CS Onset Research Articles

Capgras Syndrome Accompanying Schizophrenia: An Adolescent Case Report

In Capgras syndrome, the patient believes that the original person or objects have been replaced by identical ones (fakes). The syndrome rarely occurs in its pure form. It often accompanies psychotic illness and organic pathology. Capgras syndrome can occur in all age groups and is more common in women. In this article, the case of a 16-year-old female patient who applied to the hospital with complaints of aggression, harming her environment and wanting to have a DNA test will be presented. During her first admission examination, she was found to have Capgras delusions, and she was hospitalized and monitored in a psychiatric clinic. The patient, who was followed up with a diagnosis of early-onset psychotic disorder, was determined to be a case of CS accompanying Schizophrenia. Early-onset Schizophrenia is already a rare condition, and the onset of CS at this age is uncommon. Our case is valuable as it shows that CS, a rare condition, can also be seen in adolescence.

Circulating biomarkers of the CS4P and CLIP scores are not altered in a pig model of acute cardiogenic shock and additional short-term circulatory support

BackgroundCardiogenic shock (CS) is the leading cause of death in patients with myocardial infarction with a mortality rate greater than 50%. Recently, the CS 4 Proteins (CS4P) and CLIP scores have been developed to predict survival in CS patients. However, their impact in acute CS and additional short-term left ventricular (LV) circulatory support as prognostic markers is currently not known. Methods and resultsCS was induced in a porcine model by injecting microsphere particles into the left main coronary artery. Mechanical circulatory support was performed by additional percutaneous LV unloading using an Impella microaxial flow-pump for 30 minutes. Serum samples were collected at baseline, following the onset of CS, and additional LV unloading. Serum levels of biomarkers of the CS4P (beta-2-microglobulin, ALDOB, L-FABP, SerpinG1) and the CLIP scores (Cystatin C, Lactate, Interleukin-6, NT-proBNP) were neither different at any time point investigated nor did they correlate with cardiac output. ConclusionThe CS4P and CLIP scores do not reflect immediate whole-body dysregulation in acute CS and have not been able to predict the potential reversal following additional short-term mechanical support by LV unloading in our experimental model. The impact of both scores as prognostic markers after the immediate onset of CS and following additional short-term LV unloading to identify patients at greatest risk remains to be determined.

A goal-oriented hemodynamic approach to acute myocardial infarction complicated by cardiogenic shock-A single center experience.

Acute myocardial infarction complicated by cardiogenic shock (AMI-CS) is the most common cause of mortality following AMI, and treatment algorithms vary widely. We report the results of an analysis using time-sensitive, hemodynamic goals in the treatment of AMI-CS in a single center study. Consecutive patients with AMI-CS from November 2016 through December 2021 were included in our retrospective analysis. Clinical characteristics and outcomes were analyzed using the electronic medical records. We identified 63 total patients who were admitted to our center with AMI-CS, and we excluded patients who did not have clear timing of AMI onset or CS onset. We evaluated the rate of survival to hospital discharge based on the quantity of certain time-sensitive hemodynamic goals were met. We identified 63 patients who met criteria for AMI-CS, 39 (62%) of whom survived to hospital discharge. Odds of survival were closely related to the achievement of four time-dependent goals: cardiac power output (CPO) >0.6 Watts (W), pulmonary artery pulsatility index (PAPi) >1, lactate <4 mmol/L, and <2 vasopressors required. Of the 63 total patients, 36 (57%) received intra-aortic balloon pump (IABP) and 18 (29%) received an Impella CP (Abiomed) as an initial mechanical circulatory support strategy. Six patients were escalated from IABP to Impella CP for additional hemodynamic support. Nine patients were treated with vasopressors/inotropes alone. Regarding the 39 patients who survived to hospital discharge, 75% of patients met 3 or 4 goals at 24 h, whereas only 16% of deceased patients met 3 or 4 goals at 24 h. Of the 24 patients who did not survive to hospital discharge, 18 (75%) met either 0-1 goal at 24 h. There was no effect of the initial treatment strategy on achieving 3-4 goals at 24 h. Our study evaluated the association of meeting 4 time-sensitive goals (CPO >0.6 W, PAPi >1, <2 vasopressors, and lactate <4 mmol/L) at 24 h after treatment for AMI-CS with in-hospital mortality. Our data show, in line with previous data, that the higher number of goals met at 24 h was associated with improved in-hospital mortality regardless of treatment strategy.

Pupil dilation tracks divergent learning processes in aware versus unaware Pavlovian conditioning.

Evidence regarding unaware differential fear conditioning in humans is mixed and even less is known about the effects of contingency awareness on appetitive conditioning. Phasic pupil dilation responses (PDR) might be more sensitive for capturing implicit learning than other measures, such as skin conductance responses (SCR). Here, we report data from two delay conditioning experiments utilizing PDR (alongside SCR and subjective assessments) to investigate the role of contingency awareness in aversive and appetitive conditioning. In both experiments, valence of unconditioned stimuli (UCS) was varied within participants by administering aversive (mild electric shocks) and appetitive UCSs (monetary rewards). Preceding visual stimuli (CSs) predicted either the reward, the shock (65% reinforcement), or neither UCS. In Exp. 1, participants were fully instructed about CS-UCS contingencies, whereas in Exp. 2, no such information was given. PDR and SCR demonstrated successful differential conditioning in Exp. 1 and in (learned) aware participants in Exp. 2. In non-instructed participants who remained fully unaware of contingencies (Exp. 2), differential modulation of early PDR (immediately after CS onset) by appetitive cues emerged. Associations with model-derived learning parameters further suggest that early PDR in unaware participants mainly reflect implicit learning of expected outcome value, whereas early PDR in aware (instructed/learned-aware) participants presumably index attentional processes (related to uncertainty/prediction error processing). Similar, but less clear results emerged for later PDR (preceding UCS onset). Our data argue in favor of a dual-process account of associative learning, suggesting that value-related processing can take place irrespective of mechanisms involved in conscious memory formation.

Gap in the conditioned stimulus: Differential impacts on temporal expectancy in appetitive and aversive conditions in rats

We analyzed, through a Pavlovian conditioning procedure in rats, the temporal pattern of behavior in appetitive and aversive conditions within subjects, and the difference in inferred temporal working memory functioning with the Gap paradigm. For both conditions, we paired a 60-s conditioned stimulus (CS: tone1 or tone2) with an unconditioned stimulus (US: shock or chocolate pellet) delivered 20s after CS onset. The analyses of mean response rate and individual-trial data were performed during Probe trials, consisting of CS alone, and trials in which gaps of different position or duration were inserted, to assess the effect of the temporal manipulation on behavior. The results showed: (1) An anticipatory peak time in the aversive condition but better accuracy in the appetitive condition, (2) constancy in the Weber fraction suggesting that the difference in peak time was under clock control, (3) a graded effect of gap parameters only in the aversive condition and (4) different gap effects between conditions when a gap was inserted early in the CS. These results highlight behavioral differences between aversive and appetitive conditions and suggest that the temporal working memory mechanism was not engaged in the same manner in each condition.

MiRNA-200b-A Potential Biomarker Identified in a Porcine Model of Cardiogenic Shock and Mechanical Unloading.

BackgroundCardiogenic shock (CS) alters whole body metabolism and circulating biomarkers serve as prognostic markers in CS patients. Percutaneous ventricular assist devices (pVADs) unload the left ventricle by actively ejecting blood into the aorta. The goal of the present study was to identify alterations in circulating metabolites and transcripts in a large animal model that might serve as potential prognostic biomarkers in acute CS and additional left ventricular unloading by Impella ® pVAD support.MethodsCS was induced in a preclinical large animal model by injecting microspheres into the left coronary artery system in six pigs. After the induction of CS, mechanical pVAD support was implemented for 30 min total. Serum samples were collected under basal conditions, after the onset of CS, and following additional pVAD unloading. Circulating metabolites were determined by metabolomic analysis, circulating RNA entities by RNA sequencing.ResultsCS and additional pVAD support alter the abundance of circulating metabolites involved in Aminoacyl-tRNA biosynthesis and amino acid metabolism. RNA sequencing revealed decreased abundance of the hypoxia sensitive miRNA-200b following the induction of CS, which was reversed following pVAD support.ConclusionThe hypoxamir miRNA-200b is a potential circulating marker that is repressed in CS and is restored following pVAD support. The early transcriptional response with increased miRNA-200b expression following only 30 min of pVAD support suggests that mechanical unloading alters whole body metabolism. Future studies are required to delineate the impact of serum miRNA-200b levels as a prognostic marker in patients with acute CS and pVAD unloading.

A prefrontal-bed nucleus of the stria terminalis circuit limits fear to uncertain threat.

In many cases of trauma, the same environmental stimuli that become associated with aversive events are experienced on other occasions without adverse consequence. We examined neural circuits underlying partially reinforced fear (PRF), whereby mice received tone-shock pairings on half of conditioning trials. Tone-elicited freezing was lower after PRF conditioning than fully reinforced fear (FRF) conditioning, despite an equivalent number of tone-shock pairings. PRF preferentially activated medial prefrontal cortex (mPFC) and bed nucleus of the stria terminalis (BNST). Chemogenetic inhibition of BNST-projecting mPFC neurons increased PRF, not FRF, freezing. Multiplexing chemogenetics with in vivo neuronal recordings showed elevated infralimbic cortex (IL) neuronal activity during CS onset and freezing cessation; these neural correlates were abolished by chemogenetic mPFC→BNST inhibition. These data suggest that mPFC→BNST neurons limit fear to threats with a history of partial association with an aversive stimulus, with potential implications for understanding the neural basis of trauma-related disorders.

Hippocampal and lateral entorhinal cortex physiological activity during trace conditioning under urethane anesthesia.

Significant evidence shows that the acquisition of delay conditioning can occur in out-of-awareness states, such as under anesthesia. However, it is unclear to what extent and what type of conditioning animals may achieve during nonawake states. Trace conditioning is an appealing protocol to study under anesthesia, given the long empty gap separating the conditioned and unconditioned stimuli, which must be bridged for acquisition to happen. Here, we show evidence that rats develop physiological responses during the trace conditioning paradigm under anesthesia. We recorded the activity of the hippocampus (HPC) and lateral entorhinal cortex (LEC) in urethane-anesthetized rats, along with an electromyogram and an electrocardiogram. The protocol consisted of randomly presenting two distinct sound stimuli (CS- and CS+), where only one stimulus (CS+) was assigned to be trace-paired with a footshock. A trial-average analysis revealed that animals developed significant climbing heart rate activity initiating at the CS onset and persisting during the trace period. Such climbing arose for both CS- and CS+ with similar slopes but different intercepts, suggesting CS+ heart rates were typically above CS-. The power and coherence of HPC and LEC high-frequency bands (>100 Hz) significantly increased during CS presentation and trace, similarly to CS- and CS+ and insensitive to either activated or deactivated states. To the best of our knowledge, this is the first attempt to perform a trace conditioning protocol under anesthesia. Confirmation of this procedure acquisition can allow a new preparation for the exploration of brain mechanisms that bind time-discontinuous events.NEW & NOTEWORTHY Some forms of learning, such as some types of conditioning, can occur in anesthetized states. However, the extent to which memories can be formed in these states is still an open question. Here, we investigated the trace conditioning under urethane anesthesia and found heart rate, hippocampus, and lateral entorhinal cortex physiological changes to stimuli presentation. This new preparation may allow for exploration of memory acquisition of time-discontinuous events in the nonawake brain.

P1723Predictors of in-hospital mortality in STEMI patients complicated by cardiogenic shock treated with primary percutaneous coronary intervention

Abstract Introduction Cardiogenic shock (CS) is an uncommon complex syndrome in patients (pts) with acute myocardial infarction (AMI). However, it remains the most serious complication and the most common cause of in-hospital mortality, with mortality rates ranging from 40% to 60%. The majority of pts are thought to develop CS after admission (late CS), but the incidence in a contemporary STEMI cohort admitted for percutaneous coronary intervention (PCI) remains unknown. Objective The aim of the present study was to evaluate pts with STEMI and cardiogenic shock undergoing pPCI, in order to establish the timing of CS onset, mortality rates and predictors of in-hospital mortality. Methods The records of 1679 STEMI pts admitted, consecutively, in our coronary care unit during six years were analysed retrospectively. Of this pts, 137 (8%) developed CS based on clinical criteria. Univariate and multivariate logistic regression analyses were used to identify independent predictors of in-hospital mortality. Primary endpoint was the occurrence of death at 30 days and 1 year; follow-up was completed in 100% of patients. Statistical analysis was performed using SPSS 20.0. Results The sample was formed by 90 (65.7%) men and 47 (34.3%) women, with mean age of 67±15 years. The incidence of CS was 8%. The majority of this pts (48%) were transferred from a non-PCI centre, 27% were rescued by an emergency medical system and 26% were admitted directly at a PCI centre. Around of 39% of pts had to be resuscitated before coronary intervention. Regarding the timing of CS onset, 66% of pts had CS on admission and 34% developed late CS. The left anterior descending artery was the most affected artery (47%), and 55% of the patients had multivessel disease. All-cause in-hospital and 1 year mortality was 45% and 53%, respectively. A multivariate analysis identified age &gt;75 (HR 1.1, p=0.002), eGFR &lt;60 ml/min/1.73 m2 (HR 2.2, p=0.02), left ventricular dysfunction (LVEF&lt;40%) (HR 2.1, p=0.027), resuscitation before PCI (HR 1.2, p=0.045), and Intra-Aortic Balloon Pump (IABP) implantation after PCI (HR 4.4, p=0.026) as independent predictors of in-hospital mortality. Conclusion Despite the therapeutic advances and early revascularization have substantially improved the survival of pts with STEMI and CS, the in-hospital mortality is still significant. This study identified age, acute renal failure, left ventricular dysfunction, resuscitation before PCI, and IABP implantation after PCI as independent predictors of in-hospital mortality in patients with cardiogenic shock due to AMI. Consequently, only the timing of IABP insertion was the only modifiable factor predicting in-hospital mortality in our study, and its implantation before PCI can be considered to improve the outcome of these patients. These results should motivate the search for potentially modifiable factors that can lead to better results in the prognosis of these patients.

Paroxysmal and unusual symptoms as first clinical manifestation of multiple sclerosis do not indicate benign prognosis-The PaSiMS II study.

BackgroundParoxysmal (PS) and unusual symptoms (US) account for approximately 1.6% of initial manifestations of multiple sclerosis (MS) and have comparable conversion rates to clinically definite MS (CDMS) as classical bout onset symptoms (CS). However, long-term prognosis and clinical outcome of patients experiencing PS or US as first clinical manifestation are unclear.MethodsClinical, MRI and cerebrospinal fluid data were obtained retrospectively and patients presenting with PS or US were compared to patients with CS presentation.ResultsIn a cohort of 532 relapsing onset MS patients followed for a mean period of 11.4 years (SD 3.6), 10 (1.9%) patients initially presented with PS/US. PS/US patients received disease modifying treatment (DMT) in a significantly smaller proportion immediately after the first clinical symptom (30% vs. 61.7%; p = 0.021) and during the observation period (60% vs. 83.5%; p = 0.033). In multivariate models correcting for sex, age at initial symptoms, complete remission of initial symptoms, total number of T2 and contrast-enhancing lesions, presence of oligoclonal bands and DMT exposure, PS/US were not associated with lower annualized relapse rate or lower EDSS over time.ConclusionIn addition to a similar conversion rate to CDMS, patients presenting with PS/US at disease onset display very similar relapse and disability rates as patients with CS onset. Consequently, initial presentation with PS/US does not indicate benign or atypical MS, but requires DMT initiation based on the same criteria as in CS patients.

Sensory system development influences the ontogeny of hippocampal associative coding and trace eyeblink conditioning

Until recently, it was believed that hippocampal development was the primary rate-limiting factor in the developmental emergence of hippocampal forms of learning, such as trace eyeblink conditioning (EBC). Indeed, hippocampal neuronal activity shows an age-related increase in both complexity and task responsiveness during trace EBC. However, recent work from our laboratory suggests that sensory system development may also play a role. Training with the earlier-developing somatosensory system results in an earlier emergence of trace EBC in rats, suggesting that the development of sensory input to the hippocampus may influence the development of trace EBC. The goal of the current study was to examine the activity of hippocampal CA1 pyramidal cells during acquisition of trace EBC with an early-developing somatosensory CS. Rat pups were trained with a vibration CS on postnatal days (P) 17-19, P21-23, and P24-26 while CA1 pyramidal cell activity was recorded. Results indicated that CA1 neurons show an age-related increase in responsiveness to trial events. Although the magnitude of neuronal responding showed age-related increases in activity, all three age groups demonstrated learning-related increases in firing rate magnitude and peaks in firing rate were evident both at CS onset and offset. These findings suggest that the ontogeny of trace eyeblink conditioning is related to both hippocampal and sensory system development.

2005–2015: Ten years clinical experience in treating DMD patients by corticosteroids in Lyon

Since 2005, in France, corticosteroid therapy is now widely used in Duchenne muscular dystrophy (DMD). This treatment has changed our practice of pediatric rehabilitation teams. We describe here our 10-year clinical experience in treating DMD patients by CS according to international guidelines i.e. prednisone 0.75 mg/kg/day started from the plateau of motor function. We conducted a prospective study. Information was given on the expected effects and side effects. A diet was prescribed. At baseline, a cardiac ultrasound, an ophthalmologic examination, a bone density test, a physical and biological examination to ensure the absence of against indication, check the anti-varicella immunization. The motor function measure were performed each 6 months with a medical examination and blood sample to verify the tolerance and adapt the treatment function to weight and side effects. During this 10-year period, CS was proposed to 51 patients and 48 patients were finally treated up to 10.5 years. The age of onset of CS varies from 6 years to 20 years between 2005 and 2010, from 5 to 8 years after 2010. Premature stops were observed for 14 patients: 9 in the first 2 years, 5 after 2 years for side effects or inefficacy. No acute adrenal insufficiency was observed. During the first 2 years of treatment, MFM D1 score (standing position and transfers) remained stable. Then a slow decrease was observed after 2years to be null at M72. MFM D3 score (distal motor function) is more preserved than D2 (axial and proximal motor function) and remained stable during the follow up for the great majority of patients. Eleven patients started corticosteroids after losing the ability to walk (mean age 9.1 ± 1.6 years), 7/11 had spinal fusion. Thirty-seven ambulant patients started, in this group, the mean age of losing ambulation was 11.3 ± 2.2 years and no patient had spinal surgery. Increased appetite, irritability, cushingoid facies are common but well tolerated by children in view of efficacy. Dose adjustments were discussed case by case if accelerated weight gain, sluggish growth in stature and behavioral disorders.

Baseline theta activities in medial prefrontal cortex and deep cerebellar nuclei are associated with the extinction of trace conditioned eyeblink responses in guinea pigs

It has been shown that both the medial prefrontal cortex (mPFC) and the cerebellum are involved in the extinction of trace conditioned eyeblink responses (CR). However, the neural mechanisms underlying the extinction are still relatively unclear. Theta oscillation in either the mPFC or the cerebellum has been revealed to correlate with the performance of trace CRs during the asymptotic acquisition. Therefore, we sought to further evaluate the impacts of pre-conditioned stimulus (CS) spontaneous theta (5.0–10.0Hz) oscillations in the mPFC and the deep cerebellar nuclei (DCN) on the extinction of trace CRs. Albino guinea pigs were given acquisition training for ten daily sessions followed by seven daily sessions of extinction. Local field potential (LFP) signals in the mPFC and the DCN were recorded when the animals received the CS-alone extinction training. It was found that higher mPFC relative theta ratios [theta/(delta+beta)] during the baseline period (850-ms prior to the CS onset) were predictive of fewer CR incidences rather than more adaptive CR performance (i.e., higher CR magnitude and later CR peak/onset latencies). Likewise, the pre-CS DCN theta activity was associated with the faster CR extinction. Furthermore, it was revealed that the power of pre-CS theta activities in the mPFC and the DCN were correlated until the extinction training day 2. Collectively, these results suggest that the mPFC and the DCN may interact with each other, and the brain oscillation state in which baseline theta activities in both areas are present contributes to the subsequent extinction of trace CRs.

Neonatal ethanol exposure results in dose-dependent impairments in the acquisition and timing of the conditioned eyeblink response and altered cerebellar interpositus nucleus and hippocampal CA1 unit activity in adult rats

Exposure to ethanol in neonatal rats results in reduced neuronal numbers in the cerebellar cortex and deep nuclei of juvenile and adult animals. This reduction in cell numbers is correlated with impaired delay eyeblink conditioning (EBC), a simple motor learning task in which a neutral conditioned stimulus (CS; tone) is repeatedly paired with a co-terminating unconditioned stimulus (US; periorbital shock). Across training, cell populations in the interpositus (IP) nucleus model the temporal form of the eyeblink-conditioned response (CR). The hippocampus, though not required for delay EBC, also shows learning-dependent increases in CA1 and CA3 unit activity. In the present study, rat pups were exposed to 0, 3, 4, or 5 mg/kg/day of ethanol during postnatal days (PD) 4–9. As adults, CR acquisition and timing were assessed during 6 training sessions of delay EBC with a short (280 ms) interstimulus interval (ISI; time from CS onset to US onset) followed by another 6 sessions with a long (880 ms) ISI. Neuronal activity was recorded in the IP and area CA1 during all 12 sessions. The high-dose rats learned the most slowly and, with the moderate-dose rats, produced the longest CR peak latencies over training to the short ISI. The low dose of alcohol impaired CR performance to the long ISI only. The 3E (3 mg/kg/day of ethanol) and 5E (5 mg/kg/day of ethanol) rats also showed slower-than-normal increases in learning-dependent excitatory unit activity in the IP and CA1. The 4E (4 mg/kg/day of ethanol) rats showed a higher rate of CR production to the long ISI and enhanced IP and CA1 activation when compared to the 3E and 5E rats. The results indicate that binge-like ethanol exposure in neonatal rats induces long-lasting, dose-dependent deficits in CR acquisition and timing and diminishes conditioning-related neuronal excitation in both the cerebellum and hippocampus.

Rapid, accurate time estimation in zebrafish (Danio rerio)

Zebrafish were tested in an appetitive Pavlovian delayed conditioning task. After an intertrial interval of k*T s (k=11.25; T=8, 16 or 32s), a small, translucent vertical pole was illuminated (CS) for Ts. Food was presented at T/2s. Pole-biting response latencies from CS onset were a linear function of the food delay T/2, with slope approximating unity (proportional timing), and standard deviation proportional to latency (scalar timing). Response latencies tracked changes in food delays even when they changed every other day. These findings are significant because the zebrafish genome has recently been sequenced, opening the door to studies in the genetics of interval timing.

Why trace and delay conditioning are sometimes (but not always) hippocampal dependent: A computational model

A recurrent-network model provides a unified account of the hippocampal region in mediating the representation of temporal information in classical eyeblink conditioning. Much empirical research is consistent with a general conclusion that delay conditioning (in which the conditioned stimulus CS and unconditioned stimulus US overlap and co-terminate) is independent of the hippocampal system, while trace conditioning (in which the CS terminates before US onset) depends on the hippocampus. However, recent studies show that, under some circumstances, delay conditioning can be hippocampal-dependent and trace conditioning can be spared following hippocampal lesion. Here, we present an extension of our prior trial-level models of hippocampal function and stimulus representation that can explain these findings within a unified framework. Specifically, the current model includes adaptive recurrent collateral connections that aid in the representation of intra-trial temporal information. With this model, as in our prior models, we argue that the hippocampus is not specialized for conditioned response timing, but rather is a general-purpose system that learns to predict the next state of all stimuli given the current state of variables encoded by activity in recurrent collaterals. As such, the model correctly predicts that hippocampal involvement in classical conditioning should be critical not only when there is an intervening trace interval, but also when there is a long delay between CS onset and US onset. Our model simulates empirical data from many variants of classical conditioning, including delay and trace paradigms in which the length of the CS, the inter-stimulus interval, or the trace interval is varied. Finally, we discuss model limitations, future directions, and several novel empirical predictions of this temporal processing model of hippocampal function and learning.

A Gateway between Recent and Remote Memory

A Gateway between Recent and Remote Memory

Conditioned stimulus informativeness governs conditioned stimulus−unconditioned stimulus associability.

In a conditioning protocol, the onset of the conditioned stimulus ([CS]) provides information about when to expect reinforcement (unconditioned stimulus [US]). There are two sources of information from the CS in a delay conditioning paradigm in which the CS-US interval is fixed. The first depends on the informativeness, the degree to which CS onset reduces the average expected time to onset of the next US. The second depends only on how precisely a subject can represent a fixed-duration interval (the temporal Weber fraction). In three experiments with mice, we tested the differential impact of these two sources of information on rate of acquisition of conditioned responding (CS-US associability). In Experiment 1, we showed that associability (the inverse of trials to acquisition) increased in proportion to informativeness. In Experiment 2, we showed that fixing the duration of the US-US interval or the CS-US interval or both had no effect on associability. In Experiment 3, we equated the increase in information produced by varying the C/T ratio with the increase produced by fixing the duration of the CS-US interval. Associability increased with increased informativeness, but, as in Experiment 2, fixing the CS-US duration had no effect on associability. These results are consistent with the view that CS-US associability depends on the increased rate of reward signaled by CS onset. The results also provide further evidence that conditioned responding is temporally controlled when it emerges.

Interoceptive Fear Conditioning and Panic Disorder: The Role of Conditioned Stimulus–Unconditioned Stimulus Predictability

Interoceptive fear conditioning is at the core of contemporary behavioral accounts of panic disorder. Yet, to date only one study has attempted to evaluate interoceptive fear conditioning in humans (see Acheson, Forsyth, Prenoveau, & Bouton, 2007). That study used brief (physiologically inert) and longer-duration (panicogenic) inhalations of 20% CO2-enriched air as an interoceptive conditioned (CS) and unconditioned (US) stimulus and evaluated fear learning in three conditions: CS only, CS–US paired, and CS–US unpaired. Results showed fear conditioning in the paired condition, and fearful responding and resistance to extinction in an unpaired condition. The authors speculated that such effects may be due to difficulty discriminating between the CS and the US. The aims of the present study are to (a) replicate and expand this line of work using an improved methodology, and (b) clarify the role of CS–US discrimination difficulties in either potentiating or depotentiating fear learning. Healthy participants (N=104) were randomly assigned to one of four conditions: (a) CS only, (b) contingent CS–US pairings, (c) unpaired CS and US presentations, or (d) an unpaired “discrimination” contingency, which included an exteroceptive discrimination cue concurrently with CS onset. Electrodermal and self-report ratings served as indices of conditioned responding. Consistent with expectation, the paired contingency and unpaired contingencies yielded elevated fearful responding to the CS alone. Moreover, adding a discrimination cue to the unpaired contingency effectively attenuated fearful responding. Overall, findings are consistent with modern learning theory accounts of panic and highlight the role of interoceptive conditioning and unpredictability in the etiology of panic disorder.

Fear-Conditioning Mechanisms Associated with Trait Vulnerability to Anxiety in Humans

SummaryInvestigations of fear conditioning in rodents and humans have illuminated the neural mechanisms underlying cued and contextual fear. A critical question is how personality dimensions such as trait anxiety act through these mechanisms to confer vulnerability to anxiety disorders, and whether humans' ability to overcome acquired fears depends on regulatory skills not characterized in animal models. In a neuroimaging study of fear conditioning in humans, we found evidence for two independent dimensions of neurocognitive function associated with trait vulnerability to anxiety. The first entailed increased amygdala responsivity to phasic fear cues. The second involved impoverished ventral prefrontal cortical (vPFC) recruitment to downregulate both cued and contextual fear prior to omission (extinction) of the aversive unconditioned stimulus. These two dimensions may contribute to symptomatology differences across anxiety disorders; the amygdala mechanism affecting the development of phobic fear and the frontal mechanism influencing the maintenance of both specific fears and generalized anxiety.