Causally Probing the Role of the Hippocampus in Fear Discrimination: A Precision Functional Mapping-Guided, Transcranial Magnetic Stimulation Study in Participants With Posttraumatic Stress Symptoms.

Background: Fear overgeneralization is a promising pathogenic mechanism of clinical anxiety. A dominant model posits that hippocampal pattern separation failures drive overgeneralization. Hippocampal network-targeted transcranial magnetic stimulation (HNT-TMS) has been shown to strengthen hippocampal-dependent learning/memory processes. However, no study has examined whether HNT-TMS can alter fear learning/memory. Methods: Continuous theta burst stimulation was delivered to individualized left posterior parietal stimulation sites derived via seed-based connectivity, precision functional mapping, and electric field modeling methods. A vertex control site was also stimulated in a within-participant, randomized controlled design. Continuous theta burst stimulation was delivered prior to 2 visual discrimination tasks (1 fear based, 1 neutral). Multilevel models were used to model and test data. Participants were undergraduates with posttraumatic stress symptoms (final n = 25). Results: Main analyses did not indicate that HNT-TMS strengthened discrimination. However, multilevel interaction analyses revealed that HNT-TMS strengthened fear discrimination in participants with lower fear sensitization (indexed by responses to a control stimulus with no similarity to the conditioned fear cue) across multiple indices (anxiety ratings: ß = 0.10, 95% CI, 0.04 to 0.17, p = .001; risk ratings: ß = 0.07, 95% CI, 0.00 to 0.13, p = .037). Conclusions: Overgeneralization is an associative process that reflects deficient discrimination of the fear cue from similar cues. In contrast, sensitization reflects nonassociative responding unrelated to fear cue similarity. Our results suggest that HNT-TMS may selectively sharpen fear discrimination when associative response patterns, which putatively implicate the hippocampus, are more strongly engaged.

Fear overgeneralization is a promising pathogenic mechanism of clinical anxiety that is thought to be driven by deficient hippocampal discrimination. Using hippocampal network­targeted transcranial magnetic stimulation (HNT-TMS) in healthy participants with symptoms of posttraumatic stress, Webler et al. report that HNT-TMS did not strengthen discrimination overall, but it did strengthen fear discrimination in participants with lower fear sensitization. Sensitization reflects nonassociative fear responding unrelated to fear cue similarity and therefore is not expected to engage the hippocampal discrimination function. These results suggest that HNT-TMS may selectively sharpen fear discrimination when the hippocampal discrimination function is more strongly engaged.

Adaptation in Young Military Recruits: Protocol for the Advancing Research on Mechanisms of Resilience (ARMOR) Prospective Longitudinal Study.

BACKGROUND: Military services provide a unique opportunity for studying resilience, a dynamic process of successful adaptation (ie, doing well in terms of functioning and symptoms) in response to significant adversity. Despite the tremendous interest in positive adaptation among military service members, little is known about the processes underlying their resilience. Understanding the neurobiological, cognitive, and social mechanisms underlying adaptive functioning following military stressor exposure is essential for enhancing the resilience of military service members. OBJECTIVE: The primary objective of the Advancing Research on Mechanisms of Resilience (ARMOR) longitudinal study is to characterize the trajectories of positive adaptation among young military recruits in response to basic combat training (BCT), a well-defined, uniform, and 10-week period of intense stress (aim 1), and identify promotive and protective processes contributing to individual variations in resilience (aim 2). The secondary objective is to investigate the pathways by which neurobehavioral markers of self-regulation assessed using electroencephalography and magnetic resonance imaging contribute to adaptive trajectories (aim 3). METHODS: ARMOR is an ongoing, prospective longitudinal cohort study of young military recruits who recently joined the National Guard but have not yet shipped out for BCT. Participants (N=1201) are assessed at 5 time points over the initial >2 years of military service beginning before BCT (baseline) and followed up at 2 weeks and 6, 12, and 18 months after BCT. Participants complete web-based questionnaires assessing vulnerability and protective factors, mental health, and socioemotional functioning at each time point and a battery of neurocognitive tests at time 0. A subset of participants also complete structured diagnostic interviews and additional self-report measures and perform neurobehavioral tasks before and after BCT during electroencephalography sessions and before BCT only during magnetic resonance imaging sessions. RESULTS: This UG3/UH3 project was initially funded in August 2017, with the UG3 pilot work completed at the end of 2018. The UH3 phase of the project was funded in March 2019. Study enrollment for the UH3 phase began on April 14, 2019, and ended on October 16, 2021. A total of 1201 participants are enrolled in the study. Follow-up data collection for the UH3 phase is ongoing and projected to continue through February 2024. We will disseminate the findings through conferences, webinars, open access publications, and communications with participants and stakeholders. CONCLUSIONS: The ARMOR study provides a rich data set to identify the predictors and mechanisms of resilient and nonresilient outcomes in the context of military stressors, which are intended to empirically inform the development of prevention and intervention strategies to enhance the resilience of military trainees and potentially other young people facing significant life challenges. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51235.

Consensus design of a calibration experiment for human fear conditioning.

Fear conditioning is a widely used laboratory model to investigate learning, memory, and psychopathology across species. The quantification of learning in this paradigm is heterogeneous in humans and psychometric properties of different quantification methods can be difficult to establish. To overcome this obstacle, calibration is a standard metrological procedure in which well-defined values of a latent variable are generated in an established experimental paradigm. These intended values then serve as validity criterion to rank methods. Here, we develop a calibration protocol for human fear conditioning. Based on a literature review, series of workshops, and survey of N = 96 experts, we propose a calibration experiment and settings for 25 design variables to calibrate the measurement of fear conditioning. Design variables were chosen to be as theory-free as possible and allow wide applicability in different experimental contexts. Besides establishing a specific calibration procedure, the general calibration process we outline may serve as a blueprint for calibration efforts in other subfields of behavioral neuroscience that need measurement refinement.

Causally mapping human threat extinction relevant circuits with depolarizing brain stimulation methods.

Laboratory threat extinction paradigms and exposure-based therapy both involve repeated, safe confrontation with stimuli previously experienced as threatening. This fundamental procedural overlap supports laboratory threat extinction as a compelling analogue of exposure-based therapy. Threat extinction impairments have been detected in clinical anxiety and may contribute to exposure-based therapy non-response and relapse. However, efforts to improve exposure outcomes using techniques that boost extinction - primarily rodent extinction - have largely failed to date, potentially due to fundamental differences between rodent and human neurobiology. In this review, we articulate a comprehensive pre-clinical human research agenda designed to overcome these failures. We describe how connectivity guided depolarizing brain stimulation methods (i.e., TMS and DBS) can be applied concurrently with threat extinction and dual threat reconsolidation-extinction paradigms to causally map human extinction relevant circuits and inform the optimal integration of these methods with exposure-based therapy. We highlight candidate targets including the amygdala, hippocampus, ventromedial prefrontal cortex, dorsal anterior cingulate cortex, and mesolimbic structures, and propose hypotheses about how stimulation delivered at specific learning phases could strengthen threat extinction.

The Placement of Obsessive-Compulsive Symptoms Within a Five-Factor Model of Maladaptive Personality.

Dimensional models of obsessive-compulsive (OC) symptoms, as seen in obsessive-compulsive disorder (OCD), are instrumental in explaining the heterogeneity observed in this condition and for informing cutting-edge assessments. Prior structural work in this area finds that OC symptoms cross-load under both Negative Affectivity and Psychoticism traits within the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) Alternative Model of Personality Disorder (AMPD). However, tests of OC symptoms in conjunction with assessments of the full AMPD structure and its 25 lower-level facets representing narrower symptom content are lacking. We applied joint exploratory factor analysis to an AMPD measure (Personality Inventory for DSM-5; PID-5) and OC symptom data from two separate samples (total N = 1,506) to locate OC symptoms within AMPD space. OC symptoms cross-loaded on Negative Affectivity, Psychoticism, and on the low end of Disinhibition. We also report exploratory analyses of OC symptom subscales with PID-5 variables. Results are discussed in the context OC symptoms' location in PID-5 space, implications for assessment, and placement of OCD within the Hierarchical Taxonomy of Psychopathology.

Sequential fear generalization and network connectivity in trauma exposed humans with and without psychopathology.

While impaired fear generalization is known to underlie a wide range of psychopathology, the extent to which exposure to trauma by itself results in deficient fear generalization and its neural abnormalities is yet to be studied. Similarly, the neural function of intact fear generalization in people who endured trauma and did not develop significant psychopathology is yet to be characterized. Here, we utilize a generalization fMRI task, and a network connectivity approach to clarify putative behavioral and neural markers of trauma and resilience. The generalization task enables longitudinal assessments of threat discrimination learning. Trauma-exposed participants (TE; N = 62), compared to healthy controls (HC; N = 26), show lower activity reduction in salience network (SN) and right executive control network (RECN) across the two sequential generalization stages, and worse discrimination learning in SN measured by linear deviation scores (LDS). Comparison of resilient, trauma-exposed healthy control participants (TEHC; N = 31), trauma exposed individuals presenting with psychopathology (TEPG; N = 31), and HC, reveals a resilience signature of network connectivity differences in the RECN during generalization learning measured by LDS. These findings may indicate a trauma exposure phenotype that has the potential to advance the development of innovative treatments by targeting and engaging specific neural dysfunction among trauma-exposed individuals, across different psychopathologies.

Elucidating behavioral and functional connectivity markers of aberrant threat discrimination in PTSD.

BACKGROUND: Patients with posttraumatic stress disorder (PTSD) tend to overgeneralize threat to safe stimuli, potentially reflecting aberrant stimuli discrimination. Yet, it is not clear whether threat overgeneralization reflects general discrimination deficits, or rather a specific bias related to aversive stimuli. Here we tested this question and characterized the neural correlates of threat discrimination. METHODS: One-hundred and eight participants (33 PTSD; 43 trauma-exposed controls; 32 healthy controls) completed an emotionally neutral complex shape discrimination task involving identifying in 42 similar pairs the previously observed shape; and an emotionally aversive discrimination task, involving providing risk ratings for an aversive conditioned stimulus (CS+), and for several stimuli gradually differing in size from the original CS+. Resting state functional connectivity (rsFC) was collected before completing the tasks. RESULTS: No group differences emerged on the emotionally neutral task. Conversely, on the emotionally aversive task, individuals with PTSD had steeper linear risk rating slopes as the stimuli more resembled the conditioned stimulus. Finally, lower rsFC of amygdala-default mode network (DMN) and DMN-salience network (SN) were associated with steeper risk slopes, while for hippocampus-SN, lower rsFC was found only among participants with PTSD. CONCLUSIONS: Individuals with PTSD show deficits in discrimination only when presented with aversive stimuli. Dysregulated discrimination pattern may relate to a lack of input from regulatory brain areas (e.g., DMN/hippocampus) to threat-related brain areas (e.g., SN/amygdala).

Emotional numbing in PTSD is associated with lower amygdala reactivity to pain.

Posttraumatic stress disorder (PTSD) is associated with altered pain perception, namely increased pain threshold and higher pain response. While pain consists of physiological and affective components, affective components are often overlooked. Similar patterns of increased threshold-high response in PTSD were shown in response to emotional stimuli, i.e., emotional numbing. As both emotional numbing and pain processing are modulated by the amygdala, we aimed to examine whether individuals diagnosed with PTSD show lower amygdala activation to pain compared with combat controls, and whether the amygdala responses to pain correlates with emotional numbing. To do so, two independent samples of veterans (original study: 44 total (20 PTSD); conceptual replication study: 40 total (20 PTSD)) underwent threat conditioning, where a conditioned stimulus (CS+; visual stimulus) was paired with an unconditioned stimulus (US; electric-shock). We contrasted the amygdala activity to the CS + US pairing with the CS+ presented alone and correlated it with emotional numbing severity. In both samples, the PTSD group showed a robust reduction in amygdala reactivity to shock compared to the Combat Controls group. Furthermore, amygdala activation was negatively correlated with emotional numbing severity. These patterns were unique to the amygdala, and did not appear in comparison to a control region, the insula, a pivotal region for the processing of pain. To conclude, amygdala response to pain is lower in individuals with PTSD, and is associated with emotional numbing symptoms. Lower amygdala reactivity to mild pain may contribute to the "all-or-none" reaction to stressful situations often observed in PTSD.

A meta-analysis of conditioned fear generalization in anxiety-related disorders.

Generalization of conditioned fear is adaptive in some situations but maladaptive when fear excessively generalizes to innocuous stimuli with incidental resemblance to a genuine threat cue. Recently, empirical interest in fear generalization as a transdiagnostic explanatory mechanism underlying anxiety-related disorders has accelerated. As there are now several studies of fear generalization across multiple types of anxiety-related disorders, the authors conducted a meta-analysis of studies reporting behavioral measures (subjective ratings and psychophysiological indices) of fear generalization in anxiety-related disorder vs. comparison groups. We conducted systematic searches of electronic databases (conducted from January-October 2020) for fear generalization studies involving anxiety-related disorder groups or subclinical analog groups. A total of 300 records were full-text screened and two unpublished datasets were obtained, yielding 16 studies reporting behavioral fear generalization measures. Random-effects meta-analytic models and meta-regressions were applied to the identified data. Fear generalization was significantly heightened in anxiety-related disorder participants (N = 439) relative to comparison participants (N = 428). We did not identify any significant clinical, sample, or methodological moderators. Heightened fear generalization is quantitatively supported as distinguishing anxiety-related disorder groups from comparison groups. Evidence suggests this effect is transdiagnostic, relatively robust to experimental or sample parameters, and that generalization paradigms are a well-supported framework for neurobehavioral investigations of learning and emotion in anxiety-related disorders. We discuss these findings in the context of prior fear conditioning meta-analyses, past neuroimaging investigations of fear generalization in anxiety-related disorders, and future directions and challenges for the field.

Heightened generalized conditioned fear and avoidance in women and underlying psychological processes.

Heightened generalization of conditioned fear and avoidance to safe stimuli resembling threat is a key feature of pathological anxiety and might contribute to the increased prevalence of anxiety-related disorders among women. Though animal studies have documented over-generalized fear in female versus male rodents, analogous work in humans is sparse, and no studies to date have examined gender differences in generalized avoidance. We addressed this gap by testing 170 self-identified women (n = 85) and men (n = 85) using a video game-based task assessing generalized Pavlovian fear (perceived threat, fear-potentiated startle) and generalized instrumental avoidance. Instrumental measures of generalization reflected maladaptive avoidance by virtue of being unnecessary to secure safety and incurring a cost of losing the game in which the task is embedded. Women displayed increases in both Pavlovian generalization of perceived threat and maladaptive generalized avoidance. Additionally, decreased motivation to win the game among women mediated the effect of gender on generalized avoidance, and generalized perceived risk and tendencies toward experiential avoidance positively predicted generalized avoidance in women but not men. Overall, findings implicate the undue spread of fear and avoidance to safe stimuli resembling danger among women as a candidate mechanism for differential rates of clinical anxiety across the genders.

Pre-COVID-19 fear conditioning responses predict COVID-19-related anxiety: evidence from an exploratory study.

BACKGROUND AND OBJECTIVES: Fear conditioning represents the prevailing model by which organisms acquire novel threat contingencies. However, little work has been devoted to linking laboratory measures of fear conditioning to the development of real-world threat responses. To fill this gap, the present study explored whether individual differences in a laboratory-based fear conditioning measure could predict levels of COVID-19-related anxiety and avoidance assessed during the first month of the pandemic. DESIGN AND METHOD: Forty-eight undergraduate students who had previously participated in two fear conditioning experiments prior to COVID-19 completed a survey assessing COVID-19 anxiety and avoidance. The fear conditioning experiment involved learning to discriminate between a shape contingently associated with mild electric shock (CS+) and two other shapes that were not (CS-). RESULTS: Increased subjective anxiety to our laboratory CS+ prior to the pandemic predicted heightened COVID-19 anxiety. Follow-up analyses revealed that participants with high COVID-19 anxiety exhibited increased anxiety to CS+ during the final experimental block relative to participants with low COVID-19 anxiety. CONCLUSIONS: Findings from this exploratory study tentatively implicate fear conditioning in the development of real-world fear responses and underscore the importance of investigating laboratory fear conditioning as a predictor of anxiety responses to real-world threats.

Heightened false alarms of conditioned threat predict longitudinal increases in GAD and SAD symptoms over the first year of college.

Lab-based fear-conditioning studies have repeatedly implicated exaggerated threat reactivity to benign (unreinforced) stimuli as concurrent markers of clinical anxiety, but little work has examined the strength of false alarms as a longitudinal predictor of anxiety problems. As such, we tested whether heightened false alarms of conditioned threat assessed in participants' first semester of college predicted second-semester symptoms of generalized anxiety disorder (GAD) and social anxiety disorder (SAD) - two anxiety conditions that are common in college students, have been associated with excessive false alarms, and have yet to be assessed with longitudinal conditioning designs. Here, we focused on the predictive effects of behavioral threat responses (threat expectancy, subjective anxiety, avoidance) given their greater potential for translation to the clinic. Results implicate conditioning-related increases in anxiety to safe stimuli resembling the danger-cue as prospective predictors of GAD. In contrast, SAD was predicted by non-specific elevations in anxiety to a broad set of safe stimuli, as well as by increased threat expectancy toward cues least resembling the conditioned danger cue. These findings suggest that risk for GAD and SAD are captured by distinct, behavioral indicators of false-alarms that may be more feasibly collected in clinical settings compared to alternative experimental anxiety measures like psychophysiological responses.

Advancing Research on Mechanisms of Resilience (ARMOR) Longitudinal Cohort Study of New Military Recruits: Results from a Feasibility Pilot Study.

Psychological resilience as a longitudinal process is highly relevant for understanding the functioning outcomes of military populations. Here, we review the extant literature on resilience among military service members, focusing on National Guard Soldiers. Our specific project (Advancing Research on Mechanisms of Resilience, "ARMOR") aims to develop a comprehensive model of resilience using a multilevel perspective. We report results from our prospective pilot study (n = 103) conducted in preparation for our large-scale longitudinal cohort study of Basic Combat Training (BCT) and its impact on military recruits' wellbeing. Results support feasibility of the larger study, evidence for a new measure of BCT stressor exposure, and demonstrate preliminary associations with BCT-related stressors and longitudinal changes in adaptive functioning. Future directions for our larger study will utilize data from survey responses, structured clinical interviews, neurobehavioral tasks, and neurobiological measures (functional and structural MRI and electroencephalography [EEG]) to examine individual differences in self-regulation as a predictor of resilience-related processes. ARMOR is well positioned to elucidate mechanisms that could be targeted for promoting wellbeing, preventing psychopathology, and facilitating long-term recovery.

Characterization of Comorbid Posttraumatic Stress Disorder and Major Depressive Disorder Using Ketamine as an Experimental Medicine Probe †.

Comorbid posttraumatic stress disorder and major depressive disorder (PTSD + MDD) is the most common pathological response to trauma, yet despite their synergistic detriment to health, knowledge regarding the neurobiological mechanism underlying PTSD + MDD is extremely limited. This study proposes a novel model of PTSD + MDD that is built on biological systems shown to underlay PTSD + MDD and takes advantage of ketamine's unique suitability to probe PTSD + MDD due to its rescue of stress-related neuroplasticity deficits. The central hypothesis is that changes in PTSD + MDD clinical symptoms are associated with functional connectivity changes and cognitive dysfunction and that ketamine infusions improve clinical symptoms by correction of functional connectivity changes and improvement in cognition. Participants with PTSD + MDD (n = 42) will be randomized to receive a series of six ketamine infusions or saline-placebo over three weeks. Pre/post-measures will include: (1) neuroimaging; (2) cognitive functioning task performance; and (3) PTSD, MDD, and rumination self-report measures. These measures will also be collected once in a trauma-exposed group including PTSD-only (n = 10), trauma-exposed-MDD (TE-MDD; n = 10), and healthy controls (HC, n = 21). Successful completion of the study will strongly support the concept of a biologically-based model of PTSD + MDD. The results will (1) identify functional imaging signatures of the mechanisms underpinning pathological responses to trauma, (2) shift focus from mono-diagnostic silos to unified biological and behavioral disease processes and, thus, (3) inform interventions to correct dysregulation of PTSD + MDD symptom clusters thereby supporting more precise treatments and better outcomes.

Generalization of conditioned disgust and the attendant maladaptive avoidance: Validation of a novel paradigm and effects of trait disgust-proneness.

Overgeneralization of conditioned fear to safe stimuli that resemble a previously-learned threat-cue is a well-studied correlate of clinical anxiety, yet whether conditioned disgust generalizes remains unknown, as does the extent to which such generalization is associated with disgust-related traits and maladaptive outcomes. The present study addresses this gap by adapting a validated fear-generalization paradigm to assess conditioned disgust and behavioral avoidance to a disgust-cue (CS+) paired with a disgusting video clip, and safe generalization stimuli parametrically varying in perceptual similarity to CS+. For comparison, levels of fear generalization were also assessed using the original fear-generalization paradigm. In both paradigms, costly and unnecessary avoidance to safe threat-cue approximations analogues maladaptive outcomes of generalization. In the disgust paradigm only, disgust-proneness was associated with elevated perceived risk to safe stimuli and increases in the extent to which such elevations were accompanied by maladaptive avoidance. Comparable levels of generalization, and positive associations between generalization and maladaptive avoidance, were found across disgust and fear paradigms. Results confirm that conditioned disgust is subject to generalization, implicate generalized disgust as a source of maladaptive avoidance particularly among those prone to disgust, and suggest a potential role for these processes in the etiology and maintenance of disgust-related disorders.

The neurobiology of human fear generalization: meta-analysis and working neural model.

Fear generalization to stimuli resembling a conditioned danger-cue (CS+) is a fundamental dynamic of classical fear-conditioning. Despite the ubiquity of fear generalization in human experience and its known pathogenic contribution to clinical anxiety, neural investigations of human generalization have only recently begun. The present work provides the first meta-analysis of this growing literature to delineate brain substrates of conditioned fear-generalization and formulate a working neural model. Included studies (K = 6, N = 176) reported whole-brain fMRI results and applied generalization-gradient methodology to identify brain activations that gradually strengthen (positive generalization) or weaken (negative generalization) as presented stimuli increase in CS+ resemblance. Positive generalization was instantiated in cingulo-opercular, frontoparietal, striatal-thalamic, and midbrain regions (locus coeruleus, periaqueductal grey, ventral tegmental area), while negative generalization was implemented in default-mode network nodes (ventromedial prefrontal cortex, hippocampus, middle temporal gyrus, angular gyrus) and amygdala. Findings are integrated within an updated neural account of generalization centering on the hippocampus, its modulation by locus coeruleus and basolateral amygdala, and the excitation of threat- or safety-related loci by the hippocampus.

Salience and central executive networks track overgeneralization of conditioned-fear in post-traumatic stress disorder.

BACKGROUND: Generalization of conditioned-fear, a core feature of post-traumatic stress disorder (PTSD), has been the focus of several recent neuroimaging studies. A striking outcome of these studies is the frequency with which neural correlates of generalization fall within hubs of well-established functional networks including salience (SN), central executive (CEN), and default networks (DN). Neural substrates of generalization found to date may thus reflect traces of large-scale brain networks that form more expansive neural representations of generalization. The present study includes the first network-based analysis of generalization and PTSD-related abnormalities therein. METHODS: fMRI responses in established intrinsic connectivity networks (ICNs) representing SN, CEN, and DN were assessed during a generalized conditioned-fear task in male combat veterans (N = 58) with wide-ranging PTSD symptom severity. The task included five rings of graded size. Extreme sizes served as conditioned danger-cues (CS+: paired with shock) and safety-cues (CS-), and the three intermediate sizes served as generalization stimuli (GSs) forming a continuum-of-size between CS+ and CS-. Generalization-gradients were assessed as behavioral and ICN response slopes from CS+, through GSs, to CS-. Increasing PTSD symptomatology was predicted to relate to less-steep slopes indicative of stronger generalization. RESULTS: SN, CEN, and DN responses fell along generalization-gradients with levels of generalization within and between SN and CEN scaling with PTSD symptom severity. CONCLUSIONS: Neural substrates of generalized conditioned-fear include large-scale networks that adhere to the functional organization of the brain. Current findings implicate levels of generalization in SN and CEN as promising neural markers of PTSD.

Posttraumatic stress symptomatology and abnormal neural responding during emotion regulation under cognitive demands: mediating effects of personality.

Posttraumatic stress disorder (PTSD) is often complicated by the after-effects of mild traumatic brain injury (mTBI). The mixture of brain conditions results in abnormal affective and cognitive functioning, as well as maladaptive behavior. To better understand how brain activity explains cognitive and emotional processes in these conditions, we used an emotional N-back task and functional magnetic resonance imaging (fMRI) to study neural responses in US military veterans after deployments to Iraq and Afghanistan. Additionally, we sought to examine whether hierarchical dimensional models of maladaptive personality could account for the relationship between combat-related brain conditions and fMRI responses under cognitive and affective challenge. FMRI data, measures of PTSD symptomatology (PTSS), blast-induced mTBI (bmTBI) severity, and maladaptive personality (MMPI-2-RF) were gathered from 93 veterans. Brain regions central to emotion regulation were selected for analysis, and consisted of bilateral amygdala, bilateral dorsolateral prefrontal (dlPFC), and ventromedial prefrontal/subgenual anterior cingulate (vmPFC-sgACC). Cognitive load increased activity in dlPFC and reduced activity in emotional responding brain regions. However, individuals with greater PTSS showed blunted deactivations in bilateral amygdala and vmPFC-sgACC, and weaker responses in right dlPFC. Additionally, we found that elevated emotional/internalizing dysfunction (EID), specifically low positive emotionality (RC2), accounted for PTSS-related changes in bilateral amygdala under increased cognitive load. Findings suggest that PTSS might result in amygdala and vmPFC-sgACC activity resistant to moderation by cognitive demands, reflecting emotion dysregulation despite a need to marshal cognitive resources. Anhedonia may be an important target for interventions that improve the affective and cognitive functioning of individuals with PTSD.

Reduced emotional responsiveness in individuals with marginal elevation in blood pressure within the normal range: Evidence from altered affect-modulated startle response.

Reduced responsiveness to emotional stimuli ('emotional dampening') has been observed in normotensives with elevated blood pressure (BP) and hypertensives but it is not known whether this is due to aberrant responding to emotional information at the involuntary level and whether it is also associated with minimal elevations in BP in the normal range. In this study, we examined emotional dampening using the affect-modulated startle paradigm given its proven sensitivity to motivational states of approach and withdrawal, typically independent of conscious intentional control. Acoustically elicited startle eye-blink modulation was measured using electromyography of the orbicularis oculi muscle beneath the left eye in 59 healthy individuals while they viewed pleasant, unpleasant and neutral standardized pictures. The expected startle attenuation to pleasant pictures, and startle potentiation to unpleasant pictures, relative to neutral pictures, was found in people in the comparison (N = 29) but not elevated BP (N = 30) group. This finding was further supported by significant moderating effect (assessed using ANCOVA and sub-sample analysis) of BP on valence-startle amplitude relationship. The comparison BP group also showed slower latencies to response onset for pleasant stimuli compared to neutral and unpleasant, with no effect of valence in the elevated BP group. However, BP did not moderate the valence-onset latency relationship. Our findings indicate that previously reported emotional dampening associated with elevated BP extends to reduced involuntary emotional reactivity and to individuals with even minimal BP elevations (i.e. higher but still within the normal range). Future research needs to confirm these findings in hypertensive individuals, preferably using within-subjects designs.

The temporal course of over-generalized conditioned threat expectancies in posttraumatic stress disorder.

One key conditioning abnormality in posttraumatic stress disorder (PTSD) is heightened generalization of fear from a conditioned danger-cue (CS+) to similarly appearing safe stimuli. The present work represents the first effort to track the time-course of heightened generalization in PTSD with the prediction of heightened PTSD-related over-generalization in earlier but not later trials. This prediction derives from past discriminative fear-conditioning studies providing incidental evidence that over-generalization in PTSD may be reduced with sufficient learning trials. In the current study, we re-analyzed previously published conditioned fear-generalization data (Kaczkurkin et al., 2017) including combat veterans with PTSD (n = 15) or subthreshold PTSD (SubPTSD: n = 18), and trauma controls (TC: n = 19). This re-analysis aimed to identify the trial-by-trial course of group differences in generalized perceived risk across three classes of safe generalization stimuli (GSs) parametrically varying in similarity to a CS+ paired with shock. Those with PTSD and SubPTSD, relative to TC, displayed significantly elevated generalization to all GSs combined in early but not late generalization trials. Additionally, over-generalization in PTSD and SubPTSD persisted across trials to a greater extent for classes of GSs bearing higher resemblance to CS+. Such results suggest that PTSD-related over-generalization of conditioned threat expectancies can be reduced with sufficient exposure to unreinforced GSs and accentuate the importance of analyzing trial-by-trial changes when assessing over-generalization in clinical populations.