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.

Automated recognition and classification of brain diseases are of tremendous value to society. Attention deficit hyperactivity disorder (ADHD) is a diverse spectrum disorder whose diagnosis is based on behavior and hence will benefit from classification utilizing objective neuroimaging measures. Toward this end, an international competition was conducted for classifying ADHD using functional magnetic resonance imaging data acquired from multiple sites worldwide. Here, we consider the data from this competition as an example to illustrate the utility of fully connected cascade (FCC) artificial neural network (ANN) architecture for performing classification. We employed various directional and nondirectional brain connectivity-based methods to extract discriminative features which gave better classification accuracy compared to raw data. Our accuracy for distinguishing ADHD from healthy subjects was close to 90% and between the ADHD subtypes was close to 95%. Further, we show that, if properly used, FCC ANN performs very well compared to other classifiers such as support vector machines in terms of accuracy, irrespective of the feature used. Finally, the most discriminative connectivity features provided insights about the pathophysiology of ADHD and showed reduced and altered connectivity involving the left orbitofrontal cortex and various cerebellar regions in ADHD.

Using resting-state functional magnetic resonance imaging, we test the hypothesis that subjects with post-traumatic stress disorder (PTSD) are characterized by reduced temporal variability of brain connectivity compared to matched healthy controls. Specifically, we test whether PTSD is characterized by elevated static connectivity, coupled with decreased temporal variability of those connections, with the latter providing greater sensitivity toward the pathology than the former. Static functional connectivity (FC; nondirectional zero-lag correlation) and static effective connectivity (EC; directional time-lagged relationships) were obtained over the entire brain using conventional models. Dynamic FC and dynamic EC were estimated by letting the conventional models to vary as a function of time. Statistical separation and discriminability of these metrics between the groups and their ability to accurately predict the diagnostic label of a novel subject were ascertained using separate support vector machine classifiers. Our findings support our hypothesis that PTSD subjects have stronger static connectivity, but reduced temporal variability of connectivity. Further, machine learning classification accuracy obtained with dynamic FC and dynamic EC was significantly higher than that obtained with static FC and static EC, respectively. Furthermore, results also indicate that the ease with which brain regions engage or disengage with other regions may be more sensitive to underlying pathology than the strength with which they are engaged. Future studies must examine whether this is true only in the case of PTSD or is a general organizing principle in the human brain. Hum Brain Mapp 38:4479-4496, 2017. © 2017 Wiley Periodicals, Inc.

PTSD/mTBI are associated with hippocampal-striatal hyperconnectivity from which it is difficult to disengage, leading to a habit-like response toward episodic traumatic memories, which fits well with behavioral manifestations of combat-related PTSD/mTBI. Hum Brain Mapp 38:2843-2864, 2017. © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

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.

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7Alabama Advanced Imaging Consortium, USA r r Abstract: Brain connectivity studies report group differences in pairwise connection strengths. While informative, such results are difficult to interpret since our understanding of the brain relies on regionbased properties, rather than on connection information. Given that large disruptions in the brain are often caused by a few pivotal sources, we propose a novel framework to identify the sources of functional disruption from effective connectivity networks. Our approach integrates static and time-varying effective connectivity modeling in a probabilistic framework, to identify aberrant foci and the corresponding aberrant connectomics network. Using resting-state fMRI, we illustrate the utility of this novel approach in U.S. Army soldiers (N 5 87) with posttraumatic stress disorder (PTSD), mild traumatic brain injury (mTBI) and combat controls. Additionally, we employed machine-learning classification to identify those significant connectivity features that possessed high predictive ability. We identified three disrupted foci (middle frontal gyrus [MFG], insula, hippocampus), and an aberrant prefrontal-subcortical-parietal network of information flow. We found the MFG to be the pivotal focus of network disruption, with aberrant strength and temporal-variability of effective connectivity to the insula, amygdala and hippocampus. These connectivities also possessed high predictive ability (giving a classification accuracy of 81%); and they exhibited significant associations with symptom severity and neurocognitive functioning. In summary, dysregulation originating in the MFG caused elevated and temporally less-variable connectivity in subcortical regions, followed by a similar effect on parietal memory-related regions. This mechanism likely contributes to the reduced control over traumatic

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.