Trauma history and course of therapy in a naturalistic cognitive behavior therapy outpatient sample: An archive data study.

OBJECTIVE: Cognitive Behavior Therapy (CBT) is an effective treatment for anxiety and depression disorders. Nonetheless, nearly 50% of all patients do not respond. Besides other factors, nonresponse may be linked to traumatic life events. This study aims to assess the relationship between trauma history, applied therapy interventions, and therapy outcomes. METHODS: We analyzed data from 340 CBT outpatients diagnosed with a depression or anxiety disorder and possibly a trauma history treated under naturalistic conditions. Based on their therapy files, we collected information on trauma history, diagnoses, applied interventions, and severity of depression and anxiety symptoms at the start and end of therapy. The relationship between trauma, diagnoses, and intervention use and the development of depression and anxiety symptoms was analyzed using Linear Mixed Models. RESULTS: Patients with a trauma history reported higher pre- and posttreatment symptom severity than those without trauma. No differences in applied interventions or decrease in symptom severity were found between patients with and without a trauma history. Specialized interventions were seldom applied. CONCLUSION: Although no differences between patients with and without a trauma history were found in therapy response, patients with a trauma history maintained higher levels of symptom severity. These results indicate a need for more personalized interventions and evidence-based guidelines to personalize CBT for patients with a trauma history and high symptom severity.

Brain-Derived Neurotrophic Factor/Tropomyosin Receptor Kinase B Signaling Controls Excitability and Long-Term Depression in Oval Nucleus of the BNST.

Dysregulation of proteins involved in synaptic plasticity is associated with pathologies in the CNS, including psychiatric disorders. The bed nucleus of the stria terminalis (BNST), a brain region of the extended amygdala circuit, has been identified as the critical hub responsible for fear responses related to stress coping and pathologic systems states. Here, we report that one particular nucleus, the oval nucleus of the BNST (ovBNST), is rich in brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) receptor. Whole-cell patch-clamp recordings of neurons from male mouse ovBNST in vitro showed that the BDNF/TrkB interaction causes a hyperpolarizing shift of the membrane potential from resting value, mediated by an inwardly rectifying potassium current, resulting in reduced neuronal excitability in all major types of ovBNST neurons. Furthermore, BDNF/TrkB signaling mediated long-term depression (LTD) at postsynaptic sites in ovBNST neurons. LTD of ovBNST neurons was prevented by a BDNF scavenger or in the presence of TrkB inhibitors, indicating the contribution to LTD induction. Our data identify BDNF/TrkB signaling as a critical regulator of synaptic activity in ovBNST, which acts at postsynaptic sites to dampen excitability at short and long time scales. Given the central role of ovBNST in mediating maladaptive behaviors associated with stress exposure, our findings suggest a synaptic entry point of the BDNF/TrkB system for adaptation to stressful environmental encounters.

Fear conditioning and stimulus generalization in association with age in children and adolescents.

The aim of the study was to investigate age-related differences in fear learning and generalization in healthy children and adolescents (n = 133), aged 8-17 years, using an aversive discriminative fear conditioning and generalization paradigm adapted from Lau et al. (2008). In the current task, participants underwent 24 trials of discriminative conditioning of two female faces with neutral facial expressions, with (CS+) or without (CS-) a 95-dB loud female scream, presented simultaneously with a fearful facial expression (US). The discriminative conditioning was followed by 72 generalization trials (12 CS+, 12 GS1, 12 GS2, 12 GS3, 12 GS4, and 12 CS-): four generalization stimuli depicting gradual morphs from CS+ to CS- in 20%-steps were created for the generalization phases. We hypothesized that generalization in children and adolescents is negatively correlated with age. The subjective ratings of valence, arousal, and US expectancy (the probability of an aversive noise following each stimulus), as well as skin conductance responses (SCRs) were measured. Repeated-measures ANOVAs on ratings and SCR amplitudes were calculated with the within-subject factors stimulus type (CS+, CS-, GS1-4) and phase (Pre-Acquisition, Acquisition 1, Acquisition 2, Generalization 1, Generalization 2). To analyze the modulatory role of age, we additionally calculated ANCOVAs considering age as covariate. Results indicated that (1) subjective and physiological responses were generally lower with increasing age irrespective to the stimulus quality, and (2) stimulus discrimination improved with increasing age paralleled by reduced overgeneralization in older individuals. Longitudinal follow-up studies are required to analyze fear generalization with regard to brain maturational aspects and clarify whether overgeneralization of conditioned fear promotes the development of anxiety disorders or vice versa.

The role of intolerance of uncertainty in the acquisition and extinction of reward.

Individuals, who score high in self-reported intolerance of uncertainty (IU), tend to find uncertainty anxiety-provoking. IU has been reliably associated with disrupted threat extinction. However, it is unclear whether IU would be related to disrupted extinction to other arousing stimuli that are not threatening (i.e., rewarding). We addressed this question by conducting a Pavlovian reward conditioning task with acquisition and extinction training phases (n = 58). In the Pavlovian reward conditioning task, we recorded liking ratings, skin conductance response (SCR), and corrugator supercilii activity (i.e., brow muscle indicative or negative and positive affect) to learned reward (CS+) and neutral (CS-) cues. Typical patterns of reward acquisition and extinction training were observed for liking ratings. There was evidence for conditioning in SCR during the extinction training phase but not the acquisition training phase. However, no evidence of conditioning in either the acquisition or extinction training phase was observed for the corrugator supercilii. IU was not related to any measures during the acquisition or extinction training phases. Taken together, these results suggest that the current Pavlovian reward conditioning task was not sufficient for eliciting a reliable conditioned reward response, and therefore, further research with optimized reward conditioning designs are required to test whether IU-related deficits occur during the extinction of reward.

Conjunctive and Elemental Representations of a Context in Humans.

The dual-process theory assumes that contexts are encoded in an elemental and in a conjunctive representation. However, this theory was developed from animal studies, and we still have to explore if and how elemental and conjunctive representations contribute to, for example, contextual anxiety in humans. Therefore, 28 participants underwent differential context conditioning in a newly developed flip-book paradigm. Virtual rooms were presented similar to a flip-book, that is, as a stream of 49 consecutive screenshots creating the impression of walking through the rooms. This allowed registration of event-related brain potentials triggered by specific screenshots. During two acquisition phases, two rooms were shown in this way for six times each. In one room, the anxiety context (CTX+), mildly painful electric stimuli (unconditioned stimuli [USs]) were administered unpredictably after 12 distinct screenshots, which became threat elements, whereas 12 selected comparable screenshots became nonthreat elements (elemental representation); all screenshots represented the anxiety context (conjunctive representation). In the second room, the safety context (CTX-), no USs were applied; thus, all screenshots created the safety context whereby 12 preselected screenshots represented safety elements. Increased US expectancy ratings for threat versus nonthreat or safety elements reflected elemental representation. Conjunctive representation was evident in differential ratings (arousal and contingency) and increased P100 and early posterior negativity amplitudes for threat and nonthreat CTX+ versus safety CTX- screenshots. These differences disappeared during two test phases without US delivery indicating successful extinction. In summary, we revealed the first piece of evidence for the simultaneous contributions of elemental and conjunctive representation during context conditioning in humans.

Evidence for impaired extinction learning in humans after distal stress exposure.

Stressful or traumatic events can be risk factors for anxiety or trauma- and stressor-related disorders. In this regard, it has been shown that stress affects aversive learning and memory processes. In rodents, stress exposure 10 days prior to fear acquisition impairs fear extinction. However, in humans the effect of distal stress on fear conditioning is sparse. Therefore, we examined the influence of distal stress on fear memory in humans in two studies. In Study 1, participants underwent either socially evaluated cold-pressor test (SECPT) or sham procedure 10 days or 40 min before a fear conditioning paradigm (four groups, N = 78). In Study 2, context effects were examined by conducting SECPT and sham procedures 10 days prior conditioning either in the later fear conditioning context or in another context (three groups, N = 69). During acquisition phase, one geometrical shape (conditioned stimulus, CS+) was paired with painful electric shocks (unconditioned stimulus, US), but never a second shape (CS-). Extinction phase was identical to acquisition, but without US delivery. Importantly, for Study 1 these phases were conducted on one day, while for Study 2 on two separated days. Successful fear acquisition was indicated by aversive ratings and startle potentiation to CS+ versus CS- in both studies. Interestingly, participants stressed 10 days earlier showed impaired extinction on the implicit level (startle potentiation to CS+ vs. CS-) in Study 1 and only in the acquisition context on the explicit level (aversive ratings for CS+ vs. CS-) in Study 2. In sum, distal stress may strengthen later acquired fear memories and thereby impair fear extinction. This finding could have clinical implications, showing that prior stress exposure sensitizes later aversive processing and impairs therapy.

Human BDNF rs6265 polymorphism as a mediator for the generalization of contextual anxiety.

The Met allele of the human brain-derived neurotrophic factor (BDNF) gene might be a risk factor for anxiety disorders and is associated with reduced hippocampal volume. Notably, hippocampus plays a crucial role in contextual learning and generalization. The role of the BDNF gene variation in human context-conditioning and generalization is still unknown. We investigated 33 carriers of the Met allele (18 females) and 32 homozygous carriers of the Val allele (15 females) with a virtual-reality context-conditioning paradigm. Electric stimulations (unconditioned stimulus, US) were unpredictably delivered in one virtual office (CTX+), but never in another virtual office (CTX-). During generalization, participants revisited CTX+ and CTX- and a generalization office (G-CTX), which was a mix of the other two. Rating data indicated successful conditioning (more negative valence, higher arousal, anxiety and contingency ratings for CTX+ than CTX-), and generalization of conditioned anxiety by comparable ratings for G-CTX and CTX+. The startle data indicated discriminative learning for Met allele carriers, but not for Val homozygotes. Moreover, a trend effect suggests that startle responses of only the Met carriers were slightly potentiated in G-CTX versus CTX-. In sum, the BDNF polymorphism did not affect contextual learning and its generalization on a verbal level. However, the physiological data suggest that Met carriers are characterized by fast discriminative contextual learning and a tendency to generalize anxiety responses to ambiguous contexts. We propose that such learning may be related to reduced hippocampal functionality and the basis for the risk of Met carriers to develop anxiety disorders.

Effects of context preexposure and delay until anxiety retrieval on generalization of contextual anxiety.

Animal studies suggest that time delay between acquisition and retrieval of contextual anxiety increases generalization. Moreover, such generalization is prevented by preexposure to the context (CTX), presumably due to an improved representation of such context. We investigated whether preexposure and time-passing modulate generalization of contextual anxiety, in humans. On Day 1, 42 participants (preexposure group) explored two virtual offices, while 41 participants (no-preexposure group) explored a virtual stadium. On Day 2 (24 h later), all participants learned to associate one office (CTX+) with unpredictable unconditioned stimuli (USs), and another office (CTX-) with safety. On Day 3, either 24 h (recent test) or 2 wk (remote test) later, participants revisited CTX- and CTX+ without USs, as well as a generalization context (G-CTX). Results revealed successfully conditioned anxiety and anxiety generalization for ratings (G-CTX was as aversive as CTX+ was), while safety generalization was found for startle responses (G-CTX elicited startle attenuation as CTX- did). Time between learning and testing enhanced generalization as reflected by comparable startle responses to all three offices in the remote test. Contextual preexposure facilitated extinction of explicit conditioned anxiety assessed with ratings. These results suggest that memory trace of a context degrades with passage of time in humans like in animals and, consequently, anxiety generalization enhances. After context preexposure, high cognitive processes seem to be crucially involved in facilitating extinction (or safety) learning.

Learning mechanisms underlying threat absence and threat relief: Influences of trait anxiety.

Impaired safety learning has been proposed asa risk factor for anxiety disorders, but safety can be indicated by either threat absence or threat termination (i.e., relief). Here, we investigated the role of trait anxiety for both kinds of safety learning. Ninety-one participants underwent an acquisition phase during which one shape (threatCS) predicted a painful electric shock (unconditioned stimulus, US), one shape (reliefCS) followed the US, and one shape (absenceCS) became never associated with the US. In a following extinction phase, the three cues were presented again plus a control shape (controlCS). We found successful threat conditioning as threatCS was rated as more aversive (negative, arousing, anxiogenic and associated with US) than the other cues, and it elicited startle potentiation as well asa larger skin conductance response (SCR). Safety cues were rated equally positive and (non-)anxiogenic, but still lower than controlCS, whereas physiologically reliefCS elicited stronger appetitive responses (startle attenuation and low SCR) than absenceCS. Interestingly, an increase in trait anxiety was associated with a decrease in the differences between absenceCS and threatCS responses reflected in contingency ratings during extinction as well as stronger fear-startle responses to absenceCS. In sum, physiological responses but not ratings triggered by a relief signal compared to a threat-absence signal, indicated that the former is more appetitive than the latter. Strikingly, trait anxiety specifically mediated learning of threat absence, but not of threat termination, indicating that high trait anxious individuals experience relief normally, but have deficits in identifying signals of threat absence.

Elemental and configural representation of a conditioned context.

A context can be conceptualized as a stable arrangement of elements or as the sum of single elements. Both configural and elemental representations play a role in associative processes. This study aimed to explore the respective contributions of these two representations of a context in the acquisition of conditioned anxiety in humans. Virtual reality (VR) can be an ecologically valid tool to investigate context-related mechanisms, yet the influence of the sense of presence within the virtual environment remains unclear. Forty-eight healthy individuals participated in a VR-based context conditioning wherein electric shocks (unconditioned stimulus, US) were unpredictably delivered in one virtual office (CTX+), but not in the other (CTX-). During the test phase, nine elements from each context were presented singularly. We found a cluster of participants, who exhibited heightened anticipation of the US for anxiety-related elements as compared to the other group. In contrast to their clear elemental representation, these individuals showed diminished discriminative responses between the two context's configurations. Discriminative responses to the contexts were boosted in those individuals, who had a weaker elemental representation. Importantly, the individual sense of presence significantly influenced the conditioned responses. These findings align with the dual-representation view of context and provide insights into the role of presence in eliciting (conditioned) anxiety responses.

Multimodal assessment of the role of intolerance of uncertainty in fear acquisition and extinction.

Personality traits linked to internalizing disorders influence the way we develop fears, but also how we regain a sense of safety. In the present study, we investigated the effect of intolerance of uncertainty (IU) on defensive responses using a differential fear conditioning protocol with an extinction phase. The conditioned stimulus was associated with an aversive sound (90 dB) in 75 % of the presentations during acquisition. A final sample of 176 participants completed the experiment. We measured self-reports of associative (expectancy of the unconditioned stimulus in acquisition) and evaluative learning (arousal and valence), and both physiological (skin conductance response) and electrocortical responses (steady-state visually evoked potentials, ssVEPs; late positive potentials, LPP) to the conditioned stimuli. Our results show that IU's impact is limited, with no effect in both acquisition and extinction. These findings emphasize the necessity of large samples in research on inter-individual differences and contribute to our understanding of how IU may or may not be involved in fear and safety learning processes considering multiple aspects of fear responding.

Is there a negative interpretation bias in depressed patients? An affective startle modulation study.

BACKGROUND/AIMS: Scientists proposed that patients with depression favour negative interpretations when appraising ambiguity. As self-report measures seem prone to response bias, implicit measures of emotional valence should be additionally used. METHODS: A total of 16 patients with depression and 19 controls underwent an acoustic imagery task comprising neutral and negative words, as well as ambiguous words that could be understood either way. Affective startle modulation and direct interrogation were used to assess implicit and explicit emotional valence, respectively. We expected a negative bias for ambiguous words in the patient group, resulting in augmented startle magnitudes and preference for negative interpretations of the ambiguous words in the interrogation. RESULTS: Surprisingly, both groups preferred neutral interpretations and showed augmented startle magnitudes to ambiguous words. Furthermore, both groups displayed an emotional startle potentiation for negative words. CONCLUSION: In summary, our results do not confirm a negative interpretation bias or a blunted emotional response in patients with major depression. The mismatch between self-report and affective startle reaction to ambiguous targets might reflect defensive mobilization or attention effects.

Onset and offset of aversive events establish distinct memories requiring fear and reward networks.

Two things are worth remembering about an aversive event: What made it happen? What made it cease? If a stimulus precedes an aversive event, it becomes a signal for threat and will later elicit behavior indicating conditioned fear. However, if the stimulus is presented upon cessation of the aversive event, it elicits behavior indicating conditioned "relief." What are the neuronal bases for such learning? Using functional magnetic resonance imaging (fMRI) in humans we found that a fear-conditioned stimulus activates amygdala but not striatum, whereas a relief-conditioned stimulus activates striatum but not amygdala. Correspondingly, acute inactivation of amygdala or of ventral striatum in rats respectively abolished only conditioned fear or only conditioned relief. Thus, the behaviorally opponent memories supported by onset and offset of aversive events engage and require fear and reward networks, respectively. This may explain attraction to stimuli associated with the cessation of trauma or of panic attacks.

Context-Dependent Responses to the Spread of COVID-19 Among National and International Students During the First Lockdown: An Online Survey.

BACKGROUND: Restrictions to minimize social contact was necessary to prevent the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus but may have impacted individuals' mental well-being. Emotional responses are modulated by contextual information. Living abroad during the coronavirus disease 2019 (COVID-19) pandemic may have boosted the feeling of isolation as the context is unfamiliar. OBJECTIVES: This study compared the psychological impact of social distancing in national students (living in a familiar context) versus international students (living in an unfamiliar context). METHODS: During March/April 2020 (first lockdown in the Netherlands), 850 university students completed an online survey. Structural equation modeling (SEM) was conducted to compare how students' responses to the virus were predicted by health anxiety, emotional distress, and personal traits. RESULTS: Compared with national students, international students showed higher levels in 4 identified factors (COVID-19-related worry, perceived risk of infection, distance from possibly contaminated objects, distance from social situations). The factors were mainly predicted by health anxiety across international students, while emotional distress and individual traits (eg, intolerance of uncertainty) played a role across national students. CONCLUSIONS: In the familiar context, individual characteristics (traits) predicted the responses to the virus, while the unfamiliar context drove individuals' health-focused responses. Living in a foreign country is associated with psychological burdens and this should be considered by universities for more pronounced social support and clear references to health-related institutions.

The effect of inherently threatening contexts on visuocortical engagement to conditioned threat.

Fear and anxiety are crucial for adaptive responding in life-threatening situations. Whereas fear is a phasic response to an acute threat accompanied by selective attention, anxiety is characterized by a sustained feeling of apprehension and hypervigilance during situations of potential threat. In the current literature, fear and anxiety are usually considered mutually exclusive, with partially separated neural underpinnings. However, there is accumulating evidence that challenges this distinction between fear and anxiety, and simultaneous activation of fear and anxiety networks has been reported. Therefore, the current study experimentally tested potential interactions between fear and anxiety. Fifty-two healthy participants completed a differential fear conditioning paradigm followed by a test phase in which the conditioned stimuli were presented in front of threatening or neutral contextual images. To capture defense system activation, we recorded subjective (threat, US-expectancy), physiological (skin conductance, heart rate) and visuocortical (steady-state visual evoked potentials) responses to the conditioned stimuli as a function of contextual threat. Results demonstrated successful fear conditioning in all measures. In addition, threat and US-expectancy ratings, cardiac deceleration, and visuocortical activity were enhanced for fear cues presented in threatening compared with neutral contexts. These results are in line with an additive or interactive rather than an exclusive model of fear and anxiety, indicating facilitated defensive behavior to imminent danger in situations of potential threat.

Investigating sustained attention in contextual threat using steady-state VEPs evoked by flickering video stimuli.

Anxiety is characterized by anxious anticipation and heightened vigilance to uncertain threat. However, if threat is not reliably indicated by a specific cue, the context in which threat was previously experienced becomes its best predictor, leading to anxiety. A suitable means to induce anxiety experimentally is context conditioning: In one context (CTX+), an unpredictable aversive stimulus (US) is repeatedly presented, in contrast to a second context (CTX-), in which no US is ever presented. In this EEG study, we investigated attentional mechanisms during acquisition and extinction learning in 38 participants, who underwent a context conditioning protocol. Flickering video stimuli (32 s clips depicting virtual offices representing CTX+/-) were used to evoke steady-state visual evoked potentials (ssVEPs) as an index of visuocortical engagement with the contexts. Analyses of the electrocortical responses suggest a successful induction of the ssVEP signal by video presentation in flicker mode. Furthermore, we found clear indices of context conditioning and extinction learning on a subjective level, while cortical processing of the CTX+ was unexpectedly reduced during video presentation. The differences between CTX+ and CTX- diminished during extinction learning. Together, these results indicate that the dynamic sensory input of the video presentation leads to disruptions in the ssVEP signal, which is greater for motivationally significant, threatening contexts.

Examining the impact of cue similarity and fear learning on perceptual tuning.

Past research on the effects of associative aversive learning on discrimination acuity has shown mixed results, including increases, decreases, and no changes in discrimination ability. An animal study found that the type of learning experience determined the direction and extent of learning-induced changes. The current preregistered web-based study aimed to translate these findings to humans. Experiment 1 (N = 245) compared changes in stimulus discrimination between simple learning (only one oriented grating cue), coarse differential conditioning (physically distinct cues), and fine differential conditioning (physically similar cues) as well as to their three respective control groups. The discrimination task consisted of a two-alternative-forced-choice task with oriented grating stimuli. During learning, a specific orientation was paired with unpleasant pictures. Our analysis using generative modeling demonstrated weak to moderate evidence that aversive learning did not alter discrimination acuity in any of the groups. In a follow-up experiment (N = 121), we replicated these findings despite successful learning trajectories in all three groups and a more detailed assessment of discrimination acuity. Contrary to prior assumptions, our findings indicate that aversive learning does not enhance perceptual discrimination, and the presence of additional safety cues does not appear to moderate this effect.

VR for Studying the Neuroscience of Emotional Responses.

Emotions are frequently considered as the driving force of behavior, and psychopathology is often characterized by aberrant emotional responding. Emotional states are reflected on a cognitive-verbal, physiological-humoral, and motor-behavioral level but to date, human research lacks an experimental protocol for a comprehensive and ecologically valid characterization of such emotional states. Virtual reality (VR) might help to overcome this situation by allowing researchers to study mental processes and behavior in highly controlled but reality-like laboratory settings. In this chapter, we first elucidate the role of presence and immersion as requirements for eliciting emotional states in a virtual environment and discuss different VR methods for emotion induction. We then consider the organization of emotional states on a valence continuum (i.e., from negative to positive) and on this basis discuss the use of VR to study threat processing and avoidance as well as reward processing and approach behavior. Although the potential of VR has not been fully realized in laboratory and clinical settings yet, this technological tool can open up new avenues to better understand the neurobiological mechanisms of emotional responding in healthy and pathological conditions.

Altered processing of emotional stimuli in migraine: an event-related potential study.

BACKGROUND: Migraine patients report psychosocial stress to be among the major triggers for their migraine attacks. The mechanisms underlying the onset of migraine attacks are not yet fully understood. Neuroimaging studies have shown changes in the cortical excitability of migraine patients. Here, we investigated cortical activation related to processing of emotional stimuli in individuals with migraine. METHOD: Twenty-four participants suffering from migraine attacks and 25 healthy volunteers had to passively observe pictures of emotional facial expressions (angry, happy and neutral). Electro-cortical activity was continuously recorded by means of an electroencephalogram (EEG), and ratings of valence (unpleasant vs. pleasant) and arousal (calm vs. exciting) were collected. RESULTS: The migraine and control group did not differ in their ratings of valence and arousal of the visual stimuli. However, participants with migraine, in contrast to healthy controls, showed larger N170 amplitudes toward angry facial expressions compared to neutral ones. DISCUSSION: Individuals with migraine may have an altered cortical activity linked to the processing of emotional information. Thus, these individuals may process high arousing and threatening events preferentially, and this facilitated processing may be related to their already high cortical excitability.

Contextual fear conditioning predicts subsequent avoidance behaviour in a virtual reality environment.

Avoidance behaviour is a crucial component of fear and is importantly involved in the maintenance of anxiety disorders. Presumably, fear conditioning leads to avoidance of the feared object or context. A virtual reality contextual fear conditioning paradigm was used to investigate the association between explicit conditioning effects and subsequent avoidance behaviour. Mild electric shocks were administered in one context (anxiety context), but never in a second context (safety context). Subsequent avoidance behaviour was assessed by asking participants to choose two out of three contexts (a neutral context was added) to visit again. Participants avoided the anxiety context, but did not prefer the safety over the neutral context. Participants with substantial conditioning effects, as reflected in differential valence, arousal and anxiety ratings, avoided the anxiety context but not the safety context. In sum, we demonstrated an association between context conditioning effects on an explicit level and later avoidance behaviour.