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

Retrieving the hemodynamic response function in resting state fMRI: methodology and application

In this paper we present a procedure to retrieve the hemodynamic response function (HRF) from resting state functional magnetic resonance imaging (fMRI) data. The fundamentals of the procedures are further validated by considering simultaneous electroencephalographic (EEG) recordings. The typical HRF shape at rest for a group of healthy subject is presented. Then we present the modifications to the shape of the HRF at rest following two physiological modulations: eyes open versus eyes closed and propofol-induced modulations of consciousness

Investigating Focal Connectivity Deficits in Alzheimer's Disease Using Directional Brain Networks Derived from Resting-State fMRI

Connectivity analysis of resting-state fMRI has been widely used to identify biomarkers of Alzheimer's disease (AD) based on brain network aberrations. However, it is not straightforward to interpret such connectivity results since our understanding of brain functioning relies on regional properties (activations and morphometric changes) more than connections. Further, from an interventional standpoint, it is easier to modulate the activity of regions (using brain stimulation, neurofeedback, etc.) rather than connections. Therefore, we employed a novel approach for identifying focal directed connectivity deficits in AD compared to healthy controls. In brief, we present a model of directed connectivity (using Granger causality) that characterizes the coupling among different regions in healthy controls and Alzheimer's disease. We then characterized group differences using a (between-subject) generative model of pathology, which generates latent connectivity variables that best explain the (within-subject) directed connectivity. Crucially, our generative model at the second (between-subject) level explains connectivity in terms of local or regionally specific abnormalities. This allows one to explain disconnections among multiple regions in terms of regionally specific pathology; thereby offering a target for therapeutic intervention. Two foci were identified, locus coeruleus in the brain stem and right orbitofrontal cortex. Corresponding disrupted connectivity network associated with the foci showed that the brainstem is the critical focus of disruption in AD. We further partitioned the aberrant connectomic network into four unique sub-networks, which likely leads to symptoms commonly observed in AD. Our findings suggest that fMRI studies of AD, which have been largely cortico-centric, could in future investigate the role of brain stem in AD

North American Football Fans Show Neurofunctional Differences in Response to Violence: Implications for Public Health and Policy

While social and behavioral effects of violence in the media have been studied extensively, much less is known about how sports affect perceptions of violence. The current study examined neurofunctional differences between fans and non-fans of North American football (a contact sport) while viewing violent imagery. Participants viewed images of violence in both football and non-football settings while high-resolution functional magnetic resonance imaging (fMRI) data were acquired from their brains. Neurological activation was compared between these violence types and between groups. Fans of football show diminished activation in brain regions involved in pain perception and empathy such as the anterior cingulate cortex, fusiform gyrus, insula, and temporal pole when viewing violence in the context of football compared to more broadly violent images. Non-fans of football showed no such effect for the types of violent imagery and had higher activation levels than fans of football for the specified brain regions. These differences show that fans of football may perceive violence differently when it is in the context of football. These fan attitudes have potential policy implications for addressing the issue of concussions in North American football

Resting state fMRI connectivity is sensitive to laminar connectional architecture in the human brain

Previous invasive studies indicate that human neocortical graymatter contains cytoarchitectonically distinct layers, with notable differences in their structural connectivity with the rest of the brain. Given recent improvements in the spatial resolution of anatomical and functional magnetic resonance imaging (fMRI), we hypothesize that resting state functional connectivity (FC) derived from fMRI is sensitive to layer-specific thalamo-cortical and cortico-cortical microcircuits. Using sub-millimeter resting state fMRI data obtained at 7 T, we found that: (1) FC between the entire thalamus and cortical layers I and VI was significantly stronger than between the thalamus and other layers. Furthermore, FC between somatosensory thalamus (ventral posterolateral nucleus, VPL) and layers IV, VI of the primary somatosensory cortex were stronger than with other layers; (2) Inter-hemispheric cortico-cortical FC between homologous regions in superficial layers (layers I–III) was stronger compared to deep layers (layers V–VI). These findings are in agreement with structural connections inferred from previous invasive studies that showed that: (i) M-type neurons in the entire thalamus project to layer-I; (ii) Pyramidal neurons in layer-VI target all thalamic nuclei, (iii) C-type neurons in the VPL project to layer-IV and receive inputs from layer-VI of the primary somatosensory cortex, and (iv) 80% of collosal projecting neurons between homologous cortical regions connect superficial layers. Our results demonstrate for the first time that resting state fMRI is sensitive to structural connections between cortical layers (previously inferred through invasive studies), specifically in thalamo-cortical and cortico-cortical networks

Parameterized hemodynamic response function data of healthy individuals obtained from resting-state functional MRI in a 7T MRI scanner

Functional magnetic resonance imaging (fMRI), being an indirect measure of brain activity, is mathematically defined as a convolution of the unmeasured latent neural signal and the hemodynamic response function (HRF). The HRF is known to vary across the brain and across individuals, and it is modulated by neural as well as non-neural factors. Three parameters characterize the shape of the HRF, which is obtained by performing deconvolution on resting-state fMRI data: response height, time-to-peak and full-width at half-max. The data provided here, obtained from 47 healthy adults, contains these three HRF parameters at every voxel in the brain, as well as HRF parameters from the default-mode network (DMN). In addition, we have provided functional connectivity (FC) data from the same DMN regions, obtained for two cases: data with deconvolution (HRF variability minimized) and data with no deconvolution (HRF variability corrupted). This would enable researchers to compare regional changes in HRF with corresponding FC differences, to assess the impact of HRF variability on FC. Importantly, the data was obtained in a 7T MRI scanner. While most fMRI studies are conducted at lower field strengths, like 3T, ours is the first study to report HRF data obtained at 7T. FMRI data at ultra-high fields contains larger contributions from small vessels, consequently HRF variability is lower for small vessels at higher field strengths. This implies that findings made from this data would be more conservative than from data acquired at lower fields, such as 3T. Results obtained with this data and further interpretations are available in our recent research study (Rangaprakash et al., in press) [1]. This is a valuable dataset for studying HRF variability in conjunction with FC, and for developing the HRF profile in healthy individuals, which would have direct implications for fMRI data analysis, especially resting-state connectivity modeling. This is the first public HRF data at 7T