Pavlovian Research Articles

A Systematic Review and Meta-Analysis of Conditioned Pain Modulation in Children and Young People with Chronic Pain

Background/Objectives: Conditioned pain modulation (CPM) is a psychophysical experimental measure of the endogenous pain inhibitory pathway in humans, wherein one pain stimulus (the conditioning stimulus) is used to inhibit an individual’s perception of a second painful (test) stimulus. Research provides evidence of impaired endogenous inhibitory pain responses in adults with chronic pain. CPM is now increasingly applied in paediatric research and clinical practice. The primary aim of this systematic review was to examine the efficacy of CPM in paediatric chronic pain populations (6–24-year-olds) compared to pain-free children and young people (CYP). Methods: The protocol was registered on PROSPERO (CRD42020221927). A systematic search of seven databases was conducted from database inception to 20th June 2024. Study inclusion criteria were as follows: (i) recruited a sample of CYP aged 6 to 24 (inclusive) with chronic pain or who were pain-free; and (ii) applied a CPM paradigm comprising both a painful test and conditioning stimuli that were sufficiently detailed to allow for replication,(iii) adhered to a study design of randomised control trial, case control or cohort study, including cross-sectional or longitudinal; (iv) available in the English language. Study exclusion criteria were: (i) The CPM paradigm used a non-painful test or conditioning stimulus only; and (ii) was only available as an abstract, letter, poster, editorial, case report, or review with or without meta-analyses. Risk of bias was assessed using the Appraisal Tool for Cross Sectional Studies (AXIS). Meta-analyses were conducted in Comprehensive Meta Analysis 3.0 using random effects models to compare the overall CPM responses in CYP with chronic pain conditions to healthy control CYP. Results: Thirty-two studies were eligible for inclusion, six of which were included in one or more meta-analysis (n = 407 chronic pain, n = 205 control). Meta-analysis revealed significantly weaker CPM responses in CYP with a variety of chronic pain conditions compared to healthy controls (standardized mean difference (SMD) = 0.352), and significantly weaker CPM responses in CYP with abdominal pain conditions compared to healthy controls (SMD = 0.685). No significant difference in CPM response was found between CYP with migraine and healthy controls (SMD = −0.201). Conclusions: Variable results were found across individual studies, and the meta-analysis of the small number of eligible studies provides tentative evidence for impaired CPM in CYP with chronic pain compared to healthy controls. Further research is clearly needed. In particular, studies should present CPM results separately for different age groups, ethnic groups, and sexes, as these variables shape clinical pain responses.

Parabrachial Calca neurons mediate second-order conditioning

Learning to associate cues, both directly and indirectly, with biologically significant events is essential for survival. Second-order conditioning (SOC) involves forming an association between a previously reinforced conditioned stimulus (CS1) and a new conditioned stimulus (CS2) without the presence of an unconditioned stimulus (US). The neural substrates mediating SOC, however, remain unclear. Parabrachial Calca neurons, which react to the noxious US, also respond to a CS after pairing with a US, suggesting that Calca neurons mediate SOC. We established an aversive SOC behavioral paradigm in mice and monitored Calca neuron activity via single-cell calcium imaging during conditioning and subsequent recall phases. These neurons were activated by both CS1 and CS2 after SOC. Chemogenetically inhibiting Calca neurons during CS1-CS2 pairing attenuated SOC. Thus, reactivation of the US pathway by a learned CS plays an important role in forming the association between the old and a new CS, promoting the formation of second-order memories.

Neurophysiological and Autonomic Dynamics of Threat Processing during Sustained Social Fear Generalization

Abstract Survival in dynamic environments requires that organisms learn to predict danger from situational cues. One key facet of threat prediction is generalization from a predictive cue to similar cues, ensuring that a cue-outcome contingency is applied beyond the original learning environment. Generalization has been observed in laboratory studies of aversive conditioning: Behavioral and physiological processes generalize responses from a stimulus paired with threat (the conditioned stimulus [CS+]) to unpaired stimuli, with response magnitudes varying with CS+ similarity. In contrast, work focusing on sensory responses in visual cortex has found a sharpening pattern, in which responses to stimuli closely resembling the CS+ are maximally suppressed, potentially reflecting lateral inhibitory interactions with the CS+ representation. Originally demonstrated with simple visual cues, changes in visuocortical tuning have also been observed in threat generalization learning across facial identities. It is unclear to what extent these visuocortical changes represent transient or sustained effects and if generalization learning requires prior conditioning to the CS+. The present study addressed these questions using EEG and pupillometry in an aversive generalization paradigm involving hundreds of trials using a gradient of facial identities. Visuocortical steady-state visual evoked potential sharpening occurred after dozens of trials of generalization learning without prior differential conditioning, but diminished as learning continued. By contrast, generalization of alpha power suppression, pupil dilation, and self-reported valence and arousal was seen throughout the experiment. Findings are consistent with threat processing models emphasizing the role of changing visucocortical and attentional dynamics when forming, curating, and shaping fear memories as observers continue learning about stimulus-outcome contingencies.

Understanding the Patient's Rigid Patterns in Psychotherapy From the Perspective of Compensation under Classical Conditioning

It is common in psychotherapy to get bogged down in treatment progress because of patients' rigid patterns, and the first step to better dealing with this problem is to understand rigid patterns better. Therefore, it is essential to start with the concept of compensation under classical conditioning to help understand the rigid pattern of patients in psychotherapy. Given that the understanding from this perspective is relatively new and largely fragmented, it is theoretically important to evaluate what is being studied and gain meaningful insights through a structural review of the literature. After reviewing the extensive literature, this study also made some feasible suggestions on how to better understand and deal with patients' rigid patterns to assist therapists in dealing with such issues, combining the approaches taken by different schools of psychotherapy. This article is believed can provide a useful basis of understanding for future psychotherapists to better deal with patients' rigid patterns in practice.

Hippocampal contextualization of social rewards in mice

Acquiring and exploiting memories of rewarding experiences is critical for survival. The spatial environment in which a rewarding stimulus is encountered regulates memory retrieval. The ventral hippocampus (vH) has been implicated in contextual memories involving rewarding stimuli such as food, social cues or drugs. Yet, the neuronal representations and circuits underlying contextual memories of socially rewarding stimuli are poorly understood. Here, using in vivo electrophysiological recordings, in vivo one-photon calcium imaging, and optogenetics during a social reward contextual conditioning paradigm in male mice, we show that vH neurons discriminate between contexts with neutral or acquired social reward value. The formation of context-discriminating vH neurons following learning was contingent upon the presence of unconditioned stimuli. Moreover, vH neurons showed distinct contextual representations during the retrieval of social reward compared to fear contextual memories. Finally, optogenetic inhibition of locus coeruleus (LC) projections in the vH selectively disrupted social reward contextual memory by impairing vH contextual representations. Collectively, our findings reveal that the vH integrates contextual and social reward information, with memory encoding of these representations supported by input from the LC.

Investigating the effect of continuous and partial reinforcement in conceptual fear generalization

Fear generalization plays a major role in the acquisition and maintenance of anxiety disorders. In fear generalization, conditioned fear responses are observed for novel stimuli sharing perceptually or conceptually similar properties with the conditioned stimulus (CS). The reinforcement rates of the unconditioned stimulus (UCS) impact fear acquisition and generalization. Fear generalization can be studied using the category-based conditioning paradigm, where individuals are conditioned to members of a category rather than a single stimulus. The current study explored the effect of UCS reinforcement (i.e., continuous and partial) on conceptual fear generalization due to category-based similarity using a visual aversive UCS. The CSs were exemplars from four categories, i.e., animals, insects, household appliances, and tools. Thirty healthy participants underwent fear acquisition with exemplars from the four stimulus categories, presented with varying levels of UCS reinforcement (100%, 62.5%, and 37.5%). Subsequently, fear generalization was tested with novel unreinforced exemplars from each category. A significant effect of reinforcement on the UCS expectancy and CS-UCS contingency ratings was observed. UCS expectancy ratings increased with increasing certainty of UCS occurrence in the generalization phase. Our results may help to understand how fear generalizes to conceptually related stimuli based on the certainty of the UCS occurrence.

Dopamine release in striatal striosome compartments in response to rewards and aversive outcomes during classical conditioning in mice

The striatum consists of two anatomically and neurochemically distinct compartments, striosomes and the matrix, which receive dopaminergic inputs from the midbrain and exhibit distinct dopamine release dynamics in acute brain slices. Striosomes comprise approximately 15 % of the striatum by volume and are distributed mosaically. Therefore, it is difficult to selectively record dopamine dynamics in striosomes using traditional neurochemical measurements in behaving animals, and it is unclear whether distinct dynamics play a role in associative learning. In this study, we used transgenic mice selectively expressing Cre in striosomal neurons, combined with a fiber photometry technique, to selectively record dopamine release in striosomes during classical conditioning. Water-restricted mice could distinguish the conditioned stimulus (CS) associated with saccharin water from the air-puff-associated CS. The air-puff-associated CS evoked phasic dopamine release only in striosomes. Furthermore, air puff presentation induced dopamine release to striosomal neurons but suppressed release to striatal neurons non-selectively recorded. These findings suggest that dopamine is released in a differential manner in striosomes and the matrix in behaving animals and that dopamine release in striosomes is preferentially induced by the air-puff-associated CS and air puff presentation. These findings support the hypothesis that striosomal neurons play a dominant role in aversive stimuli prediction.

Activation, but not inactivation, of the medial or lateral orbitofrontal cortex impaired context-specific fear encoding

In laboratories, classical fear conditioning and extinction procedures are commonly used to study the behavioral and neural mechanisms underlying fear regulation. Contextual fear conditioning involves the association of an aversive event with the environment where it occurs, which engages the hippocampus and its interactions with the amygdala. The orbitofrontal cortex (OFC), divided into the lateral OFC (lOFC) and medial OFC (mOFC) subregions, plays a crucial role in integrating contextual information from the hippocampus and modulating behavioral responses based on the anticipated outcomes of the context. Because of the extensive anatomical connections of the OFC with the fear circuit, including the hippocampus, the amygdala, and the medial prefrontal cortex, and the reasoning that proper retrieval of fear-related memory is context-dependent, we raised the question to investigate the ability of the animals to discriminate between contexts when they were trained under differential OFC activation levels during the encoding of contextual fear memory. In this study, we conducted a contextual fear conditioning procedure in rats using footshock as an unconditioned stimulus (US), followed by the test of their fear levels in contexts same (dangerous) or different (safe) from the conditioning context. We used a pharmacological approach to modulate the activation levels of the lOFC or the mOFC during conditioning to examine their roles on context-specific fear encoding. Our findings showed that the animals could accurately distinguish between the two contexts in control and OFC hypoactivation groups, but failed to do so if they were trained under OFC hyperactivation. Therefore, OFC hyperactivity disturbed the encoding of contextual information during fear acquisition.

Pavlovian cue-evoked alcohol seeking is disrupted by ventral pallidal inhibition

Cues paired with alcohol can be potent drivers of craving, alcohol-seeking, consumption, and relapse. While the ventral pallidum is implicated in appetitive and consummatory responses across several reward classes and types of behaviors, its role in behavioral responses to Pavlovian alcohol cues has not previously been established. Here, we tested the impact of optogenetic inhibition of ventral pallidum on Pavlovian-conditioned alcohol-seeking in male Long Evans rats. Rats underwent Pavlovian conditioning with an auditory cue predicting alcohol delivery to a reward port and a control cue predicting no alcohol delivery, until they consistently entered the reward port more during the alcohol cue than the control cue. We then tested the within-session effects of optogenetic inhibition during 50% of cue presentations. We found that optogenetic inhibition of ventral pallidum during the alcohol cue reduced port entry likelihood and time spent in the port, and increased port entry latency. Overall, these results suggest that normal ventral pallidum activity is necessary for Pavlovian alcohol-seeking.

Behavioral and neural correlates of diverse conditioned fear responses in male and female rats

Pavlovian fear conditioning is a widely used tool that models associative learning in rodents. For decades the field has used predominantly male rodents and focused on a sole conditioned fear response: freezing. However, recent work from our lab and others has identified darting as a female-biased conditioned response, characterized by an escape-like movement across a fear conditioning chamber. It is also accompanied by a behavioral phenotype: Darters reliably show decreased freezing compared to Non-darters and males and reach higher velocities in response to the foot shock (“shock response”). However, the relationship between shock response and conditioned darting is not known. This study investigated if this link is due to differences in general processing of aversive stimuli between Darters, Non-darters and males. Across a variety of modalities, including corticosterone measures, the acoustic startle test, and sensitivity to thermal pain, Darters were found not to be more reactive or sensitive to aversive stimuli, and, in some cases, they appear less reactive to Non-darters and males. Analyses of cFos activity in regions involved in pain and fear processing following fear conditioning identified discrete patterns of expression among Darters, Non-darters, and males exposed to low and high intensity foot shocks. The results from these studies further our understanding of the differences between Darters, Non-darters and males and highlight the importance of studying individual differences in fear conditioning as indicators of fear state.

Xanthan gum biopolymer gated low voltage-operating photo synaptic organic field-effect transistor for neuromorphic electronics

Low voltage-operating light-stimulated organic field effect transistors (OFETs) are attracting huge attention due to their potential for developing photonic neuromorphic synapse-based neural networks resembling the human brain. The OFETs based on environment friendly biocompatible materials and processability are highly desired for realizing photo synaptic elements. In this report, we demonstrate a low voltage operating xanthan gum-gated poly(2,5-bis(3-alkylthiophen-2-yl) thieno[3,2-b] thiophene) [PBTTT-C14] based OFETs, exhibiting photo synaptic behavior at −0.3V. The basic photo response parameters such as photoresponsivity, detectivity, and photocurrent to dark current ratio of the OFETs are estimated to quantify the photo synaptic behavior of the OFETs. We report the fundamental neurobiological characteristics such as excitatory post-synaptic current (EPSC), pair pulse facilitation (PPF), short-term plasticity (STP), long-term plasticity (LTP), learning-forgetting-memorizing (LFM), and conversion of STP to LTP for the xanthan gum-gated PBTTT-C14-based OFETs. Furthermore, we showcase the electronic "OR" logic operations by employing the OFETs and replicate the Pavlovian conditioning experiment to mimic the classical learning phenomenon. Using these photo synaptic OFETs, we replicate human emotion and mood-swing-dependence learning and memory behavior which is an important aspect of cognitive learning. The OFETs exhibit fairly low energy consumption ~100 pJ per optical operation to perform synaptic responses. We interpret and attribute the observed neuromorphic behavior to the charge-trapping occurring at the semiconductor-dielectric interface and bulk traps in OFETs. The presented phenomena broaden opportunities to the device communities for building an artificial complex neural network using energy-efficient bio-polymer gated photo synaptic OFETs.

Ultrasensitive Flexible Organic Synaptic Transistors Modulated by a Chemically Cross-Linked Solvent-Resistive Ion Composite.

We demonstrate a flexible organic synaptic transistor (FOST) with an ion-composite electrolyte film resistant to chemical reagents, which uses a three-dimensionally cross-linked polyimide matrix to accommodate a high-concentration ionic liquid. FOST shows versatile synaptic plasticity for classical conditioning, high-pass filtering, and the learning-forgetting process. The device achieves low-energy consumption down to 1.02 femtojoule per synaptic event with an ultrasensitive impulse to presynaptic spike down to 0.5 mV. Moreover, the electrical performance of the device is still stable after 1000 mechanical bending cycles. These results demonstrate that the device can be applied to future flexible neuromorphic electronics.

A Computational Framework for Understanding the Impact of Prior Experiences on Pain Perception and Neuropathic Pain.

Pain perception is influenced not only by sensory input from afferent neurons but also by cognitive factors such as prior expectations. It has been suggested that overly precise priors may be a key contributing factor to chronic pain states such as neuropathic pain. However, it remains an open question how overly precise priors in favor of pain might arise. Here, we first verify that a Bayesian approach can describe how statistical integration of prior expectations and sensory input results in pain phenomena such as placebo hypoalgesia, nocebo hyperalgesia, chronic pain, and spontaneous neuropathic pain. Our results indicate that the value of the prior, which is determined by the internal model parameters, may be a key contributor to these phenomena. Next, we apply a hierarchical Bayesian approach to update the parameters of the internal model based on the difference between the predicted and the perceived pain, to reflect that people integrate prior experiences in their future expectations. In contrast with simpler approaches, this hierarchical model structure is able to show for placebo hypoalgesia and nocebo hyperalgesia how these phenomena can arise from prior experiences in the form of a classical conditioning procedure. We also demonstrate the phenomenon of offset analgesia, in which a disproportionally large pain decrease is obtained following a minor reduction in noxious stimulus intensity. Finally, we turn to simulations of neuropathic pain, where our hierarchical model corroborates that persistent non-neuropathic pain is a risk factor for developing neuropathic pain following denervation, and additionally offers an interesting prediction that complete absence of informative painful experiences could be a similar risk factor. Taken together, these results provide insight to how prior experiences may contribute to pain perception, in both experimental and neuropathic pain, which in turn might be informative for improving strategies of pain prevention and relief.

Transformation of valence signaling in a mouse striatopallidal circuit

The ways in which sensory stimuli acquire motivational valence through association with other stimuli is one of the simplest forms of learning. Although we have identified many brain nuclei that play various roles in reward processing, a significant gap remains in understanding how valence encoding transforms through the layers of sensory processing. To address this gap, we carried out a comparative investigation of the mouse anteromedial olfactory tubercle (OT), and the ventral pallidum (VP) - 2 connected nuclei of the basal ganglia which have both been implicated in reward processing. First, using anterograde and retrograde tracing, we show that both D1 and D2 neurons of the anteromedial OT project primarily to the VP and minimally elsewhere. Using two-photon calcium imaging, we then investigated how the identity of the odor and reward contingency of the odor are differently encoded by neurons in either structure during a classical conditioning paradigm. We find that VP neurons robustly encode reward contingency, but not identity, in low-dimensional space. In contrast, the OT neurons primarily encode odor identity in high-dimensional space. Although D1 OT neurons showed larger responses to rewarded odors than other odors, consistent with prior findings, we interpret this as identity encoding with enhanced contrast. Finally, using a novel conditioning paradigm that decouples reward contingency and licking vigor, we show that both features are encoded by non-overlapping VP neurons. These results provide a novel framework for the striatopallidal circuit in which a high-dimensional encoding of stimulus identity is collapsed onto a low-dimensional encoding of motivational valence.

Transformation of valence signaling in a mouse striatopallidal circuit.

The ways in which sensory stimuli acquire motivational valence through association with other stimuli is one of the simplest forms of learning. Although we have identified many brain nuclei that play various roles in reward processing, a significant gap remains in understanding how valence encoding transforms through the layers of sensory processing. To address this gap, we carried out a comparative investigation of the mouse anteromedial olfactory tubercle (OT), and the ventral pallidum (VP) - 2 connected nuclei of the basal ganglia which have both been implicated in reward processing. First, using anterograde and retrograde tracing, we show that both D1 and D2 neurons of the anteromedial OT project primarily to the VP and minimally elsewhere. Using two-photon calcium imaging, we then investigated how the identity of the odor and reward contingency of the odor are differently encoded by neurons in either structure during a classical conditioning paradigm. We find that VP neurons robustly encode reward contingency, but not identity, in low-dimensional space. In contrast, the OT neurons primarily encode odor identity in high-dimensional space. Although D1 OT neurons showed larger responses to rewarded odors than other odors, consistent with prior findings, we interpret this as identity encoding with enhanced contrast. Finally, using a novel conditioning paradigm that decouples reward contingency and licking vigor, we show that both features are encoded by non-overlapping VP neurons. These results provide a novel framework for the striatopallidal circuit in which a high-dimensional encoding of stimulus identity is collapsed onto a low-dimensional encoding of motivational valence.

Penerapan Teori Behavioristik Classical Conditioning Oleh I.P Pavlov dalam Pembelajaran IPA Siswa Kelas 5 Sekolah Dasar

This research was conducted in response to a number of difficulties faced as well as the low level of interest in learning from grade 5 elementary school students in the context of science learning. This study focuses on the science learning ability of grade 5 students in elementary schools in response to the results of PISA 2018, Indonesian Education Report Card Data, and AKM Scores which show the low level of students' science literacy skills. Using the Nonequivalent Pretest Posttest Control Group design, experimental research was conducted to evaluate the impact of the application of Behavioristic Classical Conditioning Theory by I.P Pavlov in science learning. Class V students were divided into experimental and control groups with the Cluster Random Sampling Technique. The test method was used to collect science learning ability data, and the data analysis used the Polled Variance T test due to homogeneous data variance. The results showed a significant difference in science learning ability between the group that applied the Behavioristic Classical Conditioning Theory and the control group. The implications of this research provide a solid foundation for designing effective learning strategies in the future, focusing on curriculum development and learning approaches that can enhance students' understanding and interest in learning. As an effort to improve the quality of science learning in elementary schools, this research provides significant conceptual and applicative contributions.

Effects of Standard Tai Chi on Exercise Capacity and Mental Health in Exercise-Deprived Overweight/Obese Adults and Assessment of Participant Adherence.

To explore the effects of Tai Chi on body mass index (BMI), exercise capacity, and mental health of overweight/obese adults, and investigate factors influencing adherence to enhance adherence of Tai Chi as a sustainable exercise method. A randomized, controlled, exploratory clinical trial was conducted paired with a qualitative study of adherence management. A total of 20 overweight/obese participants were randomly assigned to a standard Tai Chi group (experimental) and a simplified Tai Chi group (control) for an 8-week intervention, 10 patients in each group, with a 12-month follow-up. BMI was calculated and exercise capacity including an isokinetic muscle strength and balance ability test were evaluated. Mental health was assessed using the General Well-Being Schedule (GWB), Pittsburgh Sleep Quality Index (PSQI), and Coping Self Efficacy Scale (CSES) at baseline, 4th week, and 8th week, respectively. The qualitative research included open-interviews with Tai Chi practitioners and semi-structured interviews with subjects. The intervention was conducted in Haidian Park, Beijing, China from October 6, 2022, to January 1, 2023, without dropouts. After an 8-week intervention, the participants in the experimental group exhibited a significant decrease in BMI (P<0.05). Both groups demonstrated significant improvements in exercise capacity (P<0.05). The experimental group exhibited a significant enhancement in the GWB, PSQI and CSES (P<0.05). Only GWB had significant difference in the control group (P<0.05). The experimental group surpassed the control group in GWB and CSES (P<0.05). The adherence rate was 87.5% in the experimental group and 57.9% in the control group after 8 weeks intervention. Analysis on adherence identified 15 themes, the top 3 themes mentioned were as follows: mind-body effects, online and on-site guidance, training schedule (for subjects); mind-body effects, difficulties in practicing, and understanding of Tai Chi (for practitioners). Both interventions were effective in improving exercise capacity. Tai Chi, integrating both physical and mental conditioning, reduced weight, improved exercise capacity and mental happiness, and increased adherence, providing a sustainable exercise program (ChiCTR2200063599).

High-Energy Ball Milling Enables an Ultra-Fast Wittig Olefination Under Ambient and Solvent-free Conditions.

30 Seconds to success!-The Wittig reaction, a fundamental and extensively utilized reaction in organic chemistry, enables the efficient conversion of carbonyl compounds to olefins using phosphonium salts. Traditionally, meticulous reaction setup, including the pre-formation of a reactive ylide species via deprotonation of a phosphonium salt, is crucial for achieving high-yielding reactions under classical solution-based conditions. In this report, we present an unprecedented protocol for an ultra-fast mechanically induced Wittig reaction under solvent-free and ambient conditions, often eliminating the need for tedious ylide pre-formation under strict air and moisture exclusion. A range of aldehydes and ketones were reacted with diverse phosphonium salts under high-energy ball milling conditions, frequently giving access to the respective olefins in only 30 seconds.

Coupling of Fluid and Particle-in-Cell Simulations of Ambipolar Plasma Thrusters

Ambipolar plasma thrusters are an appealing technology due to multiple system-related advantages, including propellant flexibility and the absence of electrodes or neutralizer. Understanding the plasma generation and acceleration mechanisms is key to improving the performance and capabilities of these thrusters. However, the source and plume regions inside are often simulated separately, and no self-consistent strategy exists which can couple these different simulations together. This paper introduces the MUlti-regime Plasma Equilibrium Transport Solver (MUPETS), a self-consistent coupled model integrating a fluid solver for the plasma dynamics in the source, which are collision-driven, with a kinetic Particle-In-Cell (PIC) code for the plasma dynamics in the magnetic nozzle, which involve expansion across a diverging magnetic field. The methodology begins by solving the plasma source with the classical Bohm condition at the thruster’s throat. The resulting plasma profiles (density, temperature, speed) are input into the PIC code for the magnetic nozzle. The PIC code calculates the plasma plume expansion and determines the electric field at the thruster’s throat. This electric field is then used as a boundary condition in the fluid code, where it replaces the Bohm assumption, and the fluid simulation is repeated. This iterative process continues until convergence. In comparing the MUPETS results with those for an experimental thruster, the plasma densities at the thruster’s throat differed by less than 2–5% between the fluid and PIC regions. The thrust predictions agreed with the experimental trend, and were kept well within the measurement’s uncertainty band. These results validate the effectiveness of the coupling strategy for enhancing plasma thruster simulation accuracy.

Effects of separate and combined estradiol and progesterone administration on fear extinction in healthy pre-menopausal women

Altered fear conditioning and extinction learning are discussed as key etiological features in anxiety disorders. Women have an increased risk for anxiety disorders and fear conditioning has been shown to be influenced by the menstrual cycle phase and circulating gonadal hormones. The objective of our study was to investigate the effects of separate and combined estradiol and progesterone administration on fear extinction in healthy women. We conducted a placebo-controlled, randomized study in healthy women, who completed a fear conditioning paradigm on three consecutive days: fear acquisition training on day 1, fear extinction training on day 2, and return of fear test on day 3. Skin conductance responses (SCRs) served as main outcome variable. Two hours before testing on day 2, participants received pills containing either placebo, estradiol (2 mg), progesterone (400 mg) or the combination of both. We examined 116 women (mean age 25.7 ± 6.0 years), who showed significantly stronger conditioned SCRs to the CS+ than CS- during fear acquisition training indicating successful fear learning. At the beginning of the fear extinction training, estradiol administration reduced the differentiation between the conditioned stimuli. In the return of fear test, the estradiol groups showed heightened SCR responses to the previously extinguished stimulus, i.e., impaired extinction recall. Administration of progesterone did not have any significant influence on SCRs. There were also no effects on fear potentiated startle response. In our interpretation, exogenous estradiol administration affected the extinction of the conditioned fear response which led subsequently to a stronger return of fear. From a clinical perspective our findings suggest that estradiol levels may have an influence on the success of exposure therapy and could be taken into consideration when planning exposure sessions.