Gary H. Glover

YNIMG Journal 2022 Journal Article

Response to Scholkmann Commentary: “Effect of wearing a face mask on fMRI BOLD contrast”

• Christine S.W. Law
• Patricia S. Lan
• Gary H. Glover

YNIMG Journal 2021 Journal Article

Effect of wearing a face mask on fMRI BOLD contrast

• Christine S.W. Law
• Patricia S. Lan
• Gary H. Glover

International spread of the coronavirus SARS-CoV-2 has prompted many MRI scanning facilities to require scan subjects to wear a facial covering (“mask”) during scanning as a precaution against transmission of the virus. Because wearing a mask mixes expired air with the subject's inspired air stream, the concentration of inspired carbon dioxide [CO2] is elevated, resulting in mild hypercapnia. Changes in the inspired gas mixture have been demonstrated to alter R2*-weighted Blood Oxygen Dependent (BOLD) contrast. In this study, we investigate a potential for face masking to alter BOLD contrast during a sensory-motor task designed to activate visual, auditory, and sensorimotor cortices in 8 subjects. We utilize a nasal cannula to supply air to the subject wearing a surgical mask in on-off blocks of 90s to displace expired CO2, while the subject performs the sensory-motor task. While only a small fraction (2. 5%) of the sensory-motor task activation is related to nasal air modulation, a 30. 0% change in gray matter BOLD signal baseline is found due to air modulation. Repeating the scan with mask removed produces a small subject-specific bias in BOLD baseline signal from nasal air supply, which may be due to cognitive influence of airflow or cannula-induced hypoxia. Measurements with capnography demonstrate wearing a mask induces an average increase in ETCO2 of 7. 4%. Altogether, these results demonstrate that wearing a face mask during gradient-echo fMRI can alter BOLD baseline signal but minimally affects task activation.

YNIMG Journal 2021 Journal Article

Investigating mechanisms of fast BOLD responses: The effects of stimulus intensity and of spatial heterogeneity of hemodynamics

• Jingyuan E. Chen
• Gary H. Glover
• Nina E. Fultz
• Bruce R. Rosen
• Jonathan R. Polimeni
• Laura D. Lewis

Recent studies have demonstrated that fast fMRI can track neural activity well above the temporal limit predicted by the canonical hemodynamic response model. While these findings are promising, the biophysical mechanisms underlying these fast fMRI phenomena remain underexplored. In this study, we discuss two aspects of the hemodynamic response, complementary to several existing hypotheses, that can accommodate faster fMRI dynamics beyond those predicted by the canonical model. First, we demonstrate, using both visual and somatosensory paradigms, that the timing and shape of hemodynamic response functions (HRFs) vary across graded levels of stimulus intensity-with lower-intensity stimulation eliciting faster and narrower HRFs. Second, we show that as the spatial resolution of fMRI increases, voxel-wise HRFs begin to deviate from the canonical model, with a considerable portion of voxels exhibiting faster temporal dynamics than predicted by the canonical HRF. Collectively, both stimulus/task intensity and image resolution can affect the sensitivity of fMRI to fast brain activity, which may partly explain recent observations of fast fMRI signals. It is further noteworthy that, while the present investigations focus on fast neural responses, our findings suggest that a revised hemodynamic model may benefit the many fMRI studies using paradigms with wide ranges of contrast levels (e.g., resting or naturalistic conditions) or with modern, high-resolution MR acquisitions.

YNIMG Journal 2020 Journal Article

Imaging brain function with simultaneous BOLD and viscoelasticity contrast: fMRI/fMRE

• Patricia S. Lan
• Kevin J. Glaser
• Richard L. Ehman
• Gary H. Glover

Magnetic resonance elastography (MRE) is emerging as a new tool for studying viscoelastic changes in the brain resulting from functional processes. Here, we demonstrate a novel time series method to generate robust functional magnetic resonance elastography (fMRE) activation maps in response to a visual task with a flashing checkerboard stimulus. Using a single-shot spin-echo (SS-SE) pulse sequence, the underlying raw images inherently contain blood-oxygen-level dependent (BOLD) contrast, allowing simultaneous generation of functional magnetic resonance imaging (fMRI) activation maps from the magnitude and functional magnetic resonance elastography (fMRE) maps from the phase. This allows an accurate comparison of the spatially localized stiffness (fMRE) and BOLD (fMRI) changes within a single scan, eliminating confounds inherent in separately acquired scans. Results indicate that tissue stiffness within the visual cortex increases 6–11% with visual stimuli, whereas the BOLD signal change was 1–2%. Furthermore, the fMRE and fMRI activation maps have strong spatial overlap within the visual cortex, providing convincing evidence that fMRE is possible in the brain. However, the fMRE temporal SNR ( tSN R fMRE ) maps are heterogeneous across the brain. Using a dictionary matching approach to characterize the time series, the viscoelastic changes are consistent with a viscoelastic response function (VRF) time constant of 12. 1 ​s ± 3. 0 ​s for a first-order exponential decay, or a shape parameter of 8. 1 ​s ± 1. 4 ​s for a gamma-variate.

YNIMG Journal 2019 Journal Article

On the analysis of rapidly sampled fMRI data

• Jingyuan E. Chen
• Jonathan R. Polimeni
• Saskia Bollmann
• Gary H. Glover

Recent advances in parallel imaging and simultaneous multi-slice techniques have permitted whole-brain fMRI acquisitions at sub-second sampling intervals, without significantly sacrificing the spatial coverage and resolution. Apart from probing brain function at finer temporal scales, faster sampling rates may potentially lead to enhanced functional sensitivity, owing possibly to both cleaner neural representations (due to less aliased physiological noise) and additional statistical benefits (due to more degrees of freedom for a fixed scan duration). Accompanying these intriguing aspects of fast acquisitions, however, confusion has also arisen regarding (1) how to preprocess/analyze these fast fMRI data, and (2) what exactly is the extent of benefits with fast acquisitions, i. e. , how fast is fast enough for a specific research aim? The first question is motivated by the altered spectral distribution and noise characteristics at short sampling intervals, while the second question seeks to reconcile the complicated trade-offs between the functional contrast-to-noise ratio and the effective degrees of freedom. Although there have been recent efforts to empirically approach different aspects of these two questions, in this work we discuss, from a theoretical perspective accompanied by some illustrative, proof-of-concept experimental in vivo human fMRI data, a few considerations that are rarely mentioned, yet are important for both preprocessing and optimizing statistical inferences for studies that employ acquisitions with sub-second sampling intervals. Several summary recommendations include concerns regarding advisability of relying on low-pass filtering to de-noise physiological contributions, employment of statistical models with sufficient complexity to account for the substantially increased serial correlation, and cautions regarding using rapid sampling to enhance functional sensitivity given that different analysis models may associate with distinct trade-offs between contrast-to-noise ratios and the effective degrees of freedom. As an example, we demonstrate that as TR shortens, the intrinsic differences in how noise is accommodated in general linear models and Pearson correlation analyses (assuming Gaussian distributed stochastic signals and noise) can result in quite different outcomes, either gaining or losing statistical power.

YNICL Journal 2016 Journal Article

Multisite, multimodal neuroimaging of chronic urological pelvic pain: Methodology of the MAPP Research Network

• Jeffry R. Alger
• Benjamin M. Ellingson
• Cody Ashe-McNalley
• Davis C. Woodworth
• Jennifer S. Labus
• Melissa Farmer
• Lejian Huang
• A. Vania Apkarian

The Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network is an ongoing multi-center collaborative research group established to conduct integrated studies in participants with urologic chronic pelvic pain syndrome (UCPPS). The goal of these investigations is to provide new insights into the etiology, natural history, clinical, demographic and behavioral characteristics, search for new and evaluate candidate biomarkers, systematically test for contributions of infectious agents to symptoms, and conduct animal studies to understand underlying mechanisms for UCPPS. Study participants were enrolled in a one-year observational study and evaluated through a multisite, collaborative neuroimaging study to evaluate the association between UCPPS and brain structure and function. 3D T1-weighted structural images, resting-state fMRI, and high angular resolution diffusion MRI were acquired in five participating MAPP Network sites using 8 separate MRI hardware and software configurations. We describe the neuroimaging methods and procedures used to scan participants, the challenges encountered in obtaining data from multiple sites with different equipment/software, and our efforts to minimize site-to-site variation.

YNIMG Journal 2016 Journal Article

The Function Biomedical Informatics Research Network Data Repository

• David B. Keator
• Theo G.M. van Erp
• Jessica A. Turner
• Gary H. Glover
• Bryon A. Mueller
• Thomas T. Liu
• James T. Voyvodic
• Jerod Rasmussen

The Function Biomedical Informatics Research Network (FBIRN) developed methods and tools for conducting multi-scanner functional magnetic resonance imaging (fMRI) studies. Method and tool development were based on two major goals: 1) to assess the major sources of variation in fMRI studies conducted across scanners, including instrumentation, acquisition protocols, challenge tasks, and analysis methods, and 2) to provide a distributed network infrastructure and an associated federated database to host and query large, multi-site, fMRI and clinical data sets. In the process of achieving these goals the FBIRN test bed generated several multi-scanner brain imaging data sets to be shared with the wider scientific community via the BIRN Data Repository (BDR). The FBIRN Phase 1 data set consists of a traveling subject study of 5 healthy subjects, each scanned on 10 different 1. 5 to 4T scanners. The FBIRN Phase 2 and Phase 3 data sets consist of subjects with schizophrenia or schizoaffective disorder along with healthy comparison subjects scanned at multiple sites. In this paper, we provide concise descriptions of FBIRN's multi-scanner brain imaging data sets and details about the BIRN Data Repository instance of the Human Imaging Database (HID) used to publicly share the data.

YNIMG Journal 2015 Journal Article

BOLD fractional contribution to resting-state functional connectivity above 0.1 Hz

• Jingyuan E. Chen
• Gary H. Glover

Blood oxygen level dependent (BOLD) spontaneous signals from resting-state (RS) brains have typically been characterized by low-pass filtered timeseries at frequencies ≤0. 1Hz, and studies of these low-frequency fluctuations have contributed exceptional understanding of the baseline functions of our brain. Very recently, emerging evidence has demonstrated that spontaneous activities may persist in higher frequency bands (even up to 0. 8Hz), while presenting less variable network patterns across the scan duration. However, as an indirect measure of neuronal activity, BOLD signal results from an inherently slow hemodynamic process, which in fact might be too slow to accommodate the observed high-frequency functional connectivity (FC). To examine whether the observed high-frequency spontaneous FC originates from BOLD contrast, we collected RS data as a function of echo time (TE). Here we focus on two specific resting state networks — the default-mode network (DMN) and executive control network (ECN), and the major findings are fourfold: (1) we observed BOLD-like linear TE-dependence in the spontaneous activity at frequency bands up to 0. 5Hz (the maximum frequency that can be resolved with TR=1s), supporting neural relevance of the RSFC at a higher frequency range; (2) conventional models of hemodynamic response functions must be modified to support resting state BOLD contrast, especially at higher frequencies; (3) there are increased fractions of non-BOLD-like contributions to the RSFC above the conventional 0. 1Hz (non-BOLD/BOLD contrast at 0. 4–0. 5Hz is ~4 times that at <0. 1Hz); and (4) the spatial patterns of RSFC are frequency-dependent. Possible mechanisms underlying the present findings and technical concerns regarding RSFC above 0. 1Hz are discussed.

YNIMG Journal 2015 Journal Article

Introducing co-activation pattern metrics to quantify spontaneous brain network dynamics

• Jingyuan E. Chen
• Catie Chang
• Michael D. Greicius
• Gary H. Glover

Recently, fMRI researchers have begun to realize that the brain's intrinsic network patterns may undergo substantial changes during a single resting state (RS) scan. However, despite the growing interest in brain dynamics, metrics that can quantify the variability of network patterns are still quite limited. Here, we first introduce various quantification metrics based on the extension of co-activation pattern (CAP) analysis, a recently proposed point-process analysis that tracks state alternations at each individual time frame and relies on very few assumptions; then apply these proposed metrics to quantify changes of brain dynamics during a sustained 2-back working memory (WM) task compared to rest. We focus on the functional connectivity of two prominent RS networks, the default-mode network (DMN) and executive control network (ECN). We first demonstrate less variability of global Pearson correlations with respect to the two chosen networks using a sliding-window approach during WM task compared to rest; then we show that the macroscopic decrease in variations in correlations during a WM task is also well characterized by the combined effect of a reduced number of dominant CAPs, increased spatial consistency across CAPs, and increased fractional contributions of a few dominant CAPs. These CAP metrics may provide alternative and more straightforward quantitative means of characterizing brain network dynamics than time-windowed correlation analyses.

YNIMG Journal 2014 Journal Article

Control of nucleus accumbens activity with neurofeedback

• Stephanie M. Greer
• Andrew J. Trujillo
• Gary H. Glover
• Brian Knutson

The nucleus accumbens (NAcc) plays critical roles in healthy motivation and learning, as well as in psychiatric disorders (including schizophrenia and attention deficit hyperactivity disorder). Thus, techniques that confer control of NAcc activity might inspire new therapeutic interventions. By providing second-to-second temporal resolution of activity in small subcortical regions, functional magnetic resonance imaging (fMRI) can resolve online changes in NAcc activity, which can then be presented as “neurofeedback. ” In an fMRI-based neurofeedback experiment designed to elicit NAcc activity, we found that subjects could increase their own NAcc activity, and that display of neurofeedback significantly enhanced their ability to do so. Subjects were not as capable of decreasing their NAcc activity, however, and enhanced control did not persist after subsequent removal of neurofeedback. Further analyses suggested that individuals who recruited positive aroused affect were better able to increase NAcc activity in response to neurofeedback, and that NAcc neurofeedback also elicited functionally correlated activity in the medial prefrontal cortex. Together, these findings suggest that humans can modulate their own NAcc activity and that fMRI-based neurofeedback may augment their efforts. The observed association between positive arousal and effective NAcc control further supports an anticipatory affect account of NAcc function.

YNIMG Journal 2013 Journal Article

Association between heart rate variability and fluctuations in resting-state functional connectivity

• Catie Chang
• Coraline D. Metzger
• Gary H. Glover
• Jeff H. Duyn
• Hans-Jochen Heinze
• Martin Walter

Functional connectivity has been observed to fluctuate across the course of a resting state scan, though the origins and functional relevance of this phenomenon remain to be shown. The present study explores the link between endogenous dynamics of functional connectivity and autonomic state in an eyes-closed resting condition. Using a sliding window analysis on resting state fMRI data from 35 young, healthy male subjects, we examined how heart rate variability (HRV) covaries with temporal changes in whole-brain functional connectivity with seed regions previously described to mediate effects of vigilance and arousal (amygdala and dorsal anterior cingulate cortex; dACC). We identified a set of regions, including brainstem, thalamus, putamen, and dorsolateral prefrontal cortex, that became more strongly coupled with the dACC and amygdala seeds during states of elevated HRV. Effects differed between high and low frequency components of HRV, suggesting specific contributions of parasympathetic and sympathetic tone on individual connections. Furthermore, dynamics of functional connectivity could be separated from those primarily related to BOLD signal fluctuations. The present results contribute novel information about the neural basis of transient changes of autonomic nervous system states, and suggest physiological and psychological components of the recently observed non-stationarity in resting state functional connectivity.

YNIMG Journal 2013 Journal Article

Dynamic functional connectivity: Promise, issues, and interpretations

• R. Matthew Hutchison
• Thilo Womelsdorf
• Elena A. Allen
• Peter A. Bandettini
• Vince D. Calhoun
• Maurizio Corbetta
• Stefania Della Penna
• Jeff H. Duyn

The brain must dynamically integrate, coordinate, and respond to internal and external stimuli across multiple time scales. Non-invasive measurements of brain activity with fMRI have greatly advanced our understanding of the large-scale functional organization supporting these fundamental features of brain function. Conclusions from previous resting-state fMRI investigations were based upon static descriptions of functional connectivity (FC), and only recently studies have begun to capitalize on the wealth of information contained within the temporal features of spontaneous BOLD FC. Emerging evidence suggests that dynamic FC metrics may index changes in macroscopic neural activity patterns underlying critical aspects of cognition and behavior, though limitations with regard to analysis and interpretation remain. Here, we review recent findings, methodological considerations, neural and behavioral correlates, and future directions in the emerging field of dynamic FC investigations.

YNIMG Journal 2012 Journal Article

Maternal history of reading difficulty is associated with reduced language-related gray matter in beginning readers

• Jessica M. Black
• Hiroko Tanaka
• Leanne Stanley
• Masanori Nagamine
• Nahal Zakerani
• Alexandra Thurston
• Shelli Kesler
• Charles Hulme

Family history and poor preliteracy skills (referred to here as familial and behavioral risk, respectively) are critical predictors of developmental dyslexia. This study systematically investigated the independent contribution of familial and behavioral risks on brain structures, which had not been explored in past studies. We also examined the differential effects of maternal versus paternal history on brain morphometry, and familial risk dimensionally versus categorically, which were also novel aspects of the study. We assessed 51 children (5 to 6years of age) with varying degrees of familial and behavioral risks for developmental dyslexia and examined associations with brain morphometry. We found that greater maternal history of reading disability was associated with smaller bilateral prefrontal and parieto-temporal gray, but not white matter volumes. Regressing out behavioral risk, socioeconomic status, and maternal education and other confounds did not change the results. No such relationship was observed for paternal reading history and behavioral risk. Results of cortical surface area and thickness further showed that there was a significant negative relationship between cortical surface area (but not thickness) and greater severity of maternal history, in particular within the left inferior parietal lobule, suggesting prenatal influence of maternal history on children's brain morphometry. The results suggested greater maternal, possibly prenatal, influence on language-related brain structures. These results help to guide future neuroimaging research focusing on environmental and genetic influences and provide new information that may help predict which child will develop dyslexia in the future.

YNIMG Journal 2012 Journal Article

Spiral imaging in fMRI

• Gary H. Glover

T2*-weighted Blood Oxygen Level Dependent (BOLD) functional magnetic resonance imaging (fMRI) requires efficient acquisition methods in order to fully sample the brain in a several second time period. The most widely used approach is Echo Planar Imaging (EPI), which utilizes a Cartesian trajectory to cover k-space. This trajectory is subject to ghosts from off-resonance and gradient imperfections and is intrinsically sensitive to cardiac-induced pulsatile motion from substantial first- and higher order moments of the gradient waveform near the k-space origin. In addition, only the readout direction gradient contributes significant energy to the trajectory. By contrast, the spiral method samples k-space with an Archimedean or similar trajectory that begins at the k-space center and spirals to the edge (spiral-out), or its reverse, ending at the origin (spiral-in). Spiral methods have reduced sensitivity to motion, shorter readout times, improved signal recovery in most frontal and parietal brain regions, and exhibit blurring artifacts instead of ghosts or geometric distortion. Methods combining spiral-in and spiral-out trajectories have further advantages in terms of diminished susceptibility-induced signal dropout and increased BOLD signal. In measurements of temporal signal to noise ratio measured in 8 subjects, spiral-in/out exhibited significant increases over EPI in voxel volumes recovered in frontal and whole brain regions (18% and 10%, respectively).

YNIMG Journal 2011 Journal Article

A quantitative comparison of NIRS and fMRI across multiple cognitive tasks

• Xu Cui
• Signe Bray
• Daniel M. Bryant
• Gary H. Glover
• Allan L. Reiss

Near infrared spectroscopy (NIRS) is an increasingly popular technology for studying brain function. NIRS presents several advantages relative to functional magnetic resonance imaging (fMRI), such as measurement of concentration changes in both oxygenated and deoxygenated hemoglobin, finer temporal resolution, and ease of administration, as well as disadvantages, most prominently inferior spatial resolution and decreased signal-to-noise ratio (SNR). While fMRI has become the gold standard for in vivo imaging of the human brain, in practice NIRS is a more convenient and less expensive technology than fMRI. It is therefore of interest to many researchers how NIRS compares to fMRI in studies of brain function. In the present study we scanned participants with simultaneous NIRS and fMRI on a battery of cognitive tasks, placing NIRS probes over both frontal and parietal brain regions. We performed detailed comparisons of the signals in both temporal and spatial domains. We found that NIRS signals have significantly weaker SNR, but are nonetheless often highly correlated with fMRI measurements. Both SNR and the distance between the scalp and the brain contributed to variability in the NIRS/fMRI correlations. In the spatial domain, we found that a photon path forming an ellipse between the NIRS emitter and detector correlated most strongly with the BOLD response. Taken together these findings suggest that, while NIRS can be an appropriate substitute for fMRI for studying brain activity related to cognitive tasks, care should be taken when designing studies with NIRS to ensure that: 1) the spatial resolution is adequate for answering the question of interest and 2) the design accounts for weaker SNR, especially in brain regions more distal from the scalp.

YNIMG Journal 2011 Journal Article

Resting-state fMRI can reliably map neural networks in children

• Moriah E. Thomason
• Emily L. Dennis
• Anand A. Joshi
• Shantanu H. Joshi
• Ivo D. Dinov
• Catie Chang
• Melissa L. Henry
• Rebecca F. Johnson

Resting-state MRI (rs-fMRI) is a powerful procedure for studying whole-brain neural connectivity. In this study we provide the first empirical evidence of the longitudinal reliability of rs-fMRI in children. We compared rest–retest measurements across spatial, temporal and frequency domains for each of six cognitive and sensorimotor intrinsic connectivity networks (ICNs) both within and between scan sessions. Using Kendall'sW, concordance of spatial maps ranged from. 60 to. 86 across networks, for various derived measures. The Pearson correlation coefficient for temporal coherence between networks across all Time 1–Time 2 (T1/T2) z-converted measures was. 66 (p <. 001). There were no differences between T1/T2 measurements in low-frequency power of the ICNs. For the visual network, within-session T1 correlated with the T2 low-frequency power, across participants. These measures from resting-state data in children were consistent across multiple domains (spatial, temporal, and frequency). Resting-state connectivity is therefore a reliable method for assessing large-scale brain networks in children.

YNIMG Journal 2010 Journal Article

COMT genotype affects prefrontal white matter pathways in children and adolescents

• Moriah E. Thomason
• Robert F. Dougherty
• Natalie L. Colich
• Lee M. Perry
• Elena I. Rykhlevskaia
• Hugo M. Louro
• Joachim F. Hallmayer
• Christian E. Waugh

Diffusion tensor imaging is widely used to evaluate the development of white matter. Information about how alterations in major neurotransmitter systems, such as the dopamine (DA) system, influence this development in healthy children, however, is lacking. Catechol-O-metyltransferase (COMT) is the major enzyme responsible for DA degradation in prefrontal brain structures, for which there is a corresponding genetic polymorphism (val158met) that confers either a more or less efficient version of this enzyme. The result of this common genetic variation is that children may have more or less available synaptic DA in prefrontal brain regions. In the present study we examined the relation between diffusion properties of frontal white matter structures and the COMT val158met polymorphism in 40 children ages 9–15. We found that the val allele was associated with significantly elevated fractional anisotropy values and reduced axial and radial diffusivities. These results indicate that the development of white matter in healthy children is related to COMT genotype and that alterations in white matter may be related to the differential availability of prefrontal DA. This investigation paves the way for further studies of how common functional variants in the genome might influence the development of brain white matter.

YNIMG Journal 2010 Journal Article

Time–frequency dynamics of resting-state brain connectivity measured with fMRI

• Catie Chang
• Gary H. Glover

Most studies of resting-state functional connectivity using fMRI employ methods that assume temporal stationarity, such as correlation and data-driven decompositions computed across the duration of the scan. However, evidence from both task-based fMRI studies and animal electrophysiology suggests that functional connectivity may exhibit dynamic changes within time scales of seconds to minutes. In the present study, we investigated the dynamic behavior of resting-state connectivity across the course of a single scan, performing a time–frequency coherence analysis based on the wavelet transform. We focused on the connectivity of the posterior cingulate cortex (PCC), a primary node of the default-mode network, examining its relationship with both the “anticorrelated” (“task-positive”) network as well as other nodes of the default-mode network. It was observed that coherence and phase between the PCC and the anticorrelated network was variable in time and frequency, and statistical testing based on Monte Carlo simulations revealed the presence of significant scale-dependent temporal variability. In addition, a sliding-window correlation procedure identified other regions across the brain that exhibited variable connectivity with the PCC across the scan, which included areas previously implicated in attention and salience processing. Although it is unclear whether the observed coherence and phase variability can be attributed to residual noise or modulation of cognitive state, the present results illustrate that resting-state functional connectivity is not static, and it may therefore prove valuable to consider measures of variability, in addition to average quantities, when characterizing resting-state networks.

YNIMG Journal 2009 Journal Article

COMT genotype and resting brain perfusion in children

• Moriah E. Thomason
• Christian E. Waugh
• Gary H. Glover
• Ian H. Gotlib

Levels of extra-synaptic dopamine in the brain vary as a function of polymorphisms at the val158met locus of the catechol-O-methyltransferase (COMT) gene. In vivo studies of this polymorphism in the human brain have typically measured patterns of neural activation during dopamine-mediated tasks in adults. This study is the first to investigate the effects of COMT on brain physiology during rest and in children. We used flow-sensitive arterial spin-labeling (ASL) magnetic resonance imaging to examine brain blood flow (CBF) in 42 children. Compared with val-allele carriers, met-allele homozygotes exhibited greater CBF in mesolimbic, mesocortical, and nigrostriatal dopamine (DA) pathways. Higher CBF in DA-rich brain structures reflects COMT-related baseline differences that (1) underlie the selective behavioral advantages associated with each genotype; (2) affect interpretations of previously reported genotype differences in BOLD signal changes; and (3) serve as a foundation for future studies on the effects of COMT on brain development.

YNIMG Journal 2009 Journal Article

Effects of model-based physiological noise correction on default mode network anti-correlations and correlations

• Catie Chang
• Gary H. Glover

Previous studies have reported that the spontaneous, resting-state time course of the default-mode network is negatively correlated with that of the “task-positive network”, a collection of regions commonly recruited in demanding cognitive tasks. However, all studies of negative correlations between the default-mode and task-positive networks have employed some form of normalization or regression of the whole-brain average signal (“global signal”); these processing steps alter the time series of voxels in an uninterpretable manner as well as introduce spurious negative correlations. Thus, the extent of negative correlations with the default mode network without global signal removal has not been well characterized, and it is has recently been hypothesized that the apparent negative correlations in many of the task-positive regions could be artifactually induced by global signal pre-processing. The present study aimed to examine negative and positive correlations with the default-mode network when model-based corrections for respiratory and cardiac noise are applied in lieu of global signal removal. Physiological noise correction consisted of (1) removal of time-locked cardiac and respiratory artifacts using RETROICOR (Glover, G. H. , Li, T. Q. , Ress, D. , 2000. Image-based method for retrospective correction of physiological motion effects in fMRI: RETROICOR. Magn. Reson. Med. 44, 162–167), and (2) removal of low-frequency respiratory and heart rate variations by convolving these waveforms with pre-determined transfer functions (Birn et al. , 2008; Chang et al. , 2009) and projecting the resulting two signals out of the data. It is demonstrated that negative correlations between the default-mode network and regions of the task-positive network are present in the majority of individual subjects both with and without physiological noise correction. Physiological noise correction increased the spatial extent and magnitude of negative correlations, yielding negative correlations within task-positive regions at the group-level (p <0. 05, uncorrected; no regions at the group level were significant at FDR=0. 05). Furthermore, physiological noise correction caused region-specific decreases in positive correlations within the default-mode network, reducing apparent false positives. It was observed that the low-frequency respiratory volume and cardiac rate regressors used within the physiological noise correction algorithm displayed significant (but not total) shared variance with the global signal, and constitute a model-based alternative to correcting for non-neural global noise.

YNIMG Journal 2009 Journal Article

Influence of heart rate on the BOLD signal: The cardiac response function

• Catie Chang
• John P. Cunningham
• Gary H. Glover

It has previously been shown that low-frequency fluctuations in both respiratory volume and cardiac rate can induce changes in the blood-oxygen level dependent (BOLD) signal. Such physiological noise can obscure the detection of neural activation using fMRI, and it is therefore important to model and remove the effects of this noise. While a hemodynamic response function relating respiratory variation (RV) and the BOLD signal has been described [Birn, R. M. , Smith, M. A. , Jones, T. B. , Bandettini, P. A. , 2008b. The respiration response function: The temporal dynamics of fMRI signal fluctuations related to changes in respiration. Neuroimage 40, 644–654. ], no such mapping for heart rate (HR) has been proposed. In the current study, the effects of RV and HR are simultaneously deconvolved from resting state fMRI. It is demonstrated that a convolution model including RV and HR can explain significantly more variance in gray matter BOLD signal than a model that includes RV alone, and an average HR response function is proposed that well characterizes our subject population. It is observed that the voxel-wise morphology of the deconvolved RV responses is preserved when HR is included in the model, and that its form is adequately modeled by Birn et al. 's previously-described respiration response function. Furthermore, it is shown that modeling out RV and HR can significantly alter functional connectivity maps of the default-mode network.

YNIMG Journal 2009 Journal Article

Relationship between respiration, end-tidal CO2, and BOLD signals in resting-state fMRI

• Catie Chang
• Gary H. Glover

A significant component of BOLD fMRI physiological noise is caused by variations in the depth and rate of respiration. It has previously been demonstrated that a breath-to-breath metric of respiratory variation (respiratory volume per time; RVT), computed from pneumatic belt measurements of chest expansion, has a strong linear relationship with resting-state BOLD signals across the brain. RVT is believed to capture breathing-induced changes in arterial CO2, which is a cerebral vasodilator; indeed, separate studies have found that spontaneous fluctuations in end-tidal CO2 (PETCO2) are correlated with BOLD signal time series. The present study quantifies the degree to which RVT and PETCO2 measurements relate to one another and explain common aspects of the resting-state BOLD signal. It is found that RVT (particularly when convolved with a particular impulse response, the “respiration response function”) is highly correlated with PETCO2, and that both explain remarkably similar spatial and temporal BOLD signal variance across the brain. In addition, end-tidal O2 is shown to be largely redundant with PETCO2. Finally, the latency at which PETCO2 and respiration belt measures are correlated with the time series of individual voxels is found to vary across the brain and may reveal properties of intrinsic vascular response delays.

YNIMG Journal 2008 Journal Article

Controlled inspiration depth reduces variance in breath-holding-induced BOLD signal

• Moriah E. Thomason
• Gary H. Glover

Recent studies have shown that blood oxygen level dependent (BOLD) response amplitude during short periods of breath holding (BH) measured by functional magnetic resonance imaging (fMRI) can be an effective metric for intersubject calibration procedures. However, inconsistency in the depth of inspiration during the BH scan may account for a portion of BOLD variation observed in such scans, and it is likely to reduce the effectiveness of the calibration measurement. While modulation of BOLD signal has been correlated with end-tidal CO2 and other measures of breathing, fluctuations in performance of BH have not been studied in the context of their impact on BOLD signal. Here, we studied the degree to which inspiration depth corresponds to BOLD signal change and tested the effectiveness of a method designed to control inspiration level through visual cues during the BH task paradigm. We observed reliable differences in BOLD signal amplitude corresponding to the depth of inspiration. It was determined that variance in BOLD signal response to BH could be significantly reduced when subjects were given visual feedback during task inspiration periods. The implications of these findings for routine BH studies of BOLD-derived neurovascular response are discussed.

YNIMG Journal 2008 Journal Article

Default-mode function and task-induced deactivation have overlapping brain substrates in children

• Moriah E. Thomason
• Catherine E. Chang
• Gary H. Glover
• John D.E. Gabrieli
• Michael D. Greicius
• Ian H. Gotlib

The regions that comprise the functionally connected resting-state default-mode network (DMN) in adults appear to be the same as those that are characterized by task-induced decreases in blood-oxygen-level-dependent (BOLD) signal. Independent component analysis can be used to produce a picture of the DMN as an individual rests quietly in the scanner. Contrasts across conditions in which cognitive load is parametrically modulated can delineate neural structures that have decreases in activation in response to high-demand task conditions. Examination of the degree to which these networks subsume dissociable brain substrates, and of the degree to which they overlap, provides insight concerning their purpose, function, and the nature of their associations. Few studies have examined the DMN in children, and none have tested whether the neural regions that comprise the DMN during a resting condition are the same regions that show reduced activity when children engage in cognitive tasks. In this paper we describe regions that show both task-related decreases and spontaneous intrinsic activity at rest in children, and we examine the co-localization of these networks. We describe ways in which the DMN in 7–12-year-old children is both similar to and different from the DMN in adults; moreover, we document that task-induced deactivations and default-mode resting-state activity in children share common neural substrates. It appears, therefore, that even before adolescence a core aspect of task-induced deactivation involves reallocating processing resources that are active at rest. We describe how future studies assessing the development of these systems would benefit from examining these constructs as part of one continuous system.

YNIMG Journal 2008 Journal Article

Mapping and correction of vascular hemodynamic latency in the BOLD signal

• Catie Chang
• Moriah E. Thomason
• Gary H. Glover

Correlation and causality metrics can be applied to blood-oxygen level-dependent (BOLD) signal time series in order to infer neural synchrony and directions of information flow from fMRI data. However, the BOLD signal reflects both the underlying neural activity and the vascular response, the latter of which is governed by local vasomotor physiology. The presence of potential vascular latency differences thus poses a confound in the detection of neural synchrony as well as inferences about the causality of neural processes. In the present study, we investigate the use of a breath holding (BH) task for characterizing and correcting for voxel-wise neurovascular latency differences across the whole brain. We demonstrate that BH yields reliable measurements of relative timing differences between voxels, and further show that a BH-derived latency correction can impact both functional connectivity maps of the resting-state default-mode network and activation maps of an event-related working memory (WM) task.

YNIMG Journal 2008 Journal Article

Resilience after 9/11: Multimodal neuroimaging evidence for stress-related change in the healthy adult brain

• Barbara L. Ganzel
• Pilyoung Kim
• Gary H. Glover
• Elise Temple

Exposure to psychological trauma is common and predicts long-term physical and mental health problems, even in those who initially appear resilient. Here, we used multimodal neuroimaging in healthy adults who were at different distances from the World Trade Center on 9/11/01 to examine the neural mechanisms that may underlie this association. More than 3 years after 9/11/01, adults with closer proximity to the disaster had lower gray matter volume in amygdala, hippocampus, insula, anterior cingulate, and medial prefrontal cortex, with control for age, gender, and total gray matter volume. Further analysis showed a nonlinear (first-order quadratic) association between total number of traumas in lifetime and amygdala gray matter volume and function in the whole group. Post hoc analysis of subgroups with higher versus lower levels of lifetime trauma exposure revealed systematic associations between amygdala gray matter volume, amygdala functional reactivity, and anxiety that suggest a nonlinear trajectory in the neural response to accumulated trauma in healthy adults

YNIMG Journal 2007 Journal Article

Laminar profiles of functional activity in the human brain

• David Ress
• Gary H. Glover
• Junjie Liu
• Brian Wandell

Functional magnetic resonance imaging (fMRI) data were obtained in human visual cortex using sub-millimeter voxels at a field strength of 3 T. Reliable functional signals were largely confined to the gray matter and these responses measure the retinotopic organization of visual cortex. Functional signals were further characterized with respect to their laminar position within the cortical gray matter. The laminar response profiles during our visuospatial attention task, normalized for cortical thickness, had a stereotypical shape, with a peak in the superficial gray matter and declining in the deeper layers. The thickness of the sheet producing functional signals was in excellent agreement with the estimated structural thickness of the gray matter throughout early visual cortex (error<0. 5 mm). Thickness measurements were highly repeatable from session-to-session (error<0. 4 mm). Hence, it is feasible and useful to use high-resolution fMRI to measure laminar activity profiles. The ability to distinguish signals arising in different lamina has significant potential scientific and clinical applications.

YNIMG Journal 2006 Journal Article

An adaptive filter for suppression of cardiac and respiratory noise in MRI time series data

• Roel H.R. Deckers
• Peter van Gelderen
• Mario Ries
• Olivier Barret
• Jeff H. Duyn
• Vasiliki N. Ikonomidou
• Masaki Fukunaga
• Gary H. Glover

The quality of MRI time series data, which allows the study of dynamic processes, is often affected by confounding sources of signal fluctuation, including the cardiac and respiratory cycle. An adaptive filter is described, reducing these signal fluctuations as long as they are repetitive and their timing is known. The filter, applied in image domain, does not require temporal oversampling of the artifact-related fluctuations. Performance is demonstrated for suppression of cardiac and respiratory artifacts in 10-minute brain scans on 6 normal volunteers. Experimental parameters resemble a typical fMRI experiment (17 slices; 1700 ms TR). A second dataset was acquired at a rate well above the Nyquist frequency for both cardiac and respiratory cycle (single slice; 100 ms TR), allowing identification of artifacts specific to the cardiac and respiratory cycles, aiding assessment of filtering performance. Results show significant reduction in temporal standard deviation (SDt) in all subjects. For all 6 datasets with 1700 ms TR combined, the filtering method resulted in an average reduction in SDt of 9. 2% in 2046 voxels substantially affected by respiratory artifacts, and 12. 5% for the 864 voxels containing substantial cardiac artifacts. The maximal SDt reduction achieved was 52. 7% for respiratory and 55. 3% for cardiac filtering. Performance was found to be at least equivalent to the previously published RETROICOR method. Furthermore, the interaction between the filter and fMRI activity detection was investigated using Monte Carlo simulations, demonstrating that filtering algorithms introduce a systematic error in the detected BOLD-related signal change if applied sequentially. It is demonstrated that this can be overcome by combining physiological artifact filtering and detection of BOLD-related signal changes simultaneously. Visual fMRI data from 6 volunteers were analyzed with and without the filter proposed here. Inclusion of the cardio-respiratory regressors in the design matrix yielded a 4. 6% t-score increase and 4. 0% increase in the number of significantly activated voxels.

YNIMG Journal 2006 Journal Article

Reducing inter-scanner variability of activation in a multicenter fMRI study: Role of smoothness equalization

• Lee Friedman
• Gary H. Glover
• Diana Krenz
• Vince Magnotta

Scanner-to-scanner variability of activation in multicenter fMRI studies is often considered undesirable. The purpose of this investigation was to evaluate the effect of a new procedure, “smoothness equalization”, on reducing scanner differences in activation effect size as part of a multicenter fMRI project (FIRST BIRN). Five subjects were sent to 9 centers (10 scanners) and scanned on 2 consecutive days using a sensorimotor fMRI protocol. High-field (4 T and 3 T) and low-field (1. 5 T) scanners from three vendors (GE, Siemens, and Picker) were included. The activation effect size of the scanners for the detection of neural activation during a sensorimotor task was evaluated as the percent of temporal variance accounted for by our model (percent of variance accounted for or PVAF). Marked scanner effects were noted for both PVAF as well as the degree of smoothness of the raw and processed images. After smoothness equalization, there was a dramatic (low field) or consistent (high-field) reduction in scanner-to-scanner variation of activation. It was shown that the likely basis of the scanner differences in smoothness was differences in k-space filtering algorithms. This work highlights the need to account for differences in smoothness when comparing scanners on activation effect size in multicenter fMRI studies.

YNIMG Journal 2006 Journal Article

Reducing interscanner variability of activation in a multicenter fMRI study: Controlling for signal-to-fluctuation-noise-ratio (SFNR) differences

• Lee Friedman
• Gary H. Glover
• The FBIRN Consortium

Variation in scanner performance will lead to variation in activation patterns in multicenter fMRI studies. The purpose of this investigation was to evaluate the effect of statistically covarying for scanner differences in signal-to-fluctuation-noise-ratio (SFNR) on reducing scanner differences in activation effect size as part of a multicenter fMRI project (FIRST BIRN). For SFNR, “signal” is typically the mean intensity over time and “fluctuation noise” is the temporal standard deviation. Five subjects were sent to 9 centers (10 scanners) and scanned on two consecutive days using a sensorimotor fMRI protocol. High-field (4 T and 3 T) and low-field (1. 5 T) scanners from three vendors (GE, Siemens and Picker) were included. The effect size for the detection of neural activation during a sensorimotor task was evaluated as the percent of temporal variance accounted for by our model (percent of variance accounted for, or PVAF). Marked scanner effects were noted for both PVAF as well as SFNR. After covariate adjustment with one of several measures of SFNR, there were dramatic reductions in scanner-to-scanner variations in activation effect size. Variance components analyses revealed 75%–81% reductions in variance due to scanner with this method. Thus, controlling for scanner variation in SFNR may be an effective method to homogenize activation effect sizes in multicenter studies.

YNIMG Journal 2005 Journal Article

Breath holding reveals differences in fMRI BOLD signal in children and adults

• Moriah E. Thomason
• Brittany E. Burrows
• John D.E. Gabrieli
• Gary H. Glover

Application of fMRI to studies of cognitive development is of growing interest because of its sensitivity and non-invasive nature. However, interpretation of fMRI results in children is presently based on vascular dynamics that have been studied primarily in healthy adults. Comparison of the neurological basis of cognitive development is valid to the extent that the neurovascular responsiveness between children and adults is equal. The present study was designed to detect age-related vascular differences that may contribute to altered BOLD fMRI signal responsiveness. We examined BOLD signal changes in response to breath holding, a global, systemic state change in brain oxygenation. Children exhibited greater percent signal changes than adults in grey and white matter, and this was accompanied by an increase in noise. Consequently, the volume of activation exceeding statistical threshold was reduced in children. The reduced activation in children was well modeled by adding noise to adult data. These findings raise the possibility that developmental differences in fMRI findings between children and adults could, under some circumstances, reflect greater noise in the BOLD response in the brains of children than adults. BOLD responses varied across brain regions, but showed similar regional variation in children and adults.

YNIMG Journal 2005 Journal Article

The neural bases of amusement and sadness: A comparison of block contrast and subject-specific emotion intensity regression approaches

• Philippe R. Goldin
• Cendri A.C. Hutcherson
• Kevin N. Ochsner
• Gary H. Glover
• John D.E. Gabrieli
• James J. Gross

Neuroimaging studies have made substantial progress in elucidating the neural bases of emotion. However, few studies to date have directly addressed the subject-specific, time-varying nature of emotional responding. In the present study, we employed functional magnetic resonance imaging to examine the neural bases of two common emotions–amusement and sadness–using both (a) a stimulus-based block contrast approach and (b) a subject-specific regression analysis using continuous ratings of emotional intensity. Thirteen women viewed a set of nine 2-min amusing, sad, or neutral film clips two times. During the first viewing, participants watched the film stimuli. During the second viewing, they made continuous ratings of the intensity of their own amusement and sadness during the first film viewing. For sad films, both block contrast and subject-specific regression approaches resulted in activations in medial prefrontal cortex, inferior frontal gyrus, superior temporal gyrus, precuneus, lingual gyrus, amygdala, and thalamus. For amusing films, the subject-specific regression analysis demonstrated significant activations not detected by the block contrast in medial, inferior frontal gyrus, dorsolateral prefrontal cortex, posterior cingulate, temporal lobes, hippocampus, thalamus, and caudate. These results suggest a relationship between emotion-specific temporal dynamics and the sensitivity of different data analytic methods for identifying emotion-related neural responses. These findings shed light on the neural bases of amusement and sadness, and highlight the value of using emotional film stimuli and subject-specific continuous emotion ratings to characterize the dynamic, time-varying components of emotional responses.

YNIMG Journal 2003 Journal Article

Neural Correlates of Auditory Perception in Williams Syndrome: An fMRI Study

• Daniel J. Levitin
• Vinod Menon
• J.Eric Schmitt
• Stephan Eliez
• Christopher D. White
• Gary H. Glover
• Jay Kadis
• Julie R. Korenberg

Williams syndrome (WS), a neurogenetic developmental disorder, is characterized by a rare fractionation of higher cortical functioning: selective preservation of certain complex faculties (language, music, face processing, and sociability) in contrast to marked and severe deficits in nearly every other cognitive domain (reasoning, spatial ability, motor coordination, arithmetic, problem solving). WS people are also known to suffer from hyperacusis and to experience heightened emotional reactions to music and certain classes of noise. We used functional magnetic resonance imaging to examine the neural basis of auditory processing of music and noise in WS patients and age-matched controls and found strikingly different patterns of neural organization between the groups. Those regions supporting music and noise processing in normal subjects were found not to be consistently activated in the WS participants (e. g. , superior temporal and middle temporal gyri). Instead, the WS participants showed significantly reduced activation in the temporal lobes coupled with significantly greater activation in the right amygdala. In addition, WS participants (but not controls) showed a widely distributed network of activation in cortical and subcortical structures, including the brain stem, during music processing. Taken together with previous ERP and cytoarchitectonic studies, this first published report of WS using fMRI provides additional evidence of a different neurofunctional organization in WS people than normal people, which may help to explain their atypical reactions to sound. These results constitute an important first step in drawing out the links between genes, brain, cognition, and behavior in Williams syndrome.

YNIMG Journal 2002 Journal Article

A Developmental fMRI Study of the Stroop Color-Word Task

• Nancy E. Adleman
• Vinod Menon
• Christine M. Blasey
• Christopher D. White
• Ilana S. Warsofsky
• Gary H. Glover
• Allan L. Reiss

We used fMRI to investigate developmental changes in brain activation during a Stroop color-word interference task. A positive correlation was observed between age and Stroop-related activation (n = 30) in the left lateral prefrontal cortex, the left anterior cingulate, and the left parietal and parieto-occipital cortices. No regions showed a negative correlation between activation and age. We further investigated age-related differences by stratifying the sample into three age groups: children (ages 7–11), adolescents (ages 12–16), and young adults (ages 18–22). Young adult subjects (n = 11) displayed significant activation in the inferior and middle frontal gyri bilaterally, the left anterior cingulate, and bilateral inferior and superior parietal lobules. Between-group comparisons revealed that young adults had significantly greater activation than adolescent subjects (n = 11) in the left middle frontal gyrus and that young adults showed significantly greater activation than children (n = 8) in the anterior cingulate and left parietal and parieto-occipital regions, as well as in the left middle frontal gyrus. Compared to children, both adult and adolescent subjects exhibited significantly greater activation in the parietal cortex. Adult and adolescent groups, however, did not differ in activation for this region. Together, these data suggest that Stroop task-related functional development of the parietal lobe occurs by adolescence. In contrast, prefrontal cortex function contributing to the Stroop interference task continues to develop into adulthood. This neuromaturational process may depend on increased ability to recruit focal neural resources with age. Findings from this study, the first developmental fMRI investigation of the Stroop interference task, provide a template with which normal development and neurodevelopmental disorders of prefrontal cortex function can be assessed.

YNIMG Journal 2002 Journal Article

Changes of Cerebral Blood Flow, Oxygenation, and Oxidative Metabolism during Graded Motor Activation

• Andreas Kastrup
• Gunnar Krüger
• Tobias Neumann-Haefelin
• Gary H. Glover
• Michael E. Moseley

In the present studies fMRI and a hypercapnic calibration procedure were used to monitor simultaneous changes in cerebral blood flow (CBF), cerebral blood oxygenation, and cerebral metabolic rate of oxygen (CMRO2) during activation in the sensorimotor cortex. In the first set of experiments seven volunteers performed bilateral, self-paced finger tapping and in the second set of experiments six volunteers performed bilateral finger tapping with six different frequencies (0. 5–3 Hz). During the latter task relative CBF and BOLD signal intensity changes varied linearly as a function of stimulus frequency. In good agreement with recent PET and fMRI data increases in CMRO2 were smaller than the corresponding changes in CBF during self-paced finger tapping and at all levels of graded motor activation. At a single level of activation and during graded activation there was a positive linear relationship between CBF and CMRO2 with ratios of approximately 3: 1. Comparable proportionality constants have been found in the visual cortex and primary sensory cortex, indicating similarities between the relationship of CBF and CMRO2 in various cortical regions.

YNIMG Journal 2001 Journal Article

Reorganization of Frontal Systems Used by Alcoholics for Spatial Working Memory: An fMRI Study

• Adolf Pfefferbaum
• John E. Desmond
• Christopher Galloway
• Vinod Menon
• Gary H. Glover
• Edith V. Sullivan

Chronic alcoholism is associated with impairment in sustained attention and visual working memory. Thus, alcoholics have reduced ability, but not necessarily inability, to perform these executive tasks, assumed to be subserved by regions of prefrontal cortex. To identify neural substrates associated with this impairment, we used functional MRI (fMRI) to determine whether alcoholics invoke the same or different brain systems as controls when engaged in working memory tasks that the two groups were able to perform at equivalent levels. The fMRI spatial working memory paradigm instructed subjects to respond with a button press when a target position was either in the center of the field (match to center) or matched the spatial position of one presented two items previously (match 2-back) or to rest. Using whole-brain fMRI, alcoholics showed diminished activation frontal cortical systems compared to controls (bilateral dorsolateral prefrontal cortex) when responding 2-back vs rest. In the center vs rest contrast, the control group compared with the alcoholic group activated a large expanse of prefrontal cortex (including Brodmann areas 9, 10, and 45), whereas there was significantly greater activation by the alcoholic group relative to the control group localized more posteriorly and inferiorly in the frontal cortex (area 47). Examination of within group activation patterns revealed two different patterns of activation: the control group exhibited activation of the dorsal (“Where? ”) stream for visual spatial working memory processing, whereas the alcoholic group exhibited activation of the ventral (“What? ”) stream and declarative memory systems to accomplish the spatial working memory task. The differences in the pattern of brain activations exhibited by the alcoholic and control groups, despite equivalence in behavioral performance, is consistent with a functional reorganization of the brain systems invoked by alcoholic individuals or invocation of an inappropriate brain system when engaged in a visual spatial task requiring working memory.

YNIMG Journal 2000 Journal Article

Assessment of Hemodynamic Response during Focal Neural Activity in Human Using Bolus Tracking, Arterial Spin Labeling and BOLD Techniques

• Tie-Qiang Li
• Tobias Neumann Haefelin
• Bernard Chan
• Andreas Kastrup
• Tomas Jonsson
• Gary H. Glover
• Michael E. Moseley

In this study, the hemodynamic response and changes in oxidative metabolism during functional activation were measured using three functional magnetic resonance imaging (fMRI) techniques: the blood oxygenation level-dependent (BOLD) technique, flow-sensitive alternating inversion recovery (FAIR), and bolus tracking (BT) of an MR contrast agent. With these three techniques we independently determined changes in BOLD signal, relative cerebral blood flow (rCBF), and cerebral blood volume (rCBV) associated with brain activation in eight healthy volunteers. In the motor cortex, the BOLD signal increased by 1. 8 ± 0. 5%, rCBF by 36. 3 ± 8. 2% (FAIR), and 35. 1 ± 8. 6% (BT), and rCBV by 19. 4 ± 4. 1% (BT) in response to simultaneous bilateral finger tapping. In the visual cortex, BOLD signal increased by 2. 6 ± 0. 5%, rCBF by 38. 5% ± 7. 6 (FAIR), and 36. 9 ± 8. 8% (BT), and rCBV by 18. 8 ± 2. 8% (BT) during flickering checkerboard stimulation. Comparing the experimentally measured rCBV with the calculated rCBV using Grubb's power-law relation, we conclude that the use of power-law relationship results in systematic underestimate of rCBV.

YNIMG Journal 1999 Journal Article

Deconvolution of Impulse Response in Event-Related BOLD fMRI1

• Gary H. Glover

The temporal characteristics of the BOLD response in sensorimotor and auditory cortices were measured in subjects performing finger tapping while listening to metronome pacing tones. A repeated trial paradigm was used with stimulus durations of 167 ms to 16 s and intertrial times of 30 s. Both cortical systems were found to be nonlinear in that the response to a long stimulus could not be predicted by convolving the 1-s response with a rectangular function. In the short-time regime, the amplitude of the response varied only slowly with stimulus duration. It was found that this character was predicted with a modification to Buxton's balloon model. Wiener deconvolution was used to deblur the response to concatenated short episodes of finger tapping at different temporal separations and at rates from 1 to 4 Hz. While the measured response curves were distorted by overlap between the individual episodes, the deconvolved response at each rate was found to agree well with separate scans at each of the individual rates. Thus, although the impulse response cannot predict the response to fully overlapping stimuli, linear deconvolution is effective when the stimuli are separated by at least 4 s. The deconvolution filter must be measured for each subject using a short-stimulus paradigm. It is concluded that deconvolution may be effective in diminishing the hemodynamically imposed temporal blurring and may have potential applications in quantitating responses in eventrelated fMRI.

YNIMG Journal 1999 Journal Article

Functional Specialization for Semantic and Phonological Processing in the Left Inferior Prefrontal Cortex

• Russell A. Poldrack
• Anthony D. Wagner
• Matthew W. Prull
• John E. Desmond
• Gary H. Glover
• John D.E. Gabrieli

Neuroimaging and neuropsychological studies have implicated left inferior prefrontal cortex (LIPC) in both semantic and phonological processing. In this study, functional magnetic resonance imaging was used to examine whether separate LIPC regions participate in each of these types of processing. Performance of a semantic decision task resulted in extensive LIPC activation compared to a perceptual control task. Phonological processing of words and pseudowords in a syllable-counting task resulted in activation of the dorsal aspect of the left inferior frontal gyrus near the inferior frontal sulcus (BA 44/45) compared to a perceptual control task, with greater activation for nonwords compared to words. In a direct comparison of semantic and phonological tasks, semantic processing preferentially activated the ventral aspect of the left inferior frontal gyrus (BA 47/45). A review of the literature demonstrated a similar distinction between left prefrontal regions involved in semantic processing and phonological/lexical processing. The results suggest that a distinct region in the left inferior frontal cortex is involved in semantic processing, whereas other regions may subserve phonological processes engaged during both semantic and phonological tasks.

YNIMG Journal 1999 Journal Article

Load-Dependent Roles of Frontal Brain Regions in the Maintenance of Working Memory

• Bart Rypma
• Vivek Prabhakaran
• John E. Desmond
• Gary H. Glover
• John D.E. Gabrieli

Brain imaging studies have suggested a critical role for prefrontal cortex in working memory (WM) tasks that require both maintainenance and manipulation of information over time in delayed-response WM tasks. In the present study, functional magnetic resonance imaging (fMRI) was used to examine whether prefrontal areas are activated when only maintenance is required in a delayed-response WM task, without the overt requirement to manipulate the stored information. In two scans, six subjects performed WM tasks in which, on each trial, they (1) encoded 1, 3, or 6 to-be-remembered letters, (2) maintained these letters across a 5-second unfilled delay, and (3) determined whether a single probe letter was or was not part of the memory set. Activation of left caudal inferior frontal gyrus was observed, relative to the 1-letter task, when subjects were required to maintain 3 letters in WM. When subjects were required to maintain 6 letters in WM, additional prefrontal areas, most notably middle and superior frontal gyri, were activated bilaterally. Thus, increasing the amount of to-be-maintained information, without any overt manipulation requirement, resulted in the recruitment of wide-spread frontal-lobe regions. Inferior frontal gyrus activation was left-hemisphere dominant in both the 3- and 6-letter conditions, suggesting that such activation reflected material-specific verbal processes. Activation in middle and superior frontal gyri appeared only in the 6-letter condition and was right-hemisphere dominant, suggesting that such activation reflected material-independent executive processes.

YNIMG Journal 1999 Journal Article

Regional Variability of Cerebral Blood Oxygenation Response to Hypercapnia

• Andreas Kastrup
• Gunnar Krüger
• Gary H. Glover
• Tobias Neumann-Haefelin
• Michael E. Moseley

In functional magnetic resonance imaging studies changes in blood oxygenation level-dependent (BOLD) signal intensities during task activation are related to multiple physiological parameters such as cerebral blood flow, volume, and oxidative metabolism, as well as to the regional microvascular anatomy. Consequently, the magnitude of activation-induced BOLD signal changes may vary regionally and between subjects. The aim of this study was to use a uniform global stimulus such as hypercapnia to quantitatively investigate the regional BOLD response in the human brain. In 10 healthy volunteers, T2*-weighted gradient echo images were acquired for a total dynamic scanning time of 9 min during alternating periods of breath holding for 30 s after expiration and self-paced normal breathing for 60 s. Hypercapnia-induced BOLD signal changes in the sensorimotor cortex, frontal cortex, basal ganglia, visual cortex, and cerebellum were significantly different (P < 0. 001) and varied from 1. 8 to 5. 1%. The highest BOLD signal changes were found in the cerebellum and visual cortex, whereas the lowest BOLD signal increase was observed in the frontal cortex. These results demonstrate a regional dependence of the BOLD signal changes during breath hold-induced hypercapnia, indirectly supporting the notion of regional different sensitivities of BOLD responses to task activation.

YNIMG Journal 1998 Journal Article

Dissociation of Frontal and Cerebellar Activity in a Cognitive Task: Evidence for a Distinction between Selection and Search

• John E. Desmond
• John D.E. Gabrieli
• Gary H. Glover

Human brain imaging studies have found that increases in functional activation in left-frontal cortex during cognitive tasks are often accompanied by similar increases in right-cerebellar regions. The present study used functional magnetic resonance imaging (fMRI) to investigate the distinctive contributions of these regions using a word stem completion task. Stems with many possible completions (MANY condition) were alternately presented with stems that had few possible completions (FEW condition), and subjects were asked to covertly complete each stem with a word and press a response switch for each successful completion. Prominent increases in activation in the MANY, relative to the FEW, condition were observed in the left middle frontal gyrus (Brodmann areas 9/10) and left caudate nucleus. In contrast, portions of the right-cerebellar hemisphere (posterior quadrangular lobule and superior semilunar lobule) and cerebellar vermis exhibited increases in the FEW, relative to the MANY, condition. This double dissociation suggests that the frontal and cerebellar regions make distinctive contributions to cognitive performance, with left-frontal (and striatal) activations reflecting response selection, which increases in difficulty when there are many appropriate responses, and right-cerebellar activation reflecting the search for responses, which increases in difficulty when even a single appropriate response is hard to retrieve.