Kevin Wen-Kai Tsai

Increasing fMRI Sampling Rate Improves Granger Causality Estimates

Estimation of causal interactions between brain areas is necessary for elucidating large-scale functional brain networks underlying behavior and cognition. Granger causality analysis of time series data can quantitatively estimate directional information flow between brain regions. Here, we show that such estimates are significantly improved when the temporal sampling rate of functional magnetic resonance imaging (fMRI) is increased 20-fold. Specifically, healthy volunteers performed a simple visuomotor task during blood oxygenation level dependent (BOLD) contrast based whole-head inverse imaging (InI). Granger causality analysis based on raw InI BOLD data sampled at 100-ms resolution detected the expected causal relations, whereas when the data were downsampled to the temporal resolution of 2 s typically used in echo-planar fMRI, the causality could not be detected. An additional control analysis, in which we SINC interpolated additional data points to the downsampled time series at 0.1-s intervals, confirmed that the improvements achieved with the real InI data were not explainable by the increased time-series length alone. We therefore conclude that the high-temporal resolution of InI improves the Granger causality connectivity analysis of the human brain.

Whole-head rapid fMRI acquisition using echo-shifted magnetic resonance inverse imaging.

The acquisition time of BOLD contrast functional MRI (fMRI) data with whole-brain coverage typically requires a sampling rate of one volume in 1-3s. Although the volumetric sampling time of a few seconds is adequate for measuring the sluggish hemodynamic response (HDR) to neuronal activation, faster sampling of fMRI might allow for monitoring of rapid physiological fluctuations and detection of subtle neuronal activation timing information embedded in BOLD signals. Previous studies utilizing a highly accelerated volumetric MR inverse imaging (InI) technique have provided a sampling rate of one volume per 100 ms with 5mm spatial resolution. Here, we propose a novel modification of this technique, the echo-shifted InI, which allows TE to be longer than TR, to measure BOLD fMRI at an even faster sampling rate of one volume per 25 ms with whole-brain coverage. Compared with conventional EPI, echo-shifted InI provided an 80-fold speedup with similar spatial resolution and less than 2-fold temporal SNR loss. The capability of echo-shifted InI to detect HDR timing differences was tested empirically. At the group level (n=6), echo-spaced InI was able to detect statistically significant HDR timing differences of as low as 50 ms in visual stimulus presentation. At the level of individual subjects, significant differences in HDR timing were detected for 400 ms stimulus-onset differences. Our results also show that the temporal resolution of 25 ms is necessary for maintaining the temporal detecting capability at this level. With the capabilities of being able to distinguish the timing differences in the millisecond scale, echo-shifted InI could be a useful fMRI tool for obtaining temporal information at a time scale closer to that of neuronal dynamics.

K-space reconstruction of magnetic resonance inverse imaging (K-InI) of human visuomotor systems

Using simultaneous measurements from multiple channels of a radio-frequency coil array, magnetic resonance inverse imaging (InI) can achieve ultra-fast dynamic functional imaging of the human with whole-brain coverage and a good spatial resolution. Mathematically, the InI reconstruction is a generalization of parallel MRI (pMRI), which includes image space and k-space reconstructions. Because of the auto-calibration technique, the pMRI k-space reconstruction offers more robust and adaptive reconstructions compared to the image space algorithm. Here we present the k-space InI (K-InI) reconstructions to reconstruct the highly accelerated BOLD-contrast fMRI data of the human brain to achieve 100 ms temporal resolution. Simulations show that K-InI reconstructions can offer 3D image reconstructions at each time frame with reasonable spatial resolution, which cannot be obtained using the previously proposed image space minimum-norm estimates (MNE) or linear constraint minimum variance (LCMV) spatial filtering reconstructions. The InI reconstructions of in vivo BOLD-contrast fMRI data during a visuomotor task show that K-InI offer 3 to 5 fold more sensitive detection of the brain activation than MNE and a comparable detection sensitivity to the LCMV reconstructions. The group average of the high temporal resolution K-InI reconstructions of the hemodynamic response also shows a relative onset timing difference between the visual (first) and somatomotor (second) cortices by 400 ms (600 ms time-to-peak timing difference). This robust and sensitive K-InI reconstruction can be applied to dynamic MRI acquisitions using a large-n coil array to improve the spatiotemporal resolution.

Significant feed-forward connectivity revealed by high frequency components of BOLD fMRI signals

Granger causality analysis has been suggested as a method of estimating causal modulation without specifying the direction of information flow a priori. Using BOLD-contrast functional MRI (fMRI) data, such analysis has been typically implemented in the time domain. In this study, we used magnetic resonance inverse imaging, a method of fast fMRI enabled by massively parallel detection allowing up to 10 Hz sampling rate, to investigate the causal modulation at different frequencies up to 5 Hz. Using a visuomotor two-choice reaction-time task, both the spectral decomposition of Granger causality and isolated effective coherence revealed that the BOLD signal at frequency up to 3 Hz can still be used to estimate significant dominant directions of information flow consistent with results from the time-domain Granger causality analysis. We showed the specificity of estimated dominant directions of information flow at high frequencies by contrasting causality estimates using data collected during the visuomotor task and resting state. Our data suggest that hemodynamic responses carry physiological information related to inter-regional modulation at frequency higher than what has been commonly considered.

Effective Cerebral Connectivity during Silent Speech Reading Revealed by Functional Magnetic Resonance Imaging

Seeing the articulatory gestures of the speaker (“speech reading”) enhances speech perception especially in noisy conditions. Recent neuroimaging studies tentatively suggest that speech reading activates speech motor system, which then influences superior-posterior temporal lobe auditory areas via an efference copy. Here, nineteen healthy volunteers were presented with silent videoclips of a person articulating Finnish vowels /a/, /i/ (non-targets), and /o/ (targets) during event-related functional magnetic resonance imaging (fMRI). Speech reading significantly activated visual cortex, posterior fusiform gyrus (pFG), posterior superior temporal gyrus and sulcus (pSTG/S), and the speech motor areas, including premotor cortex, parts of the inferior (IFG) and middle (MFG) frontal gyri extending into frontal polar (FP) structures, somatosensory areas, and supramarginal gyrus (SMG). Structural equation modelling (SEM) of these data suggested that information flows first from extrastriate visual cortex to pFS, and from there, in parallel, to pSTG/S and MFG/FP. From pSTG/S information flow continues to IFG or SMG and eventually somatosensory areas. Feedback connectivity was estimated to run from MFG/FP to IFG, and pSTG/S. The direct functional connection from pFG to MFG/FP and feedback connection from MFG/FP to pSTG/S and IFG support the hypothesis of prefrontal speech motor areas influencing auditory speech processing in pSTG/S via an efference copy.

Ultrafast inverse imaging techniques for fMRI

Inverse imaging (InI) supercharges the sampling rate of traditional functional MRI 10-100 fold at a cost of a moderate reduction in spatial resolution. The technique is inspired by similarities between multi-sensor magnetoencephalography (MEG) and highly parallel radio-frequency (RF) MRI detector arrays. Using presently available 32-channel head coils at 3T, InI can be sampled at 10 Hz and provides about 5-mm cortical spatial resolution with whole-brain coverage. Here we discuss the present applications of InI, as well as potential future challenges and opportunities in further improving its spatiotemporal resolution and sensitivity. InI may become a helpful tool for clinicians and neuroscientists for revealing the complex dynamics of brain functions during task-related and resting states.

fMRI hemodynamics accurately reflects neuronal timing in the human brain measured by MEG

Neuronal activation sequence information is essential for understanding brain functions. Extracting such timing information from blood oxygenation level dependent (BOLD) fMRI is confounded by interregional neurovascular differences and poorly understood relations between BOLD and electrophysiological response delays. Here, we recorded whole-head BOLD fMRI at 100 ms resolution and magnetoencephalography (MEG) during a visuomotor reaction-time task. Both methods detected the same activation sequence across five regions, from visual towards motor cortices, with linearly correlated interregional BOLD and MEG response delays. The smallest significant interregional BOLD delay was 100 ms; all delays ≥400 ms were significant. Switching the order of external events reversed the sequence of BOLD activations, indicating that interregional neurovascular differences did not confound the results. This may open new avenues for using fMRI to follow rapid activation sequences in the brain.

Essential role of PKCδ in histone deacetylase inhibitor-induced Epstein–Barr virus reactivation in nasopharyngeal carcinoma cells

Histone deactylase inhibitors (HDACi) are common chemotherapeutic agents that stimulate Epstein-Barr virus (EBV) reactivation; the detailed mechanism remains obscure. In this study, it is demonstrated that PKCdelta is required for induction of the EBV lytic cycle by HDACi. Inhibition of PKCdelta abrogates HDACi-mediated transcriptional activation of the Zta promoter and downstream lytic gene expression. Nuclear translocation of PKCdelta is observed following HDACi stimulation and its overexpression leads to progression of the EBV lytic cycle. Our study suggests that PKCdelta is a crucial mediator of EBV reactivation and provides a novel insight to study the regulation of the EBV lytic cycle.

Multi-projection magnetic resonance inverse imaging of the human visuomotor system

Using highly parallel radiofrequency (RF) detection, magnetic resonance inverse imaging (InI) can achieve 100 ms temporal resolution with whole brain coverage. This is achieved by trading off partition encoding steps and thus spatial resolution for a higher acquisition rate. The reduced spatial information is estimated by solving under-determined inverse problems using RF coil sensitivity information. Here we propose multi projection inverse imaging (mInI) to combine different projection images to improve the spatial resolution of InI. Specifically, coronal, sagittal, and transverse projection images were acquired from different runs of the fMRI acquisitions using a 32-channel head coil array. Simulations show that mInI improves the quality of the instantaneous image reconstruction significantly. Going from one projection to three projections, the spatial resolution quantified by the full width at half maximum of the point-spread function (PSF) is improved from 2.6 pixels to 1.4 pixels (4 mm nominal resolution per pixel). Considering the shape of the PSF, the effective spatial resolution is improved from 16.9 pixels to 4.7 pixels. In vivo fMRI experiments using a two-choice reaction time tasks show visual and sensorimotor cortical activities spatially consistent with typical EPI data, yet mInI offers 100 ms temporal resolution with the whole brain coverage. The mInI data with three projections revealed that the sensorimotor cortex was activated 700 ms after the visual cortex. mInI can be applied to BOLD-contrast fMRI experiments to characterize the dynamics of the activated brain areas with a high spatiotemporal resolution.

Relative latency and temporal variability of hemodynamic responses at the human primary visual cortex.

&NA; The blood‐oxygen‐level‐dependent (BOLD) functional MRI (fMRI) signal is a robust surrogate for local neuronal activity. However, it has been shown to vary substantially across subjects, brain regions, and repetitive measurements. This variability represents a limit to the precision of the BOLD response and the ability to reliably discriminate brain hemodynamic responses elicited by external stimuli or behavior that are nearby in time. While the temporal variability of the BOLD signal at human visual cortex has been found in the range of a few hundreds of milliseconds, the spatial distributions of the average and standard deviation of this temporal variability have not been quantitatively characterized. Here we use fMRI measurements with a high sampling rate (10 Hz) to map the latency, intra‐ and inter‐subject variability of the evoked BOLD signal in human primary (V1) visual cortices using an event‐related fMRI paradigm. The latency relative to the average BOLD signal evoked by 30 stimuli was estimated to be 0.03±0.20 s. Within V1, the absolute value of the relative BOLD latency was found correlated to intra‐ and inter‐subject temporal variability. After comparing these measures to retinotopic maps, we found that locations with V1 areas sensitive to smaller eccentricity have later responses and smaller inter‐subject variabilities. These correlations were found from data with either short inter‐stimulus interval (ISI; average 4 s) or long ISI (average 30 s). Maps of the relative latency as well as inter‐/intra‐subject variability were found visually asymmetric between hemispheres. Our results suggest that the latency and variability of regional BOLD signal measured with high spatiotemporal resolution may be used to detect regional differences in hemodynamics to inform fMRI studies. However, the physiological origins of timing index distributions and their hemispheric asymmetry remain to be investigated. HighlightsThe BOLD latency and variability was measured with 0.1 s precision.The latency of the V1 BOLD signal evoked from 30 trials was 0.03±0.20 s.Smaller eccentricity locations have larger latencySmaller eccentricity locations have smaller inter‐subject variability.