Does development moderate the effect of early life assaultive violence on resting-state networks? An exploratory study.

Current neurocircuitry models of PTSD do not account for developmental effects, despite that early life assaultive violence is a potent risk factor for PTSD. Here, we preliminarily evaluated developmental stage as a moderator of the effect of early life assaultive violence on resting-state connectivity amongst regions associated with emotion generation and regulation using fMRI. Participants were adult women (n = 25) and adolescent girls (n = 36) who had or had not experienced early life assaultive violence. We found significant interactions between developmental stage and trauma exposure on resting-state functional connectivity (FC). Left amygdala connectivity with the left ventral anterior cingulate gyrus (BA 32) was reduced among trauma-exposed compared to control adolescents, but increased among trauma-exposed compared to control adults. A corresponding pattern of results was identified for FC between rostral anterior cingulate gyrus seed region and a similar right ventral anterior superior frontal gyrus cluster. Increased FC in both regions for assaulted adult women scaled positively with self-reported emotion regulation difficulties. Our results should be viewed tentatively due to sample limitations, but provide impetus to examine whether neurocircuitry models of PTSD may be strengthened by accounting for developmental stage.

Large-scale brain organization during facial emotion processing as a function of early life trauma among adolescent girls.

Background: A wealth of research has investigated the impact of early life trauma exposure on functional brain activation during facial emotion processing and has often demonstrated amygdala hyperactivity and weakened connectivity between amygdala and medial PFC (mPFC). There have been notably limited investigations linking these previous node-specific findings into larger-scale network models of brain organization. Method: To address these gaps, we applied graph theoretical analyses to fMRI data collected during a facial emotion processing task among 88 adolescent girls (n = 59 exposed to direct physical or sexual assault; n = 29 healthy controls), aged 11-17, during fMRI. Large-scale organization indices of modularity, assortativity, and global efficiency were calculated for stimulus-specific functional connectivity using an 883 region-of-interest parcellation. Results: Among the entire sample, more severe early life trauma was associated with more modular and assortative, but less globally efficient, network organization across all stimulus categories. Among the assaulted girls, severity of early life trauma and PTSD diagnoses were both simultaneously related to increased modular brain organization. We also found that more modularized network organization was related both to amygdala hyperactivation and weakened connectivity between amygdala and medial PFC. Conclusions: These results demonstrate that early life trauma is associated with enhanced brain organization during facial emotion processing and that this pattern of brain organization might explain the commonly observed association between childhood trauma and amygdala hyperactivity and weakened connectivity with mPFC. Implications of these results for neurocircuitry models are discussed.

Implicit emotion regulation in adolescent girls: An exploratory investigation of Hidden Markov Modeling and its neural correlates.

Numerous data demonstrate that distracting emotional stimuli cause behavioral slowing (i.e. emotional conflict) and that behavior dynamically adapts to such distractors. However, the cognitive and neural mechanisms that mediate these behavioral findings are poorly understood. Several theoretical models have been developed that attempt to explain these phenomena, but these models have not been directly tested on human behavior nor compared. A potential tool to overcome this limitation is Hidden Markov Modeling (HMM), which is a computational approach to modeling indirectly observed systems. Here, we administered an emotional Stroop task to a sample of healthy adolescent girls (N = 24) during fMRI and used HMM to implement theoretical behavioral models. We then compared the model fits and tested for neural representations of the hidden states of the most supported model. We found that a modified variant of the model posited by Mathews et al. (1998) was most concordant with observed behavior and that brain activity was related to the model-based hidden states. Particularly, while the valences of the stimuli themselves were encoded primarily in the ventral visual cortex, the model-based detection of threatening targets was associated with increased activity in the bilateral anterior insula, while task effort (i.e. adaptation) was associated with reduction in the activity of these areas. These findings suggest that emotional target detection and adaptation are accomplished partly through increases and decreases, respectively, in the perceived immediate relevance of threatening cues and also demonstrate the efficacy of using HMM to apply theoretical models to human behavior.

Modes of Large-Scale Brain Network Organization during Threat Processing and Posttraumatic Stress Disorder Symptom Reduction during TF-CBT among Adolescent Girls.

Posttraumatic stress disorder (PTSD) is often chronic and disabling across the lifespan. The gold standard treatment for adolescent PTSD is Trauma-Focused Cognitive-Behavioral Therapy (TF-CBT), though treatment response is variable and mediating neural mechanisms are not well understood. Here, we test whether PTSD symptom reduction during TF-CBT is associated with individual differences in large-scale brain network organization during emotion processing. Twenty adolescent girls, aged 11-16, with PTSD related to assaultive violence completed a 12-session protocol of TF-CBT. Participants completed an emotion processing task, in which neutral and fearful facial expressions were presented either overtly or covertly during 3T fMRI, before and after treatment. Analyses focused on characterizing network properties of modularity, assortativity, and global efficiency within an 824 region-of-interest brain parcellation separately during each of the task blocks using weighted functional connectivity matrices. We similarly analyzed an existing dataset of healthy adolescent girls undergoing an identical emotion processing task to characterize normative network organization. Pre-treatment individual differences in modularity, assortativity, and global efficiency during covert fear vs neutral blocks predicted PTSD symptom reduction. Patients who responded better to treatment had greater network modularity and assortativity but lesser efficiency, a pattern that closely resembled the control participants. At a group level, greater symptom reduction was associated with greater pre-to-post-treatment increases in network assortativity and modularity, but this was more pronounced among participants with less symptom improvement. The results support the hypothesis that modularized and resilient brain organization during emotion processing operate as mechanisms enabling symptom reduction during TF-CBT.

Amygdala response predicts trajectory of symptom reduction during Trauma-Focused Cognitive-Behavioral Therapy among adolescent girls with PTSD.

Trauma-Focused Cognitive-Behavioral Therapy (TF-CBT) is the gold standard treatment for pediatric PTSD. Nonetheless, clinical outcomes in TF-CBT are highly variable, indicating a need to identify reliable predictors that allow forecasting treatment response. Here, we test the hypothesis that functional neuroimaging correlates of emotion processing predict PTSD symptom reduction during Trauma-Focused Cognitive-Behavioral Therapy (TF-CBT) among adolescent girls with PTSD. Thirty-four adolescent girls with PTSD related to physical or sexual assault were enrolled in TF-CBT, delivered in an approximately 12 session format, in an open trial. Prior to treatment, they were engaged in an implicit threat processing task during 3T fMRI, during which they viewed faces depicting fearful or neutral expressions. Among adolescent girls completing TF-CBT (n = 23), slopes of PTSD symptom trajectories during TF-CBT were significantly related to pre-treatment degree of bilateral amygdala activation while viewing fearful vs neutral images. Adolescents with less symptom reduction were characterized by greater amygdala activation to both threat and neutral images (i.e., less threat-safety discrimination), whereas adolescents with greater symptom reduction were characterized by amygdala activation only to threat images. These clinical outcome relationships with pre-treatment bilateral amygdala activation remained when controlling for possible confounding demographic or clinical variables (e.g., concurrent psychotropic medication, comorbid diagnoses). While limited by a lack of a control group, these preliminary results suggest that pre-treatment amygdala reactivity to fear stimuli, a component of neurocircuitry models of PTSD, positively predicts symptom reduction during TF-CBT among assaulted adolescent girls, providing support for an objective measure for forecasting treatment response in this vulnerable population.

Decoding the Traumatic Memory among Women with PTSD: Implications for Neurocircuitry Models of PTSD and Real-Time fMRI Neurofeedback.

Posttraumatic Stress Disorder (PTSD) is characterized by intrusive recall of the traumatic memory. While numerous studies have investigated the neural processing mechanisms engaged during trauma memory recall in PTSD, these analyses have only focused on group-level contrasts that reveal little about the predictive validity of the identified brain regions. By contrast, a multivariate pattern analysis (MVPA) approach towards identifying the neural mechanisms engaged during trauma memory recall would entail testing whether a multivariate set of brain regions is reliably predictive of (i.e., discriminates) whether an individual is engaging in trauma or non-trauma memory recall. Here, we use a MVPA approach to test 1) whether trauma memory vs neutral memory recall can be predicted reliably using a multivariate set of brain regions among women with PTSD related to assaultive violence exposure (N=16), 2) the methodological parameters (e.g., spatial smoothing, number of memory recall repetitions, etc.) that optimize classification accuracy and reproducibility of the feature weight spatial maps, and 3) the correspondence between brain regions that discriminate trauma memory recall and the brain regions predicted by neurocircuitry models of PTSD. Cross-validation classification accuracy was significantly above chance for all methodological permutations tested; mean accuracy across participants was 76% for the methodological parameters selected as optimal for both efficiency and accuracy. Classification accuracy was significantly better for a voxel-wise approach relative to voxels within restricted regions-of-interest (ROIs); classification accuracy did not differ when using PTSD-related ROIs compared to randomly generated ROIs. ROI-based analyses suggested the reliable involvement of the left hippocampus in discriminating memory recall across participants and that the contribution of the left amygdala to the decision function was dependent upon PTSD symptom severity. These results have methodological implications for real-time fMRI neurofeedback of the trauma memory in PTSD and conceptual implications for neurocircuitry models of PTSD that attempt to explain core neural processing mechanisms mediating PTSD.

Brain and behavioral evidence for altered social learning mechanisms among women with assault-related posttraumatic stress disorder.

Current neurocircuitry models of PTSD focus on the neural mechanisms that mediate hypervigilance for threat and fear inhibition/extinction learning. Less focus has been directed towards explaining social deficits and heightened risk of revictimization observed among individuals with PTSD related to physical or sexual assault. The purpose of the present study was to foster more comprehensive theoretical models of PTSD by testing the hypothesis that assault-related PTSD is associated with behavioral impairments in a social trust and reciprocity task and corresponding alterations in the neural encoding of social learning mechanisms. Adult women with assault-related PTSD (n = 25) and control women (n = 15) completed a multi-trial trust game outside of the MRI scanner. A subset of these participants (15 with PTSD and 14 controls) also completed a social and non-social reinforcement learning task during 3T fMRI. Brain regions that encoded the computationally modeled parameters of value expectation, prediction error, and volatility (i.e., uncertainty) were defined and compared between groups. The PTSD group demonstrated slower learning rates during the trust game and social prediction errors had a lesser impact on subsequent investment decisions. PTSD was also associated with greater encoding of negative expected social outcomes in perigenual anterior cingulate cortex and bilateral middle frontal gyri, and greater encoding of social prediction errors in the left temporoparietal junction. These data suggest mechanisms of PTSD-related deficits in social functioning and heightened risk for re-victimization in assault victims; however, comorbidity in the PTSD group and the lack of a trauma-exposed control group temper conclusions about PTSD specifically.

Effects of childhood maltreatment on the neural correlates of stress- and drug cue-induced cocaine craving.

Childhood adversity negatively influences all stages of the addiction process and is associated with persistent alterations in neuroendocrine, autonomic and brain responses to stress. We sought to characterize the impact of childhood abuse and neglect on the neural correlates of stress- and drug cue-induced drug craving associated with cocaine addiction. Cocaine-dependent men with (n = 20) and without (n = 18) moderate to severe childhood maltreatment histories underwent functional magnetic resonance imaging during script-guided mental imagery of personalized stress, drug use and neutral experiences. Compared to the neutral script, the stress and drug use scripts activated striatal, prefrontal, posterior cingulate, temporal and cerebellar regions consistent with prior studies of induced states of stress and drug craving. For the stress script, maltreated men exhibited reduced activation of the anterior precuneus and supplementary motor area (SMA); the interaction of maltreatment severity and stress-induced craving responses predicted lesser rostral anterior cingulate cortex activation. For the drug use script, maltreated men exhibited greater left dorsolateral prefrontal cortex activation. The interaction of maltreatment severity and craving responses was associated with greater activation of the visual cortex and SMA, whereas a maltreatment-by-anxiety interaction effect included lesser ventromedial prefrontal cortex activation. The outcomes indicate an association of childhood maltreatment with a heightened appetitive anticipatory response to drug cues and a diminished engagement of regulatory and controlled action selection processes in response to stress- or drug cue-induced drug craving and anxiety responses for cocaine-dependent men. These findings provide novel insights into possible brain mechanisms by which childhood maltreatment heightens risk for relapse in drug-dependent individuals.

Attenuated behavioral and brain responses to trust violations among assaulted adolescent girls.

Physical and sexual assault during adolescence is a potent risk factor for mental health and psychosocial problems, as well as revictimization, especially among female victims. To better understand this conferred risk, we conducted an exploratory study comparing assaulted and non-assaulted girls׳ behavioral and brain responses during a trust learning task. Adolescent girls (14 assaulted, 16 non-assaulted) performed a functional magnetic resonance imaging task that manipulated the percentages of which three different faces delivered positive and negative outcomes. Analyses focused on comparing unexpected to expected outcomes. We found that assaulted adolescent girls demonstrated less behavioral slowing in response to unexpected negative social outcomes, or trust violations (i.e., when a presumably trustworthy face delivered a negative outcome), relative to control girls. Trust violations were also associated with less activation in anterior insular and anterior cingulate regions among the assaulted group compared to the control group. Furthermore, we found that the severity of participants׳ exposure to assaultive events scaled negatively with recruitment of these regions. These preliminary results suggest that assault victims may engage differential learning processes upon unexpected negative social outcomes. These findings have implications for understanding impaired trust learning and social functioning among assault victims.

Neural network activation during a stop-signal task discriminates cocaine-dependent from non-drug-abusing men.

Cocaine dependence is defined by a loss of inhibitory control over drug-use behaviors, mirrored by measurable impairments in laboratory tasks of inhibitory control. The current study tested the hypothesis that deficits in multiple subprocesses of behavioral control are associated with reliable neural-processing alterations that define cocaine addiction. While undergoing functional magnetic resonance imaging (fMRI), 38 cocaine-dependent men and 27 healthy control men performed a stop-signal task of motor inhibition. An independent component analysis on fMRI time courses identified task-related neural networks attributed to motor, visual, cognitive and affective processes. The statistical associations of these components with five different stop-signal task conditions were selected for use in a linear discriminant analysis to define a classifier for cocaine addiction from a subsample of 26 cocaine-dependent men and 18 controls. Leave-one-out cross-validation accurately classified 89.5% (39/44; chance accuracy = 26/44 = 59.1%) of subjects with 84.6% (22/26) sensitivity and 94.4% (17/18) specificity. The remaining 12 cocaine-dependent and 9 control men formed an independent test sample, for which accuracy of the classifier was 81.9% (17/21; chance accuracy = 12/21 = 57.1%) with 75% (9/12) sensitivity and 88.9% (8/9) specificity. The cocaine addiction classification score was significantly correlated with a measure of impulsiveness as well as the duration of cocaine use for cocaine-dependent men. The results of this study support the ability of a pattern of multiple neural network alterations associated with inhibitory motor control to define a binary classifier for cocaine addiction.

Functional reorganization of neural networks during repeated exposure to the traumatic memory in posttraumatic stress disorder: an exploratory fMRI study.

BACKGROUND: Repeated exposure to the traumatic memory (RETM) is a common component of treatments for posttraumatic stress disorder (PTSD). This treatment is based on a fear extinction model; however, the degree to which this treatment actually engages and modifies neural networks mediating fear extinction is unknown. Therefore, the purpose of the current exploratory study was to define the dynamic changes in neural processing networks while participants completed a novel adaptation of RETM. METHOD: Participants were adult women (N = 16) with PTSD related to physical or sexual assault. Prior to scanning, participants provided written narratives of a traumatic event related to their PTSD as well as a neutral control event. RETM during fMRI consisted of 5 sequential presentations of the blocked narrative types, lasting three minutes each. Self-reported anxiety was assessed after each presentation. RESULTS: Relative to changes in functional connectivity during the neutral control script, RETM was associated with strengthened functional connectivity of the right amygdala with the right hippocampus and right anterior insular cortex, left amygdala with the right insular cortex, medial PFC with right anterior insula, left hippocampus with striatum and dorsal cingulate cortex, and right hippocampus with striatum and orbitofrontal cortex. Greater PTSD severity generally led to less changes in functional connectivity with the right insular cortex. CONCLUSIONS: These results provide evidence that RETM engages and modifies functional connectivity pathways with neural regions implicated in fear extinction. The results also implicate the engagement of the right insular cortex and striatum during RETM and suggest their importance in human fear extinction to trauma memories. However, comorbidity in the sample and the lack of a control group limit inferences regarding RETM with PTSD populations specifically.

Neural processing correlates of assaultive violence exposure and PTSD symptoms during implicit threat processing: a network-level analysis among adolescent girls.

Assaultive violence exposure during childhood is a significant risk factor for posttraumatic stress disorder (PTSD). The purpose of the present study was to characterize the relationships of assault and PTSD severity with the organization of large-scale networks identified during emotion processing. Adolescent girls aged 12-16 with (N=15) and without (N=15) histories of assault underwent functional magnetic resonance imaging (fMRI) while engaged in a task that presented images of fearful or neutral facial expressions. Independent component analysis (ICA) identified a frontocingulate network, a frontoparietal network, and a default mode network. Assault exposure was associated with significantly greater activation of the frontocingulate network for fear versus neutral faces. Within the frontocingulate network, Posttraumatic stress disorder (PTSD) severity was associated with weakened functional connectivity between the left amygdala and the perigenual anterior cingulate. Within the frontoparietal network, assaulted girls demonstrated weakened connectivity of the premotor cortex with the right middle frontal gyrus. Within the default mode network, assault exposure and PTSD severity were associated with strengthening functional connectivity of the parahippocampus with the medial and lateral prefrontal cortex, respectively. Individual differences in functional connections within the frontocingulate network and frontoparietal network among the assaulted group were strongly associated with caregiver-rated family disengagement. These results demonstrate associations between assault and PTSD symptoms with the functional organization of large-scale frontoparietal, frontocingulate, and default mode networks during emotion processing. The relationship with caregiver-rated family disengagement suggests the impact of family support on the neural processing correlates of assault and PTSD symptoms.

Altered functional connectivity of the insular cortex across prefrontal networks in cocaine addiction.

Interoception is theorized to be an important process mediating substance use disorders, and the insular cortex is recognized as a core neural region supporting interoception. The purpose of this study was to compare the integration of the insular cortex into prefrontal-related resting-state networks between individuals with cocaine dependence and healthy controls. Participants comprised 41 patients with cocaine dependence and 19 controls who underwent a resting-state 3-T functional magnetic resonance imaging scan. Individuals with cocaine dependence demonstrated altered functional connectivity of the insular cortex, predominantly the right insular cortex, with all eight prefrontal-related resting-state networks identified through Independent Component Analysis (ICA). A conjunction analysis demonstrated that the right insular cortex was the neural region with the highest number of common group differences across the networks. There was no evidence that insular cortex connectivity commonly differed between groups for non-prefrontal-related networks. Further, seed-based functional connectivity analyses extended the network analyses and indicated that cocaine dependence was associated with greater connectivity of the right insula with the dorsomedial prefrontal cortex, inferior frontal gyrus, and bilateral dorsolateral prefrontal cortex. These data support the hypothesis that cocaine dependence is related to altered functional interactions of the insular cortex with prefrontal networks. The results suggest possible neural mechanisms by which the insular cortex and interoceptive information influence cognitive control and decision-making processes presumably mediated by prefrontal networks in the cocaine dependence process.