Can glucose facilitate fear exposure? Randomized, placebo-controlled trials on the effects of glucose administration on fear extinction processes.

Previous studies showed that glucose has beneficial effects on memory function and can enhance contextual fear learning. To derive potential therapeutic interventions, further research is needed regarding the effects of glucose on fear extinction. In two experimental studies with healthy participants (Study 1: N = 68, 39 females; Study 2: N = 89, 67 females), we investigated the effects of glucose on fear extinction learning and its consolidation. Participants completed a differential fear conditioning paradigm consisting of acquisition, extinction, and return of fear tests: reinstatement, and extinction recall. US-expectancy ratings, skin conductance response (SCR), and fear potentiated startle (FPS) were collected. Participants were pseudorandomized and double-blinded to one of two groups: They received either a drink containing glucose or saccharine 20 min before (Study 1) or immediately after extinction (Study 2). The glucose group showed a significantly stronger decrease in differential FPS during extinction (Study 1) and extinction recall (Study 2). Additionally, the glucose group showed a significantly lower contextual anxiety at test of reinstatement (Study 2). Our findings provide first evidence that glucose supports the process of fear extinction, and in particular the consolidation of fear extinction memory, and thus has potential as a beneficial adjuvant to extinction-based treatments. Registered through the German Clinical Trials Registry (https://www.bfarm.de/EN/BfArM/Tasks/German-Clinical-Trials-Register/_node.html; Study 1: DRKS00010550; Study 2: DRKS00018933).

Elementary integrate-and-fire process underlies pulse amplitudes in Electrodermal activity.

Electrodermal activity (EDA) is a direct read-out of sweat-induced changes in the skin's electrical conductance. Sympathetically-mediated pulsatile changes in skin sweat measured as EDA resemble an integrate-and-fire process, which yields an inverse Gaussian model as the inter-pulse interval distribution. We have previously showed that the inter-pulse intervals in EDA follow an inverse Gaussian distribution. However, the statistical structure of EDA pulse amplitudes has not yet been characterized based on the physiology. Expanding upon the integrate-and-fire nature of sweat glands, we hypothesized that the amplitude of an EDA pulse is proportional to the excess volume of sweat produced compared to what is required to just reach the surface of the skin. We modeled this as the difference of two inverse Gaussian models for each pulse, one which represents the time required to produce just enough sweat to rise to the surface of the skin and one which represents the time requires to produce the actual volume of sweat. We proposed and tested a series of four simplifications of our hypothesis, ranging from a single difference of inverse Gaussians to a single simple inverse Gaussian. We also tested four additional models for comparison, including the lognormal and gamma distributions. All models were tested on EDA data from two subject cohorts, 11 healthy volunteers during 1 hour of quiet wakefulness and a different set of 11 healthy volunteers during approximately 3 hours of controlled propofol sedation. All four models which represent simplifications of our hypothesis outperformed other models across all 22 subjects, as measured by Akaike's Information Criterion (AIC), as well as mean and maximum distance from the diagonal on a quantile-quantile plot. Our broader model set of four simplifications offered a useful framework to enhance further statistical descriptions of EDA pulse amplitudes. Some of the simplifications prioritize fit near the mode of the distribution, while others prioritize fit near the tail. With this new insight, we can summarize the physiologically-relevant amplitude information in EDA with at most four parameters. Our findings establish that physiologically based probability models provide parsimonious and accurate description of temporal and amplitude characteristics in EDA.

Can changes in skin impedance be used to monitor sedation after midazolam and during recovery from anesthesia?

It has been suggested that sympathetic activity, measured as changes in electrical skin impedance (SI), can be used to assess the adequacy of general anesthesia. Our prospective study investigated if measurements of skin impedance can determine levels of sedation induced by midazolam. Twenty-seven patients scheduled for arthroscopy requiring general anesthesia were served as their own control. These were blinded to the order of injections by telling them that they will be randomly administered a placebo (saline) orsedative agent. A DM 3900 multimeter was used for SI measurements. The degree of sedation was measured using the modified Observer's Assessment of Alertness and Sedation (mOAAS) scale. Resting SI values were noted, and all participants were then administered the placebo followed 5 min later by midazolam 2 mg i.v. Five min after that, patients were administered standard general anesthesia with propofol, oxygen, nitrous oxide 60 %, and isoflurane 1 MAC via a laryngeal mask, and sufentanil 5 - 10 µg. SI significantly increased after administration of midazolam and induction of anesthesia. There were no significant differences between pre-administration (baseline) and placebo and end of surgery and end of anesthesia with closed eyes. There were highly significant differences (p<0.001) between pre-administration vs. midazolam, placebo vs. midazolam, pre-administration vs. induction of anesthesia. We found slight correlation between mOAAS and SI. There were no significant changes between the end of surgery and the end of anesthesia with closed eyes, but SI significantly decreased (p<0.01) after eyes opened.

Initial evidence for pharmacological modulation of observational threat learning by the GABAergic, but not the noradrenergic system in humans.

Threat responses are often shaped by social information, such as observation of aversive outcomes for others. Yet, the neurochemistry regulating observational learning of threats is largely unknown. Here, we examined the impact of the GABAergic and noradrenergic system, which are central in regulating threat learning from first-hand experiences, on observational threat learning in humans. To this end, 61 participants received either 1 mg Lorazepam (enhancing GABAergic signalling N = 18), 20 mg Yohimbine (enhancing Noradrenergic transmission, N = 16), Placebo (double blind and randomized control for Lorazepam and Yohimbine, N = 12) or no treatment (N = 15) prior to observational threat conditioning. Participants acquired conditioned threat responses by observation of another individual who is presented with a conditioned stimulus (CS) and an aversive unconditioned stimulus (US). Participants' threat responses were tested by direct exposure to the CSs immediately after learning, as well as two days later (drug free). Our results indicate decreased fear ratings to socially acquired CSs by enhanced GABAergic transmission as compared to the control group (placebo and no treatment) during the immediate test. We could not provide evidence for noradrenergic modulation of socially acquired threat responses. Further, we found no differences in psychophysiological responses (Skin conductance responses) or long-term persistence of conditioned responses. Our results provide initial evidence for an impact of the GABAergic system on social acquisition of threats.

Baclofen modulates cardiovascular responses to appetitive cues in treatment-seeking alcohol use disorder individuals.

OBJECTIVE: To assess whether baclofen-treated alcohol dependent participants show different subjective and psychophysiological responses to appetitive cues during an alcohol cue reactivity task compared to placebo, and whether these responses are associated with prospective drinking outcomes. METHODS: Forty-two alcohol dependent participants (placebo: n = 12, low-dose baclofen [30 mg/day] n = 18, high-dose baclofen [75 mg/day]: n = 12) completed an alcohol cue reactivity task, whereby water and alcohol beverage cues were presented, with subsequent recovery periods, and subjective alcohol craving and psychophysiological indices (skin conductance; cardiovascular measures: heart rate, high-frequency heart rate variability) were recorded. RESULTS: High-dose baclofen-treated participants showed both overall cue reactivity to water and alcohol cues and greater recovery effects during recovery periods, revealed by high-frequency heart rate variability, when compared to low-dose- and placebo-treated participants. There were no medication effects on subjective craving. In high-dose baclofen participants only, there was a predictive effect of lower baseline heart rate variability and fewer post-test percentage of heavy drinking days. CONCLUSION: There was a dose-specific rescuing effect of high-dose baclofen on the dynamic modulation of cardiovascular responses to eliciting cues. Investigation of treatment responses using psychophysiological techniques may elucidate baclofen's mechanisms of action, and identify subgroups amenable to treatment.

Is autonomic nervous system function atypical in attention deficit hyperactivity disorder (ADHD)? A systematic review of the evidence.

Although arousal mechanisms have frequently been found to be atypical in ADHD, these findings usually emerged from indirect behavioural measures which give only a limited understanding of arousal dysregulation in this condition. To assess the hypothesis that functioning of the autonomic nervous system (ANS), one component of arousal, is atypical in ADHD, we carried out a systematic review of the literature on 55 studies investigating electro-dermal, heart rate and pupillometry measures under different experimental conditions (resting-state, cognitive tasks and in response to reinforcers or socio-emotional stimuli). Our literature review identified ANS dysfunction in individuals with ADHD, more often in the direction of hypo-arousal than hyper-arousal, particularly at rest and during tasks requiring response regulation and sustained attention. Almost half of the reported findings were null. Stimulant medications increased ANS activity and, in some studies, reinforcers and rewards produced a similar effect, suggesting that ANS function can be modified in ADHD. Further research is needed to assess the influence of comorbid symptoms and to explore methodological parameters that may influence findings.

Film clips smoking behavior and nicotine craving: The interrelationship between stress, smoking cues and craving.

Αn abundance of research has demonstrated that substance addicted individuals, when they are exposed to a substance related stimulus, show a positive correlation between physiological measurements, such as an increase in heart rate and sweating, and behavioral reactions, that include craving and substance use or consumption. Films depicting smoking behavior are regarded as cues to induce smoking behavior. The current study aimed to investigate the effects of smoking behavior portrayed in movies on actual craving experienced by smokers who watch on screen actors consume tobacco products. In addition, the effects of receiving orally administered nicotine (chewing gum), a regular chewing gum or no additional intervention were examined. In particular, the study aimed to investigate how these factors impact nicotine craving as well as the heart rate and sweating. The majority of the participants were University of Bedfordshire students and staff. Thirty smokers (12 males and 18 females) having received a nicotine gum, a regular chewing gum or no gum, were exposed to a digital video clip showing actors smoking. The participants chose the type of chewing gum they wanted. Heart rate (HR) and galvanic skin response (GSR) were measured during the course of the experiment. Prior to and after watching the movie clip participants completed the Brief Questionnaire of Smoking Urges (QSU-Brief) and the Perceived Stress Scale (PSS). According to the results, the craving was increased when compared to the baseline score (t=-3.76, p<0.001). Additionally, a correlation was found between the baseline level of craving and perceived stress before and after the movie (r=0.39). Nicotine chewing gum was found to have a significant impact on participants' heart rate (p<0.05) but not on GSR. A significant difference was found in participants in the normal chewing gum condition reporting higher levels of craving than the other two groups (p<0.05). Age was found to positively related to post-measures of nicotine craving which was found to be higher for young respondents (r=-0.47, p<0.01). The data further show that the depiction of smoking behavior in the media is likely to have a significant impact on smoking craving, smoking behavior and nicotine consumption. The current study confirms and replicates some of the previous findings within the field of smoking behavior and nicotine craving such as high susceptibility of younger adults to media influence.

"New methods of assessing autonomic disorders in Parkinson disease patients: skin-galvanic reaction".

The aim of this study was to assess quantitatively sweating in PD patients. In the study, the galvanic-skin reaction (GSR) was used. The GSR was tested using eSense Skin Reaction device. The results show that sweating in patients with Parkinson's disease on drugs (PD ON) and control patients is similar, while patients with PD without levodopa (PD OFF) have higher perspiration.

In vivo studies of resveratrol contained in cosmetic emulsions.

The cosmetic and pharmaceutical industry is constantly on the lookout for new and efficient active substances. In this article, we focus on resveratrol, an active substance with beneficial health properties, which is obtained, among others, from vines and knotweed (Reynoutria japonica). In this study, we assessed the level of skin hydration in a group of probands who used cream with or without resveratrol. The compound has been shown to have moisturizing and tightening properties, improving the overall condition of the skin.

Influence of Δ9-tetrahydrocannabinol on long-term neural correlates of threat extinction memory retention in humans.

The neural mechanisms and durability of Δ9-tetrahydrocannabinol (THC) impact on threat processing in humans are not fully understood. Herein, we used functional MRI and psychophysiological tools to examine the influence of THC on the mechanisms of conditioned threat extinction learning, and the effects of THC on extinction memory retention when assessed 1 day and 1 week from learning. Healthy participants underwent threat conditioning on day 1. On day 2, participants were randomized to take one pill of THC or placebo (PBO) 2-h before threat extinction learning. Extinction memory retention was assessed 1 day and 1 week after extinction learning. We found that THC administration increased amygdala and ventromedial prefrontal cortex (vmPFC) activation during early extinction learning with no significant impact on skin conductance responses (SCR). When extinction memory retention was tested 24 h after learning, the THC group exhibited lower SCRs to the extinguished cue with no significant extinction-induced activations within the extinction network. When extinction memory retention was tested 1 week after learning, the THC group exhibited significantly decreased responses to the extinguished cues within the vmPFC and amygdala, but significantly increased functional coupling between the vmPFC, hippocampus, and dorsal anterior cingulate cortex during this extinction retention test. Our results are the first to report a long-term impact of one dose of THC on the functional activation of the threat extinction network and unveil a significant change in functional connectivity emerging after a week from engagement. We highlight the need for further investigating the long-term impact of THC on threat and anxiety circuitry.

Intimate partner violence moderates the association between oxytocin and reactivity to dyadic conflict among couples.

Emerging literature indicates individual and contextual differences impact response to oxytocin (OT). Intimate partner violence (IPV) is one chronic stressor that may moderate OT response. To test the hypothesis that IPV moderates the association between OT and reactivity to a dyadic conflict task, data from a larger randomized controlled study was collected from heterosexual couples (N = 60 individuals; 30 couples) at high risk for IPV due to substance misuse. Partners within each dyad completed a 10-minute dyadic conflict task in the laboratory, and then self-administered a single dose of OT (40 IU) or placebo. Forty-five minutes later, participants completed another 10-minute dyadic conflict task. Stress reactivity was measured before and after the second conflict task using neuroendocrine (i.e., salivary cortisol), physiological (i.e., skin conductance), and subjective responses. Couple conflict behaviors were observed during the conflict tasks and assessed using a validated coding system. Among women, physical IPV modulated skin conductance in those administered OT, and OT interacted with physical and psychological IPV to yield less positive subjective and behavioral responses. No main or moderating effects were found for men. Findings support emerging literature on sex differences in response to OT. Future research is needed to effectively translate OT into therapeutic intervention.

Validation of the PMD100 and its NOL Index to detect nociception at different infusion regimen of remifentanil in patients under general anesthesia.

BACKGROUND: The NOL index is based on multiparametric analysis of heart rate (HR), skin conductance, wave plethysmography, and their time derivative. The aim of this study was to evaluate the NOL to detect standardized nociceptive stimuli with various remifentanil dosages under general anesthesia. METHODS: A prospective, observational study at a single center (NCT02602379) included 40 ASA I to III patients undergoing laparotomy under remifentanil-desflurane anesthesia with epidural analgesia. A tetanic stimulation was applied (forearm) at remifentanil intravenous (IV) infusion of 0.005, 0.05, 0.1, and 0.15 µg/kg/min. NOL and its variations were compared with other parameters namely heart rate, mean arterial pressure, Bispectral Index, and Analgesia Nociception Index (ANI). Receiver operating characteristic (ROC) curves were plotted to assess the response to both intubation and standardized stimulus under remifentanil infusion of 0.005 µg/kg/min. RESULTS: The post-stimulation NOL values at remifentanil doses of 0.005, 0.05, 0.1 and 0.15 µg/kg/min (39 [23-55], 15 [7-30], 8 [4-14] and 8.5 [4-15]) were significantly higher than pre-stimulation counterparts (P<0.0001). For all other parameters, there was also significant difference between pre- and post-stimulation values at all remifentanil dosages (P<0.0001). Area under the ROC curve (AUC) for the NOL during standardized stimulation was larger than for all other parameters at the exception of ANI (P=0.94). The AUC of NOL for nociception during tracheal intubation was greater (0.93 vs. 0.84 and 0.64 for ANI and HR, respectively). CONCLUSIONS: NOL monitoring is a promising index to assess the level of nociception in patients under general anesthesia.

The effects of the selective muscarinic M3 receptor antagonist darifenacin, and of hyoscine (scopolamine), on motion sickness, skin conductance & cognitive function.

AIMS: The aim of this study was to compare the effects of the selective M3 muscarinic acetylcholine receptor antagonist darifenacin, oral hyoscine hydrobromide and placebo on motion sickness induced by cross-coupled stimulation. METHODS: The effects of darifenacin 10 mg or 20 mg, hyoscine hydrobromide 0.6 mg and placebo were assessed in a randomized, double-blind, four-way cross over trial of 16 healthy subjects. Motion sickness, skin conductance (a measure of sweating) and psychomotor cognitive function tests were investigated. RESULTS: Hyoscine hydrobromide produced significantly increased tolerance to motion versus placebo (P < 0.05 to P < 0.01). The motion protection effect of darifenacin (10 or 20 mg) was approximately one third that of hyoscine hydrobromide but was not significant versus placebo. Darifenacin and hyoscine hydrobromide both significantly reduced skin conductance versus placebo. Darifenacin produced either no effect or an enhanced effect on cognitive function in contrast to hyoscine hydrobromide, where there was significant impairment of psychomotor performance. CONCLUSION: The results suggest that selective antagonism of the M3 receptor may not be important in the prevention of motion sickness. However, selective M3 antagonism does not impair cognitive function. These observations may be important given that long-term treatment with non-selective anti-muscarinic agents such as oxybutynin may lead to an increased incidence of dementia.

Neural Underpinnings of Cortisol Effects on Fear Extinction.

Extinction of conditioned fear embodies a crucial mechanism incorporated in exposure therapy. Clinical studies demonstrated that application of the stress hormone cortisol before exposure sessions facilitates exposure success, but the underlying neural correlates remain unknown. Context- and stimulus-dependent cortisol effects on extinction learning will be characterized in this study and tested in the extinction and in a new context. Forty healthy men participated in a 3-day fear conditioning experiment with fear acquisition in context A (day 1), extinction training in context B (day 2), and recall in context B and a new context C one week later (day 3). Hydrocortisone (30 mg) or placebo was given before extinction training. Blood-oxygen-level-dependent responses and skin conductance responses (SCRs) served as dependent measures. At the beginning of extinction training, cortisol reduced conditioned SCRs, diminished activation of the amygdala-hippocampal complex, and enhanced functional connectivity of the anterior parahippocampal gyrus with the ventromedial prefrontal cortex (vmPFC). After one week, the cortisol group showed increased hippocampal activation and connectivity to the vmPFC toward an extinguished stimulus and reduced insula activation toward a nonextinguished stimulus in the extinction context. However, this inhibitory cortisol effect did not extend to the new context. Taken together, cortisol reduced fear recall at the beginning of extinction and facilitated the consolidation of the extinction memory as evidenced by an inhibitory activation pattern one week later. The stress hormone exerted a critical impact on the amygdala-hippocampus-vmPFC network underlying fear and extinction memories. However, cortisol did not attenuate the context dependency of extinction.

Heightened sympathetic arousal is demonstrated by skin conductance responsivity to auditory stimuli in a small cohort of neonates with opiate withdrawal.

To determine the effects of auditory stimulus on skin conductance (SC) in infants with severe neonatal abstinence syndrome (NAS) that required morphine treatment (MT) compared with NAS infants that did not require morphine treatment (non-MT). We prospectively enrolled opiate-exposed term infants without polysubstance exposure. Skin conductance responses to an auditory stimulus (ringing a bell for 3s) near the time of discharge were obtained. Skin conductance was measured before, during, and after the stimulus. Non-parametric tests were used to determine between group and within phase differences. Infants were off MT at the time of SC measurement in response to an auditory stimulus. In a 2-group comparison of MT vs. non-MT infants, there was significantly higher SC responsivity to an auditory stimulus (p <0.05) in the MT group as compared with the non-MT group near discharge. The mean +SE peak morphine dose was 0.85+0.20mg/kg/day in the MT group. The mean Length of Stay (LOS) was 32 vs. 7 (p <0.05) days respectively, for the MT vs. the non-MT group. Our preliminary data suggest that in infants with severe NAS symptoms, higher sympathetic arousal in response to an auditory stimulus persists at discharge, underscoring the need for ongoing evaluation and specialized care at home.

Repeated cortisol administration does not reduce intrusive memories - A double blind placebo controlled experimental study.

PTSD is a severe mental disorder, which may develop after exposure to traumatic events and is characterized by intrusive memories. Intrusions are sudden brief sensory memories of the traumatic event, that cause immense distress and impairment in every day functioning. Thus, the reduction of intrusive memories is one of the main aims of PTSD therapy. Recently, the glucocorticoid cortisol has been proposed as a pharmacological option to reduce intrusive memories, because cortisol is known to have memory retrieval inhibiting effects. However, the research on the effects of cortisol administration on intrusive memories is not conclusive. The aim of the present study was to examine if repeated cortisol administration inhibits intrusions and recognition memory in an experimental study using the trauma film paradigm. In a randomized double-blind placebo controlled design participants were exposed to a traumatic film (known to induce intrusions in healthy participants) and received either a low dose of cortisol (20mg) or placebo on the three days following "trauma exposure". Intrusive memories were assessed with an Electronic Diary and an Intrusion Triggering Task. Furthermore, we assessed explicit memory for the traumatic film clip with a recognition test. Contrary to our predictions, the cortisol group did not report fewer intrusions than the placebo group nor did it show diminished performance on the recognition test. Our results show that sole cortisol administration after a traumatic experience cannot reduce intrusive re-experiencing.

The not-so-bitter pill: Effects of combined oral contraceptives on peripheral physiological indicators of emotional reactivity.

Combined oral contraceptives (COC) are used by millions of women worldwide. Although findings are not entirely consistent, COC have been found to impact on brain function and, thus, to modulate affective processes. Here, we investigated electro-physiological responses to emotional stimuli in free cycling women in both the early follicular and late luteal phase as well as in COC users. Skin conductance response (SCR), startle reflex, corrugator and zygomaticus activity were assessed. COC users showed reduced overall startle magnitude and SCR amplitude, but heightened overall zygomaticus activity, although effect sizes were small. Thus, COC users displayed reduced physiological reactions indicating negative affect and enhanced physiological responses signifying positive affect. In free cycling women, endogenous 17ß-estradiol levels were associated with fear potentiated startle in both cycle phases as well as with SCR and zygomaticus activity during the follicular phase. Testosterone was associated with corrugator and zygomaticus activity during the luteal phase, while progesterone levels correlated with corrugator activity in the follicular phase. To the contrary, in COC users, endogenous hormones were not associated with electro-physiological measures. The results further underscore the importance of considering COC use in psychophysiological studies on emotional processing.

Oxytocin differentially modulates pavlovian cue and context fear acquisition.

Fear acquisition and extinction have been demonstrated as core mechanisms for the development and maintenance of mental disorders, with different contributions of processing cues vs contexts. The hypothalamic peptide oxytocin (OXT) may have a prominent role in this context, as it has been shown to affect fear learning. However, investigations have focused on cue conditioning, and fear extinction. Its differential role for cue and context fear acquisition is still not known. In a randomized, double-blind, placebo (PLC)-controlled design, we administered an intranasal dose of OXT or PLC before the acquisition of cue and context fear conditioning in healthy individuals (n = 52), and assessed brain responses, skin conductance responses and self-reports (valence/arousal/contingency). OXT compared with PLC significantly induced decreased responses in the nucleus accumbens during early cue and context acquisition, and decreased responses of the anterior cingulate cortex and insula during early as well as increased hippocampal response during late context, but not cue acquisition. The OXT group additionally showed significantly higher arousal in late cue and context acquisition. OXT modulates various aspects of cue and context conditioning, which is relevant from a mechanism-based perspective and might have implications for the treatment of fear and anxiety.