Neural dynamics of shooting decisions and the switch from freeze to fight

Real-life shooting decisions typically occur under acute threat and require fast switching between vigilant situational assessment and immediate fight-or-flight actions. Recent studies suggested that freezing facilitates action preparation and decision-making but the neurocognitive mechanisms remain unclear. We applied functional magnetic resonance imaging, posturographic and autonomic measurements while participants performed a shooting task under threat of shock. two independent studies, in unselected civilians (N = 22) and police recruits (N = 54), revealed that preparation for shooting decisions under threat is associated with postural freezing, bradycardia, midbrain activity (including the periaqueductal gray-PAG) and PAG-amygdala connectivity. Crucially, stronger activity in the midbrain/pAG during this preparatory stage of freezing predicted faster subsequent accurate shooting. Finally, the switch from preparation to active shooting was associated with tachycardia, perigenual anterior cingulate cortex (pgACC) activity and pgACC-amygdala connectivity. These findings suggest that threat-anticipatory midbrain activity centred around the PAG supports decision-making by facilitating action preparation and highlight the role of the pgACC when switching from preparation to action. These results translate animal models of the neural switch from freeze-to-action. In addition, they reveal a core neural circuit for shooting performance under threat and provide empirical evidence for the role of defensive reactions such as freezing in subsequent action decision-making

Emotional orienting during interoceptive threat in orthostatic intolerance: dysautonomic contributions to psychological symptomatology in the postural tachycardia syndrome and vasovagal syncope

Cognitive and emotional processes are influenced by interoception (homeostatic somatic feedback), particularly when physiological arousal is unexpected and discrepancies between predicted and experienced interoceptive signals may engender anxiety. Due to the vulnerability for comorbid psychological symptoms in forms of orthostatic intolerance (OI), this study investigated psychophysiological contributions to emotional symptomatology in 20 healthy control participants (13 females, mean age 36 ± 8 years), 20 postural tachycardia syndrome (PoTS) patients (18 females, mean age 38 ± 13 years) and 20 vasovagal syncope (VVS) patients (15 females, mean age 39 ± 12 years). We investigated indices of emotional orienting responses (OR) to randomly presented neutral, pleasant and unpleasant images in the supine position and during the induced interoceptive threat of symptom provocation of head-up tilt (HUT). PoTS and VVS patients produced greater indices of emotional responsivity to unpleasant images and, to a lesser degree, pleasant images, during interoceptive threat. Our findings are consistent with biased deployment of response-focused emotion regulation (ER) while patients are symptomatic, providing a mechanistic underpinning of how pathological autonomic overexcitation predisposes to anxiogenic traits in PoTS and VVS patients. This hypothesis may improve our understanding of why orthostasis exacerbates cognitive symptoms despite apparently normal cerebral autoregulation, and offer novel therapeutic targets for behavioural interventions aimed at reducing comorbid cognitive-affective symptoms in PoTS and VVS

A pupil size response model to assess fear learning

During fear conditioning, pupil size responses dissociate between conditioned stimuli that are contingently paired (CS+) with an aversive unconditioned stimulus, and those that are unpaired (CS-). Current approaches to assess fear learning from pupil responses rely on ad hoc specifications. Here, we sought to develop a psychophysiological model (PsPM) in which pupil responses are characterized by response functions within the framework of a linear time-invariant system. This PsPM can be written as a general linear model, which is inverted to yield amplitude estimates of the eliciting process in the central nervous system. We first characterized fear-conditioned pupil size responses based on an experiment with auditory CS. PsPM-based parameter estimates distinguished CS+/CS- better than, or on par with, two commonly used methods (peak scoring, area under the curve). We validated this PsPM in four independent experiments with auditory, visual, and somatosensory CS, as well as short (3.5 s) and medium (6 s) CS/US intervals. Overall, the new PsPM provided equal or decisively better differentiation of CS+/CS- than the two alternative methods and was never decisively worse. We further compared pupil responses with concurrently measured skin conductance and heart period responses. Finally, we used our previously developed luminance-related pupil responses to infer the timing of the likely neural input into the pupillary system. Overall, we establish a new PsPM to assess fear conditioning based on pupil responses. The model has a potential to provide higher statistical sensitivity, can be applied to other conditioning paradigms in humans, and may be easily extended to nonhuman mammals

Neural mediators of subjective and autonomic responding during threat learning and regulation

Threat learning elicits robust changes across multiple affective domains, including changes in autonomic indices and subjective reports of fear and anxiety. It has been argued that the underlying causes of such changes may be dissociable at a neural level, but there is currently limited evidence to support this notion. To address this, we examined the neural mediators of trial-by-trial skin conductance responses (SCR), and subjective reports of anxious arousal and valence in participants (n = 27; 17 females) performing a threat reversal task during ultra-high field functional magnetic resonance imaging. This allowed us to identify brain mediators during initial threat learning and subsequent threat reversal. Significant neural mediators of anxious arousal during threat learning included the dorsal anterior cingulate, anterior insula cortex (AIC), and ventromedial prefrontal cortex (vmPFC), subcortical regions including the amygdala, ventral striatum, caudate and putamen, and brain-stem regions including the pons and midbrain. By comparison, autonomic changes (SCR) were mediated by a subset of regions embedded within this broader circuitry that included the caudate, putamen and thalamus, and two distinct clusters within the vmPFC. The neural mediators of subjective negative valence showed prominent effects in posterior cortical regions and, with the exception of the AIC, did not overlap with threat learning task effects. During threat reversal, positive mediators of both subjective anxious arousal and valence mapped to the default mode network; this included the vmPFC, posterior cingulate, temporoparietal junction, and angular gyrus. Decreased SCR during threat reversal was positively mediated by regions including the mid cingulate, AIC, two sub-regions of vmPFC, the thalamus, and the hippocampus. Our findings add novel evidence to support distinct underlying neural processes facilitating autonomic and subjective responding during threat learning and threat reversal. The results suggest that the brain systems engaged in threat learning mostly capture the subjective (anxious arousal) nature of the learning process, and that appropriate responding during threat reversal is facilitated by participants engaging self- and valence-based processes. Autonomic changes (SCR) appear to involve distinct facilitatory and regulatory contributions of vmPFC sub-regions

Anticipated attack slows responses in a cued virtual attack emotional sternberg task

Threatening stimuli have varying effects, including reaction time increase in working memory tasks. This could reflect disruption of working memory or, alternatively, a reversible state of freezing. In the current series of experiments, reversible slowing due to anticipated threat was studied using the cued Virtual Attack Emotional Sternberg Task (cVAEST). In this task visually neutral cues indicate whether a future virtual attack could or could not occur during the maintenance period of a Sternberg task. Three studies (N = 47, 40, and 40, respectively) were performed by healthy adult participants online. The primary hypothesis was that the cVAEST would evoke anticipatory slowing. Further, the studies aimed to explore details of this novel task, in particular the interval between the cue and probe stimuli and the memory set size. In all studies it was found that threat anticipation slowed RTs on the working memory task. Further, Study 1 (memory set size 3) showed a decrease in RT when the attack occurred over all CSIs. In Study 2 a minimal memory set of one item was used, under which circumstances RTs following attacks were only faster shortly after cue presentation (CSI 200 and 500 ms), when RTs were high for both threat and safe cues. Study 3 replicated results of Study 2 with more fine-grained time intervals. The results confirm that anticipation of attack stimuli can reversibly slow responses on an independent working memory task. The cVAEST may provide a useful method to study such threat-induced response slowing

Organización columnar de la sustancia gris del acueducto humano

Treball Final de Grau en Medicina. Codi: MD1758. Curs acadèmic: 2022/2023La sustancia gris periacueductal (PAG) constituye un elemento central en la coordinación de muchas respuestas emocionales que van desde las respuestas de ataque/huida frente a un depredador, a vocalizaciones o modulación del dolor. La investigación en roedores ha permitido diferenciar cuatro columnas, cada una de las cuales tiene un papel específico en el desarrollo de estas funciones. Sin embargo, esta organización no ha sido estudiada en humanos. El objetivo del presente trabajo es el del comienzo de un proceso experimental que permita establecer comparaciones neuoanatómicas mediante la visualización de distintos marcadores y técnicas específicas en el cerebro humano frente al de roedores. Para ello, las muestras de un cerebro humano se han revelado en paralelo a las del cerebro de rata para los marcadores acetil-colinesterasa, NADPHdiaforasa, calbindina 2,8kD, calretinina, parvalbúmina, tirosin-hidroxilasa, 5HT y NOS. El estudio simple mediante la técnica de Nissl ha permitido discriminar las columnas dorsomedial, dorsolateral, lateral y ventrolateral. Además, ha quedado evidenciada una columna impar dorsal que también había sido descrita en rata. La mayor parte de marcadores no han funcionado en tejido postmortem, pero la calbindina 2,8kD muestra células perfectamente teñidas con su árbol dendrítico aparentemente sano, indicando que son las células más resistentes a la muerte neuronal. Estas células se localizan en la columna lateral lo que puede constituir un buen marcador. Estudios postmortem con un menor tiempo de retraso entre el fallecimiento y la fijación pueden permitir un estudio más detallado de las columnas de la PAG y establecer las analogías correspondientes.The periaqueductal gray matter (PAG) constitutes a central element in the coordination of many emotional responses, ranging from fight/flight responses to predators, vocalizations, or pain modulation. Research in rodents has allowed differentiation of four columns, each of which has a specific role in the development of these functions. However, this organization has not been studied in humans. The objective of this study is to begin an experimental process that allows for neuroanatomical comparisons through the visualization of different markers and specific techniques in the human brain compared to that of rodents. To this end, samples from a human brain were revealed in parallel to those from a rat brain for markers including acetylcholinesterase, NADPHdiaforase, calbindin 2,8kD, calretinin, parvalbumin, tyrosine hydroxylase, 5HT, and NOS. Simple study using the Nissl technique allowed for discrimination of the dorsomedial, dorsolateral, lateral, and ventrolateral columns. In addition, a single dorsal column that had also been described in rats was evident. Most markers did not work in postmortem tissue, but calbindin 2,8kD showed perfectly stained cells with apparently healthy dendritic trees, indicating that they are the most resistant to neuronal death. These cells are located in the lateral column, which may constitute a good marker. Postmortem studies with shorter delays between death and fixation may allow for a more detailed study of the PAG columns and establish corresponding analogies

Effects of testosterone administration on threat and escape anticipation in the orbitofrontal cortex.

Recent evidence suggests that the steroid hormone testosterone can decrease the functional coupling between orbitofrontal cortex (OFC) and amygdala. Theoretically this decoupling has been linked to a testosterone-driven increase of goal-directed behaviour in case of threat, but this has never been studied directly. Therefore, we placed twenty-two women in dynamically changing situations of escapable and inescapable threat after a within-subject placebo controlled testosterone administration. Using functional magnetic resonance imaging (fMRI) we provide evidence that testosterone activates the left lateral OFC (LOFC) in preparation of active goal-directed escape and decouples this OFC area from a subcortical threat system including the central-medial amygdala, hypothalamus and periaqueductal gray. This LOFC decoupling was specific to threatening situations, a point that was further emphasized by an absence of such decoupling in a second experiment focused on resting-state connectivity. These results not only confirm that testosterone administration decouples the LOFC from the subcortical threat system, but also show that this is specifically the case in response to acute threat, and ultimately leads to an increase in LOFC activity when the participant prepares a goal-directed action to escape. Together these results for the first time provide a detailed understanding of functional brain alterations induced by testosterone under threat conditions, and corroborate and extend the view that testosterone prepares the brain for goal-directed action in case of threat.FSW – Publicaties zonder aanstelling Universiteit Leide

Prepronociceptin-expressing neurons in the extended amygdala encode and promote rapid arousal responses to motivationally salient stimuli

Motivational states consist of cognitive, emotional, and physiological components controlled by multiple brain regions. An integral component of this neural circuitry is the bed nucleus of the stria terminalis (BNST). Here, we identify that neurons within BNST that express the gene prepronociceptin (Pno