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Previous studies have shown that activating the attachment system attenuates fear learning. This study aimed to explore whether attachment priming can also impact on fear extinction processes, which underpin the management of anxiety disorders. In this study, 81 participants underwent a standard fear conditioning and extinction protocol on day 1 and returned 24 h later for an extinction recall and reinstatement test. Half the participants were primed to imagine their closest attachment figure prior to undergoing extinction training, while the other half were instructed to imagine a positive situation. Fear-potentiated startle and subjective expectancies of shock were measured as the primary indicators of fear. Attachment priming led to less relapse during the reinstatement test at the physiological but not subjective levels. These findings have translational potential to imply that activating awareness of attachment figures might augment long-term safety memories acquired in existing treatments to reduce relapse of fear.

Background Recent studies have found that attachment security primes can inhibit fear acquisition. This current study aimed to examine whether a brief imaginal prime of one's attachment figure could impact on fear consolidation. Methods A total of 75 participants underwent fear conditioning on Day 1 and fear recall was tested on Day 2. Immediately following conditioning, half the participants were instructed to imagine an attachment figure while the other half imagined a nonattachment positive situation. Fear-potentiated startle and subjective expectancy of shock ratings were used as the measures of fear learning across trials. Results The attachment group showed significantly lower levels of fear recall on Day 2 at both physiological and subjective levels. Furthermore, this effect was moderated by attachment anxiety, such that it was greatest for individuals who were securely attached. Conclusions These findings suggest that attachment relationships are protective during the consolidation of fear memories, and may have implications for how social attachments may impact how anxiety disorders can develop.

A putative biomarker of anxiety risk, the startle response is typically enhanced by negative compared to neutral emotion modulation in adults, but remains understudied in children. To determine the extent to which neutral, negative, and positively valenced emotional conditions modulate startle response in early life, a child-friendly film paradigm was used to vary emotion across these conditions during startle induction in sixty-four 4- to 7-year-old children. Association of emotion-modulated startle with parent-reported anxiety symptom severity and child behavioral inhibition, a risk factor for anxiety problems, were assessed. Analyses revealed no difference in startle magnitude during negative compared to neutral film clips. By contrast, startle during both negative and neutral conditions was greater than startle during the positive condition. Larger startle magnitude during the neutral condition associated with higher levels of child behavioral inhibition (BI). These results are consistent with possible immaturity of startle response in young children, and suggest that startle amplitude in more emotionally ambiguous, neutral conditions could serve as an early biomarker for anxiety risk.

The relative contributions of reticulospinal versus corticospinal pathways for movement production are thought to be dependent on the type of response involved. For example, unilateral distal movements involving the hand and finger have been thought to be primarily driven by corticospinal output, whereas bilateral responses are considered to have greater reticulospinal drive. The current study investigated whether a difference in the relative contribution of reticulospinal drive to a bimanual versus unimanual finger movement could be assessed using a StartReact protocol. The StartReact effect refers to the early and involuntary initiation of a prepared movement when a startle reflex is elicited. A decreased response latency on loud stimulus trials where a startle reflex is observed in sternocleidomastoid (SCM+ trials) confirms the StartReact effect, which is attributed to increased reticulospinal drive associated with engagement of the startle reflex circuitry. It was predicted that a StartReact effect would be absent for the predominantly corticospinal-mediated unimanual finger movement but present for the bimanual finger movement due to stronger reticulospinal drive. Results supported both predictions as reaction time was statistically equivalent for SCM+ and SCM- trials during unimanual finger movements but significantly shorter for SCM+ trials during bimanual finger movements. These results were taken as strong and novel evidence for increased reticulospinal output for bimanual finger movements.

Worry is a form of repetitive negative thought that is closely associated with anxiety disorders. Worry has been described as anxious apprehension and conceptualized as reflecting heightened anticipation of potentially threatening future events. However, it is unclear whether people who tend to worry show heightened physiological reactivity when anticipating threat, especially if the threat is uncertain. In the current study, community participants (n = 52) completed a threat anticipation task featuring uncertain threat, certain threat, and safety while the startle response to auditory probes was measured. Self-reported tendency to worry was assessed using the Penn State Worry Questionnaire, and anxiety disorder status was assessed via a clinical interview. A repeated-measures general linear model showed a main effect of threat level on the startle response, as well as a significant three-way interaction among threat level, worry, and anxiety disorder status. Follow-up tests showed that higher worry was associated with blunted startle responses to threat but particularly to uncertain threat among participants with a history of anxiety disorders. Worry did not moderate startle responding in participants without a history of anxiety disorders. These results indicate that psychophysiological correlates of worry depend on clinical status and suggest that trait worry is associated with physiological blunting to threat in individuals with a history of anxiety disorders, particularly when threat is uncertain. Implications for theoretical models of worry are discussed.

BACKGROUND Sexual minorities (e.g. lesbian, gay, bisexual) are at increased risk for alcohol use disorder (AUD) compared to heterosexuals. The minority stress model postulates that disparities in AUD stem, in part, from stress specific to sexual minorities (e.g. heterosexism). However, little research has examined psychophysiological markers of minority stress reactivity and how psychophysiological stress reactivity is associated with lifetime minority stress and alcohol use among sexual minorities. Emotion modulation of the startle response is a well-established paradigm for capturing psychophysiological stress reactivity under controlled laboratory conditions. Purpose: This preliminary study is the first to use the startle experimental paradigm to examine psychophysiological reactivity to stigma among sexual minorities. Procedures: Sexual minority participants (N = 20; 55% female), aged 18 to 27 years (M = 21.80, SD = 2.65), were recruited from the community. We compared startle reactivity in response to three types of stimuli (stigma, negative, and neutral) among heavy drinking sexual minority young adults. Although statistically underpowered, we also explored the associations between startle reactivity and self-reported drinking behaviors and lifetime minority stress. Results: Both stigma and general unpleasant stimuli produced more psychophysiological stress reactivity than neutral stimuli among sexual minorities. Psychophysiological stress reactivity was correlated with greater quantity of drinks reported on drinking days in the past month, but not greater frequency. Additionally, lifetime exposure to minority stress was associated with a blunted reactivity to stigma stimuli. Conclusions: These findings provide methodological advances and important implications for minority stress theory and alcohol use among sexual minorities.

Background: Given its emotional and autobiographical properties, music appears as a potential aid in diagnostic assessment and therapeutics in patients with disorders of consciousness (DOCs). Several studies have shown boosting effects on behavior and brain functioning when patients were exposed to (their preferred) music. Objective: The aim of this study was to investigate if these effects on the brain's spontaneous activity are dependent on the level of consciousness. Methods: Nine postcomatose patients and eight healthy control subjects were assessed using functional magnetic resonance imaging in two conditions: rest (without stimulation) and music. All patients presented at least an auditory startle, thereby suggesting the presence of residual auditory function. A gradient of consciousness (from unresponsive wakefulness syndrome to healthy subjects) was formulated to evaluate consciousness-level-dependent increases in brain activity and connectivity. Network-based functional connectivity assessed auditory, default-mode, frontoparietal, and music-evoked emotion networks. Furthermore, exploratory voxel-to-voxel analyses were performed at the whole brain level using intrinsic connectivity contrast and (fractional) amplitude of low-frequency fluctuations. Results: Stronger consciousness-level-dependent increases within network-to-voxel analysis of connectivity were found in the frontoparietal network with the precuneus during music stimulation compared with rest. Voxel-to-voxel analyses showed stronger increases of intrinsic connectivity in the music condition compared with rest in regions previously related to music processing. There were consistently more regions with increased connectivity during the main effect of music compared with rest. These increases of connectivity during music were observed in brain regions involved in consciousness, language, emotion, and memory processing. Conclusions: Our results show that music seems to trigger more substantial connectivity changes compared with rest, pointing toward the potential ability of music to stimulate patients' brain function. Further research should focus on effects of music in general, its specific acoustical features, and the effects of simple auditory stimuli, as well as the possible therapeutic and diagnostic effects of music in well-controlled clinical trials. Impact statement Due to its emotional and autobiographical properties, music is a particularly salient stimulus. A few studies using musical stimuli have shown promising results in terms of behavioral responsiveness in patients with disorders of consciousness (Magee, 2005; Raglio et al., 2014; Verger et al., 2014). Our study confirms the presence of a beneficial effect of music on brain connectivity in these severely brain-injured patients, which moreover seems to be dependent on the level of consciousness. Our findings therefore strengthen the hypothesis that music could play a role from a diagnostic and therapeutic standpoint in this population, paving the way for future well-controlled clinical trials.

Disorders of consciousness are challenging to diagnose. Hermann et al. identify a new clinical sign, the habituation of auditory startle reflex, which indexes the activity of a fronto-parietal network and predicts improved consciousness at 6 months. The measure could be a new bedside sign of minimally conscious state., Neurological examination of non-communicating patients relies on a few decisive items that enable the crucial distinction between vegetative state (VS)—also coined unresponsive wakefulness syndrome (UWS)—and minimally conscious state. Over the past 10 years, this distinction has proven its diagnostic value as well as its important prognostic value on consciousness recovery. However, clinicians are currently limited by three factors: (i) the current behavioural repertoire of minimally conscious state items is limited and restricted to a few cognitive domains in the goldstandard revised version of the Coma Recovery Scale; (ii) a proportion of ∼15–20% clinically VS/UWS patients are actually in a richer state than VS/UWS as evidenced by functional brain imaging; and (iii) the neurophysiological and cognitive interpretation of each minimally conscious state item is still unclear and debated. In the current study we demonstrate that habituation of the auditory startle reflex (hASR) tested at bedside constitutes a novel, simple and powerful behavioural sign that can accurately distinguish minimally conscious state from VS/UWS. In addition to enlarging the minimally conscious state items repertoire, and therefore decreasing the low sensitivity of current behavioural measures, we also provide an original and rigorous description of the neurophysiological basis of hASR through a combination of functional (high density EEG and 18F-fluorodeoxyglucose PET imaging) and structural (diffusion tensor imaging MRI) measures. We show that preservation of hASR is associated with the functional and structural integrity of a brain-scale fronto-parietal network, including prefrontal regions related to control of action and inhibition, and meso-parietal areas associated with minimally conscious and conscious states. Lastly, we show that hASR predicts 6-month improvement of consciousness. Taken together, our results show that hASR is a cortically-mediated behaviour, and suggest that it could be a new clinical item to clearly and accurately identify non-communicating patients who are in the minimally conscious state.

Introduction: According to the fully-dimensional approach, schizotypy is a personality trait present in the population in a continuous manner while the quasi-dimensional approach emphasises its extreme presentations. In this study we examined the relationship between sensorimotor gating, a core risk-index of the schizophrenia-spectrum, and four schizotypal factors in a dimensional-wise and a dichotomising-wise approach. Methods: Two-hundred and eighty-three participants were assessed with the Schizotypal Personality Questionnaire and were tested for Prepulse Inhibition (PPI). Associations between the schizotypal factors and startle measures were examined with stepwise regressions (dimensional-wise approach). Individuals in the lower 20% or the upper 20% for each schizotypal factor were identified and between-group comparisons were conducted (dichotomising-wise approach). Results: We found that with both approaches, only high paranoid or negative schizotypy were associated with reduced PPI. The low negative schizotypy group had prolonged onset and peak latencies, indicating that prolonged stimulus detection accompanies superior sensorimotor gating in this group. Conclusions: The findings suggest that although differentiating the effects of the various schizotypal factors is primary, the approach employed is secondary. The study also adds evidence in the literature supporting PPI as a useful endophenotypic marker of the schizophrenia-spectrum and highlights the contribution of specific aspects of schizotypy.

Measuring animal behavior in the context of experimental manipulation is critical for modeling, and understanding neuropsychiatric disease. Prepulse inhibition of the acoustic startle response (PPI) is a behavioral phenomenon studied extensively for this purpose, but the results of PPI studies are often inconsistent. As a result, the utility of this phenomenon remains uncertain. Here, we deconstruct the phenomenon of PPI and confirm several limitations of the methodology traditionally utilized to describe PPI, including that the underlying startle response has a non-Gaussian distribution, and that the traditional PPI metric changes with different stimuli. We then develop a novel model that reveals PPI to be a combination of the previously appreciated scaling of the startle response, as well as a scaling of sound processing. Using our model, we find no evidence for differences in PPI in a rat model of Fragile-X Syndrome (FXS) compared with wild-type controls. These results in the rat provide a reliable methodology that could be used to clarify inconsistent PPI results in mice and humans. In contrast, we find robust differences between wild-type male and female rats. Our model allows us to understand the nature of these differences, and we find that both the startle-scaling and sound-scaling components of PPI are a function of the baseline startle response. Males and females differ specifically in the startle-scaling, but not the sound-scaling, component of PPI. These findings establish a robust experimental and analytical approach that has the potential to provide a consistent biomarker of brain function.

Background The startle eye-blink is the cross-species translational tool to study defensive behavior in affective neuroscience with relevance to a broad range of neuropsychiatric conditions. It makes use of the startle reflex, a defensive response elicited by an immediate, unexpected sensory event, which is potentiated when evoked during threat and inhibited during safety. In contrast to skin conductance responses or pupil dilation, modulation of the startle reflex is valence specific. Rodent models implicate a modulatory pathway centering on the brainstem (i.e., nucleus reticularis pontis caudalis) and the centromedial amygdala as key hubs for flexibly integrating valence information into differential startle magnitude. Technical advances now allow for the investigation of this pathway using combined facial electromyography and functional magnetic resonance imaging in humans. Methods We employed a multimethodological approach combining trial-by-trial facial eye-blink startle electromyography and brainstem- and amygdala-specific functional magnetic resonance imaging in humans. Validating the robustness and reproducibility of our findings, we provide evidence from two different paradigms (fear-potentiated startle, affect-modulated startle) in two independent studies (N = 43 and N = 55). Results We provide key evidence for a conserved neural pathway for acoustic startle modulation between humans and rodents. Furthermore, we provide the crucial direct link between electromyography startle eye-blink magnitude and neural response strength. Finally, we demonstrate a dissociation between arousal-specific amygdala responding and triggered valence-specific amygdala responding. Conclusions We provide neurobiologically based evidence for the strong translational value of startle responding and argue that startle-evoked amygdala responding and its affective modulation may hold promise as an important novel tool for affective neuroscience and its clinical translation.

Contextual information can modulate the conditioned response to a threat signal (conditioned stimulus, CS+): fear responses are either potentiated or attenuated depending on whether the context is threatening or safe. In this study, we investigated the influence of context on conditioned fear as well as on generalization of conditioned fear. Thirty-two participants underwent a cue-in-context learning protocol in virtual reality (VR). On Day 1 (acquisition), participants received a mild painful electric shock (unconditioned stimulus, US) in one virtual room (fear context, CTX+) at the offset of one colored light (CS+), but never at the offset of another colored light (CS-). In a second room (safety context, CTX-), the two lights were also presented, but not the US. Successful cue conditioning was indicated by aversive ratings and startle potentiation but not skin conductance responses (SCR) to CS+ versus CS- in CTX+ and not in CTX-. On Day 2 (generalization), participants re-visited both fear and safety contexts plus a generalization context (G-CTX), which was an equal mix of CTX+ and CTX-. The two CSs were shown again in all three contexts. Generalization of conditioned fear was revealed in affective ratings (CS+ was rated more aversive than CS- in G-CTX), but not in physiological measures (equal startle potentiation to CS+ versus CS- in all contexts). In sum, contextual information modulates the responses to a threat signal such that a safety context can inhibit conditioned fear. Interestingly, generalization processes also depend on contextual information.

Rationale Psychotic disorders, such as schizophrenia, as well as some mood disorders, such as bipolar disorder, have been suggested to share common biological risk factors. One such factor is reelin, a large extracellular matrix glycoprotein that regulates neuronal migration during development as well as numerous activity-dependent processes in the adult brain. The current study sought to evaluate whether a history of stress exposure interacts with endogenous reelin levels to modify behavioural endophenotypes of relevance to psychotic and mood disorders. Methods Heterozygous Reeler Mice (HRM) and wildtype (WT) controls were treated with 50 mg/L of corticosterone (CORT) in their drinking water from 6 to 9 weeks of age, before undergoing behavioural testing in adulthood. We assessed methamphetamine-induced locomotor hyperactivity, prepulse inhibition (PPI) of acoustic startle, short-term spatial memory in the Y-maze, and depression-like behaviour in the Forced-Swim Test (FST). Results HRM genotype or CORT treatment did not affect methamphetamine-induced locomotor hyperactivity, a model of psychosis-like behaviour. At baseline, HRM showed decreased PPI at the commonly used 100 msec interstimulus interval (ISI), but not at the 30 msec ISI or following challenge with apomorphine. A history of CORT exposure potentiated immobility in the FST amongst HRM, but not WT mice. In the Y-maze, chronic CORT treatment decreased novel arm preference amongst HRM, reflecting reduced short-term spatial memory. Conclusion These data confirm a significant role of endogenous reelin levels on stress-related behaviour, supporting a possible role in both bipolar disorder and schizophrenia. However, an interaction of reelin deficiency with dopaminergic regulation of psychosis-like behaviour remains unclear.

Anxiety patients overgeneralize fear responses, possibly because they cannot distinguish between cues never been associated with a threat (i.e., safe) and threat-associated cues. However, as contexts and not cues are discussed as the relevant triggers for prolonged anxiety responses characterizing many anxiety disorders, we speculated that it is rather overgeneralization of contextual anxiety, which constitutes a risk factor for anxiety disorders. To this end, we investigated generalization of conditioned contextual anxiety and explored modulatory effects of anxiety sensitivity, a risk factor for anxiety disorders. Fifty-five participants underwent context conditioning in a virtual reality paradigm. On Day 1 (acquisition), participants received unpredictable mildly painful electric stimuli (unconditioned stimulus, US) in one virtual office (anxiety context, CTX+), but never in a second office (safety context, CTX−). Successful acquisition of conditioned anxiety was indicated by aversive ratings and defensive physiological responses (i.e., SCR) to CTX+ vs CTX−. On Day 2 (generalization), participants re-visited both the anxiety and the safety contexts plus three generalization contexts (G-CTX), which were gradually dissimilar to CTX+ (from 75 to 25%). Generalization of conditioned anxiety was evident for ratings, but less clear for physiological responses. The observed dissociation between generalization of verbal and physiological responses suggests that these responses depend on two distinct context representations, likely elemental and contextual representations. Importantly, anxiety sensitivity was positively correlated with the generalization of reported contextual anxiety. Thus, this study demonstrates generalization gradients for conditioned contextual anxiety and that anxiety sensitivity facilitates such generalization processes suggesting the importance of generalization of contextual anxiety for the development of anxiety disorders. Electronic supplementary material The online version of this article (10.1007/s13311-020-00831-8) contains supplementary material, which is available to authorized users.

Contains fulltext : 244068.pdf (Publisher’s version ) (Open Access) Freezing to impending threat is a core defensive response. It has been studied primarily using fear conditioning in non-human animals, thwarting advances in translational human anxiety research that has used other indices, such as skin conductance responses. Here we examine postural freezing as a human conditioning index for translational anxiety research. We employed a mixed cued/contextual fear-conditioning paradigm where one context signals the occurrence of the US upon the presentation of the CS, and another context signals that the CS is not followed by the US. Critically, during the following generalization phase, the CS is presented in a third and novel context. We show that human freezing is highly sensitive to fear conditioning, generalizes to ambiguous contexts, and amplifies with threat imminence. Intriguingly, stronger parasympathetically driven freezing under threat, but not sympathetically mediated skin conductance, predicts subsequent startle magnitude. These results demonstrate that humans show fear-conditioned animal-like freezing responses, known to aid in active preparation for unexpected attack, and that freezing captures real-life anxiety expression. Conditioned freezing offers a promising new, non-invasive, and continuous, readout for human fear conditioning, paving the way for future translational studies into human fear and anxiety. 20 p.

Open Access funding enabled and organized by Projekt DEAL., Looking at pictures of loved ones, such as one’s romantic partner or good friends, has been shown to alleviate the experience of pain and reduce defensive reactions. However, little is known about such modulatory effects on threat and safety learning and the psychophysiological processes involved. Here, we explored the hypothesis that beloved faces serve as implicit safety cues and attenuate the expression of fear responses and/or accelerate extinction learning in a threatening context. Thirtytwo participants viewed pictures of their loved ones (romantic partner, parents, and best friend) as well as of unknown individuals within contextual background colors indicating threat-of-shock or safety. Focusing on the extinction of non-reinforced threat associations (no shocks were given), the experiment was repeated on two more test days while the defensive startle-EMG, SCR, and threat ratings were obtained. Results confirmed pronounced defensive responding to instructed threatof- shock relative to safety context (e.g., threat-enhanced startle reflex and SCR). Moreover, threatpotentiated startle response slowly declined across test days indicating passive extinction learning in the absence of shocks. Importantly, neither a main effect of face category (loved vs. unknown) nor a significant interaction with threat/safety instructions was observed. Thus, a long-term learning history of beneficial relations (e.g., with supportive parents) did not interfere with verbal threat learning and aversive apprehensions. These findings reflect the effects of worries and apprehensions that persist despite the repeated experience of safety and the pictorial presence of loved ones. How to counter such aversive expectations is key to changing mal-adaptive behaviors (e.g., avoidance or stockpiling), biased risk perceptions, and stereotypes., Projekt DEAL

Fibroblast growth factor binding protein 3 (Fgfbp3) have been known to be crucial for the process of neural proliferation, differentiation, migration, and adhesion. However, the specific role and the molecular mechanisms of fgfbp3 in regulating the development of motor neurons remain unclear. In this study, we have investigated the function of fgfbp3 in morphogenesis and regeneration of motor neuron in zebrafish. Firstly, we found that fgfbp3 was localized in the motor neurons and loss of fgfbp3 caused the significant decrease of the length and branching number of the motor neuron axons, which could be partially rescued by fgfbp3 mRNA injection. Moreover, the fgfbp3 knockdown (KD) embryos demonstrated similar defects of motor neurons as identified in fgfbp3 knockout (KO) embryos. Furthermore, we revealed that the locomotion and startle response of fgfbp3 KO embryos were significantly restricted, which were partially rescued by the fgfbp3 overexpression. In addition, fgfbp3 KO remarkably compromised axonal regeneration of motor neurons after injury. Lastly, the malformation of motor neurons in fgfbp3 KO embryos was rescued by overexpressing drd1b or neurod6a, respectively, which were screened by transcriptome sequencing. Taken together, our results provide strong cellular and molecular evidence that fgfbp3 is crucial for the axonal morphogenesis and regeneration of motor neurons in zebrafish.

We tested whether surprise elicits similar physiological changes as those associated with orienting and freezing after threat, as surprise also involves a state of interruption and attention for effective action. Moreover, because surprise is primarily driven by the unexpectedness of an event, initial physiological responses were predicted to be similar for positive, neutral, and negative surprises. Results of repetition-change studies (4 + 1 in Supplemental Materials) showed that surprise lowers heart rate (Experiments 1-4) and increases blood pressure (Experiment 4). No effects on body movement (Experiment 2) or finger temperature (Experiment 4) were found. When unexpected stimuli were presented more often (making them less surprising) heart rate returned to baseline, while blood pressure remained high (Experiment 4). These effects were not influenced by stimulus valence. However, second-to-second analyses within the first (surprising) block showed a tendency for a stronger increase in systolic blood pressure after negative vs. positive surprise.

Individuals with high self-reported Intolerance of uncertainty (IU) tend to interpret uncertainty negatively. Recent research has been inconclusive on evidence of an association between IU and physiological responses during instructed uncertain threat. To address this gap, we conducted secondary analyses of IU and physiology data recorded during instructed uncertain threat tasks from two lab sites (Wisconsin-Madison; n = 128; Yale, n = 95). No IU-related effects were observed for orbicularis oculi activity (auditory startle-reflex). Higher IU was associated with: (1) greater corrugator supercilii activity to predictable and unpredictable threat of shock, compared to the safety from shock, and (2) poorer discriminatory skin conductance response between the unpredictable threat of shock, relative to the safety from shock. These findings suggest that IU-related biases may be captured differently depending on the physiological measure during instructed uncertain threat. Implications of these findings for neurobiological models of uncertainty and anticipation in anxiety are discussed.

Play has been recognized as a complex and diverse set of behaviors that has been difficult to define. Play can range from rough and tumble play among rats to a human child playing a computer game. Play has been understood to exist in multiple forms such as social, object, and locomotor (Burghardt, 2005). In this article we review the literatures on the neural basis of social play, on heart rate variability, on behavioral switching and set-shifting, on prepulse inhibition of the acoustic startle reflex, and on learning at the level of the basal ganglia. Each of these neuronal pathways, aside from heart rate variability, is rooted in the parafascicular nucleus of the thalamus, an important neural substrate for social play. We argue that social play optimally balances a number of opposing neural pathways by engaging systems involved in safety versus danger (heart rate variability), automatized reactions versus learned reactions to new stimuli (behavioral switching and set-shifting), and gating relevant versus less relevant stimuli (prepulse inhibition of the acoustic startle reflex). The idea that play, in addition to its role in interpersonal adaptation to social life, may have a central role in optimizing flexibility and creativity in individual response to novelty has been explored by previous authors ( Huizinga, 1955 ; Spinka et al., 2001; Pellegrini et al., 2007; Pellis and Pellis, 2017 ). In this paper we explore the possible underlying neural basis for this function of play, having to do with balancing various neural networks, and in doing so propose an expanded understanding of the nature and function of social play.

Much of the mechanistic research on anxiety focuses on subcortical structures such as the amygdala; however, less is known about the distributed cortical circuit that also contributes to anxiety expression. One way to learn about this circuit is to probe candidate regions using transcranial magnetic stimulation (TMS). In this study, we tested the involvement of the dorsolateral prefrontal cortex (dlPFC), in anxiety expression using 10 Hz repetitive TMS (rTMS). In a within-subject, crossover experiment, the study measured anxiety in healthy subjects before and after a session of 10 Hz rTMS to the right dorsolateral prefrontal cortex (dlPFC). It used threat of predictable and unpredictable shock to induce anxiety and anxiety potentiated startle to assess anxiety. Counter to our hypotheses, results showed an increase in anxiety-potentiated startle following active but not sham rTMS. These results suggest a mechanistic link between right dlPFC activity and physiological anxiety expression. This result supports current models of prefrontal asymmetry in affect, and lays the groundwork for further exploration into the cortical mechanisms mediating anxiety, which may lead to novel anxiety treatments.

Translational neuroscience bridges insights from specific mechanisms in rodents to complex functions in humans and is key to advance our general understanding of central nervous function. A prime example of translational research is the study of cross-species mechanisms that underlie responding to learned threats, by employing Pavlovian fear conditioning protocols in rodents and humans. Hitherto, evidence for (and critique of) these cross-species comparisons in fear conditioning research was based on theoretical viewpoints. Here, we provide a perspective to substantiate these theoretical concepts with empirical considerations of cross-species methodology. This meta-research perspective is expected to foster cross-species comparability and reproducibility to ultimately facilitate successful transfer of results from basic science into clinical applications.

Significance Many biological systems exhibit an emergent ability to process information about their environment. This collective cognition emerges as a result of both the behavior of system components and their interactions, yet the relative importance of the two is often hard to disentangle. Here, we combined experiments and modeling to examine how fish schools collectively encode information about the external environment. We demonstrate that risk is predominantly encoded in the physical structure of groups, which individuals modulate in a way that augments or dampens behavioral cascades. We show that this modulation is necessary for behavioral cascades to spread and that it allows collective systems to be responsive to their environments even without changes in individual computation., The need to make fast decisions under risky and uncertain conditions is a widespread problem in the natural world. While there has been extensive work on how individual organisms dynamically modify their behavior to respond appropriately to changing environmental conditions (and how this is encoded in the brain), we know remarkably little about the corresponding aspects of collective information processing in animal groups. For example, many groups appear to show increased “sensitivity” in the presence of perceived threat, as evidenced by the increased frequency and magnitude of repeated cascading waves of behavioral change often observed in fish schools and bird flocks under such circumstances. How such context-dependent changes in collective sensitivity are mediated, however, is unknown. Here we address this question using schooling fish as a model system, focusing on 2 nonexclusive hypotheses: 1) that changes in collective responsiveness result from changes in how individuals respond to social cues (i.e., changes to the properties of the “nodes” in the social network), and 2) that they result from changes made to the structural connectivity of the network itself (i.e., the computation is encoded in the “edges” of the network). We find that despite the fact that perceived risk increases the probability for individuals to initiate an alarm, the context-dependent change in collective sensitivity predominantly results not from changes in how individuals respond to social cues, but instead from how individuals modify the spatial structure, and correspondingly the topology of the network of interactions, within the group. Risk is thus encoded as a collective property, emphasizing that in group-living species individual fitness can depend strongly on coupling between scales of behavioral organization.

The timing and magnitude of muscle responses to perturbations are critical for acting in uncertain environments. A planned movement can strongly influence average muscle responses to perturbations, but certainty in when a perturbation will arrive changes this effect. The objective of this study was to investigate how uncertainty in perturbation timing influences the preparation and release of involuntary, perturbation-triggered responses. We hypothesized that uncertainty would influence the average magnitude of triggered responses and how they develop in time. We investigated three levels of uncertainty in when a proprioceptive cue to move would arrive by changing the duration and variability of the time between a preparation and movement cue. Participants performed ballistic elbow extension movements in response to the movement cue. Unexpected, large perturbations that flexed the elbow were delivered at various times between the preparation and movement cues to evaluate how cue uncertainty influenced the development of triggered responses. We found that this uncertainty strongly influences how a motor response is prepared, and the efficacy of triggering that response by a postural perturbation. When timing was certain, the motor plan was prepared within 150 ms of the expected disturbance, and consistently released earlier by a perturbation than could be done voluntarily. Less predictable stimuli led to much earlier planning and a lower probability of releasing the plan early. These results clarify how uncertainty in when to move influences the planning and early release of perturbation-triggered responses, demonstrating an effect similar to previous reports on the planning of volitional movements.

Non-suicidal self-injury is a risk factor for suicidal behavior, particularly in females. Two prominent theories of suicide suggest that habituation to the psychophysiological aversiveness of NSSI is a mechanism by which NSSI exposure may lead to increased risk for suicide. Several laboratory studies examining the relationship between physiological habituation and suicide attempt history have yielded mixed results, potentially due to their use of broad measures of physiological arousal and/or focus on specific psychopathologies. However, no studies have examined the association between the time course (e.g., habituation, initial reactivity) of responding to aversiveness and NSSI, which may help to elucidate psychophysiological mechanisms of NSSI. Therefore, we examined habituation and initial reactivity to aversiveness (indexed by the time course of acoustic startle reflex, a well-validated measure of defensive responding) in three groups of young adult females – those with a history of NSSI, psychiatric controls matched on potential confounds (e.g., psychopathology, trauma history, demographics), and healthy controls. Results indicated that individuals with a history of NSSI exhibited blunted initial reactivity and marginally slower habituation to aversiveness relative to the two control groups. The NSSI group’s insensitivity to aversiveness may reflect prior psychophysiological habituation, and may be a mechanism through which prior NSSI exposure leads to increased risk for suicidal behavior.

In classical fear conditioning, neutral conditioned stimuli that have been paired with aversive physical unconditioned stimuli eventually trigger fear responses. Here, we tested whether aversive mental images systematically paired with a conditioned stimulus also cause de novo fear learning in the absence of any external aversive stimulation. In two experiments ( N = 45 and N = 41), participants were first trained to produce aversive, neutral, or no imagery in response to three different visual-imagery cues. In a subsequent imagery-based differential-conditioning paradigm, each of the three cues systematically coterminated with one of three different neutral faces. Although the face that was paired with the aversive-imagery cue was never paired with aversive external stimuli or threat-related instructions, participants rated it as more arousing, unpleasant, and threatening and displayed relative fear bradycardia and fear-potentiated startle. These results could be relevant for the development of fear and related disorders without trauma.

Generalization of Pavlovian fear to safe stimuli resembling conditioned-danger cues (CS+) is a widely accepted conditioning correlate of clinical anxiety. Though much of the pathogenic influence of such generalization may lie in the associated avoidance, few studies have assessed maladaptive avoidance decisions associated with Pavlovian generalization. Lab-based assessments of this process, here referred to as aversive Pavlovian-instrumental covariation during generalization (APIC-G), have recently begun. The current study represents a next step in this line of work by conducting the first examination of anxiety-related dimensions of personality that may exacerbate APIC-G. Specifically, we test anxiety sensitivity (AS) and intolerance of uncertainty (IU) as moderators of relations between Pavlovian generalization and maladaptive avoidance decisions in 102 undergraduate students with wide-ranging levels of IU and AS. Results indicate a facilitative effect of AS on this APIC-G process, with AS strengthening relations between Pavlovian generalization and maladaptive generalized avoidance whether operationalizing Pavlovian generalization with psychophysiological (fear-potentiated startle) or behavioral measures. Additionally, IU was found to facilitate APIC-G when indexing Pavlovian generalization with behavioral but not fear-potentiated startle measures. Moderating effects of AS were most pronounced for stimulus classes bearing the highest resemblance to CS+, whereas effects of IU were most pronounced for the stimulus class with the highest level of threat ambiguity. Results implicate AS and IU as risk factors for the maladaptive decisional correlates of Pavlovian generalization and suggest that established associations between these traits and clinical anxiety may derive, in part, from their enhancement of maladaptive APIC-G. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

One-trial contextual fear conditioning in laboratory mice results in a fear memory which is relatively specific to the original conditioning context shortly after conditioning but becomes more unspecific after an incubation time of one month. This process is called generalization of fear memory and is used to investigate processes which might be involved in the pathogenesis of post-traumatic stress disorder. In the present study, we investigated the effects of sex and neuropeptide S receptor (NPSR) deficiency in one-trial contextual fear conditioning. In addition to contextual fear, we also measured startle reactivity, anxiety and corticosterone plasma levels of the mice. Our data show main effects of sex and NPSR-deficiency on freezing behavior, startle magnitude, and anxiety levels. However, generalization of contextual fear memory after incubation time was not affected by sex. Notably, NPSR-deficient mice had a more specific fear memory shortly after conditioning than their wildtype littermates but after incubation time, all genotypes had a generalized fear memory. The present data further show that plasma corticosterone levels are increased after incubation time. This increase was significantly more pronounced in NPSR-deficient mice. Taken together, our study confirms the suitability of one-trial contextual fear conditioning to study the effects of incubation time on fear memory generalization but also indicates the need for control groups without incubation. We further demonstrate that the increase of plasma corticosterone levels after incubation time is exaggerated in NPSR-deficient mice. The latter finding suggests an important role of the NPS system in the regulation of corticosterone release.

Background and objectives Following an aversive experience, fears often generalize across contexts. Contextual fear generalization is modeled in a laboratory paradigm in which one context (CTX+) is paired with an aversive unconditional stimulus (US), while the other context (CTX-) is not. The current study sought to validate a novel paradigm assessing contextual fear generalization, and to determine the extent to which stress and anxiety symptoms enhanced contextual fear generalization. Methods Fifty-nine participants were randomized to a stress induction or control arithmetic test, followed by a differential context fear conditioning paradigm. One to three days later, participants completed a generalization gradient test with CTX+, CTX, and four generalization contexts. Results We found successful contextual fear conditioning on measures of US expectancy, self-report fear and valence, and startle reflex, and linear generalization across the contextual gradient on expectancies and self-report measures. Acute stress induction impaired learning of the US-CTX + association during context fear acquisition. Anxiety significantly predicted greater contextual fear generalization as measured by US expectancy. Limitations Our study provides pilot data introducing a novel fear conditioning paradigm to assess contextual generalization of fear. There is a need for further replication to validate its utility. Conclusions Findings suggest that individuals high in anxiety show greater contextual fear generalization as measured by US expectancy. Results are discussed in terms of potential mechanisms that contribute to pervasive anxiety.

The elite athlete is fine-tuned all around to deliver favorable results in sporting events. In this study, we address the question of whether basic movements—such as reflexes—and heterogeneous attentional modulation components—such as sensorimotor gating mechanisms—are also tuned up to maximize the results of middle-distance runners in physical conditioning tests. We selected an array of professional middle-distance runners and healthy counterparts that were submitted to measurement of (1) physical conditioning parameters, including somatotype, jump, strength, and flexibility tests; and (2) sensorimotor gating mechanisms, including acoustic startle reflex, prepulse inhibition, and habituation. Our results showed athletes scored better on the athletic tests compared to controls, as expected. They also exhibited a lower startle amplitude, while maintaining higher prepulse inhibition values. They reacted faster to the acoustic stimuli, and sex-related differences—found in controls—were not present in athletes. Our data also pointed out to substantial correlations between sensorimotor gating and physical conditioning parameters. All in all, these data may point to physical conditioning-driven neural plasticity of brain sensorimotor gating circuits in charge of triggering involuntary movements to harness control and efficiency over reflexed muscle activity.

Objective Patients with anorexia nervosa (AN) often show difficulties in the perception, expression, and regulation of emotions and a strong avoidance of aversive feelings. According to psychobiological models, dietary restraint and accompanying weight loss may serve as a maladaptive mechanism of emotion regulation by attenuating aversive emotional states in AN, thereby contributing to the maintenance of the disorder. Method Twenty-seven women with AN and 26 age-matched healthy women were shown short film-clips to elicit fear, sadness, amusement, and neutral emotional states. Eyeblink startle response was measured by electromyography in reaction to startle-eliciting acoustic stimuli presented 12 times binaurally during each film-clip. Results As compared to healthy controls, patients with AN showed a blunted startle response to the fear- but not to the sadness-eliciting stimulus. Discussion The findings support the assumption that underweight is associated with attenuated emotional reactivity to fear-eliciting material in AN. This is in line with the hypothesis that starvation and low body weight constitute a maladaptive mechanism of emotion regulation in AN, contributing to the maintenance of the disorder.

The startle reflex has been suggested to operate as a psychophysiological marker of psychopathic personality, based on findings from studies using a range of different methodologies and participant samples. The present review aims at synthesizing existing evidence of the relationship between psychopathy and the startle reflex across task paradigms, psychopathic personality subtypes and subdimensions, participant samples (i.e., incarcerated/ clinical or non-offenders), and age groups using the triarchic model of psychopathy as a frame of reference. Systematic literature searches were conducted up until the 24th of March 2020 in PubMed, PsycINFO, and Web of Science. A total of 2311 potential studies were identified, out of which 40 met relevancy and quality criteria. Results indicate that reduced aversive startle potentiation is associated with psychopathic personality in general, but clusters of traits relating to the triarchic model constructs of boldness and meanness in particular. Available evidence suggest that startle paradigms could be meaningful for differentiating individuals with and without psychopathic personality. Findings support suggestions of psychopathic personality as a multifaceted, rather than a unitary construct. Reduced aversive startle potentiation has also been found in relation to psychopathic features in child-aged samples but work of this kind is limited and more research is needed. Future studies should focus on greater consistency in task paradigms and analytic strategies to enhance the capacity to compare and integrate findings across studies.

During fear conditioning, a cue (CS) signals an inevitable distal threat (US) and evokes a conditioned response that can be described as attentive immobility (freezing). The organism remains motionless and monitors the source of danger while startle responses are potentiated, indicating a state of defensive hypervigilance. Although in animals vagally mediated fear bradycardia is also reliably observed under such circumstances, results are mixed in human fear conditioning. Using a single-cue fear conditioning and extinction protocol, we tested cardiac reactivity and startle potentiation indexing low-level defensive strategies in a fear-conditioned (n = 40; paired presentations of CS and US) compared with a non-conditioned control group (n = 40; unpaired presentations of CS and US). Additionally, we assessed shock expectancy ratings on a trial-by-trial basis indexing declarative knowledge of the previous contingencies. Half of each group underwent extinction under sham or active transcutaneous vagus nerve stimulation (tVNS), serving as additional proof of concept. We found stronger cardiac deceleration during CS presentation in the fear learning relative to the control group. This learned fear bradycardia was positively correlated with conditioned startle potentiation but not with declarative knowledge of CS-US contingencies. TVNS abolished differences in heart rate changes between both groups and removed the significant correlation between late cardiac deceleration and startle potentiation in the fear learning group. Results suggest, fear-conditioned cues evoke attentive immobility in humans, characterized by cardiac deceleration and startle potentiation. Such defensive response pattern is elicited by cues predicting inevitable distal threat and resembles conditioned fear responses observed in rodents.

BackgroundAlthough pain-related avoidance is mainly intended to reduce the accompanying anticipatory fear, avoidance behavior may paradoxically increase fear when a previous avoidance response is no longer available, suggesting that there is a bidirectional relationship between pain-related fear and avoidance.PurposeWe hypothesized that avoidance can serve as a source of information that fuels irrational pain-related threat appraisals, which, in turn, increases pain-related fear.MethodsParticipants (N = 66) were exposed to a painful heat stimulus and randomly assigned to the avoidance or control group. They were instructed to avoid the full heat intensity by pressing a stop button in the presence of a stop cue. Only avoidance group participants received a stop cue and were allowed to press the stop button, while control group participants received the same instructions but never had the opportunity to avoid the full heat intensity. In reality and unknown to participants, the intensity and duration of the heat stimulus was independent of the avoidance response. In the subsequent test phase, the avoidance response was unavailable for both groups. We measured pain-related fear, threat appraisals/harmfulness, and pain intensity.ResultsIn line with our expectations, pain-related fear levels were higher when the avoidance response was no longer available compared to those when the avoidance response was available. Increased threat appraisals mediated the relationship between avoidance behavior and increased pain-related fear.ConclusionsThe perceived opportunity to avoid increased pain-related fear through threat appraisals, suggesting a more complicated relationship between pain-related fear, threat appraisals, and avoidance behavior than the unidirectional relationships proposed in the fear-avoidance model. Clinical implications are discussed.

Recent meta-analyses indicated differences in fear acquisition and extinction between patients with anxiety related disorders and comparison subjects. However, these effects are small and may hold for only a subsample of patients. To investigate individual trajectories in fear acquisition and extinction across patients with anxiety-related disorders (N = 104; before treatment) and comparison subjects (N = 93), data from a previous study (Duits et al., 2017) were re-analyzed using data-driven latent class growth analyses. In this explorative study, subjective fear ratings, shock expectancy ratings and startle responses were used as outcome measures. Fear and expectancy ratings, but not startle data, yielded distinct fear conditioning trajectories across participants. Patients were, compared to controls, overrepresented in two distinct dysfunctional fear conditioning trajectories: impaired safety learning and poor fear extinction to danger cues. The profiling of individual patterns allowed to determine that whereas a subset of patients showed trajectories of dysfunctional fear conditioning, a significant proportion of patients (?50 %) did not. The strength of trajectory analyses as opposed to group analyses is that it allows the identification of individuals with dysfunctional fear conditioning. Results suggested that dysfunctional fear learning may also be associated with poor treatment outcome, but further research in larger samples is needed to address this question.

Contains fulltext : 228384.pdf (Publisher’s version ) (Open Access) Excessive avoidance behaviour is a cardinal symptom of anxiety disorders. Avoidance is not only associated with the benefits of avoiding threats, but also with the costs of missing out on rewards upon exploration. Psychological and psychophysiological mechanisms contributing to these costly avoidance decisions in prospect of mixed outcomes remain unclear. We developed a novel Fearful Avoidance Task (FAT) that resembles characteristics of real-life approach-avoidance conflicts, enabling to disentangle reward and threat effects. Using the FAT, we investigated individual differences in avoidance behaviour and anticipatory psychophysiological states (i.e. startle reflex and skin conductance) in a relatively large sample of 343 (78 females) participants. Avoidance under acute threat of shock depends on a trade-off between perceived reward and threat. Both increased startle and skin conductance in the absence of threat of shock emerged as predictors of increased avoidance (potentially indicative of fear generalization). Increased avoidance was also associated with female sex and trait anxiety, dependent on reward and threat levels. Our findings highlight distinct possible predictors of heightened avoidance and add to mechanistic understanding of how individual propensity for costly avoidance may emerge. Distinct avoidance typologies based on differential reward and threat sensitivities may have different mechanistic origins and thereby could benefit from different treatment strategies. 9 p.

A startling auditory stimulus (SAS) induces a reflex response involving, among other reactions, a strong contraction of the orbicularis oculi muscle (OOc) and subsequent eye closure. A SAS also induces the StartReact effect, a significant shortening of reaction time in subjects ready for task execution. We examined the obvious conflict appearing when a StartReact paradigm requires participants with eyes closed to open their eyes to look for a visual target. We recorded OOc EMG activity and eyelid movements in healthy volunteers who were instructed to open their eyes at perception of a somatosensory imperative stimulus (IS) and locate the position of a Libet's clock's hand shown on a computer screen at 80 cm distance. In 6 out of 20 trials, we delivered a SAS simultaneously with the IS. The main outcome measures were reaction time at onset of eyelid movement and the time gap (TG) separating subjective assessment of the clock's hand position from real IS issuing. Control experiments included reaction time to eye closing and target location with eyes open to the same IS. Reaction time was significantly faster in SAS than in noSAS trials and slower for eye opening than for eye closing in both conditions. In the eye-opening task, TG was significantly shorter in SAS with respect to noSAS trials, despite the presence of the SAS-related burst in the OOc before EMG cessation. Our results indicate that the StartReact effect speeds up eye opening and location of a target in the visual field despite the startle reaction opposing the task.

Acoustic startle stimuli inhibit pain, but whether this is due to a cross-modal inhibitory process or some other mechanism is uncertain. To investigate this, electrical stimulation of the sural nerve either preceded or followed an acoustic startle stimulus (by 200 ms) or was presented alone in 30 healthy participants. Five electrical stimuli, five acoustic startle stimuli, 10 startle + electrical stimuli, and 10 electrical + startle stimuli were presented in mixed order at intervals of 30-60 s. Effects of the startle stimulus on pain ratings, pupillary dilatation and nociceptive flexion reflexes to the electric shock were assessed. The acoustic startle stimulus inhibited electrically evoked pain to the ensuing electric shock (p < .001), and the electrical stimulus inhibited the perceived loudness of a subsequent acoustic startle stimulus (p < .05). However, the startle stimulus did not affect electrically evoked pain when presented 200 ms after the electric shock, and electrically evoked pain did not influence the perceived loudness of a prior startle stimulus. Furthermore, stimulus order did not influence the pupillary responses or nociceptive flexion reflexes. These findings suggest that acoustic startle stimuli transiently inhibit nociceptive processing and, conversely, that electrical stimuli inhibit subsequent auditory processing. These inhibitory effects do not seem to involve spinal gating as nociceptive flexion reflexes to the electric shock were unaffected by stimulus order. Thus, cross-modal interactions at convergence points in the brainstem or higher centers may inhibit responses to the second stimulus in a two-stimulus train.

Instructions highlighting that backward conditional stimuli (CSs) stop unconditional stimuli (USs) result in their acquiring valence opposite to that of the US on explicit measures of valence. We assessed whether such instructions would influence startle blink modulation in the same way. Two groups were presented with concurrent forward and backward evaluative conditioning (CS-US-CS) using cartoon aliens as CSs, and pleasant, neutral, and unpleasant sounds as USs. Startle magnitude was measured during conditioning and valence ratings were assessed after conditioning. Participants in the "start-stop" instructions group (n = 41) were instructed to learn whether CSs started or stopped US presentations, while participants in the "observe" instructions group (n = 41) were told to pay attention to the stimuli as they would be asked questions about them after the experiment. In the start-stop instructions group backward CSs paired with positive USs were rated as less pleasant than backward CSs paired with neutral and negative USs (contrast effect), whereas ratings of backward CSs did not differ in the observe instructions group. Startle magnitude was larger during backward CSs paired with positive USs in comparison to CSs paired with neutral or negative USs in both instruction groups. Startle blink modulation was unaffected by instructions, suggesting that startle indexes the emotional state at the time of probe presentation rather than CS valence based on propositional information about the function of the CS.

Atypical responses to fearful stimuli and the presence of various forms of anxiety are commonly seen in children with autism spectrum disorder (ASD). The fear potentiated startle paradigm (FPS), which has been studied both in relation to anxiety and as a probe for amygdala function, was carried out in 97 children aged 9-14 years including 48 (12 female) with ASD and 49 (14 female) with typical development (TD). In addition, exploratory analyses were conducted examining the association between FPS and amygdala volume as assessed with magnetic resonance imaging in a subset of the children with ASD with or without an anxiety disorder with available MRI data. While the startle latency was increased in the children with ASD, there was no group difference in FPS. FPS was not significantly associated with traditional Diagnostic and Statistical Manual (DSM) or "autism distinct" forms of anxiety. Within the autism group, FPS was negatively correlated with amygdala volume. Multiple regression analyses revealed that the association between FPS and anxiety severity was significantly moderated by the size of the amygdala, such that the association between FPS and anxiety was significantly more positive in children with larger amygdalas than smaller amygdalas. These findings highlight the heterogeneity of emotional reactivity associated with ASD and the difficulties in establishing biologically meaningful probes of altered brain function. LAY SUMMARY: Many children with autism spectrum disorder (ASD) have additional problems such as anxiety that can greatly impact their lives. How these co-occurring symptoms develop is not well understood. We studied the amygdala, a region of the brain critical for processing fear and a laboratory method called fear potentiated startle for measuring fear conditioning, in children with ASD (with and without an anxiety disorder) and typically developing children. Results showed that the connection between fear conditioning and anxiety is dependent on the size of the amygdala in children with ASD.

Risk for adverse outcomes, including the onset of mental illness, increases during adolescence. This increase may be linked to both new exposures, such as violence at home or in the community, or to physiological changes driven by puberty. There are significant sex differences in adolescent risk, for instance, anxiety disorders are significantly more prevalent in girls than boys. Fear learning is linked to mental health and may develop during adolescence, but the role of puberty in adolescent-specific change has not yet been systematically evaluated. We conducted a longitudinal study of fear learning that tested fear-potentiated startle (FPS) in 78 children (40 girls) aged 8-16 years. Participants completed two to three visits that included a differential fear conditioning task and self-report of both pubertal status and violence exposure. We tested for effects of sex, pubertal status, and violence exposure on FPS over time with latent growth curve models. We also examined the association between FPS and later anxiety symptoms. We found significant changes in FPS to the threat cue, but not the safety cue, across visits. Higher pubertal status was significantly associated with increased FPS to threat cues at each visit, whereas sex and violence exposure were not. FPS to threat during the baseline visit also predicted later anxiety symptoms. These findings suggest that puberty drives increased fear response to threat cues similarly for girls and boys, and that this effect may not be significantly impacted by individual differences in violence exposure during early adolescence.

The gap-prepulse inhibition of the acoustic startle reflex has been widely used as a behavioral method for tinnitus screening in animal studies. The cortical-evoked potential gap-induced inhibition has also been investigated in animals as well as in human subjects. The present study aimed to investigate the effect of age on the cortical N1-P2 complex in the gap-prepulse inhibition paradigm. Fifty-seven subjects, aged 20 to 68 years, without continuous tinnitus, were tested with two effective gap conditions (embedded gap of 50- or 20-ms duration). Retest sessions were performed within one month. A significant gap-induced inhibition of the N1-P2 complex was found in both gap durations. Age differently affected the inhibition, depending on gap duration. With a 50-ms gap, the inhibition decreased significantly with the increase in age. This age-inhibition relationship was not found when using a 20-ms gap. The results were reproducible in the retest session. Our findings suggest that the interaction between age and gap duration should be considered when applying the gap-induced inhibition of the cortical-evoked potential as an objective measure of tinnitus in human subjects. Further studies with tinnitus patients are warranted to identify gap duration that would minimize the effects of age and maximize the difference in the inhibition between those with and without tinnitus.

Animal temperament is complex and has implications for productivity and economic profitability. Quantifying an animal's response to differing stimuli may facilitate breeding selections and identify animals that are better suited to specific management strategies. Multiple tests have been developed to evaluate cattle temperament (e.g., exit velocity, chute score, pen score, open field test, startle test, bovine zero maze), but each of these tests evaluates the animal's response to different stimuli (e.g., isolation, novel environment, startle, willingness to enter an enclosed area). Cattle temperament has been observed to be relatively stable over time. However, the evaluation of temperament has the potential to be influenced by current conditions, previous experiences, and observer bias. Many of these temperament tests have been improperly categorized as fear tests and have also been criticized for being subjective. This paper provides a framework for standardizing behavioral tests for cattle and suggests that these different evaluations assess different aspects of the animal's overall temperament.

Experimental paradigms used to study reinstatement of fear in humans are characterized by procedural heterogeneity. Reinstatement protocols involve unexpected (re)-presentations of the unconditioned stimulus (USs) after fear extinction training. Here, we address the number of reinstatement USs administered as a potential boundary condition that may explain divergent findings in the field. A sample of 171 participants is exposed to a fear acquisition training, immediate extinction training, and reinstatement test experiment. Three groups differing in the number of reinstatement US are employed: one (n = 57) or four (n = 55) in experimental groups and zero (n = 59) in the control group. We adopt Bayesian statistical approaches beyond classical null hypothesis significance testing (NHST) to qualify evidence for or against this potential methodological boundary condition in reinstatement-induced return of fear. Startle potentiation to the reinstatement administration context was increased for the RI-USone compared to the RI-USzero group, supporting the role of context conditioning in reinstatement. This effect was weaker in the RI-USfour group. This, however, did not transfer to responding to conditioned stimuli during the return of fear-test: no evidence for an effect of the number of reinstatement USs (zero, one, four) was observed in behavioral or physiological measures. In sum, our results speak against the number of reinstatement USs as a potential boundary condition in experimentally induced return of fear in humans. This may challenge what we think we know about the reinstatement phenomenon in humans and call for critical reconsideration of paradigms as well as mechanisms that may underlie some reinstatement effects in the literature.

Autism spectrum disorder (ASD) is characterized by social interaction and communication impairments, as well as restrictive/repetitive patterns of behavior, interests or activities, which can coexist with intellectual disability and altered sensory processing. To study the mechanisms underlying these core features of ASD, preclinical research has developed animal models with manipulations in ASD-linked genes, such as CNTNAP2. In order to fully interpret the findings from mechanistic studies, the extent to which these models display behaviors consistent with ASD must be determined. Toward that goal, we conducted an investigation of the consequences of a functional loss of Cntnap2 on ASD-related behaviors by comparing the performance of rats with a homozygous or heterozygous knockout of Cntnap2 to their wildtype littermates across a comprehensive test battery. Cntnap2-/- rats showed deficits in sociability and social novelty, and they displayed repetitive circling and hyperlocomotion. Moreover, Cntnap2-/- rats demonstrated exaggerated acoustic startle responses, increased avoidance to sounds of moderate intensity, and a lack of rapid audiovisual temporal recalibration; indicating changes in sensory processing at both the pre-attentive and perceptual levels. Notably, sensory behaviors requiring learned associations did not reveal genotypic differences, whereas tasks relying on automatic/implicit behaviors did. Ultimately, because these collective alterations in social, stereotypic, and sensory behaviors are phenotypically similar to those reported in individuals with ASD, our results establish the Cntnap2 knockout rat model as an effective platform to study not only the molecular and cellular mechanisms associated with ASD, but also the complex relationship between altered sensory processing and other core ASD-related behaviors. LAY SUMMARY: Autism spectrum disorder (ASD) is characterized by social interaction differences, and restrictive/repetitive patterns of behavior. We studied the behavioral alterations caused by the loss of an autism-linked gene, Cntnap2, in the rat to determine how mutations in this gene contribute to autism-related behaviors. We show the loss of Cntnap2 leads to changes in social, stereotypic, and sensory behaviors, indicating this rat model can be used to better understand the brain changes underlying ASD. Autism Res 2020, 13: 1698-1717. © 2020 International Society for Autism Research and Wiley Periodicals LLC.

Negative emotionality is a well-established and stable risk factor for affective disorders. Individual differences in negative emotionality have been linked to associative learning processes which can be captured experimentally by computing CS-discrimination values in fear conditioning paradigms. Literature suffers from underpowered samples, suboptimal methods, and an isolated focus on single questionnaires and single outcome measures. First, the specific and shared variance across three commonly employed questionnaires [STAI-T, NEO-FFI-Neuroticism, Intolerance of Uncertainty (IU) Scale] in relation to CS-discrimination during fear-acquisition in multiple analysis units (ratings, skin conductance, startle) is addressed (NStudy1 = 356). A specific significant negative association between STAI-T and CS-discrimination in SCRs and between IU and CS-discrimination in startle responding was identified in multimodal and dimensional analyses, but also between latent factors negative emotionality and fear learning, which capture shared variance across questionnaires/scales and across outcome measures. Second, STAI-T was positively associated with CS-discrimination in a number of brain areas linked to conditioned fear (amygdala, putamen, thalamus), but not to SCRs or ratings (NStudy2 = 113). Importantly, we replicate potential sampling biases between fMRI and behavioral studies regarding anxiety levels. Future studies are needed to target wide sampling distributions for STAI-T and verify whether current findings are generalizable to other samples.

The Gap Prepulse Inhibition of the Acoustic Startle Reflex (GPIAS) is a paradigm used to assess auditory temporal processing in both animals and humans. It consists of the presentation of a silent gap embedded in noise and presented a few milliseconds before a startle sound. The silent gap produces the inhibition of the startle reflex, a phenomenon called gap-prepulse inhibition (GPI). This paradigm is also used to detect tinnitus in animal models. The lack of inhibition by the silent gaps is suggested to be indicative of the presence of tinnitus "filling-in" the gaps. The current research aims at improving the GPIAS technique by comparing the GPI produced by monaural versus binaural silent gaps in 29 normal-hearing subjects. Two gap durations (5 or 50 ms), each embedded in two different frequency backgrounds (centered around 500 or 4 kHz). Both low- and high- frequency narrowband noises had a bandwidth of half an octave. Overall, the startle magnitude was greater for the binaural versus the monaural presentation, which might reflect binaural loudness summation. In addition, the GPI was similar between the monaural and the binaural presentations for the high-frequency background noise. However, the GPI was greater for the low-frequency background noise for the binaural, compared to the monaural, presentation. These findings suggest that monaural GPIAS might be more suited to detect tinnitus compared to the binaural presentation.

The ability to update responding to threat cues is an important adaptive ability. Recently, Morriss et al. (2019) demonstrated that participants scoring high in Intolerance of Uncertainty (IU) were more capable of threat reversal. The current report aimed to conceptually replicate these results of Morriss et al. (2019) in an independent sample using a comparable paradigm (n = 102). Following a threat conditioning phase, participants were told that cues associated with threat and safety from electric shock would reverse. Responding was measured with skin conductance and fear potentiated startle. We failed to conceptually replicate the results of Morriss et al. (2019). Instead, we found that, for participants who received precise contingency instructions prior to acquisition, lower IUS (controlling for STAI-T) relative to higher IUS was associated with greater threat reversal, indexed via skin conductance responses. These results suggest that IU and contingency instructions differentially modulate the course of threat reversal.

There is increased interest in the development of cognitive training targeting working memory (WM) to alleviate anxiety symptoms, but the effectiveness of such an approach is unclear. Improved understanding of the effect of cognitive training on anxiety may facilitate the development of more effective cognitive training treatment for anxiety disorders. This study uses an experimental approach to examine the interplay of WM and anxiety following WM training. Previous studies show that increased demand on WM reduces concurrent anxiety evoked by threat of shock (induced anxiety). However, improving WM pharmacologically or via exercise prevents this anxiolytic effect. Conceivably, improving WM frees up cognitive resources to process threat information, thereby increasing anxiety. The present study tested the hypothesis that practicing a high load WM (i.e., increased demand) task would improve WM, and thus, free cognitive resources to process threat of shock, resulting in more anxiety (i.e., greater startle) during a subsequent WM task. Participants were randomly assigned to two training groups. The active-training group (N = 20) was trained on a 1- (low load) & 3-back (high load) WM task, whereas the control-training group (N = 20) performed a 0-back WM task. The experimental phase, similar in both groups, consisted of a 1- & 3-back WM task performed during both threat of shock and safety. As predicted, active training improved WM accuracy and increased anxiety during the experimental 3-back WM task. Therefore, improving WM efficiency can increase anxiety, possibly by freeing WM resources to process threat information.