The neural signature of the decision value of future pain.

Pain is a primary driver of action. We often must voluntarily accept pain to gain rewards. Conversely, we may sometimes forego potential rewards to avoid associated pain. In this study, we investigated how the brain represents the decision value of future pain. Participants (n = 57) performed an economic decision task, choosing to accept or reject offers combining various amounts of pain and money presented visually. Functional MRI (fMRI) was used to measure brain activity throughout the decision-making process. Using multivariate pattern analyses, we identified a distributed neural representation predicting the intensity of the potential future pain in each decision and participants' decisions to accept or avoid pain. This neural representation of the decision value of future pain included negative weights located in areas related to the valuation of rewards and positive weights in regions associated with saliency, negative affect, executive control, and goal-directed action. We further compared this representation to future monetary rewards, physical pain, and aversive pictures and found that the representation of future pain overlaps with that of aversive pictures but is distinct from experienced pain. Altogether, the findings of this study provide insights on the valuation processes of future pain and have broad potential implications for our understanding of disorders characterized by difficulties in balancing potential threats and rewards.

Brain mechanisms associated with facial encoding of affective states.

Affective states are typically accompanied by facial expressions, but these behavioral manifestations are highly variable. Even highly arousing and negative valent experiences, such as pain, show great instability in facial affect encoding. The present study investigated which neural mechanisms are associated with variations in facial affect encoding by focusing on facial encoding of sustained pain experiences. Facial expressions, pain ratings, and brain activity (BOLD-fMRI) during tonic heat pain were recorded in 27 healthy participants. We analyzed facial expressions by using the Facial Action Coding System (FACS) and examined brain activations during epochs of painful stimulation that were accompanied by facial expressions of pain. Epochs of facial expressions of pain were coupled with activity increase in motor areas (M1, premotor and SMA) as well as in areas involved in nociceptive processing, including primary and secondary somatosensory cortex, posterior and anterior insula, and the anterior part of the mid-cingulate cortex. In contrast, prefrontal structures (ventrolateral and medial prefrontal) were less activated during incidences of facial expressions, consistent with a role in down-regulating facial displays. These results indicate that incidences of facial encoding of pain reflect activity within nociceptive pathways interacting or possibly competing with prefrontal inhibitory systems that gate the level of expressiveness.

Trajectories of psychological distress during the COVID-19 pandemic among community-dwelling older adults in Quebec: A longitudinal study.

OBJECTIVE: The COVID-19 pandemic and its associated public health measures may increase the risk for psychological distress among vulnerable older adults. This longitudinal study aimed to identify predictors of psychological distress trajectories among community-dwelling older adults in Quebec, Canada. METHODS: The study spanned four time points across 13 months and three waves of the COVID-19 pandemic. The sample included 645 community-dwelling older adults ages 60 years and older in Quebec. Participants completed telephone-based interviews that included the Kessler 6-item Psychological Distress Scale (K6) to assess psychological distress at each time point as well as information on socioeconomic, medical, psychological and COVID-19 related factors. Group-based trajectory modelling was used to identify distinct trajectories of psychological distress across time. RESULTS: Three group-based trajectories of psychological distress were identified: the resilient (50.5%), reactive (34.9%), and elevated distress groups (14.6%). Individuals with mobility issues, insomnia symptoms, COVID-19 related acute stress, general health anxiety, increased loneliness symptoms, and those unable to use technology to see others were more likely to be in the reactive and elevated groups than the resilient group. Those with past mental health problems had uniquely increased odds of being in the reactive group compared to the resilient group. Individuals living in poverty and those who reported taking psychotropic medication had increased odds of being in the elevated distress group compared to the resilient group. CONCLUSION: These findings characterized distinct trajectories of psychological distress in older adults and identified risk factors for elevated distress levels.

Feasibility and acceptability of hypnosis-derived communication administered by trained nurses to improve patient well-being during outpatient chemotherapy: a pilot-controlled trial.

PURPOSE: This pilot-controlled trial aimed to examine the feasibility and acceptability of hypnosis-derived communication (HC) administered by trained nurses during outpatient chemotherapy to optimize symptom management and emotional support - two important aspects of patient well-being in oncology. METHODS: The trial was conducted in two outpatient oncology units: (1) intervention site (usual care with HC), and (2) control site (usual care). Nurses at the intervention site were invited to take part in an 8-h training in HC. Participants' self-ratings of symptoms and emotional support were gathered at predetermined time points during three consecutive outpatient visits using the Edmonton Symptom Assessment Scale and the Emotional Support Scale. RESULTS: Forty-nine patients (24 in the intervention group, 25 in the control group) with different cancer types/stages were recruited over a period of 3 weeks and completed the study. All nurses (N = 10) at the intervention site volunteered to complete the training and were able to include HC into their chemotherapy protocols (about ± 5 min/intervention). Compared to usual care, patients exposed to HC showed a significant reduction in physical symptoms during chemotherapy. In contrast, perception of emotional support did not show any significant effect of the intervention. Participants exposed to HC report that the intervention helped them relax and connect on a more personal level with the nurse during chemotherapy infusion. CONCLUSIONS: Our results suggest that HC is feasible, acceptable, and beneficial for symptom management during outpatient chemotherapy. While future studies are needed, hypnosis techniques could facilitate meaningful contacts between cancer patients and clinicians in oncology. TRIAL REGISTRATION: Clinical Trial Identifier: NCT04173195, first posted on November 19, 2019.

Long-Term Efficacy of a Home-Care Hypnosis Program in Elderly Persons Suffering From Chronic Pain: A 12-Month Follow-Up.

BACKGROUND: Pain is a major public health concern in the aging population. However, medication brings about negative effects that compel healthcare professionals to seek alternative management techniques to alleviate pain. Hypnosis has been recognized as an effective technique to manage pain, but its long-term efficacy has yet to be examined in older adults. AIMS: The aim was to assess the effectiveness, over a 12-month period, of home-care hypnosis in elderly participants suffering from chronic pain. DESIGN: Real-life retrospective one-arm study with a 12-month follow-up. SETTINGS: Elderly Persons Suffering From Chronic Pain enrolled in a clinical health care program that offered home medical follow-up. PARTICIPANTS/SUBJECTS: Fourteen elderly women (mean age 81 years) with chronic pain participated in the home-care hypnosis program. All participants presented chronic pain (≥6 months) with average pain score >4/10. METHODS: Participants took part in seven 15-minute hypnosis sessions within 12 months. The Brief Pain Inventory questionnaire was used to evaluate pain perception and pain interference at baseline and at 3-, 6-, and 12-month follow-up period. RESULTS: Hypnosis home-care program significantly decreased pain perception and pain interference compared to baseline after 3 months (-29% and -40%, p < .001), and remained lower at 6 (-31% and -54%, p < .001) and 12 (-31% and -47%, p < .001) months. CONCLUSIONS: Seven sessions of 15 minutes allocated throughout a 12-month period produced clinically significant decreases in pain perception and pain interference. Hypnosis could be considered as an optimal additional way for health practitioners to manage chronic pain in an elderly population with long-term efficacy. This study offers a new long-term option to improve chronic pain management at home in elderly populations through a low-cost nonpharmacological intervention.

Nurses' perception of integrating an innovative clinical hypnosis-derived intervention into outpatient chemotherapy treatments.

Introduction: Conversational hypnosis (CH) is known to optimize the management of symptoms resulting from antineoplastic treatment. However, the perception of nurses who have been called upon to integrate this practice into their care has yet to be documented. Goal: Describe how nurses perceive the integration of CH into chemotherapy-related care. Methods: Individual interviews and an iterative analysis were conducted with six nurses who had previous experience in CH in an outpatient oncology clinic. Findings: Six themes emerged: 1) the outpatient oncology clinic, a saturated care setting; 2) the key elements supporting the integration of CH into care; 3) an added value for patients; 4) a positive and rewarding experience for nurses; 5) collateral benefits; and 6) CH, an approach that warrants consideration amid the pandemic. Conclusion: These findings shed light on nurses' unique point of view regarding the challenges and benefits of integrating CH into oncology care.

Immersive virtual reality vs. non-immersive distraction for pain management of children during bone pins and sutures removal: A randomized clinical trial protocol.

AIMS: To examine the efficacy of an immersive virtual reality distraction compared with an active non-immersive distraction, such as video games on a tablet, for pain and anxiety management and memory of pain and anxiety in children requiring percutaneous bone pins and/or suture removal procedures. DESIGN: Three-centre randomized clinical trial using a parallel design with two groups: experimental and control. METHODS: Study to take place in the orthopaedic department of three children hospital of the Montreal region starting in 2019. Children, from 7-17 years old, requiring bone pins and/or suture removal procedures will be recruited. The intervention group (N = 94) will receive a virtual reality game (Dreamland), whereas the control group (N = 94) will receive a tablet with video games. The primary outcomes will be both the mean self-reported pain score measured by the Numerical Rating Scale and mean anxiety score, measured by the Child Fear Scale. Recalls of pain and anxiety will be measured 1 week after the procedure using the same scales. We aim to recruit 188 children to achieve a power of 80% with a significance level (alpha) of 5%. DISCUSSION: While multiple pharmacological methods have previously been tested for children, no studies have evaluated the impact of immersive virtual reality distraction for pain and anxiety management in the orthopaedic setting. IMPACT: Improved pain management can be achieved using virtual reality during medical procedures for children. This method is innovative, non-pharmacological, adapted to the hospital setting, and user-friendly. TRIAL REGISTRATION: NCT03680625, registered on clinicaltrials.gov.

Keeping an eye on pain expression in primary somatosensory cortex.

Facial expressions of pain are composed of a subset of pain-indicative muscle movements. Amongst this subset, contracting the muscles surrounding the eyes (orbicularis oculi muscle) is the most frequent response and has been linked specifically to pain intensity, a fundamental aspect of the sensory dimension of pain. To further explore this link, the present study used functional magnetic resonance imaging (fMRI) to test the hypothesis that orbicularis oculi activation during pain reflects the magnitude of brain responses in areas being involved in processing the sensory dimension of pain. Facial and brain (BOLD) responses to experimentally-induced heat pain applied to the left lower leg were assessed in twenty-two healthy participants after verbal suggestions were given to specifically increase perceived pain intensity and in control conditions involving no suggestion. Increases in pain intensity produced the expected changes in facial responses characterized by a stronger contraction of the orbicularis oculi muscle. A regression model further demonstrated that stronger increases in orbicularis oculi activity reflected a larger increase in the BOLD response to the noxious stimulus in the leg area of the primary somatosensory cortex (S1) and a larger decrease in medial prefrontal activity consistent with previous finding suggesting disinhibition. Importantly, the positive coupling of orbicularis oculi with S1 activity was not accounted for by changes in other facial muscles. These results are consistent with the notion that facial expressions of pain differentially encode the multi-dimensional pain experience and reflect, at least partly, the activity of the spino-thalamo-cortical pathway targeting the primary somatosensory cortex.

Distinct fMRI patterns colocalized in the cingulate cortex underlie the after-effects of cognitive control on pain.

Demanding tasks can influence following behaviors but the underlying mechanisms remain largely unclear. In the present functional magnetic resonance imaging (fMRI) study, we used multivariate pattern analyses (MVPA) to compare patterns of brain activity associated with pain in response to noxious stimuli administered after a task requiring cognitive control (Stroop) and evaluate their functional interaction based on a mediation analysis model. We found that performing a difficult cognitive task leads to subsequent increases in pain and pain-related multivariate responses across the brain and within the anterior mid-cingulate cortex (aMCC). Moreover, an aMCC pattern predictive of task performance was further reactivated during pain and predicted ensuing increases in pain-related brain responses. This suggests functional interactions between distinct but partly co-localized neural networks underlying executive control and pain. These findings offer a new perspective on the functional role of the cingulate cortex in pain and cognition and provide a promising framework to investigate dynamical interactions between partly overlapping brain networks.

Mindfulness induction and cognition: A systematic review and meta-analysis.

Mindfulness meditation might improve a variety of cognitive processes, but the available evidence remains fragmented. This preregistered meta-analysis (PROSPERO-CRD42018100320) aimed to provide insight into this hypothesis by assessing the effects of brief mindful attention induction on cognition. Articles were retrieved from Pubmed, PsycInfo and Web of Science up until August 1, 2018. A total of 34 studies were included. The outcomes were categorized into four cognitive domains: attentional functioning, memory, executive functioning and higher-order function. A small effect was found across all cognitive domains (Hedges' g = 0.18, 95% IC = 0.07-0.29). Separated analyses for each cognitive domain revealed an effect only in higher-order cognitive functions (k = 10, Hedges' g = 0.35, 95% IC = 0.20-0.50). Results suggest that mindfulness induction improves cognitive performance in tasks involving complex higher-order functions. There was no evidence of publication bias, but studies generally presented many methodological flaws.

Long-range temporal correlations in the brain distinguish conscious wakefulness from induced unconsciousness.

Rhythmic neuronal synchronization across large-scale networks is thought to play a key role in the regulation of conscious states. Changes in neuronal oscillation amplitude across states of consciousness have been widely reported, but little is known about possible changes in the temporal dynamics of these oscillations. The temporal structure of brain oscillations may provide novel insights into the neural mechanisms underlying consciousness. To address this question, we examined long-range temporal correlations (LRTC) of EEG oscillation amplitudes recorded during both wakefulness and anesthetic-induced unconsciousness. Importantly, the time-varying EEG oscillation envelopes were assessed over the course of a sevoflurane sedation protocol during which the participants alternated between states of consciousness and unconsciousness. Both spectral power and LRTC in oscillation amplitude were computed across multiple frequency bands. State-dependent differences in these features were assessed using non-parametric tests and supervised machine learning. We found that periods of unconsciousness were associated with increases in LRTC in beta (15-30Hz) amplitude over frontocentral channels and with a suppression of alpha (8-13Hz) amplitude over occipitoparietal electrodes. Moreover, classifiers trained to predict states of consciousness on single epochs demonstrated that the combination of beta LRTC with alpha amplitude provided the highest classification accuracy (above 80%). These results suggest that loss of consciousness is accompanied by an augmentation of temporal persistence in neuronal oscillation amplitude, which may reflect an increase in regularity and a decrease in network repertoire compared to the brain's activity during resting-state consciousness.

Reduced Fear-Conditioned Pain Modulation in Experienced Meditators: A Preliminary Study.

OBJECTIVE: Mindfulness-based practice is a form of cognitive/affective training that may help reduce suffering by attenuating maladaptive anticipatory processes. This study's objective was to examine the pain modulating impact of classical fear learning in meditation practitioners. METHODS: The hyperalgesic effects of pain expectation and uncertainty were assessed outside formal meditation in 11 experienced meditators (>1000 hours) compared with meditation-naive controls during a Pavlovian classical fear-conditioning paradigm involving two visual stimuli (CS+/CS-), one of which (CS+) co-terminated with a noxious electrical stimulus (unconditioned stimulus) on 50% of trials. A Rescorla-Wagner/Pearce-Hall hybrid model was fitted onto the conditioned skin conductance responses using computational modeling to estimate two learning parameters: expected shock probability and associability (i.e., uncertainty). RESULTS: Using a scale ranging between 0 (no pain) and 100 (extremely painful), meditators reported less pain (M = 19.9, SE = 5.1 for meditators, M = 32.4, SE = 2.4 for controls) but had comparable spinal motor responses (nociceptive flexion reflex) to the unconditioned stimulus. Multilevel mediation analyses revealed that meditators also exhibited reduced hyperalgesic effects of fear learning on higher-order pain responses but comparable effects on the nociceptive flexion reflex. These results suggest that mindfulness affects higher-order perceptual processes to a greater extent than from descending inhibitory controls. Furthermore, meditators showed reduced hyperalgesic effects of fear conditioning with no significant group difference in conditioned learning as evidenced by discriminative anticipatory skin conductance responses and learning parameters derived from computational modeling. CONCLUSIONS: These results highlight potential mechanisms underlying mindfulness-related hypoalgesia, relevant to clinical conditions in which repeated pain exposure might reinforce hyperalgesic processes through fear conditioning.

The Corticocortical Structural Connectivity of the Human Insula.

The insula is a complex structure involved in a wide range of functions. Tracing studies on nonhuman primates reveal a wide array of cortical connections in the frontal (orbitofrontal and prefrontal cortices, cingulate areas and supplementary motor area), parietal (primary and secondary somatosensory cortices) and temporal (temporal pole, auditory, prorhinal and entorhinal cortices) lobes. However, recent human tractography studies have not observed connections between the insula and the cingulate cortices, although these structures are thought to be functionally intimately connected. In this work, we try to unravel the structural connectivity between these regions and other known functionally connected structures, benefiting from a higher number of subjects and the latest state-of-the-art high angular resolution diffusion imaging (HARDI) tractography algorithms with anatomical priors. By performing an HARDI tractography analysis on 46 young normal adults, our study reveals a wide array of connections between the insula and the frontal, temporal, parietal and occipital lobes as well as limbic regions, with a rostro-caudal organization in line with tracing studies in macaques. Notably, we reveal for the first time in humans a clear structural connectivity between the insula and the cingulate, parahippocampal, supramarginal and angular gyri as well as the precuneus and occipital regions.

Sensitivity to Movement-Evoked Pain and Multi-Site Pain are Associated with Work-Disability Following Whiplash Injury: A Cross-Sectional Study.

Objectives Previous research has shown that sensitivity to movement-evoked pain is associated with higher scores on self-report measures of disability in individuals who have sustained whiplash injuries. However, it remains unclear whether sensitivity to movement-evoked pain is associated with work-disability. The aim of the present study was to examine the relation between sensitivity to movement-evoked pain and occupational status in individuals receiving treatment for whiplash injury. Methods A sample of 105 individuals with whiplash injuries participated in a testing session where different measures of pain (i.e. spontaneous pain, multi-site pain, sensitivity to movement-evoked pain) were collected during the performance of a simulated occupational lifting task. Results Hierarchical logistic regression analysis revealed that the measures of multisite pain and sensitivity to movement-evoked pain made significant independent contributions to the prediction of work-disability. Discussion The findings suggest that including measures of multisite pain and sensitivity to movement evoked pain in assessment protocols has the potential to increase the value of pain assessments for the prediction of occupational disability associated with whiplash injury. Clinical and theoretical implications of the findings are addressed.

The delayed reproduction of long time intervals defined by innocuous thermal sensation.

The presence of discrete events during an interval to be estimated generally causes a dilation of perceived duration (event-filling effect). Here, we investigated this phenomenon in the thermal modality using multi-seconds (19 s) innocuous cool stimuli that were either constant (continuous interval) or fluctuating to create three discrete sensory events (segmented interval). Moreover, we introduced a delay following stimulus offset, before the reproduction phase, to allow for a direct comparison with our recent study showing an underestimation of duration in a delayed reproduction task of heat pain sensations (Khoshnejad et al. in Pain 155:581-590, 2014. doi: 10.1016/j.pain.2013.12.015 ). The event-filling effect was tested by comparing the delayed reproduction of the segmented and the continuous stimuli in experimental conditions asking participants to (1) reproduce the dynamics of the sensation (i.e., changes in sensory intensity over time) or (2) reproduce only the interval duration (i.e., sensation onset-to-offset). A perceptual (control) condition required participants to report changes in sensation concurrently with the stimulus. Results of the dynamic task confirmed the underestimation of duration in the delayed reproduction task, but this effect was only found with the continuous and not with the segmented stimulus. This implies that the dilation of duration produced by segmentation might compensate for the underestimation of duration in this delayed reproduction task. However, this temporal dilation effect was only observed when participants were required to attend and reproduce the dynamics of sensation. These results suggest that the event-filling effect can be observed in the thermal sensory modality and that attention directed toward changes in sensory intensity might contribute to this effect.

Negative childhood experiences alter a prefrontal-insular-motor cortical network in healthy adults: A preliminary multimodal rsfMRI-fMRI-MRS-dMRI study.

Research in humans and animals has shown that negative childhood experiences (NCE) can have long-term effects on the structure and function of the brain. Alterations have been noted in grey and white matter, in the brain's resting state, on the glutamatergic system, and on neural and behavioural responses to aversive stimuli. These effects can be linked to psychiatric disorder such as depression and anxiety disorders that are influenced by excessive exposure to early life stressors. The aim of the current study was to investigate the effect of NCEs on these systems. Resting state functional MRI (rsfMRI), aversion task fMRI, glutamate magnetic resonance spectroscopy (MRS), and diffusion magnetic resonance imaging (dMRI) were combined with the Childhood Trauma Questionnaire (CTQ) in healthy subjects to examine the impact of NCEs on the brain. Low CTQ scores, a measure of NCEs, were related to higher resting state glutamate levels and higher resting state entropy in the medial prefrontal cortex (mPFC). CTQ scores, mPFC glutamate and entropy, correlated with neural BOLD responses to the anticipation of aversive stimuli in regions throughout the aversion-related network, with strong correlations between all measures in the motor cortex and left insula. Structural connectivity strength, measured using mean fractional anisotropy, between the mPFC and left insula correlated to aversion-related signal changes in the motor cortex. These findings highlight the impact of NCEs on multiple inter-related brain systems. In particular, they highlight the role of a prefrontal-insular-motor cortical network in the processing and responsivity to aversive stimuli and its potential adaptability by NCEs.

Acute stress contributes to individual differences in pain and pain-related brain activity in healthy and chronic pain patients.

Individual differences in pain sensitivity and reactivity are well recognized but the underlying mechanisms are likely to be diverse. The phenomenon of stress-induced analgesia is well documented in animal research and individual variability in the stress response in humans may produce corresponding changes in pain. We assessed the magnitude of the acute stress response of 16 chronic back pain (CBP) patients and 18 healthy individuals exposed to noxious thermal stimulations administered in a functional magnetic resonance imaging experiment and tested its possible contribution to individual differences in pain perception. The temperature of the noxious stimulations was determined individually to control for differences in pain sensitivity. The two groups showed similar significant increases in reactive cortisol across the scanning session when compared with their basal levels collected over 7 consecutive days, suggesting normal hypothalamic-pituitary-adrenal axis reactivity to painful stressors in CBP patients. Critically, after controlling for any effect of group and stimulus temperature, individuals with stronger cortisol responses reported less pain unpleasantness and showed reduced blood oxygenation level-dependent activation in nucleus accumbens at the stimulus onset and in the anterior mid-cingulate cortex (aMCC), the primary somatosensory cortex, and the posterior insula. Mediation analyses indicated that pain-related activity in the aMCC mediated the relationship between the reactive cortisol response and the pain unpleasantness. Psychophysiological interaction analysis further revealed that higher stress reactivity was associated with reduced functional connectivity between the aMCC and the brainstem. These findings suggest that acute stress modulates pain in humans and contributes to individual variability in pain affect and pain-related brain activity.

The stress model of chronic pain: evidence from basal cortisol and hippocampal structure and function in humans.

Recent theories have suggested that chronic pain could be partly maintained by maladaptive physiological responses of the organism facing a recurrent stressor. The present study examined the associations between basal levels of cortisol collected over seven consecutive days, the hippocampal volumes and brain activation to thermal stimulations administered in 16 patients with chronic back pain and 18 healthy control subjects. Results showed that patients with chronic back pain have higher levels of cortisol than control subjects. In these patients, higher cortisol was associated with smaller hippocampal volume and stronger pain-evoked activity in the anterior parahippocampal gyrus, a region involved in anticipatory anxiety and associative learning. Importantly, path modelling-a statistical approach used to examine the empirical validity of propositions grounded on previous literature-revealed that the cortisol levels and phasic pain responses in the parahippocampal gyrus mediated a negative association between the hippocampal volume and the chronic pain intensity. These findings support a stress model of chronic pain suggesting that the sustained endocrine stress response observed in individuals with a smaller hippocampii induces changes in the function of the hippocampal complex that may contribute to the persistent pain states.

Investigating the Impact of Stress on Pain: A Scoping Review on Sense of Control, Social-Evaluative Threat, Unpredictability, and Novelty (STUN Model).

Background: Stress can have paradoxical effects on pain, namely hyperalgesia and hypoalgesia. Four situational characteristics activate the hypothalamic-pituitary-adrenal axis, leading to a physiological stress response: lacking Sense of control, social-evaluative Threat, Unpredictability and Novelty (STUN). This scoping review reports on the types of evidence published on the effects of STUN characteristics on pain outcomes. Databases/Data Treatment: Searches of primary electronic databases were performed to identify articles published on adults between 1990 and 2021 that contained search terms on pain and stress/STUN characteristics. A total of 329 articles were included in the analysis. Results: Only 3.3% of studies examined simultaneously >1 STUN component. Almost all observational studies (177/180) examined the association between perceived stress and pain without measuring physiological stress responses. Of the 130 experimental studies, 78 (60.0%) manipulated stressful characteristics through nociception, and only 38.5% assessed if/how stress manipulation impacted perceived stress. Conclusion: There is a clear lack of integration of the characteristics that trigger a physiological stress response in the pain field. Only 3.3% of studies examined simultaneously more than one STUN component and there is an unequal attention given to individual components of the STUN framework. Recommendations for future research include selection of stress manipulations/measurements that are more precisely inducing/reflecting neurobiological mechanisms of stress responses to insure valid integration of scientific knowledge.