Dynamic correction of artifacts due to susceptibility effects and time-varying eddy currents in diffusion tensor imaging. NeuroImage, 57(4), 1343-7.
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  In diffusion tensor imaging (DTI), spatial and temporal variations of the static magnetic field (B(0)) caused by susceptibility effects and time-varying eddy currents result in severe distortions, blurring, and misregistration artifacts, which in turn lead to errors in DTI metrics and in fiber tractography. Various correction methods have been proposed, but typically assume that the eddy current-induced magnetic field can be modeled as a constant or a single exponential decay within the DTI readout window. Here, we show that its temporal dependence is more complex because of the interaction of multiple eddy currents with different time constants, but that it remains very consistent over time. As such, we propose a novel dynamic B(0) mapping and off-resonance correction method that measures the exact spatial, temporal, and diffusion-weighting direction dependence of the susceptibility- and eddy current-induced magnetic fields to effectively and efficiently correct for artifacts caused by both susceptibility effects and time-varying eddy currents, thereby resulting in a high spatial fidelity and accuracy.
• Chen, N. (2010). Application of k-Space Energy Spectrum Analysis for Inherent and Dynamic B(0) Mapping and Deblurring in Spiral Imaging. Magnetic Resonance in Medicine.
• Truong, T., Chen, N., & Song, A. W. (2010). Application of k-space energy spectrum analysis for inherent and dynamic B0 mapping and deblurring in spiral imaging. Magnetic resonance in medicine, 64(4), 1121-7.
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  Spiral imaging is vulnerable to spatial and temporal variations of the amplitude of the static magnetic field (B(0)) caused by susceptibility effects, eddy currents, chemical shifts, subject motion, physiological noise, and system instabilities, resulting in image blurring. Here, a novel off-resonance correction method is proposed to address these issues. A k-space energy spectrum analysis algorithm is first applied to inherently and dynamically generate a B(0) map from the k-space data at each time point, without requiring any additional data acquisition, pulse sequence modification, or phase unwrapping. A simulated phase evolution rewinding algorithm and an automatic residual deblurring algorithm are then used to correct for the blurring caused by both spatial and temporal B(0) variations, resulting in a high spatial and temporal fidelity. This method is validated against conventional B(0) mapping and deblurring methods, and its advantages for dynamic MRI applications are demonstrated in functional MRI studies.
• Chen, N. (2009). Measurement of spontaneous signal fluctuations in fMRI: adult age differences in intrinsic functional connectivity. Brain Structure & Function.
• Chen, N. (2009). Quantification of Non-Water-Suppressed MR Spectra With Correction for Motion-Induced Signal Reduction. Magnetic Resonance in Medicine.
• Chen, N. (2009). SUSCEPTIBILITY-ENHANCED 3-TESLA T1-WEIGHTED SPOILED GRADIENT ECHO OF THE MIDBRAIN NUCLEI FOR GUIDANCE OF DEEP BRAIN STIMULATION IMPLANTATION. Neurosurgery.
• Chen, N., Chou, Y., Song, A. W., & Madden, D. J. (2009). Measurement of spontaneous signal fluctuations in fMRI: adult age differences in intrinsic functional connectivity. Brain structure & function, 213(6), 571-85.
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  Functional connectivity (FC) reflects the coherence of spontaneous, low-frequency fluctuations in functional magnetic resonance imaging (fMRI) data. We report a behavior-based connectivity analysis method, in which whole-brain data are used to identify behaviorally relevant, intrinsic FC networks. Nineteen younger adults (20-28 years) and 19 healthy, older adults (63-78 years) were assessed with fMRI and diffusion tensor imaging (DTI). Results indicated that FC involving a distributed network of brain regions, particularly the inferior frontal gyri, exhibited age-related change in the correlation with perceptual-motor speed (choice reaction time; RT). No relation between FC and RT was evident for younger adults, whereas older adults exhibited a significant age-related slowing of perceptual-motor speed, which was mediated by decreasing FC. Older adults' FC values were in turn associated positively with white matter integrity (from DTI) within the genu of the corpus callosum. The developed FC analysis illustrates the value of identifying connectivity by combining structural, functional, and behavioral data.
• Lin, J., Tsai, S., Liu, H., Chung, H., Mulkern, R. V., Cheng, C., Yeh, T., & Chen, N. (2009). Quantification of non-water-suppressed MR spectra with correction for motion-induced signal reduction. Magnetic resonance in medicine, 62(6), 1394-403.
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  Intrascan subject movement in clinical MR spectroscopic examinations may result in inconsistent water suppression that distorts the metabolite signals, frame-to-frame variations in spectral phase and frequency, and consequent reductions in the signal-to-noise ratio due to destructive averaging. Frame-to-frame phase/frequency corrections, although reported to be successful in achieving constructive averaging, rely on consistent water suppression, which may be difficult in the presence of intrascan motion. In this study, motion correction using non-water-suppressed data acquisition is proposed to overcome the above difficulties. The time-domain matrix-pencil postprocessing method was used to extract water signals from the non-water-suppressed spectroscopic data, followed by phase and frequency corrections of the metabolite signals based on information obtained from the water signals. From in vivo experiments on seven healthy subjects at 3.0 T, quantification of metabolites using the unsuppressed water signal as a reference showed improved correlation with water-suppressed data acquired in the absence of motion (R(2) = 0.9669; slope = 0.94). The metabolite concentrations derived using the proposed approach were in good agreement with literature values. Computer simulations under various degrees of frequency and phase variations further demonstrated robust performance of the time-domain postprocessing approach.
• Young, G. S., Feng, F., Shen, H., & Chen, N. (2009). Susceptibility-enhanced 3-Tesla T1-weighted spoiled gradient echo of the midbrain nuclei for guidance of deep brain stimulation implantation. Neurosurgery, 65(4), 809-15.
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  Surgical planning for deep brain stimulation implantation procedures requires T1-weighted imaging (T1WI) for stereotactic navigation. Because the subthalamic nucleus, the main target for deep brain stimulation, and other midbrain nuclei cannot be visualized on the stereotactic guidance T1WI, additional T2-weighted imaging (T2WI) is generally obtained and registered to the T1WI for surgical targeting. Surgical planning based on the registration of the 2 data sets is subject to error resulting from inconsistent geometric distortions and any subject movement between the 2 scans. In this article, we propose a new method to produce susceptibility-enhanced, contrast-optimized T1-weighted 3-dimensional spoiled gradient recalled acquisition in steady state images with enhanced contrast for midbrain nuclei within the volumetric T1WI data set itself, eliminating the need for additional T2WI. The scan parameters of 3-dimensional spoiled gradient recalled acquisition in steady state are chosen in a way that T1WI can be obtained from conventional magnitude reconstruction and images with improved contrast between midbrain nuclei and surrounding tissues can be produced from the same data by performing susceptibility-weighted imaging reconstruction on a chosen region of interest. In addition, our preliminary experience suggests that the resulting contrast between the midbrain nuclei is superior to the current state-of-the-art fast spin echo T2WI in depicting the subthalamic nucleus as distinct from the substantia nigra pars reticulata and clear depiction of the nucleus ventrointermedius externus of thalamus.
• Chen, N., Oshio, K., & Panych, L. P. (2008). Improved image reconstruction for partial Fourier gradient-echo echo-planar imaging (EPI). Magnetic resonance in medicine, 59(4), 916-24.
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  The partial Fourier gradient-echo echo planar imaging (EPI) technique makes it possible to acquire high-resolution functional MRI (fMRI) data at an optimal echo time. This technique is especially important for fMRI studies at high magnetic fields, where the optimal echo time is short and may not be achieved with a full Fourier acquisition scheme. In addition, it has been shown that partial Fourier EPI provides better anatomic resolvability than full Fourier EPI. However, the partial Fourier gradient-echo EPI may be degraded by artifacts that are not usually seen in other types of imaging. Those unique artifacts in partial Fourier gradient-echo EPI, to our knowledge, have not yet been systematically evaluated. Here we use the k-space energy spectrum analysis method to understand and characterize two types of partial Fourier EPI artifacts. Our studies show that Type 1 artifact, originating from k-space energy loss, cannot be corrected with pure postprocessing, and Type 2 artifact can be eliminated with an improved reconstruction method. We propose a novel algorithm, that combines images obtained from two or more reconstruction schemes guided by k-space energy spectrum analysis, to generate partial Fourier EPI with greatly reduced Type 2 artifact. Quality control procedures for avoiding Type 1 artifact in partial Fourier EPI are also discussed.
• Chen, N. (2007). Reproducibility of trial-based functional MRI on motor imagery. International Journal of Neuroscience.
• Chen, N. (2007). Temperature mapping considerations in the breast with line scan echo planar spectroscopic imaging. Magnetic Resonance in Medicine.
• McDannold, N., Barnes, A. S., Rybicki, F. J., Oshio, K., Chen, N., Hynynen, K., & Mulkern, R. V. (2007). Temperature mapping considerations in the breast with line scan echo planar spectroscopic imaging. Magnetic resonance in medicine, 58(6), 1117-23.
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  A line-scan echo planar spectroscopic imaging (LSEPSI) sequence was used to serially acquire spectra from 4,096 voxels every 6.4 s throughout the breasts of nine female subjects in vivo. Data from the serial acquisitions were analyzed to determine the potential of the technique to characterize temperature changes using either the water frequency alone or the water-methylene frequency difference. Fluctuations of the apparent temperature change under these conditions of no heating were smallest using the water-methylene frequency difference, most probably due to a substantial reduction of motion effects both within and without the imaged plane. The approach offers considerable advantages over other methods for temperature change monitoring in the breast with magnetic resonance but suffers from some limitations, including the unavailability of lipid and water resonances in some voxels as well as a surprisingly large distribution of water-methylene frequency differences, which may preclude absolute temperature measurement.
• Yoo, S., O'Leary, H. M., Lee, J., Chen, N., Panych, L. P., & Jolesz, F. A. (2007). Reproducibility of trial-based functional MRI on motor imagery. The International journal of neuroscience, 117(2), 215-27.
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  The investigation of the reproducibility in functional MRI (fMRI) is an important step in the quantification and analysis of paradigm-related brain activation. This article reports on reproducibility of cortical activation characterized by repeated fMRI runs (10 times) during the performance of a motor imagery and a passive auditory stimulation as a control task. Two parameters, the size of activation and BOLD signal contrast, were measured from regions-of-interest for 10 subjects across different threshold conditions. The variability of these parameters was normalized with respect to the mean obtained from 10 runs, and represented as the intrasession variability. It was found that the variability was significantly lower in the measurement of BOLD signal contrast as compared to the measurement of the size of activation. The variability of the activation volume measurement was greater in the motor imagery task than in the auditory tasks across all thresholds. This task-dependent difference was not apparent from the measurement of the BOLD signal contrast. The presence of threshold dependence in the variability measurement was also examined, but no such dependency was found. The results suggest that a measurement of BOLD signal itself is a more reliable indicator of paradigm-related brain activation during repeated fMRI scans.
• Brass, S. D., Chen, N., Mulkern, R. V., & Bakshi, R. (2006). Magnetic resonance imaging of iron deposition in neurological disorders. Topics in magnetic resonance imaging : TMRI, 17(1), 31-40.
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  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', 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.
• Chen, N. (2006). 76-space analysis of grey matter diffusivity: Methods and applications. Neuroimage.
• Chen, N. (2006). Application of k-space energy spectrum analysis to susceptibility field mapping and distortion correction in gradient-echo EPI. Neuroimage.
• Chen, N. (2006). Computation of transmitted and received B1 fields in magnetic resonance imaging. Ieee Transactions on Biomedical Engineering.
• Chen, N. (2006). Creutzfeldt-Jakob disease involvement of rolandic cortex: A quantitative apparent diffusion coefficient evaluation. American Journal of Neuroradiology.
• Chen, N. (2006). Increasing cortical activity in auditory areas through neurofeedback functional magnetic resonance imaging. Neuroreport.
• Chen, N., Oshio, K., & Panych, L. P. (2006). Application of k-space energy spectrum analysis to susceptibility field mapping and distortion correction in gradient-echo EPI. NeuroImage, 31(2), 609-22.
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  Echo-planar imaging (EPI) is widely used in functional MRI studies. It is well known that EPI quality is usually degraded by geometric distortions, when there exist susceptibility field inhomogeneities. EPI distortions may be corrected if the field maps are available. It is possible to estimate the susceptibility field gradients from the phase reconstruction of a single-TE EPI image, after a successful phase-unwrapping procedure. However, in regions affected by pronounced field gradients, the phase-unwrapping of a single-TE image may fail, and therefore the estimated field maps may be incorrect. It has been reported that the field inhomogeneity may be calculated more reliably from T2*-weighted images corresponding to multiple TEs. However, the multi-TE MRI field mapping increases the scan time. Furthermore, the measured field maps may be invalid if the subject's position changes during dynamic scans. To overcome the limitations in conventional field mapping approaches, a novel k-space energy spectrum analysis algorithm is developed, which quantifies the spatially dependent echo-shifting effect and the susceptibility field gradients directly from the k-space data of single-TE gradient-echo EPI. Using the k-space energy spectrum analysis, susceptibility field gradients can be reliably measured without phase-unwrapping, and EPI distortions can be corrected without extra field mapping scans or pulse sequence modification. The reported technique can be used to retrospectively improve the image quality of the previously acquired EPI and functional MRI data, provided that the complex-domain k-space data are still available.
• Liu, T., Young, G., Huang, L., Chen, N., & Wong, S. T. (2006). 76-space analysis of grey matter diffusivity: methods and applications. NeuroImage, 31(1), 51-65.
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  Diffusion-weighted imaging (DWI) and diffusion tensor imaging (DTI) allow in vivo investigation of molecular motion of tissue water at a microscopic level in cerebral gray matter (GM) and white matter (WM). DWI/DTI measure of water diffusion has been proven to be invaluable for the study of many neurodegenerative diseases (e.g., Alzheimer's disease and Creutzfeldt-Jakob disease) that predominantly involve GM. Thus, quantitative analysis of GM diffusivity is of scientific interest and is promised to have a clinical impact on the investigation of normal brain aging and neuropathology. In this paper, we propose an automated framework for analysis of GM diffusivity in 76 standard anatomic subdivisions of gray matter to facilitate studies of neurodegenerative and other gray matter neurological diseases. The computational framework includes three enabling technologies: (1) automatic parcellation of structural MRI GM into 76 precisely defined neuroanatomic subregions ("76-space"), (2) automated segmentation of GM, WM and CSF based on DTI data, and (3) automatic measurement of the average apparent diffusion coefficient (ADC) in each segmented GM subregion. We evaluate and validate this computational framework for 76-space GM diffusivity analysis using data from normal volunteers and from patients with Creutzfeldt-Jakob disease.
• Milles, J., Zhu, Y. M., Chen, N., Panych, L. P., Gimenez, G., & Guttmann, C. R. (2006). Computation of transmitted and received B1 fields in magnetic resonance imaging. IEEE transactions on bio-medical engineering, 53(5), 885-95.
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  Computation of B1 fields is a key issue for determination and correction of intensity nonuniformity in magnetic resonance images. This paper presents a new method for computing transmitted and received B1 fields. Our method combines a modified MRI acquisition protocol and an estimation technique based on the Levenberg-Marquardt algorithm and spatial filtering. It enables accurate estimation of transmitted and received B1 fields for both homogeneous and heterogeneous objects. The method is validated using numerical simulations and experimental data from phantom and human scans. The experimental results are in agreement with theoretical expectations.
• Yoo, S., O'Leary, H. M., Fairneny, T., Chen, N., Panych, L. P., Park, H., & Jolesz, F. A. (2006). Increasing cortical activity in auditory areas through neurofeedback functional magnetic resonance imaging. Neuroreport, 17(12), 1273-8.
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  We report a functional magnetic resonance imaging method to deliver task-specific brain activities as biofeedback signals to guide individuals to increase cortical activity in auditory areas during sound stimulation. A total of 11 study participants underwent multiple functional magnetic resonance imaging scan sessions, while the changes in the activated cortical volume within the primary and secondary auditory areas were fed back to them between scan sessions. On the basis of the feedback information, participants attempted to increase the number of significant voxels during the subsequent trial sessions by adjusting their level of attention to the auditory stimuli. Results showed that the group of individuals who received the feedback were able to increase the activation volume and blood oxygenation level-dependent signal to a greater degree than the control group.
• Chen, N. (2005). Functional MRI using regularized parallel imaging acquisition. Magnetic Resonance in Medicine.
• Chen, N. (2005). PROPELLER EPI: An MRI technique suitable for diffusion tensor Imaging at high field strength with reduced geometric distortions. Magnetic Resonance in Medicine.
• Lin, F., Huang, T., Chen, N., Wang, F., Stufflebeam, S. M., Belliveau, J. W., Wald, L. L., & Kwong, K. K. (2005). Functional MRI using regularized parallel imaging acquisition. Magnetic resonance in medicine, 54(2), 343-53.
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  Parallel MRI techniques reconstruct full-FOV images from undersampled k-space data by using the uncorrelated information from RF array coil elements. One disadvantage of parallel MRI is that the image signal-to-noise ratio (SNR) is degraded because of the reduced data samples and the spatially correlated nature of multiple RF receivers. Regularization has been proposed to mitigate the SNR loss originating due to the latter reason. Since it is necessary to utilize static prior to regularization, the dynamic contrast-to-noise ratio (CNR) in parallel MRI will be affected. In this paper we investigate the CNR of regularized sensitivity encoding (SENSE) acquisitions. We propose to implement regularized parallel MRI acquisitions in functional MRI (fMRI) experiments by incorporating the prior from combined segmented echo-planar imaging (EPI) acquisition into SENSE reconstructions. We investigated the impact of regularization on the CNR by performing parametric simulations at various BOLD contrasts, acceleration rates, and sizes of the active brain areas. As quantified by receiver operating characteristic (ROC) analysis, the simulations suggest that the detection power of SENSE fMRI can be improved by regularized reconstructions, compared to unregularized reconstructions. Human motor and visual fMRI data acquired at different field strengths and array coils also demonstrate that regularized SENSE improves the detection of functionally active brain regions.
• Liu, T., Young, G., Huang, L., Chen, N., & Wong, S. T. (2005). 76-space analysis of grey matter diffusivity: methods and applications. Medical image computing and computer-assisted intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention, 8(Pt 1), 148-55.
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  Diffusion Weighted Imaging (DWI) and Diffusion Tensor Imaging (DTI) are widely used in the study and diagnosis of neurological diseases involving the White Matter (WM). However, many neurological and neurodegenerative diseases (e.g., Alzheimer's disease and Creutzfeldt-Jakob disease) are generally considered to involve the Grey Matter (GM). Investigation of GM diffusivity of normal aging and pathological brains has both scientific significance and clinical applications. Most of previous research reports on quantification of GM diffusivity were based on the manually labeled Region of Interests (ROI) analysis of specific neuroanatomic regions. The well-known drawbacks of ROI analysis include inter-rater variations, irreproducible results, tediousness, and requirement of a priori definition of interested regions. In this paper, we present a new framework of automated 76-space analysis of GM diffusivity using DWI/DTI. The framework will be evaluated using clinical data, and applied for study of normal brain, Creutzfeldt-Jakob disease and Schizophrenia.
• Wang, F., Huang, T., Lin, F., Chuang, T., Chen, N., Chung, H., Chen, C., & Kwong, K. K. (2005). PROPELLER EPI: an MRI technique suitable for diffusion tensor imaging at high field strength with reduced geometric distortions. Magnetic resonance in medicine, 54(5), 1232-40.
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  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.
• Chen, N. (2004). Brain-computer interface using fMRI: spatial navigation by thoughts. Neuroreport.
• Chen, N. (2004). Fast spectroscopic imaging strategies for potential applications in fMRI. Magnetic Resonance Imaging.
• Chen, N. (2004). Spatially selective T2 and T2*measurement with line-scan echo-planar spectroscopic imaging. Journal of Magnetic Resonance.
• Chen, N., & Wyrwicz, A. M. (2004). Removal of EPI Nyquist ghost artifacts with two-dimensional phase correction. Magnetic resonance in medicine, 51(6), 1247-53.
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  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.
• Chen, N., Oshio, K., Panych, L. P., Rybicki, F. J., & Mulkern, R. V. (2004). Spatially selective T2 and T2 * measurement with line-scan echo-planar spectroscopic imaging. Journal of magnetic resonance (San Diego, Calif. : 1997), 171(1), 90-6.
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  Line-scan echo planar spectroscopic imaging (LSEPSI) is applied to quickly measure the T2 and T2* relaxation time constants in pre-selected 2D or 3D regions. Results from brain imaging studies at 3T suggest that the proposed method may prove valuable for both basic research (e.g., quantifying the changes of T2/T2* values in functional MRI with blood oxygenation level-dependent contrast) and clinical studies (e.g., measuring the T2' shortening due to iron deposition). The proposed spatially selective T2 and T2* mapping technique is especially well suited for studies, where T2/T2* quantification needs to be performed dynamically in a pre-selected 2D or 3D region.
• Mulkern, R. V., Chen, N., Oshio, K., Panych, L. P., Rybicki, F. J., & Gambarota, G. (2004). Fast spectroscopic imaging strategies for potential applications in fMRI. Magnetic resonance imaging, 22(10), 1395-405.
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  Technical aspects of two general fast spectroscopic imaging (SI) strategies, one based on gradient echo trains and the other on spin echo trains, are reviewed within the context of potential applications in the field of functional magnetic resonance imaging (fMRI). Fast spectroscopic imaging of water may prove useful for identifying mechanisms underlying the blood oxygenation level dependence (BOLD) of the water signal during brain activation studies. Reasonably rapid mapping of changes in proton signals from brain metabolites, like lactate, creatine or even neurotransmitter associated metabolites like GABA, is substantially more challenging but technically feasible particularly as higher field strengths become available. Fast spectroscopic methods directed towards the 31P signals from phosphocreatine (PCr) and adenosine tri-phosphates (ATP) are also technically feasible and may prove useful for studying cerebral energetics within fMRI contexts.
• Yoo, S., Fairneny, T., Chen, N., Choo, S., Panych, L. P., Park, H., Lee, S., & Jolesz, F. A. (2004). Brain-computer interface using fMRI: spatial navigation by thoughts. Neuroreport, 15(10), 1591-5.
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  A brain-computer interface (BCI) is a way of conveying an individual's thoughts to control computer or electromechanical hardware. Capitalizing on the ability to characterize brain activity in a reproducible manner, we explored the possibility of using real-time fMRI to interpret the spatial distribution of brain function as BCI commands. Using a high-field (3T) MRI scanner, brain activities associated with four distinct covert functional tasks were detected and subsequently translated into predetermined computer commands for moving four directional cursors. The proposed fMRI-BCI method allowed volunteer subjects to navigate through a simple 2D maze solely through their thought processes.
• Chen, N. (2003). Functional MRI with variable echo time acquisition. Neuroimage.
• Chen, N. (2003). Selection of voxel size and slice orientation for fMRI in the presence of susceptibility field gradients: application to imaging of the amygdala. Neuroimage.
• Chen, N. (2003). fMRI of the conscious rabbit during unilateral classical eyeblink conditioning reveals bilateral cerebellar activation. Journal of Neuroscience.
• Chen, N., Dickey, C. C., Yoo, S., Guttmann, C. R., & Panych, L. P. (2003). Selection of voxel size and slice orientation for fMRI in the presence of susceptibility field gradients: application to imaging of the amygdala. NeuroImage, 19(3), 817-25.
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  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.
• Chen, N., Egorova, S., Guttmann, C. R., & Panych, L. P. (2003). Functional MRI with variable echo time acquisition. NeuroImage, 20(4), 2062-70.
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  A new functional MRI protocol that integrates variable echo time (TE) acquisition and a block-design paradigm is proposed and evaluated with finger-tapping motor task. Simulations and experimental data show that the blood oxygenation level-dependent (BOLD) sensitivity achieved with this approach is comparable to that achieved using a conventional constant-TE protocol. The proposed variable-TE fMRI protocol provides valuable information that cannot be obtained with the constant-TE protocol. First, a field inhomogeneity map can be derived from the multi-TE data and used to correct EPI geometric distortions. Second, changes of T2* values due to the BOLD effect can be quantified. Third, for brain regions with pronounced susceptibility field gradients, the reduced BOLD sensitivity may be compensated for when the acquired multi-TE data are processed appropriately (e.g., with weighted summation). Fourth, large venules and veins may possibly be identified (depending on the vessel orientation and volume fraction) by evaluating the phase values of the multi-TE data. Finally, magnetic field drift over time can be measured from dynamic field maps available with this protocol.
• Miller, M. J., Chen, N., Li, L., Tom, B., Weiss, C., Disterhoft, J. F., & Wyrwicz, A. M. (2003). fMRI of the conscious rabbit during unilateral classical eyeblink conditioning reveals bilateral cerebellar activation. The Journal of neuroscience : the official journal of the Society for Neuroscience, 23(37), 11753-8.
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  The relative contributions of the ipsilateral and contralateral cerebellar cortex and deep nuclei to delay eyeblink conditioning have been debated and are difficult to survey entirely using typical electrophysiological and lesion techniques. To address these issues, we used single-event functional magnetic resonance imaging (fMRI) in the conscious rabbit to visualize the entire cerebellum simultaneously during eyeblink conditioning sessions. Examination of the blood oxygenation level-dependent (BOLD) response to a visual conditioning stimulus early in training revealed significant bilateral learning-related increases in the BOLD response in the anterior interpositus nucleus (IPA) and significant bilateral deactivation in hemispheric lobule VI (HVI) of the cerebellar cortex. Later in training, the BOLD response remained bilateral in the cortex and predominantly ipsilateral in the IPA. Conditioning stimulus-alone trials after conditioning revealed that both sides of HVI were affected similarly but that only the ipsilateral interpositus nucleus was activated. These results suggest that both sides of HVI normally influence the side of the IPA being conditioned and illustrate how fMRI can be used to examine multiple brain regions simultaneously in an awake, behaving animal to discover more rapidly the neural substrates of learning and memory.
• Chen, N. (2001). Optimized distortion correction technique for echo planar imaging. Magnetic Resonance in Medicine.
• Chen, N. K., & Wyrwicz, A. M. (2001). Optimized distortion correction technique for echo planar imaging. Magnetic resonance in medicine, 45(3), 525-8.
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  A new phase-shifted EPI pulse sequence is described that encodes EPI phase errors due to all off-resonance factors, including B(o) 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.
• Chen, N. (2000). fMRI of visual system activation in the conscious rabbit. Magnetic Resonance in Medicine.
• Wyrwicz, A. M., Chen, N., Li, L., Weiss, C., & Disterhoft, J. F. (2000). fMRI of visual system activation in the conscious rabbit. Magnetic resonance in medicine, 44(3), 474-8.
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  A conscious rabbit preparation developed for fMRI, and the results from visual stimulation studies at a 4.7T magnetic field are described. The rabbit is ideal for these experiments because of its natural tolerance for restraint. High spatial and temporal resolution magnetic resonance images, without movement artifacts, were obtained during long periods of restraint. Functional activation in primary visual cortex and lateral geniculate nucleus (LGN) were reproducibly observed in response to light stimulus. In comparison to existing anesthetized animal models, a functional response free of the anesthetic modulation can be recorded with the new approach. The conscious animal model can be applied to functional studies of sensory systems, learning and memory, and drug-induced cerebral activation.
• Chen, N. (1999). Correction for EPI distortions using multi-echo gradient-echo imaging. Magnetic Resonance in Medicine.
• Chen, N. K., & Wyrwicz, A. M. (1999). Correction for EPI distortions using multi-echo gradient-echo imaging. Magnetic resonance in medicine, 41(6), 1206-13.
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  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.
• Chen, N. k., & Wyrwicz, A. M. (1999). Removal of intravoxel dephasing artifact in gradient-echo images using a field-map based RF refocusing technique. Magnetic resonance in medicine, 42(4), 807-12.
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  A technique is proposed to compensate for the slice dephasing artifact and improve the signal-to-noise ratio (SNR) of gradient-echo images. This method is composed of two components: mapping of the internal gradient and design of the slice-selective radiofrequency (RF) pulse. The RF pulse is designed with its phase response as the negative of the product of a chosen echo time and the intravoxel internal gradient profile in a specified region of interest (ROI). The designed RF pulse can refocus the spin phases at a selected echo time and therefore effectively recover the signal loss due to both linear and nonlinear internal gradients. Principles, implementation, and application of the method are described in this note. Magn Reson Med 42:807-812, 1999.

Proceedings Publications

• Bilgin, A., Do, L., Martin, P. A., Lockhart, E., Bernstein, A. S., Ugonna, C., Dieckhaus, L., Comrie, C., Hutchinson, E. B., Chen, N., Alexander, G. E., Barnes, C. A., & Trouard, T. P. (2021). Accelerating Diffusion Tensor Imaging of the Rat Brain using Deep Learning. In Annual Meeting of the International Society for Magnetic Resonance in Medicine.
• Weinkauf, C. C., Trouard, T. P., Chou, Y., Chen, N., Guzman Perez-Carrillo, G., Ryan, T. L., Altbach, M. I., Johnson, K., Bruck, D., Ugonna, C., McKinnon, A., Bernstein, A. S., & Lindley, M. (2019, Spring). Functional and Microstructural Changes in the Brain After Carotid Endarterectomy. In International Society for Magnetic Resonance in Medicine.
• Bernstein, A., Chen, N., & Trouard, T. P. (2018, June). A Bootstrap Analysis of Diffusion MRI Parameters Derived from Simultaneous Multislice Diffusion MRI. In Joint International Society for Magnetic Resonance in Medicine & The European Society for Magnetic Resonance in Medicine and Biology (ISMRM-ESMRMB) Annual Meeting.
• Chen, N., Chen, N., Chang, H. C., Chang, H. C., Bilgin, A., Bilgin, A., Bernstein, A., Bernstein, A., Trouard, T. P., Trouard, T. P., Chen, N., Chang, H. C., Bilgin, A., Bernstein, A., & Trouard, T. P. (2018, June). A diffusion-matched principal component analysis (DM-PCA) based denoising procedure for high-resolution diffusion-weighted MRI. In Joint International Society for Magnetic Resonance in Medicine & The European Society for Magnetic Resonance in Medicine and Biology (ISMRM-ESMRMB) Annual Meeting.
• Lindley, M., Bernstein, A., Ugonna, C., Bruck, D., Johnson, K., Altbach, M. I., Ryan, L., Chen, N., Chou, Y., Guzman Perez-Carrillo, G., Trouard, T. P., & Weinkauf, C. C. (2018, June). Impact of Carotid Endarterectomy on Functional Connectivity. In Joint International Society for Magnetic Resonance in Medicine & The European Society for Magnetic Resonance in Medicine and Biology (ISMRM-ESMRMB) Annual Meeting, 5562.

Poster Presentations

• Fisher, J. M., Rubio, A., Dolby, A., Ugonna, C. P., Bedrick, E. J., & Chen, N. (2023, May). Threshold-Free Identification of Group-Difference Networks in Neural Connectivity Data. Statistical Methods in Imaging. Minneapolis, Minnesota: Statistics in Imaging Section of the American Statistical Association.