Mitigating Initial Orthostatic Hypotension: Mechanistic Roles of Muscle Contraction Versus Sympathetic Activation

Background: Initial orthostatic hypotension (IOH) is defined by a large drop in blood pressure (BP) within 15 s of standing. IOH often presents during an active stand, but not with a passive tilt, suggesting that a muscle activation reflex involving lower body muscles plays an important role. To our knowledge, there is no literature exploring how sympathetic activation affects IOH. We hypothesized involuntary muscle contractions before standing would significantly reduce the drop in BP seen in IOH while increasing sympathetic activity would not. Methods: Study participants performed 4 sit-to-stand maneuvers including a mental stress test (serial 7 mental arithmetic stress test), cold pressor test, electrical stimulation, and no intervention. Continuous heart rate and beat-to-beat BP were measured. Cardiac output and systemic vascular resistance were estimated from these waveforms. Data are presented as mean±SD. Results: A total of 23 female IOH participants (31±8 years) completed the study. The drops in systolic BP following the serial 7 mental arithmetic stress test (−26±12 mm Hg; P =0.004), cold pressor test (−20±15 mm Hg; P <0.001), and electrical stimulation (−28±12 mm Hg; P =0.01) were significantly reduced compared with no intervention (−34±11 mm Hg). The drops in systemic vascular resistance following the serial 7 mental arithmetic stress test (−391±206 dyne×s/cm 5 ; P =0.006) and cold pressor test (−386±179 dyne×s/cm 5 ; P =0.011) were significantly reduced compared with no intervention (−488±173 dyne×s/cm 5 ). Cardiac output was significantly increased upon standing (7±2 L/min) compared with during the sit (6±1 L/min; P <0.001) for electrical stimulation. Conclusion: Sympathetic activation mitigates the BP response in IOH, while involuntary muscle contraction mitigates the BP response and reduces symptoms. Active muscle contractions may induce both of these mechanisms of action in their pretreatment of IOH. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03970551.

Pain Perception in Contact Sport Athletes: A Scoping Review

Contact sports athletes are regularly facing acute physical pain in part of their practice. However, the literature investigating pain perception in these athletes remains scarce. This scoping review aimed to explore the literature surrounding pain perception in contact sport athletes and to compile and understand how it is studied. The search strategy consisted of using index terms and keywords in Medline, EMBASE, Sport-Discus, Web of Science, PsycINFO, CINAHL and ProQuest Dissertations &amp; Theses Global search engines. Results revealed that a mix of team contact sports and combat sports are studied and included under the umbrella of contact sports. These athletes are being compared to non-athletes as well as athletes from non-contact sports. The cold pressor test and the pain pressure test are the two predominant methods used to investigate physical pain. This review highlights the need to clearly define sports based on contact levels expected in play to better define the types of pain athletes are facing in their practice. Athlete’s level of play as well as years of experience should also be more rigorously reported. While contact sport athletes seem to have a higher level of pain tolerance than both active controls and non-contact athletes, the methods of pain testing are not always justified and appropriate in relation to the pain induced during contact sports. Future experimental studies should use pain testing methods relevant to the pain experienced during contact sports and better justify the rationale for the choice of these methods.

The Influence of Examiner Gender on Responses to Tonic Heat Pain Assessments: A Preliminary Investigation

Background: The influence of examiner gender on pain reporting has been previously explored in both research and clinical settings. However, previous investigations have been limited, with the majority of studies employing single, static assessments of pain (e.g., cold pressor test, verbal pain ratings). The impact of examiner gender on both static and dynamic heat-based pain assessments is currently unknown.Methods: Thirty eight participants (20 females aged 24.1 ± 4.44, and 18 males, aged 24.8 ± 4.54) completed two identical testing sessions, randomized to a male and female examiner in a cross-over design. Pain sensitivity was examined using heat pain thresholds, verbal pain ratings to tonic heat, computerized visual analog scale (CoVAS) rating to tonic heat, and participant-controlled temperature (PCT) heat pain assessments.Results: Female participants reported higher verbal pain to tonic heat with a female examiner compared to male participants, with similar trends for CoVAS responses to tonic heat. Conversely heat pain thresholds and PCT were not significantly influenced by experimenter gender.Conclusions: Overall, verbal ratings were the most impacted by examiner gender, with temperature-based methods such as PCT and pain thresholds showing little to no examiner gender effects. While the gender of the examiner may be an important consideration in the measurement of sex and gender differences in pain research, the choice of pain assessment method may be of similar consequence.

Classification of Game Demand and the Presence of Experimental Pain Using Functional Near-Infrared Spectroscopy

Pain tolerance can be increased by the introduction of an active distraction, such as a computer game. This effect has been found to be moderated by game demand, i.e., increased game demand = higher pain tolerance. A study was performed to classify the level of game demand and the presence of pain using implicit measures from functional Near-InfraRed Spectroscopy (fNIRS) and heart rate features from an electrocardiogram (ECG). Twenty participants played a racing game that was configured to induce low (Easy) or high (Hard) levels of demand. Both Easy and Hard levels of game demand were played with or without the presence of experimental pain using the cold pressor test protocol. Eight channels of fNIRS data were recorded from a montage of frontal and central-parietal sites located on the midline. Features were generated from these data, a subset of which were selected for classification using the RELIEFF method. Classifiers for game demand (Easy vs. Hard) and pain (pain vs. no-pain) were developed using five methods: Support Vector Machine (SVM), k-Nearest Neighbour (kNN), Naive Bayes (NB) and Random Forest (RF). These models were validated using a ten fold cross-validation procedure. The SVM approach using features derived from fNIRS was the only method that classified game demand at higher than chance levels (accuracy = 0.66, F1 = 0.68). It was not possible to classify pain vs. no-pain at higher than chance level. The results demonstrate the viability of utilising fNIRS data to classify levels of game demand and the difficulty of classifying pain when another task is present.

The key to superior memory encoding under stress: the relationship between cortisol response and mnemonic discrimination

Some previous studies have shown that increased stress hormone levels have beneficial effects on memory encoding; however, there is no clear consensus on which encoding-related processes are affected by stress hormones. In the present study, we investigated the relationship between interindividual differences in neuroendocrine response to acute stress and interference resolution (i.e., mnemonic discrimination). Participants were healthy young adults who were exposed to physical and psychological stressors (Socially Evaluated Cold Pressor Test). Then participants completed the modified version of the Mnemonic Similarity Task. Specifically, they were presented with photographs of emotionally arousing (negative and positive) and nonarousing (neutral) scenes followed by a recognition memory test where they saw a mixture of old and new stimuli. Crucially, participants were also presented with critical lure items, that is, visually similar stimuli to ones presented at encoding. We found that participants who had higher cortisol response to the stressors were better in discriminating between the studied items and their visually similar lures. This effect was present for the arousing and nonarousing materials as well. These findings suggest that increased hormonal response to acute stress has a beneficial impact on the formation of distinct, nonoverlapping, unique memory representations, and consequently, on episodic memory encoding processes.

Perceived chronic stress influences the effect of acute stress on cognitive flexibility

Executive functions are cognitive processes that facilitate goal-directed behavior by enabling us to direct and control our thoughts. Cognitive flexibility is an executive function characterized by the ability to mentally shift between rules, strategies, or tasks. Several studies have reported that acute (brief) stress impairs cognitive flexibility. Even though an individual’s perception of their chronic stress levels is shown to influence effects of future stressors, the interactive effect of acute and perceived chronic stress on cognitive flexibility is not known. We conducted two experiments to address this gap. In both studies, perceived chronic stress was measured using the Perceived Stress Scale. Acute stress was induced using the Cold Pressor Test. Number of perseverative errors on the Wisconsin Card Sorting Test was used as an indicator of cognitive flexibility. In Study 2, we also measured salivary alpha amylase as a marker of the physiological stress response. Data from our two studies are consistent with the hypothesis that an individual’s perception of their chronic stress level may impact the effect of acute stress on perseveration. In Study 1, we observed a significant interaction between acute and perceived chronic stress on perseverative errors, such that only individuals who reported high levels of perceived chronic stress prior to acute stress exposure showed no change in perseveration following the acute stress manipulation. This effect did not differ based on participant sex. In Study 2, we found a similar interaction effect of acute and perceived chronic stress on perseverative errors in an all-woman sample. After identifying salivary alpha amylase responders and non-responders, we observed a strong, negative correlation between perceived chronic stress and perseverative errors amongst the responders only. Our data highlight the value in studying salivary alpha amylase in response to acute stress exposure. Additionally, perceived chronic stress emerged as a key variable in the relationship between acute stress and cognitive flexibility. Overall, our work suggests that future research interested in interrogating moderators in the relationship between acute stress and cognition would benefit from inclusion of measures of chronic stress.

Low-Dose Fentanyl Reduces Pain Perception, Muscle Sympathetic Nerve Activity Responses, and Blood Pressure Responses During the Cold Pressor Test

Our knowledge about how low-dose (analgesic) fentanyl affects autonomic cardiovascular regulation is primarily limited to animal experiments. Notably, it is unknown if low-dose fentanyl influences human autonomic cardiovascular responses during painful stimuli in humans. Therefore, we tested the hypothesis that low-dose fentanyl reduces perceived pain and subsequent sympathetic and cardiovascular responses in humans during an experimental noxious stimulus. Twenty-three adults (10F/13M; 27±7 y; 26±3 kg•m-2, mean ± SD) completed this randomized, crossover, placebo-controlled trial during two laboratory visits. During each visit, participants completed a cold pressor test (CPT; hand in ~0.4 °C ice bath for two minutes) before and five minutes after drug/placebo administration (75 μg fentanyl or saline). We compared pain perception (100 mm visual analog scale), muscle sympathetic nerve activity (MSNA; microneurography, 11 paired recordings), and beat-to-beat blood pressure (BP; photoplethysmography) between trials (at both pre- and post-drug/placebo time points) using paired, two-tailed t-tests. Before drug/placebo administration, perceived pain (p=0.8287), Δ MSNA burst frequency (p=0.7587), and Δ mean BP (p=0.8649) during the CPT were not different between trials. After the drug/placebo administration, fentanyl attenuated perceived pain (36 vs. 66 mm, p<0.0001), Δ MSNA burst frequency (9 vs. 17 bursts/minute, p=0.0054), and Δ mean BP (7 vs. 13 mmHg, p=0.0174) during the CPT compared to placebo. Fentanyl-induced reductions in pain perception and Δ mean BP were moderately related (r=0.40, p=0.0641). These data provide valuable information regarding how low-dose fentanyl reduces autonomic cardiovascular responses during an experimental painful stimulus.

Endothelin Receptor Blockade Blunts the Pressor Response to Acute Stress in Obese Men and Women

Obesity is associated with dysregulation of the endothelin system. In obese individuals, an exaggerated pressor response to acute stress is accompanied by increased circulating endothelin-1. The impact of combined endothelin A/B receptor (ETA/B) antagonism on the stress-induced pressor response in overweight/obese individuals is unknown. Objective: To test the hypothesis that treatment with an ETA/B antagonist (bosentan) would reduce the stress-induced pressor response and arterial stiffness in overweight/obese compared to normal weight individuals. Methods: 40 participants [Normal weight (NW): n=20, BMI: 21.7 ± 2.4 kg/m2 & Overweight/obese (OB): n=20, BMI: 33.8 ± 8.2 kg/m2] were randomized to placebo or 125 mg of bosentan twice a day (250 mg total) for 3 days. Hemodynamics were assessed before, during, and after a cold pressor test (CPT). Endothelin-1 was assessed at baseline and immediately after CPT. Following a washout period, the same protocol was repeated with the opposite treatment. Results: The change from baseline in mean arterial pressure (MAP) during CPT following bosentan was significantly lower (p=0.039) in the OB group, compared to the NW group (OB: 28±12 vs LN: 34±15 mm Hg). Conclusions: These results suggest that ETA/B antagonism favorably blunts the pressor response to acute stress in overweight/obese individuals.

Pain sensitivity in men who have never experienced a headache: an observer blinded case control study

Background Headache affects 90–99% of the population. Based on the question “Do you think that you never ever in your whole life have had a headache?” 4% of the population say that they have never experienced a headache. The rarity of never having had a headache suggests that distinct biological and environmental factors may be at play. We hypothesized that people who have never experienced a headache had a lower general pain sensitivity than controls. Methods We included 99 male participants, 47 headache free participants and 52 controls, in an observer blinded nested case-control study. We investigated cold pain threshold and heat pain threshold using a standardized quantitative sensory testing protocol, pericranial tenderness with total tenderness score and pain tolerance with the cold pressor test. Differences between the two groups were assessed with the unpaired Student’s t-test or Mann-Whitney U test as appropriate. Results There was no difference in age, weight or mean arterial pressure between headache free participants and controls. We found no difference in pain detection threshold, pericranial tenderness or pain tolerance between headache free participants and controls. Conclusion Our study clearly shows that freedom from headache is not caused by a lower general pain sensitivity. The results support the hypothesis that headache is caused by specific mechanisms, which are present in the primary headache disorders, rather than by a decreased general sensitivity to painful stimuli. Trial registration Registered at ClinicalTrials.gov (NCT04217616), 3rd January 2020, retrospectively registered.