ß-Adrenergic Receptors Regulate the Acquisition and Consolidation Phases of Aversive Memory Formation Through Distinct, Temporally Regulated Signaling Pathways.

Memory formation requires the temporal coordination of molecular events and cellular processes following a learned event. During Pavlovian threat (fear) conditioning (PTC), sensory and neuromodulatory inputs converge on post-synaptic neurons within the lateral nucleus of the amygdala (LA). By activating an intracellular cascade of signaling molecules, these G-protein-coupled neuromodulatory receptors are capable of recruiting a diverse profile of plasticity-related proteins. Here we report that norepinephrine, through its actions on ß-adrenergic receptors (ßARs), modulates aversive memory formation following PTC through two molecularly and temporally distinct signaling mechanisms. Specifically, using behavioral pharmacology and biochemistry in adult rats, we determined that ßAR activity during, but not after PTC training initiates the activation of two plasticity-related targets: AMPA receptors (AMPARs) for memory acquisition and short-term memory and extracellular regulated kinase (ERK) for consolidating the learned association into a long-term memory. These findings reveal that ßAR activity during, but not following PTC sets in motion cascading molecular events for the acquisition (AMPARs) and subsequent consolidation (ERK) of learned associations.

The selectivity of aversive memory reconsolidation and extinction processes depends on the initial encoding of the Pavlovian association.

In reconsolidation studies, memories are typically retrieved by an exposure to a single conditioned stimulus (CS). We have previously demonstrated that reconsolidation processes are CS-selective, suggesting that memories retrieved by the CS exposure are discrete and reconsolidate separately. Here, using a compound stimulus in which two distinct CSs are concomitantly paired with the same aversive unconditioned stimulus (US), we show in rats that reexposure to one of the components of the compound CS triggers extinction or reconsolidation of the other component. This suggests that the original training conditions play a critical role in memory retrieval and reconsolidation.

Basal variability in CREB phosphorylation predicts trait-like differences in amygdala-dependent memory.

Much of what is known about the neurobiology of learning and memory comes from studies of the average behavior. In contrast, intersubject differences that emerge within groups are difficult to study systematically and are often excluded from scientific discussion. Nevertheless, population-wide variability is a virtually universal feature of both complex traits, such as intelligence, and hardwired responses, such as defensive behaviors. Here, we use outbred rats to investigate if cAMP response element-binding protein (CREB), a transcription factor that has long been known in experimental settings to be crucial for associative plasticity, participates in natural memory phenotypes. Using a combination of behavioral, biochemical, and viral techniques, we show that a subset of rats with trait-like deficits in aversive memory have basally reduced CREB activity in the lateral amygdala but can be induced to perform at average levels by directly or indirectly enhancing pretraining CREB phosphorylation. These data suggest that endogenous CREB activity in the amygdala may set a critical threshold for plasticity during memory formation.

Heterogeneity in threat extinction learning: substantive and methodological considerations for identifying individual difference in response to stress.

Pavlovian threat (fear) conditioning (PTC) is an experimental paradigm that couples innate aversive stimuli with neutral cues to elicit learned defensive behavior in response to the neutral cue. PTC is commonly used as a translational model to study neurobiological and behavioral aspects of fear and anxiety disorders including Posttraumatic Stress Disorder (PTSD). Though PTSD is a complex multi-faceted construct that cannot be fully captured in animals PTC is a conceptually valid model for studying the development and maintenance of learned threat responses. Thus, it can inform the understanding of PTSD symptomatology. However, there are significant individual differences in posttraumatic stress that are not as of yet accounted for in studies of PTC. Individuals exposed to danger have been shown to follow distinct patterns: some adapt rapidly and completely (resilience) others adapt slowly (recovery) and others failure to adapt (chronic stress response). Identifying similar behavioral outcomes in PTC increases the translatability of this model. In this report we present a flexible methodology for identifying individual differences in PTC by modeling latent subpopulations or classes characterized by defensive behavior during training. We provide evidence from a reanalysis of previously examined PTC learning and extinction data in rats to demonstrate the effectiveness of this methodology in identifying outcomes analogous to those observed in humans exposed to threat. By utilizing Latent Class Growth Analysis (LCGA) to test for heterogeneity in freezing behavior during threat conditioning and extinction learning in adult male outbred rats (n = 58) three outcomes were identified: rapid extinction (57.3%), slow extinction (32.3%), and failure to extinguish (10.3%) indicating that heterogeneity analogous to that in naturalistic human studies is present in experimental animal studies strengthening their translatability in understanding stress responses in humans.

Patterns of coronary arterial lesion calcification by a novel, cross-sectional CT angiographic assessment.

To investigate the patterns and diagnostic implications of coronary arterial lesion calcification by CT angiography (CTA) using a novel, cross-sectional grading method, we studied 371 patients enrolled in the CorE-64 study who underwent CTA and invasive angiography for detecting coronary artery stenoses by quantitative coronary angiography (QCA). The number of quadrants involving calcium on a cross-sectional view for ≥ 30 and ≥ 50 % lesions in 4,511 arterial segments was assessed by CTA according to: noncalcified, mild (one-quadrant), moderate (two-quadrant), severe (three-quadrant) and very severe (four-quadrant calcium). Area under the receiver operating characteristic curve (AUC) were used to evaluate CTA diagnostic accuracy and agreement versus. QCA for plaque types. Only 4 % of ≥ 50 % stenoses by QCA were very severely calcified while 43 % were noncalcified. AUC for CTA to detect ≥ 50 % stenoses by QCA for non-calcified, mildly, moderately, severely, and very severely calcified plaques were 0.90, 0.88, 0.83, 0.76 and 0.89, respectively (P < 0.05). In 198 lesions with severe calcification, the presence or absence of a visible residual lumen by CTA was associated with ≥ 50 % stenosis by QCA in 20.3 and 76.9 %, respectively. Kappa was 0.93 for interobserver variability in evaluating plaque calcification. We conclude that calcification of individual coronary artery lesions can be reliably graded using CTA. Most ≥ 50 % coronary artery stenoses are not or only mildly calcified. If no residual lumen is seen on CTA, calcified lesions are predictive of ≥ 50 % stenoses and vice versa. CTA diagnostic accuracy for detecting ≥ 50 % stenoses is reduced in lesions with more than mild calcification due to lower specificity.

Contrasting effects of pretraining, posttraining, and pretesting infusions of corticotropin-releasing factor into the lateral amygdala: attenuation of fear memory formation but facilitation of its expression.

BACKGROUND: The lateral nucleus of the amygdala (LA) is a crucial part of the neural circuitry underlying the formation and storage of memories established through fear conditioning. To investigate corticotropin-releasing factor (CRF) contributions to fear memory in LA, the present experiments tested the effects of intra-LA infusions on the formation and expression of memory after Pavlovian fear conditioning. METHODS: In experiment 1, CRF was infused bilaterally into LA of rats 1 hour before fear conditioning training. Two days later, rats were tested for conditioned stimulus (CS)-elicited freezing behavior in a distinct context. In experiment 2, rats were infused with CRF in LA immediately after auditory fear conditioning and then tested 2 days later. In experiment 3, rats were fear conditioned and then 2 days later infused with CRF in LA 1 hour before fear memory testing to assess effects on the expression of fear memory. Finally, we repeated the pretraining and pretesting experiments with the central nucleus of the amygdala infusions. RESULTS: Rats given either pretraining or posttraining CRF infusions in LA showed dose-dependent suppression of CS-elicited freezing in the fear memory test session. In contrast, rats given pretesting CRF showed facilitation of CS-elicited freezing. Corticotropin-releasing factor infusions into the central nucleus of the amygdala had no effect when given before-training or testing. CONCLUSIONS: Corticotropin-releasing factor infusions into LA impair the consolidation of memory for fear conditioning but enhance the expression of pre-established fear memories. These findings may have important implications for understanding mechanisms underlying contributions of CRF to fear-related disorders.

The role of the lateral amygdala in the retrieval and maintenance of fear-memories formed by repeated probabilistic reinforcement.

The lateral nucleus of the amygdala (LA) is a key element in the neural circuit subserving Pavlovian fear-conditioning, an animal model of fear and anxiety. Most studies have focused on the role of the LA in fear acquisition and extinction, i.e., how neural plasticity results from changing contingencies between a neutral conditioned stimulus (CS) (e.g., a tone) and an aversive unconditioned stimulus (US) (e.g., a shock). However, outside of the lab, fear-memories are often the result of repeated and unpredictable experiences. Examples include domestic violence, child abuse or combat. To better understand the role of the LA in the expression of fear resulting from repeated and uncertain reinforcement, rats experienced a 30% partial reinforcement (PR) fear-conditioning schedule four days a week for four weeks. Rats reached asymptotic levels of conditioned-fear expression after the first week. We then manipulated LA activity with drug (or vehicle) (VEH) infusions once a week, for the next three weeks, before the training session. LA infusions of muscimol (MUSC), a GABA-A agonist that inhibits neural activity, reduced CS evoked fear-behavior to pre-conditioning levels. LA infusions of pentagastrin (PENT), a cholecystokinin-2 (CCK) agonist that increases neural excitability, resulted in CS-evoked fear-behavior that continued past the offset of the CS. This suggests that neural activity in the LA is required for the retrieval of fear memories that stem from repeated and uncertain reinforcement, and that CCK signaling in the LA plays a role in the recovery from fear after the removal of the fear-evoking stimulus.

Finger photoplethysmography during the Valsalva maneuver reflects left ventricular filling pressure.

It is often challenging to assess cardiac filling pressure clinically. An improved system for detecting or ruling out elevated cardiac filling pressure may help reduce hospitalizations for heart failure. The blood pressure response to the Valsalva maneuver reflects left heart filling pressure, but its underuse clinically may be due in part to lack of continuous blood pressure recording along with lack of standardization of expiratory effort. In this study, we tested whether Valsalva-induced changes in the pulse amplitude of finger photoplethysmography (PPG), a technology already widely available in medical settings, correlate with invasively measured left ventricular end-diastolic pressure (LVEDP). We tested 33 subjects before clinically scheduled cardiac catheterizations. A finger photoplethysmography waveform was recorded during a Valsalva effort of 20 mmHg expiratory pressure sustained for 10 s, an effort most patients can achieve. Pulse amplitude ratio (PAR) was calculated as the PPG waveform amplitude just before release of expiratory effort divided by the waveform amplitude at baseline. PAR was well correlated with LVEDP (r = 0.68; P < 0.0001). For identifying LVEDP > 15 mmHG, PAR > 0.4 was 85% sensitive [95% confidence interval (95CI): 54-97%] and 80% specific (95CI: 56-93%). In conclusion, finger PPG, a technology already ubiquitous in medical centers, may be useful for assessing clinically meaningful categories of left heart filling pressure, using simple analysis of the waveform after a Valsalva maneuver effort that most patients can achieve.

Diagnostic accuracy of computed tomography coronary angiography according to pre-test probability of coronary artery disease and severity of coronary arterial calcification. The CORE-64 (Coronary Artery Evaluation Using 64-Row Multidetector Computed Tomography Angiography) International Multicenter Study.

OBJECTIVES: The purpose of this study was to assess the impact of patient population characteristics on accuracy by computed tomography angiography (CTA) to detect obstructive coronary artery disease (CAD). BACKGROUND: The ability of CTA to exclude obstructive CAD in patients of different pre-test probabilities and in presence of coronary calcification remains uncertain. METHODS: For the CORE-64 (Coronary Artery Evaluation Using 64-Row Multidetector Computed Tomography Angiography) study, 371 patients underwent CTA and cardiac catheterization for the detection of obstructive CAD, defined as ≥50% luminal stenosis by quantitative coronary angiography (QCA). This analysis includes 80 initially excluded patients with a calcium score ≥600. Area under the receiver-operating characteristic curve (AUC) was used to evaluate CTA diagnostic accuracy compared to QCA in patients according to calcium score and pre-test probability of CAD. RESULTS: Analysis of patient-based quantitative CTA accuracy revealed an AUC of 0.93 (95% confidence interval [CI]: 0.90 to 0.95). The AUC remained 0.93 (95% CI: 0.90 to 0.96) after excluding patients with known CAD but decreased to 0.81 (95% CI: 0.71 to 0.89) in patients with calcium score ≥600 (p = 0.077). While AUCs were similar (0.93, 0.92, and 0.93, respectively) for patients with intermediate, high pre-test probability for CAD, and known CAD, negative predictive values were different: 0.90, 0.83, and 0.50, respectively. Negative predictive values decreased from 0.93 to 0.75 for patients with calcium score <100 or ≥100, respectively (p = 0.053). CONCLUSIONS: Both pre-test probability for CAD and coronary calcium scoring should be considered before using CTA for excluding obstructive CAD. For that purpose, CTA is less effective in patients with calcium score ≥600 and in patients with a high pre-test probability for obstructive CAD.

Coronary artery stenoses: accuracy of 64-detector row CT angiography in segments with mild, moderate, or severe calcification--a subanalysis of the CORE-64 trial.

PURPOSE: To evaluate the influence of cross-sectional arc calcification on the diagnostic accuracy of computed tomography (CT) angiography compared with conventional coronary angiography for the detection of obstructive coronary artery disease (CAD). MATERIALS AND METHODS: Institutional Review Board approval and written informed consent were obtained from all centers and participants for this HIPAA-compliant study. Overall, 4511 segments from 371 symptomatic patients (279 men, 92 women; median age, 61 years [interquartile range, 53-67 years]) with clinical suspicion of CAD from the CORE-64 multicenter study were included in the analysis. Two independent blinded observers evaluated the percentage of diameter stenosis and the circumferential extent of calcium (arc calcium). The accuracy of quantitative multidetector CT angiography to depict substantial (≥ 50%) stenoses was assessed by using quantitative coronary angiography (QCA). Cross-sectional arc calcium was rated on a segment level as follows: noncalcified or mild (< 90°), moderate (90°-180°), or severe (> 180°) calcification. Univariable and multivariable logistic regression, receiver operation characteristic curve, and clustering methods were used for statistical analyses. RESULTS: A total of 1099 segments had mild calcification, 503 had moderate calcification, 338 had severe calcification, and 2571 segments were noncalcified. Calcified segments were highly associated (P < .001) with disagreement between CTA and QCA in multivariable analysis after controlling for sex, age, heart rate, and image quality. The prevalence of CAD was 5.4% in noncalcified segments, 15.0% in mildly calcified segments, 27.0% in moderately calcified segments, and 43.0% in severely calcified segments. A significant difference was found in area under the receiver operating characteristic curves (noncalcified: 0.86, mildly calcified: 0.85, moderately calcified: 0.82, severely calcified: 0.81; P < .05). CONCLUSION: In a symptomatic patient population, segment-based coronary artery calcification significantly decreased agreement between multidetector CT angiography and QCA to detect a coronary stenosis of at least 50%.

Noradrenergic enhancement of reconsolidation in the amygdala impairs extinction of conditioned fear in rats--a possible mechanism for the persistence of traumatic memories in PTSD.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with enhanced noradrenergic activity. Animal and human studies demonstrate that noradrenergic stimulation augments consolidation of fear learning. Retrieval of well-established memories by presenting a learned fear cue triggers reconsolidation processes during which memories may be updated, weakened, or strengthened. We previously reported that noradrenergic blockade in the rat amygdala impairs reconsolidation of fear memories. Here we investigated the effects of noradrenergic enhancement on reconsolidation of learned fear. METHODS: Using auditory fear conditioning in rats, we tested the effects of postretrieval intraamygdala infusion of the ß-adrenergic receptor agonist isoproterenol or the antagonist propranolol on conditioned fear in the amygdala. RESULTS: A single intraamygdala infusion of isoproterenol following a retrieval of a well-consolidated memory enhanced fear memory elicited by the learned fear stimulus and impaired extinction of this memory 48 hr later. Intraamygdala infusion of the ß-adrenergic receptor antagonist propranolol following a consecutive retrieval trial blocked the enhancing effects of isoproterenol on fear memory. CONCLUSIONS: Postretrieval ß-adrenergic stimulation in the amygdala enhances reconsolidation of fear memories, making them resistant to extinction. Noradrenergic augmentation during retrieval of fear memories may thus contribute to persistence and severity of traumatic memories. Reconsolidation may be a useful tool in understanding the pathology of PTSD and may thus help in developing new and in modifying existing treatments of traumatic memories.

Beta-adrenergic receptors in the lateral nucleus of the amygdala contribute to the acquisition but not the consolidation of auditory fear conditioning.

Beta-adrenergic receptors (ßARs) have long been associated with fear disorders and with learning and memory. However, the contribution of these receptors to Pavlovian fear conditioning, a leading behavioral model for studying fear learning and memory, is still poorly understood. The aim of this study was to investigate the involvement of ßAR activation in the acquisition, consolidation and expression of fear conditioning. We focused on manipulations of ßARs in the lateral nucleus of the amygdala (LA) because of the well-established contribution of this area to fear conditioning. Specifically, we tested the effects of intra-LA microinfusions of the ßAR antagonist, propranolol, on learning and memory for auditory Pavlovian fear conditioning in rats. Pre-training propranolol infusions disrupted the initial acquisition, short-term memory (STM), and long-term memory (LTM) for fear conditioning, but infusions immediately after training had no effect. Further, infusion of propranolol prior to testing fear responses did not affect fear memory expression. These findings indicate that amygdala ßARs are important for the acquisition but not the consolidation of fear conditioning.

The amygdala encodes specific sensory features of an aversive reinforcer.

Studies of reconsolidation, in which retrieved memories are altered and restored, offer an approach for exploring the associative structure of fear memory. We found that exposure to the unconditioned stimulus initiates an unconditioned stimulus-specific reconsolidation of learned fear in rats that depended on the amygdala. Thus, specific features of the unconditioned stimulus appear to be encoded in the amygdala as part of fear memories stored there.

The absence of coronary calcification does not exclude obstructive coronary artery disease or the need for revascularization in patients referred for conventional coronary angiography.

OBJECTIVES: This study was designed to evaluate whether the absence of coronary calcium could rule out >or=50% coronary stenosis or the need for revascularization. BACKGROUND: The latest American Heart Association guidelines suggest that a calcium score (CS) of zero might exclude the need for coronary angiography among symptomatic patients. METHODS: A substudy was made of the CORE64 (Coronary Evaluation Using Multi-Detector Spiral Computed Tomography Angiography Using 64 Detectors) multicenter trial comparing the diagnostic performance of 64-detector computed tomography to conventional angiography. Patients clinically referred for conventional angiography were asked to undergo a CS scan up to 30 days before. RESULTS: In all, 291 patients were included, of whom 214 (73%) were male, and the mean age was 59.3 +/- 10.0 years. A total of 14 (5%) patients had low, 218 (75%) had intermediate, and 59 (20%) had high pre-test probability of obstructive coronary artery disease. The overall prevalence of >or=50% stenosis was 56%. A total of 72 patients had CS = 0, among whom 14 (19%) had at least 1 >or=50% stenosis. The overall sensitivity for CS = 0 to predict the absence of >or=50% stenosis was 45%, specificity was 91%, negative predictive value was 68%, and positive predictive value was 81%. Additionally, revascularization was performed in 9 (12.5%) CS = 0 patients within 30 days of the CS. From a total of 383 vessels without any coronary calcification, 47 (12%) presented with >or=50% stenosis; and from a total of 64 totally occluded vessels, 13 (20%) had no calcium. CONCLUSIONS: The absence of coronary calcification does not exclude obstructive stenosis or the need for revascularization among patients with high enough suspicion of coronary artery disease to be referred for coronary angiography, in contrast with the published recommendations. Total coronary occlusion frequently occurs in the absence of any detectable calcification. (Coronary Evaluation Using Multi-Detector Spiral Computed Tomography Angiography Using 64 Detectors [CORE-64]; NCT00738218).

Self-assessed physical health predicts 10-year mortality after myocardial infarction.

PURPOSE: In spite of their widespread use in other fields, global measures of health are not commonly used in determining the prognosis of patients with myocardial infarction (MI). The objective of the present study was to ascertain the relationship between self-assessed physical health at the time of the MI and long-term mortality. METHODS: This was a prospective cohort study of 284 patients with MI admitted to an academic community hospital between July 1995 and December 1996 who completed the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). The physical component scale from the SF-36 was used as a self-assessment of physical health. All-cause mortality was assessed 10 years later by using the Social Security Death Index. RESULTS: Patients with lower self-reported physical health were significantly more likely to be women; older; depressed; have a history of coronary artery disease; have a family history of MI; have a non-Q wave MI; have a Killip class 3 or 4 MI; have hypertension, diabetes mellitus, renal insufficiency, and chronic obstructive pulmonary disease; and have a longer hospitalization period. Patients with higher physical component scores had significantly lower mortality in the 10 years after MI and this persisted after adjusting for confounders (hazard ratio = 0.97 [95% CI 0.96-0.99], P = .001). CONCLUSIONS: These data suggest that self-assessed physical health provides information on the long-term prognosis of patients with MI above and beyond that provided by traditional risk predictors.

Relation of anxiety and adherence to risk-reducing recommendations following myocardial infarction.

Unlike depression, the relation between anxiety and the adherence to risk-reducing recommendations after myocardial infarction (MI) has not been well studied. The aim of this study was to explore the effect of anxiety on adherence after MI. Patients (n = 278) hospitalized for MI were assessed for anxiety using the Beck Anxiety Inventory during the hospitalization (baseline) and at 4 months of follow-up. The measures of adherence included following a low-sodium, low-fat diet, exercising regularly, taking medications, decreasing stress, carrying medical supplies, increasing socialization, following a diabetic diet, measuring blood glucose levels, and smoking cessation (where applicable). Baseline anxiety was associated with younger age, female gender, hypertension, tobacco use, depression, and current mood disorder. At 4 months of follow-up, anxiety was also associated with living alone, a history of coronary artery disease, and Killip class >1. An anxiety summary score was calculated to assess anxiety across both points. Summary anxiety was associated with worse adherence to exercise, reducing stress, increasing socialization, and smoking cessation but with better adherence to carrying supplies (all p <0.05). After controlling for demographic, cardiovascular, and psychological factors, summary anxiety predicted worse adherence to reducing stress (p = 0.004) and increasing socialization (p = 0.033) and was the only significant predictor of worse adherence to smoking cessation (p = 0.001) and better adherence to carrying supplies (p = 0.04). Anxiety during the initial hospitalization and 4 months later was associated with lower adherence to many important risk-reducing recommendations after MI. In conclusion, additional research is needed to evaluate whether treating anxiety can improve adherence in this setting.

Coronary CT angiography using 64 detector rows: methods and design of the multi-centre trial CORE-64.

Multislice computed tomography (MSCT) for the noninvasive detection of coronary artery stenoses is a promising candidate for widespread clinical application because of its non-invasive nature and high sensitivity and negative predictive value as found in several previous studies using 16 to 64 simultaneous detector rows. A multi-centre study of CT coronary angiography using 16 simultaneous detector rows has shown that 16-slice CT is limited by a high number of nondiagnostic cases and a high false-positive rate. A recent meta-analysis indicated a significant interaction between the size of the study sample and the diagnostic odds ratios suggestive of small study bias, highlighting the importance of evaluating MSCT using 64 simultaneous detector rows in a multi-centre approach with a larger sample size. In this manuscript we detail the objectives and methods of the prospective "CORE-64" trial ("Coronary Evaluation Using Multidetector Spiral Computed Tomography Angiography using 64 Detectors"). This multi-centre trial was unique in that it assessed the diagnostic performance of 64-slice CT coronary angiography in nine centres worldwide in comparison to conventional coronary angiography. In conclusion, the multi-centre, multi-institutional and multi-continental trial CORE-64 has great potential to ultimately assess the per-patient diagnostic performance of coronary CT angiography using 64 simultaneous detector rows.

Dissociable roles for the ventromedial prefrontal cortex and amygdala in fear extinction: NR2B contribution.

Fear extinction, which involves learning to suppress the expression of previously learned fear, requires N-methyl-D-aspartate receptors (NMDARs) and is mediated by the amygdala and ventromedial prefrontal cortex (vmPFC). Like other types of learning, extinction involves acquisition and consolidation phases. We recently demonstrated that NR2B-containing NMDARs (NR2Bs) in the lateral amygdala (LA) are required for extinction acquisition, but whether they are involved in consolidation is not known. Further, although it has been shown that NMDARs in the vmPFC are required for extinction consolidation, whether NR2Bs in vmPFC are involved in consolidation is not known. In this report, we investigated the possible role of LA and vmPFC NR2Bs in the consolidation of fear extinction using the NR2B-selective antagonist ifenprodil. We show that systemic treatment with ifenprodil immediately after extinction training disrupts extinction consolidation. Ifenprodil infusion into vmPFC, but not the LA, immediately after extinction training also disrupts extinction consolidation. In contrast, we also show pre-extinction training infusions into vmPFC has no effect. These results, together with our previous findings showing that LA NR2Bs are required during the acquisition phase in extinction, indicate a double dissociation for the phase-dependent role of NR2Bs in the LA (acquisition, not consolidation) and vmPFC (consolidation, not acquisition).

Diagnostic performance of coronary angiography by 64-row CT.

BACKGROUND: The accuracy of multidetector computed tomographic (CT) angiography involving 64 detectors has not been well established. METHODS: We conducted a multicenter study to examine the accuracy of 64-row, 0.5-mm multidetector CT angiography as compared with conventional coronary angiography in patients with suspected coronary artery disease. Nine centers enrolled patients who underwent calcium scoring and multidetector CT angiography before conventional coronary angiography. In 291 patients with calcium scores of 600 or less, segments 1.5 mm or more in diameter were analyzed by means of CT and conventional angiography at independent core laboratories. Stenoses of 50% or more were considered obstructive. The area under the receiver-operating-characteristic curve (AUC) was used to evaluate diagnostic accuracy relative to that of conventional angiography and subsequent revascularization status, whereas disease severity was assessed with the use of the modified Duke Coronary Artery Disease Index. RESULTS: A total of 56% of patients had obstructive coronary artery disease. The patient-based diagnostic accuracy of quantitative CT angiography for detecting or ruling out stenoses of 50% or more according to conventional angiography revealed an AUC of 0.93 (95% confidence interval [CI], 0.90 to 0.96), with a sensitivity of 85% (95% CI, 79 to 90), a specificity of 90% (95% CI, 83 to 94), a positive predictive value of 91% (95% CI, 86 to 95), and a negative predictive value of 83% (95% CI, 75 to 89). CT angiography was similar to conventional angiography in its ability to identify patients who subsequently underwent revascularization: the AUC was 0.84 (95% CI, 0.79 to 0.88) for multidetector CT angiography and 0.82 (95% CI, 0.77 to 0.86) for conventional angiography. A per-vessel analysis of 866 vessels yielded an AUC of 0.91 (95% CI, 0.88 to 0.93). Disease severity ascertained by CT and conventional angiography was well correlated (r=0.81; 95% CI, 0.76 to 0.84). Two patients had important reactions to contrast medium after CT angiography. CONCLUSIONS: Multidetector CT angiography accurately identifies the presence and severity of obstructive coronary artery disease and subsequent revascularization in symptomatic patients. The negative and positive predictive values indicate that multidetector CT angiography cannot replace conventional coronary angiography at present. (ClinicalTrials.gov number, NCT00738218.)