Dongqiang Liu

Spontaneous Brain Activity in the Default Mode Network Is Sensitive to Different Resting-State Conditions with Limited Cognitive Load

Background Recent functional MRI (fMRI) studies have demonstrated that there is an intrinsically organized default mode network (DMN) in the resting brain, primarily made up of the posterior cingulate cortex (PCC) and the medial prefrontal cortex (MPFC). Several previous studies have found that the DMN is minimally disturbed during different resting-state conditions with limited cognitive demand. However, this conclusion was drawn from the visual inspection of the functional connectivity patterns within the DMN and no statistical comparison was performed. Methodology/Principal Findings Four resting-state fMRI sessions were acquired: 1) eyes-closed (EC) (used to generate the DMN mask); 2) EC; 3) eyes-open with no fixation (EO); and 4) eyes-open with a fixation (EO-F). The 2–4 sessions were counterbalanced across participants (n = 20, 10 males). We examined the statistical differences in both functional connectivity and regional amplitude of low frequency fluctuation (ALFF) within the DMN among the 2–4 resting-state conditions (i.e., EC, EO, and EO-F). Although the connectivity patterns of the DMN were visually similar across these three different conditions, we observed significantly higher functional connectivity and ALFF in both the EO and the EO-F conditions as compared to the EC condition. In addition, the first and second resting EC conditions showed significant differences within the DMN, suggesting an order effect on the DMN activity. Conclusions/Significance Our findings of the higher DMN connectivity and regional spontaneous activities in the resting state with the eyes open suggest that the participants might have more non-specific or non-goal-directed visual information gathering and evaluation, and mind wandering or daydreaming during the resting state with the eyes open as compared to that with the eyes closed, thus providing insights into the understanding of unconstrained mental activity within the DMN. Our results also suggest that it should be cautious when choosing the type of a resting condition and designating the order of the resting condition in multiple scanning sessions in experimental design.

An open science resource for establishing reliability and reproducibility in functional connectomics.

Efforts to identify meaningful functional imaging-based biomarkers are limited by the ability to reliably characterize inter-individual differences in human brain function. Although a growing number of connectomics-based measures are reported to have moderate to high test-retest reliability, the variability in data acquisition, experimental designs, and analytic methods precludes the ability to generalize results. The Consortium for Reliability and Reproducibility (CoRR) is working to address this challenge and establish test-retest reliability as a minimum standard for methods development in functional connectomics. Specifically, CoRR has aggregated 1,629 typical individuals’ resting state fMRI (rfMRI) data (5,093 rfMRI scans) from 18 international sites, and is openly sharing them via the International Data-sharing Neuroimaging Initiative (INDI). To allow researchers to generate various estimates of reliability and reproducibility, a variety of data acquisition procedures and experimental designs are included. Similarly, to enable users to assess the impact of commonly encountered artifacts (for example, motion) on characterizations of inter-individual variation, datasets of varying quality are included.

Functional connectivity between the thalamus and visual cortex under eyes closed and eyes open conditions: a resting-state fMRI study.

The thalamus and visual cortex are two key components associated with the alpha power of electroencephalography. However, their functional relationship remains to be elucidated. Here, we employ resting‐state functional MRI to investigate the temporal correlations of spontaneous fluctuations between the thalamus [the whole thalamus and its three largest nuclei (bilateral mediodorsal, ventrolateral and pulvinar nuclei)] and visual cortex under both eyes open and eyes closed conditions. The whole thalamus show negative correlations with the visual cortex and positive correlations with its contralateral counterpart in eyes closed condition, but which are significantly decreased in eyes open condition, consistent with previous findings of electroencephalography desynchronization during eyes open resting state. Furthermore, we find that bilateral thalamic mediodorsal nuclei and bilateral ventrolateral nuclei have remarkably similar connectivity maps, and resemble to those of the whole thalamus, suggesting their crucial contributions to the thalamus‐visual correlations. The bilateral pulvinar nuclei are found to show distinct functional connectivity patterns, compatible with previous findings of the asymmetry of anatomical and functional organization in the nuclei. Our data provides evidence for the associations of intrinsic spontaneous neuronal activity between the thalamus and visual cortex under different resting conditions, which might have implications on the understanding of the generation and modulation of the alpha rhythm. Hum Brain Mapp 2009.

Using coherence to measure regional homogeneity of resting-state fMRI signal

In this study, we applied coherence to voxel-wise measurement of regional homogeneity of resting-state functional magnetic resonance imaging (RS-fMRI) signal. We compared the current method, regional homogeneity based on coherence (Cohe-ReHo), with previously proposed method, ReHo based on Kendalls coefficient of concordance (KCC-ReHo), in terms of correlation and paired t-test in a large sample of healthy participants. We found the two measurements differed mainly in some brain regions where physiological noise is dominant. We also compared the sensitivity of these methods in detecting difference between resting-state conditions [eyes open (EO) vs. eyes closed (EC)] and in detecting abnormal local synchronization between two groups [attention deficit hyperactivity disorder (ADHD) patients vs. normal controls]. Our results indicated that Cohe-ReHo is more sensitive than KCC-ReHo to the difference between two conditions (EO vs. EC) as well as that between ADHD and normal controls. These preliminary results suggest that Cohe-ReHo is superior to KCC-ReHo. A possible reason is that coherence is not susceptible to random noise induced by phase delay among the time courses to be measured. However, further investigation is still needed to elucidate the sensitivity and specificity of these methods.

Disrupted Causal Connectivity in Mesial Temporal Lobe Epilepsy

Although mesial temporal lobe epilepsy (mTLE) is characterized by the pathological changes in mesial temporal lobe, function alteration was also found in extratemporal regions. Our aim is to investigate the information flow between the epileptogenic zone (EZ) and other brain regions. Resting-state functional magnetic resonance imaging (RS-fMRI) data were recorded from 23 patients with left mTLE and matched controls. We first identified the potential EZ using the amplitude of low-frequency fluctuation (ALFF) of RS-fMRI signal, then performed voxel-wise Granger causality analysis between EZ and the whole brain. Relative to controls, patients demonstrated decreased driving effect from EZ to thalamus and basal ganglia, and increased feedback. Additionally, we found an altered causal relation between EZ and cortical networks (default mode network, limbic system, visual network and executive control network). The influence from EZ to right precuneus and brainstem negatively correlated with disease duration, whereas that from the right hippocampus, fusiform cortex, and lentiform nucleus to EZ showed positive correlation. These findings demonstrate widespread brain regions showing abnormal functional interaction with EZ. In addition, increased ALFF in EZ was positively correlated with the increased driving effect on EZ in patients, but not in controls. This finding suggests that the initiation of epileptic activity depends not only on EZ itself, but also on the activity emerging in large-scale macroscopic brain networks. Overall, this study suggests that the causal topological organization is disrupted in mTLE, providing valuable information to understand the pathophysiology of this disorder.

Eyes-Open/Eyes-Closed Dataset Sharing for Reproducibility Evaluation of Resting State fMRI Data Analysis Methods

The multi-scan resting state fMRI (rs-fMRI) dataset was recently released; thus the test-retest (TRT) reliability of rs-fMRI measures can be assessed. However, because this dataset was acquired only from a single group under a single condition, we cannot directly evaluate whether the rs-fMRI measures can generate reproducible between-condition or between-group results. Because the modulation of resting state activity has gained increasing attention, it is important to know whether one rs-fMRI metric can reliably detect the alteration of the resting activity. Here, we shared a public Eyes-Open (EO)/Eyes-Closed (EC) dataset for evaluating the split-half reproducibility of the rs-fMRI measures in detecting changes of the resting state activity between EO and EC. As examples, we assessed the split-half reproducibility of three widely applied rs-fMRI metrics: amplitude of low frequency fluctuation, regional homogeneity, and seed-based correlation analysis. Our results demonstrated that reproducible patterns of EO-EC differences can be detected by all three measures, suggesting the feasibility of the EO/EC dataset for performing reproducibility assessment for other rs-fMRI measures.

Amplitude differences in high-frequency fMRI signals between eyes open and eyes closed resting states.

Recent studies employing rapid sampling techniques have demonstrated that the resting state fMRI (rs-fMRI) signal exhibits synchronized activities at frequencies much higher than the conventional frequency range (<0.1 Hz). However, little work has investigated the changes in the high-frequency fluctuations between different resting states. Here, we acquired rs-fMRI data at a high sampling rate (TR = 400 ms) from subjects with both eyes open (EO) and eyes closed (EC), and compared the amplitude of fluctuation (AF) between EO and EC for both the low- and high-frequency components. In addition to robust AF differences in the conventional low frequency band (<0.1 Hz) in visual cortex, primary auditory cortex and primary sensorimotor cortex (PSMC), we also detected high-frequency (primarily in 0.1–0.35 Hz) differences. The high-frequency results without covariates regression exhibited noisy patterns. For the data with nuisance covariates regression, we found a significant and reproducible reduction in high-frequency AF between EO and EC in the bilateral PSMC and the supplementary motor area (SMA), and an increase in high-frequency AF in the left middle occipital gyrus (MOG). Furthermore, we investigated the effect of sampling rate by down-sampling the data to effective TR = 2 s. Briefly, by using the rapid sampling rate, we were able to detect more regions with significant differences while identifying fewer artifactual differences in the high-frequency bands as compared to the down-sampled dataset. We concluded that (1) high-frequency fluctuations of rs-fMRI signals can be modulated by different resting states and thus may be of physiological importance; and (2) the regression of covariates and the use of fast sampling rates are superior for revealing high-frequency differences in rs-fMRI signals.

Detecting static and dynamic differences between eyes-closed and eyes-open resting states using ASL and BOLD fMRI.

Resting-state fMRI studies have increasingly focused on multi-contrast techniques, such as BOLD and ASL imaging. However, these techniques may reveal different aspects of brain activity (e.g., static vs. dynamic), and little is known about the similarity or disparity of these techniques in detecting resting-state brain activity. It is therefore important to assess the static and dynamic characteristics of these fMRI techniques to guide future applications. Here we acquired fMRI data while subjects were in eyes-closed (EC) and eyes-open (EO) states, using both ASL and BOLD techniques, at two research centers (NIDA and HNU). Static brain activity was calculated as voxel-wise mean cerebral blood flow (CBF) using ASL, i.e., CBF-mean, while dynamic activity was measured by the amplitude of low frequency fluctuations (ALFF) of BOLD, i.e., BOLD-ALFF, at both NIDA and HNU, and CBF, i.e., CBF-ALFF, at NIDA. We showed that mean CBF was lower under EC than EO in the primary visual cortex, while BOLD-ALFF was higher under EC in the primary somatosensory cortices extending to the primary auditory cortices and lower in the lateral occipital area. Interestingly, mean CBF and BOLD-ALFF results overlapped at the visual cortex to a very small degree. Importantly, these findings were largely replicated by the HNU dataset. State differences found by CBF-ALFF were located in the primary auditory cortices, which were generally a subset of BOLD-ALFF and showed no spatial overlap with CBF-mean. In conclusion, static brain activity measured by mean CBF and dynamic brain activity measured by BOLD- and CBF-ALFF may reflect different aspects of resting-state brain activity and a combination of ASL and BOLD may provide complementary information on the biophysical and physiological processes of the brain.

Increased local synchronization of resting-state fMRI signal after episodic memory encoding reflects off-line memory consolidation.

The changes of spontaneous activity from before and after a memory or learning task had been considered to be related to off-line memory consolidation process in human brain by using resting-state functional connectivity (RSFC) MRI (fMRI). However, RSFC reflects temporal synchronization of timecourses of spatially distinct brain regions and therefore could not determine which specific brain region is involved in the memory consolidation process. Here we used regional homogeneity (ReHo), a method for measuring local synchronization, to link the local spontaneous activity change to off-line episodic memory consolidation. We hypothesized that the spontaneous activity change would be different between people with better memory performance and those with worse performance in memory-related regions. All participants completed two resting-state sessions, that is, before (REST-1) and after (REST-2) an episodic memory encoding task (picture indoor or outdoor judgment). Then, based on the d′ of a later surprise memory retrieval test, a high-performance group and a low-performance group, each consisting of 16 participants, were chosen from whole 58 participants. We defined a ReHo ratio, that is, ReHo of REST-2 divided by ReHo of REST-1, as a change induced by memory consolidation. The high-performance group showed a significant higher ReHo ratio than low-performance group in medial temporal lobe (MTL) including parahippocampal and anterior temporal regions. The current results provide neuroimaging evidence supporting that the MTL is involved in off-line memory consolidation of episodic memory. Moreover, this study may provide a paradigm for understanding of episodic memory deficit in Alzheimer’s disease.

Global signal regression has complex effects on regional homogeneity of resting state fMRI signal

Regional homogeneity (ReHo) quantifies spatially local synchronization of resting state fMRI signal and has been applied to lots of clinic studies. Accumulating evidences demonstrated that the synchronization between spatially distinct brain regions, i.e. functional connectivity, can be remarkably influenced if the global mean time course is regressed out, namely global signal regression (GSR). Very recently, it was reported GSR reduces the test-retest reliability of ReHo, and reduces the positive correlation between ReHo and head motion. In this study, we were interested in two questions: 1) how GSR affects the raw ReHo values and its spatial distribution over the brain; 2) how GSR affects the differences of ReHo between two resting states, eyes open (EO) and eyes closed (EC), in healthy individuals. We found that the ReHo values were reduced by GSR but the spatial distribution of ReHo was not changed remarkably. In addition, split-half reproducibility analysis showed reproducible ReHo difference between EO and EC in some areas (e.g., thalamus and caudate) only with GSR, but showed reproducible ReHo difference in some other area (right temporal pole) only without GSR. The effects of GSR were almost independent of regression of other nuisance covariates. Our results suggest that the influences of GSR on ReHo are remarkable, reliable and complex. For the between-condition comparison, the GSR effects are region specific. We suggest that, for application studies using ReHo approach, it would be helpful to report results both with and without GSR.