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

Analysis Of Multichannel And Multimodal Biomedical Signals Using Recurrence Plot Based Techniques

For most of the naturally occurring signals, especially biomedical signals, the underlying physical process generating the signal is often not fully known, making it difficult to obtain a parametric model. Therefore, signal processing techniques are used to analyze the signal for non-parametrically characterizing the underlying system from which the signals are produced. Most of the real life systems are nonlinear and time varying, which poses a challenge while characterizing them. Additionally, multiple sensors are used to extract signals from such systems, resulting in multichannel signals which are inherently coupled. In this thesis, we counter this challenge by using Recurrence Plot based techniques for characterizing biomedical systems such as heart or brain, using signals such as heart rate variability (HRV), electroencephalogram(EEG) or functional magnetic resonance imaging (fMRI), respectively, extracted from them. In time series analysis, it is well known that a system can be represented by a trajectory in an N-dimensional state space, which completely represents an instance of the system behavior. Such a system characterization has been done using dynamical invariants such as correlation dimension, Lyapunov exponent etc. Takens has shown that when the state variables of the underlying system are not known, one can obtain a trajectory in ‘phase space’ using only the signals obtained from such a system. The phase space trajectory is topologically equivalent to the state space trajectory. This enables us to characterize the system behavior from only the signals sensed from them. However, estimation of correlation dimension, Lyapunov exponent, etc, are vulnerable to non-stationarities in the signal and require large number of sample points for accurate computation, both of which are important in the case of biomedical signals. Alternatively, a technique called Recurrence Plots (RP) has been proposed, which addresses these concerns, apart from providing additional insights. Measures to characterize RPs of single and two channel data are called Recurrence Quantification Analysis (RQA) and cross RQA (CRQA), respectively. These methods have been applied with a good measure of success in diverse areas. However, they have not been studied extensively in the context of experimental biomedical signals, especially multichannel data. In this thesis, the RP technique and its associated measures are briefly reviewed. Using the computational tools developed for this thesis, RP technique has been applied on select single channel, multichannel and multimodal (i.e. multiple channels derived from different modalities) biomedical signals. Connectivity analysis is demonstrated as post-processing of RP analysis on multichannel signals such as EEG and fMRI. Finally, a novel metric, based on the modification of a CRQA measure is proposed, which shows improved results. For the case of single channel signal, we have considered a large database of HRV signals of 112 subjects recorded for both normal and abnormal (anxiety disorder and depression disorder) subjects, in both supine and standing positions. Existing RQA measures, Recurrence Rate and Determinism, were used to distinguish between normal and abnormal subjects with an accuracy of 58.93%. A new measure, MLV has been introduced, using which a classification accuracy of 98.2% is obtained. Correlation between probabilities of recurrence (CPR) is a CRQA measure used to characterize phase synchronization between two signals. In this work, we demonstrate its utility with application to multimodal and multichannel biomedical signals. First, for the multimodal case, we have computed running CPR (rCPR), a modification proposed by us, which allows dynamic estimation of CPR as a function of time, on multimodal cardiac signals (electrocardiogram and arterial blood pressure) and demonstrated that the method can clearly detect abnormalities (premature ventricular contractions); this has potential applications in cardiac care such as assisted automated diagnosis. Second, for the multichannel case, we have used 16 channel EEG signals recorded under various physiological states such as (i) global epileptic seizure and pre-seizure and (ii) focal epilepsy. CPR was computed pair-wise between the channels and a CPR matrix of all pairs was formed. Contour plot of the CPR matrix was obtained to illustrate synchronization. Statistical analysis of CPR matrix for 16 subjects of global epilepsy showed clear differences between pre-seizure and seizure conditions, and a linear discriminant classifier was used in distinguishing between the two conditions with 100% accuracy. Connectivity analysis of multichannel EEG signals was performed by post-processing of the CPR matrix to understand global network-level characterization of the brain. Brain connectivity using thresholded CPR matrix of multichannel EEG signals showed clear differences in the number and pattern of connections in brain connectivity graph between epileptic seizure and pre-seizure. Corresponding brain headmaps provide meaningful insights about synchronization in the brain in those states. K-means clustering of connectivity parameters of CPR and linear correlation obtained from global epileptic seizure and pre-seizure showed significantly larger cluster centroid distances for CPR as opposed to linear correlation, thereby demonstrating the efficacy of CPR. The headmap in the case of focal epilepsy clearly enables us to identify the focus of the epilepsy which provides certain diagnostic value. Connectivity analysis on multichannel fMRI signals was performed using CPR matrix and graph theoretic analysis. Adjacency matrix was obtained from CPR matrices after thresholding it using statistical significance tests. Graph theoretic analysis based on communicability was performed to obtain community structures for awake resting and anesthetic sedation states. Concurrent behavioral data showed memory impairment due to anesthesia. Given the fact that previous studies have implicated the hippocampus in memory function, the CPR results showing the hippocampus within the community in awake state and out of it in anesthesia state, demonstrated the biological plausibility of the CPR results. On the other hand, results from linear correlation were less biologically plausible. In biological systems, highly synchronized and desynchronized systems are of interest rather than moderately synchronized ones. However, CPR is approximately a monotonic function of synchronization and hence can assume values which indicate moderate synchronization. In order to emphasize high synchronization/ desynchronization and de-emphasize moderate synchronization, a new method of Correlation Synchronization Convergence Time (CSCT) is proposed. It is obtained using an iterative procedure involving the evaluation of CPR for successive autocorrelations until CPR converges to a chosen threshold. CSCT was evaluated for 16 channel EEG data and corresponding contour plots and histograms were obtained, which shows better discrimination between synchronized and asynchronized states compared to the conventional CPR. This thesis has demonstrated the efficacy of RP technique and associated measures in characterizing various classes of biomedical signals. The results obtained are corroborated by well known physiological facts, and they provide physiologically meaningful insights into the functioning of the underlying biological systems, with potential diagnostic value in healthcare

FMRI hemodynamic response function (HRF) as a novel marker of brain function: applications for understanding obsessive-compulsive disorder pathology and treatment response

The hemodynamic response function (HRF) represents the transfer function linking neural activity with the functional MRI (fMRI) signal, modeling neurovascular coupling. Since HRF is influenced by non-neural factors, to date it has largely been considered as a confound or has been ignored in many analyses. However, underlying biophysics suggests that the HRF may contain meaningful correlates of neural activity, which might be unavailable through conventional fMRI metrics. Here, we estimated the HRF by performing deconvolution on resting-state fMRI data from a longitudinal sample of 25 healthy controls scanned twice and 44 adults with obsessive-compulsive disorder (OCD) before and after 4-weeks of intensive cognitive-behavioral therapy (CBT). HRF response height, time-to-peak and full-width at half-maximum (FWHM) in OCD were abnormal before treatment and normalized after treatment in regions including the caudate. Pre-treatment HRF predicted treatment outcome (OCD symptom reduction) with 86.4% accuracy, using machine learning. Pre-treatment HRF response height in the caudate head and time-to-peak in the caudate tail were top-predictors of treatment response. Time-to-peak in the caudate tail, a region not typically identified in OCD studies using conventional fMRI activation or connectivity measures, may carry novel importance. Additionally, pre-treatment response height in caudate head predicted post-treatment OCD severity (R = -0.48, P = 0.001), and was associated with treatment-related OCD severity changes (R = -0.44, P = 0.0028), underscoring its relevance. With HRF being a reliable marker sensitive to brain function, OCD pathology, and intervention-related changes, these results could guide future studies towards novel discoveries not possible through conventional fMRI approaches like standard BOLD activation or connectivity

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

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

Can excitatory neuromodulation change distorted perception of one's appearance?

Body dysmorphic disorder (BDD) is marked by preoccupation with misperceived appearance flaws. Previous functional magnetic resonance imaging (fMRI) studies have found reduced neural activity and connectivity of visual areas specialized for global/holistic visual processing in BDD [[1], [2], [3]], suggesting that aberrant dorsal visual system functioning might contribute to distorted perception. In this proof-of-concept study we tested if intermittent theta-burst stimulation (iTBS), a form of excitatory repetitive transcranial magnetic stimulation (rTMS), would enhance dorsal visual system utilization as quantified through dynamic effective connectivity (DEC) modeling [4]. This is a single-session study with the application of iTBS and an fMRI scan immediately afterwards (within 15 min after the stimulation). We hypothesized that those undergoing active iTBS would show enhanced connectivity in dorsal visual areas responsible for global/holistic visual processing compared with sham

Investigating the Correspondence of Clinical Diagnostic Grouping With Underlying Neurobiological and Phenotypic Clusters Using Unsupervised Machine Learning

Many brain-based disorders are traditionally diagnosed based on clinical interviews and behavioral assessments, which are recognized to be largely imperfect. Therefore, it is necessary to establish neuroimaging-based biomarkers to improve diagnostic precision. Resting-state functional magnetic resonance imaging (rs-fMRI) is a promising technique for the characterization and classification of varying disorders. However, most of these classification methods are supervised, i.e., they require a priori clinical labels to guide classification. In this study, we adopted various unsupervised clustering methods using static and dynamic rs-fMRI connectivity measures to investigate whether the clinical diagnostic grouping of different disorders is grounded in underlying neurobiological and phenotypic clusters. In order to do so, we derived a general analysis pipeline for identifying different brain-based disorders using genetic algorithm-based feature selection, and unsupervised clustering methods on four different datasets; three of them—ADNI, ADHD-200, and ABIDE—which are publicly available, and a fourth one—PTSD and PCS—which was acquired in-house. Using these datasets, the effectiveness of the proposed pipeline was verified on different disorders: Attention Deficit Hyperactivity Disorder (ADHD), Alzheimer's Disease (AD), Autism Spectrum Disorder (ASD), Post-Traumatic Stress Disorder (PTSD), and Post-Concussion Syndrome (PCS). For ADHD and AD, highest similarity was achieved between connectivity and phenotypic clusters, whereas for ASD and PTSD/PCS, highest similarity was achieved between connectivity and clinical diagnostic clusters. For multi-site data (ABIDE and ADHD-200), we report site-specific results. We also reported the effect of elimination of outlier subjects for all four datasets. Overall, our results suggest that neurobiological and phenotypic biomarkers could potentially be used as an aid by the clinician, in additional to currently available clinical diagnostic standards, to improve diagnostic precision. Data and source code used in this work is publicly available at https://github.com/xinyuzhao/identification-of-brain-based-disorders.git