Neural networks of information processing in posttraumatic stress disorder: a functional magnetic resonance imaging study.

BACKGROUND: Neuroimaging studies report reduced medial prefrontal cortical (particularly anterior cingulate) but enhanced amygdala response to fear signals in posttraumatic Stress Disorder (PTSD). We investigated whether anterior cingulate-amygdala dysregulation in PTSD would generalize to salient, but nonthreat related signals. METHODS: Individuals with PTSD (n = 14) and age and sex-matched nontraumatized controls (n = 14) completed an auditory oddball paradigm adapted to functional magnetic resonance imaging at a 1.5-T field strength. RESULTS: Controls displayed bilateral activation in ventral anterior cingulate and amygdala networks, and PTSD subjects showed bilateral dorsal anterior cingulate and amygdala activation to targets relative to nontargets. Compared to controls, PTSD subjects showed enhanced responses to targets in the dorsal and rostral anterior cingulate, and left amygdala. Whole-brain analyses confirmed the expected pattern of distributed prefrontal-parietal responses to targets in the oddball task. Greater activity in posterior parietal somatosensory regions was observed in PTSD. CONCLUSIONS: Our findings of enhanced anterior cingulate responses in PTSD contrast with reports of reduced activity for threat stimuli, suggesting that the latter may be specific to processing of threat-related content. Activation in rostral and dorsal anterior cingulate, left amygdala and posterior parietal networks in response to salient, nonthreatening stimuli may reflect generalized hypervigilance.     

Disrupted amygdala-prefrontal functional connectivity in civilian women with posttraumatic stress disorder

Many features of posttraumatic stress disorder (PTSD) can be linked to exaggerated and dysregulated emotional responses. Central to the neurocircuitry regulating emotion are functional interactions between the amygdala and the ventromedial prefrontal cortex (vmPFC). Findings from human and animal studies suggest that disruption of this circuit predicts individual differences in emotion regulation. However, only a few studies have examined amygdala-vmPFC connectivity in the context of emotional processing in PTSD. The aim of the present research was to investigate the hypothesis that PTSD is associated with disrupted functional connectivity of the amygdala and vmPFC in response to emotional stimuli, extending previous findings by demonstrating such links in an understudied, highly traumatized, civilian population. 40 African-American women with civilian trauma (20 with PTSD and 20 non-PTSD controls) were recruited from a large urban hospital. Participants viewed fearful and neutral face stimuli during functional magnetic resonance imaging (fMRI). Relative to controls, participants with PTSD showed an increased right amygdala response to fearful stimuli (p_corr < .05). Right amygdala activation correlated positively with the severity of hyperarousal symptoms in the PTSD group. Participants with PTSD showed decreased functional connectivity between the right amygdala and left vmPFC (p_corr < .05). The findings are consistent with previous findings showing PTSD is associated with an exaggerated response of amygdala-mediated emotional arousal systems. This is the first study to show that the amygdala response may be accompanied by disruption of an amygdala-vmPFC functional circuit that is hypothesized to be involved in prefrontal cortical regulation of amygdala responsivity.     

Resting-state functional connectivity of anterior and posterior hippocampus in posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) has been associated with altered resting-state functional connectivity (rs-FC) of several brain regions within the salience (SN) and default-mode (DMN) networks, including the hippocampus. However, most rs-FC studies have not focused primarily on the hippocampus, nor have they appreciated its structural heterogeneity, despite clear evidence for a dissociation between posterior and anterior hippocampal connectivity. Here, we examine rs-FC of anterior and posterior hippocampus with key regions in the SN (amygdala, insula, and dorsal anterior cingulate cortex/pre-supplementary motor area) and DMN (ventromedial prefrontal cortex, posterior cingulate cortex, and precuneus) previously implicated in PTSD, using a seed-based approach. Resting-state magnetic resonance images were obtained from 48 PTSD patients and 34 trauma-exposed healthy participants (TEHC). Results indicated no group differences when examining the hippocampus as a whole. However, examining the anterior and posterior hippocampus revealed a loss of anterior to posterior connectivity differentiation in PTSD patients. The PTSD group also demonstrated lower negative connectivity of the posterior hippocampus-precuneus pathway compared with the TEHC group. Finally, as differences in anterior and posterior hippocampus connectivity have been also related to age, we performed a secondary analysis exploring the association between age and posterior- and anterior-hippocampus connectivity in both groups. Results showed that among PTSD patients, increased age had the effect of normalizing posterior hippocampus-precuneus and hippocampus-posterior cingulate cortex connectivity, whereas no such effect was noted for the control group. These findings highlight the need for PTSD connectivity research to consider sub-parts of the hippocampus and to account for age-related connectivity differences.     

The cerebellum after trauma: Resting‐state functional connectivity of the cerebellum in posttraumatic stress disorder and its dissociative subtype

The cerebellum plays a key role not only in motor function but also in affect and cognition. Although several psychopathological disorders have been associated with overall cerebellar dysfunction, it remains unclear whether different regions of the cerebellum contribute uniquely to psychopathology. Accordingly, we compared seed‐based resting‐state functional connectivity of the anterior cerebellum (lobule IV–V), of the posterior cerebellum (Crus I), and of the anterior vermis across posttraumatic stress disorder (PTSD; n = 65), its dissociative subtype (PTSD + DS; n = 37), and non‐trauma‐exposed healthy controls (HC; n = 47). Here, we observed decreased functional connectivity of the anterior cerebellum and anterior vermis with brain regions involved in somatosensory processing, multisensory integration, and bodily self‐consciousness (temporo‐parietal junction, postcentral gyrus, and superior parietal lobule) in PTSD + DS as compared to PTSD and HC. Moreover, the PTSD + DS group showed increased functional connectivity of the posterior cerebellum with cortical areas related to emotion regulation (ventromedial prefrontal and orbito‐frontal cortex, subgenual anterior cingulum) as compared to PTSD. By contrast, PTSD showed increased functional connectivity of the anterior cerebellum with cortical areas associated with visual processing (fusiform gyrus), interoceptive awareness (posterior insula), memory retrieval, and contextual processing (hippocampus) as compared to HC. Finally, we observed decreased functional connectivity between the posterior cerebellum and prefrontal regions involved in emotion regulation, in PTSD as compared to HC. These findings not only highlight the crucial role of each cerebellar region examined in the psychopathology of PTSD but also reveal unique alterations in functional connectivity distinguishing the dissociative subtype of PTSD versus PTSD.     

Resting‐state brain fluctuation and functional connectivity dissociate moral injury from posttraumatic stress disorder

Moral injury is closely associated with posttraumatic stress disorder (PTSD) and characterized by disturbances in social and moral cognition. Little is known about the neural underpinnings of moral injury, and whether the neural correlates are different between moral injury and PTSD. A sample of 26 U.S. military veterans (two females: 28–55 years old) were investigated to determine how subjective appraisals of morally injurious events measured by Moral Injury Event Scale (MIES) and PTSD symptoms are differentially related to spontaneous fluctuations indexed by amplitude of low frequency fluctuation (ALFF) as well as functional connectivity during resting‐state functional magnetic resonance imaging scanning. ALFF in the left inferior parietal lobule (L‐IPL) was positively associated with MIES subscores of transgressions, negatively associated with subscores of betrayals, and not related with PTSD symptoms. Moreover, functional connectivity between the L‐IPL and bilateral precuneus was positively related with PTSD symptoms and negatively related with MIES total scores. Our results provide the first evidence that morally injurious events and PTSD symptoms have dissociable neural underpinnings, and behaviorally distinct subcomponents of morally injurious events are different in neural responses. The findings increase our knowledge of the neural distinctions between moral injury and PTSD and may contribute to developing nosology and interventions for military veterans afflicted by moral injury.     

Nonlinear functional network connectivity in resting functional magnetic resonance imaging data

In this work, we focus on explicitly nonlinear relationships in functional networks. We introduce a technique using normalized mutual information (NMI) that calculates the nonlinear relationship between different brain regions. We demonstrate our proposed approach using simulated data and then apply it to a dataset previously studied by Damaraju et al. This resting‐state fMRI data included 151 schizophrenia patients and 163 age‐ and gender‐matched healthy controls. We first decomposed these data using group independent component analysis (ICA) and yielded 47 functionally relevant intrinsic connectivity networks. Our analysis showed a modularized nonlinear relationship among brain functional networks that was particularly noticeable in the sensory and visual cortex. Interestingly, the modularity appears both meaningful and distinct from that revealed by the linear approach. Group analysis identified significant differences in explicitly nonlinear functional network connectivity (FNC) between schizophrenia patients and healthy controls, particularly in the visual cortex, with controls showing more nonlinearity (i.e., higher normalized mutual information between time courses with linear relationships removed) in most cases. Certain domains, including subcortical and auditory, showed relatively less nonlinear FNC (i.e., lower normalized mutual information), whereas links between the visual and other domains showed evidence of substantial nonlinear and modular properties. Overall, these results suggest that quantifying nonlinear dependencies of functional connectivity may provide a complementary and potentially important tool for studying brain function by exposing relevant variation that is typically ignored. Beyond this, we propose a method that captures both linear and nonlinear effects in a “boosted” approach. This method increases the sensitivity to group differences compared to the standard linear approach, at the cost of being unable to separate linear and nonlinear effects.     

Size versus shape differences: contrasting voxel-based and volumetric analyses of the anterior cingulate cortex in individuals with acute posttraumatic stress disorder.

BACKGROUND: Two studies found morphological differences in the anterior cingulate cortex (ACC) of individuals with chronic posttraumatic stress disorder (PTSD). We sought to replicate and extend these findings in a sample of individuals with acute PTSD. METHODS: The ACCs of individuals with acute PTSD (n = 14) and matched healthy control subjects (n = 14) were compared using voxel-based morphometry (VBM), semi-automated volumetric analyses, and probabilistic maps. Posttraumatic stress disorder diagnosis was ascertained by a psychologist using a structured interview. RESULTS: Voxel-based morphometry analyses revealed significantly less gray-matter density in the right pregenual ACC and in the left insula of the PTSD group. However, volumetric analyses of the ACC revealed no significant differences between groups. Probabilistic maps of the labels of the pregenual ACC indicated that the difference between groups in gray matter density was due to shape differences. CONCLUSIONS: Although there are no volumetric differences in the ACC of acute PTSD individuals compared with normal control subjects, significant shape differences exist, which might indicate volumetric differences in the surrounding structures.     

Dissimilarity of functional connectivity uncovers the influence of participant's motion in functional magnetic resonance imaging studies

Head motion is a major confounding factor impairing the quality of functional magnetic resonance imaging (fMRI) data. In particular, head motion can reduce analytical efficiency, and its effects are still present even after preprocessing. To examine the validity of motion removal and to evaluate the remaining effects of motion on the quality of the preprocessed fMRI data, a new metric of group quality control (QC), dissimilarity of functional connectivity, is introduced. Here, we investigate the association between head motion, represented by mean framewise displacement, and dissimilarity of functional connectivity by applying four preprocessing methods in two independent resting‐state fMRI datasets: one consisting of healthy participants (N = 167) scanned in a 3T GE‐Discovery 750 with longer TR (2.5 s), and the other of chronic back pain patients (N = 143) in a 3T Siemens Magnetom Prisma scanner with shorter TR (0.555 s). We found that dissimilarity of functional connectivity uncovers the influence of participant''s motion, and this relationship is independent of population, scanner, and preprocessing method. The association between motion and dissimilarity of functional connectivity, and how the removal of high‐motion participants affects this association, is a new strategy for group‐level QC following preprocessing.     

Higher-order functional connectivity analysis of resting-state functional magnetic resonance imaging data using multivariate cumulants

Blood-level oxygenation-dependent (BOLD) functional magnetic resonance imaging (fMRI) is the most common modality to study functional connectivity in the human brain. Most research to date has focused on connectivity between pairs of brain regions. However, attention has recently turned towards connectivity involving more than two regions, that is, higher-order connectivity. It is not yet clear how higher-order connectivity can best be quantified. The measures that are currently in use cannot distinguish between pairwise (i.e., second-order) and higher-order connectivity. We show that genuine higher-order connectivity can be quantified by using multivariate cumulants. We explore the use of multivariate cumulants for quantifying higher-order connectivity and the performance of block bootstrapping for statistical inference. In particular, we formulate a generative model for fMRI signals exhibiting higher-order connectivity and use it to assess bias, standard errors, and detection probabilities. Application to resting-state fMRI data from the Human Connectome Project demonstrates that spontaneous fMRI signals are organized into higher-order networks that are distinct from second-order resting-state networks. Application to a clinical cohort of patients with multiple sclerosis further demonstrates that cumulants can be used to classify disease groups and explain behavioral variability. Hence, we present a novel framework to reliably estimate genuine higher-order connectivity in fMRI data which can be used for constructing hyperedges, and finally, which can readily be applied to fMRI data from populations with neuropsychiatric disease or cognitive neuroscientific experiments.     

A magnetic resonance imaging study of cortical thickness in animal phobia

Background

Despite the high prevalence of specific phobia (SP), its neural substrates remain undetermined. Although an initial series of functional neuroimaging studies have implicated paralimbic and sensory cortical regions in the pathophysiology of SP, to date contemporary morphometric neuroimaging methods have not been applied to test specific hypotheses regarding structural abnormalities.

Methods

Morphometric magnetic resonance imaging (MRI) methods were used to measure regional cortical thickness in 10 subjects with SP (animal type) and 20 healthy comparison (HC) subjects.

Results

Consistent with a priori hypotheses, between-group differences in cortical thickness were found within paralimbic and sensory cortical regions. Specifically, in comparison with the HC group, the SP group exhibited increased cortical thickness in bilateral insular, bilateral pregenual anterior cingulate, and bilateral posterior cingulate cortex as well as left visual cortical regions.

Conclusions

Taken together, these structural findings parallel results from initial functional imaging studies that implicate paralimbic and sensory cortical regions in the mediating anatomy of SP symptoms. Further research will be necessary to replicate these findings and to determine their specificity as well as their pathophysiologic significance.     

Two systems of resting state connectivity between the insula and cingulate cortex

The insula and cingulate cortices are implicated in emotional, homeostatic/allostatic, sensorimotor, and cognitive functions. Non‐human primates have specific anatomical connections between sub‐divisions of the insula and cingulate. Specifically, the anterior insula projects to the pregenual anterior cingulate cortex (pACC) and the anterior and posterior mid‐cingulate cortex (aMCC and pMCC); the mid‐posterior insula only projects to the posterior MCC (pMCC). In humans, functional neuroimaging studies implicate the anterior insula and pre/subgenual ACC in emotional processes, the mid‐posterior insula with awareness and interoception, and the MCC with environmental monitoring, response selection, and skeletomotor body orientation. Here, we tested the hypothesis that distinct resting state functional connectivity could be identified between (1) the anterior insula and pACC/aMCC; and (2) the entire insula (anterior, middle, and posterior insula) and the pMCC. Functional connectivity was assessed from resting state fMRI scans in 19 healthy volunteers using seed regions of interest in the anterior, middle, and posterior insula. Highly correlated, low‐frequency oscillations (< 0.05 Hz) were identified between specific insula and cingulate subdivisions. The anterior insula was shown to be functionally connected with the pACC/aMCC and the pMCC, while the mid/posterior insula was only connected with the pMCC. These data provide evidence for a resting state anterior insula–pACC/aMCC cingulate system that may integrate interoceptive information with emotional salience to form a subjective representation of the body; and another system that includes the entire insula and MCC, likely involved in environmental monitoring, response selection, and skeletomotor body orientation. Human Brain Mapp 2009. © 2008 Wiley‐Liss, Inc.     

Abnormal functional architecture of amygdala‐centered networks in adolescent posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is a prevalent, debilitating, and difficult to treat psychiatric disorder. Very little is known of how PTSD affects neuroplasticity in the developing adolescent brain. Whereas multiple lines of research implicate amygdala‐centered network dysfunction in the pathophysiology of adult PTSD, no study has yet examined the functional architecture of amygdala subregional networks in adolescent PTSD. Using intrinsic functional connectivity analysis, we investigated functional connectivity of the basolateral (BLA) and centromedial (CMA) amygdala in 19 sexually abused adolescents with PTSD relative to 23 matched controls. Additionally, we examined whether altered amygdala subregional connectivity coincides with abnormal grey matter volume of the amygdaloid complex. Our analysis revealed abnormal amygdalar connectivity and morphology in adolescent PTSD patients. More specifically, PTSD patients showed diminished right BLA connectivity with a cluster including dorsal and ventral portions of the anterior cingulate and medial prefrontal cortices (p < 0.05, corrected). In contrast, PTSD patients showed increased left CMA connectivity with a cluster including the orbitofrontal and subcallosal cortices (p < 0.05, corrected). Critically, these connectivity changes coincided with diminished grey matter volume within BLA and CMA subnuclei (p < 0.05, corrected), with CMA connectivity shifts additionally relating to more severe symptoms of PTSD. These findings provide unique insights into how perturbations in major amygdalar circuits could hamper fear regulation and drive excessive acquisition and expression of fear in PTSD. As such, they represent an important step toward characterizing the neurocircuitry of adolescent PTSD, thereby informing the development of reliable biomarkers and potential therapeutic targets. Hum Brain Mapp 37:1120–1135, 2016. © 2016 Wiley Periodicals, Inc .     

Test–retest reliability of dynamic functional connectivity in naturalistic paradigm functional magnetic resonance imaging

Dynamic functional connectivity (dFC) has been increasingly used to characterize the brain transient temporal functional patterns and their alterations in diseased brains. Meanwhile, naturalistic neuroimaging paradigms have been an emerging approach for cognitive neuroscience with high ecological validity. However, the test–retest reliability of dFC in naturalistic paradigm neuroimaging is largely unknown. To address this issue, we examined the test–retest reliability of dFC in functional magnetic resonance imaging (fMRI) under natural viewing condition. The intraclass correlation coefficients (ICC) of four dFC statistics including standard deviation (Std), coefficient of variation (COV), amplitude of low frequency fluctuation (ALFF), and excursion (Excursion) were used to measure the test–retest reliability. The test–retest reliability of dFC in naturalistic viewing condition was then compared with that under resting state. Our experimental results showed that: (a) Global test–retest reliability of dFC was much lower than that of static functional connectivity (sFC) in both resting‐state and naturalistic viewing conditions; (b) Both global and local (including visual, limbic and default mode networks) test–retest reliability of dFC could be significantly improved in naturalistic viewing condition compared to that in resting state; (c) There existed strong negative correlation between sFC and dFC, weak negative correlation between dFC and dFC‐ICC (i.e., ICC of dFC), as well as weak positive correlation between dFC‐ICC and sFC‐ICC (i.e., ICC of sFC). The present study provides novel evidence for the promotion of naturalistic paradigm fMRI in functional brain network studies.