Objective-Classical conditioning features prominently in many etiological accounts of panic disorder. According to such accounts, neutral conditioned stimuli present during panic attacks acquire panicogenic properties. Conditioned stimuli triggering panic symptoms are not limited to the original conditioned stimuli but are thought to generalize to stimuli resembling those co-occurring with panic, resulting in the proliferation of panic cues. The authors conducted a laboratory-based assessment of this potential correlate of panic disorder by testing the degree to which panic patients and healthy subjects manifest generalization of conditioned fear.Method-Nineteen patients with a DSM-IV-TR diagnosis of panic disorder and 19 healthy comparison subjects were recruited for the study. The fear-generalization paradigm consisted of 10 rings of graded size presented on a computer monitor; one extreme size was a conditioned danger cue, the other extreme a conditioned safety cue, and the eight rings of intermediary size created a continuum of similarity from one extreme to the other. Generalization was assessed by conditioned fear potentiating of the startle blink reflex as measured with electromyography (EMG).Results-Panic patients displayed stronger conditioned generalization than comparison subjects, as reflected by startle EMG. Conditioned fear in panic patients generalized to rings with up to three units of dissimilarity to the conditioned danger cue, whereas generalization in comparison subjects was restricted to rings with only one unit of dissimilarity.Conclusions-The findings demonstrate a marked proclivity toward fear overgeneralization in panic disorder and provide a methodology for laboratory-based investigations of this central, yet understudied, conditioning correlate of panic. Given the putative molecular basis of fear conditioning, these results may have implications for novel treatments and prevention in panic disorder.Many etiological accounts of panic disorder implicate classical conditioning as a central pathogen (1-4). According to these accounts, neutral conditioned stimuli that are present during an aversive panic attack acquire the capacity to trigger anticipatory anxiety for, or an actual occurrence of, panic attacks through classical conditioning (1,2,5). Conditioned stimuli contributing to the onset and maintenance of panic disorder are thought to extend to exteroceptive and interoceptive stimulus events resembling those co-occurring with panic (1, 2,6) via stimulus generalization-a learning mechanism whereby fear responses extend to a range of stimuli resembling the original conditioned stimuli (7). For example, conditioned fear to the environment where a panic attack occurs (e.g., a specific shopping mall) might transfer, Address correspondence and reprint requests to Dr. Lissek, NIMH, 15K North Dr., Rm. 200, Bethesda, MD 20892-2670; lisseks@mail.nih.gov. Presented in part at the 161st annual meeting of the American Psychiatric Association, Washington, D.C., May 3-8, 2008; and the 47...

Background Meta-analytic results of fear-conditioning studies in the anxiety disorders implicate generalization of conditioned fear to stimuli resembling the conditioned danger cue as one of the more robust conditioning markers of anxiety pathology. Due to the absence of conditioning studies assessing generalization in generalized anxiety disorder (GAD), results of this meta-analysis do not reveal whether such generalization abnormalities also apply to GAD. The current study fills this gap by behaviorally and psychophysiologically assessing levels of conditioned fear-generalization across adults with and without GAD. Methods Twenty-two patients with a DSM-IV-TR diagnosis of GAD and 26 healthy comparisons were recruited and tested. The employed generalization paradigm consists of quasi-randomly presented rings of gradually increasing size, with extreme sizes serving as conditioned danger cues (CS+) and conditioned safety-cues (CS−). The rings of intermediary size serve as generalization stimuli, creating a continuum-of-similarity between CS+ and CS− across which to assess response slopes, referred to as generalization gradients. Primary outcome variables included slopes for fear-potentiated startle (EMG) and self-reported risk ratings. Results Behavioral and psychophysiological findings demonstrate overgeneralization of conditioned fear among patients with GAD. Specifically, generalization gradients were abnormally shallow among GAD patients, reflecting less degradation of the conditioned fear response as the presented stimulus differentiated from the CS+. Conclusions Overgeneralization of conditioned fear, to safe encounters resembling feared situations, may contribute importantly to the psychopathology of GAD by proliferating anxiety cues in the individual’s environment that are then capable of evoking and maintaining anxiety and worry associated with GAD.

The pattern of TD-induced regional cerebral glucose utilization changes in patients with remitted MDD suggests that TD unmasks a disease-specific, serotonin system-related trait dysfunction and identifies a circuit that probably plays a key role in the pathogenesis of MDD.

Classical fear-conditioning is central to many etiologic accounts of panic disorder (PD), but few lab-based conditioning studies in PD have been conducted. One conditioning perspective proposes associative-learning deficits characterized by deficient safety learning among PD patients. The current study of PD assesses acquisition and retention of discriminative aversive conditioning using a fear-potentiated startle paradigm. This paradigm was chosen for its specific capacity to independently assess safety- and danger-learning in the service of characterizing putative anomalies in each type of learning among those with PD. Though no group difference in fear-potentiated startle was found at retention, acquisition results demonstrate impaired discrimination learning among PD patients as indexed by measures of conditioned startle-potentiation to learned safety and danger cues. Importantly, this discrimination deficit was driven by enhanced startle potentiation to the learned safety-cue rather than aberrant reactivity to the danger cue. Consistent with this finding, PD patients relative to healthy individuals reported higher expectancies of dangerous outcomes in the presence of the safety cue, but equal danger expectancies during exposure to the danger cue. Such results link PD to impaired discrimination learning, reflecting elevated fear responding to learned safety-cues.

Imipramine improved the symptoms of patients with chest pain and normal coronary angiograms, possibly through a visceral analgesic effect.

Context:The pathophysiologic mechanism of major depressive disorder (MDD) has been consistently associated with altered catecholaminergic function, especially with decreased dopamine neurotransmission, by various sources of largely indirect evidence. An instructive paradigm for more directly investigating the relationship between catecholaminergic function and depression has involved the mood response to experimental catecholamine depletion (CD). Objectives:To determine whether catecholaminergic dysfunction represents a trait abnormality in MDD and to identify brain circuitry abnormalities involved in the pathophysiologic mechanism of MDD.Design: Randomized, double-blind, placebocontrolled, crossover, single-site experimental trial.Setting: Psychiatric outpatient clinic.Participants: Fifteen unmedicated subjects with MDD in full remission (hereinafter referred to as RMDD subjects) and 13 healthy controls.Intervention: Induction of CD by oral administration of ␣-methylparatyrosine. Sham depletion used identical capsules containing hydrous lactose. Main Outcome Measures:Quantitative positron emission tomography of regional cerebral glucose utiliza-tion to study the neural effects of CD and sham depletion. Behavioral assessments included the Montgomery-Asberg Depression Rating Scale and the Snaith-Hamilton Pleasure Scale (anhedonia).Results: Depressive and anhedonic symptoms increased during CD to a greater extent in RMDD subjects than in controls. In both groups, CD increased metabolism in the anteroventral striatum and decreased metabolism in the orbital gyri. In a limbic-cortical-striatalpallidal-thalamic network previously implicated in MDD, composed of the ventromedial frontal polar cortex, midcingulate and subgenual anterior cingulate cortex, temporopolar cortex, ventral striatum, and thalamus, metabolism increased in RMDD subjects but decreased or remained unchanged in controls. Metabolic changes induced by CD in the left ventromedial frontal polar cortex correlated positively with depressive symptoms, whereas changes in the anteroventral striatum were correlated with anhedonic symptoms. Conclusions:This study provides direct evidence for catecholaminergic dysfunction as a trait abnormality in MDD. It demonstrates that depressive and anhedonic symptoms as a result of decreased catecholaminergic neurotransmission are related to elevated activity within the limbic-cortical-striatal-pallidal-thalamic circuitry.

Background Generalized Social Phobia (GSP) and Generalized Anxiety Disorder (GAD) are both associated with emotion dysregulation. In healthy subjects, research implicates dorsal anterior cingulate (dACC) in both explicit emotion regulation and top-down attentional control. While studies have examined these processes in GSP or GAD, no work compares findings across the two disorders. Moreover, no work examines functioning in cases comorbid for both disorders (GSP/GAD). Here we compare the neural correlates of explicit emotion regulation (EER) and top-down attentional control (TAC) in GSP, GAD, and GSP/GAD. Method Medication-free adults with GSP (EER n=19; TAC n=18), GAD (EER n=17; TAC n =17), GSP/GAD (EER n=17; TAC=15), or no psychopathology (EER n=18; TAC n=18). During EER, individuals alternatively viewed, up-regulated, and down-regulated responses to emotional pictures. During TAC, they performed an emotional Stroop task. Results For both tasks, significant group-by-condition interactions emerged in dACC and parietal cortices. Healthy adults showed significantly increased recruitment during emotion regulation, relative to emotion-picture viewing. GAD, GSP, and GSP/GAD subjects showed no such increases, with all three groups differing from healthy adults but not from each other. Evidence of emotion-related disorder-specificity emerged in medial prefrontal cortex (MPFC) and amygdala. This disorder-specific responding varied as a function of stimulus emotion content but not emotion-regulatory demands. Conclusions GSP and GAD both involve reduced capacity for engaging emotion-regulation brain networks, whether explicitly or via top-down attentional control. A reduced ability to recruit regions implicated in top-down attention might represent a general risk factor for anxiety disorders.

Context Generalized social phobia (GSP) is characterized by fear/avoidance of social situations. Previous studies have examined the neural responses in GSP to one class of social stimuli, facial expressions. However, studies have not examined the neural response in GSP to another equally important class of social stimuli, the communication of praise or criticism. Objective To examine the neural response to receipt of praise or criticism in GSP; specifically, to determine whether patients with GSP show an increased response to the receipt of both praise and criticism and whether self-relevance modulates this relationship. Design Case-control study. Setting Government clinical research institute. Participants Unmedicated individuals with GSP (n=17) and age-, IQ-, and sex-matched healthy comparison individuals (n=17). Main Outcome Measure Blood oxygenation level–dependent signal, as measured via functional magnetic resonance imaging. During functional magnetic resonance imaging scans, individuals read positive (eg, You are beautiful), negative (eg, You are ugly), and neutral (eg, You are human) comments that could be either about the self or about somebody else (eg, He is beautiful). Results Hypothesized significant group×valence×referent interactions were observed within regions of the medial prefrontal cortex and bilateral amygdala. In these regions, the patients with GSP showed significantly increased blood oxygenation level–dependent responses, relative to comparison individuals, to negative comments (criticism) referring to themselves. However, in contrast, there were no significant group differences with respect to negative comments referring to others or neutral or positive comments referring to self or others. Conclusions These results implicate the medial prefrontal cortex, involved in the representation of the self, together with the amygdala, in the pathophysiology of GSP. Further, findings demonstrate a meaningful effect of psychological context on neural-circuitry hyperactivity in GSP.