The Dichotomy of Threat and Deprivation as Subtypes of Childhood Maltreatment: Differential Functional Connectivity Patterns of Threat and Reward Circuits in an Adult Trauma Sample.

BACKGROUND: Childhood maltreatment is associated with reduced activation of the nucleus accumbens, a central region in the reward network, and overactivity in the amygdala, a key region in threat processing. However, the long-lasting impact of these associations in the context of later-life stress is not well understood. The current study explored the association between childhood threat and deprivation and functional connectivity of threat and reward regions in an adult trauma sample. METHODS: Trauma survivors (N = 169; mean age [SD] = 32.2 [10.3] years; female = 55.6%) were recruited from a level I trauma center. Two weeks after injury, participants completed the Childhood Trauma Questionnaire (measuring experiences of threat and deprivation) and underwent resting-state functional magnetic resonance imaging. Seed-to-voxel analyses evaluated the effect of childhood threat and deprivation on amygdala and nucleus accumbens resting-state connectivity. RESULTS: Higher levels of threat were associated with increased connectivity between the right nucleus accumbens with temporal fusiform gyrus/parahippocampal gyrus and the left amygdala and the precuneus (false discovery rate-corrected p < .05). After controlling for posttraumatic symptoms 2 weeks posttrauma and lifetime trauma exposure, only the nucleus accumbens findings survived. There were no significant relationships between experiences of childhood deprivation and amygdala or nucleus accumbens connectivity. CONCLUSIONS: Experiences of threat are associated with increased nucleus accumbens and amygdala connectivity, which may reflect a preparedness to detect salient and visual stimuli. This may also reflect a propensity toward dysregulated reward processing. Overall, these results suggest that childhood threat may be contributing to aberrant neural baseline reward and threat sensitivity later in life in an adult trauma sample.

Neighborhood Socioeconomic Disadvantage and the Neurobiology of Uncertainty in Traumatically Injured Adults.

BACKGROUND: Individuals residing in more socioeconomically disadvantaged neighborhoods experience greater uncertainty through insecurity of basic needs such as food, employment, and housing, compared with more advantaged neighborhoods. Although the neurobiology of uncertainty has been less frequently examined in relation to neighborhood disadvantage, there is evidence that neighborhood disadvantage is associated with widespread neural alterations. METHODS: Recently traumatically injured participants (n = 90) completed a picture anticipation task in the magnetic resonance imaging scanner, in which they viewed images presented in a temporally predictable or unpredictable manner. We investigated how neighborhood disadvantage (via area deprivation index [ADI]) was related to neural activation during anticipation and presentation of negative and neutral images after accounting for individual factors (i.e., age, gender, income, acute posttraumatic stress symptoms). RESULTS: There was a significant interaction during the anticipation period such that higher ADI rankings were related to greater activation of the right anterior cingulate cortex to predictable versus unpredictable neutral stimuli. Although no other robust interactions emerged related to ADI, we note several novel simple effects of ADI during anticipation and presentation periods in the hippocampus and prefrontal, cingulate, and occipital cortices. CONCLUSIONS: Together, these results may represent an adaptive response to predictable and/or negative stimuli, stemming from chronic exposure to socioeconomic-based uncertainties. Although effects were modest, future work should continue to examine pretrauma context on posttrauma outcomes. To better understand trauma outcomes, it is imperative that researchers consider the broader context in which trauma survivors reside.

Hippocampal Resting-State Functional Connectivity Forecasts Individual Posttraumatic Stress Disorder Symptoms: A Data-Driven Approach.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a debilitating disorder, and there is no current accurate prediction of who develops it after trauma. Neurobiologically, individuals with chronic PTSD exhibit aberrant resting-state functional connectivity (rsFC) between the hippocampus and other brain regions (e.g., amygdala, prefrontal cortex, posterior cingulate), and these aberrations correlate with severity of illness. Previous small-scale research (n < 25) has also shown that hippocampal rsFC measured acutely after trauma is predictive of future severity using a region-of-interest-based approach. While this is a promising biomarker, to date, no study has used a data-driven approach to test whole-brain hippocampal FC patterns in forecasting the development of PTSD symptoms. METHODS: A total of 98 adults at risk of PTSD were recruited from the emergency department after traumatic injury and completed resting-state functional magnetic resonance imaging (8 min) within 1 month; 6 months later, they completed the Clinician-Administered PTSD Scale for DSM-5 for assessment of PTSD symptom severity. Whole-brain rsFC values with bilateral hippocampi were extracted (using CONN) and used in a machine learning kernel ridge regression analysis (PRoNTo); a k-folds (k = 10) and 70/30 testing versus training split approach were used for cross-validation (1000 iterations to bootstrap confidence intervals for significance values). RESULTS: Acute hippocampal rsFC significantly predicted Clinician-Administered PTSD Scale for DSM-5 scores at 6 months (r = 0.30, p = .006; mean squared error = 120.58, p = .006; R2 = 0.09, p = .025). In post hoc analyses, hippocampal rsFC remained significant after controlling for demographics, PTSD symptoms at baseline, and depression, anxiety, and stress severity at 6 months (B = 0.59, SE = 0.20, p = .003). CONCLUSIONS: Findings suggest that functional connectivity of the hippocampus across the brain acutely after traumatic injury is associated with prospective PTSD symptom severity.

Acute White Matter Integrity Post-trauma and Prospective Posttraumatic Stress Disorder Symptoms.

Background: Little is known about what distinguishes those who are resilient after trauma from those at risk for developing posttraumatic stress disorder (PTSD). Previous work indicates white matter integrity may be a useful biomarker in predicting PTSD. Research has shown changes in the integrity of three white matter tracts-the cingulum bundle, corpus callosum (CC), and uncinate fasciculus (UNC)-in the aftermath of trauma relate to PTSD symptoms. However, few have examined the predictive utility of white matter integrity in the acute aftermath of trauma to predict prospective PTSD symptom severity in a mixed traumatic injury sample. Method: Thus, the current study investigated acute brain structural integrity in 148 individuals being treated for traumatic injuries in the Emergency Department of a Level 1 trauma center. Participants underwent diffusion-weighted magnetic resonance imaging 2 weeks post-trauma and completed several self-report measures at 2-weeks (T1) and 6 months (T2), including the Clinician Administered PTSD Scale for DSM-V (CAPS-5), post-injury. Results: Consistent with previous work, T1 lesser anterior cingulum fractional anisotropy (FA) was marginally related to greater T2 total PTSD symptoms. No other white matter tracts were related to PTSD symptoms. Conclusions: Results demonstrate that in a traumatically injured sample with predominantly subclinical PTSD symptoms at T2, acute white matter integrity after trauma is not robustly related to the development of chronic PTSD symptoms. These findings suggest the timing of evaluating white matter integrity and PTSD is important as white matter differences may not be apparent in the acute period after injury.

Multi-voxel pattern analysis of amygdala functional connectivity at rest predicts variability in posttraumatic stress severity.

INTRODUCTION: Resting state functional magnetic resonance imaging (rsfMRI) studies demonstrate that individuals with posttraumatic stress disorder (PTSD) exhibit atypical functional connectivity (FC) between the amygdala, involved in the generation of emotion, and regions responsible for emotional appraisal (e.g., insula, orbitofrontal cortex [OFC]) and regulation (prefrontal cortex [PFC], anterior cingulate cortex). Consequently, atypical amygdala FC within an emotional processing and regulation network may be a defining feature of PTSD, although altered FC does not seem constrained to one brain region. Instead, altered amygdala FC involves a large, distributed brain network in those with PTSD. The present study used a machine-learning data-driven approach, multi-voxel pattern analysis (MVPA), to predict PTSD severity based on whole-brain patterns of amygdala FC. METHODS: Trauma-exposed adults (N = 90) completed the PTSD Checklist-Civilian Version to assess symptoms and a 5-min rsfMRI. Whole-brain FC values to bilateral amygdala were extracted and used in a relevance vector regression analysis with a leave-one-out approach for cross-validation with permutation testing (1,000) to obtain significance values. RESULTS: Results demonstrated that amygdala FC predicted PCL-C scores with statistically significant accuracy (r = .46, p = .001; mean sum of squares = 130.46, p = .001; R2  = 0.21, p = .001). Prediction was based on whole-brain amygdala FC, although regions that informed prediction (top 10%) included the OFC, amygdala, and dorsolateral PFC. CONCLUSION: Findings demonstrate the utility of MVPA based on amygdala FC to predict individual severity of PTSD symptoms and that amygdala FC within a fear acquisition and regulation network contributed to accurate prediction.

Resting-State Functional Connectivity of Supplementary Motor Area Associated with Skin-Picking Symptom Severity.

Pathological skin picking (excoriation) is a relatively common disorder. Although it has been hypothesized to share a similar pathophysiological basis as other obsessive-compulsive (OC) spectrum disorders, to date, little work has specifically examined the precise neurobiological mechanisms involved in excoriation. Disruption in functional circuits involving the right inferior frontal gyrus (rIFG) and supplementary motor area (SMA) may be particularly relevant to skin-picking pathology as these regions have been implicated in other OC-spectrum disorders for their roles in response inhibition and voluntary motor action, respectively. To this end, the present study examined the associations between skin-picking symptom severity and resting-state functional connectivity of the rIFG and bilateral SMA. Participants endorsing elevated symptoms of excoriation completed a self-report measure of symptom severity and resting-state functional magnetic resonance imaging scan. Results indicated that symptom severity was associated with weaker connectivity between the SMA and clusters within the orbitofrontal cortex and angular gyrus. Contrary to hypotheses, there were no effects of symptom severity on functional connectivity of the rIFG. Overall, these findings suggest that skin-picking symptom severity may be associated with disruption in higher-order motor networks contributing to deficits in top-down regulation of motor behavior.

Reward-related distracters and working memory filtering.

Reward-related stimuli capture attention, even when they are task irrelevant. A consequence of attentional prioritization of reward-related stimuli is that they may also have preferential access to working memory like other forms of emotional information. However, whether reward-related distracters leak into working memory remains unknown. Here, using a well-validated change detection task of visual working memory capacity and filtering, we conducted two studies to directly assess the impact of reward-related distracters on working memory. In both studies, the distracters consisted of colored bars or circles that were previously associated with monetary reward. In Experiment 1, results indicated that previously rewarded distracters did not impact behavioral measures of working memory filtering efficiency compared to neutral distracters. In Experiment 2, using ERPs, we measured the contralateral delay activity (CDA), a psychophysiological index of the number of items retained in working memory, to further assess filtering efficiency. We observed that the CDA for high reward distracters was similar to low reward and neutral distracters. However, in early trials, behavioral measures revealed that previously rewarded stimuli negatively impacted working memory capacity, an effect not observed with neutral distracters. This effect, though, was not found for the CDA in early trials. In summary, our findings across two studies suggest that attentional capture by task-irrelevant reward may have minimal impact on visual working memory-findings that have important implications for delineating the boundaries of reward-cognition interactions.

Structural Connectivity of the Posterior Cingulum Is Related to Reexperiencing Symptoms in Posttraumatic Stress Disorder.

Posttraumatic stress disorder (PTSD) is a heterogeneous disorder with disturbances in hyper-arousal or avoidance behaviors, and intrusive or re-experiencing thoughts. The uncinate fasciculus (UF) and cingulum bundle are white matter pathways implicated in stress and trauma pathophysiology, yet their structural integrity related to PTSD symptom domains is yet to be understood. Forty-four trauma-exposed young adults underwent structural and diffusion-weighted MRI. Stress and trauma exposure indices and severity of PTSD symptoms were collected and used to predict current integrity of the UF and cingulum bundle. Severity of re-experiencing PTSD symptoms was significantly related to increased fractional anisotropy (r=.469 p<.001) and decreased mean diffusivity (r=-.373, p=.013) of the right posterior cingulum bundle. No other findings emerged with respect to stress exposure or of hyper-arousal (p's>0.05) or avoidance (p's>0.2) PTSD symptoms. The posterior cingulum connects medial temporal lobe structures with visual areas in the occipital lobe and has been implicated in visual memory and self-referential thought. Increased structural connectivity along this pathway may therefore explain the emergence of re-experiencing PTSD symptoms. This along with the lack of results with respect to stress exposure suggests structural aberrations in white matter pathways are more strongly linked with the actual experience of stress-related psychological symptoms than just exposure to stress.

Moderating Effects of Harm Avoidance on Resting-State Functional Connectivity of the Anterior Insula.

As an index of behavioral inhibition and an individual's propensity to avoid, rather than seek, potentially dangerous situations, harm avoidance has been linked to internalizing psychopathology. Altered connectivity within intrinsic functional neural networks (i.e., default mode [DMN], central executive [CEN] and salience networks [SN]) has been related to internalizing psychopathology; however, less is known about the effects of harm avoidance on functional connectivity within and between these networks. Importantly, harm avoidance may be distinguishable from trait anxiety and have clinical relevance as a risk factor for internalizing psychopathology. A sample of young adults (n = 99) completed a resting state functional magnetic resonance imaging (fMRI) scan and self-report measures of harm avoidance and trait anxiety. Whole brain seed-to-voxel and seed-to-network connectivity analyses were conducted using anterior insula seeds to examine associations between harm avoidance/trait anxiety and connectivity. After adjusting for sex and age, there was a significant negative effect of harm avoidance on connectivity between the anterior insula and clusters in the precuneus/posterior cingulate cortex (PCC) left superior/middle frontal gyrus, dorsal anterior cingulate cortex (dACC) and bilateral inferior parietal lobule (IPL)/angular gyrus. Seed-to-network analyses indicated a negative effect of harm avoidance on connectivity between the right anterior insula and anterior and posterior DMN. There were no effects of trait anxiety on functional connectivity of the anterior insula. Overall, the results indicate that individual differences in harm avoidance relate to disruptions in internetwork connectivity that may contribute to deficits in appropriately modulating attentional focus.

Cortico-limbic connectivity changes following fear extinction and relationships with trait anxiety.

Fear extinction is a powerful model of adaptive and anxiety-related maladaptive fear inhibition. This learning process is dependent upon plastic interactions between the amygdala, the anterior midcingulate cortex (aMCC), the hippocampus, and the ventromedial prefrontal cortex (vmPFC). With regard to the amygdala, the basolateral (BLA) and centromedial amygdala (CMA) serve unique roles in fear extinction. In a large sample (N = 91), the current study examined pre- to post-extinction changes in resting state functional connectivity (RSFC) of fear inhibition and expression pathways. We also examined how trait anxiety and extinction performance were associated with extinction-related changes within these neural pathways. We found stronger pre- to post-extinction RSFC in pathways known to play a role in the down-regulation of fear responses (BLA-hippocampus, aMCC-hippocampus, CMA-hippocampus, CMA-aMCC). We also found that trait anxiety was associated with strengthening of a BLA-aMCC circuit supporting fear expression following extinction learning. Furthermore, we found that physiological indices of poorer extinction learning were linked to weaker pre- to post-extinction RSFC of a BLA-hippocampus pathway important for fear extinction consolidation. Our results highlight the network changes that occur during extinction, the separable role of CMA and BLA-based circuitry and a key pathway linked to risk for anxiety pathology.

Abnormal cortical gyrification in criminal psychopathy.

Background: Psychopathy is a personality disorder characterized by interpersonal and emotional abnormalities (e.g., lack of empathy and guilt) and antisocial behavior. Psychopathy has been associated with a number of structural brain abnormalities, most notably in orbital frontal and anterior/medial temporal regions, that may underlie psychopathic individuals' problematic behaviors. Past research evaluating cortical structure in psychopathy has considered thickness and volume, but to date no study has investigated differences in cortical gyrification, a measure of cortical complexity thought to reflect early neurodevelopmental cortical connectivity. Methods: We measured the local gyrification index (LGI) in a sample of 716 adult male inmates and performed a whole brain analysis assessing the relationship between LGI and total and factor scores on the Hare Psychopathy Checklist-Revised (PCL-R). Results: PCL-R scores were negatively associated with LGI measures within the right hemisphere in the midcingulate cortex (MCC) and adjacent regions of the superior frontal gyrus as well as lateral superior parietal cortex. Additionally, PCL-R Factor 1 scores (interpersonal/affective traits) predicted less LGI within the right MCC and adjacent dorsomedial frontal cortex and greater LGI in bilateral occipital cortex. Scores on PCL-R Factor 2, indicating impulsivity and antisocial behaviors, did not predict LGI in any regions. Conclusions: These findings suggest that psychopathy, particularly the interpersonal and affective traits, are associated with specific structural abnormalities that form during neurodevelopment and these abnormalities may underlie aberrant brain functioning in regions important in emotional processing and cognitive control.

State Anxiety Impairs Proactive but Enhances Reactive Control.

Cognitive control is a construct that prioritizes how we process stimuli and information to flexibly and efficiently adapt to internal goals and external environmental changes. The Dual Mechanism of Control (DMC) theory delineates two distinct cognitive control operations: proactive control and reactive control (Braver, 2012). Anxiety has been posited to differentially affect proactive and reactive control, due to its influence on working memory and attention allocation (Eysenck et al., 2007; Fales et al., 2008). However, no study has yet directly compared the influence of anxiety on proactive and reactive control in the same individuals. In this study, we examined how state anxiety affected proactive control, using the AX-continuous performance task (AX-CPT), and reactive control, using the classic Stroop task. Based on theory and previous investigations, we expected that state anxiety would enhance reactive control but impair proactive control. Consistent with our predictions, we found that state anxiety, induced with a threat of shock manipulation, inhibited proactive control on the AX-CPT test, but increased reactive control in the Stroop task. Anxiety may impair proactive control in contexts requiring goal maintenance by occupying limited working memory capacity, whereas it may enhance reactive control via facilitated attention allocation to threat and engaging the conflict monitoring system to quickly modify behavior.

Neural circuitry governing anxious individuals' mis-allocation of working memory to threat.

Dispositional anxiety is a trait-like phenotype that confers increased risk for a range of debilitating neuropsychiatric disorders. Like many patients with anxiety disorders, individuals with elevated levels of dispositional anxiety are prone to intrusive and distressing thoughts in the absence of immediate threat. Recent electrophysiological research suggests that these symptoms are rooted in the mis-allocation of working memory (WM) resources to threat-related information. Here, functional MRI was used to identify the network of brain regions that support WM for faces and to quantify the allocation of neural resources to threat-related distracters in 81 young adults. Results revealed widespread evidence of mis-allocation. This was evident in both face-selective regions of the fusiform cortex and domain-general regions of the prefrontal and parietal cortices. This bias was exaggerated among individuals with a more anxious disposition. Mediation analyses provided compelling evidence that anxious individuals' tendency to mis-allocate WM resources to threat-related distracters is statistically explained by heightened amygdala reactivity. Collectively, these results provide a neurocognitive framework for understanding the pathways linking anxious phenotypes to the development of internalizing psychopathology and set the stage for developing improved intervention strategies.

The effects of stimulus novelty and negativity on BOLD activity in the amygdala, hippocampus, and bed nucleus of the stria terminalis.

Key words: novelty; bed nucleus of the stria terminalis; BNST; amygdale; fMRI; BST.

Cortical Gyrification Patterns Associated with Trait Anxiety.

Dispositional anxiety is a stable personality trait that is a key risk factor for internalizing disorders, and understanding the neural correlates of trait anxiety may help us better understand the development of these disorders. Abnormal cortical folding is thought to reflect differences in cortical connectivity occurring during brain development. Therefore, assessing gyrification may advance understanding of cortical development and organization associated with trait anxiety. Previous literature has revealed structural abnormalities in trait anxiety and related disorders, but no study to our knowledge has examined gyrification in trait anxiety. We utilized a relatively novel measure, the local gyrification index (LGI), to explore differences in gyrification as a function of trait anxiety. We obtained structural MRI scans using a 3T magnetic resonance scanner on 113 young adults. Results indicated a negative correlation between trait anxiety and LGI in the left superior parietal cortex, specifically the precuneus, reflecting less cortical complexity among those high on trait anxiety. Our findings suggest that aberrations in cortical gyrification in a key region of the default mode network is a correlate of trait anxiety and may reflect disrupted local parietal connectivity.