Hemodynamic Response Function Variability Research Articles

Subject-Specific Modeling of EEG-fNIRS Neurovascular Coupling by Task-Related Tensor Decomposition.

Neurovascular coupling (NVC) connects neural activity with hemodynamics and plays a vital role in sustaining brain function. Combining electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS) is a promising way to explore the NVC. However, the high-order property of EEG data and variability of hemodynamic response function (HRF) across subjects have not been well considered in existing NVC studies. In this study, we proposed a novel framework to enhance the subject-specific parametric modeling of NVC from simultaneous EEG-fNIRS measurement. Specifically, task-related tensor decomposition of high-order EEG data was performed to extract the underlying connections in the temporal-spectral-spatial structures of EEG activities and identify the most relevant temporal signature within multiple trials. Subject-specific HRFs were estimated by parameters optimization of a double gamma function model. A canonical motor task experiment was designed to induce neural activity and validate the effectiveness of the proposed framework. The results indicated that the proposed framework significantly improves the reproducibility of EEG components and the correlation between the predicted hemodynamic activities and the real fNIRS signal. Moreover, the estimated parameters characterized the NVC differences in the task with two speeds. Therefore, the proposed framework provides a feasible solution for the quantitative assessment of the NVC function.

The confound of hemodynamic response function variability in human resting-state functional MRI studies.

Functional magnetic resonance imaging (fMRI) is an indirect measure of neural activity with the hemodynamic response function (HRF) coupling it with unmeasured neural activity. The HRF, modulated by several non-neural factors, is variable across brain regions, individuals and populations. Yet, a majority of human resting-state fMRI connectivity studies continue to assume a non-variable HRF. In this article, with supportive prior evidence, we argue that HRF variability cannot be ignored as it substantially confounds within-subject connectivity estimates and between-subjects connectivity group differences. We also discuss its clinical relevance with connectivity impairments confounded by HRF aberrations in several disorders. We present limited data on HRF differences between women and men, which resulted in a 15.4% median error in functional connectivity estimates in a group-level comparison. We also discuss the implications of HRF variability for fMRI studies in the spinal cord. There is a need for more dialogue within the community on the HRF confound, and we hope that our article is a catalyst in the process.

Characterization of Hemodynamic Alteration in Parkinson's Disease and Effect on Resting-State Connectivity

Functional magnetic resonance imaging (fMRI) is a convolution of latent neural activity and the hemodynamic response function (HRF). According to prior studies, the neurodegenerative process in idiopathic Parkinson's Disease (PD) interacts significantly with neuromuscular abnormalities. Although these underlying neuromuscular changes might influence the temporal characteristics of HRF and fMRI signals, relatively few studies have explored this possibility. We hypothesized that such alterations would engender changes in estimated functional connectivity (FC) in fMRI space compared to latent neural space. To test these theories, we calculated voxel-level HRFs by deconvolving resting-state fMRI data from PD patients (n = 61) and healthy controls (HC) (n = 47). Significant group differences in HRF (P < 0.05, Gaussian random field-corrected) were observed in several regions previously associated with PD. Subsequently, we focused on putamen-seed-based FC differences between the PD and HC groups using fMRI and latent neural signals. The results suggested that neglecting HRF variability may cultivate false-positive and false-negative FC group differences. Furthermore, HRF was related to dopamine receptor type 2 (DRD2) gene expression (P < 0.001, t = −7.06, false discover rate-corrected). Taken together, these findings reveal HRF variation and its possible underlying molecular mechanism in PD, and suggest that deconvolution could reduce the impact of HRF variation on FC group differences.

Characterization of Hemodynamic Alterations in Schizophrenia and Bipolar Disorder and Their Effect on Resting-State fMRI Functional Connectivity.

Common and distinct neural bases of Schizophrenia (SZ) and bipolar disorder (BP) have been explored using resting-state fMRI (rs-fMRI) functional connectivity (FC). However, fMRI is an indirect measure of neural activity, which is a convolution of the hemodynamic response function (HRF) and latent neural activity. The HRF, which models neurovascular coupling, varies across the brain within and across individuals, and is altered in many psychiatric disorders. Given this background, this study had three aims: quantifying HRF aberrations in SZ and BP, measuring the impact of such HRF aberrations on FC group differences, and exploring the genetic basis of HRF aberrations. We estimated voxel-level HRFs by deconvolving rs-fMRI data obtained from SZ (N = 38), BP (N = 19), and matched healthy controls (N = 35). We identified HRF group differences (P < .05, FDR corrected) in many regions previously implicated in SZ/BP, with mediodorsal, habenular, and central lateral nuclei of the thalamus exhibiting HRF differences in all pairwise group comparisons. Thalamus seed-based FC analysis revealed that ignoring HRF variability results in false-positive and false-negative FC group differences, especially in insula, superior frontal, and lingual gyri. HRF was associated with DRD2 gene expression (P < .05, 1.62 < |Z| < 2.0), as well as with medication dose (P < .05, 1.75 < |Z| < 3.25). In this first study to report HRF aberrations in SZ and BP, we report the possible modulatory effect of dopaminergic signalling on HRF, and the impact that HRF variability can have on FC studies in clinical samples. To mitigate the impact of HRF variability on FC group differences, we suggest deconvolution during data preprocessing.

Hemodynamic response function (HRF) variability confounds resting-state fMRI functional connectivity.

fMRI is the convolution of the hemodynamic response function (HRF) and unmeasured neural activity. HRF variability (HRFv) across the brain could, in principle, alter functional connectivity (FC) estimates from resting-state fMRI (rs-fMRI). Given that HRFv is driven by both neural and non-neural factors, it is problematic when it confounds FC. However, this aspect has remained largely unexplored even though FC studies have grown exponentially. We hypothesized that HRFv confounds FC estimates in the brain's default-mode-network. We tested this hypothesis using both simulations (where the ground truth is known and modulated) as well as rs-fMRI data obtained in a 7T MRI scanner (N = 47, healthy). FC was obtained using 2 pipelines: data with hemodynamic deconvolution (DC) to estimate the HRF and minimize HRFv, and data with no deconvolution (NDC, HRFv-ignored). DC and NDC FC networks were compared, along with regional HRF differences, revealing potential false connectivities that resulted from HRFv. We found evidence supporting our hypothesis using both simulations and experimental data. With simulations, we found that HRFv could cause a change of up to 50% in FC. With rs-fMRI, several potential false connectivities attributable to HRFv, with majority connections being between different lobes, were identified. We found a double exponential relationship between the magnitude of HRFv and its impact on FC, with a mean/median error of 30.5/11.5% caused in FC by HRF confounds. HRFv, if ignored, could cause identification of false FC. FC findings from HRFv-ignored data should be interpreted cautiously. We suggest deconvolution to minimize HRFv.

Hemodynamic variability in soldiers with trauma: Implications for functional MRI connectivity studies.

Functional MRI (fMRI) is an indirect measure of neural activity as a result of the convolution of the hemodynamic response function (HRF) and latent (unmeasured) neural activity. Recent studies have shown variability of HRF across brain regions (intra-subject spatial variability) and between subjects (inter-subject variability). Ignoring this HRF variability during data analysis could impair the reliability of such fMRI results. Using whole-brain resting-state fMRI (rs-fMRI), we employed hemodynamic deconvolution to estimate voxel-wise HRF. Studying the impact of mental disorders on HRF variability, we identified HRF aberrations in soldiers (N = 87) with posttraumatic stress disorder (PTSD) and mild-traumatic brain injury (mTBI) compared to combat controls. Certain subcortical and default-mode regions were found to have significant HRF aberrations in the clinical groups. These brain regions have been previously associated with neurochemical alterations in PTSD, which are known to impact the shape of the HRF. We followed-up these findings with seed-based functional connectivity (FC) analysis using regions-of-interest (ROIs) whose HRFs differed between the groups. We found that part of the connectivity group differences reported from traditional FC analysis (no deconvolution) were attributable to HRF variability. These findings raise the question of the degree of reliability of findings from conventional rs-fMRI studies (especially in psychiatric populations like PTSD and mTBI), which are corrupted by HRF variability. We also report and discus, for the first time, voxel-level HRF alterations in PTSD and mTBI. To the best of our knowledge, this is the first study to report evidence for the impact of HRF variability on connectivity group differences. Our work has implications for rs-fMRI connectivity studies. We encourage researchers to incorporate hemodynamic deconvolution during pre-processing to minimize the impact of HRF variability.

Nonparametric hemodynamic deconvolution of FMRI using homomorphic filtering.

Functional magnetic resonance imaging (fMRI) is an indirect measure of neural activity which is modeled as a convolution of the latent neuronal response and the hemodynamic response function (HRF). Since the sources of HRF variability can be nonneural in nature, the measured fMRI signal does not faithfully represent underlying neural activity. Therefore, it is advantageous to deconvolve the HRF from the fMRI signal. However, since both latent neural activity and the voxel-specific HRF is unknown, the deconvolution must be blind. Existing blind deconvolution approaches employ highly parameterized models, and it is unclear whether these models have an over fitting problem. In order to address these issues, we 1) present a nonparametric deconvolution method based on homomorphic filtering to obtain the latent neuronal response from the fMRI signal and, 2) compare our approach to the best performing existing parametric model based on the estimation of the biophysical hemodynamic model using the Cubature Kalman Filter/Smoother. We hypothesized that if the results from nonparametric deconvolution closely resembled that obtained from parametric deconvolution, then the problem of over fitting during estimation in highly parameterized deconvolution models of fMRI could possibly be over stated. Both simulations and experimental results demonstrate support for our hypothesis since the estimated latent neural response from both parametric and nonparametric methods were highly correlated in the visual cortex. Further, simulations showed that both methods were effective in recovering the simulated ground truth of the latent neural response.

An investigation of positive and inverted hemodynamic response functions across multiple visual areas

Recent studies have demonstrated significant regional variability in the hemodynamic response function (HRF), highlighting the difficulty of correctly interpreting functional MRI (fMRI) data without proper modeling of the HRF. The focus of this study was to investigate the HRF variability within visual cortex. The HRF was estimated for a number of cortical visual areas by deconvolution of fMRI blood oxygenation level dependent (BOLD) responses to brief, large-field visual stimulation. Significant HRF variation was found across visual areas V1, V2, V3, V4, VO-1,2, V3AB, IPS-0,1,2,3, LO-1,2, and TO-1,2. Additionally, a subpopulation of voxels was identified that exhibited an impulse response waveform that was similar, but not identical, to an inverted version of the commonly described and modeled positive HRF. These voxels were found within the retinotopic confines of the stimulus and were intermixed with those showing positive responses. The spatial distribution and variability of these HRFs suggest a vascular origin for the inverted waveforms. We suggest that the polarity of the HRF is a separate factor that is independent of the suppressive or activating nature of the underlying neuronal activity. Correctly modeling the polarity of the HRF allows one to recover an estimate of the underlying neuronal activity rather than discard the responses from these voxels on the assumption that they are artifactual. We demonstrate this approach on phase-encoded retinotopic mapping data as an example of the benefits of accurately modeling the HRF during the analysis of fMRI data.

Lag-based effective connectivity applied to fMRI: A simulation study highlighting dependence on experimental parameters and formulation

A vast repertoire of methods is currently available to study effective brain connectivity based on neuroimaging data, among which lag-based measures can be distinguished. Although several studies have previously assessed the performance of such measures, their validity in different conditions remains unclear. In the current study, several lag-based effective connectivity measures are tested and benchmarked using simulated fMRI data, conceived to reflect a broad range of different situations with practical interest. The main goal is two-fold: 1) to provide a thorough overview of lag-based effective connectivity measures, and 2) to assess their performance in specific experimental conditions, thereby providing guidance for future effective connectivity studies involving fMRI. We focus on well-known lag-based measures, cover existing improvements and alternative formulations in some cases: Granger causality (GC), Geweke's Granger causality (GGC), directed transfer function (DTF), partial directed coherence (PDC), phase slope index (PSI), and transfer entropy (TE). Benchmarking consists in identifying causal relations in local field potential (LFP) networks that have their output convolved with a canonical hemodynamic response function (HRF) with varying node number, topology, coupling strength, neuronal delay, repetition time (TR), signal-to-noise ratio (SNR) and HRF variability. In a first set of simulations, we cover all possible combinations of discretized values of the previous variables, for networks with 2 and 3 nodes, and find that the measure with best performance (time-domain Granger Causality) is able to detect neuronal delays of a few hundreds of milliseconds with TRs between 0.25 and 2s and neuronal delays below 100ms for TRs that are also below 100ms, with more than 80% accuracy in realistic conditions. For networks with more than 3 nodes, we find that the number of nodes and the density of causal links degrade sensitivity, especially if the number of observations does not compensate for the increase in nodes, and that clustered networks can be more easily identified. In conclusion, this study argues in favor of the applicability of lag-based measures in the context of fMRI, provided that a stringent set of experimental specifications is met and that the chosen measure is applied with full knowledge of its limitations and specific constraints.

Hemodynamic Response Function Variability in Patients with Aphasia (P06.066)

Hemodynamic Response Function Variability in Patients with Aphasia (P06.066)

Paradigm free mapping with sparse regression automatically detects single-trial functional magnetic resonance imaging blood oxygenation level dependent responses.

The ability to detect single trial responses in functional magnetic resonance imaging (fMRI) studies is essential, particularly if investigating learning or adaptation processes or unpredictable events. We recently introduced paradigm free mapping (PFM), an analysis method that detects single trial blood oxygenation level dependent (BOLD) responses without specifying prior information on the timing of the events. PFM is based on the deconvolution of the fMRI signal using a linear hemodynamic convolution model. Our previous PFM method (Caballero-Gaudes et al., 2011: Hum Brain Mapp) used the ridge regression estimator for signal deconvolution and required a baseline signal period for statistical inference. In this work, we investigate the application of sparse regression techniques in PFM. In particular, a novel PFM approach is developed using the Dantzig selector estimator, solved via an efficient homotopy procedure, along with statistical model selection criteria. Simulation results demonstrated that, using the Bayesian information criterion to select the regularization parameter, this method obtains high detection rates of the BOLD responses, comparable with a model-based analysis, but requiring no information on the timing of the events and being robust against hemodynamic response function variability. The practical operation of this sparse PFM method was assessed with single-trial fMRI data acquired at 7T, where it automatically detected all task-related events, and was an improvement on our previous PFM method, as it does not require the definition of a baseline state and amplitude thresholding and does not compromise on specificity and sensitivity.

Modulation by EEG features of BOLD responses to interictal epileptiform discharges

Introduction. EEG-fMRI of interictal epileptiform discharges (IEDs) usually assumes a fixed hemodynamic response function (HRF). This study investigates HRF variability with respect to IED amplitude fluctuations using independent component analysis (ICA), with the goal of improving the specificity of EEG-fMRI analyses. Methods. We selected EEG-fMRI data from 10 focal epilepsy patients with a good quality EEG. IED amplitudes were calculated in an average reference montage. The fMRI data were decomposed by ICA and a deconvolution method identified IED-related components by detecting time courses with a significant HRF time-locked to the IEDs (F-test, p<0.05). Individual HRF amplitudes were then calculated for each IED. Components with a significant HRF/IED amplitude correlation (Spearman test, p<0.05) were compared to the presumed epileptogenic focus and to results of a general linear model (GLM) analysis. Results. In 7 patients, at least one IED-related component was concordant with the focus, but many IED-related components were at distant locations. When considering only components with a significant HRF/IED amplitude correlation, distant components could be discarded, significantly increasing the relative proportion of activated voxels in the focus (p=0.02). In the 3 patients without concordant IED-related components, no HRF/IED amplitude correlations were detected inside the brain. Integrating IED-related amplitudes in the GLM significantly improved fMRI signal modeling in the epileptogenic focus in 4 patients (p<0.05). Conclusion. Activations in the epileptogenic focus appear to show significant correlations between HRF and IED amplitudes, unlike distant responses. These correlations could be integrated in the analysis to increase the specificity of EEG-fMRI studies in epilepsy.

A signal subspace approach for modeling the hemodynamic response function in fMRI.

Many fMRI analysis methods use a model for the hemodynamic response function (HRF). Common models of the HRF, such as the Gaussian or Gamma functions, have parameters that are usually selected a priori by the data analyst. A new method is presented that characterizes the HRF over a wide range of parameters via three basis signals derived using principal component analysis (PCA). Covering the HRF variability, these three basis signals together with the stimulation pattern define signal subspaces which are applicable to both linear and nonlinear modeling and identification of the HRF and for various activation detection strategies. Analysis of simulated fMRI data using the proposed signal subspace showed increased detection sensitivity compared to the case of using a previously proposed trigonometric subspace. The methodology was also applied to activation detection in both event-related and block design experimental fMRI data using both linear and nonlinear modeling of the HRF. The activated regions were consistent with previous studies, indicating the ability of the proposed approach in detecting brain activation without a priori assumptions about the shape parameters of the HRF. The utility of the proposed basis functions in identifying the HRF is demonstrated by estimating the HRF in different activated regions.