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Abstract The agonist–antagonist myoneural interface (AMI) is an amputation surgery that preserves sensorimotor signaling mechanisms of the central-peripheral nervous systems. Our first neuroimaging study investigating AMI subjects conducted by Srinivasan et al. (2020) focused on task-based neural signatures, and showed evidence of proprioceptive feedback to the central nervous system. The study of resting state neural activity helps non-invasively characterize the neural patterns that prime task response. In this study on resting state functional magnetic resonance imaging in AMI subjects, we compared functional connectivity in patients with transtibial AMI (n = 12) and traditional (n = 7) amputations (TA). To test our hypothesis that we would find significant neurophysiological differences between AMI and TA subjects, we performed a whole-brain exploratory analysis to identify a seed region; namely, we conducted ANOVA, followed by t-test statistics to locate a seed in the salience network. Then, we implemented a seed-based connectivity analysis to gather cluster-level inferences contrasting our subject groups. We show evidence supporting our hypothesis that the AMI surgery induces functional network reorganization resulting in a neural configuration that significantly differs from the neural configuration after TA surgery. AMI subjects show significantly less coupling with regions functionally dedicated to selecting where to focus attention when it comes to salient stimuli. Our findings provide researchers and clinicians with a critical mechanistic understanding of the effect of AMI amputation on brain networks at rest, which has promising implications for improved neurorehabilitation and prosthetic control.

Abstract In individuals with body dysmorphic disorder (BDD), perceptual appearance distortions may be related to selective attention biases and aberrant visual scanning, contributing to imbalances in global vs. detailed visual processing. Treatments for the core symptom of perceptual distortions are underexplored in BDD; yet understanding their mechanistic effects on brain function is critical for rational treatment development. This study tested a behavioral strategy of visual-attention modification on visual system brain connectivity and eye behaviors. We acquired fMRI data in 37 unmedicated adults with BDD and 30 healthy controls. Participants viewed their faces naturalistically (naturalistic viewing), and holding their gaze on the image center (modulated viewing), monitored with an eye-tracking camera. We analyzed dynamic effective connectivity and visual fixation duration. Modulated viewing resulted in longer mean visual fixation duration compared to during naturalistic viewing, across groups. Further, modulated viewing resulted in stronger connectivity from occipital to parietal dorsal visual stream regions, also evident during the subsequent naturalistic viewing, compared with the initial naturalistic viewing, in BDD. Longer fixation duration was associated with a trend for stronger connectivity during modulated viewing. Those with more severe BDD symptoms had weaker dorsal visual stream connectivity during naturalistic viewing, and those with more negative appearance evaluations had weaker connectivity during modulated viewing. In sum, holding a constant gaze on a non-concerning area of one’s face may confer increased communication in the occipital/parietal dorsal visual stream, facilitating global/holistic visual processing. This effect shows persistence during subsequent naturalistic viewing. Results have implications for perceptual retraining treatment designs.

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.

In individuals with body dysmorphic disorder (BDD), perceptual appearance distortions may be related to imbalances in global vs. local visual processing. Understanding the mechanistic brain effects of potential interventions is crucial for rational treatment development. The dorsal visual stream (DVS) is tuned to rapid image presentation, facilitating global/holistic processing, whereas the ventral visual stream (VVS), responsible for local/detailed processing, reduces activation magnitude with shorter stimulus duration. This study tested a strategy of rapid, short-duration face presentation on visual system connectivity. Thirty-eight unmedicated adults with BDD and 29 healthy controls viewed photographs of their faces for short (125 ms, 250 ms, 500 ms) and long (3000 ms) durations during fMRI scan. Dynamic effective connectivity in DVS and VVS was analyzed. BDD individuals exhibited weaker connectivity from occipital to parietal DVS areas than controls for all stimuli durations. Short compared with long viewing durations (125 ms vs. 3,000 ms and 500 ms vs. 3,000 ms) resulted in significantly weaker VVS connectivity from calcarine cortex to inferior occipital gyri in controls; however, there was only a trend for similar results in BDD. The DVS to VVS ratio, representing a balance between global and local processing, incrementally increased with shorter viewing durations in BDD, although it was not statistically significant. In sum, visual systems in those with BDD are not as responsive as in controls to rapid face presentation. Whether rapid face presentation could reduce connectivity in visual systems responsible for local/detailed processing in BDD may necessitate different parameters or strategies. These results provide mechanistic insights for perceptual retraining treatment designs.

Abstract Various machine-learning classification techniques have been employed previously to classify brain states in healthy and disease populations using functional magnetic resonance imaging (fMRI). These methods generally use supervised classifiers that are sensitive to outliers and require labeling of training data to generate a predictive model. Density-based clustering, which overcomes these issues, is a popular unsupervised learning approach whose utility for high-dimensional neuroimaging data has not been previously evaluated. Its advantages include insensitivity to outliers and ability to work with unlabeled data. Unlike the popular k-means clustering, the number of clusters need not be specified. In this study, we compare the performance of two popular density-based clustering methods, DBSCAN and OPTICS, in accurately identifying individuals with three stages of cognitive impairment, including Alzheimer’s disease. We used static and dynamic functional connectivity features for clustering, which captures the strength and temporal variation of brain connectivity respectively. To assess the robustness of clustering to noise/outliers, we propose a novel method called recursive-clustering using additive-noise (R-CLAN). Results demonstrated that both clustering algorithms were effective, although OPTICS with dynamic connectivity features outperformed in terms of cluster purity (95.46%) and robustness to noise/outliers. This study demonstrates that density-based clustering can accurately and robustly identify diagnostic classes in an unsupervised way using brain connectivity.

Abstract Objective It is important to identify brain-based biomarkers that progressively deteriorate from healthy to mild cognitive impairment (MCI) to Alzheimer’s disease (AD). Cortical thickness, amyloid-ß deposition, and graph measures derived from functional connectivity (FC) networks obtained using functional MRI (fMRI) have been previously identified as potential biomarkers. Specifically, in the latter case, betweenness centrality (BC), a nodal graph measure quantifying information flow, is reduced in both AD and MCI. However, all such reports have utilized BC calculated from undirected networks that characterize synchronization rather than information flow, which is better characterized using directed networks. Methods Therefore, we estimated BC from directed networks using Granger causality (GC) on resting-state fMRI data (N = 132) to compare the following populations (p

This article provides data for five different neuropsychiatric disorders—Attention Deficit Hyperactivity Disorder, Alzheimer's Disease, Autism Spectrum Disorder, Post-Traumatic Stress Disorder, and Post-Concussion Syndrome–along with healthy controls. The data includes clinical diagnostic labels, phenotypic variables, and resting-state functional magnetic resonance imaging connectivity features obtained from individuals. In addition, it provides the source MATLAB codes used for data analyses. Three existing clustering methods have been incorporated into the provided code, which do not require a priori specification of the number of clusters. A genetic algorithm based feature selection method has also been included to find the relevant subset of features and clustering the subset of data simultaneously. Findings from this data set and further detailed interpretations are available in our recent research study (Zhao et al., 2017) [1]. This contribution is a valuable asset for performing unsupervised machine learning on fMRI data to investigate the correspondence of clinical diagnostic grouping with the underlying neurobiological/phenotypic clusters. Keywords: Functional magnetic resonance imaging, Functional connectivity, Effective connectivity, Unsupervised learning, Clustering, Genetic algorithm, Psychiatric disorders

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the central nervous system that results in a progressive loss of motor function and ultimately death. It is critical, yet also challenging, to develop non-invasive biomarkers to identify, localize, measure and/or track biological mechanisms implicated in ALS. Such biomarkers may also provide clues to identify potential molecular targets for future therapeutic trials. Herein we report on a pilot study involving twelve participants with ALS and nine age-matched healthy controls who underwent high-resolution resting state functional magnetic resonance imaging at an ultra-high field of 7 Tesla. A group-level whole-brain analysis revealed a disruption in long-range functional connectivity between the superior sensorimotor cortex (in the precentral gyrus) and bilateral cerebellar lobule VI. Post hoc analyses using atlas-derived left and right cerebellar lobule VI revealed decreased functional connectivity in ALS participants that predominantly mapped to bilateral postcentral and precentral gyri. Cerebellar lobule VI is a transition zone between anterior motor networks and posterior non-motor networks in the cerebellum, and is associated with a wide range of key functions including complex motor and cognitive processing tasks. Our observation of the involvement of cerebellar lobule VI adds to the growing number of studies implicating the cerebellum in ALS. Future avenues of scientific investigation should consider how high-resolution imaging at 7T may be leveraged to visualize differences in functional connectivity disturbances in various genotypes and phenotypes of ALS along the ALS-frontotemporal dementia spectrum.

Resting-state functional Magnetic Resonance Imaging (rs-fMRI) has been extensively used for diagnostic classification because it does not require task compliance and is easier to pool data from multiple imaging sites, thereby increasing the sample size. A MATLAB-based toolbox called Machine Learning in NeuroImaging (MALINI) for feature extraction and disease classification is presented. The MALINI toolbox extracts functional and effective connectivity features from preprocessed rs-fMRI data and performs classification between healthy and disease groups using any of 18 popular and widely used machine learning algorithms that are based on diverse principles. A consensus classifier combining the power of multiple classifiers is also presented. The utility of the toolbox is illustrated by accompanying data consisting of resting-state functional connectivity features from healthy controls and subjects with various brain-based disorders: autism spectrum disorder from autism brain imaging data exchange (ABIDE), Alzheimer's disease and mild cognitive impairment from Alzheimer's disease neuroimaging initiative (ADNI), attention deficit hyperactivity disorder from ADHD-200, and post-traumatic stress disorder and post-concussion syndrome acquired in-house. Results of classification performed on the above datasets can be obtained from the main article titled “Supervised machine learning for diagnostic classification from large-scale neuroimaging datasets” [1]. The data was divided into homogeneous and heterogeneous splits, such that 80% could be used for training, model building and cross-validation, while the remaining 20% of the data could be used as a hold-out independent test data for replication of the classification performance, to ensure the robustness of the classifiers to population variance in image acquisition site and age of the sample. Keywords: Resting-state functional MRI, Supervised machine learning, Diagnostic classification, Functional connectivity, Autism, ADHD, Alzheimer's disease, PTSD

In Functional magnetic resonance imaging (fMRI), the blood oxygen level dependent (BOLD) signal is modeled as a convolution of the hemodynamic response function (HRF) and the unmeasured latent neural signal. Although most cortical and subcortical brain regions share the canonical shape of the HRF, the temporal structure of HRFs are variable across brain regions and subjects. This variability is induced by both neural and non-neural factors. The variability between subjects can be examined by three parameters that characterize the HRF: response height (RH), time-to-peak (TTP) and full-width at half-max (FWHM). This data provides three HRF parameters at every voxel, obtained from Autism Spectrum Disorder (ASD) patients (N = 531), and matched healthy controls (N = 571). Since ongoing studies suggest that non-standard populations have important differences in their HRFs when compared with healthy control, this data set is valuable in studying variability of HRF in ASD group and inferring the underlying pathology that also affects the HRF. It also has implications for fMRI analyses like resting-sate connectivity analysis.

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.

Functional MRI (fMRI) is modeled as a convolution of the hemodynamic response function (HRF) and an unmeasured latent neural signal. However, HRF itself is variable across brain regions and subjects. This variability is induced by both neural and non-neural factors. Aberrations in underlying neurochemical mechanisms, which control HRF shape, have been reported in autism spectrum disorders (ASD). Therefore, we hypothesized that this will lead to voxel-specific, yet systematic differences in HRF shape between ASD and healthy controls. As a corollary, we also hypothesized that such alterations will lead to differences in estimated functional connectivity in fMRI space compared to latent neural space. To test these hypotheses, we performed blind deconvolution of resting-state fMRI time series acquired from large number of ASD and control subjects obtained from the Autism Brain Imaging Data Exchange (ABIDE) database (N = 1102). Many brain regions previously implicated in autism showed systematic differences in HRF shape in ASD. Specifically, we found that precuneus had aberrations in all HRF parameters. Consequently, we obtained precuneus-seed-based functional connectivity differences between ASD and controls using fMRI as well as using latent neural signals. We found that non-deconvolved fMRI data failed to detect group differences in connectivity between precuneus and certain brain regions that were instead observed in deconvolved data. Our results are relevant for the understanding of hemodynamic and neurochemical aberrations in ASD, as well as have methodological implications for resting-state functional connectivity studies in Autism, and more generally in disorders that are accompanied by neurochemical alterations that may impact HRF shape. Keywords: Resting-state fMRI, Deconvolution, Autism, Hemodynamic response function (HRF), HRF variability, Seed-based functional connectivity

Functional magnetic resonance imaging (fMRI) is an indirect measure of brain activity, i.e. it is a convolution of the latent (unmeasured) neural signal and the hemodynamic response function (HRF). As such, the HRF has been shown to vary across brain regions and individuals. The shape of the HRF is controlled by both neural and non-neural factors. The shape of the HRF can be characterized by three parameters (response height, time-to-peak and full-width at half-max). The data presented here provides the three HRF parameters at every voxel, obtained from U.S. Army soldiers (N=87) diagnosed with posttraumatic stress disorder (PTSD), with comorbid PTSD and mild-traumatic brain injury (mTBI), and matched healthy combat controls. Findings from this data and further interpretations are available in our recent research study (Rangaprakash et al., 2017) [1]. This data is a valuable asset in studying the impact of HRF variability on fMRI data analysis, specifically resting state functional connectivity.

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. Keywords: Functional magnetic resonance imaging, Hemodynamic response function variability, Functional connectivity, Posttraumatic stress disorder, Mild-traumatic brain injury

Brain functioning relies on various segregated/specialized neural regions functioning as an integrated-interconnected network (i.e., metastability). Various psychiatric and neurologic disorders are associated with aberrant functioning of these brain networks. In this study, we present a novel framework integrating the strength and temporal variability of metastability in brain networks. We demonstrate that this approach provides novel mechanistic insights which enables better imaging-based predictions. Using whole-brain resting-state fMRI and a graph-theoretic framework, we integrated strength and temporal-variability of complex-network properties derived from effective connectivity networks, obtained from 87 U.S. Army soldiers consisting of healthy combat controls (n = 28), posttraumatic stress disorder (PTSD; n = 17), and PTSD with comorbid mild-traumatic brain injury (mTBI; n = 42). We identified prefrontal dysregulation of key subcortical and visual regions in PTSD/mTBI, with all network properties exhibiting lower variability over time, indicative of poorer flexibility. Larger impairment in the prefrontal-subcortical pathway but not prefrontal-visual pathway differentiated comorbid PTSD/mTBI from the PTSD group. Network properties of the prefrontal-subcortical pathway also had significant association (R2 = 0.56) with symptom severity and neurocognitive performance; and were also found to possess high predictive ability (81.4% accuracy in classifying the disorders, explaining 66–72% variance in symptoms), identified through machine learning. Our framework explained 13% more variance in behaviors compared to the conventional framework. These novel insights and better predictions were made possible by our novel framework using static and time-varying network properties in our three-group scenario, advancing the mechanistic understanding of PTSD and comorbid mTBI. Our contribution has wide-ranging applications for network-level characterization of healthy brains as well as mental disorders.

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.

Anorexia nervosa (AN) and body dysmorphic disorder (BDD) share distorted perceptions of appearance with extreme negative emotion, yet the neural phenotypes of emotion processing remain underexplored in them, and they have never been directly compared. We sought to determine if shared and disorder-specific fronto-limbic connectivity patterns characterize these disorders. FMRI data was obtained from three unmedicated groups: BDD (n = 32), weight-restored AN (n = 25), and healthy controls (HC; n = 37), while they viewed fearful faces and rated their own degree of fearfulness in response. We performed dynamic effective connectivity modeling with medial prefrontal cortex (mPFC), rostral anterior cingulate cortex (rACC), and amygdala as regions-of-interest (ROI), and assessed associations between connectivity and clinical variables. HCs exhibited significant within-group bidirectional mPFC-amygdala connectivity, which increased across the blocks, whereas BDD participants exhibited only significant mPFC-to-amygdala connectivity (P < 0.05, family-wise error corrected). In contrast, participants with AN lacked significant prefrontal-amygdala connectivity in either direction. AN showed significantly weaker mPFC-to-amygdala connectivity compared to HCs (P = 0.0015) and BDD (P = 0.0050). The mPFC-to-amygdala connectivity was associated with greater subjective fear ratings (R2 = 0.11, P = 0.0016), eating disorder symptoms (R2 = 0.33, P = 0.0029), and anxiety (R2 = 0.29, P = 0.0055) intensity scores. Our findings, which suggest a complex nosological relationship, have implications for understanding emotion regulation circuitry in these related psychiatric disorders, and may have relevance for current and novel therapeutic approaches.

A Brain-Computer Interface (BCI) is a setup permitting the control of external devices by decoding brain activity. Electroencephalography (EEG) has been extensively used for decoding brain activity since it is non-invasive, cheap, portable, and has high temporal resolution to allow real-time operation. Due to its poor spatial specificity, BCIs based on EEG can require extensive training and multiple trials to decode brain activity (consequently slowing down the operation of the BCI). On the other hand, BCIs based on functional magnetic resonance imaging (fMRI) are more accurate owing to its superior spatial resolution and sensitivity to underlying neuronal processes which are functionally localized. However, due to its relatively low temporal resolution, high cost, and lack of portability, fMRI is unlikely to be used for routine BCI. We propose a new approach for transferring the capabilities of fMRI to EEG, which includes simultaneous EEG/fMRI sessions for finding a mapping from EEG to fMRI, followed by a BCI run from only EEG data, but driven by fMRI-like features obtained from the mapping identified previously. Our novel data-driven method is likely to discover latent linkages between electrical and hemodynamic signatures of neural activity hitherto unexplored using model-driven methods, and is likely to serve as a template for a novel multi-modal strategy wherein cross-modal EEG-fMRI interactions are exploited for the operation of a unimodal EEG system, leading to a new generation of EEG-based BCIs.